US 2013 0164376A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0164376 A1 BHAT et al. (43) Pub. Date: Jun. 27, 2013

(54) FORMULATIONS OF (+)-2-1-(3-ETHOXY-4- Publication Classification METHOXY-PHENYL)-2-METHANESULFO NYL-ETHYL-4-ACETYLAMINOISOINDO (51) Int. Cl. LINE-1,3-DIONE A613 L/4035 (2006.01) (52) U.S. Cl. (71) Applicant: Celgene Corporation, Summit, NJ (US) CPC ...... A61K 31/4035 (2013.01) USPC ...... 424/465: 514/417; 424/400 (72) Inventors: Sreenivas S. BHAT, Kendall Park, NJ (US); Michael T. Kelly, Lake Hopatcong, NJ (US) (57) ABSTRACT (73) Assignee: Celgene Corporation, Summit, NJ (US) Pharmaceutical compositions and single unit dosage forms of (21) Appl. No.: 13/727,366 (+)-2-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl (22) Filed: Dec. 26, 2012 ethyl-4-acetylaminoisoindoline-1,3-dione, or a pharmaceu tically acceptable stereoisomer, prodrug, salt, Solvate, Related U.S. Application Data hydrate, or clathrate thereof, are provided herein. Also pro (60) Provisional application No. 61/580,626, filed on Dec. vided are methods of treating, managing, or preventing vari 27, 2011. ous diseases or disorders. US 2013/0164376 A1 Jun. 27, 2013

FORMULATIONS OF (+)-2-1-(3-ETHOXY-4- ods of treating, managing, or preventing diseases and condi METHOXY-PHENYL)-2-METHANESULFO tions such as, but not limited to, cancer, pain, Macular Degen NYL-ETHYL-4-ACETYLAMINOISOINDO eration, a skin disease, a pulmonary disorder, an asbestos LINE-1,3-DIONE related disorder, a parasitic disease, an immunodeficiency disorder, a CNS disorder, CNS injury, atherosclerosis, a sleep CROSS REFERENCE TO RELATED disorder, hemoglobinopathy, anemia, an inflammatory dis APPLICATIONS ease, an autoimmune disease, a viral disease, a genetic dis 0001. This application claims the benefit of priority to ease, an allergic disease, a bacterial disease, an ocular neovas cular disease, a choroidal neovascular disease, a retina U.S. Provisional Patent Application Ser. No. 61/580,626, neovascular disease, and rubeosis, using Compound A, or a filed Dec. 27, 2011, the disclosure of which is incorporated by pharmaceutically acceptable stereoisomer, prodrug, salt, Sol reference herein in its entirety. Vate, hydrate, or clathrate thereof, in the dosage forms 1 FIELD described herein. 0002 Provided herein are formulations and dosage forms 4. DETAILED DESCRIPTION of (+)-2-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfo nyl-ethyl-4-acetylaminoisoindoline-1,3-dione. Methods of 4.1 Definitions using the formulations and dosage forms are also provided 0007 As used herein, the term “Compound A’ refers to herein. enantiomerically pure 2-1-(3-ethoxy-4-methoxy-phenyl)-2- 2. BACKGROUND methanesulfonyl-ethyl-4-acetylaminoisoindoline-1,3-di one. Without being limited by theory, Compound A is 0003 Drug substances are usually administered as part of believed to be (+)-2-1-(3-ethoxy-4-methoxy-phenyl)-2- a formulation in combination with one or more other agents methanesulfonyl-ethyl-4-acetylaminoisoindoline-1,3-di that serve varied and specialized pharmaceutical functions. one, which has the following structure: Dosage forms of various types may be made through selective use of pharmaceutical excipients. As pharmaceutical excipi ents have various functions and contribute to the pharmaceu Compound A tical formulations in many different ways, e.g., solubilization, dilution, thickening, stabilization, preservation, coloring, fla O Voring, etc. The properties that are commonly considered when formulating an active drug Substance include bioavail ability, ease of manufacture, ease of administration, and sta O O bility of the dosage form. Due to the varying properties of the active drug Substance to be formulated, dosage forms typi N O cally require pharmaceutical excipients that are uniquely tai lored to the active drug Substance in order to achieve advan / tageous physical and pharmaceutical properties. /\ 0004 (+)-2-1-(3-ethoxy-4-methoxy-phenyl)-2-meth anesulfonyl-ethyl-4-acetylaminoisoindoline-1,3-dione N" O O (“Compound A') is a compound with anti-inflammatory O activity in clinical development for the treatment of a variety of chronic inflammatory conditions. Pharmacologically, 0008. As used herein and unless otherwise indicated, a Compound A blocks the degradation of cyclic adenosine composition that is “substantially free” of a compound means monophosphate (cAMP) via inhibition of the phosphodi that the composition contains less than about 20 percent by esterase type IV (PDE4) enzyme, resulting in an increase in weight, more preferably less than about 10 percent by weight, cAMP in PDE4-expressing cells including monocytes, T even more preferably less than about 5 percent by weight, and cells, and neutrophils. Enzyme assay data using purified most preferably less than about 3 percent by weight of the PDE4 enzyme from U937 human monocytic cells indicate compound. that Compound A has a PDE4 ICs of about 74 nM. Com 0009. As used herein and unless otherwise indicated, the pound A and methods for its synthesis are described, e.g., in term "stereomerically pure’ means a composition that com U.S. Pat. No. 6,962,940, the disclosure of which is hereby prises one stereoisomer of a compound and is substantially incorporated by reference in its entirety. free of other stereoisomers of that compound. For example, a 0005. Due to its diversified pharmacological properties, Stereomerically pure composition of a compound having one Compound A is useful in treating, preventing, and/or manag chiral center will be substantially free of the opposite enan ing various diseases or disorders. Thus, a need exists as to tiomer of the compound. A stereomerically pure composition dosage forms of Compound Ahaving advantageous physical of a compound having two chiral centers will be substantially and pharmaceutical properties. free of other diastereomers of the compound. A typical ste reomerically pure compound comprises greater than about 80 3. SUMMARY percent by weight of one stereoisomer of the compound and 0006 Provided herein are pharmaceutical dosage forms of less than about 20 percent by weight of other stereoisomers of (+)-2-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl the compound, more preferably greater than about 90 percent ethyl-4-acetylaminoisoindoline-1,3-dione (“Compound by weight of one stereoisomer of the compound and less than A”), or a pharmaceutically acceptable prodrug, salt, Solvate, about 10 percent by weight of the other stereoisomers of the hydrate, or clathrate thereof. Also provided herein are meth compound, even more preferably greater than about 95 per US 2013/0164376 A1 Jun. 27, 2013 cent by weight of one stereoisomer of the compound and less ethylenediamines, aminoacids, hydroxyalkylamines, hetero than about 5 percent by weight of the other stereoisomers of cyclic and heteroaromatic amines, and polyether amines. the compound, and most preferably greater than about 97 0015. As used herein and unless otherwise indicated, the percent by weight of one stereoisomer of the compound and term “biohydrolyzable ester” means an ester of a compound less than about 3 percent by weight of the other stereoisomers that either: 1) does not interfere with the biological activity of of the compound. the compound but can confer upon that compound advanta 0010. As used herein and unless otherwise indicated, the geous properties in Vivo, Such as uptake, duration of action, or term “enantiomerically pure’ means a stereomerically pure onset of action; or 2) is biologically inactive but is converted composition of a compound having one chiral center. in vivo to the biologically active compound. Examples of 0011. As used herein, unless otherwise specified, the term biohydrolyzable esters include, but are not limited to, lower “pharmaceutically acceptable salt(s)' includes, but is not lim alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl ited to, salts of acidic or basic moieties of a compound pro esters, and choline esters. vided herein. Basic moieties are capable of forming a wide 0016. As used herein and unless otherwise indicated, the variety of salts with various inorganic and organic acids. The term “biohydrolyzable amide' means an amide of a com acids that can be used to prepare pharmaceutically acceptable pound that either: 1) does not interfere with the biological acid addition salts of Such basic compounds are those that activity of the compound but can confer upon that compound form non-toxic acid addition salts, i.e., salts containing phar advantageous properties in Vivo, Such as uptake, duration of macologically acceptable anions. Suitable organic acids action, or onset of action; or 2) is biologically inactive but is include, but are not limited to, maleic, fumaric, benzoic, converted in vivo to the biologically active compound. ascorbic. Succinic, acetic, formic, oxalic, propionic, tartaric, Examples of biohydrolyzable amides include, but are not salicylic, citric, gluconic, lactic, mandelic, cinnamic, oleic, limited to, lower alkyl amides, C.-amino acid amides, tannic, aspartic, Stearic, palmitic, glycolic, glutamic, glu alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. conic, glucaronic, saccharic, isonicotinic, methanesulfonic, 0017. As used herein, and unless otherwise specified, the ethanesulfonic, p-toluenesulfonic, benzenesulfonic acids, or terms “treat,” “treating” and “treatment contemplate an pamoic (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate) action that occurs while a patient is Suffering from the speci acids. Suitable inorganic acids include, but are not limited to, fied disease or disorder, which reduces the severity of the hydrochloric, hydrobromic, hydroiodic, Sulfuric, phosphoric, disease or disorder, or retards or slows the progression of the or nitric acids. Compounds that include an amine moiety can disease or disorder. form pharmaceutically acceptable salts with various amino 0018. As used herein, and unless otherwise specified, the acids, in addition to the acids mentioned above. Chemical terms “prevent,” “preventing and “prevention” refer to the moieties that are acidic in nature are capable of forming base prevention of the onset, recurrence or spread of a disease or salts with various pharmacologically acceptable cations. disorder, or of one or more symptoms thereof. The terms Examples of such salts are alkali metal or alkaline earth metal “prevent,” “preventing” and “prevention' contemplate an salts and, particularly, calcium, magnesium, Sodium, lithium, action that occurs before a patient begins to suffer from the Zinc, potassium, or iron salts. specified disease or disorder, which inhibits or reduces the 0012. As used herein, and unless otherwise specified, the severity of the disease or disorder. term "solvate” means a compound provided herein or a salt 0019. As used herein, and unless otherwise indicated, the thereof, that further includes a stoichiometric or non-sto terms “manage.” “managing” and “management encompass ichiometric amount of solvent bound by non-covalent inter preventing the recurrence of the specified disease or disorder molecular forces. Where the solvent is water, the solvate is a in a patient who has already suffered from the disease or hydrate. disorder, and/or lengthening the time that a patient who has 0013. As used herein and unless otherwise indicated, the suffered from the disease or disorder remains in remission. term “prodrug means a derivative of a compound that can The terms encompass modulating the threshold, development hydrolyze, oxidize, or otherwise react under biological con and/or duration of the disease or disorder, or changing the ditions (in vitro or in vivo) to provide the compound. way that a patient responds to the disease or disorder. Examples of prodrugs include, but are not limited to, deriva 0020. As used herein, and unless otherwise specified, the tives of thalidomide that include biohydrolyzable moieties term “about when used in connection with doses, amounts, such as biohydrolyzable amides, biohydrolyzable esters, bio or weight percent of ingredients of a composition or a dosage hydrolyzable carbamates, biohydrolyzable carbonates, bio form, means dose, amount, or weight percent that is recog hydrolyzable ureides, and biohydrolyzable phosphate ana nized by those of ordinary skill in the art to provide a phar logues. Other examples of prodrugs include derivatives of macological effect equivalent to that obtained from the speci thalidomide that include —NO, NO. —ONO, or—ONO fied dose, amount, or weight percent is encompassed. moieties. Specifically, the term “about contemplates a dose, amount, 0014. As used herein and unless otherwise indicated, the or weight percent within 30%, 25%, 20%, 15%, 10%, 5%, terms “biohydrolyzable carbamate.” “biohydrolyzable car 1%, 0.5%, or 0.25% of the specified dose, amount, or weight bonate.” “biohydrolyzable ureide.” “biohydrolyzable phos percent is encompassed. phate” mean a carbamate, carbonate, ureide, or phosphate, 0021. As used herein, and unless otherwise specified, the respectively, of a compound that either: 1) does not interfere term “stable, when used in connection with a formulation or with the biological activity of the compound but can confer a dosage form, means that the active ingredient of the formu upon that compound advantageous properties in Vivo, Such as lation or dosage form remains solubilized for a specified uptake, duration of action, or onset of action; or 2) is biologi amount of time and does not significantly degrade or aggre cally inactive but is converted in vivo to the biologically gate or become otherwise modified (e.g., as determined, for active compound. Examples of biohydrolyzable carbamates example, by physical methods such as visual inspection or include, but are not limited to, lower alkylamines, substituted analytical methods such as HPLC). US 2013/0164376 A1 Jun. 27, 2013

4.2 Formulations and Dosage Forms 0029. In one embodiment, the disintegrant is croscarmel 0022 Provided herein are pharmaceutical formulations lose. In a specific embodiment, the disintegrant is croScarmel and dosage forms of (+)-2-1-(3-ethoxy-4-methoxy-phenyl)- lose sodium (e.g., Ac-di-SolR). In one embodiment, the core 2-methanesulfonyl-ethyl-4-acetylaminoisoindoline-1,3-di formulation comprises croScarmellose in an amount of about one (Compound A), or a pharmaceutically acceptable pro 0.1% to about 10%, about 0.5% to about 8%, about 1% to drug, salt, Solvate, hydrate, or clathrate thereof. In some about 5%, or about 2% to about 8% by weight of the total core embodiments, the dosage forms are suitable for oral admin composition. In one embodiment, the core formulation com istration to a patient. In other embodiments, the formulations prises croscarmellose in an amount of about 0.1%, 1%, 2%, and dosage forms provided herein exhibit advantageous 3%, 4%, 5%, 6%, 7% or 8% by weight of the total core physical and/or pharmacological properties. Such properties composition. In a specific embodiment, the core formulation include, but are not limited to, fast disintegration, low friabil comprises croScarmellose in an amount of about 3% by ity, ease of assay, content uniformity, flow properties for weight of the total core composition. manufacture, dissolution and bioavailability, and/or stability. 0030. In one embodiment, the lubricant is magnesium Also provided herein are kits comprising pharmaceutical for Stearate. In one embodiment, the core formulation comprises mulations and dosage forms provided herein. Also provided magnesium Stearate in an amount of about 0.1% to about 5%, herein are methods of treating, managing, and/or preventing a about 0.25% to about 5%, about 0.3% to about 2%, about disease or condition, which comprises administering to a 0.5% to about 1%, or about 0.5% to about 2% by weight of the patient in need thereof a pharmaceutical formulation or a total core composition. In one embodiment, the core formu dosage form provided herein. lation comprises magnesium Stearate in an amount of about 0023. In some embodiments, the formulations and dosage 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% 1%, forms provided herein are suitable for oral administration, in 2%. 3%, 4% or 5% by weight of the total core composition. In particular, in the form of a tablet. In certain embodiments, the a specific embodiment, the core formulation comprises mag formulations and dosage forms comprise a core containing nesium stearate in an amount of about% by weight of the total the active ingredient and non-functional film coating. core composition. 0024. In one embodiment, provided herein is a core for 0031. In one embodiment, provided herein is a core for mulation comprising Compound A. In one embodiment, the mulation comprising: Compound A at an amount of about core formulation comprises Compound A in an amount of 10% by weight of the total core composition; lactose at an about 0.5% to about 30%, about 1% to about 25%, about 5% amount of about 60% by weight of the total core composition; to about 25%, about 5% to about 20%, about 10% to about microcrystalline cellulose at an amount of about 26.25% by 15%, or about 5% to 15% by the weight of the total core weight of the total core composition; croScarmellose at an composition. In one embodiment, the core formulation com amount of about 3% by weight of the total core composition; prises Compound A in an amount of about 1%. 5%, 10%, and magnesium Stearate at an amount of about 0.75% by 15%, 20% or 25% by the weight of the total core composition. weight of the total core composition. In a specific embodiment, the core formulation comprises Compound A in an amount of about 10% by the weight of the 0032. Without being limited by a particular theory, color total core composition. change (e.g., fading) is frequently observed in tablet formu 0025. In one embodiment, the core formulation compris lations. This phenomenon, known as blooming effect, is ing Compound A further comprises one or more fillers, dis caused when lower molecular weight material used in the integrants and/or lubricants. formulation diffuses to the surface under higher temperature 0026. In one embodiment, the filler is lactose. In a specific and humidity conditions. For example, excipients such as embodiment, the filler is lactose monohydrate (e.g., Fast medium chain triglycerides, which are commonly used as FloR). In one embodiment, the core formulation comprises plasticizers in film coatings can migrate or diffuse to the tablet lactose in an amount of about 20% to about 85%, about 30% Surface causing the color change. However, the phenomenon to about 75%, about 40% to about 70%, or about 50% to about is not always observed when lower molecular weight mate 65% by weight of the total core composition. In one embodi rials are used informulations, i.e., presence of lower molecu ment, the core formulation comprises lactose in an amount of lar weight materials may or may not cause blooming effect. It about 20%, 30%, 40%, 50%, 60%, 70%, 80% or 85% by was discovered that interaction of a particular lower molecu weight of the total core composition. In a specific embodi lar weight material with other ingredients of the formulation, ment, the core formulation comprises lactose in an amount of as well as the actual amount of the lower molecular weight about 60% by weight of the total core composition. material and other ingredients, are critical in assessing 0027. In one embodiment, the filler is cellulose. In a spe whether a particular formulation would exhibit instability in cific embodiment, the filler is microcrystalline cellulose (e.g., terms of change of color or appearance. Avicel(R). In one embodiment, the core formulation com 0033 Accordingly, in certain embodiments, the formula prises cellulose in an amount of about 5% to about 60%, about tions or dosage forms provided herein do not comprise a 10% to about 50%, about 15% to about 40%, about 20% to lower molecular weight excipient that may diffuse to the about 30%, or about 25% to about 30% by weight of the total surface of the composition. In other embodiments, the oral core composition. In one embodiment, the core formulation formulations or dosage forms provided herein comprise a comprises cellulose in an amount of about 5%, 10%, 15%, lower molecular weight excipient, but at an amount that does 20%, 25%, 30%, 35%, 40%, 45% and 50% by weight of the not trigger blooming effect. In other embodiments, the oral total core composition. In a specific embodiment, the core formulations or dosage forms provided herein comprise a formulation comprises cellulose in an amount of about lower molecular weight excipient in the presence of other 26.25% by weight of the total core composition. excipients in a way that blooming effect is not observed in 0028. In one embodiment, formulations or dosage forms connection with the resulting formulations or dosage forms. provided herein may contain two or more fillers. Consequently, formulations and dosage forms provided US 2013/0164376 A1 Jun. 27, 2013 herein exhibit improved stability, particularly in terms of coating formulations. In one embodiment, the coloring agents change of color or appearance. comprise titanium dioxide and red iron oxide. In another 0034. In one embodiment, provided herein are formula embodiment, the coloring agents comprise titanium dioxide, tions for coating of tablets. In one embodiment, such formu red iron oxide, and yellow iron oxide. In another embodi lations do not comprise medium chain triglycerides. In Such ment, the coloring agents comprise titanium dioxide, red iron an embodiment, the formulations may contain other various oxide, yellow iron oxide, and black iron oxide. excipients such as, but not limited to, coating agents, binders, 0041. In another aspect of this embodiment, the coloring lubricants, stabilizing agents, plasticizers, adhesives, agents are present at an amount of about 10% to about 60%, glidants, and/or diluents. In some embodiments, the coating about 15% to about 50%, about 20% to about 40%, or about formulations provided herein optionally contain coloring 25% to about 35% by weight of the total coating formulation. agents. These excipients are well-known in the art. In another embodiment, the coloring agents are present at an 0035. In one embodiment, provided herein are coating amount of about 5%, 10%, 15%, 20%, 25%, 30% or 35% by formulations that do not comprise medium chain triglycer weight of the total coating formulation. In a specific embodi ides. ment, the coloring agents are present at an amount of about 0036. In one embodiment wherein coating formulations 31% by weight of the total coating formulation. do not contain medium chain triglycerides, the excipient is 0042. In a specific embodiment, provided herein is a coat polydextrose. In a specific embodiment, polydesctrose is ing formulation comprising: polydextrose at an amount of polydextrose FCC. In one embodiment, polydexrose is about 26% by weight of the total coating formulation; present at an amount of about 10% to about 60%, about 15% hypromellose at an amount of about 31% by weight of the to about 50%, about 20% to about 40%, or about 25% to about total coating formulation; talc at an amount of about 7% by 30% by weight of the total coating formulation. In another weight of the total coating formulation; maltodextrin at an embodiment, polydextrose is present at an amount of about amount of about 5% by weight of the total coating formula 5%, 10%, 15%, 20%, 25% or 30% by weight of the total tion; and a mixture of coloring agents at an amount of about coating formulation. In a specific embodiment, polydextrose 31% by weight of the total coating formulation. is present at an amount of about 26% by weight of the total coating formulation. 0043. In another embodiment wherein coating formula 0037. In one aspect of this embodiment, the excipient is tions do not contain medium chain triglycerides, the excipient hypromellose. In a specific embodiment, the excipient is is polydextrose. In a specific embodiment, polydesctrose is hypromellose 15cP. In one embodiment, hypromellose is polydextrose FCC. In one embodiment, polydexrose is present at an amount of about 10% to about 60%, about 15% present at an amount of about 10% to about 60%, about 15% to about 50%, about 25% to about 40%, or about 30% to about to about 50%, about 20% to about 40%, or about 25% to about 35% by weight of the total coating formulation. In another 30% by weight of the total coating formulation. In another embodiment, hypromellose is present at an amount of about embodiment, polydextrose is present at an amount of about 5%, 10%, 15%, 20%, 25%, 30% or 35% by weight of the total 5%, 10%, 15%, 20%, 25% or 30% by weight of the total coating formulation. In a specific embodiment, hypromellose coating formulation. In a specific embodiment, polydextrose is present at an amount of about 31% by weight of the total is present at an amount of about 26% by weight of the total coating formulation. coating formulation. 0038. In another aspect of this embodiment, the excipient 0044. In one aspect of this embodiment, the excipient is is talc. In one embodiment, talc is present at an amount of hypromellose. In a specific embodiment, the excipient is about 0.1% to about 25%, about 1% to about 20%, about 3% hypromellose 15cP. In one embodiment, hypromellose is to about 15%, or about 5% to about 10% by weight of the total present at an amount of about 10% to about 60%, about 15% coating formulation. In another embodiment, talc is present at to about 50%, about 25% to about 40%, or about 30% to about an amount of about 1%, 2%, 3%, 4%, 4%, 5%, 6%, 7%, 8%, 35% by weight of the total coating formulation. In another 9% or 10% by weight of the total coating formulation. In a embodiment, hypromellose is present at an amount of about specific embodiment, talc is presentatanamount of about 7% 5%, 10%, 15%, 20%, 25%, 30% or 35% by weight of the total by weight of the total coating formulation. coating formulation. In a specific embodiment, hypromellose 0039. In another aspect of this embodiment, the excipient is present at an amount of about 31% by weight of the total is maltodextrin. In one embodiment, maltodextrin is present coating formulation. at an amount of about 0.1% to about 25%, about 1% to about 0045. In another aspect of this embodiment, the excipient 20%, about 3% to about 15%, or about 5% to about 10% by is talc. In one embodiment, talc is present at an amount of weight of the total coating formulation. In another embodi about 0.1% to about 25%, about 1% to about 20%, about 3% ment, maltodextrin is present at an amount of about 1%, 2%, to about 15%, or about 5% to about 10% by weight of the total 3%, 4%, 4%, 5%, 6%, 7%, 8%, 9% or 10% by weight of the coating formulation. In another embodiment, talc is present at total coating formulation. In a specific embodiment, malto an amount of about 1%, 2%, 3%, 4%, 4%, 5%, 6%, 7%, 8%, dextrin is present at an amount of about 5% by weight of the 9% or 10% by weight of the total coating formulation. In a total coating formulation. specific embodiment, talc is presentatanamount of about 7% 0040. In another aspect of this embodiment, the excipients by weight of the total coating formulation. are one or more coloring agents, which can be useful in 0046. In another aspect of this embodiment, the excipient distinguishing dosage forms containing different amounts of is maltodextrin. In one embodiment, maltodextrin is present active ingredient. Examples of coloring agents include, but at an amount of about 0.1% to about 25%, about 1% to about are not limited to, iron oxides (e.g., red, yellow and black) and 20%, about 3% to about 15%, or about 5% to about 10% by titanium dioxide. Appropriate coloring agents may be mixed weight of the total coating formulation. In another embodi to obtain a desired color of the coating formulation. In some ment, maltodextrin is present at an amount of about 1%, 2%, embodiments, two or more coloring agents can be used in 3%, 4%, 4%, 5%, 6%, 7%, 8%, 9% or 10% by weight of the US 2013/0164376 A1 Jun. 27, 2013

total coating formulation. In a specific embodiment, malto ment, talc is present at an amount of about 15% (e.g., 14.8%) dextrin is present at an amount of about 5% by weight of the by weight of the total coating formulation. total coating formulation. 0053. In another aspect of this embodiment, the excipients 0047. In another aspect of this embodiment, the excipient are one or more coloring agents. In one embodiment, the is triacetin. In one embodiment, triacetin is present at an coloring agents are present at an amount of about 10% to amount of about 0.1% to about 20%, about 0.5% to about about 60%, about 15% to about 50%, about 20% to about 25%, about 1% to about 10%, or about 1% to about 5% by 40%, or about 25% to about 30% by weight of the total weight of the total coating formulation. In another embodi coating formulation. In another embodiment, the coloring ment, triacetin is present at an amount of about 1%, 2%. 3%, agents are present at an amount of about 5%, 10%, 15%, 20%, 4%, 4%, 5%, 6%, 7%, 8%, 9% or 10% by weight of the total 25% or 30% by weight of the total coating formulation. In a coating formulation. In a specific embodiment, triacetin is specific embodiment, the coloring agents are present at an present at an amount of about 4% by weight of the total amount of about 25% by weight of the total coating formu coating formulation. lation. 0048. In another aspect of this embodiment, the coloring 0054. In a specific embodiment, provided herein is a coat agents are present at an amount of about 10% to about 60%, ing formulation comprising: polyvinyl alcohol at an amount about 15% to about 50%, about 20% to about 40%, or about of about 40% by weight of the total coating formulation; 25% to about 30% by weight of the total coating formulation. polyethylene glycol at an amount of about 20% by weight of In another embodiment, the coloring agents are present at an the total coating formulation; talc at an amount of about 15% amount of about 5%, 10%, 15%, 20%, 25% or 30% by weight by weight of the total coating formulation; and a mixture of of the total coating formulation. In a specific embodiment, the coloring agents at an amount of about 25% by weight of the coloring agents are present at an amount of about 27% by total coating formulation. weight of the total coating formulation. 0055. In another embodiment wherein coating formula 0049. In a specific embodiment, provided herein is a coat tions do not contain medium chain triglycerides, the excipient ing formulation comprising: polydextrose at an amount of is lactose. In one embodiment, lactose is presentatanamount about 26% by weight of the total coating formulation; of about 10% to about 60%, about 20% to about 50%, about hypromellose at an amount of about 31% by weight of the 25% to about 40%, or about 30% to about 35% by weight of total coating formulation; talc at an amount of about 7% by the total coating formulation. In another embodiment, lactose weight of the total coating formulation; maltodextrin at an is present at an amount of about 5%, 15%, 25%, 35%, 45%, amount of about 5% by weight of the total coating formula 55% or 65% by weight of the total coating formulation. In a tion; triacetin at an amount of about 4% by weight of the total specific embodiment, polyvinyl alcohol is present at an coating formulation; and a mixture of coloring agents at an amount of about 33% by weight of the total coating formu amount of about 27% by weight of the total coating formu lation. lation. 0050. In another embodiment wherein coating formula 0056. In one aspect of this embodiment, the excipient is tions do not contain medium chain triglycerides, the excipient hypromellose. In a specific embodiment, the excipient is is polyvinyl alcohol. In one embodiment, polyvinyl alcohol is hypromellose 6cP. In one embodiment, hypromellose is present at an amount of about 20% to about 75%, about 25% present at an amount of about 10% to about 60%, about 15% to about 65%, about 30% to about 55%, or about 35% to about to about 50%, about 25% to about 40%, or about 30% to about 45% by weight of the total coating formulation. In another 35% by weight of the total coating formulation. In another embodiment, polyvinyl alcohol is present at an amount of embodiment, hypromellose is present at an amount of about about 10%, 20%, 30%, 40%, 50% or 60% by weight of the 5%, 10%, 15%, 20%, 25%, 30% or 35% by weight of the total total coating formulation. In a specific embodiment, polyvi coating formulation. In a specific embodiment, hypromellose nyl alcohol is presentatan amount of about 40% by weight of is present at an amount of about 31% by weight of the total the total coating formulation. coating formulation. 0051. In one aspect of this embodiment, the excipient is 0057. In another aspect of this embodiment, the excipient polyethylene glycol. In one specific embodiment, the excipi is polyethylene glycol. In one specific embodiment, the ent is polyethylene glycol 3350. In one embodiment, poly excipient is polyethylene glycol 3350. In one embodiment, ethylene glycol is present at an amount of about 5% to about polyethylene glycol is present at an amount of about 0.1% to 50%, about 10% to about 40%, about 15% to about 30%, or about 20%, about 0.3% to about 10%, about 0.5% to about about 20% to about 25% by weight of the total coating for 15%, or about 1% to about 5% by weight of the total coating mulation. In another embodiment, polyethylene glycol is formulation. In another embodiment, polyethylene glycol is present at an amount of about 10%, 20%, 30%, 40% or 50% presentatan amount of about 1%, 2%. 3%, 4%. 5%, 6%, 7%, by weight of the total coating formulation. In a specific 8%, 9% or 10% by weight of the total coating formulation. In embodiment, polyethylene glycol is present at an amount of a specific embodiment, polyethylene glycol is present at an about 20% (e.g., 20.2%) by weight of the total coating for amount of about 5% by weight of the total coating formula mulation. tion. 0052. In another aspect of this embodiment, the excipient 0058. In another aspect of this embodiment, the excipient is talc. In one embodiment, talc is present at an amount of is triacetin. In one embodiment, triacetin is present at an about 1% to about 30%, about 3% to about 25%, about 5% to amount of about 0.1% to about 20%, about 0.5% to about about 20%, or about 10% to about 15% by weight of the total 25%, about 1% to about 10%, or about 1% to about 5% by coating formulation. In another embodiment, talc is present at weight of the total coating formulation. In another embodi an amount of about 1%. 5%, 10%, 15%, 20%, 25% or 30% by ment, triacetin is present at an amount of about 1%, 2%. 3%, weight of the total coating formulation. In a specific embodi 4%. 5%, 6%, 7%, 8%, 9% or 10% by weight of the total US 2013/0164376 A1 Jun. 27, 2013

coating formulation. In a specific embodiment, triacetin is is present at an amount of about 1%. 5%, 10%, 15% or 20% present at an amount of about 4% by weight of the total by weight of the total coating formulation. In a specific coating formulation. embodiment, talc is present at an amount of about 7% by 0059. In another aspect of this embodiment, the excipients weight of the total coating formulation. are one or more coloring agents. In one embodiment, the 0066. In another aspect of this embodiment, another coloring agents are present at an amount of about 10% to excipientis maltodextrin. In one embodiment, maltodextrin is about 60%, about 15% to about 50%, about 20% to about presentatanamount of about 0.1% to about 20%, about 0.5% 40%, or about 25% to about 30% by weight of the total to about 25%, about 1% to about 10%, or about 1% to about coating formulation. In another embodiment, the coloring 5% by weight of the total coating formulation. In another agents are present at an amount of about 5%, 10%, 15%, 20%, embodiment, maltodextrin is present at an amount of about 25% or 30% by weight of the total coating formulation. In a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% by weight of specific embodiment, the coloring agents are present at an the total coating formulation. In a specific embodiment, mal amount of about 27% by weight of the total coating formu todextrin is presentatanamount of about 5% by weight of the lation. total coating formulation. 0060. In a specific embodiment, provided herein is a coat 0067. In another aspect of this embodiment, the excipients ing formulation comprising: lactose at an amount of about are one or more coloring agents. In one embodiment, the 33% by weight of the total coating formulation; hypromellose coloring agents are present at an amount of about 10% to at an amount of about 31% by weight of the total coating about 60%, about 15% to about 50%, about 20% to about formulation; polyethylene glycol at an amount of about 5% 40%, or about 25% to about 30% by weight of the total by weight of the total coating formulation; triacetin at an coating formulation. In another embodiment, the coloring amount of about 4% by weight of the total coating formula agents are present at an amount of about 5%, 10%, 15%, 20%, tion; and a mixture of coloring agents at an amount of about 25% or 30% by weight of the total coating formulation. In a 27% of the total weight of the coating formulation. specific embodiment, the coloring agents are present at an 0061. In other embodiments, provided herein are coating amount of about 29% by weight of the total coating formu formulations that contain medium chain triglycerides and lation. other excipients, yet do not cause blooming effect, e.g., 0068. In a specific embodiment, provided herein is a coat changes in color or appearance under storage. ing formulation comprising: polydextrose at an amount of 0062. In one embodiment where coating formulations about 26% by weight of the total coating formulation; contain medium chain triglycerides, medium chain triglycer hypromellose at an amount of about 31% by weight of the ides are presentatanamount of about 0.1 to about 15%, about total coating formulation; talc at an amount of about 7% by 0.5 to about 10%, about 1% to about 5%, or about 1% to 3% weight of the total coating formulation; maltodextrin at an by weight of the total coating formulation. In another embodi amount of about 5% by weight of the total coating formula ment, medium chain triglycerides are present at an amount of tion; medium chain triglycerides at an amount of about 2% by about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% weight of the total coating formulation; and a mixture of or 5% by weight of the total coating formulation. In a specific coloring agents at an amount of about 29% of the total weight embodiment, medium chain triglycerides are present at an of the coating formulation. amount of about 2% by weight of the total coating formula 0069. In another embodiment where coating formulations tion. contain medium chain triglycerides, medium chain triglycer 0063. In one aspect of this embodiment, another excipient ides are presentatanamount of about 0.1 to about 15%, about is polydextrose. In one embodiment, polydextrose is present 0.5 to about 10%, about 1% to about 5%, or about 1% to 3% at an amount of about 10% to about 60%, about 15% to about by weight of the total coating formulation. In another embodi 50%, about 20% to about 40%, or about 25% to about 30% by ment, medium chain triglycerides are present at an amount of weight of the total coating formulation. In another embodi about 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% ment, polydextrose is presentatan amount of about 5%, 10%, or 5% by weight of the total coating formulation. In a specific 15%, 20%, 25% or 30% by weight of the total coating for embodiment, medium chain triglycerides are present at an mulation. In a specific embodiment, polydextrose is present amount of about 4% by weight of the total coating formula at an amount of about 26% by weight of the total coating tion. formulation. 0070. In one aspect of this embodiment, another excipient 0064. In another aspect of this embodiment, another is polydextrose. In one embodiment, polydextrose is present excipient is hypromellose. In one specific embodiment, at an amount of about 1% to about 40%, about 5% to about hypromellose is hypromellose 15cP. In one embodiment, 30%, about 10% to about 20%, or about 10% to about 15% by hypromellose is present at an amount of about 10% to about weight of the total coating formulation. In another embodi 60%, about 15% to about 50%, about 25% to about 40%, or ment, polydextrose is presentatan amount of about 5%, 10%, about 30% to about 35% by weight of the total coating for 15%, 20%, 25% or 30% by weight of the total coating for mulation. In another embodiment, hypromellose is present at mulation. In a specific embodiment, polydextrose is present an amount of about 5%, 10%, 15%, 20%, 25%, 30% or 35% at an amount of about 13% by weight of the total coating by weight of the total coating formulation. In a specific formulation. embodiment, hypromellose is present at an amount of about 0071. In another aspect of this embodiment, another 31% by weight of the total coating formulation. excipient is hypromellose. In one specific embodiment, 0065. In another aspect of this embodiment, another hypromellose is hypromellose 15cP. In one embodiment, excipient is talc. In one embodiment, talc is present at an hypromellose is present at an amount of about 10% to about amount of about 1% to about 20%, about 3% to about 15%, 65%, about 20% to about 60%, about 25% to about 50%, or about 5% to about 10%, or about 5% to about 10% by weight about 35% to about 45% by weight of the total coating for of the total coating formulation. In another embodiment, talc mulation. In another embodiment, hypromellose is present at US 2013/0164376 A1 Jun. 27, 2013

an amount of about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 0078. In one embodiment, the pharmaceutical composi 45%, 50%, 55% or 60% by weight of the total coating for tion is coated with a coating formulation, wherein the coating mulation. In a specific embodiment, hypromellose is present formulation comprises one or more excipients, wherein the at an amount of about 44% by weight of the total coating excipient is polyvinyl alcohol and present at an amount of formulation. about 35% to about 45% by weight of the total coating for 0072. In another aspect of this embodiment, another mulation. In another embodiment the excipient is polyethyl excipient is talc. In one embodiment, talc is present at an ene glycol is presentatan amount of about 20% to about 25% amount of about 1% to about 20%, about 3% to about 15%, by weight of the total coating formulation. In another embodi about 5% to about 10%, or about 5% to about 10% by weight ment the excipient is talc and is present at an amount of about of the total coating formulation. In another embodiment, talc 10% to about 15% by weight of the total coating formulation. is present at an amount of about 1%. 5%, 10%, 15% or 20% In another embodiment, the excipients are one or more col by weight of the total coating formulation. In a specific oring agents present at an amount of about 25% to about 30% embodiment, talc is present at an amount of about 7% by by weight of the total coating formulation. weight of the total coating formulation. 0079. In a specific embodiment, provided herein is a for 0073. In another aspect of this embodiment, another mulation comprising (1) Compound A or a pharmaceutically excipientis maltodextrin. In one embodiment, maltodextrin is acceptable salt thereof; at an amount of about 5% to about presentatanamount of about 0.1% to about 20%, about 0.5% 25% by weight of the total composition; (2) lactose at an to about 25%, about 1% to about 10%, or about 1% to about amount of about 20% to 85% by weight of the total compo 5% by weight of the total coating formulation. In another sition; (3) cellulose at an amount of about 10% to about 50% embodiment, maltodextrin is present at an amount of about by weight of the total composition; (4) croScarmellose at an 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% by weight of amount of about 2% to about 8% by weight of the total the total coating formulation. In a specific embodiment, mal composition; and (5) magnesium Stearate at an amount of todextrin is presentatanamount of about 5% by weight of the about 0.25% to about 5% of the total composition. total coating formulation. 0080. In a specific embodiment, the pharmaceutical com 0074. In another aspect of this embodiment, the excipients position is coated with a coating formulation, wherein the are one or more coloring agents. In one embodiment, the coating formulation comprises: (1) polyvinyl alcohol at an coloring agents are present at an amount of about 10% to amount of about 35% to about 45% by weight of the total about 60%, about 15% to about 50%, about 20% to about coating formulation; and/or (2) polyethylene glycol at an 40%, or about 25% to about 30% by weight of the total amount of about 20% to about 25% by weight of the total coating formulation. In another embodiment, the coloring coating formulation; and/or (3) talc at an amount of about agents are present at an amount of about 5%, 10%, 15%, 20%, 10% to about 15% by weight of the total coating formulation; 25% or 30% by weight of the total coating formulation. In a and/or (4) one or more coloring agents at an amount of about specific embodiment, the coloring agents are present at an 25% to about 30% by weight of the total coating formulation. amount of about 27% by weight of the total coating formu I0081. In a specific embodiment, provided herein is a for lation. mulation of Compound A, wherein the core formulation com 0075. In a specific embodiment, provided herein is a coat prises the following: ing formulation comprising: polydextrose at an amount of 0082 Compound A at an amount of about 10% by about 13% by weight of the total coating formulation; weight of the total core composition; lactose at an hypromellose at an amount of about 44% by weight of the amount of about 60% by weight of the total core com total coating formulation; talc at an amount of about 7% by position; microcrystalline cellulose at an amount of weight of the total coating formulation; maltodextrin at an about 26.25% by weight of the total core composition; amount of about 5% by weight of the total coating formula croscarmellose at an amount of about 3% by weight of tion; medium chain triglycerides at an amount of about 4% by the total core composition; and magnesium Stearate at an weight of the total coating formulation; and a mixture of amount of about 0.75% by weight of the total core com coloring agents at an amount of about 27% of the total weight position; and of the coating formulation. the coating formulation comprises the following: 0076 Any combination between core formulations and 0.083 polyvinyl alcohol at an amount of about 40% by coating formulations provided herein can be used. weight of the total coating formulation; polyethylene 0077. In one embodiment, provided herein is a formula glycol at an amount of about 20% by weight of the total tion comprising Compound A or a pharmaceutically accept coating formulation; talc at an amount of about 15% by able salt thereof; a filler; a disintegrant; and a lubricant, weight of the total coating formulation; and a mixture of wherein compound A is present at an amount of about 5% to coloring agents at an amount of about 25% by weight of about 25% by weight of the total composition. In one aspect the total coating formulation. of this embodiment, the filler is lactose and is present at an I0084 Pharmaceutical compositions and formulations pro amount of about 20% to 85% by weight of the total compo vided herein can be presented as discrete dosage forms. sition. In another aspect of this embodiment, the composition Although a preferred oral dosage unit form is in the form of a further comprises cellulose as a filler and is present at an tablet, otherforms of dosage forms can also be employed. For amount of about 10% to about 50% by weight of the total example, it is possible to use the core formulation in connec composition. In another aspect of this embodiment, the dis tion with other forms of dosage forms such as a capsule or a integrant is croScarmellose and is present at an amount of caplet. In some embodiments, the formulation is in the form about 2% to about 8% by weight of the total composition. In of a tablet. another aspect of this embodiment, the lubricant is magne I0085. In some embodiments, because it is typical to obtain sium Stearate and is present at an amount of about 0.25% to Compound A, or a pharmaceutically acceptable prodrug, salt, about 5% of the total composition. solvate, or clathrate thereof, at a purity of less than 100%, the US 2013/0164376 A1 Jun. 27, 2013 formulations and dosage forms provided herein may be quinar Sodium; bropirimine; buSulfan; cactinomycin; calus defined as compositions, formulations, or dosage forms that terone; caracemide; carbetimer; carboplatin: carmustine; comprise Compound A, or a pharmaceutically acceptable carubicin hydrochloride; carZelesin; cedefingol; celecoxib; prodrug, salt, Solvate, or clathrate thereof, at an amount that chlorambucil; cirolemycin; cisplatin: cladribine; crisinatol provides the potency of a specified amount of 100% pure mesylate; cyclophosphamide; cytarabine; dacarbazine; dac Compound A. tinomycin; daunorubicin hydrochloride; decitabine; dexor I0086. In certain embodiments, provided herein are anhy maplatin; deZaguanine; deZaguanine mesylate; diaziquone; drous pharmaceutical compositions and dosage forms includ docetaxel: doxorubicin; doxorubicin hydrochloride; drolox ing an active ingredient, since water can facilitate the degra ifene; droloxifene citrate; dromoStanolone propionate; dua dation of Some compounds. For example, the addition of Zomycin; edatrexate; eflornithine hydrochloride; elsamitru water (e.g., 5 percent) is widely accepted in the pharmaceu cin; enloplatin; enpromate; epipropidine; epirubicin tical arts as a means of simulating shelf-life, i.e., long-term hydrochloride; erbulozole; esorubicin hydrochloride; estra storage in order to determine characteristics such as shelf-life mustine; estramustine phosphate Sodium; etanidazole; etopo or the stability of formulations over time. See, e.g., Jens T. side, etoposide phosphate; etoprine; fadrozole hydrochlo Carstensen, Drug Stability: Principles & Practice, 2d. Ed., ride; fazarabine; fenretinide; floxuridine; fludarabine Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water phosphate; fluorouracil; fluorocitabine; fosquidone; fostrie and heat accelerate decomposition. Thus, the effect of water cin Sodium; gemcitabine; gemcitabine hydrochloride; on a formulation can be of great significance since moisture hydroxyurea; idarubicin hydrochloride; ifosfamide: ilmofos and/or humidity are commonly encountered during manufac ine; iproplatin; irinotecan; irinotecan hydrochloride; lan ture, handling, packaging, storage, shipment, and use of for reotide acetate; letrozole; leuprolide acetate; liarozole hydro mulations. chloride; lometrexol Sodium; lomustine; losoxantrone 0087 An anhydrous pharmaceutical composition should hydrochloride; masoprocol; maytansine; mechlorethamine be prepared and stored Such that the anhydrous nature is hydrochloride; megestrol acetate; melengestrol acetate; mel maintained. Accordingly, in some embodiments, anhydrous phalan; menogaril; mercaptopurine; methotrexate; methotr compositions are packaged using materials known to prevent exate Sodium; metoprine; meturedepa; mitindomide; mito exposure to water such that they can be included in suitable carcin; mitocromin, mitogillin; mitomalcin, mitomycin; formulary kits. Examples of Suitable packaging include, but mitosper, mitotane; mitoxantrone hydrochloride; mycophe are not limited to, hermetically sealed foils, plastic or the like, nolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran: unit dose containers, blister packs, and strip packs. paclitaxel, pegaspargase; peliomycin; pentamustine; peplo 0088. In this regard, also provided herein is a method of mycin Sulfate; perfosfamide; pipobroman; piposulfan, piroX preparing a solid pharmaceutical formulation including an antrone hydrochloride; plicamycin; plomestane; porfimer active ingredient through admixing the active ingredient and Sodium; porfiromycin; prednimustine; procarbazine hydro an excipient under anhydrous or low moisture/humidity con chloride; puromycin; puromycin hydrochloride; pyrazofurin; ditions, wherein the ingredients are substantially free of riboprine; Safingol: Safingol hydrochloride; Semustine; water. The method can further include packaging the anhy simtraZene; sparfosate Sodium; sparsomycin; spirogerma drous or non-hygroscopic Solid formulation under low mois nium hydrochloride; spiromustine; spiroplatin; Streptonigrin: ture conditions. By using Such conditions, the risk of contact streptozocin, Sulofenur; talisomycin, tecogalan Sodium; with water is reduced and the degradation of the active ingre taxotere; tegafur, teloxantrone hydrochloride; temoporfin; dient can be prevented or substantially reduced. teniposide; teroxirone; testolactone; thiamiprine; thiogua I0089 4.1.1. Second Active Agents nine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; 0090. In certain embodiments, provided herein are com trestolone acetate; triciribine phosphate; trimetrexate; trime positions and dosage forms of Compound A, or a pharmaceu trexate glucuronate; triptorelin; tubulozole hydrochloride; tically acceptable prodrug, salt, Solvate, or clathrate thereof, uracil mustard; uredepa; vapreotide; verteporfin, vinblastine which may further comprise one or more secondary active sulfate; Vincristine sulfate; Vindesine; vindesine sulfate; Vine ingredients. Certain combinations may work synergistically pidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; in the treatment of particular types of diseases or disorders, vinorelbine tartrate; Vinrosidine sulfate; Vinzolidine sulfate; and conditions and symptoms associated with Such diseases Vorozole; Zeniplatin: Zinostatin; and Zorubicin hydrochloride. or disorders. Compound A, or a pharmaceutically acceptable 0093. Other second agents include, but are not limited to: prodrug, salt, Solvate, or clathrate thereof, can also work to 20-epi-1.25 dihydroxyvitamin D3; 5-ethynyluracil; abirater alleviate adverse effects associated with certain second active one; aclarubicin; acylfulvene; adecypenol; adoZelesin; agents, and vice versa. aldesleukin; ALL-TK antagonists; altretamine; ambamus 0091 Specific second active compounds that can be con tine; amidox; amifostine; aminolevulinic acid; amrubicin; tained in the formulations and dosage forms provided herein amsacrine; anagrelide; anastrozole; andrographolide; angio vary depending on the specific indication to be treated, pre genesis inhibitors; antagonist D; antagonist G, antarelix; anti vented or managed. dorsalizing morphogenetic protein-1, antiandrogen, prostatic 0092. For instance, for the treatment, prevention or man carcinoma; antiestrogen; antineoplaston; antisense oligo agement of cancer, second active agents include, but are not nucleotides; aphidicolin glycinate; apoptosis gene modula limited to: Semaxanib; cyclosporin; etanercept, doxycycline; tors; apoptosis regulators; apurinic acid; ara-CDP-DL bortezomib; acivicin; aclarubicin; acodazole hydrochloride; PTBA, arginine deaminase; asulacrine; atamestane; acronine; adoZelesin; aldesleukin; altretamine; ambomycin; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; aza ametantrone acetate; amsacrine; anastrozole; anthramycin; setron; azatoxin; azatyrosine; baccatin III derivatives; bal asparaginase; asperlin; azacitidine; azetepa; azotomycin; anol; batimastat; BCR/ABL antagonists; benzochlorins; ben batimastat; benzodepa; bicalutamide; bisantrene hydrochlo Zoylstaurosporine; beta lactam derivatives; beta-alethine; ride; bisnafide dimesylate: bizelesin; bleomycin sulfate; bre betaclamycin B; betulinic acid; bFGF inhibitor; bicaluta US 2013/0164376 A1 Jun. 27, 2013 mide; bisantrene; bisaziridinylspermine; bisnafide; bistratene ytriol; panomifene; parabactin; paZelliptine; pegaspargase; A: bizelesin; breflate; bropirimine; budotitane; buthionine peldesine; pentosan polysulfate sodium; pentostatin: pentro Sulfoximine; calcipotriol; calphostin C; camptothecin deriva Zole; perflubron; perfosfamide; perillyl alcohol; phenazino tives; capecitabine; carboxamide-amino-triazole; carboxya mycin; phenylacetate; phosphatase inhibitors; picibanil; pilo midotriazole; CaRest M3; CARN 700; cartilage derived carpine hydrochloride; pirarubic in: piritrexim; placetin A; inhibitor; carzelesin: casein kinase inhibitors (ICOS); placetin B; plasminogen activator inhibitor; platinum com castanospermine; cecropin B; cetrorelix; chlorins; chloroqui plex; platinum compounds; platinum-triamine complex; por noxaline Sulfonamide, cicaprost, cis-porphyrin, cladribine; fimer Sodium; porfiromycin; prednisone; propyl bis-acri clomifene analogues; clotrimazole; collismycin A; collismy done; prostaglandin J2, proteasome inhibitors; protein Abased immune modulator, protein kinase C inhibitor, pro cin B; combretastatin A4, combretastatin analogue; conage tein kinase C inhibitors, microalgal; protein tyrosine phos nin; crambescidin 816; crisinatol; cryptophycin 8: cryptophy phatase inhibitors; purine nucleoside phosphorylase inhibi cin A derivatives; curacin A; cyclopentanthraquinones; tors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin cycloplatam, cypemycin; cytarabine ocfosfate; cytolytic fac polyoxyethylene conjugate; raf antagonists; raltitrexed: tor; cytostatin: dacliximab; decitabine; dehydrodidemnin B; ramosetron; ras farnesyl protein transferase inhibitors; ras deslorelin; dexamethasone; dexifosfamide; dexraZOxane: inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhe deXVerapamil: diaziquone; didemnin B; didox; diethylnor nium Re 186 etidronate; rhizoxin: ribozymes: RII retinamide: spermine; dihydro-5-azacytidine; dihydrotaxol. 9-; dioxamy rohitukine; romurtide; roquinimex: rubiginone B1; ruboxyl, cin; diphenyl spiromustine; docetaxel, docosanol; dolas Safingol; Saintopin; SarCNU; sarcophytol A. SargramoStim; etron: doxifluridine: doxorubicin; droloxifene; dronabinol; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; duocarmycin SA; ebSelen; ecomustine, edelfosine; edrecolo sense oligonucleotides; signal transduction inhibitors; siZo mab; eflornithine; elemene; emitefur; epirubicin; epristeride; furan; Sobuzoxane; sodium borocaptate; sodium phenylac estramustine analogue; estrogen agonists; estrogen antago etate; solverol; somatomedin binding protein; Sonermin; nists; etanidazole; etoposide phosphate; exemestane; fadro sparfosic acid; spicamycin D; spiromustine; splenopentin; Zole; fazarabine; fenretinide; filgrastim; finasteride; fla spongistatin 1; squalamine; stipiamide; stromelysin inhibi Vopiridol; flezelastine; fluasterone; fludarabine; tors; Sulfinosine; Superactive vasoactive intestinal peptide fluorodaunorunicin hydrochloride; forfenimex; formestane: antagonist; Suradista; Suramin; Swainsonine; tallimustine; fostriecin, fotemustine; gadolinium texaphyrin; gallium tamoxifen methiodide; tauromustine; tazarotene; tecogalan nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcit Sodium, tegafur, tellurapyrylium; telomerase inhibitors; abine; glutathione inhibitors; hepsulfam; heregulin; hexam temoporfin, teniposide; tetrachlorodecaoxide; tetraZomine; ethylene bisacetamide; hypericin; ibandronic acid; idarubi thaliblastine; thiocoraline; thrombopoietin; thrombopoietin cin; idoxifene; idramantone; ilmofosine; illomastat; imatinib mimetic; thymalfasin; thymopoietin receptor agonist; thy (Gleevec.R.), imiquimod; immunostimulant peptides; insulin motrinan; thyroid stimulating hormone; tin ethyl etiopurpu like growth factor-1 receptor inhibitor; interferon agonists; rin; tirapazamine; titanocene bichloride; topsentin; interferons; interleukins; iobenguane; iododoxorubicin; toremifene; translation inhibitors; tretinoin; triacetyluridine: ipomeanol, 4-, iroplact; irsogladine; isobengaZole; isohomo triciribine; trimetrexate; triptorelin; tropisetron; turosteride; halicondrin B; itasetron; jasplakinolide; kahalalide F; lamel tyrosine kinase inhibitors; tyrphostins; UBC inhibitors: ube larin-N triacetate; lanreotide; leinamycin; lenograstim; len nimex: urogenital sinus-derived growth inhibitory factor; tinan Sulfate; leptolstatin; letrozole; leukemia inhibiting factor, leukocyte alpha interferon; leuprolide+estrogen urokinase receptor antagonists; vapreotide; variolin B; progesterone; leuprorelin; levamisole; liarozole; linear velaresol; veramine; verdins; verteporfin; vinorelbine; vinx polyamine analogue; lipophilic disaccharide peptide; lipo altine; vitaxin; Vorozole; Zanoterone; Zeniplatin: Zilascorb: philic platinum compounds; lissoclinamide 7: lobaplatin: and Zinostatin stimalamer. lombricine; lometrexol; lonidamine; losoxantrone; loxorib 0094. Yet other second active agents include, but are not ine; lurtotecan; lutetium texaphyrin; lysofylline; lytic pep limited to, 2-methoxyestradiol, telomestatin, inducers of apo tides; maitansine; mannostatin A; marimastat; masoprocol; ptosis in multiple myeloma cells (such as, for example, maspin; matrilysin inhibitors; matrix metalloproteinase TRAIL), statins, Semaxanib, cyclosporin, etanercept, doxy inhibitors; menogaril; merbarone; meterelin; methioninase; cycline, bortezomib, oblimersen (Genasense(R), remicade, metoclopramide; MIF inhibitor; mifepristone; miltefosine; docetaxel, celecoxib, melphalan, dexamethasone (Decad mirimoStim, mitoguaZone; mitolactol; mitomycin analogues; ronR), Steroids, gemcitabine, cisplatinum, temozolomide, mitonafide; mitotoxin fibroblast growth factor-saporin; etoposide, cyclophosphamide, temodar, carboplatin, procar mitoxantrone; mofarotene; molgramoStim; ErbituX, human bazine, gliadel, tamoxifen, topotecan, methotrexate, Arisa R, chorionic gonadotrophin, monophosphoryl lipid A+myobac taxol, taxotere, fluorouracil, leucovorin, irinotecan, Xeloda, terium cell wall sk; mopidamol, mustard anticancer agent; CPT-11, interferon alpha, pegylated interferon alpha (e.g., my caperoxide B; mycobacterial cell wall extract; myriapor PEG INTRON-A), capecitabine, cisplatin, thiotepa, fludara one; N-acetyldinaline; N-substituted benzamides; nafarelin; bine, carboplatin, liposomal daunorubicin, cytarabine, dox nagrestip; naloxone-pentazocine; napavin; naphterpin, nar etaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, tograstim; nedaplatin; memorubicin; neridronic acid; niluta Vinorelbine, Zoledronic acid, palmitronate, biaxin, buSul mide; nisamycin; nitric oxide modulators; nitroxide antioxi phan, prednisone, bisphosphonate, arsenic trioxide, Vincris dant; nitrullyn; oblimersen (Genasense(R): tine, doxorubicin (DOXil(R), paclitaxel, ganciclovir, adriamy O6-benzylguanine; octreotide; okicenone; oligonucleotides; cin, estramustine Sodium phosphate (EmcytR), Sulindac, and onapristone; ondansetron; ondansetron; oracin; oral cytokine etoposide. inducer, ormaplatin: osaterone; Oxaliplatin, oxaunomycin; 0095. In another embodiment, examples of specific sec paclitaxel; paclitaxel analogues; paclitaxel derivatives; ond agents according to the indications to be treated, pre palauamine; palmitoylrhizoxin; pamidronic acid; panax vented, or managed can be found in the following references, US 2013/0164376 A1 Jun. 27, 2013

all of which are incorporated herein in their entireties: U.S. 0098. Examples of second active agents that may be used Pat. Nos. 6,281.230 and 5,635,517: U.S. publication nos. for the treatment, prevention and/or management of skin dis 2004/0220144, 2004/0190609, 2004/0087546, 2005/ eases include, but are not limited to, keratolytics, retinoids, 0203142, 2004/0091455, 2005/0100529, 2005/0143344, C-hydroxy acids, antibiotics, collagen, botulinum toxin, 2005/0214328, 2005/0239842, 2006/0122228, 2006/ interferon, Steroids, and immunomodulatory agents. Specific O154880 and 2006/0188475. examples include, but are not limited to, 5-fluorouracil, maso 0096. Examples of second active agents that may be used procol, trichloroacetic acid, Salicylic acid, lactic acid, ammo for the treatment, prevention and/or management of pain nium lactate, urea, tretinoin, isotretinoin, antibiotics, col include, but are not limited to, conventional therapeutics used lagen, botulinum toxin, interferon, corticosteroid, to treat or prevent pain such as antidepressants, anticonvul transretinoic acid and collagens such as human placental sants, antihypertensives, anxiolytics, calcium channel block collagen, animal placental collagen, Dermalogen, Alloderm, ers, muscle relaxants, non-narcotic analgesics, opioid anal Fascia, Cymetra, Autologen, Zyderm, Zyplast, Resoplast, gesics, anti-inflammatories, coX-2 inhibitors, and Isolagen. immunomodulatory agents, alpha-adrenergic receptor ago 0099 Examples of second active agents that may be used nists or antagonists, immunosuppressive agents, corticoster for the treatment, prevention and/or management of pulmo oids, hyperbaric oxygen, ketamine, other anesthetic agents, nary hepertension and related disorders include, but are not NMDA antagonists, and other therapeutics found, for limited to, anticoagulants, diuretics, cardiac glycosides, cal example, in the Physician's Desk Reference 2003. Specific cium channel blockers, vasodilators, prostacyclin analogues, examples include, but are not limited to, salicylic acid acetate endothelin antagonists, phosphodiesterase inhibitors (e.g., (AspirinR), celecoxib (Celebrex(R), Enbrel(R), ketamine, PDE V inhibitors), endopeptidase inhibitors, lipid lowering gabapentin (NeurontinR), phenyloin (DilantinR), carbam agents, thromboxane inhibitors, and other therapeutics azepine (Tegretol R), oxcarbazepine (Trileptal(R), valproic known to reduce pulmonary artery pressure. Specific acid (DepakeneR), morphine Sulfate, hydromorphone, pred examples include, but are not limited to, warfarin (Couma nisone, griseofulvin, penthonium, alendronate, dyphenhy din R), a diuretic, a cardiac glycoside, digoxin-oxygen, dilt dramide, guanethidine, ketorolac (Acular R), thyrocalcitonin, iazem, nifedipine, a vasodilator Such as prostacyclin (e.g., dimethylsulfoxide (DMSO), clonidine (Catapress.(R), brety prostaglandin 12 (PG12), epoprostenol (EPO, Florae), tre lium, ketanserin, reserpine, droperidol, atropine, phentola prostinil (Remodulin(R), nitric oxide (NO), bosentan (Tra mine, bupivacaine, lidocaine, acetaminophen, nortriptyline cleer(R), amlodipine, epoprostenol (Florae), treprostinil (Re (Pamelor(R), amitriptyline (ElaviR), imipramine (Tofra modulin(R), prostacyclin, tadalafil (Clalis(R), simvastatin nil.R.), doxepin (Sinequan R), clomipramine (AnafranilR), (Zocor R), omapatrilat (Vanlev(R), irbesartan (AvaproR), fluoxetine (Prozac), sertraline (Zoloft(R), naproxen, nefaz pravastatin (PravacholR), digoxin, L-arginine, iloprost, odone (SerZone(R), Venlafaxine (Effexor(R), trazodone (De betaprost, and sildenafil (ViagraR). syrel(R), bupropion (WellbutrinR), mexiletine, nifedipine, 0100 Examples of second active agents that may be used propranolol, tramadol, lamotrigine, vioXX, Ziconotide, ket for the treatment, prevention and/or management of asbestos amine, dextromethorphan, benzodiazepines, baclofen, tizani related disorders include, but are not limited to, anthracy dine and phenoxybenzamine. cline, platinum, alkylating agent, oblimersen (Genasense(R). 0097 Examples of second active agents that may be used cisplatinum, cyclophosphamide, temodar, carboplatin, pro for the treatment, prevention and/or management of macular carbazine, gliadel, tamoxifen, topotecan, methotrexate, taxo degeneration and related syndromes include, but are not lim tere, irinotecan, capecitabine, cisplatin, thiotepa, fludarabine, ited to, a steroid, a light sensitizer, an integrin, an antioxidant, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol. an interferon, a Xanthine derivative, a growth hormone, a pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorel neutrotrophic factor, a regulator of neovascularization, an bine, Zoledronic acid, palmitronate, biaxin, buSulphan, pred anti-VEGF antibody, a prostaglandin, an antibiotic, a phy nisone, bisphosphonate, arsenic trioxide, Vincristine, doxo toestrogen, an anti-inflammatory compound or an antiangio rubicin (DOXil(R), paclitaxel, ganciclovir, adriamycin, genesis compound, or a combination thereof. Specific bleomycin, hyaluronidase, mitomycin C, mepacrine, examples include, but are not limited to, Verteporfin, purly tin, thiotepa, tetracycline and gemcitabine. an angiostatic steroid, rhuFab, interferon-2C. pentoxifylline, 0101 Examples of second active agents that may be used tin etiopurpurin, motexafin, lucentis, lutetium, 9-fluoro-11, for the treatment, prevention and/or management of parasitic 21-dihydroxy-16, 17-1-methylethylidinebis(oxy)pregna-1,4- diseases include, but are not limited to, chloroquine, quinine, diene-3,20-dione, latanoprost (see U.S. Pat. No. 6,225.348), quinidine, pyrimethamine, Sulfadiazine, doxycycline, clinda tetracycline and its derivatives, rifamycin and its derivatives, mycin, mefloquine, halofantrine, primaquine, hydroxychlo macrollides, metronidazole (U.S. Pat. Nos. 6,218,369 and roquine, proguanil, atovaquone, azithromycin, Suramin, pen 6,015,803), genistein, genistin, 6'-O-Mal genistin, 6'-O-Ac tamidine, melarsoprol, nifurtimox, benznidazole, genistin, daidzein, daidzin, 6'-O-Mal daidzin, 6'-O-Ac daid amphotericin B, pentavalent antimony compounds (e.g., Zin, glycitein, glycitin, 6'-O-Mal glycitin, biochanin A, for Sodium Stiboglucuronate), interfereon gamma, itraconazole, mononetin (U.S. Pat. No. 6,001,368), triamcinolone aceto a combination of dead promastigotes and BCG, leucovorin, mide, dexamethasone (U.S. Pat. No. 5,770.589), corticosteroids, Sulfonamide, spiramycin, IgG (serology), tri thalidomide, glutathione (U.S. Pat. No. 5,632.984), basic methoprim, and Sulfamethoxazole. fibroblast growth factor (bFGF), transforming growth factorb 0102) Examples of second active agents that may be used (TGF-b), brain-derived neurotrophic factor (BDNF), plasmi for the treatment, prevention and/or management of immu nogen activator factor type 2 (PAI-2), EYE 101 (Eyetech nodeficiency disorders include, but are not limited to: antibi Pharmaceuticals), LY333531 (Eli Lilly), Miravant, and otics (therapeutic or prophylactic) Such as, but not limited to, RETISERT implant (Bausch & Lomb). All of the references ampicillin, tetracycline, penicillin, cephalosporins, strepto cited herein are incorporated in their entireties by reference. mycin, kanamycin, and erythromycin; antivirals such as, but US 2013/0164376 A1 Jun. 27, 2013

not limited to, amantadine, rimantadine, acyclovir, and rib steroids (e.g., glucocorticoids, such as, but not limited to, avirin; immunoglobulin; plasma; immunologic enhancing methylprednisolone, dexamethasone and betamethasone); an drugs such as, but not limited to, levami Sole and isoprinosine; anti-inflammatory agent, including, but not limited to, biologics such as, but not limited to, gammaglobulin, transfer naproxen Sodium, diclofenac sodium, diclofenac potassium, factor, interleukins, and interferons; hormones such as, but celecoxib, Sulindac, oxaprozin, diflunisal, etodolac, meloxi not limited to, thymic, and other immunologic agents such as, cam, ibuprofen, ketoprofen, nabumetone, refecoxib, methotr but not limited to, B cell stimulators (e.g., BAFF/BlyS), exate, leflunomide, Sulfasalazine, gold salts, RHo-D Immune cytokines (e.g., IL-2, IL-4, and IL-5), growth factors (e.g., Globulin, mycophenylate mofetil, cyclosporine, azathio TGF-C.), antibodies (e.g., anti-CD 40 and IgM), oligonucle prine, tacrolimus, basiliximab, daclizumab, Salicylic acid, otides containing unmethylated CpG motifs, and vaccines acetylsalicylic acid, methyl salicylate, diflunisal, Salsalate, (e.g., viral and tumor peptide vaccines). olsalazine, SulfaSalazine, acetaminophen, indomethacin, 0103 Examples of second active agents that may be used Sulindac, mefenamic acid, meclofenamate Sodium, tolmetin, for the treatment, prevention and/or management of CNS ketorolac, dichlofenac, flurbinprofen, oxaprozin, piroxicam, disorders include, but are not limited to: opioids; a dopamine meloxicam, ampiroXicam, droxicam, pivoxicam, tenoxicam, agonist or antagonist, Such as, but not limited to, Levodopa, phenylbutaZone, oxyphenbutaZone, antipyrine, aminopyrine, L-DOPA, cocaine, C.-methyl-tyrosine, reserpine, tetrabena apaZone, Zileuton, aurothioglucose, gold Sodium thiomalate, Zine, benzotropine, pargyline, fenodolpam mesylate, caber auranofin, methotrexate, colchicine, allopurinol, probenecid, goline, pramipexole dihydrochloride, ropinorole, amantadine Sulfinpyrazone and benzbromarone; a cAMP analog includ hydrochloride, selegiline hydrochloride, carbidopa, per ing, but not limited to, db-cAMP; an agent comprising a golide mesylate. Sinemet CR, and Symmetrel; a MAO inhibi methylphenidate drug, which comprises 1-threo-meth tor, Such as, but not limited to, iproniazid, clorgyline, ylphenidate, d-threo-methylphenidate, dl-threo-meth phenelzine and isocarboxazid; a COMT inhibitor, such as, but ylphenidate, 1-erythro-methylphenidate, d-erythro-meth not limited to, tolcapone and entacapone; a cholinesterase ylphenidate, dl-erythro-methylphenidate, and a mixture inhibitor, Such as, but not limited to, physostigmine saliclate, thereof, and a diuretic agent such as, but not limited to, physostigmine Sulfate, physostigmine bromide, meostigmine mannitol, furosemide, glycerol, and urea. bromide, neostigmine methylsulfate, ambenonim chloride, 0105 Examples of second active agent that may be used edrophonium chloride, tacrine, pralidoxime chloride, obi for the treatment, prevention and/or management of dysfunc doXime chloride, trimedoxime bromide, diacetyl monoxim, tional sleep and related syndromes include, but are not limited endrophonium, pyridostigmine, and demecarium; an anti to, a tricyclic antidepressant agent, a selective serotonin inflammatory agent, Such as, but not limited to, naproxen reuptake inhibitor, an antiepileptic agent (gabapentin, pre Sodium, diclofenac sodium, diclofenac potassium, celecoxib, gabalin, carbamazepine, Oxcarbazepine, levitiracetam, topi Sulindac, oxaprozin, diflunisal, etodolac, meloxicam, ibupro ramate), an antiaryhthmic agent, a Sodium channel blocking fen, ketoprofen, nabumetone, refecoxib, methotrexate, agent, a selective inflammatory mediator inhibitor, an opioid leflunomide, SulfaSalazine, gold salts, Rho-D Immune agent, a second immunomodulatory compound, a combina Globulin, mycophenylate mofetil, cyclosporine, azathio tion agent, and other known or conventional agents used in prine, tacrolimus, basiliximab, daclizumab, Salicylic acid, sleep therapy. Specific examples include, but are not limited acetylsalicylic acid, methyl salicylate, diflunisal, Salsalate, to, Neurontin, oxycontin, morphine, topiramate, amitryp olsalazine, SulfaSalazine, acetaminophen, indomethacin, tiline, nortryptiline, carbamazepine, Levodopa, L-DOPA. Sulindac, mefenamic acid, meclofenamate Sodium, tolmetin, cocaine, C.-methyl-tyrosine, reserpine, tetrabenazine, ben ketorolac, dichlofenac, flurbinprofen, oxaprozin, piroxicam, Zotropine, pargyline, fenodolpam mesylate, cabergoline, meloxicam, ampiroxicam, droxicam, pivoxicam, tenoxicam, pramipexole dihydrochloride, ropinorole, amantadine hydro phenylbutaZone, oxyphenbutaZone, antipyrine, aminopyrine, chloride, selegiline hydrochloride, carbidopa, pergolide apaZone, Zileuton, aurothioglucose, gold sodium thiomalate, mesylate, Sinemet CR, Symmetrel, iproniazid, clorgyline, auranofin, methotrexate, colchicine, allopurinol, probenecid, phenelZine, isocarboxazid, tolcapone, entacapone, physos Sulfinpyrazone and benzbromarone or betamethasone and tigmine saliclate, physostigmine Sulfate, physostigmine bro other glucocorticoids; and an antiemetic agent, such as, but mide, meostigmine bromide, neostigmine methylsulfate, not limited to, metoclopromide, domperidone, prochlorpera ambenonim chloride, edrophonium chloride, tacrine, prali Zine, promethazine, chlorpromazine, trimethobenzamide, doxime chloride, obidoxime chloride, trimedoxime bromide, ondansetron, granisetron, hydroxy Zine, acetylleucine mono diacetyl monoxim, endrophonium, pyridostigmine, deme ethanolamine, alizapride, azasetron, benzquinamide, biet carium, naproxen Sodium, diclofenac sodium, diclofenac anautine, bromopride, buclizine, clebopride, cyclizine, potassium, celecoxib, Sulindac, oxaprozin, diflunisal, etod dimenhydrinate, diphenidol, dolasetron, meclizine, methal olac, meloxicam, ibuprofen, ketoprofen, nabumetone, refe latal, metopimazine, nabilone, oxyperndyl, pipamazine, Sco coxib, methotrexate, leflunomide, Sulfasalazine, gold salts, polamine, Sulpiride, tetrahydrocannabinol, thiethylperazine, RHo-D Immune Globulin, mycophenylate mofetil, cyclospo thioproperazine, tropisetron, and a mixture thereof. rine, azathioprine, tacrolimus, basiliximab, daclizumab, Sali 0104 Examples of second active agents that may be used cylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, for the treatment, prevention and/or management of CNS Salsalate, olsalazine, Sulfasalazine, acetaminophen, injuries and related syndromes include, but are not limited to, indomethacin, Sulindac, mefenamic acid, meclofenamate immunomodulatory agents, immunosuppressive agents, anti Sodium, tolmetin, ketorolac, dichlofenac, flurbinprofen, hypertensives, anticonvulsants, fibrinolytic agents, antiplate oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, let agents, antipsychotics, antidepressants, benzodiazepines, pivoxicam, tenoxicam, phenylbutaZone, oxyphenbutaZone, buspirone, amantadine, and other known or conventional antipyrine, aminopyrine, apaZone, Zileuton, aurothioglucose, agents used in patients with CNS injury/damage and related gold sodium thiomalate, auranofin, methotrexate, colchicine, syndromes. Specific examples include, but are not limited to: allopurinol, probenecid, Sulfinpyrazone, benzbromarone, US 2013/0164376 A1 Jun. 27, 2013 betamethasone and other glucocorticoids, metoclopromide, often milled into smaller particles for further processing. The domperidone, prochlorperazine, promethazine, chlorprom milling operation can produce significant amounts of air azine, trimethobenzamide, ondansetron, granisetron, hydrox borne particles, since the purpose for this step in manufactur yZine, acetylleucine monoethanolamine, aliZapride, aza ing is to reduce the materials particle size. The milled material setron, benzquinamide, bietanautine, bromopride, buclizine, is then blended with other ingredients prior to manufacturing clebopride, cyclizine, dimenhydrinate, diphenidol, dolas the final dosage form. etron, meclizine, methallatal, metopimazine, nabilone, 0111 For certain active ingredients, in particular for a oxyperndyl, pipamazine, Scopolamine, Sulpiride, tetrahydro compound with a low solubility, the active ingredient’s par cannabinol, thiethylperazine, thioproperazine, tropisetron, ticle size is reduced to a fine powder in order to help increase and a mixture thereof. the active ingredient’s rate of solubilization. The increase in 0106 Examples of second active agents that may be used the rate of solubilization is often necessary for the active for the treatment, prevention and/or management of hemo ingredient to be effectively absorbed in the gastrointestinal globinopathy and related disorders include, but are not lim tract. However for fine powders to be directly-blended and ited to: interleukins, such as IL-2 (including recombinant loaded onto capsules, the excipients should preferably pro IL-II (rIL2) and canarypox IL-2), IL-10, IL-12, and IL-18: vide certain characteristics which render the ingredients Suit interferons, such as interferon alfa-2a, interferon alfa-2b, able for the direct-blend process. Examples of such charac interferon alfa-n1, interferon alfa-n3, interferon beta-Ia, and teristics include, but are not limited to, acceptable flow interferon gamma-Ib; and G-CSF; hydroxyurea; butyrates or characteristics. In one embodiment, therefore, provided butyrate derivatives; nitrous oxide; hydroxy urea; herein is the use of, and compositions comprising, excipients HEMOXINTM (NIPRISANTM; see U.S. Pat. No. 5,800.819); which may provide characteristics, which render the resulting Gardos channel antagonists such as clotrimazole and triary1 mixture Suitable for direct-blend process, e.g., good flow methane derivatives; Deferoxamine; protein C; and transfu characteristics. In certain embodiments, a dry blend tablet sions of blood, or of a blood substitute such as HemospanTM formulation is the preferred way of making the tablets pro or HemospanTM PS (Sangart). vided herein. 4.2. Process for Making Dosage Forms O112 4.2.1. Screening 0113. The process for making the pharmaceutical compo 0107 Dosage forms provided herein can be prepared by sitions of the invention preferably includes the screening of any of the methods of pharmacy, but all methods include the the active ingredient and the excipient(s). In one embodiment, step of bringing the active ingredient into association with the the active ingredient is passed through a screen having open excipient, which constitutes one or more necessary ingredi ings of about 200 microns to about 750 microns. In another ents. In general, the compositions are prepared by uniformly embodiment, the active ingredient is passed through a screen admixing (e.g., direct blend) the active ingredient with liquid with openings of about 200 microns to about 400 microns. In excipients or finely divided solid excipients or both, and then, one embodiment, the active ingredient is passed through a if necessary, shaping the product into the desired presentation screen having openings of about 300 to about 400 microns. (e.g., compaction such as roller-compaction). If desired, tab Depending on the excipient(s) used, the screen openings vary. lets can be coated by Standard aqueous or non-aqueous tech For example, disintegrants and binders are passed through niques. openings of about 430 microns to about 750 microns, from 0108. A dosage form provided herein can be prepared by about 600 microns to about 720 microns, or about 710 compression or molding, optionally with one or more acces microns. Lubricants are typically passed through Smaller sory ingredients. Compressed tablets can be prepared by openings, e.g., about 150 microns to about 250 microns compressing in a Suitable machine the active ingredient in a screen. In one embodiment, the lubricant is passed through a free-flowing form Such as powder or granules, optionally screen opening of about 210 microns. mixed with an excipient as above and/or a Surface active or dispersing agent. Molded tablets can be made by molding in 0114. 4.2.2. Pre-Blending a suitable machine a mixture of the powdered compound 0.115. After the ingredients are screened, the excipient and moistened with an inert liquid diluent. Encapsulation of the active ingredient are mixed in a diffusion mixer. In one dosage forms provided herein can be done using capsules of embodiment, the mixing time is from about 1 minute to about methylcellulose, calcium alginate, or gelatin. 50 minutes, from about 5 minutes to about 45 minutes, from 0109. In some embodiments, the active ingredients and about 10 minutes to about 40 minutes, or from about 10 excipients are directly blended and loaded into, for example, minutes to about 25 minutes. In another embodiment, the a capsule, or compressed directly into tablets. A direct mixing time is about 15 minutes. blended dosage form may be more advantageous than a com 0116. When more than one excipient is used, the excipi pacted (e.g., roller-compacted) dosage form in certain ents may be admixed in a tumble blender for about 1 minute instances, since direct-blending can reduce or eliminate the to about 20 minutes, or for about 5 minutes to about 10 harmful health effects that may be caused by airborne par minutes, prior to mixing with the active ingredient. ticles of ingredients during the manufacture using compac 0117 4.2.3. Roller Compaction tion process. 0118. In one embodiment, the pre-blend may optionally 0110 Direct blend formulations may be advantageous in certain instances because they require only one blending step, be passed through a roller compactor with a hammer mill that of the active and excipients, before being processed into attached at the discharge of the compactor. the final dosage form, e.g., tablet or capsule. This can reduce 0119 4.2.4. Final Blend the production of airborne particle or dust to a minimum, I0120 When a lubricant, e.g., sodium stearyl fumarate and while roller-compaction processes may be prone to produce magnesium Stearate, is used, the lubricant is mixed with the dust. In roller-compaction process, the compacted material is pre-blend at the end of the process to complete the pharma US 2013/0164376 A1 Jun. 27, 2013

ceutical composition. This additional mixing is from about 1 0.130. In another embodiment, the disease is arthritis. In minute to about 10 minutes, or from about 3 minutes to about another embodiment, arthritis is psoriatic arthritis, rheuma 5 minutes. toid arthritis, osteoarthritis or acute gouty arthritis. 0121 4.2.5. Tableting 0.131. In another embodiment, the disease is a skin disease. 0122) The formulation mixture can be tableted (e.g., via In another embodiment, skin disease is acne, dermatitis or compaction, compression, or molding) into the desired size dermatomyositis. In another embodiment, dermatitis is and shape tablet using, for example, a tablet press or other atopic dermatitis or contact dermatitis. conventional tableting equipment and standard techniques. (0132. In another embodiment, the disease is ulcerative 0123 4.2.6. Encapsulation colitis. 0.124. The formulation mixture can also be optionally 0133. In another embodiment, the disease is Behcet’s dis encapsulated into the desired size capsule shell using, for CaSC. example, a capsule filling machine or a rotary tablet press. 0.134. In another embodiment, the disease is Crohn's dis CaSC. 4.3. Kits 0.135. In another embodiment, the disease is sarcoidosis. In another embodiment, sarcoidosis is chronic cutaneous sar 0.125 Pharmaceutical packs or kits which comprise phar coidosis. maceutical compositions or dosage forms provided herein are 0.136. In another embodiment, the disease is uveitis. also provided. An example of a kit comprises notice in the 0.137 In another embodiment, the disease is rosacea. form prescribed by a governmental agency regulating the 0.138. In another embodiment, the disease is Lichen Pla manufacture, use or sale of pharmaceuticals or biological US products, which notice reflects approval by the agency of 0.139. In other embodiments, provided herein are methods manufacture, use or sale for human administration. of treating, preventing and/or managing various other dis eases or disorders using the compositions and formulations 4.4. Methods of Treatment, Prevention, and procided herein. Examples of other diseases or disorders are Management provided in the following. Examples of cancer and precan cerous conditions include, but are not limited to, those 0126 Provided herein are methods of treating, preventing, described in U.S. Pat. Nos. 6,281.230 and 5,635,517 to and/or managing certain diseases or disorders using the for Muller et al., in various U.S. patent publications to Zeldis, mulations, compositions, or dosage forms provided herein. including publication nos. 2004/022014.4A1, published Nov. 0127 Examples of diseases or disorders include, but are 4, 2004 (Treatment of Myelodysplastic Syndrome); 2004/ not limited to, those disorders related to PDE4, TNFC. cAMP 0029832A1, published Feb. 12, 2004 (Treatment of Various and/orangiogenesis and include diseases or disorders such as Types of Cancer); and 2004/0087546, published May 6, 2004 various inflammatory diseases, pulmonary diseases, autoim (Treatment of Myeloproliferative Diseases). Examples also mune diseases and immunological diseases. Specific include those described in WO 2004/103274, published Dec. examples include, but are not limited to, inflammation and 2, 2004. All of these references are incorporated herein in various forms thereof, cancer, disorders associated with their entireties by reference. angiogenesis, pain including, but not limited to, Complex 0140 Certain examples of cancer include, but are not lim Regional Pain Syndrome (“CRPS), Macular Degeneration ited to, cancers of the skin, such as melanoma: lymph node: (“MD) and related syndromes, skin diseases, pulmonary breast; cervix; uterus; gastrointestinal tract, lung; ovary; pros disorders, asbestos-related disorders, parasitic diseases, tate; colon; rectum; mouth; brain; head and neck; throat; immunodeficiency disorders, CNS disorders, CNS injury, testes; kidney; pancreas; bone; spleen; liver, bladder; larynx; atherosclerosis and related disorders, dysfunctional sleep and nasal passages; and AIDS-related cancers. The compounds related disorders, hemoglobinopathy and related disorders are also useful for treating cancers of the blood and bone (e.g., anemia), tuberculosis and related disorders, PDE4/ marrow, such as multiple myeloma and acute and chronic TNFC. related disorders, infectious diseases, and other vari leukemias, for example, lymphoblastic, myelogenous, lym ous diseases and disorders. phocytic, and myelocytic leukemias. The compounds pro 0128. In one embodiment, exemplary diseases or disor vided herein can be used for treating, preventing or managing ders include, but are not limited to, inflammatory, viral, either primary or metastatic tumors. genetic, allergic, skin, and autoimmune diseases. Specific 0.141. Other cancers include, but are not limited to, examples include, but are not limited to, arthritis, HIV, hepa advanced malignancy, amyloidosis, neuroblastoma, menin titis, acne, adult respiratory distress syndrome, bone resorp gioma, hemangiopericytoma, multiple brain metastase, glio tion diseases, chronic pulmonary inflammatory diseases, der blastoma multiforms, glioblastoma, brain stem glioma, poor matitis, dematomyositis, cystic fibrosis, Lichen Planus, septic prognosis malignant brain tumor, malignant glioma, recur shock, sepsis, endotoxic shock, hemodynamic shock, sepsis rent malignant glioma, anaplastic astrocytoma, anaplastic oli syndrome, postischemic reperfusion injury, meningitis, pso godendroglioma, neuroendocrine tumor, rectal adenocarci riasis, fibrotic disease, cachexia, graft versus host disease, noma, Dukes C & D colorectal cancer, unresectable graft rejection, auto-immune disease, rheumatoid spondyli colorectal carcinoma, metastatic hepatocellular carcinoma, tis, Behcet disease, dermatitis, Crohn's disease, ulcerative Kaposi's sarcoma, karotype acute myeloblastic leukemia, colitis, inflammatory-bowel disease, rosacea, multiple scle chronic lymphocytic leukemia (CLL), Hodgkin’s lymphoma, rosis, Systemic lupus erythrematosus, ENL in leprosy, sarcoi non-Hodgkin’s lymphoma, cutaneous T-Cell lymphoma, dosis, radiation damage, cancer, asthma, uveitis, or hyperoxic cutaneous B-Cell lymphoma, diffuse large B-Cell lym alveolar injury. phoma, low grade follicular lymphoma, metastatic melanoma 0129. In one embodiment, the disease is psoriasis. In (localized melanoma, including, but not limited to, ocular another embodiment, psoriasis is plaque psoriasis. melanoma), malignant mesothelioma, malignant pleural US 2013/0164376 A1 Jun. 27, 2013

effusion mesothelioma syndrome, peritoneal carcinoma, pap gitis, silica-induced fibrosis, asbestos-induced fibrosis, Vet illary serous carcinoma, gynecologic sarcoma, Soft tissue erinary disorder, malignancy-associated hypercalcemia, sarcoma, Scleroderma, cutaneous vasculitis, Langerhans cell stroke, circulatory shock, periodontitis, gingivitis, macro histiocytosis, leiomyosarcoma, fibrodysplasia ossificans pro cytic anemia, refractory anemia, and 5q-deletion syndrome. gressive, hormone refractory prostate cancer, resected high 0146 Examples of pain include, but are not limited to risk soft tissue sarcoma, unrescectable hepatocellular carci those described in U.S. patent publication no. 2005/0203142, noma, Waldenstrom's macroglobulinemia, Smoldering published Sep. 15, 2005, which is incorporated herein by myeloma, indolent myeloma, fallopian tube cancer, androgen reference. Specific types of pain include, but are not limited independent prostate cancer, androgen dependent stage 1 V to, nociceptive pain, neuropathic pain, mixed pain of nocice non-metastatic prostate cancer, hormone-insensitive prostate ptive and neuropathic pain, visceral pain, migraine, headache cancer, chemotherapy-insensitive prostate cancer, papillary and post-operative pain. thyroid carcinoma, follicular thyroid carcinoma, medullary 0147 Examples of nociceptive pain include, but are not thyroid carcinoma, and leiomyoma. In a specific embodi limited to, pain associated with chemical or thermal burns, ment, the cancer is metastatic. In another embodiment, the cuts of the skin, contusions of the skin, osteoarthritis, rheu cancer is refractory or resistance to chemotherapy or radia matoid arthritis, tendonitis, and myofascial pain. tion. 0148 Examples of neuropathic pain include, but are not 0142. In one embodiment, the diseases or disorders are limited to, CRPS type I, CRPS type II, reflex sympathetic various forms of leukemias Such as chronic lymphocytic leu dystrophy (RSD), reflex neurovascular dystrophy, reflex dys kemia, chronic myelocytic leukemia, acute lymphoblastic trophy, sympathetically maintained pain syndrome, causal leukemia, acute myelogenous leukemia and acute myeloblas gia, Sudeck atrophy of bone, algoneurodystrophy, shoulder tic leukemia, including leukemias that are relapsed, refrac hand syndrome, post-traumatic dystrophy, trigeminal neural tory or resistant, as disclosed in U.S. publication no. 2006/ gia, post herpetic neuralgia, cancer related pain, phantom 0030594, published Feb. 9, 2006, which is incorporated in its limb pain, fibromyalgia, chronic fatigue syndrome, spinal entirety by reference. cord injury pain, central post-stroke pain, radiculopathy, dia 0143. The term “leukemia' refers malignant neoplasms of betic neuropathy, post-stroke pain, luetic neuropathy, and the blood-forming tissues. The leukemia includes, but is not other painful neuropathic conditions such as those induced by limited to, chronic lymphocytic leukemia, chronic myelo drugs such as Vincristine and velcade. cytic leukemia, acute lymphoblastic leukemia, acute myelog 0149. As used herein, the terms “complex regional pain enous leukemia and acute myeloblastic leukemia. The leuke syndrome,” “CRPS and "CRPS and related syndromes” mia can be relapsed, refractory or resistant to conventional mean a chronic pain disorder characterized by one or more of therapy. The term “relapsed” refers to a situation where the following: pain, whether spontaneous or evoked, includ patients who have had a remission of leukemia after therapy ing allodynia (painful response to a stimulus that is not usu have a return of leukemia cells in the marrow and a decrease ally painful) and hyperalgesia (exaggerated response to a in normal blood cells. The term “refractory or resistant” refers stimulus that is usually only mildly painful); pain that is to a circumstance where patients, even after intensive treat disproportionate to the inciting event (e.g., years of severe ment, have residual leukemia cells in their marrow. pain after an ankle sprain); regional pain that is not limited to 0144. In another embodiment, the diseases or disorders a single peripheral nerve distribution; and autonomic dys are various types of lymphomas, including Non-Hodgkin’s regulation (e.g., edema, alteration in blood flow and hyper lymphoma (NHL). The term “lymphoma’ refers a heterog hidrosis) associated with trophic skin changes (hair and nail enous group of neoplasms arising in the reticuloendothelial growth abnormalities and cutaneous ulceration). and lymphatic systems. “NHL refers to malignant mono 0150. Examples of MD and related syndromes include, clonal proliferation of lymphoid cells in sites of the immune but are not limited to, those described in U.S. patent publica system, including lymph nodes, bone marrow, spleen, liver tion no. 2004/0091455, published May 13, 2004, which is and gastrointestinal tract. Examples of NHL include, but are incorporated herein by reference. Specific examples include, not limited to, mantle cell lymphoma (MCL), lymphocytic but are not limited to, atrophic (dry) MD, exudative (wet) lymphoma of intermediate differentiation, intermediate lym MD, age-related maculopathy (ARM), choroidal neovascu phocytic lymphoma (ILL), diffuse poorly differentiated lym larisation (CNVM), retinal pigment epithelium detachment phocytic lymphoma (PDL), centrocytic lymphoma, diffuse (PED), and atrophy of retinal pigment epithelium (RPE). small-cleaved cell lymphoma (DSCCL), follicular lym 0151 Examples of skin diseases include, but are not lim phoma, and any type of the mantle cell lymphomas that can be ited to, those described in U.S. publication no. 2005/ seen under the microscope (nodular, diffuse, blastic and 0214328A1, published Sep. 29, 2005, which is incorporated mentle Zone lymphoma). herein by reference. Specific examples include, but are not 0145 Examples of diseases and disorders associated with, limited to, keratoses and related symptoms, skin diseases or or characterized by, undesired angiogenesis include, but are disorders characterized with overgrowths of the epidermis, not limited to, inflammatory diseases, autoimmune diseases, acne, and wrinkles. viral diseases, genetic diseases, allergic diseases, bacterial 0152. As used herein, the term “keratosis” refers to any diseases, ocular neovascular diseases, choroidal neovascular lesion on the epidermis marked by the presence of circum diseases, retina neovascular diseases, and rubeosis (neovas scribed overgrowths of the horny layer, including but not cularization of the angle). Specific examples of the diseases limited to actinic keratosis, Seborrheic keratosis, keratoacan and disorders associated with, or characterized by, undesired thoma, keratosis follicularis (Darier disease), inverted folli angiogenesis include, but are not limited to, arthritis, cular keratosis, palmoplantar keratoderma (PPK, keratosis endometriosis, Crohn's disease, heart failure, advanced heart palmaris et plantaris), keratosis pilaris, and stucco keratosis. failure, renal impairment, endotoxemia, toxic shock Syn The term “actinic keratosis' also refers to senile keratosis, drome, osteoarthritis, retrovirus replication, wasting, menin keratosis senilis, Verruca senilis, plana senilis, Solar keratosis, US 2013/0164376 A1 Jun. 27, 2013

keratoderma or keratoma. The term “seborrheic keratosis 0156 Examples of parasitic diseases include, but are not also refers to seborrheic wart, senile wart, or basal cell pap limited to, those described in U.S. publication no. 2006/ illoma. Keratosis is characterized by one or more of the fol 0154880, published Jul. 13, 2006, which is incorporated lowing symptoms: rough appearing, scaly, erythematous pap herein by reference. Parasitic diseases include diseases and ules, plaques, spicules or nodules on exposed surfaces (e.g., disorders caused by human intracellular parasites such as, but face, hands, ears, neck, legs and thorax), excrescences of not limited to, Pfalcifarium, Povale, P. vivax, P. malariae, L. keratin referred to as cutaneous horns, hyperkeratosis, telang donovari, L. infantum, L. aethiopica, L. major; L. tropica, L. iectasias, elastosis, pigmented lentigines, acanthosis, parak mexicana, L. braziliensis, T. Gondii, B. microti, B. divergens, eratosis, dyskeratoses, papillomatosis, hyperpigmentation of B. coli, C. parvum, C. Cayetanensis, E. histolytica, L belli, S. the basal cells, cellular atypia, mitotic figures, abnormal cell mansonii, S. haematobium, Trypanosoma ssp., Toxoplasma cell adhesion, dense inflammatory infiltrates and Small preva ssp., and O. volvulus. Other diseases and disorders caused by lence of Squamous cell carcinomas. non-human intracellular parasites such as, but not limited to, Babesia bovis, Babesia Canis, Banesia Gibsoni, Besnoitia 0153. Examples of skin diseases or disorders character darlingi, Cytauxzoon fells, Eimeria ssp., Hammondia ssp., ized with overgrowths of the epidermis include, but are not and Theileria ssp., are also encompassed. Specific examples limited to, any conditions, diseases or disorders marked by include, but are not limited to, malaria, babesiosis, trypano the presence of overgrowths of the epidermis, including but Somiasis, leishmaniasis, toxoplasmosis, meningoencephali not limited to, infections associated with papilloma virus, tis, keratitis, amebiasis, giardiasis, cryptosporidiosis, isospo arsenical keratoses, sign of Leser-Trélat, warty dyskeratoma riasis, cyclosporiasis, microsporidiosis, ascariasis, (WD), trichostasis spinulosa (TS), erythrokeratodermia vari abilis (EKV), ichthyosis fetalis (harlequin ichthyosis), trichuriasis, ancylostomiasis, strongyloidiasis, toxocariasis, knuckle pads, cutaneous melanoacanthoma, porokeratosis, trichinosis, lymphatic filariasis, onchocerciasis, filariasis, psoriasis, squamous cell carcinoma, confluent and reticulated Schistosomiasis, and dermatitis caused by animal Schisto papillomatosis (CRP), acrochordons, cutaneous horn, SOS. cowden disease (multiple hamartoma syndrome), dermatosis 0157 Examples of immunodeficiency disorders include, papulosa nigra (DPN), epidermal nevus syndrome (ENS), but are not limited to, those described in U.S. publication no. ichthyosis Vulgaris, molluscum contagiosum, prurigo nodu 2006/0188475, published Aug. 24, 2006. Specific examples include, but not limited to, adenosine deaminase deficiency, laris, and acanthosis nigricans (AN). antibody deficiency with normal or elevated Igs, ataxia-ten 0154) Examples of pulmonary disorders include, but are langiectasia, bare lymphocyte syndrome, common variable not limited to, those described in U.S. publication no. 2005/ immunodeficiency, Ig deficiency with hyper-IgM, Ig heavy 0239842A1, published Oct. 27, 2005, which is incorporated chain deletions, IgA deficiency, immunodeficiency with thy herein by reference. Specific examples include pulmonary moma, reticular dysgenesis, Nezelof syndrome, selective IgG hypertension and related disorders. Examples of pulmonary Subclass deficiency, transient hypogammaglobulinemia of hypertension and related disorders include, but are not limited infancy, Wistcott-Aldrich syndrome, X-linked agamma to: primary pulmonary hypertension (PPH); secondary pull globulinemia, X-linked severe combined immunodeficiency. monary hypertension (SPH); familial PPH; sporadic PPH: 0158 Examples of CNS disorders include, but are not precapillary pulmonary hypertension; pulmonary arterial limited to, those described in U.S. publication no. 2005/ hypertension (PAH); pulmonary artery hypertension; idio 0143344, published Jun. 30, 2005, which is incorporated pathic pulmonary hypertension; thrombotic pulmonary arte herein by reference. Specific examples include, but are not riopathy (TPA); plexogenic pulmonary arteriopathy; func limited to, include, but are not limited to, Amyotrophic Lat tional classes I to IV pulmonary hypertension; and pulmonary eral Sclerosis, Alzheimer Disease, Parkinson Disease, Hun hypertension associated with, related to, or secondary to, left tington's Disease, Multiple Sclerosis other neuroimmuno Ventricular dysfunction, mitral valvular disease, constrictive logical disorders such as Tourette Syndrome, delerium, or pericarditis, aortic Stenosis, cardiomyopathy, mediastinal disturbances in consciousness that occur over a short period fibrosis, anomalous pulmonary venous drainage, pulmonary of time, and amnestic disorder, or discreet memory impair Venoocclusive disease, collagen Vasular disease, congenital ments that occur in the absence of other central nervous heart disease, HIV virus infection, drugs and toxins such as system impairments. fenfluramines, congenital heart disease, pulmonary venous hypertension, chronic obstructive pulmonary disease, inter 0159. Examples of CNS injuries and related syndromes Stitial lung disease, sleep-disordered breathing, alveolar include, but are not limited to, those described in U.S. publi hypoVentilation disorder, chronic exposure to high altitude, cation no. 2006/0122228, published Jun. 8, 2006, which is neonatal lung disease, alveolar-capillary dysplasia, sickle cell incorporated herein by reference. Specific examples include, disease, other coagulation disorder, chronic thromboemboli, but are not limited to, CNS injury/damage and related syn connective tissue disease, lupus including systemic and cuta dromes, include, but are not limited to, primary brain injury, neous lupus, Schistosomiasis, sarcoidosis or pulmonary cap secondary brain injury, traumatic brain injury, focal brain illary hemangiomatosis. injury, diffuse axonal injury, head injury, concussion, post concussion syndrome, cerebral contusion and laceration, Sub 0155 Examples of asbestos-related disorders include, but dural hematoma, epidermal hematoma, post-traumatic epi not limited to, those described in U.S. publication no. 2005/ lepsy, chronic vegetative state, complete SCI, incomplete 0100529, published May 12, 2005, which is incorporated SCI, acute SCI, subacute SCI, chronic SCI, central cord syn herein by reference. Specific examples include, but are not drome, Brown-Sequard syndrome, anterior cord syndrome, limited to, mesothelioma, asbestosis, malignant pleural effu conus medullaris Syndrome, cauda equina syndrome, neuro Sion, benign exudative effusion, pleural plaques, pleural cal genic shock, spinal shock, altered level of consciousness, cification, diffuse pleural thickening, rounded atelectasis, headache, nausea, emesis, memory loss, dizziness, diplopia, fibrotic masses, and lung cancer. blurred vision, emotional lability, sleep disturbances, irrita US 2013/0164376 A1 Jun. 27, 2013

bility, inability to concentrate, nervousness, behavioral limited to, Complex Regional Pain Syndrome, chronic low impairment, cognitive deficit, and seizure. back pain, musculoskeletal pain, arthritis, radiculopathy, pain 0160 Examples of atherosclerosis and related conditions associated with cancer, fibromyalgia, chronic fatigue Syn include, but are not limited to, those disclosed in U.S. publi drome, visceral pain, bladder pain, chronic pancreatitis, neu cation no. 2002/0054899, published May 9, 2002, which is ropathies (diabetic, post-herpetic, traumatic or inflamma incorporated herein by reference. Specific examples include, tory), and neurodegenerative disorders such as Parkinson's but are not limited to, all forms of conditions involving ath Disease, Alzheimer's Disease, amyotrophic lateral Sclerosis, erosclerosis, including restenosis after vascular intervention multiple Sclerosis, Huntington's Disease, bradykinesia; Such as angioplasty, Stenting, atherectomy and grafting. All muscle rigidity; parkinsonian tremor; parkinsonian gait; forms of vascular intervention are contemplated herein, motion freezing; depression; defective long-term memory, including diseases of the cardiovascular and renal system, Rubinstein-Taybi syndrome (RTS): dementia; postural insta Such as, but not limited to, renal angioplasty, percutaneous bility; hypokinetic disorders; synuclein disorders; multiple coronary intervention (PCI), percutaneous transluminal coro system atrophies; striatonigral degeneration; olivopontocer nary angioplasty (PTCA), carotid percutaneous transluminal ebellaratrophy; Shy-Drager syndrome; motor neuron disease angioplasty (PTA), coronary by-pass grafting, angioplasty with parkinsonian features; Lewy body dementia; Tau pathol with stent implantation, peripheral percutaneous translumi ogy disorders; progressive Supranuclear palsy, corticobasal nal intervention of the iliac, femoral or popliteal arteries, and degeneration; frontotemporal dementia; amyloid pathology Surgical intervention using impregnated artificial grafts. The disorders; mild cognitive impairment; Alzheimer disease following chart provides a listing of the major systemic arter with parkinsonism; Wilson disease; Hallervorden-Spatz dis ies that may be in need of treatment, all of which are contem ease; Chediak-Hagashi disease; SCA-3 spinocerebellar plated herein: ataxia; X-linked dystonia parkinsonism; prion disease; hyperkinetic disorders; chorea; ballismus; dystonia tremors; Amyotrophic Lateral Sclerosis (ALS); CNS trauma and myo clonus. Artery Body Areas Supplied 0162 Examples of hemoglobinopathy and related disor Axillary Shoulder and axilla ders include, but are not limited to, those described in U.S. Brachial Upper arm publication no. 2005/0143420A1, published Jun. 30, 2005, Brachiocephalic Head, neck, and arm which is incorporated herein by reference. Specific examples Celiac Divides into left gastric, splenic, and hepatic arteries Common carotid Neck include, but are not limited to, hemoglobinopathy, sickle cell Common iliac Divides into external and internal iliac arteries anemia, and any other disorders related to the differentiation Coronary Heart of CD34+ cells. Deep femoral Thigh Digital Fingers 0163 Examples of tuberculosis (TB) and related disorders Dorsalis pedis Foot include, but are not limited to, those described in PCT publi External carotid Neck and external head regions cation no. WO 2010/093588, published Feb. 9, 2010, which is External iliac Femoral artery incorporated herein by reference. Specific examples include, Femoral Thigh but are not limited to, pulmonary TB and extrapulmonary TB Gastric Stomach Hepatic Liver, gallbladder, pancreas, and duodenum (remote TB lesions) Such as, but not limited to, genitourinary inferior mesenteric Descending colon, rectum, and pelvic wall TB (e.g., kidney TB), tubeculous meningitis, military TB, internal carotid Neck and internal head regions tuberculous peritonitis, tuberculous pericarditis, tuberculous internal iliac Rectum, urinary bladder, external genitalia, buttocks lymphadentitis, TB of bones and joints, gastrointestinal TB, muscles, uterus and vagina Left gastric Esophagus and stomach and TB of the liver. In certain embodiments, provided herein Middle sacral Sacrum are methods of treating, preventing, and/or managing the Ovarian Ovaries symptoms associated with TB. Examples include, but are not Palmar arch Hand limited to, cough, dyspnea, hilar lymphadenopathy, segmen Peroneal Calf Popliteal Knee tal atelectasis, Swelling of the nodes, lobar atelectasis, pull Posterior tibial Calf monary caviation, fever, unremitting headache, nausea, Pulmonary Lungs drowsiness, stupor, coma, stiffneck, weakness, and malaise. Radial Forearm Renal Kidney 0164 Disorders related to TB often include other myco Splenic Stomach, pancreas, and spleen bacterial infections, symptom of which resemble those of TB. Subclavian Shoulder Examples of such disorders include, but are not limited to, Superior mesenteric Pancreas, Small intestine, ascending and transverse colon disorders caused by M. avium complex (MAC; M. avium and Testicular Testes M. intracellulare), M. kansasii, M. xenopy, M. marinum, M. Ulnar Forearm ulcerans, M. leprae, and M. fortuitum complex (M. fortuitum and M. chelonei). Examples of disorders caused by these mycobacteria include, but are not limited to, pulmonary dis (0161 Examples of dysfunctional sleep and related Syn eases, lymphadenitis, cutaneous diseases, wounds, and for dromes include, but are not limited to, those disclosed in U.S. eign body infections. In certain embodiments, treatment, pre publication no. 2005/0222209A1, published Oct. 6, 2005, vention and/or management of other granulomatous diseases which is incorporated herein by reference. Specific examples are also encompassed herein. Examples of Such diseases include, but are not limited to, Snoring, sleep apnea, insomnia, include, but are not limited to: infectious agents caused dis narcolepsy, restless leg syndrome, sleep terrors, sleep walk eases such as histoplasmosis, cryptococcus, Schitosomiasis, ing sleep eating, and dysfunctional sleep associated with and leishmaniasis; allergic reactions caused diseases Such as chronic neurological or inflammatory conditions. Chronic berylliosis; non-infectious agents caused diseases such as neurological or inflammatory conditions, include, but are not aspiration pneumonia and foreign body reaction; genetically US 2013/0164376 A1 Jun. 27, 2013

caused diseases such as chronic granulomatous disease; and Compound A assumes the potency of 100% w/w. The actual diseases of unknown causes such as sarcoidosis, Crohn's input weight was adjusted depending on the assigned purity disease and cat-scratch fever. and water content. Lactose was adjusted to maintain the batch (0165 Examples of TNFC. related disorders include, but weight. are not limited to, those described in WO98/03502 and WO 98/54170, both of which are incorporated herein in their 5.2. Coating Formulations entireties by reference. Specific examples include, but are not limited to: endotoxemia or toxic shock syndrome; cachexia; 0170 5.2.1. Coating Formulation 1 adult respiratory distress syndrome; bone resorption diseases such as arthritis; hypercalcemia; Graft versus Host Reaction; 0171 Three coating formulations, having pink, brown and cerebral malaria; inflammation; tumor growth; chronic pull beige color, respectively, were made using the ingredients monary inflammatory diseases; reperfusion injury; myocar listed in Table 2 below: dial infarction; stroke; circulatory shock; rheumatoid arthri tis; Crohn's disease; HIV infection and AIDS; other disorders TABLE 2 Such as rheumatoid arthritis, rheumatoid spondylitis, osteoar Ingredient (% w/w) Pink Brown Beige thritis, psoriatic arthritis and other arthritic conditions, septic shock, septis, endotoxic shock, graft versus host disease, Poly Vinyl Alcohol 40.0 40.O 40.0 Macrogol/PEG 3350 2O2 2O2 2O2 wasting, Crohn's disease, ulcerative colitis, multiple Sclero Talc 14.8 14.8 14.8 sis, systemic lupus erythromatosis, ENL in leprosy, HIV. Titanium Dioxide 24.6 12.13 22.99 AIDS, and opportunistic infections in AIDS; disorders such Red Iron Oxide 0.4 122 1.18 as septic shock, sepsis, endotoxic shock, hemodynamic shock Yellow Iron Oxide 11.65 O43 and sepsis syndrome, post ischemic reperfusion injury, Black Iron Oxide 0.4 malaria, mycobacterial infection, meningitis, psoriasis, con gestive heart failure, fibrotic disease, cachexia, graft rejec tion, oncogenic or cancerous conditions, asthma, autoim 0172 5.2.2. Coating Formulation 2 mune disease, radiation damages, and hyperoxic alveolar 0173 Three coating formulations, having pink, brown and injury; viral infections, such as those caused by the herpes beige color, respectively, were made using the ingredients viruses; viral conjunctivitis; or atopic dermatitis. listed in Table 3 below: (0166 In other embodiments, the use of formulations, compositions or dosage forms provided herein in various TABLE 3 immunological applications, in particular, as vaccine adju vants, particularly anticancer vaccine adjuvants, as disclosed Ingredient (% w/w) Pink Brown Beige in U.S. Publication No. 2007/0048327, published Mar. 1, Lactose 33.O 33.0 31.0 correct? 2007, which is incorporated herein in its entirety by refer Monohydrate Hypromellose 6 cP 31.0 31.0 31.0 ence, is also encompassed. These embodiments also relate to Macrogol/PEG 3350 S.O S.O S.O the uses of the compositions, formulations, or dosage forms Triacetin 4.0 4.0 4.0 provided herein in combination with vaccines to treat or pre Titanium Dioxide 26.5 12.47 26.0 correct? vent cancer or infectious diseases, and other various uses Such Red Iron Oxide O.S 2.1 1.7 Yellow Iron Oxide 12.43 O6 as reduction or desensitization of allergic reactions. Black Iron Oxide 0.7 5. EXAMPLES 0167 Embodiments provided herein may be more fully (0174 5.2.3. Coating Formulation 3 understood by reference to the following examples. These 0.175. Three coating formulations, having pink, brown and examples are meant to be illustrative of pharmaceutical com beige color, respectively, were made using the ingredients positions and dosage forms provided herein, but are not in any way limiting. listed in Table 4 below: TABLE 4 5.1. Core Formulation 0168 Table 1 illustrates a batch formulation and oral dos Ingredient (% w/w) Pink Brown Beige age formulation for a core portion containing Compound A. Polydextrose FCC 26.O 26.O 26.0 Hypromellose 15 cP 31.0 31.0 31.0 Talc 7.0 7.0 7.0 TABLE 1. Maltodextrin S.O S.O S.O Medium Chain 2.0 2.0 2.0 Trade Name Common Name Weight Percent Triglycerides Titanium Dioxide 28S 14.47 26.0 Compound A 10.00% Red Iron Oxide O.S 2.1 1.7 316, Fast-Flo (R) Lactose Monohydrate 60.00% Yellow Iron Oxide 12.43 O6 Avicel (R) PH-102 Microcrystalline Cellulose 26.25% Black Iron Oxide 0.7 Ac-Di-Sol (R) Croscarmellose Sodium 3.00% Magnesium stearate 0.75% 100.0% 0176 5.2.4. Coating Formulation 4 0177. Three coating formulations, having pink, brown and 0169. The core formulation was prepared according to the beige color, respectively, were made using the ingredients weight percentage provided above. In the table, the value of listed in Table 5 below: US 2013/0164376 A1 Jun. 27, 2013 18

TABLE 5 -continued Ingredient (% w/w) Pink Brown Beige Ingredient (% w/w) Pink Brown Beige Polydextrose FCC 26.0 26.O 26.0 Croscarmellose Sodium 3.00 3.00 3.00 Hypromellose 15 cP 31.0 31.0 31.0 (Ac-di-sol (R) Talc 7.0 7.0 7.0 Magnesium Stearate 0.75 0.75 0.75 Maltodextrin S.O S.O S.O Titanium Dioxide 3O.S 1647 28.0 Total 1OO 100 100 Red Iron Oxide O.S 2.1 1.7 Coating Yellow Iron Oxide 1243 O6 Black Iron Oxide 0.7 Poly Vinyl Alcohol 40.00 40.OO 40.OO Macrogol/PEG 3350 20.2O 20.2O 20.2O Talc 14.80 14.80 14.80 Titanium Dioxide 24.60 12.13 22.99 (0178 5.2.5. Coating Formulation 5 Red Iron Oxide O.40 122 1.18 0179 Three coating formulations, having pink, brown and Yellow Iron Oxide 11.65 O43 beige color, respectively, were made using the ingredients Black Iron Oxide O4O listed in Table 6 below: Total 1OO 100 100

TABLE 6 Ingredient (% w/w) Pink Brown Beige 5.4. Stability of Formulation Polydextrose FCC 26.0 26.O 26.0 Hypromellose 15 cP 31.0 31.0 31.0 0183 Tablets were coated with different color formula Talc 7.0 7.0 7.0 tions based on the poly vinyl alcohol. (See Section 5.3, Maltodextrin S.O S.O S.O above). Color coating was applied to achieve 4% weight gain Triacetin 4.0 4.0 4.0 of core formulations. For Some of the tablets, coating was Titanium Dioxide 26.5 12.47 24.0 continued with clear coating Suspension to achieve a target of Red Iron Oxide O.S 2.1 1.7 1% weight gain (i.e., a total of 5% weight gain). Tablets were Yellow Iron Oxide 1243 O6 placed in open dish stability chambers under accelerated tem Black Iron Oxide 0.7 perature and humidity conditions (40°C./75% RH) to assess color changes. 0180 5.2.6. Coating Formulation 6 0.184 There was no color fading observed for tablets after 24 hours, 48 hours and 72 hours. A slight dullness in the color 0181. Three coating formulations, having pink, brown and was observed for color and clear coated tablets after 72 hours. beige color, respectively, were made using the ingredients The results indicate that the formulation described in Section listed in Table 7 below: 5.3 above, with or without clear coating, have adequate sta bility, particularly with regard to color changes. TABLE 7 0185. While examples of certain particular embodiments are provided herein, it will be apparent to those skilled in the Ingredient (% w/w) Pink Brown Beige art that various changes and modifications may be made. Polydextrose FCC 13.0 13.0 13.0 Such modifications are also intended to fall within the scope Hypromellose 15 cP 44.0 44.0 44.0 of the appended claims. Talc 7.0 7.0 7.0 Maltodextrin S.O S.O S.O What is claimed is: Medium Chain 4.0 4.0 4.0 1. A pharmaceutical composition comprising compound Triglycerides A: Titanium Dioxide 26.5 12.47 24.0 Red Iron Oxide O.S 2.1 1.7 (A) Yellow Iron Oxide 1243 O6 O o Black Iron Oxide 0.7

O O 5.3. Tablet Formulation (Core--Coating) \— 0182. A complete tablet formulation, including core and N O coating, was prepared using the ingredients listed in Table 8 / below: , /\ N." O Ingredient (% w/w) Pink Brown Beige or a pharmaceutically acceptable salt thereof a filler; a Core disintegrant; and a lubricant. Compound A 1O.OO 1O.OO 1O.OO 2. The pharmaceutical composition of claim 1, wherein the Lactose Monohydrate 6O.OO 6O.OO 6O.OO (316, Fast-Flo (R) compound of formula (A) is presentatanamount of about 5% Microcrystalline Cellulose 26.25 26.25 26.25 to about 25 by weight of the total composition. (Avicel (R) PH-102) 3. The pharmaceutical composition of claim 1, wherein the filler is lactose. US 2013/0164376 A1 Jun. 27, 2013

4. The pharmaceutical composition of claim3, wherein the or a pharmaceutically acceptable salt thereof, at an lactose is present at an amount of about 20% to 85% by amount of about 10% by weight of the total core com weight of the total composition. position; 5. The pharmaceutical composition of claim3, wherein the composition further comprises cellulose as a filler. (ii) lactose at an amount of about 60% by weight of the total 6. The pharmaceutical composition of claim 5, wherein the core composition; cellulose is present at an amount of about 10% to about 50% by weight of the total composition. (iii) microcrystalline cellulose at an amount of about 7. The pharmaceutical composition of claim 1, wherein the 26.25% by weight of the total core composition; disintegrant is croScarmellose. (iv) croscarmellose at an amount of about 3% by weight of 8. The pharmaceutical composition of claim 7, wherein the the total core composition; and croScarmellose is present at an amount of about 2% to about 8% by weight of the total composition. (v) magnesium stearate at an amount of about 0.75% by 9. The pharmaceutical composition of claim 1, wherein the weight of the total core composition; and lubricant is magnesium Stearate. 10. The pharmaceutical composition of claim 9, wherein (B) a coating formulation, wherein the coating formulation the magnesium Stearate is present at an amount of about comprises: 0.25% to about 5% of the total composition. (i) polyvinyl alcohol at an amount of about 40% by 11. The pharmaceutical composition of claim 1, wherein weight of the total coating formulation; the composition is coated with a coating formulation. 12. The pharmaceutical composition of claim 1, wherein (ii) polyethylene glycol at an amount of about 20% by the coating formulation comprises one or more excipients, weight of the total coating formulation; wherein the excipient is a coating agent, a binder, a lubricant, a stabilizing agent, a plasticizer, an adhesive, a glidant, a (iii) talcatanamount of about 15% by weight of the total diluent, or a combination thereof. coating formulation; and 13. The pharmaceutical composition of claim 12, wherein (iv) a mixture of coloring agents at an amount of about the excipient is polyvinyl alcohol. 25% by weight of the total coating formulation. 14. The pharmaceutical composition of claim 13, wherein the polyvinyl alcohol is presentatan amount of about 35% to 22. A method of treating, preventing or managing a disease about 45% by weight of the total coating formulation. or disorder comprising administering to a patient the pharma 15. The pharmaceutical composition of claim 12, wherein ceutical composition of claim 1, wherein the disease or dis the excipient is polyethylene glycol. order is psoriasis, arthritis, dermatitis, acne, dermatomyosi 16. The pharmaceutical composition of claim 15, wherein tis, ulcerative colitis, Behcet’s disease, Crohn's disease, the polyethylene glycol is present at an amount of about 20% sarcoidosis, uveitis, rosacea or lichen planus. to about 25% by weight of the total coating formulation. 17. The pharmaceutical composition of claim 12, wherein 23. The method of claim 22, wherein the psoriasis is the excipient is talc. plaque-type psoriasis. 18. The pharmaceutical composition of claim 17, wherein 24. The method of claim 22, wherein the arthritis is psori the talc is presentatan amount of about 10% to about 15% by atic arthritis, rheumatoid arthritis, osteoarthritis or acute weight of the total coating formulation. gouty arthritis. 19. The pharmaceutical composition of claim 12, wherein the excipients are one or more coloring agents. 25. The method of claim 22, wherein the dermatitis is 20. The pharmaceutical composition of claim 19, wherein atopic dermatitis or contact dermatitis. the coloring agents are present at an amount of about 25% to about 30% by weight of the total coating formulation. 26. The method of claim 22, wherein the sarcoidosis is 21. A tablet comprising: chronic cutaneous sarcoidosis. (A) a core composition, wherein the core composition 27. A method of treating, preventing or managing a disease comprises: or disorder comprising administering to a patient the pharma ceutical composition of claim 21, wherein the disease or (i) compound A disorder is psoriasis, arthritis, dermatitis, acne, dermatomyo sitis, ulcerative colitis, Behcet’s disease, Crohn's disease, (A) O o sarcoidosis, uveitis, rosacea or lichen planus. 28. The method of claim 27, wherein the psoriasis is plaque-type psoriasis. O O \— 29. The method of claim 27, wherein the arthritis is psori atic arthritis, rheumatoid arthritis, osteoarthritis or acute N O gouty arthritis. / 30. The method of claim 27, wherein the dermatitis is , /\ atopic dermatitis or contact dermatitis. 31. The method of claim 27, wherein the sarcoidosis is chronic cutaneous sarcoidosis.

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