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 ?????????????????????????????????????????????????????????????????????

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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. In an exemplary 0038 Topical formulations of JAK kinase inhibitors such embodiment, the active agent is 5-(3,4-dicyanophenoxy)-1, as Tofacitinib, JTE-052, Baricitinib, and Upadacitinib; 3-dihydro-1-hydroxy-2,1-benzoxaborole, or a pharmaceuti 0039 Topical Non-steroidal anti-inflammatories such as cally acceptable salt, hydrate, or Solvate thereof. In an WBI-1001, and MRX-6; exemplary embodiment, the active agent is crisaborole, also 0040 Topcial ROR agents such as GSK2.981278: known as 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2, 0041 Injectable Anti-IL4, IL-31, IL-22, IL-33, IL-12, 1-benzoxaborole, or a pharmaceutically acceptable salt, IL-23, IL-17, IgE, IL-4 treatments such as Dupilumab, hydrate, or Solvate thereof. In an exemplary embodiment, Lebrikizumab, Nemolizumab, Tralokinumab, Etanercept, the active agent is 5-(3-cyanophenoxy)-1,3-dihydro-1-hy Adalimumab, Infliximab, Ustekinumab, Secukinumab, droxy-2, 1-benzoxaborole, or a pharmaceutically acceptable OmaZumilab, CIM-331; salt, hydrate, or Solvate thereof. In an exemplary embodi 0042 Vitamin D analogs such as calcipotriene; ment, the active agent is 5-(2-cyanophenoxy)-1,3-dihydro 0043. Oral Retinoic Acid derivatives such as alitretinoin: 1-hydroxy-2,1-benzoxaborole, or a pharmaceutically 0044 Oral Liver X Receptor (LXR) selective agonists acceptable salt, hydrate, or solvate thereof. such as VTP-38543: 0031. In an exemplary embodiment, the active ingredient 0045 Oral H4 receptor antagonists such as ZPL-389; is a steroid. In an exemplary embodiment, the active ingre 0046 Oral NK1 receptor antagonists such as Aprepitant dient is pimecrolimus or tazarotene or tacrolimus or triam and Tradipitant; cinolone or calcitriol or calcipotriene or betamethasone or 0047 Oral CRTH2 receptor antagonists such as Fevipip clobatsol or halobetasol or diflorasone or mometasone. rant and OC-459: 0032. In an exemplary embodiment, the active agent is 0048 Oral Chymase inhibitors such as SUN. 13834; present in a concentration of about 0.1% to about 3.0% 0049 Oral GATA-3 inhibitors such as SB-011; (w/w). In an exemplary embodiment, the active agent is 0050 Oral ROR inverse agonists such as VTP-43742, present in a concentration of about 0.1% to about 2.0% ARN6039, TAK-828 and JTE-451; (w/w). In an exemplary embodiment, the active agent is 0051) Oral JAK inhibitors; including inhibitors of JAK1, present in a concentration of about 0.1% to about 1.0% JAK2, JAK3 and TYK2 such as PF-04965842, (w/w). In an exemplary embodiment, the active agent is PF-06651600, and PF-06700.841; present in a concentration of about 1.0% to about 2.0% 0.052 Oral PDE agents such as apremilast, roflumilast, (w/w). In an exemplary embodiment, the active agent is and ibudilast; present in a concentration of about 1.5% to about 2.0% 0053 Oral IRAK4 inhibitors such as PF-06650833; (w/w). In an exemplary embodiment, the active agent is 0054) Injectable aTNF inhibitors such as infliximab, present in a concentration of about 1.5% to about 2.5% adalimumab, golimumab, and certolizumab pegol; (w/w). In an exemplary embodiment, the active agent is 0055. Injectable galectin-3 inhibitor such as GR-MD-02 present in a concentration of about 1.0% to about 3.0% 0056. In an exemplary embodiment, the invention pro (w/w). In an exemplary embodiment, the active agent is vides an active agent described herein, or a salt, hydrate or present in a concentration of about 2.0% (w/w). In an solvate thereof. In an exemplary embodiment, the invention exemplary embodiment, the active agent is present in a provides an active agent described herein, or a salt thereof. concentration of 2.0% (w/w). In an exemplary embodiment, the salt is a pharmaceutically US 2017/0152273 A1 Jun. 1, 2017

acceptable salt. In an exemplary embodiment, the invention tion of from about 65% (w/w) to about 85% (w/w). In an provides an active agent described herein, or a hydrate exemplary embodiment, the base is present in a concentra thereof. In an exemplary embodiment, the invention pro tion of from about 67.955% (w.fw) to about 89.8999% vides an active agent described herein, or a solvate thereof. (w/w). In an exemplary embodiment, the base is present in In an exemplary embodiment, the invention provides an a concentration of from about 50% (w/w) to about 60% active agent described herein, or a prodrug thereof. In an (w/w). In an exemplary embodiment, the base is present in exemplary embodiment, the invention provides an active a concentration of from about 60% (w/w) to about 70% agent described herein. In an exemplary embodiment, the (w/w). In an exemplary embodiment, the base is present in invention provides a pharmaceutically acceptable salt of an a concentration of from about 70% (w/w) to about 80% active agent described herein. In an exemplary embodiment, (w/w). In an exemplary embodiment, the base is present in the invention provides a hydrate of an active agent described a concentration of from about 72% (w/w) to about 82% herein. In an exemplary embodiment, the invention provides (w/w). In an exemplary embodiment, the base is present in a solvate of an active agent described herein. In an exem a concentration of from about 74% (w/w) to about 81% plary embodiment, the invention provides a prodrug of an (w/w). In an exemplary embodiment, the base is present in active agent described herein. a concentration of from about 78% (w/w) to about 82% 0057 II. a. ii. Solvent (w/w). In an exemplary embodiment, the base is present in 0058. In an exemplary embodiment, the topical pharma a concentration of from about 75% (w/w) to about 80% ceutical formulation comprises a solvent. In an exemplary (w/w). In an exemplary embodiment, the base is present in embodiment, the solvent is an alkylene glycol. In an exem a concentration of from about 75% (w/w) to about 79% plary embodiment, the solvent is propylene glycol. In an (w/w). In an exemplary embodiment, the base is present in exemplary embodiment, the solvent is propylene glycol a concentration of from about 76% (w/w) to about 79% USP. In an exemplary embodiment, the solvent is butylene (w/w). In an exemplary embodiment, the base is present in glycol. a concentration of from about 76% (w/w) to about 77% 0059. In an exemplary embodiment, the solvent is present (w/w). In an exemplary embodiment, the base is present in in a concentration of about 5.0% (w/w) to about 15.0% a concentration of from about 76.8% (w/w) to about 77% (w/w). In an exemplary embodiment, the solvent is present (w/w). In an exemplary embodiment, the base is present in in a concentration of about 6.0% (w/w) to about 10.0% a concentration of from about 78% (w/w) to about 79% (w/w). In an exemplary embodiment, the solvent is present (w/w). In an exemplary embodiment, the base is present in in a concentration of about 6.5% (w/w) to about 11.5% a concentration of from about 76.8% (w/w) to about 76.9% (w/w). In an exemplary embodiment, the solvent is present (w/w). In an exemplary embodiment, the base is present in in a concentration of about 7.0% (w/w) to about 11.0% a concentration of from about 76.89% (w/w) to about 76.9% (w/w). In an exemplary embodiment, the solvent is present (w/w). In an exemplary embodiment, the base is present in in a concentration of about 7.5% (w/w) to about 10.5% a concentration of about 76.80% (w/w). In an exemplary (w/w). In an exemplary embodiment, the solvent is present embodiment, the base is present in a concentration of about in a concentration of about 7.5% (w/w) to about 9.5% (w/w). 76.855% (w/w). In an exemplary embodiment, the base is In an exemplary embodiment, the solvent is present in a present in a concentration of about 76.8965% (w/w). In an concentration of about 8.5% (w/w) to about 9.5% (w/w). In exemplary embodiment, the base is present in a concentra an exemplary embodiment, the solvent is present in a tion of about 76.8976% (w/w). In an exemplary embodi concentration of about 8.0% (w/w) to about 10.0% (w/w). In ment, the base is present in a concentration of about an exemplary embodiment, the solvent is present in a 76.981% (w/w). In an exemplary embodiment, the base is concentration of about 9.0% (w/w). In an exemplary present in a concentration of about 76.90% (w/w). In an embodiment, the solvent is present in a concentration of exemplary embodiment, the base is present in a concentra 9.0% (w/w). tion of from about 78.89% (w/w) to about 78.9% (w/w). In 0060 II. a. iii. Base an exemplary embodiment, the base is present in a concen 0061. In an exemplary embodiment, the topical pharma tration of about 78.80% (w/w). In an exemplary embodi ceutical formulation comprises an ointment base. In an ment, the base is present in a concentration of about exemplary embodiment, the base is an ointment base. In an 78.855% (w/w). In an exemplary embodiment, the base is exemplary embodiment, the ointment base is white petrola present in a concentration of about 78.8965% (w/w). In an tum. In an exemplary embodiment, the ointment base is exemplary embodiment, the base is present in a concentra white petrolatum USP. In an exemplary embodiment, the tion of about 78.8976% (w/w). In an exemplary embodi ointment base is mineral jelly or petroleum jelly or yellow ment, the base is present in a concentration of about petrolatum or yellow soft paraffin or yellow petroleum Jelly 78.981% (w/w). In an exemplary embodiment, the base is or white petrolatum jelly or white soft paraffin. In an present in a concentration of about 78.90% (w/w). exemplary embodiment, the base is mineral oil or light Optional Components for the Topical Pharmaceutical mineral oil or paraffin or lanolin alcohol. Formulation 0062. The amount of base in the topical pharmaceutical formulations will be dependent on the amounts of the other 0063 II. a. iv. Antioxidant components. More base may be added to compensate for 0064. In an exemplary embodiment, the topical pharma Smaller amounts of other components in the desired topical ceutical formulation further comprises an antioxidant. In an pharmaceutical formulation. In an exemplary embodiment, exemplary embodiment, the antioxidant is selected from the the base is present in a quantum satis, q.S., concentration. In group consisting of butylated hydroxytoluene, ascorbic acid, an exemplary embodiment, the base is present in a concen ascorbic palmitate, butylated hydroxyanisole, 2,4,5-trihy tration of from about 65% (w/w) to about 90% (w/w). In an droxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butyl exemplary embodiment, the base is present in a concentra phenol, erythorbic acid, gum guaiac, propyl gallate, thiodi US 2017/0152273 A1 Jun. 1, 2017

propionic acid, dilauryl thiodipropionate, tert about 0.0010% (w/w) to about 0.01.00% (w/w). In an exem butylhydroquinone and a tocopherol, or a pharmaceutically plary embodiment, the stabilizer is present in a concentra acceptable salt or ester thereof, or a combination thereof. In tion of about 0.0020% (w/w) to about 0.01.00% (w/w). In an an exemplary embodiment, the antioxidant is butylated exemplary embodiment, the stabilizer is present in a con hydroxytoluene. In an exemplary embodiment, the antioxi centration of about 0.0024% (w/w) to about 0.01.00% (w/w). dant is butylated hydroxytoluene NF. In an exemplary embodiment, the stabilizer is present in a 0065. In an exemplary embodiment, the antioxidant is concentration of about 0.0024% (w/w) to about 0.0090% present in a concentration of about 0.01% (w/w) to about 1% (w/w). In an exemplary embodiment, the stabilizer is present (w/w). In an exemplary embodiment, the antioxidant is in a concentration of about 0.0035% (w/w) to about present in a concentration of about 0.01% (w/w) to about 0.01.00% (w/w). In an exemplary embodiment, the stabilizer 0.5% (w/w). In an exemplary embodiment, the antioxidant is present in a concentration of about 0.0035% (w/w) to is present in a concentration of about 0.05% (w/w) to about about 0.0090% (w/w). In an exemplary embodiment, the 0.5% (w/w). In an exemplary embodiment, the antioxidant stabilizer is present in a concentration of about 0.0010% is present in a concentration of about 0.05% (w/w) to about (w/w) to about 0.0080% (w/w). In an exemplary embodi 0.4% (w/w). In an exemplary embodiment, the antioxidant ment, the stabilizer is present in a concentration of about is present in a concentration of about 0.05% (w/w) to about 0.0010% (w/w) to about 0.0060% (w/w). In an exemplary 0.3% (w/w). In an exemplary embodiment, the antioxidant embodiment, the stabilizer is present in a concentration of is present in a concentration of about 0.07% (w/w) to about about 0.0010% (w/w) to about 0.0050% (w/w). In an exem 0.2% (w/w). In an exemplary embodiment, the antioxidant plary embodiment, the stabilizer is present in a concentra is present in a concentration of about 0.05% (w/w) to about tion of about 0.0020% (w/w) to about 0.0060% (w/w). In an 0.15% (w/w). In an exemplary embodiment, the antioxidant exemplary embodiment, the stabilizer is present in a con is present in a concentration of about 0.1% (w/w). In an centration of about 0.0015% (w/w) to about 0.0045% (w/w). exemplary embodiment, the antioxidant is present in a In an exemplary embodiment, the stabilizer is present in a concentration of 0.1% (w/w). concentration of about 0.0025% (w/w) to about 0.0045% 0066 II. a. v. Stabilizer (w/w). In an exemplary embodiment, the stabilizer is present 0067. In an exemplary embodiment, the topical pharma in a concentration of about 0.0030% (w/w) to about ceutical formulation further comprises a stabilizer. In an 0.0040% (w/w). In an exemplary embodiment, the stabilizer exemplary embodiment, the stabilizer is ethylenediaminetet is present in a concentration of about 0.0035% (w/w). In an raacetic acid, or a pharmaceutically acceptable salt thereof. exemplary embodiment, the stabilizer is present in a con In an exemplary embodiment, the stabilizer is a pharmaceu centration of 0.0035% (w/w). tically acceptable salt of ethylenediaminetetraacetic acid, 0069 II. a. vi. Emulsifying Agent and this salt is a sodium salt or a potassium salt or a calcium 0070. In an exemplary embodiment, the topical pharma salt, or a combination thereof. In an exemplary embodiment, ceutical formulation further comprises an emulsifying agent. the stabilizer is a pharmaceutically acceptable salt of ethyl In an exemplary embodiment, the emulsifying agent is a enediaminetetraacetic acid, and this salt is a sodium salt or glyceride blend. In an exemplary embodiment, the emulsi a calcium salt, or a combination thereof. In an exemplary fying agent is a glyceride blend, wherein the glyceride blend embodiment, the stabilizer is edetate calcium disodium. In comprises a monoglyceride and a diglyceride. In an exem an exemplary embodiment, the stabilizer is edetate calcium plary embodiment, the emulsifying agent is a glyceride disodium USP blend, wherein the glyceride blend comprises a monoglyc 0068. In an exemplary embodiment, the stabilizer is eride, a diglyceride, and a triglyceride. In an exemplary present in a concentration of about 0.000010% (w/w) to embodiment, the emulsifying agent is a glyceride blend, about 0.0450% (w/w). In an exemplary embodiment, the wherein the glyceride blend comprises a monoglyceride and stabilizer is present in a concentration of about 0.0010% a diglyceride, and wherein from about 40% (w/w) to about (w/w) to about 0.0450% (w/w). In an exemplary embodi 55% (w/w) of the glyceride blend is a monoglyceride. In an ment, the stabilizer is present in a concentration of about exemplary embodiment, the emulsifying agent is a glyceride 0.0010% (w/w) to about 0.04.00% (w/w). In an exemplary blend, wherein the glyceride blend comprises a monoglyc embodiment, the stabilizer is present in a concentration of eride, a diglyceride, and a triglyceride, and wherein from about 0.0010% (w/w) to about 0.0350% (w/w). In an exem about 40% (w/w) to about 55% (w/w) of the glyceride blend plary embodiment, the stabilizer is present in a concentra is a monoglyceride. In an exemplary embodiment, the tion of about 0.0010% (w/w) to about 0.0300% (w/w). In an emulsifying agent is a glyceride blend, wherein the glycer exemplary embodiment, the stabilizer is present in a con ide blend is Mono- and Di-glyceride NF. centration of about 0.0010% (w/w) to about 0.0250% (w/w). 0071. In an exemplary embodiment, the monoglyceride is In an exemplary embodiment, the stabilizer is present in a selected from the group consisting of glyceryl monostearate, concentration of about 0.0010% (w/w) to about 0.0200% glyceryl monopalmitate, glyceryl monooleate, or combina (w/w). In an exemplary embodiment, the stabilizer is present tions thereof. In an exemplary embodiment, the monoglyc in a concentration of about 0.0010% (w/w) to about eride is a monoglyceryl ester of a long chain, Saturated or 0.0150% (w/w). In an exemplary embodiment, the stabilizer unsaturated fatty acid. In an exemplary embodiment, the is present in a concentration of about 0.00010% (w/w) to monoglyceride is an alpha-monoglyceride. In an exemplary about 0.01.00% (w/w). In an exemplary embodiment, the embodiment, the diglyceride is a diglyceryl ester of a long stabilizer is present in a concentration of about 0.0010% chain, Saturated or unsaturated fatty acid. (w/w) to about 0.0090% (w/w). In an exemplary embodi 0072. In an exemplary embodiment, the glyceride blend ment, the stabilizer is present in a concentration of about is present in a concentration of about 3.0% (w/w) to about 0.000010% (w/w) to about 0.01.00% (w/w). In an exemplary 10.0% (w/w). In an exemplary embodiment, the glyceride embodiment, the stabilizer is present in a concentration of blend is present in a concentration of about 5.0% (w/w) to US 2017/0152273 A1 Jun. 1, 2017

about 10.0% (w/w). In an exemplary embodiment, the wherein the formulation comprises no more than about 0.5% glyceride blend is present in a concentration of about 6.0% (w/w) water. (w/w) to about 9.0% (w/w). In an exemplary embodiment, I0089. In an exemplary embodiment, the topical pharma the glyceride blend is present in a concentration of about ceutical formulation comprises: 5.0% (w/w) to about 8.0% (w/w). In an exemplary embodi 0090 a) an active agent which treats atopic dermatitis ment, the glyceride blend is present in a concentration of and/or psoriasis, or a pharmaceutically acceptable salt, about 6.0% (w/w) to about 8.0% (w/w). In an exemplary or a hydrate or a solvate thereof; embodiment, the glyceride blend is present in a concentra (0.091 b) from about 8% (w/w) to about 10% (w/w) tion of about 6.5% (w/w) to about 7.5% (w/w). In an propylene glycol; exemplary embodiment, the glyceride blend is present in a 0092 c) petrolatum; concentration of about 7.0% (w/w). In an exemplary (0.093 d) an antioxidant; embodiment, the glyceride blend is present in a concentra 0094) e) a stabilizer; tion of 7.0% (w/w). 0.095 f) an emulsifying agent; and 0073 II. a. vii. Stiffening Agent 0.096 g) a stiffening agent 0074. In an exemplary embodiment, the topical pharma wherein the formulation comprises no more than about 0.5% ceutical formulation further comprises a stiffening agent. In (w/w) water. an exemplary embodiment, the stiffening agent is a wax. In 0097. In an exemplary embodiment, the topical pharma an exemplary embodiment, the stiffening agent is a wax, and ceutical formulation consists of the wax is selected from the group consisting of beeswax, 0.098 a) an active agent which treats atopic dermatitis paraffin wax, and spermaceti wax. In an exemplary embodi and/or psoriasis, or a pharmaceutically acceptable salt, ment, the stiffening agent is paraffin wax. In an exemplary or a hydrate or a solvate thereof; embodiment, the stiffening agent is paraffin wax NF. 0099 b) from about 8% (w/w) to about 10% (w/w) 0075. In an exemplary embodiment, the stiffening agent propylene glycol; is present in a concentration of about 2.0% (w/w) to about 0100 c) petrolatum; 6.0% (w/w). In an exemplary embodiment, the stiffening 0101 d) an antioxidant; agent is present in a concentration of about 2.0% (w/w) to 0102 e) edetate calcium disodium; about 8.0% (w/w). In an exemplary embodiment, the stiff 0.103 f) an emulsifying agent; and ening agent is present in a concentration of about 3.0% 0104 g) a stiffening agent. (w/w) to about 5.0% (w/w). In an exemplary embodiment, 0105. In an exemplary embodiment, the topical pharma the stiffening agent is present in a concentration of about ceutical formulation consists of 4.0% (w/w) to about 6.0% (w/w). In an exemplary embodi 0106 a) an active agent which treats atopic dermatitis ment, the stiffening agent is present in a concentration of and/or psoriasis, or a pharmaceutically acceptable salt, about 4.0% (w/w) to about 5.0% (w/w). In an exemplary or a hydrate or a solvate thereof; embodiment, the stiffening agent is present in a concentra 0107 b) from about 8% (w/w) to about 10% (w/w) tion of about 4.5% (w/w) to about 5.5% (w/w). In an propylene glycol; exemplary embodiment, the stiffening agent is present in a 0.108 c) petrolatum; concentration of about 5.0% (w/w). In an exemplary 0.109 d) an antioxidant; embodiment, the stiffening agent is present in a concentra 0110 e) from about 0.0020% (w/w) to about 0.0040% tion of 5.0% (w/w). (w/w) edetate calcium disodium; 0111 f) an emulsifying agent; and Specific Topical Pharmaceutical Formulations 0112 g) a stiffening agent. 0.076 II. a. viii. 0113. In an exemplary embodiment, the topical pharma 0077. In an exemplary embodiment, the topical pharma ceutical formulation consists essentially of ceutical formulation comprises: 0114 a) an active agent which treats atopic dermatitis 0078 a) an active agent which treats atopic dermatitis and/or psoriasis, or a pharmaceutically acceptable salt, and/or psoriasis, or a pharmaceutically acceptable salt, or a hydrate or a solvate thereof; or a hydrate or a solvate thereof; 0115 b) from about 8% (w/w) to about 10% (w/w) (0079 b) from about 5% (w/w) to about 15% (w/w) propylene glycol; propylene glycol, and 0116 c) petrolatum; 0080 c) petrolatum 0.117 d) an antioxidant; wherein the formulation comprises no more than about 0.5% 0118 e) a stabilizer; (w/w) water. 0119 f) a glyceride blend, wherein the glyceride blend 0081. In an exemplary embodiment, the topical pharma comprises one or more monoglycerides and one or ceutical formulation comprises: more diglycerides; and I0082 a) an active agent which treats atopic dermatitis 0120 g) a stiffening agent and/or psoriasis, or a pharmaceutically acceptable salt, wherein the formulation comprises no more than about 0.5% or a hydrate or a solvate thereof; (w/w) water. I0083 b) from about 5% (w/w) to about 15% (w/w) I0121. In an exemplary embodiment, the topical pharma propylene glycol, ceutical formulation consists essentially of I0084 c) petrolatum; 0.122 a) an active agent which treats atopic dermatitis I0085 d) an antioxidant; and/or psoriasis, or a pharmaceutically acceptable salt, I0086 e) a stabilizer; or a hydrate or a solvate thereof; I0087 f) an emulsifying agent; and (0123 b) from about 8% (w/w) to about 10% (w/w) I0088 g) a stiffening agent propylene glycol; US 2017/0152273 A1 Jun. 1, 2017

0.124 c) petrolatum; diglycerides, wherein the one or more monoglycerides 0.125 d) an antioxidant; is in a total concentration of between 40% and 55% of 0.126 e) a stabilizer; the glyceride blend; and I0127 f) a glyceride blend, wherein the glyceride blend 0152 g) a stiffening agent comprises one or more monoglycerides and one or wherein the formulation comprises no more than about 0.5% more diglycerides, wherein the one or more monoglyc (w/w) water. erides is in a total concentration of between 40% and 0153. In an exemplary embodiment, the topical pharma 55% of the glyceride blend; and ceutical formulation consists essentially of 0128 g) a stiffening agent 0154) a) an active agent which treats atopic dermatitis wherein the formulation comprises no more than about 0.5% and/or psoriasis, or a pharmaceutically acceptable salt, (w/w) water. or a hydrate or a solvate thereof; 0129. In an exemplary embodiment, the topical pharma (O155 b) from about 8% (w/w) to about 10% (w/w) ceutical formulation consists essentially of propylene glycol; 0.130 a) an active agent which treats atopic dermatitis 0156 c) petrolatum; and/or psoriasis, or a pharmaceutically acceptable salt, 0157 d) an antioxidant; or a hydrate or a solvate thereof; 0158 e) from about 0.0020% (w/w) to about 0.0040% I0131 b) from about 8% (w/w) to about 10% (w/w) (w/w) edetate calcium disodium; propylene glycol, 0159 f) from about 5% (w/w) to about 10% (w/w) of a glyceride blend, wherein the glyceride blend com I0132 c) petrolatum; prises one or more monoglycerides and one or more 0.133 d) an antioxidant; diglycerides, wherein the one or more monoglycerides I0134) e) a stabilizer; is in a total concentration of between 40% and 55% of I0135 f) from about 5% (w/w) to about 10% (w/w) of the glyceride blend; and a glyceride blend, wherein the glyceride blend com 0.160 g) a stiffening agent prises one or more monoglycerides and one or more wherein the formulation comprises no more than about 0.5% diglycerides, wherein the one or more monoglycerides (w/w) water. is in a total concentration of between 40% and 55% of 0.161. In an exemplary embodiment, the topical pharma the glyceride blend; and ceutical formulation consists essentially of 0.136 g) a stiffening agent 0162 a) 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy wherein the formulation comprises no more than about 0.5% 2, 1-benzoxaborole, or a pharmaceutically acceptable (w/w) water. salt, or a hydrate or a solvate thereof; 0.137 In an exemplary embodiment, the topical pharma (0163 b) from about 8% (w/w) to about 10% (w/w) ceutical formulation consists essentially of propylene glycol; 0.138 a) an active agent which treats atopic dermatitis 0.164 c) petrolatum; and/or psoriasis, or a pharmaceutically acceptable salt, 0.165 d) an antioxidant; or a hydrate or a solvate thereof; (0166 e) a stabilizer; I0139 b) from about 8% (w/w) to about 10% (w/w) (0167 f) from about 5% (w/w) to about 10% (w/w) of propylene glycol, a glyceride blend, wherein the glyceride blend com 0140 c) petrolatum; prises one or more monoglycerides and one or more diglycerides, wherein the one or more monoglycerides 0141 d) an antioxidant; is in a total concentration of between 40% and 55% of 0.142 e) a stabilizer; the glyceride blend; and 0143 f) from about 6% (w/w) to about 8% (w/w) of a 0168 g) a stiffening agent glyceride blend, wherein the glyceride blend comprises wherein the formulation comprises no more than about 0.5% one or more monoglycerides and one or more diglyc (w/w) water. erides, wherein the one or more monoglycerides is in a 0169. In an exemplary embodiment, the topical pharma total concentration of between 40% and 55% of the ceutical formulation consists essentially of glyceride blend; and 0170 a) 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy 014.4 g) a stiffening agent 2, 1-benzoxaborole, or a pharmaceutically acceptable wherein the formulation comprises no more than about 0.5% salt, or a hydrate or a solvate thereof; (w/w) water. (0171 b) from about 8% (w/w) to about 10% (w/w) 0145. In an exemplary embodiment, the topical pharma propylene glycol; ceutical formulation consists essentially of 0172 c) petrolatum; 0146) a) an active agent which treats atopic dermatitis 0173 d) an antioxidant; and/or psoriasis, or a pharmaceutically acceptable salt, 0.174 e) edetate calcium disodium; or a hydrate or a solvate thereof; (0175 f) from about 6% (w/w) to about 8% (w/w) of a 0147 b) from about 8% (w/w) to about 10% (w/w) glyceride blend, wherein the glyceride blend comprises propylene glycol, one or more monoglycerides and one or more diglyc 0148 c) petrolatum; erides, wherein the one or more monoglycerides is in a 0149 d) an antioxidant; total concentration of between 40% and 55% of the 0150 e) edetate calcium disodium; glyceride blend; and 0151 f) from about 5% (w/w) to about 10% (w/w) of 0176 g) a stiffening agent a glyceride blend, wherein the glyceride blend com wherein the formulation comprises no more than about 0.5% prises one or more monoglycerides and one or more (w/w) water. US 2017/0152273 A1 Jun. 1, 2017

0177. In an exemplary embodiment, the topical pharma 0204 c) white petrolatum; ceutical formulation consists essentially of 0205 d) about 0.1% (w/w) butylated hydroxytoluene: 0.178 a) 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy 0206 e) about 0.0035% (w/w) edetate calcium diso 2.1-benzoxaborole, or a pharmaceutically acceptable dium; salt, or a hydrate or a solvate thereof; 0207 f) about 7% (w/w) of a glyceride blend, wherein (0179 b) from about 8% (w/w) to about 10% (w/w) the glyceride blend comprises one or more monoglyc propylene glycol, erides and one or more diglycerides, wherein the one or 0180 c) petrolatum; more monoglycerides is in a total concentration of 0181 d) an antioxidant; between 40% and 55% of the glyceride blend; and 0182 e) from about 0.0020% (w/w) to about 0.0040% 0208 g) a stiffening agent (w/w) edetate calcium disodium; wherein the formulation comprises no more than about 0.5% 0183 f) from about 6% (w/w) to about 8% (w/w) of a (w/w) water. glyceride blend, wherein the glyceride blend comprises 0209. In an exemplary embodiment, the topical pharma one or more monoglycerides and one or more diglyc ceutical formulation consists of erides, wherein the one or more monoglycerides is in a 0210 a) 2% (w/w) 5-(4-cyanophenoxy)-1,3-dihydro total concentration of between 40% and 55% of the 1-hydroxy-2,1-benzoxaborole, or a pharmaceutically glyceride blend; and acceptable salt, or a hydrate or a solvate thereof; 0.184 g) a stiffening agent 0211 b) 9% (w/w) propylene glycol; wherein the formulation comprises no more than about 0.5% 0212 c) 76.8965% (w/w) white petrolatum; (w/w) water. 0213 d) 0.1% (w/w) butylated hydroxytoluene: 0185. In an exemplary embodiment, the topical pharma 0214) e) 0.0035% (w/w) edetate calcium disodium: ceutical formulation consists essentially of 0215 f) 7% (w/w) of a glyceride blend, wherein the 0186 a) 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy glyceride blend comprises one or more monoglycerides 2.1-benzoxaborole, or a pharmaceutically acceptable and one or more diglycerides, wherein the one or more salt, or a hydrate or a solvate thereof; monoglycerides is in a total concentration of between 0187 b) from about 5% (w/w) to about 15% (w/w) 40% and 55% of the glyceride blend; and propylene glycol, 0216 g) 5% (w/w) paraffin wax. 0188 c) petrolatum; 0217 Topical Pharmaceutical Formulation without an (0189 d) butylated hydroxytoluene: Active Agent 0.190 e) edetate calcium disodium; 0218 II. a. ix. (0191 f) from about 5% (w/w) to about 10% (w/w) of 0219. In another aspect, the invention comprises a topical a glyceride blend, wherein the glyceride blend com pharmaceutical formulation which does not comprise an prises one or more monoglycerides and one or more active agent which is useful in the treatment of inflamma diglycerides, wherein the one or more monoglycerides tory-related conditions. These topical pharmaceutical for is in a total concentration of between 40% and 55% of mulations which do not contain an active agent are also the glyceride blend; and useful in the treatment of inflammatory conditions such as 0.192 g) a stiffening agent atopic dermatitis and/or psoriasis. In an exemplary embodi wherein the formulation comprises no more than about 0.5% ment, these topical pharmaceutical formulation do not con (w/w) water. tain one or more of the active agents listed herein. In an 0193 In an exemplary embodiment, the topical pharma exemplary embodiment, the topical pharmaceutical formu ceutical formulation consists essentially of lation without an active agent further comprises up to about 0194 a) 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy 0.5% (w/w) water. In an exemplary embodiment, the topical 2.1-benzoxaborole, or a pharmaceutically acceptable pharmaceutical formulation without an active agent further salt, or a hydrate or a solvate thereof; comprises up to about 0.1% (w/w) water. In an exemplary (0195 b) from about 5% (w/w) to about 15% (w/w) embodiment, the topical pharmaceutical formulation with propylene glycol, out an active agent further comprises up to about 0.01% (0196) c) petrolatum; (w/w) water. (0197) d) butylated hydroxytoluene: 0220. The topical pharmaceutical formulation without an 0198 e) edetate calcium disodium; active agent may optionally contain a solvent, a base, an (0199 f) from about 5% (w/w) to about 10% (w/w) of antioxidant, a stabilizer, an emulsifying agent, and a stiff a glyceride blend, wherein the glyceride blend com ening agent. The identity and concentrations for each of prises one or more monoglycerides and one or more these components in the topical pharmaceutical formulation diglycerides, wherein the one or more monoglycerides without an active agent may be found in sections II. a. i., II. is in a total concentration of between 40% and 55% of a. ii., II. a. iii.; II. a. iv.; II. a. V., II. a. vi., II. a. vii.; and II. the glyceride blend; and a. viii. of this document. 0200 g) a stiffening agent Specific Topical Pharmaceutical Formulations without an wherein the formulation comprises no more than about 0.5% Active Agent (w/w) water. 0221 II. a.x. 0201 In an exemplary embodiment, the topical pharma 0222. In an exemplary embodiment, the topical pharma ceutical formulation consists essentially of ceutical formulation comprises: 0202) a) about 2% (w/w) 5-(4-cyanophenoxy)-1,3-di 0223 a) from about 5% (w/w) to about 15% (w/w) hydro-1-hydroxy-2,1-benzoxaborole, or a pharmaceu propylene glycol; tically acceptable salt, or a hydrate or a solvate thereof; 0224 b) petrolatum; 0203 b) about 9% (w/w) propylene glycol; 0225 c) an antioxidant; US 2017/0152273 A1 Jun. 1, 2017

0226 d) a stabilizer; 0257. In an exemplary embodiment, the topical pharma 0227 e) an emulsifying agent; and ceutical formulation comprises: 0228 f) a stiffening agent, 0258 a) from about 5% (w/w) to about 15% (w/w) of wherein the topical pharmaceutical formulation does not propylene glycol; comprise an active agent and wherein the formulation com 0259 b) from about 67.955% (w/w) to about prises no more than about 0.5% (w/w) water. 89.8999% (w/w) of petrolatum; 0229. In an exemplary embodiment, the topical pharma 0260 c) from about 0.1% (w/w) to about 1% (w/w) of ceutical formulation comprises: butylated hydroxytoluene: 0230 a) about 5% (w/w) of a solvent; 0261 d) from about 0.0001% (w/w) to about 0.0450% 0231 b) about 89.8999% (w/w) of petrolatum; (w/w) of edetate calcium disodium; 0232 c) about 0.1% (w/w) of an antioxidant; 0262 e) from about 3% (w/w) to about 10% (w/w) of 0233 d) about 0.0001% (w/w) of a stabilizer; a glyceride blend, wherein the glyceride blend com 0234 e) about 3% (w/w) of an emulsifying agent; and prises one or more monoglycerides and one or more 0235 f) about 2% (w/w) of a stiffening agent, diglycerides, wherein the one or more monoglycerides wherein the topical pharmaceutical formulation does not is in a total concentration of between 40% and 55% of comprise an active agent and wherein the formulation com the glyceride blend; and prises no more than about 0.5% (w/w) water. 0263 f) from about 2% (w/w) to about 6% (w/w) of 0236. In an exemplary embodiment, the topical pharma paraffin wax, ceutical formulation comprises: wherein the topical pharmaceutical formulation does not 0237) a) about 15% (w/w) of a solvent; comprise an active agent and wherein the formulation com 0238 b) about 67.955% (w/w) of petrolatum; prises no more than about 0.5% (w/w) water. 0239 c) about 1% (w/w) of an antioxidant; 0264. In an exemplary embodiment, the topical pharma 0240 d) about 0.0450% (w/w) of a stabilizer; ceutical formulation comprises: 0241 e) about 10% (w/w) of an emulsifying agent; and 0265 a) from about 8% (w/w) to about 10% (w/w) 0242 f) about 6% (w/w) of a stiffening agent, propylene glycol; wherein the topical pharmaceutical formulation does not 0266 b) petrolatum; comprise an active agent and wherein the formulation com 0267 c) an antioxidant; prises no more than about 0.5% (w/w) water. 0268 d) a stabilizer; 0243 In an exemplary embodiment, the topical pharma 0269 e) an emulsifying agent; and ceutical formulation comprises: 0270 f) a stiffening agent, wherein the topical pharmaceutical formulation does not 0244) a) from about 5% (w/w) to about 15% (w/w) of comprise an active agent and wherein the formulation com a solvent; prises no more than about 0.5% (w/w) water. 0245 b) from about 67.955% (w/w) to about 0271 In an exemplary embodiment, the topical pharma 89.8999% (w/w) of petrolatum; ceutical formulation comprises: 0246 c) from about 0.1% (w/w) to about 1% (w/w) of (0272 a) from about 8% (w/w) to about 10% (w/w) an antioxidant; propylene glycol; 0247 d) from about 0.0001% (w/w) to about 0.0450% (0273 b) petrolatum; (w/w) of a stabilizer; 0248 e) from about 3% (w/w) to about 10% (w/w) of 0274 c) an antioxidant; an emulsifying agent, and 0275 d) edetate calcium disodium; 0249 f) from about 2% (w/w) to about 6% (w/w) of a 0276 e) an emulsifying agent; and stiffening agent, 0277 f) a stiffening agent, wherein the topical pharmaceutical formulation does not wherein the topical pharmaceutical formulation does not comprise an active agent and wherein the formulation com comprise an active agent and wherein the formulation com prises no more than about 0.5% (w/w) water. prises no more than about 0.5% (w/w) water. 0250 In an exemplary embodiment, the topical pharma 0278. In an exemplary embodiment, the topical pharma ceutical formulation comprises: ceutical formulation consists of (0251 a) from about 5% (w/w) to about 15% (w/w) of (0279 a) from about 8% (w/w) to about 10% (w/w) propylene glycol, propylene glycol; 0252 b) from about 67.955% (w/w) to about 0280 b) petrolatum; 89.8999% (w/w) of petrolatum; 0281 c) an antioxidant; (0253 c) from about 0.1% (w/w) to about 1% (w/w) of 0282 d) from about 0.0020% (w/w) to about 0.0040% butylated hydroxytoluene: (w/w) edetate calcium disodium; (0254 d) from about 0.0001% (w/w) to about 0.0450% 0283 e) an emulsifying agent; and (w/w) of edetate calcium disodium; 0284 f) a stiffening agent. (0255 e) from about 3% (w/w) to about 10% (w/w) of 0285. In an exemplary embodiment, the topical pharma a glyceride blend; and ceutical formulation consists essentially of (0256 f) from about 2% (w/w) to about 6% (w/w) of 0286 a) from about 8% (w/w) to about 10% (w/w) paraffin wax, propylene glycol; wherein the topical pharmaceutical formulation does not (0287 b) petrolatum; comprise an active agent and wherein the formulation com 0288 c) an antioxidant; prises no more than about 0.5% (w/w) water. 0289 d) a stabilizer; US 2017/0152273 A1 Jun. 1, 2017

0290 e) a glyceride blend, wherein the glyceride blend erides, wherein the one or more monoglycerides is in a comprises one or more monoglycerides and one or total concentration of between 40% and 55% of the more diglycerides; and glyceride blend; and 0291 f) a stiffening agent 0319 f) a stiffening agent wherein the formulation comprises no more than about 0.5% wherein the formulation comprises no more than about 0.5% (w/w) water. (w/w) water. 0292. In an exemplary embodiment, the topical pharma 0320 In an exemplary embodiment, the topical pharma ceutical formulation consists essentially of ceutical formulation consists essentially of 0293 a) from about 8% (w/w) to about 10% (w/w) 0321) a) from about 8% (w/w) to about 10% (w/w) propylene glycol, propylene glycol; 0294 b) petrolatum; 0322 b) petrolatum; 0295 c) an antioxidant; 0323 c) an antioxidant; 0296) d) a stabilizer; 0324 d) from about 0.0020% (w/w) to about 0.0040% 0297 e) a glyceride blend, wherein the glyceride blend (w/w) edetate calcium disodium; comprises one or more monoglycerides and one or 0325 e) from about 6% (w/w) to about 8% (w/w) of a more diglycerides, wherein the one or more monoglyc glyceride blend, wherein the glyceride blend comprises erides is in a total concentration of between 40% and one or more monoglycerides and one or more diglyc erides, wherein the one or more monoglycerides is in a 55% of the glyceride blend; and total concentration of between 40% and 55% of the 0298 f) a stiffening agent glyceride blend; and wherein the formulation comprises no more than about 0.5% 0326 f) a stiffening agent (w/w) water. wherein the formulation comprises no more than about 0.5% 0299. In an exemplary embodiment, the topical pharma (w/w) water. ceutical formulation consists essentially of 0327. In an exemplary embodiment, the topical pharma (0300 a) from about 8% (w/w) to about 10% (w/w) ceutical formulation consists essentially of propylene glycol, 0328 a) from about 5% (w/w) to about 15% (w/w) (0301 b) petrolatum; propylene glycol; 0302 c) an antioxidant; 0329 b) petrolatum; (0303 d) a stabilizer; 0330 c) butylated hydroxytoluene: (0304 e) from about 5% (w/w) to about 10% (w/w) of 0331 d) edetate calcium disodium; a glyceride blend, wherein the glyceride blend com 0332 e) from about 5% (w/w) to about 10% (w/w) of prises one or more monoglycerides and one or more a glyceride blend, wherein the glyceride blend com diglycerides, wherein the one or more monoglycerides prises one or more monoglycerides and one or more is in a total concentration of between 40% and 55% of diglycerides, wherein the one or more monoglycerides the glyceride blend; and is in a total concentration of between 40% and 55% of 0305 f) a stiffening agent the glyceride blend; and wherein the formulation comprises no more than about 0.5% 0333 f) a stiffening agent (w/w) water. wherein the formulation comprises no more than about 0.5% 0306 In an exemplary embodiment, the topical pharma (w/w) water. ceutical formulation consists essentially of 0334. In an exemplary embodiment, the topical pharma (0307 a) from about 8% (w/w) to about 10% (w/w) ceutical formulation consists essentially of propylene glycol, 0335) a) from about 5% (w/w) to about 15% (w/w) (0308 b) petrolatum; propylene glycol; 0309 c) an antioxidant; 0336 b) petrolatum; 0310 d) a stabilizer; 0337 c) butylated hydroxytoluene: 0311 e) from about 6% (w/w) to about 8% (w/w) of a 0338 d) edetate calcium disodium; glyceride blend, wherein the glyceride blend comprises 0339 e) from about 5% (w/w) to about 10% (w/w) of one or more monoglycerides and one or more diglyc a glyceride blend, wherein the glyceride blend com erides, wherein the one or more monoglycerides is in a prises one or more monoglycerides and one or more total concentration of between 40% and 55% of the diglycerides, wherein the one or more monoglycerides glyceride blend; and is in a total concentration of between 40% and 55% of 0312 f) a stiffening agent the glyceride blend; and wherein the formulation comprises no more than about 0.5% (0340 f) paraffin wax (w/w) water. wherein the formulation comprises no more than about 0.5% 0313. In an exemplary embodiment, the topical pharma (w/w) water. ceutical formulation consists essentially of 0341. In an exemplary embodiment, the topical pharma 0314 a) from about 8% (w/w) to about 10% (w/w) ceutical formulation consists essentially of propylene glycol, 0342 a) about 9% (w/w) propylene glycol; 0315 b) petrolatum; (0343 b) white petrolatum; 0316 c) an antioxidant; 0344 c) about 0.1% (w/w) butylated hydroxytoluene: 0317 d) edetate calcium disodium; (0345 d) about 0.0035% (w/w) edetate calcium diso 0318 e) from about 6% (w/w) to about 8% (w/w) of a dium; glyceride blend, wherein the glyceride blend comprises 0346 e) about 7% (w/w) of a glyceride blend, wherein one or more monoglycerides and one or more diglyc the glyceride blend comprises one or more monoglyc US 2017/0152273 A1 Jun. 1, 2017

erides and one or more diglycerides, wherein the one or 0357 III.a. Cytokine and/or Chemokine more monoglycerides is in a total concentration of 0358. In another aspect, the invention provides a method between 40% and 55% of the glyceride blend; and of decreasing the release of a cytokine and/or a chemokine, (0347 f) about 5% (w/w) paraffin wax. the method comprising contacting a cell with an active agent 0348. In an exemplary embodiment, the topical pharma described herein, or a pharmaceutically acceptable salt, or a ceutical formulation consists of hydrate or a Solvate thereof. In an exemplary embodiment, 0349 a) 9% (w/w) propylene glycol; the invention provides a method of decreasing the release of 0350 b) 78.8965% (w/w) white petrolatum; a cytokine and/or a chemokine, the method comprising 0351 c) 0.1% (w/w) butylated hydroxytoluene: contacting a cell with a topical pharmaceutical formulation 0352 d) 0.0035% (w/w) edetate calcium disodium; with an active agent described herein, or a pharmaceutically 0353 e) 7% (w/w) of a glyceride blend, wherein the acceptable salt, or a hydrate or a solvate thereof. In an glyceride blend comprises one or more monoglycerides exemplary embodiment, the invention provides a method of and one or more diglycerides, wherein the one or more decreasing the release of a cytokine and/or a chemokine, the monoglycerides is in a total concentration of between method comprising contacting a cell with a topical pharma 40% and 55% of the glyceride blend; and ceutical formulation without an active agent, described 0354 f) 5% (w/w) paraffin wax herein, or a pharmaceutically acceptable salt, or a hydrate or wherein the formulation comprises no more than about 0.5% a Solvate thereof. In an exemplary embodiment, for any of (w/w) water. the methods provided herein, the release of the cytokine 0355 Information regarding, excipients of use in the and/or chemokine is decreased. In an exemplary embodi topical pharmaceutical formulations described herein, as ment, for any of the methods described herein, the cytokine well as making these topical pharmaceutical formulations, and/or chemokine is decreased. can be found herein as well as in Remington. The Science and Practice of Pharmacy, 21st Ed., Pharmaceutical Press 0359. In another aspect, the invention provides a method (2011), the content of which is incorporated by reference for of decreasing the release of a cytokine and/or a chemokine all purposes. from a cell, the method comprising contacting the cell with an active agent described herein, or a pharmaceutically III. The Methods acceptable salt, or a hydrate or a solvate thereof. In an exemplary embodiment, the active agent contacts the cell 0356. In another aspect of the invention, an active agent through administration of a topical pharmaceutical formu described herein, or a pharmaceutically acceptable salt, or a lation described herein. In an exemplary embodiment, the hydrate or a solvate thereof, can be utilized in the methods invention provides a method of decreasing the release of a described herein. In another aspect of the invention, the cytokine and/or a chemokine from a cell, the method com topical pharmaceutical formulation described herein can be prising: contacting the cell with a topical pharmaceutical utilized in the methods described herein. In another aspect of formulation without an active agent, described herein, or a the invention, the topical pharmaceutical formulation with pharmaceutically acceptable salt, or a hydrate or a solvate an active agent, described herein, can be utilized in the thereof. In an exemplary embodiment, the release of the methods described herein. In another aspect of the invention, cytokine and/or chemokine by the cell is decreased. In an the topical pharmaceutical formulation without an active exemplary embodiment, the cell is a skin cell. agent, described herein, can be utilized in the methods described herein. In an exemplary embodiment, in any of the 0360. In another aspect, the invention provides a method methods described herein, the animal being administered an of decreasing the release of a cytokine and/or a chemokine active agent described herein, or a pharmaceutically accept from a cell, the method comprising contacting the cell with able salt, or a hydrate or a solvate thereof, or a topical a topical pharmaceutical formulation without an active pharmaceutical formulation described herein is not other agent, described herein. In an exemplary embodiment, the wise in need of treatment with said active agent described release of the cytokine and/or chemokine by the cell is herein, or a pharmaceutically acceptable salt, or a hydrate or decreased. In an exemplary embodiment, the cell is a skin a Solvate thereof, or the topical pharmaceutical formulation cell. described herein. In an exemplary embodiment, in any of the 0361. In another aspect, the invention provides a method methods described herein, the animal being administered an of decreasing the release of a cytokine and/or a chemokine active agent described herein, or a pharmaceutically accept by a skin cell, the method comprising contacting the skin able salt, or a hydrate or a solvate thereof, or a topical cell with an active agent by administering a topical phar pharmaceutical formulation described herein is in need of maceutical formulation described herein. In an exemplary treatment with said active agent described herein, or a embodiment, the release of the cytokine and/or chemokine pharmaceutically acceptable salt, or a hydrate or a solvate by the skin cell is decreased. thereof, or a topical pharmaceutical formulation described herein. In an exemplary embodiment, in any of the methods 0362. In another aspect, the invention provides a method described herein, the animal being administered a topical of decreasing the release of a cytokine and/or a chemokine pharmaceutical formulation without an active agent, by a skin cell, the method comprising contacting the skin described herein, is not otherwise in need of treatment with cell with a topical pharmaceutical formulation described the topical pharmaceutical formulation without an active herein. In an exemplary embodiment, the release of the agent. In an exemplary embodiment, in any of the methods cytokine and/or chemokine by the skin cell is decreased. described herein, the animal being administered a topical 0363. In another aspect, the invention provides a method pharmaceutical formulation without an active agent, of decreasing the release of a cytokine and/or a chemokine described herein, is in need of treatment with the topical by a skin cell, the method comprising contacting the skin pharmaceutical formulation without an active agent. cell with a topical pharmaceutical formulation without an US 2017/0152273 A1 Jun. 1, 2017 active agent, described herein. In an exemplary embodi and PDE11. In an exemplary embodiment, the phosphodi ment, the release of the cytokine and/or chemokine by the esterase is PDE4. In an exemplary embodiment, the PDE4 is skin cell is decreased. selected from the group consisting of PDE4A, PDE4B, 0364. In an exemplary embodiment, the cytokine and/or PDE4C and PDE4D. In an exemplary embodiment, the chemokine is selected from the group consisting of TNF-C. PDE4 is PDE4B. In an exemplary embodiment, the phos IFN-y, IL-2, IL-4, IL-5, IL-13, IL-22, IL-23, and IL-31. In phodiesterase is PDE7. an exemplary embodiment, the cytokine and/or chemokine 0370. In an exemplary embodiment, the invention pro is TNF-C. In an exemplary embodiment, the cytokine and/or vides a method for inhibiting a phosphodiesterase4 (PDE4). chemokine is IL-23. In an exemplary embodiment, the but not significantly inhibiting at least one PDE which is cytokine and/or chemokine is IL-2. In an exemplary selected from the group consisting of PDE1, PDE2, PDE3, embodiment, the cytokine and/or chemokine is IL-17. PDE5 and PDE6, involving contacting a cell with a topical 0365. In an exemplary embodiment, for any of the meth pharmaceutical formulation described herein, thereby pro ods described herein, the active agent or the topical phar viding said inhibition. maceutical formulation is present in an amount which 0371. In an exemplary embodiment, for any of the meth decreases the release of a cytokine and/or chemokine ods described herein, the active agent or the topical phar described herein by at least about 5 to about 100%, or at least maceutical formulation is present in an amount which inhib about 30 to about 100%, 40 to about 100%, or at least about its a phosphodiesterase described herein by at least about 5 50 to about 100%, or at least about 60 to about 100%, or at to about 100%, or at least about 30 to about 100%, 40 to least about 70 to about 100%, or at least about 80 to about about 100%, or at least about 50 to about 100%, or at least 100%, or at least about 90 to about 100%, or at least about about 60 to about 100%, or at least about 70 to about 100%, 30 to about 70%, or at least about 40 to about 90%, or at least or at least about 80 to about 100%, or at least about 90 to about 45 to about 80%, or at least about 55 to about 75%, or about 100%, or at least about 30 to about 70%, or at least at least about 75 to about 98%, or at least about 55 to about about 40 to about 90%, or at least about 45 to about 80%, or 99%, or at least about 5% to about 20% or at least about 10% at least about 55 to about 75%, or at least about 75 to about to about 25%. 98%, or at least about 55 to about 99%, or at least about 5% 0366 III.b. Phosphodiesterase to about 20% or at least about 10% to about 25%. 0367. In another aspect, the invention provides a method 0372 III.c. Conditions of inhibiting a phosphodiesterase (PDE), the method com 0373) In another aspect, the invention provides a method prising contacting the phosphodiesterase with an active of treating and/or preventing a condition in an animal, the agent described herein, or a pharmaceutically acceptable method comprising administering to the animal a therapeu salt, or a hydrate or a solvate thereof. In an exemplary tically effective and/or prophylactically effective amount of embodiment, the compound of the invention is a compound a topical pharmaceutical formulation with an active agent, described herein or a pharmaceutically acceptable salt described herein. In an exemplary embodiment, the condi thereof. In an exemplary embodiment, the compound of the tion is treated and/or prevented. In an exemplary embodi invention is a compound described herein. In an exemplary ment, the animal is in need of treatment and/or prophylaxis embodiment, the amount of the compound is a therapeuti thereof. In an exemplary embodiment, the animal is not cally effective amount. In an exemplary embodiment, the otherwise in need of treatment and/or prophylaxis thereof. In compound is according to a formula described herein. In an an exemplary embodiment, the condition is a condition of exemplary embodiment, for any of the methods described the skin. In an exemplary embodiment, the condition is herein, the phosphodiesterase is inhibited. pruritis. 0368. In another aspect, the invention provides a method 0374. In another aspect, the invention provides a method of inhibiting a phosphodiesterase (PDE) in a cell, the method of treating and/or preventing a condition in an animal, the comprising contacting the cell with a topical pharmaceutical method comprising administering to the animal, a therapeu formulation with an active agent described herein, or a tically effective and/or prophylactically effective amount of pharmaceutically acceptable salt, or a hydrate or a solvate a topical pharmaceutical formulation without an active thereof. In another aspect, the invention provides a method agent, described herein. In an exemplary embodiment, the of inhibiting a phosphodiesterase (PDE) in a cell, the method condition is treated and/or prevented. In an exemplary comprising contacting the cell with a topical pharmaceutical embodiment, the animal is in need of treatment and/or formulation without an active agent described herein, or a prophylaxis thereof. In an exemplary embodiment, the con pharmaceutically acceptable salt, or a hydrate or a solvate dition is a condition of the skin. In an exemplary embodi thereof. In an exemplary embodiment, the amount of the ment, the condition is pruritis. active agent is a therapeutically effective amount. In an 0375. In another aspect, the invention provides a method exemplary embodiment, the amount of the topical pharma of treating and/or preventing an inflammatory-related con ceutical formulation with an active agent is a therapeutically dition in an animal, the method comprising administering to effective amount. In an exemplary embodiment, the amount the animal a therapeutically effective and/or prophylacti of the topical pharmaceutical formulation without an active cally effective amount of a topical pharmaceutical formula agent is a therapeutically effective amount. In an exemplary tion with an active agent, described herein. In an exemplary embodiment, for any of the methods described herein, the embodiment, the inflammatory-related condition is treated cell is a skin cell. In an exemplary embodiment, for any of and/or prevented. In an exemplary embodiment, the animal the methods described herein, the phosphodiesterase is is in need of treatment and/or prophylaxis thereof. In an inhibited. exemplary embodiment, the animal is not otherwise in need 0369. In an exemplary embodiment, the phosphodies of treatment and/or prophylaxis thereof. In an exemplary terase is selected from the group consisting of PDE1, PDE2. embodiment, the inflammatory-related condition is a condi PDE3, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10 tion of the skin. US 2017/0152273 A1 Jun. 1, 2017

0376. In another aspect, the invention provides a method described herein, to an animal. In an exemplary embodi of treating and/or preventing an inflammatory-related con ment, the plaque psoriasis is prevented. dition in an animal, the method comprising administering to 0384. In another exemplary embodiment, the method the animal, a therapeutically effective and/or prophylacti involves treating plaque psoriasis by administering a topical cally effective amount of a topical pharmaceutical formula pharmaceutical formulation with an active agent, described tion without an active agent, described herein. In an exem herein, to an animal. In an exemplary embodiment, the plary embodiment, the inflammatory-related condition is plaque psoriasis is treated. In another exemplary embodi treated and/or prevented. In an exemplary embodiment, the ment, the method involves treating plaque psoriasis by animal is in need of treatment and/or prophylaxis thereof. administering a topical pharmaceutical formulation without 0377. In an exemplary embodiment, the inflammatory an active agent, described herein, to an animal. In an related condition is psoriasis. In an exemplary embodiment, exemplary embodiment, the plaque psoriasis is treated. the inflammatory-related condition is plaque psoriasis or 0385. In another exemplary embodiment, the method flexural psoriasis (inverse psoriasis) or guttate psoriasis or involves preventing nail psoriasis by administering a topical pustular psoriasis or nail psoriasis or psoriatic arthritis or pharmaceutical formulation with an active agent, described erythrodermic psoriasis. In an exemplary embodiment, the herein, to an animal. In an exemplary embodiment, the nail inflammatory-related condition is plaque psoriasis. In an psoriasis is prevented. exemplary embodiment, the inflammatory-related condition 0386. In another exemplary embodiment, the method is nail psoriasis. involves preventing nail psoriasis by administering a topical 0378. In an exemplary embodiment, the inflammatory pharmaceutical formulation without an active agent, related condition is dermatitis. In an exemplary embodi described herein, to an animal. In an exemplary embodi ment, the inflammatory-related condition is contact derma ment, the nail psoriasis is prevented. In another exemplary titis or atopic dermatitis or nummular dermatitis or embodiment, the method involves treating nail psoriasis by Seborrheic dermatitis or stasis dermatitis. In an exemplary administering a topical pharmaceutical formulation with an embodiment, the inflammatory-related condition is atopic active agent, described herein, to an animal. In an exemplary dermatitis. In an exemplary embodiment, the inflammatory embodiment, the nail psoriasis is treated. In another exem related condition is eczema. plary embodiment, the method involves treating nail pso 0379. In an exemplary embodiment, for any of the meth riasis by administering a topical pharmaceutical formulation ods described herein, the animal is selected from the group without an active agent, described herein, to an animal. In an consisting of human, cattle, deer, reindeer, goat, honey bee, exemplary embodiment, the nail psoriasis is treated. pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, 0387. In another exemplary embodiment, the method cat, camel, yak, elephant, ostrich, otter, chicken, duck, involves preventing atopic dermatitis by administering a goose, guinea fowl, pigeon, Swan, and turkey. In another topical pharmaceutical formulation with an active agent, exemplary embodiment, for any of the methods described described herein, to an animal. In an exemplary embodi herein, the animal is selected from the group consisting of a ment, the atopic dermatitis is prevented. human, cattle, goat, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, chicken and turkey. In another 0388. In another exemplary embodiment, the method exemplary embodiment, for any of the methods described involves preventing atopic dermatitis by administering a herein, the animal is a human. topical pharmaceutical formulation without an active agent, 0380. In another exemplary embodiment, the method described herein, to an animal. In an exemplary embodi involves preventing psoriasis by administering a topical ment, the atopic dermatitis is prevented. pharmaceutical formulation with an active agent, described 0389. In another exemplary embodiment, the method herein, to an animal. In an exemplary embodiment, the involves treating atopic dermatitis by administering a topical psoriasis is prevented. In another exemplary embodiment, pharmaceutical formulation with an active agent, described the method involves preventing psoriasis by administering a herein, to an animal. In an exemplary embodiment, the topical pharmaceutical formulation without an active agent, atopic dermatitis is treated. described herein, to an animal. In an exemplary embodi 0390. In another exemplary embodiment, the method ment, the psoriasis is prevented. In another exemplary involves treating atopic dermatitis by administering a topical embodiment, the method involves treating psoriasis by pharmaceutical formulation without an active agent, administering a topical pharmaceutical formulation with an described herein, to an animal. In an exemplary embodi active agent, described herein, to an animal. In an exemplary ment, the atopic dermatitis is treated. embodiment, the psoriasis is treated. 0391 Exemplary embodiments are summarized herein 0381. In another exemplary embodiment, the method below. involves treating psoriasis by administering a topical phar 0392. In an exemplary embodiment, the invention pro maceutical formulation without an active agent, described vides a topical pharmaceutical formulation comprising: a) an herein, to an animal. In an exemplary embodiment, the active agent which treats an inflammatory-related condition, psoriasis is treated. or a pharmaceutically acceptable salt, or a hydrate or a 0382. In another exemplary embodiment, the method solvate thereof; b) from about 5% (w/w) to about 15% (w/w) involves preventing plaque psoriasis by administering a propylene glycol, and c) petrolatum. topical pharmaceutical formulation with an active agent, 0393. In an exemplary embodiment, according to the described herein, to an animal. In an exemplary embodi above paragraph, the formulation comprises no more than ment, the plaque psoriasis is prevented. about 0.5% (w/w) water. 0383. In another exemplary embodiment, the method 0394. In an exemplary embodiment, according to any of involves preventing plaque psoriasis by administering a the above paragraphs, the amount of the propylene glycol is topical pharmaceutical formulation without an active agent, from about 7% (w/w) to about 11% (w/w). US 2017/0152273 A1 Jun. 1, 2017

0395. In an exemplary embodiment, according to any of 0411. In an exemplary embodiment, according to any of the above paragraphs, the amount of the propylene glycol is the above paragraphs, the amount of the ethylenediaminetet from about 6% (w/w) to about 10% (w/w). In an exemplary raacetic acid, or a pharmaceutically acceptable salt thereof, embodiment, according to any of the above paragraphs, the is from about 0.0001% (w/w) to about 0.01% (w/w). In an amount of the propylene glycol is from about 8% (w/w) to exemplary embodiment, according to any of the above about 10% (w/w). paragraphs, the amount of the ethylenediaminetetraacetic 0396. In an exemplary embodiment, according to any of acid, or a pharmaceutically acceptable salt thereof, is from the above paragraphs, the amount of the propylene glycol is about 0.001% (w/w) to about 0.01% (w/w). about 9% (w/w). 0412. In an exemplary embodiment, according to any of 0397. In an exemplary embodiment, according to any of the above paragraphs, the amount of the ethylenediaminetet the above paragraphs, the amount of the propylene glycol is raacetic acid, or a pharmaceutically acceptable salt thereof, 9% (w/w). is from about 0.001% (w/w) to about 0.005% (w/w). 0398. In an exemplary embodiment, according to any of 0413. In an exemplary embodiment, according to any of the above paragraphs, the propylene glycol is propylene the above paragraphs, the amount of the ethylenediaminetet glycol USP. raacetic acid, or a pharmaceutically acceptable salt thereof, 0399. In an exemplary embodiment, according to any of is from about 0.0025% (w/w) to about 0.0045% (w/w). the above paragraphs, the topical pharmaceutical formula 0414. In an exemplary embodiment, according to any of tion further comprises an emulsifying agent. the above paragraphs, the amount of the ethylenediaminetet 0400. In an exemplary embodiment, according to any of raacetic acid, or a pharmaceutically acceptable salt thereof, the above paragraphs, wherein the emulsifying agent is a is about 0.0035% (w/w). glyceride blend. 0415. In an exemplary embodiment, according to any of 04.01. In an exemplary embodiment, according to any of the above paragraphs, the amount of the ethylenediaminetet the above paragraphs, wherein the emulsifying agent is a raacetic acid, or a pharmaceutically acceptable salt thereof, glyceride blend, and the glyceride blend comprises a mono is 0.0035% (w/w). glyceride and a diglyceride. 0416. In an exemplary embodiment, according to any of 0402. In an exemplary embodiment, according to any of the above paragraphs, the amount of the edetate calcium the above paragraphs, the amount of the glyceride blend is disodium USP is 0.0035% (w/w). from about 3% (w/w) to about 10% (w/w). 0417. In an exemplary embodiment, according to any of 0403. In an exemplary embodiment, according to any of the above paragraphs, further comprising an antioxidant. the above paragraphs, the amount of the glyceride blend is 0418. In an exemplary embodiment, according to any of from about 5% (w/w) to about 8% (w/w). the above paragraphs, the antioxidant is selected from the 0404 In an exemplary embodiment, according to any of group consisting of butylated hydroxytoluene, ascorbic acid the above paragraphs, the amount of the glyceride blend is or a pharmaceutically acceptable salt thereof, ascorbic from about 6% (w/w) to about 8% (w/w). palmitate, butylated hydroxyanisole, 2,4,5-trihydroxybuty 0405. In an exemplary embodiment, according to any of rophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol, ery the above paragraphs, the amount of the glyceride blend is thorbic acid, gum guaiac, propyl gallate, thiodipropionic about 7% (w/w). acid, dilauryl thiodipropionate, tert-butylhydroquinone and 0406. In an exemplary embodiment, according to any of tocopherols such as vitamin E, and the like, including the above paragraphs, the amount of the glyceride blend is pharmaceutically acceptable salts and esters thereof, and 7% (w/w). In an exemplary embodiment, according to any mixtures thereof. of the above paragraphs, the glyceride blend is Mono- and 0419. In an exemplary embodiment, according to any of Di-glyceride NF. the above paragraphs, the antioxidant is butylated hydroxy 0407. In an exemplary embodiment, according to any of toluene. the above paragraphs, from about 40% (w/w) to about 55% (w/w) of the glyceride blend is a monoglyceride. 0420. In an exemplary embodiment, according to any of 0408. In an exemplary embodiment, according to any of the above paragraphs, the amount of the antioxidant is from the above paragraphs, the topical pharmaceutical formula about 0.01% (w/w) to about 1% (w/w). tion further comprises a stabilizer. In an exemplary embodi 0421. In an exemplary embodiment, according to any of ment, according to any of the above paragraphs, the stabi the above paragraphs, the amount of the antioxidant is from lizer is ethylenediaminetetraacetic acid, or a about 0.05% (w/w) to about 0.5% (w/w). pharmaceutically acceptable salt thereof. In an exemplary 0422. In an exemplary embodiment, according to any of embodiment, according to any of the above paragraphs, the above paragraphs, the amount of the antioxidant is about further comprising a sodium salt or a potassium salt or a 0.1% (w/w). calcium salt, or a mixture thereof, of ethylenediaminetet 0423 In an exemplary embodiment, according to any of raacetic acid. In an exemplary embodiment, according to the above paragraphs, the amount of the antioxidant is 0.1% any of the above paragraphs, further comprising a sodium (w/w). salt or a calcium salt, or a mixture thereof, of ethylenedi 0424. In an exemplary embodiment, according to any of aminetetraacetic acid. the above paragraphs, the antioxidant is butylated hydroxy 04.09. In an exemplary embodiment, according to any of toluene. the above paragraphs, further comprising edetate calcium 0425. In an exemplary embodiment, according to any of disodium. the above paragraphs, the antioxidant is butylated hydroxy 0410. In an exemplary embodiment, according to any of toluene NF. the above paragraphs, further comprising edetate calcium 0426 In an exemplary embodiment, according to any of disodium USP the above paragraphs, further comprising a stiffening agent. US 2017/0152273 A1 Jun. 1, 2017

0427. In an exemplary embodiment, according to any of 0442. In an exemplary embodiment, the topical pharma the above paragraphs, the amount of the stiffening agent is ceutical formulation consists of: a) 2% (w/w) 5-(4-cyano from about 2% (w/w) to about 8% (w/w). phenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole; b) 9% 0428. In an exemplary embodiment, according to any of (w/w) propylene glycol; c) 0.1% (w/w) butylated hydroxy the above paragraphs, the amount of the stiffening agent is toluene; d) 0.0035% (w/w) edetate calcium disodium; e) 7% from about 4% (w/w) to about 6% (w/w). In an exemplary (w/w) mono- and di-glycerides; f) 5% (w/w) paraffin wax: embodiment, according to any of the above paragraphs, the and g) 76.8965% (w/w) white petrolatum. amount of the stiffening agent is about 5% (w/w). 0443) In an exemplary embodiment, the topical pharma 0429. In an exemplary embodiment, according to any of ceutical formulation consists essentially of: a) 2% (w/w) the above paragraphs, the amount of the stiffening agent is 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxa 5% (w/w). borole; b) 9% (w/w) propylene glycol; c) 0.1% (w/w) 0430. In an exemplary embodiment, according to any of butylated hydroxytoluene; d) 0.0035% (w/w) edetate cal the above paragraphs, the stiffening agent is selected from cium disodium; e) 7% (w/w) mono- and di-glycerides, the group consisting of beeswax, paraffin wax, wax, and wherein between 40% and 55% is the monoglyceride: f) 5% spermaceti wax. (w/w) paraffin wax; and g) 76.8965% (w/w) white petrola 0431. In an exemplary embodiment, according to any of tum. the above paragraphs, the stiffening agent is paraffin wax. 0444. In an exemplary embodiment, the topical pharma 0432. In an exemplary embodiment, according to any of ceutical formulation consists essentially of: a) about 2% the above paragraphs, the stiffening agent is paraffin wax (w/w) 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-ben NF. Zoxaborole; b) about 9% (w/w) propylene glycol; c) about 0433. In an exemplary embodiment, according to any of 0.1% (w/w) butylated hydroxytoluene; d) about 0.0035% the above paragraphs, the stiffening agent is 5% (w/w) (w/w) edetate calcium disodium; e) about 7% (w/w) mono paraffin wax NF. and di-glycerides, wherein between 40% and 55% is the 0434 In an exemplary embodiment, according to any of monoglyceride; f) about 5% (w/w) paraffin waX; and g) the above paragraphs, the active agent is 5-(4-cyanophe about 76.8965% (w/w) white petrolatum. noxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole. In an 0445. In an exemplary embodiment, the topical pharma exemplary embodiment, according to any of the above ceutical formulation consists of: a) about 2% (w/w) 5-(4- paragraphs, the amount of the active agent is from about cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole; 0.1% (w.fw) to about 2.0% (w/w). b) about 9% (w/w) propylene glycol; c) about 0.1% (w/w) 0435. In an exemplary embodiment, according to any of butylated hydroxytoluene; d) about 0.0035% (w/w) edetate the above paragraphs, the amount of the 5-(4-cyanophe calcium disodium; e) about 7% (w/w) mono- and di-glyc noxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole is from erides, wherein between 40% and 55% is the monoglycer about 0.1% (w/w) to about 2.0% (w/w). ide: f) about 5% (w/w) paraffin wax; and g) about 76.8965% 0436. In an exemplary embodiment, according to any of (w/w) white petrolatum. the above paragraphs, the amount of the 5-(4-cyanophe 0446. In an exemplary embodiment, the invention is a noxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole is 2.0% method of decreasing the release of a cytokine and/or a (w/w). chemokine, the method comprising contacting a cell with 0437. In an exemplary embodiment, according to any of the topical pharmaceutical formulation according to any of the above paragraphs, the remainder of the formulation is the above paragraphs. petrolatum. In an exemplary embodiment, according to any 0447. In an exemplary embodiment, the invention is a of the above paragraphs, the remainder of the formulation is method of treating an inflammatory-related condition in an White Petrolatum. animal, the method comprising administering to the animal 0438. In an exemplary embodiment, according to any of a therapeutically effective amount of the topical pharmaceu the above paragraphs, the remainder of the formulation is tical formulation according to any of the above paragraphs. White Petrolatum USP. 0448. In an exemplary embodiment, according to any of 0439. In an exemplary embodiment, the topical pharma the above method paragraphs, the inflammatory-related con ceutical formulation consists of: a) 5-(4-cyanophenoxy)-1, dition is psoriasis. 3-dihydro-1-hydroxy-2,1-benzoxaborole; b) propylene gly col; c) butylated hydroxytoluene; d) edetate calcium 0449 In an exemplary embodiment, according to any of disodium; e) mono- and di-glycerides; f) paraffin waX; and the above method paragraphs, the inflammatory-related con g) white petrolatum. dition is atopic dermatitis. 0440. In an exemplary embodiment, the topical pharma 0450. In an exemplary embodiment, according to any of ceutical formulation consists essentially of: a) 5-(4-cyano the above method paragraphs, the animal is a human. phenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole; b) 0451. In an exemplary embodiment, the invention is a propylene glycol; c) butylated hydroxytoluene; d) edetate method of treating atopic dermatitis in a human, the method calcium disodium; e) mono- and di-glycerides; f) paraffin comprising administering to the human a therapeutically wax, and g) white petrolatum. effective amount of the topical pharmaceutical formulation 0441. In an exemplary embodiment, the topical pharma according to any of the above paragraphs. ceutical formulation comprises: a) 5-(4-cyanophenoxy)-1,3- 0452. In an exemplary embodiment, the invention is a dihydro-1-hydroxy-2,1-benzoxaborole; b) propylene glycol; method of treating psoriasis in a human, the method com c) butylated hydroxytoluene; d) edetate calcium disodium; prising administering to the human a therapeutically effec e) mono- and di-glycerides; f) paraffin wax; and g) white tive amount of the topical pharmaceutical formulation petrolatum. according to any of the above paragraphs. US 2017/0152273 A1 Jun. 1, 2017

0453 The invention is further illustrated by the Examples exhibit different powder patterns because the location of the that follow. The Examples are not intended to define or limit peaks on the X-axis is a property of the Solid-state structure the scope of the invention. of the crystal. 0458 Such powder patterns, or portions thereof, can be EXPERIMENTALS used as an identifying fingerprint for a crystalline Solid form. Thus, one could take a powder pattern of an unknown Polymorphic Studies sample and compare that powder pattern with a reference powder pattern. A positive match would mean that the 0454. Different crystalline solid forms of the same com unknown sample is of the same crystalline Solid form as that pound often possess different solid-state properties such as of the reference. One could also analyze an unknown sample melting point, Solubility, dissolution rate, hygroscopicity, containing a mixture of Solid forms by adding and Subtract powder flow, mechanical properties, chemical stability and ing powder patterns of known compounds. physical stability. These solid-state properties may offer 0459. When selecting peaks in a powder pattern to char advantages in filtration, drying, and dosage form manufac acterize a crystalline solid form or when using a reference turing unit operations. Thus, once different crystalline Solid powder pattern to identify a form, one identifies a peak or forms of the same compound have been identified, the collection of peaks in one form that are not present in the optimum crystalline Solid form under any given set of other solid forms. processing and manufacturing conditions may be deter 0460. The term “characterize” as used herein means to mined as well as the different solid-state properties of each select an appropriate set of data capable of distinguishing crystalline solid form. one solid form from another. That set of data in X-ray 0455 Polymorphs of a molecule can be obtained by a powder diffraction is the position of one or more peaks. number of methods known in the art. Such methods include, Selecting which X-ray powder diffraction peaks define a but are not limited to, melt recrystallization, melt cooling, particular form is said to characterize that form. Solvent recrystallization, desolvation, rapid evaporation, 0461 The term “identify” as used herein means taking a rapid cooling, slow cooling, vapor diffusion and Sublima selection of characteristic data for a solid form and using tion. Polymorphs can be detected, identified, classified and those data to determine whether that form is present in a characterized using well-known techniques such as, but not sample. In X-ray powder diffraction, those data are the limited to, differential scanning calorimetry (DSC), thermo X-axis positions of the one or more peaks characterizing the gravimetry (TGA), X-ray powder diffractometry (XRPD). form in question as discussed above. For example, once one single crystal X-ray diffractometry, Solid state nuclear mag determines that a select number of X-ray diffraction peaks netic resonance (NMR), infrared (IR) spectroscopy, Raman characterize a particular solid form, one can use those peaks spectroscopy, and hot-stage optical microscopy. to determine whether that form is present in a sample. 0462. When characterizing and/or identifying crystalline 0456. During the development of the manufacturing pro Solid forms of the same chemical compound with X-ray cess for crisaborole drug Substance, attempts were directed powder diffraction, it is often not necessary to use the entire towards identifying the polymorphs of crisaborole. Several powder pattern. A smaller subset of the entire powder pattern solvent systems that involved polar protic solvents like can often be used to perform the characterization and/or water, polar aprotic solvents like dimethoxyethane and non identification. By selecting a collection of peaks that differ polar solvents such as heptanes were explored. These studies entiate the crystalline solid form from other crystalline solid resulted in the identification of three polymorphs of crisa forms of the compound, one can rely on those peaks to both borole drug substance that were differentiated by X-ray characterize the form and to identify the form in, for Powder Diffraction. Form 2 was the form utilized in clinical example, an unknown mixture. Additional data can be studies through Phase 2. Form 1 was identified as the added, such as from another analytical technique or addi commercial form and was utilized in Phase 3 studies. tional peaks from the powder pattern, to characterize and/or 0457. There are a number of analytical methods one of identify the form should, for instance, additional poly ordinary skill in the art in Solid-state chemistry can use to morphs be identified later. analyze solid forms. The term “analyze' as used herein 0463. Due to differences in instruments, samples, and means to obtain information about the Solid-state structure sample preparation, peak values is sometimes reported with of solid forms. For example, X-ray powder diffraction is a the modifier “about in front of the peak values. This is Suitable technique for differentiating amorphous solid forms common practice in the Solid-state chemical arts because of from crystalline solid forms and for characterizing and the variation inherent in peak values. A typical precision of identifying crystalline solid forms of a compound. X-ray the 20 X-axis value of a peak in a powder pattern is on the powder diffraction is also suitable for quantifying the order of plus or minus 0.220. Thus, a powder diffraction amount of a crystalline Solid form (or forms) in a mixture. peak that appears at “about 9.2° 20' means that the peak In X-ray powder diffraction, X-rays are directed onto a could be between 9.0° 20 and 9.4° 20 when measured on crystal and the intensity of the diffracted X-rays is measured most X-ray diffractometers under most conditions. Variabil as a function of twice the angle between the X-ray Source ity in peak intensity is a result of how individual crystals are and the beam diffracted by the sample. The intensity of these oriented in the sample container with respect to the external diffracted X-rays can be plotted on a graph as peaks with the X-ray source (known as “preferred orientation'). This ori x-axis being twice the angle (this is known as the “20 entation effect does not provide structural information about angle) between the X-ray source and the diffracted X-rays the crystal. X-ray powder diffraction is just one of several and with the y-axis being the intensity of the diffracted analytical techniques one may use to characterize and/or X-rays. This graph is called an X-ray powder diffraction identify crystalline Solid forms. Spectroscopic techniques pattern or powder pattern. Different crystalline solid forms Such as Raman (including microscopic Raman), infrared, US 2017/0152273 A1 Jun. 1, 2017

and solid state NMR spectroscopies may be used to char TABLE 1-continued acterize and/or identify crystalline solid forms. These tech niques may also be used to quantify the amount of one or more crystalline solid forms in a mixture and peak values PXRD peak list for Form 1 API. Asterisked peak can also be reported with the modifier “about in front of the positions represent characteristic peaks. peak values. A typical variability for a peak value associated with an FT-Raman and FT-Infrared measurement is on the Angle Rel. Intensity order of plus or minus 2 cm'. A typical variability for a peak value associated with a C chemical shift is on the order of plus or minus 0.2 ppm for crystalline material. A 26.2 61 typical variability for a value associated with a differential 26.5 7 scanning calorimetry onset temperature is on the order of 28.5 12 plus or minus 5° C. 29.1 3 0464. The term “room temperature' as used herein refers 31.6 7 to the temperature range of 20° C. to 23° C. 0465 1. Instrument Method (API and Drug Product 31.4 17 Scans) 31.7 7 0466 Powder X-ray diffraction analysis was conducted 32.8 2 using a Bruker AXS D8 ADVANCE diffractometer equipped 33.8 3 with a Cu radiation source (K-C. average). The system is 37.0 2 equipped with a 2.5 axial Soller slits on the primary side. The secondary side utilizes 2.5 axial Soller slits and motor ized slits. Diffracted radiation was detected by a Lynx Eye XE detector. The X-ray tube voltage and amperage were set TABLE 2 to 40 kV and 40 mA respectively. Data was collected in the Theta-Theta goniometer at the Cu wavelength from 3.0 to PXRD peak list for Form 2 API 40.0 degrees 2-Theta using a step size of 0.037 degrees and a step time of 1920 seconds. Samples were prepared by Angle 2Theta Relative Intensity % placing them in a low background holder and rotated during 7.1 6 12.3 12 collection. Data were collected using Bruker DIFFRAC Plus 14.3 18 software (Version 9.0.0.2) and analysis was performed by 14.9 4 EVA diffract plus software. 15.5 2 0467. The PXRD data file was not processed prior to 16.4 13 16.7 75 peak searching. Using the peak search algorithm in the EVA 17.7 43 software, peaks selected with a threshold value of 1 and a 17.9 7 width value of 0.3 were used to make preliminary peak 18.4 10 assignments. The output of automated assignments was 2O.O 8 20.9 1OO visually checked to ensure validity and adjustments were 21.4 29 manually made if necessary. Peaks with relative intensity of 21.8 36 2% were generally chosen. The peaks which were not 22.2 5 resolved or were consistent with noise were not selected. A 22.7 59 23.2 30 typical error associated with the peak position from PXRD 23.5 8 stated in USP up to +/-0.2° 2-Theta (USP-941). The peak 24.2 4 fitting associated with Forms 1, 2 and 3 are listed in Tables 24.9 31 1-3: Table 4 lists the peaks for Form 1 that can be distin 24.9 26 26.1 11 guished from the placebo drug product. For example, 6.0, 26.4 7 12.1, 14.1 and 15.4 peaks are associated with crisaborole. In 26.5 7 particular, peaks 6.0 and 15.4 are preferred associated peaks. 27.1 8 27.5 9 27.8 15 TABLE 1. 28.0 32 28.8 6 PXRD peak list for Form 1 API. Asterisked peak 29.1 3 positions represent characteristic peaks. 30.1 10 31.0 3 Angle Rel. Intensity 31.5 5 6.1: 100 32.1 3 12.2 14 33.7 3 14.2 9 34.4 2 15.4% 31 34.9 5 16.1 6 37.4 7 17.7 2 38.9 2 18.2 46 39.9 2 21.5 11 43.1 4 23.1 5 45.6 2 24.3 8 46.5 3 24.9 12 US 2017/0152273 A1 Jun. 1, 2017 17

TABLE 3 maintained at that temperature for approximately 15 min utes. The reaction mixture was then cooled to 50° C. (+3°C.) PXRD peak list for crisalborole Forn 3 API. over a 45 to 60 minute period and monitored by Raman Spectroscopy until the appropriate end point was reached. Angle 2-Theta Rel. Intensity % The reaction mixture was then further cooled to 20°C. (+5° 3.8 C.) over 3 to 5 hours (target: 4 hours) and monitored by 4.3 Raman Spectroscopy until the appropriate end point is 5.8 reached. The solids were filtered and washed with 3x2 6.4 volumes of water and dried at 45° C. (+10° C.). See Table 6.6 1 and FIG. 2: PXRD spectrum of Form 1 and FIG. 4: PXRD 6.7 6.8 of crisaborole drug product placebo lot overlaid with Form 7.7 1 8.4 0470 3. Method for Producing Form 2 8.4 8 0471 Crisaborole was dissolved in acetonitrile at 70 C 8.8 9.7 and approximately 2 volumes of water were added to the 20.8 solution, affording immediate precipitation of Form 2. See 21.4 Table 2 and FIG. 3: PXRD spectrum of Forms 1, 2 and 3. 21.9 9 0472. 4. Method for Producing Form 3 22.7 23.2 4 0473 Polymorphic Form 3 was typically only found 23.5 during polymorph screening utilizing fast evaporation stud 23.9 1 ies from solvents such as ethyl acetate, methyl ethyl ketone, 24.9 and methyl tert-butyl ether. Approximately 1 g of Crisab 26.4 orole was dissolved in acetonitrile at 75° C., followed by 26.2 filtration. Water was added to the filtrate as an anti-solvent 26.5 27.1 at 75° C. The resulting mixture was a clear solution, and it 27.6 was seeded with approximately 2 mg of Form III seed 27.9 3 crystal. The mixtures were then cooled to ambient tempera 28.8 ture at 20° C./h and stirred overnight. The solids were 29.1 isolated by filtration and washed with approximately 2 mL 31.4 of water. The solids were dried under vacuum at ambient 32.3 temperature for 20 hours, which was then analyzed by 34.9 XRPD to confirm the formation of Form III. See FIG. 2: 37.3 PXRD spectrum of Forms 1, 2 and 3. Solvent Selection TABLE 4 0474. One of the key aspects encountered in reformulat PXRD peak list for Crisalborole Form 1 drug product. ing crisaborole was that the active agent be fully dissolved within its solvent. A selection criterion of greater than 10% Angle 2-Theta Relative Intensity % w/w crisaborole solubility was used to select solvents 6.0 89 capable of carrying at least 1% crisaborole in a final drug 12.1 11 product formulation, assuming the drug product contained 14.1 33 10% solvent. The solubility of crisaborole in ten solvents 15.4 100 was evaluated to identify those with crisaborole solubility 16.0 17 greater than 10% w/w by visual assessment. The equilibrium 17.7 6 solubility of the best solvents was subsequently verified by 18.2 40 HPLC. See Table 5. 18.6 2 21.5 33 23.1 6 TABLE 5 24.9 37 26.2 87 Solubility Studies of Crisaborole Form II 26.5 14 27.6 2 Visual Solubity Solubity by HPLC 28.5 33 Solvent (% w/w) (mg/mL) 28.5 27 29.1 7 Transcutol (R) P, NF 28.6% 21.2 31.0 6 Hexylene Glycol, NF 25.9% 356 31.4 11 Propylene Glycol, USP 24.0% 274 31.7 9 Polyethylene Glycol 15.0% 164 31.8 8 (PEG) 400, USP 32.8 3 Propylene Carbonate, NF 9.9% 96 33.8 7 Diisopropyl Adipate 7.70% 37.1 3 Oleyl Alcohol, NF 2.3% 33 39.3 2 Ethylhexyl 1.6% 21 Hydroxystearate Isopropyl Myristate, NF O.6% 0468 2. Method for Producing Form 1 Oleic Acid, NF <0.1% 0469 Crisaborole was dissolved in acetic acid (-3.5 Vol) — Not tested at 70° C. followed by the addition of about 0.75 vol water. “Crisaborole polymorph Form 2 The mixture was cooled to ~61° C. (range: between 58° C. Transcutol P is equivalent to diethylene glycol monoethyl ether and 63° C.), seeded with crisaborole (1% seedingt1%) and US 2017/0152273 A1 Jun. 1, 2017 18

0475. The solvents that satisfied the greater than 10% 10% propylene glycol, 2% crisaborole and 5% emulsifier. w/w solubility requirement were also evaluated for crisab The samples were stored at 50° C. for 7 days before they orole compatibility by assessing degradant formation in were analyzed for degradation of crisaborole. The compat crisaborole solutions at 80% saturation after storage at 50° ibility results are summarized in Table 7. C. and 40° C./75% RH for seven days. 0476 Crisaborole solutions of three of the seven evalu TABLE 7 ated solvents (propylene glycol, propylene carbonate and PEG400) exhibited two main degradants, including Impurity CrisabOrole Compatibility with Various Emulsifiers 1. Of these three, the propylene glycol solutions had the Degradant (% Peak Area lowest overall degradation and the highest crisaborole solu Emulsifier Condition Impurity X Impurity 1 bility. Crisaborole solutions of the four remaining solvents all exhibited an additional degradant and, therefore, were Mono- and Di-glycerides 7 day, 50° C. 1.2 excluded from development. (See Table 6) Sorbitan Sesquioleate, NF 7 day, 50° C. 13.2

TABLE 6 Crisaborole Compatibility with Various Solvents Degradant (% Peak Area Solvent Condition Impurity 2 Impurity 1 Impurity 3 Total Propylene Glycol, USP To 7 day, 40° C./75% RH O.O O.O O.15 7 day, 50° C. O.1 O.1 O.26 () (2) Propylene Carbonate, To NF 7 day, 40° C./75% RH 1.3 1.37 7 day, 50° C. O.O 2.0 2.08 () () PEG 400, USP To O.2 0.27 7 day, 40° C./75% RH 0.7 O. O.82 7 day, 50° C. O.9 O.1 1.09 () () Hexylene Glycol, NF To 7 day, 40° C./75% RH O.1 O.O O.1 O.30 7 day, 50° C. O.2 O.1 O.3 O.74 () () () Transcutol P, NF To O.1 O.12 7 day, 40° C./75% RH O.2 O.22 7 day, 50° C. O.2 O.O O.1 O.47 () () () Oleyl Alcohol, NF To 0.4 O.O O.S3 7 day, 40° C./75% RH 5.9 O.1 6.02 7 day, 50° C. 9.1 O.10 O.2 9.48 () () Ethylhexyl To O.1 7.8 7.97 7 day, 40° C./75% RH O.2 11. 11.78 7 day, 50° C. 0.4 13. 13.81 () ()

RRT, relative retention time; – not detected. * Transcutol P is equivalent to diethylene glycol monoethyl ether, (2) indicates text missing or illegible when filed

Emulsifier Selection TABLE 7-continued 0477 To form an ointment containing propylene glycol phase dispersed within a petrolatum base, studies were Crisaborole Compatibility with Various Emulsifiers conducted to identify an emulsifier with an appropriate hydrophilic-lipophilic balance (HLB) value, acceptable cri Degradant (90 Peak Area saborole compatibility, and demonstrated emulsifying abil ity. An emulsifier with an HLB value of 4-6 was desired for Emulsifier Condition Impurity X Impurity 1 a water-in-oil type emulsion, and four potential emulsifiers Sorbitan Monooleate, NF 7 day, 50° C. O.45 8.4 were evaluated for crisaborole compatibility: mono- and Glyceryl Monooleate, NF 7 day, 50° C. 1S 18.9 di-glycerides (MDG), sorbitan sesquioleate, sorbitan monooleate, and glyceryl monooleate with HLB values of —, not detected. 3.8, 3.7, 4.3, and 3.8 respectively. “Identified as Glycerol monostearate, purified. 0478 Crisaborole was dissolved in propylene glycol to which each emulsifier was added, forming either a solution 0479. The MDG grade initially evaluated for crisaborole or partial Suspension. The levels of each were approximately compatibility was non-compendial and identified as glycerol equivalent to levels in an ointment formulation containing monostearate, purified. Testing demonstrated, however, that US 2017/0152273 A1 Jun. 1, 2017 19 the material conformed more closely to the mono- and 0486 During scale-up procedures, however, the presence di-glycerides, NF compendial specification than to the glyc of water in propylene glycol reduced the solubility of eryl monostearate, NF (GMS) compendial specifications. It crisaborole Form I (the commercial polymorphic Form), is, therefore described herein, as MDG. In an effort to presenting potential formulation challenges. Furthermore, improve the formulation, the non-compendial MDG was the water and boric acid combination did not adequately replaced with a compendial grade of glyceryl monostearate, stabilize crisaborole and an alternative stabilizer was there NF (Sasol Imwitor R. 491). Sasol Imwitor R. 491, however, fore pursued. exhibited poor emulsifying properties, likely due to different 0487. Edetate calcium disodium (EDTA) was evaluated proportions of mono-glyceride and di-gyceride that is inher as a stabilizer at various levels within drug product formu ent between MDG and GMS. lations utilizing the same excipients used in Crisaborole 0480 A variety of compendial and non-compendial Topical Ointment, 2%. The drug product formulations were MDG and GMS grades were subsequently evaluated for evaluated in multiple candidate tubes, including 60-glami crisaborole compatibility. For the emulsifier evaluation: nate tubes equivalent to the commercial primary container 0481 (a) a solution of the ointment active phase was closure system (with the exception of not having an orifice prepared: 2 g crisaborole, 8.91 g propylene glycol, 0.09 seal), at both 25° C./60% RH and 40° C./75% RH. g water, and 0.1 g boric acid; 0488. The evaluated formulations differed from Crisab 0482 (b) 1 gram of active phase was mixed with 0.6 orole Topical Ointment, 2% only in the stabilizers used: 0 gram of emulsifier, and ppm EDTA, Z10, 24 ppm EDTA (Ointment Z7), 90 ppm 0483 (c) the samples were stored at 50° C. for 7 days. EDTA, 450 ppm EDTA, and 0.09% water with 0.10% boric The crisaborole compatibility results are presented in Table acid (equivalent to Ointment Z6, but utilizing MDG rather 8. than GMS). Results from the evaluation in the 60-glaminate TABLE 8 Crisaborole Compatibility with Potential Emulsifier Grades Compendial Mono-glyceride - Degradant (90 Peak Source (Material) Grade Status Content (%) Impurity Impurity 1 Control A 0. O. Gattefosse (GeleolTM) MDG NF 5 0. O. Alfa Aesar (Glycerol MDG Ole 4 0. O. Sasol (Imwitor (R 491) GMS NF 9 0. O. Sasol (Imwitor (R 900K) MDG NF 4 0. 1. Caravan (BFP (R 74K) MDG Ole 4 0. 1. Caravan (BFP (R 74E) MDG Ole 4 0. 3. Abitec (Capmul (R) MCM) MDG NF 5 0. 2. Control B 0. O. Cognis (Cutina (R) GMS V) MDG NF 5 0. O. GMS, glyceryl monostearate; MDG, mono- and di-glycerides; RRT, relative retention time; — not applicable. Control A was conducted concurrently with all emulsifiers except Cutina, which was conducted concurrently with Control B.

0484 Multiple sources of mono- and di-glycerides exhib tubes are presented in Tables 5 and 6. After six months, the ited acceptable compatibility with crisaborole under these formulation without stabilizer exhibited the greatest total stability conditions. Exemplary sources included Gattefosse crisaborole degradation and lowest assay at the 40° C./75% (GeleolTM), Alfa Aesar (Glycerol monostearate), Sasol (Im RH condition, followed by the Ointment Z6 formulation witor R 491), Sasol (Imwitor R 900K), Caravan (BFPR) (water and boric acid as stabilizer). The greatest stabilizing 74K), Caravan (BFPR 74E), Abitec (Capmul R. MCM NF), effect was observed at the 24 ppm EDTA and 90 ppm EDTA Cognis (Cutina R. GMS V PH). Mono- and di-glycerides, NF levels. The 24 ppm EDTA formulation (Ointment Z7) was was selected to be the emulsifier for Crisaborole Topical Subsequently utilized in clinical studies Ointment, 2% on the basis of compendial status, HLB value, EXAMPLES chemical compatibility, and established emulsifying capa bility. Example 1 Manufacture of Topical Pharmaceutical Formulations of the Stabilizer Selection Invention 0489 a) Topical Pharmaceutical Formulation with an 0485 Early prototype formulations demonstrated Active Agent improved stability, particularly with regard to protodeboro 0490 Step 1: Preparation of Oil Phase nation, when approximately 1% of the propylene glycol 0491. In a primary compounding vessel, white petrola solvent was replaced with water. Further improvement in tum, paraffin wax and mono and diglycerides were added stability was found when a small percentage of boric acid with continuous propeller mixing while being heated to was added to the formulation. The Crisaborole Ointment Z6 70-80° C. The temperature of this mixture was maintained formulation, therefore, included small amounts of both at 70-80°C. with the mixture appearing visually melted and water and boric acid. However, the mechanism by which uniform. With propeller stirring, butylated hydroxytoluene water and boric acid reduced the rate of protodeboronation was added and mixed to dissolve while maintaining the was not well understood. temperature to 70-80° C. While being stirred, the mixture US 2017/0152273 A1 Jun. 1, 2017 20 was cooled down to 40-46° C. and maintained until addition -continued of drug Solution phase. 0492 Step 2: Preparation of Drug Solution Phase Component Y% ww. 0493. In a secondary compounding vessel, edetate cal Mono- and Di-glycerides 7.OOO cium disodium was added to propylene glycol with continu Paraffin Wax S.OOO ous propeller mixing while being heated to 40-46° C. The White Petrolatum 78.896S temperature of this mixture was maintained at 40-46° C. Edetate Calcium Disodium O.OO3S with the mixture appearing visually dissolved and uniform. With continuous mixing, crisaborole was added to dissolve while maintaining the temperature at 40-46° C. Example 2 0494 Step 3: Emulsification 0495. The drug solution phase was filtered through 80 Flux Tests for 2% and 5% Crisaborole Creams— mesh filter and added to the oil phase. It was then homog enized for 10 minutes while maintaining the temperature at 0504. In vitro penetration of crisaborole in cream formu 40-46°C. The final composition was cooled to 25°C. with lations through human ex vivo cadaver skin was measured. propeller mixing until a homogenous ointment was The composition of the 2% crisaborole cream formulation, obtained. Z1, and the 5% crisaborole cream formulation, Z2, are 0496 All components were compendial. The 2% oint provided below. Both Z1 and Z2 are disclosed in U.S. patent ment formulation, Z, was produced according to the proce application Ser. No. 12/399,015 (U.S. Pat. Pub. No. dure above and had the following components: US2009/0291917) and PCT Pat. App. No. PCT/US09/ 036250 (PCT Pat. Pub. No. WO2009/111676). b) Topical pharmaceutical formulation without an active agent Component Z1 % wiw Z2% Wiw Component Z% Wiw Crisalborole 2.0 S.O Crisalborole 2.OOO Methylparaben O.15 O.15 Propylene Glycol 9.OOO Propylparaben O.O3 O.O3 Butylated Hydroxytoluene O.100 Glyceryl Monostearate SE 8.0 8.0 Mono- and Di-glycerides 7.OOO Butylated Hydroxytoluene O.O2 O.O2 Paraffin Wax S.OOO Edetate Disodium 0.05 0.05 White Petrolatum 76.896S Pemulen TR-2 O.25 O.25 Edetate Calcium Disodium O.OO3S Carbopol Ultrez 10 O.2O O.20 25% Trolamine O.84 O.84 Propylene Glycol S.O S.O 0497 Step 1: Preparation of Oil Phase Octyldodecanol 1O.O 1O.O 0498. In a primary compounding vessel, white petrola Oleyl Alcohol 1O.O 1O.O tum, paraffin wax and mono and diglycerides were added Benzyl Alcohol 2.0 2.0 with continuous propeller mixing while being heated to Diisopropyl Adipate 1O.O 1O.O 70-80° C. The temperature of this mixture was maintained Purified Water QS 100 QS 100 at 70-80°C. with the mixture appearing visually melted and uniform. With propeller stirring, butylated hydroxytoluene was added and mixed to dissolve while maintaining the 25% Trolamine Solution temperature to 70-80° C. While being stirred, the mixture was cooled down to 40-46° C. and maintained until addition 0505 of drug Solution phase. 0499 Step 2: Preparation of Solvent Phase 0500. In a secondary compounding vessel, edetate cal Component % Wiw cium disodium was added to propylene glycol with continu Trolamine 2SO ous propeller mixing while being heated to 40-46° C. The Purified Water 75.0 temperature of this mixture was maintained at 40-46° C. with the mixture appearing visually dissolved and uniform. 0506 Testing was conducted according to the following 0501 Step 3: Emulsification protocol. 0502. The solvent phase was filtered through 80 mesh filter and added to the oil phase. It was then homogenized for Study Skin Preparation 10 minutes while maintaining the temperature at 40-46° C. The final composition was cooled to 25°C. with propeller 0507 Percutaneous penetration was measured using the mixing until a homogenous ointment was obtained. in vitro cadaver skin finite dose technique. Human, ex vivo, 0503 All components were compendial. The 2% oint trunk skin, within 1 year of collection without obvious signs ment formulation, Y, was produced according to the proce of skin disease was used in this study. It was dermatomed, dure above and had the following components: prepared for cryopreservation, sealed in a water imperme able plastic bag, and stored at s-70° C. until the day of the experiment. Prior to use it was thawed in -37°C. water, then Component Y% ww. rinsed in water to remove any adherent blood or other Propylene Glycol 9.OOO material from the surface. Butylated Hydroxytoluene O.100 0508 Skin from a single donor was cut into multiple smaller sections large enough to fit on static 1.0 cm Franz US 2017/0152273 A1 Jun. 1, 2017

diffusion cells. The dermal chamber was filled to capacity Results: with a reservoir solution of phosphate-buffered isotonic saline (PBS), pH 7.4+0.1, and the epidermal cell (chimney) 0515 Total percutaneous penetration through human left open to ambient laboratory conditions. All cells were cadaver skin over 48 hours for Z1 and Z2 are provided mounted in a diffusion apparatus in which the dermal below: bathing Solution was stirred magnetically at approximately Mean Cumulative Amounts (ug/cm) of Crisaborole 600 RPM and the skin surface temperature maintained at Through Human Cadaver Skin Over 48 Hours (Creams) 32.0-1.0° C. 0509. To assure the integrity of each skin section, its permeability to tritiated water was determined before appli cation of the test products. Franz T J et al., Abst. J Invest Mean SD 1.13 + 0.67 g/cm 4.57 it 3.51 g/cm Dermatol 1990, 94:525. Following a brief (0.5-1 hour) N = 3 donors, equilibriumperiod, H2O (NEN, Boston, Mass., sp. Act.-0.5 3 replicates per donor. uCi/mL) was layered across the top of the skin by dropper so that the entire exposed surface was covered (approxi mately 250-500 uL). After 5 minutes the HO aqueous layer Example 3 was removed. At 30 minutes the receptor solution was collected and analyzed for radioactive content by liquid Flux Tests for 2% Crisaborole Ointment Z3 and 5% Scintillation counting. Skin specimens in which absorption Crisaborole Ointment Z4— of HO was less than 1.56 uL-equ/cm were considered 0516. In vitro penetration of crisaborole in two ointment acceptable. formulations through human ex vivo cadaver skin was 0510. Following the water test the chambers were measured. The composition of the 2% crisaborole ointment arranged in formulation groups so that there was an even formulation, Z3, and the 5% crisaborole ointment formula raked distribution of the chambers with associated water tion, Z4, are provided below. Both Z3 and Z4 are disclosed penetration within each group for each formulation. in U.S. patent application Ser. No. 12/399,015 (U.S. Pat. Pub. No. US2009/0291917) and PCT Pat. App. No. PCT/ Dosing and Sample Collection US09/036250 (PCT Pat. Pub. No. WO2009/111676). 0511 Just prior to dosing, a pre-dose sample was taken and the reservoir solution was replaced with a fresh solution Component Z3% Wiw Z4% Wiw of 0.1xPBS with 0.1% Volpo. The chimney was removed Crisalborole 2.O S.O from the Franz Cell to allow full access to the epidermal Ethylhexyl Hydroxystearate 1O.O 1O.O surface of the skin. All formulations were then applied to the Oleyl Alcohol 1O.O 1O.O skin sections using a positive displacement pipette set to White Petrolatum 78.0 75.0 deliver 5 uL formulation/cm. The dose was spread across the surface with the Teflon tip of the pipette. Five to ten 0517 Testing was conducted according to the protocol of minutes after application the chimney portion of the Franz Example 2. Cell was replaced. Care was taken to keep containers of dosing Solution capped when not in use and to leave them Results: open as little as possible during dosing in order to minimize evaporation. 0518. Total percutaneous penetration through human cadaver skin over 48 hours for Z3 and Z4 are provided 0512. At pre-selected times after dosing, (4, 8, 12, 24, and below: 48 hours) the reservoir solution was removed in its entirety, replaced with fresh reservoir solution, and a predetermined Mean Cumulative Amounts (ug/cm) of Crisaborole Volume aliquot saved for Subsequent analysis. All samples Through Human Cadaver Skin Over 48 Hours were collected in 2 mL Boil-Proof Microtubes (Axygen (Ointments) Scientific MCT-200-C). 0513 Spare cells were available which were not dosed 0519 but used to evaluate for the appearance of Substances diffusing out of the skin that might interfere with the analytic Z3 Z4 method. Mean SD 3.89 + 0.87 g/cm 4.43 + 1.81 g/cm’ 0514. After the last sample was collected, the surfaces N = 3 donors, were washed twice (0.5 mL volume each) with acetonitrile 3 replicates per donor. to collect un-absorbed formulation from the surface of the skin. Following the wash, the skin was tape stripped (Trans pore(R) Tape, 3M) no more than 10 times to remove the Example 4 stratum corneum. The tape strips were extracted overnight in acetonitrile. The skin was then removed from the chamber, Flux Tests for 2% Crisalborole Cream Z1 and 2% split into epidermis and dermis. Each was extracted over Crisaborole Ointment Z– night in acetonitrile. In addition, at the end of the study, the chamber parts (dosing chimney and reservoir chamber) were 0520. In vitro penetration of crisaborole in 2% cream rinsed separately with acetonitrile and the samples retained formulation Z1 and ointment formulation Z, through human for analysis. ex vivo cadaver skin was measured. US 2017/0152273 A1 Jun. 1, 2017 22

0521. The composition of the 2% crisaborole cream, Z1. section was added to a tared vial and weights collected. To is described in Example 2. The composition of the 2% each epidermis vial, homogenization Solution (0.1% formic crisaborole ointment, Z, is described in Example 1. acid in water/propylene glycol 10:90 V/v) was added at a ratio of 10x tissue weight. To each dermis vial, homogeni Skin Samples & Donor Demographics Zation solution was added at a ratio of 4x tissue weight. 0522 Human ex vivo cadaver skin was supplied by Tissues were homogenized using a bead homogenizer Allosource (6278 South Troy Circle, Centennial, Colo.) and (Omni BeadRuptor with 2 mL micro tubes containing 2.8 stored at -80° C. until use. The thickness of dermatomed mm ceramic beads) at the following settings: skin was approximately 500 um. Human cadaver skin with 0529 Speed: 7.45 m/sec; Cycle time: 15 sec; # of Cycles: out obvious signs of skin disease from three donors was used 2. Dwell time: 1 min during the study. Sample Analysis Test Procedure 0530. The receiving medium collected from the diffusion 0523 Human ex vivo cadaver skin was stored at -80° C. cell assemblies was aliquotted into 96 well plates and frozen until the morning of the study. Skin was thawed by sub at -20°C. Epidermis and dermis homogenates and tape Strip merging in pre-warmed phosphate buffered saline (PBS) extracts of stratum corneum prepared at the conclusion of (37°C.), and was inspected for any visible holes or damage. the experiment were also frozen at -20° C. Skin was carefully sectioned using a scalpel to the appro Results priate size for placement onto the vertical diffusion cell. 0524 Receiving media (90:10 waterpropylene glycol 0531. The receiving medium collected from the diffusion V/v) that was pre-warmed to 37° C., and a stir bar, were cell assemblies was aliquotted into 96 well plates and frozen added to each diffusion cell and allowed to equilibrate for a at -20° C. minimum of 30 minutes. A section of skin was placed on top of each cell, and cells were assembled using clamps to Mean Cumulative Amounts (ug/cm) of Crisaborole secure the skin in place. Any air bubbles that were intro Penetrated Through Human Cadaver Skin into the duced during the assembly of the cells were removed. Skin Receiving Medium Over 48 Hours and media were allowed to equilibrate for a minimum of thirty minutes after assembly of the cells. 0532 0525. A 400 uL pre-dose sample of receptor media was collected for analysis, and an equal Volume was replaced Z. Z1 with pre-warmed fresh media. Formulations were warmed to Mean SD 35.04 + 10.81 g/cm 20.60 + 10.18 g/cm) 31+1° C. and equilibrated for approximately 1 hour prior to N = 3 donors, dosing. Immediately prior to dosing, formulations were 2 replicates per donor. briefly mixed using the pipette tip. At one minute intervals, each cell was dosed once with approximately 5 uL/cm of respective formulation using a positive displacement pipette. 0533. The penetration of Z into and through human skin A glass rod was used to spread the formulation evenly is greater than the penetration of Z1. covering the entire Surface area of the skin. The sampling port was occluded with parafilm to prevent evaporation of Example 5 the receptor media during the study. Each glass rod was 0534. Flux Tests for 2% Crisaborole Ointment Z3 with saved and the tip extracted overnight in 400 uL extraction Oleyl Alcohol and 2% Crisaborole Ointment Z6 with Pro solution (0.1% formic acid in acetonitrile). pylene Glycol 0526. At 3, 6, 12, 24 and 48 hours following dose 0535 In vitro penetration of crisaborole in two ointment administration, a 400 uL aliquot of receiving media was formulations through human ex vivo cadaver skin was removed through the sampling stem of each cell with a measured. The composition of the 2% crisaborole ointment pipette. After removing the media, an equal Volume of formulation with oleyl alcohol, Z3, and the 2% crisaborole pre-warmed fresh receiving medium was added to replace ointment formulation with propylene glycol, Z6, are pro the Volume removed during sampling. Care was taken to vided below. avoid generation of any air bubbles during sampling, and any bubbles were carefully removed if necessary. 0527. At the conclusion of the study, the cells were Component disassembled and the skin was carefully removed from each cell. Each skin section was washed twice with 0.5 mL of Z3% Wiw extraction solution (0.1% formic acid in acetonitrile) to Crisalborole 2.O collect un-absorbed formulation from the surface of the skin. Ethylhexyl 1O.O Hydroxystearate The skin Surface was gently cleansed with lab tissue to Oleyl Alcohol 1O.O remove any residual liquid from the wash. Tissues were tape White Petrolatum 78.0 stripped 1-2 times with 3M Transpore tape to collect the Z6% Wiw stratum corneum. Tape strips were collected, combined, and Crisalborole 2.OO extracted in 1 mL extraction solvent (0.1% formic acid in Propylene Glycol 8.91 acetonitrile). Boric Acid O.10 0528. Following tape stripping, the skin was carefully Purified Water O.09 separated into epidermis and dermis using forceps. Each US 2017/0152273 A1 Jun. 1, 2017 23

-continued Results: 0542. Total percutaneous penetration through human Component cadaver skin over 48 hours for Z3 and Z6 are provided Butylated Hydroxytoluene O.10 below: Mono- and Di-Glycerides, 7.00 40-55% Monoglycerides Mean Cumulative Amounts (ug/cm) of Crisaborole Paraffin wax S.OO Penetrated Through Human Cadaver Skin into the White Petrolatum 76.8O Receiving Medium Over 48 Hours (0543 Skin Samples & Donor Demographics: Z3 Z6 0536 Human ex vivo cadaver skin without obvious signs Mean SD 68.047 it 8.15 g/cm, 82.212 + 5.18 g/cm of skin disease was used in the study. It was stored at ~-70° N = 2 donors, C. until use. It was dermatomed, prepared for cryopreser 5 replicates per donor. Vation, sealed in a water impermeable plastic bag, and stored at ~-70° C. until the day of the experiment. 0544 Flux of crisaborole through the skin was surpris ingly greater with Z6 than with Z3. Test Procedure: Example 6 0537 Human ex vivo cadaver skin was stored at ~-70° C. until the morning of the study. Skin was thawed by Physical Stability Centrifugation Stress Tests Submerging in pre-warmed water (37° C.), and was inspected for any visible holes or damage. Skin from a single 0545 Pharmaceutical formulation Z5 contained the fol donor was cut into multiple Smaller sections large enough to lowing ingredients: fit on nominal 1.0 cm static Franz diffusion cells. 0538 Skin from a single donor was cut into multiple Component Z5% Wiw Smaller sections large enough to fit on nominal 1.0 cm static Crisalborole 2.OO Franz diffusion cells. The dermal chamber was filled to Propylene Glycol 8.91 capacity with a reservoir solution of phosphate-buffered Boric Acid O.10 Purified Water O.09 isotonic saline (PBS), pH 7.4+0.1, and the epidermal cell Butylated Hydroxytoluene O.10 (chimney) left open to ambient laboratory conditions. All Mono- and Di-Glycerides, 7.OO cells were mounted in a diffusion apparatus in which the 90% Monoglycerides dermal bathing Solution was stirred magnetically at approxi Paraffin wax S.OO mately 600 RPM and the skin surface temperature main White Petrolatum 76.8O tained at 32.0-1.0° C. and was prepared as described in Example 1 above, but with 0539 A water integrity test was determined before appli boric acid and water being added in Step 2A instead of cation of the test products. Following a brief (0.5-1 hour) EDTA equilibrium period, H2O (Perkin Elmer, sp. Act.-0.5 uCi/ 0546 Pharmaceutical formulation Z6 contained the fol mL) was layered across the top of the skin so that the entire lowing ingredients: exposed surface was covered (approximately 250-500 uL). After 5 minutes the HO aqueous layer was removed. At 30 minutes the receptor Solution was collected and analyzed for Component Z6% Wiw radioactive content by liquid Scintillation counting. Skin Crisalborole 2.OO specimens in which absorption of HO was less than 1.56 Propylene Glycol 8.91 uL-equ/cm were considered acceptable. Boric Acid O.10 Purified Water O.09 0540. Just prior to dosing, the reservoir solution was Butylated Hydroxytoluene O.10 replaced with a fresh solution of distilled deionized water Mono- and Di-Glycerides, 7.OO 40-55% Monoglycerides (ddHO) with 80 ug/mL gentamicin. The chimney was Paraffin wax S.OO removed from the Franz Cell to allow full access to the White Petrolatum 76.8O epidermal surface of the skin. The test formulations were warmed slightly at a controlled temperature of 30+2° C. and equilibrated at the maintained temperature for approxi and was prepared as described for Z5 above. mately 2 hours prior to dosing. (0547. The physical stability of Z5 and Z6 were tested by centrifugation. Samples of each ointment were placed in 15 0541. The product was applied to five replicate sections mL low density polyethylene centrifuge tubes. The sample of the same donor skin. Dosing was performed using a size was approximately 10 mL per centrifuge tube. Samples positive displacement pipette set to deliver 5ul formulation/ were equilibrated for about one hour in a 25° C./60% RH cm, or by weight (5 mg/cm) if not of sufficient viscosity to oven before centrifugation. The tubes were placed in a pipette. Beckman Coulter Allegra 6R Series Centrifuge and spun at US 2017/0152273 A1 Jun. 1, 2017 24

2890 rpm. After spinning for 1.5 hours, the percentage of TABLE 2-continued internal Volume separation was measured. H NMR and 'C NMR Assignments for Impurityl 0548. The volume of material that physically separated was determined by measuring the height of the separated 8H Multiplicity 813C phase and calculating the Volume using the equation pro Position (ppm) Jrity (HZ) (ppm) vided in FIG. 1. The percent of the total sample that 13 4.52 d, 69.26 separated was then calculated by dividing the volume of the 14 S.28 t, 5.8 separated phase by the total ointment volume. 15 118.73 d, doublet: 0549. Z6 measured 0% internal volume separation while dd, doublet of a doublet: Z5 measured 1.4% internal volume separation. The oint m, multiplet; t, triplet, ments were next spun for an additional 1.5 hours (3.0 hours Position assignment was confirmed by extended NMR (gCOSY, NOESY 1D, ghSQC and total), and the percentage of internal Volume separation was gHMBC). measured again. Z6 measured 0% internal volume separa 0554. The proposed acceptance criterion to the FDA for tion while Z5 measured 1.5% internal volume separation. Impurity 1 is not more than 2.0% crisaborole label strength, 0550 Ointment formulations utilizing mono- and di based upon stability data. Impurity 1 levels were observed to glycerides (MDG) in which the monoglyceride percentage is increase over time, up to 1.2% label strength and 1.4% label between 40-55% possess greater physical stability over strength for the primary and Supporting stability lots under ointment formulations utilizing mono- and di-glycerides long-term (25°C., 60% relative humidity) and accelerated (MDG) in which the monoglyceride percentage is at least (40°C., 75% relative humidity) storage conditions, respec 90%. tively. 0555 Accordingly, minimizing the amount of degrada Example 7 tion of crisaborole is a goal of the formulation. 0556 Pharmaceutical formulations with different types and amounts of stabilizers (Z, Z6, Z7, Z8, Z9, and Z10) were Degradant Reduction Tests: tested for their ability to reduce the amount of Impurity 1. 0557. The compositions of Zand Z6 are described herein. 0551 Impurities in stability batches have been observed The 2% ointment formulations Z7, Z8, Z9, and Z10, have and monitored, including Impurity 1, which is believed to be the following components and were produced according to a stability protodeboronation product of crisaborole. the methods described herein: 0552) Impurity 1: Component Z7% Wiw Z8% wiw Z9% Wiw Z10% wiw

N Crisalborole 2.OOO 2.OOO 2.OOO 2.OOO & Propylene Glycol 9.OOO 9.OOO 9.OOO 9.OOO Butylated O.100 O.100 O.100 O.100 Hydroxytoluene OH Mono- and 7.OOO 7.OOO 7.OOO 7.OOO Di-glycerides Paraffin Wax S.OOO S.OOO S.OOO S.OOO White Petrolatum 76.8976 76.9810 76.855 76.900 0553 Impurity 1 was characterized with nuclear mag Edetate Calcium O.0024 O.OO90 O.O4SO OOOOO netic resonance spectroscopy (NMR), mass spectrometry Disodium (MS) and the retention time of high-performance chroma tography (HPLC) was confirmed against the standard. The H 0558. In summary, these formulations contain the follow and C position assignments for Impurity 1 based on the ing types and amounts of Stabilizers. NMR data are listed in Table 2. Z6: Stabilizer: Boric Acid; Water Amt: 0.1% w/w; 0.09%

TABLE 2 Z7: Stabilizer: Edetate Calcium Disodium Amt: 0.0024% H NMR and 'C NMR Assignments for Impurity w/w 8H Multiplicity 813C Z8: Stabilizer: Edetate Calcium Disodium Amt: 0.0090% Position (ppm) Jrity (HZ) (ppm) w/w 1 OS.O2 2 7.84 d, 34.63 Z9: Stabilizer: Edetate Calcium Disodium Amt: 0.0450% 3 7.08 l 18.04 w/w 4 61.16 5 7.08 l 18.04 Z10: Stabilizer: None 6 7.84 d, 34.63 7 7.00 dd, 7.9, 2.4 1837 Z: Stabilizer: Edetate Calcium Disodium Amt: 0.0035% 8 7.41 apparent t, 7.8 30.08 w/w 9 7.21 d, 22.96 10 45.57 Analytical Method for Analysis of Impurity 1: 11 7.08 l 17.79 12 54.44 0559 Crisaborole containing ointments are assayed using a reverse phase HPLC method using a BDS Hypersil C18 US 2017/0152273 A1 Jun. 1, 2017

column (150x4.6 mm, 5 micron) and a 1.0 mL/min flow rate, Example 8 a 10 ul injection volume, with UV detection at 254 nm. The mobile phase (gradient) are described below: Safety and Efficacy of Z and Y in the Treatment of 0560 Mobile Phase A: 0.1% phosphoric acid solution/ Mild-to-Moderate Atopic Dermatitis (AD) acetonitrile 95%/5% (v/v) 0566. The objective of the trial was to determine the 0561 Mobile Phase B: 0.1% phosphoric acid solution/ safety and efficacy of Zapplied twice daily (BID) compared acetonitrile 5%/95% (v/v) to Y in the treatment of mild-to-moderate atopic dermatitis 0562. The topical pharmaceutical formulations were sub (AD) in children, adolescents, and adults (ages 2 years and jected to chemical stability testing with the following results older). The composition of Z is: in Table 5:

TABLE 5 Component Z% ww Effect of Stabilizer on Impurity 1 formation in ointments Crisalborole 2.OOO under various conditions Propylene Glycol 9.OOO Impurity 1 (% Butylated Hydroxytoluene O.100 Mono- and Di-glycerides 7.OOO Time Paraffin Wax S.OOO (Months) Z6 Z7 Z8 Z9 Z10 White Petrolatum 76.896S Edetate Calcium Disodium O.OO3S O O.O7 O.12 ND 40° C.;75% RH The composition of Y is: 1 O.31 O16 O.18 0.27 O3S 3 O.88 O.S3 O.64 O.88 1.13 6 1.73 1.07 1.25 1.63 2.08 25° C.60% RH Component Y 90 wiw

1 O.O7 O.O3 O.04 O.O6 O.08 Propylene Glycol 9.OOO 3 O.14 O.09 O.10 O.15 O.17 Butylated Hydroxytoluene O.100 6 O.25 O.18 O.20 O.29 O.30 Mono- and Di-glycerides 7.OOO Paraffin Wax S.OOO ND, not detected; White Petrolatum 78.896S RH, relative humidity, Edetate Calcium Disodium O.OO3S

0563 Table 5 demonstrates that among these recited 0567. Two multi-center, double-blind, vehicle-controlled formulations, the formulation without stabilizer, Z10, exhib studies were conducted in the U.S. which enrolled over 750 ited the highest Impurity 1 levels. The greatest stabilizing patients each. Patients enrolled were aged 2 years and older effect was observed at the 24 ppm EDTA (Z7) and 90 ppm with mild-to-moderate atopic dermatitis affecting >5% body EDTA (Z8) levels. surface area. Patients were randomized 2:1 (Z:Y) and treated 0564. Additional stability testing was performed on Z6, twice daily for 28 days. Z7, and Z and presented in Table 6: 0568. The primary efficacy endpoint was defined as the achievement of “Clear (O) or “Almost Clear” (1) status, TABLE 6 with 2 or greater grade improvement from baseline, at Day Effect of Stabilizer on Impurity 1 formation in 29 according to the Investigator's Static Global Assessment ointments under various conditions (ISGA). Impurity 1 (% 0569. The secondary efficacy endpoint was defined as the achievement of “Clear (O) or “Almost Clear” (1) status, Time irrespective of improvement from baseline, at Day 29 (Months) Z6 Z7 Z. according to the Investigator's Static Global Assessment O O.12 O.12 ND (ISGA). 40° C.;75% RH (0570. In one trial, 503 patients received Z while 256 1 O.69 O49 O.21 received Y. The mean age of those receiving Z was 12 years, 3 1.6 1.O O.62 with a range of 2 to 65 years. The mean age of those 6 2.5 1.6 1.2 receiving Y was 12.4 years, with a range of 2 to 63 years. 25° C.60% RH 39.0% of those receiving Z had a baseline ISGA of “Mild” 1 O.22 O.19 O.O7 (2), while 61.0% of those receiving Z had a baseline ISGA 3 O46 O.35 O.12 of “Moderate” (3). 36.3% of those receiving Y had a 6 O.66 O.S4 O.25 9 O.82 O.74 O.29 baseline ISGA of “Mild” (2), while 63.7% of those receiving 12 1.1 O.89 0.37 Y had a baseline ISGA of “Moderate” (3). The mean % of 18 1.7 1.2 O.S4 Body Surface Area affected by atopic dermatitis for those 24 2.0 1.6 0.73 receiving Z was 18.8%, with a range of from between 5% to ND, not detected; 95%. The mean % of Body Surface Area affected by atopic RH, relative humidity, dermatitis for those receiving Y was 18.6%, with a range of from between 5% to 90%. 0565. These tests demonstrate that a much lower amount (0571 From this trial, 32.8% of those receiving Z of Impurity 1 occurs with pharmaceutical formulation Z achieved the primary endpoint, while 25.4% of those receiv over formulations Z6 and Z7. ing Yachieved the primary endpoint. 51.7% of those receiv US 2017/0152273 A1 Jun. 1, 2017 26 ing Zachieved the secondary endpoint, while 40.6% of 10. The topical pharmaceutical formulation of claim 8. those receiving Y achieved the secondary endpoint. wherein the amount of the ethylenediaminetetraacetic acid, 0572. In another trial, 513 patients received Z while 250 or a pharmaceutically acceptable salt thereof, is about received Y. The mean age of those receiving Z was 12.6 0.0035% (w/w). years, with a range of 2 to 79 years. The mean age of those 11. The topical pharmaceutical formulation of claim 10, receiving Y was 11.8 years, with a range of 2 to 79 years. further comprising an antioxidant from about 0.01% (w/w) 38.4% of those receiving Z had a baseline ISGA of “Mild” to about 1% (w/w) selected from the group consisting of (2), while 61.6% of those receiving Z had a baseline ISGA butylated hydroxytoluene, ascorbic acid or a pharmaceuti of “Moderate” (3). 40.0% of those receiving Y had a cally acceptable salt thereof, ascorbic palmitate, butylated baseline ISGA of “Mild” (2), while 60.0% of those receiving hydroxyanisole, 2,4,5-trihydroxybutyrophenone, 4-hy Y had a baseline ISGA of “Moderate” (3). The mean % of droxymethyl-2,6-di-tert-butylphenol, erythorbic acid, gum Body Surface Area affected by atopic dermatitis for those guaiac, propyl gallate, thiodipropionic acid, dilauryl thiodi receiving Z was 17.9%, with a range of from between 5% to propionate, tert-butylhydroquinone and tocopherols such as 95%. The mean % of Body Surface Area affected by atopic Vitamin E, and the like, including pharmaceutically accept dermatitis for those receiving Y was 17.7%, with a range of able salts and esters thereof, and mixtures thereof. from between 5% to 90%. 12. The topical pharmaceutical formulation of claim 11, 0573. From this trial, 31.4% of those receiving Z wherein the antioxidant is butylated hydroxytoluene. achieved the primary endpoint, while 18.0% of those receiv 13. The topical pharmaceutical formulation of claim 11, ing Yachieved the primary endpoint. 48.5% of those receiv wherein the amount of the antioxidant is 0.1% (w/w). ing Zachieved the secondary endpoint, while 29.7% of 14. The topical pharmaceutical formulation of claim 13, those receiving Y achieved the secondary endpoint. further comprising a stiffening agent from about 2% (W/w) 0574. It is understood that the examples and embodi to about 8% (w/w). ments described herein are for illustrative purposes only and 15. The topical pharmaceutical formulation of claim 14, that various modifications or changes in light thereof will be wherein the stiffening agent is selected from the group Suggested to persons skilled in the art and are to be included consisting of beeswax, paraffin wax, wax, and spermaceti within the spirit and purview of this application and scope of Wax. the appended claims. All publications, patents, and patent 16. The topical pharmaceutical formulation of claim 15, applications cited herein are hereby incorporated by refer wherein the stiffening agent is 5% (w/w) paraffin wax NF. ence in their entirety for all purposes. 17. A topical pharmaceutical formulation comprising: 1. A topical pharmaceutical formulation comprising: a) 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-ben (a) 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-ben ZOxaborole, a pharmaceutically acceptable salt, or a ZOxaborole, or a pharmaceutically acceptable salt, or a hydrate or a solvate thereof; hydrate or a solvate thereof; b) from about 5% (w/w) to about 15% (w/w) propylene (b) from about 5% (w/w) to about 15% (w/w) propylene glycol, glycol; and c) butylated hydroxytoluene: (c) petrolatum. d) edetate calcium disodium; 2. The topical pharmaceutical formulation of claim 1, e) mono- and di-glycerides; wherein the formulation comprises no more than about 0.5% f) paraffin waX; and (w/w) water. g) white petrolatum. 3. The topical pharmaceutical formulation of claim 2, 18. The topical pharmaceutical formulation of claim 17 wherein the amount of the propylene glycol is about 9% comprising: (w/w). a) from about 0.1% (w/w) to about 2% (w/w) 5-(4- 4. The topical pharmaceutical formulation of claim 3, cyanophenoxy)-1,3-dihydro-1-hydroxy-2, 1-benzoxa further comprising a glyceride blend from about 3% (w/w) borole; to about 10% (w/w), wherein the glyceride blend comprises b) from about 5% (w/w) to about 15% (w/w) propylene a monoglyceride and a diglyceride. glycol USP; 5. The topical pharmaceutical formulation of claim 4, c) 0.1% (w/w) butylated hydroxytoluene: wherein the amount of the glyceride blend is about 7% d) 0.0035% (w/w) edetate calcium disodium; (w/w) and the glyceride blend is Mono- and Di-glyceride e) 7% (w/w) mono- and di-glycerides NF: NF. f) 5% (w/w) paraffin wax; and 6. The topical pharmaceutical formulation of claim 5, g) 76.8965% (w/w) white petrolatum. wherein from about 40% (w/w) to about 55% (w/w) of the 19. The topical pharmaceutical formulation of claim 18 glyceride blend is a monoglyceride. consisting of: 7. The topical pharmaceutical formulation of claims 1-6, a) about 2% (w/w) 5-(4-cyanophenoxy)-1,3-dihydro-1- further comprising ethylenediaminetetraacetic acid, or a hydroxy-2,1-benzoxaborole, or a pharmaceutically pharmaceutically acceptable salt thereof, from about acceptable salt thereof; 0.0001% (w/w) to about 0.01% (w/w). b) about 9% (w/w) propylene glycol USP; 8. The topical pharmaceutical formulation of claim 7. c) about 0.1% (w/w) butylated hydroxytoluene: further comprising a sodium salt or a potassium salt or a d) about 0.0035% (w/w) edetate calcium disodium; calcium salt, or a mixture thereof, of ethylenediaminetet e) about 7% (w/w) mono- and di-glycerides NF, wherein raacetic acid. between 40% and 55% is said monoglyceride; 9. The topical pharmaceutical formulation of claim 10, f) about 5% (w/w) paraffin wax; and further comprising edetate calcium disodium. g) about 76.8965% (w/w) white petrolatum. US 2017/0152273 A1 Jun. 1, 2017 27

20. A method of decreasing the release of a cytokine (a) about 2% (w/w) 5-(4-cyanophenoxy)-1,3-dihydro-1- and/or a chemokine, the method comprising contacting a hydroxy-2,1-benzoxaborole; cell with the topical pharmaceutical formulation of claims b) about 9% (w/w) propylene glycol; 18 and 19. c) about 0.1% (w/w) butylated hydroxytoluene: 21. A method of treating an inflammatory-related condi d) about 0.0035% (w/w) edetate calcium disodium; tion in an animal, the method comprising administering to e) about 7% (w/w) mono- and di-glycerides, wherein the animal a therapeutically effective amount of the topical between 40% and 55% is said monoglyceride; pharmaceutical formulation of claims 18 and 19. f) about 5% (w/w) paraffin wax; and 22. The method of claim 21, wherein the inflammatory g) about 76.8965% (w/w) white petrolatum. related condition is psoriasis. 36. A stable pharmaceutical composition in a topical 23. The method of claim 22, wherein the inflammatory dosage form consisting essentially of related condition is atopic dermatitis. (a) an active agent which is 5-(4-cyanophenoxy)-1,3- 24. A method of treating atopic dermatitis in a human, the dihydro-1-hydroxy-2,1-benzoxaborole or crisaborole, a method comprising administering to the human a therapeu pharmaceutically acceptable salt, or a hydrate or a tically effective amount of the topical pharmaceutical for solvate thereof, mulation of claims 18 and 19. (b) one or more pharmaceutically acceptable excipients 25. The method of claim 24 further comprising adminis that do not promote protodeboronation of more than trating the pharmaceutical formulation to an affected area of about 0.75% by weight of the active agent to Impurity the human on a twice daily basis. 1 when stored at 40° C. and a relative humidity of 75% 26. The method of claim 25 further comprising adminis for a period of about 1 month. tering the pharmaceutical formulation over a period of about 37. The pharmaceutical composition of claim 36, wherein 28 days. the Impurity 1 is less than about 0.5% by weight of the active 27. The method of claim 24 further comprising a second agent. active agent administered in combination with pharmaceu 38. The pharmaceutical composition of claim 37, wherein tical formulation. the Impurity 1 is less than about 0.3% by weight of the active 28. The method of claim 27 wherein the second active agent. agent is a JAK kinase inhibitor such as Tofacitinib, JTE-052, 39. The pharmaceutical composition of claim 38 wherein Baricitinib, or Upadacitinib. the dosage form is an ointment and the active agent is 2.0% 29. A stable pharmaceutical composition in a topical of the composition. dosage form consisting essentially of 40. The pharmaceutical composition of claim 39 wherein (a) an active agent which is 5-(4-cyanophenoxy)-1,3- the active ingredient is 5-(4-cyanophenoxy)-1,3-dihydro-1- dihydro-1-hydroxy-2,1-benzoxaborole or crisaborole, a hydroxy-2,1-benzoxaborole. pharmaceutically acceptable salt, or a hydrate or a 41. The pharmaceutical composition of claim 40 wherein solvate thereof, the excipient is a stabilizer; and less than 0.25% (w/w) (b) one or more pharmaceutically acceptable excipients degradation byproducts or impurities. that do not promote protodeboronation of more than 42. A crystalline Form 1 of crisaborole or 5-(4-cyanophe 2.0% by weight of the active agent to Impurity 1 when noxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole having stored at 25° C. and a relative humidity of 75% for a characteristic peaks selected from an X-ray powder diffrac period of about 24 months. tion pattern containing the following 20 values measured 30. The pharmaceutical composition of claim 29, wherein using Cu K radiation (-1.54056A): 6.0, 12.1, 14.1 and the Impurity 1 is less than 1% by weight of the active agent. 15.4° 2002° 28. 31. The pharmaceutical composition of claim 30, wherein 43. The crystalline Form of claim 42 wherein the char the Impurity 1 is less than 0.75% by weight of the active acteristic peaks are 6.0 and 15.4° 20+0.2° 20. agent. 44. The topical formulation of claim 18 or 19 wherein 32. The pharmaceutical composition of claim 31 wherein 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxa the dosage form is an ointment and the active agent is 2.0% borole is a crystalline Form. of the composition. 45. The topical formulation of claim 44 wherein the 33. The pharmaceutical composition of claim 32 wherein crystalline Form has characteristic peaks selected from an the active ingredient is 5-(4-cyanophenoxy)-1,3-dihydro-1- X-ray powder diffraction pattern containing the following hydroxy-2,1-benzoxaborole. 20 values measured using Cu K radiation (-1.54056A): 34. The pharmaceutical composition of claim 33 wherein 6.0, 12.1, 14.1 and 15.4° 20+0.2° 20. the excipient is a stabilizer; and less than 0.25% (w/w) 46. The topical formulation of claim 44 wherein the degradation byproducts or impurities. crystalline Form has characteristic peaks of 6.0 and 15.4° 35. The pharmaceutical composition of claim 34, further 2002° 20. comprising