WO2013119607A2 - Modified release formulations of (+)-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-4-acetyl aminoisoindoline-1,3-dione - Google Patents

Abstract

Provided herein are modified release formulations and dosage forms of (+)-2-[1- (3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-4-acetylaminoisoindoline-1,3- dione; and methods of their use for treating, managing, or preventing a condition or disease.

Description

MODIFIED RELEASE FORMULATIONS OF (+)-2-[l-(3-ETHOXY-4-METHOXY- PHE YL)-2-METHANESULFO YL-ETHYL]-4-

ACETYLAMINOISOINDOLINE~l,3-DIONE

1. CROSS REFERENCE TO RELATED APPLICATION(S)

[0001] This application claims the benefit of the priority of U.S. Provisional

Application No. 61/596,656, filed February 8, 2012; the disclosure of which is

incorporated herein by reference in its entirety.

2. FIELD

[0002] Provided herein are modified release formulations and dosage forms of (+)-

2-[l.~(3-ethoxy-4-met^'hoxy-phenyl.)-2-^

1 ,3-dione; and methods of their use for treating, managing, or preventing a condition or disease.

3. BACKGROUND

[0003] Drug substances are usually administered as part of a formulation in combination with one or more other agents that serve varied and specialized

pharmaceutical functions. Dosage forms of various types may be made through selective use of pharmaceutical excipients. As pharmaceutical excipients have various functions and contribute to the pharmaceutical formulations in many different ways, e.g., solubilization, modify release of active ingredient, dilution, thickening, stabilization, preservation, coloring, flavoring, etc. The properties that are commonly considered when formulating an active drug substance include bioavailability, pharmacokinetic profile, ease of manufacture, ease of administration, and stabi lity of the dosage form. Due to the varying properties of an active drug substance to be formulated, dosage forms typically require pharmaceutical excipients that are uniquely tailored to the active drug substance in order to achieve advantageous physical and pharmaceutical properties.

[0004] (+)-2-[ 1 -(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-4- acety aminoisoindoiine-1 ,3-dione ("Compound A") is a compound with anti-inflammatory activity in clinical development for the treatment of a variety of chronic inflammatory conditions. Pharmacologically, Compound A blocks the degradation of cyclic adenosine monophosphate (cAMP) via inhibition of a phosphodiesterase type IV (PDE4) enzyme, resulting in an increase in cAMP in PDE4-expressing ceils, including monocytes, T cells, and neutrophils. Enzyme assay data using purified PDE4 enzyme from U937 human monocytic cells indicate that Compound A has a PDE4 IC₅₀ of about 74 nM. Compound A and methods for its synthesis are described, e.g., in U.S. Patent No. 6,962,940, the disclosure of which is hereby incorporated by reference in its entirety.

[0005] Due to its diversified pharmacological properties, Compound A is useful in treating, preventing, and/or managing various diseases or disorders. Thus, a need exists as to dosage forms of Compound A having advantageous physical and pharmaceutical properties.

4. SUMMARY

[0006] Provided herein is a modified release formulation, comprising Compound

A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof; and a release modifying excipient.

[0007] Also provided herein is a modified release tablet formulation, comprising

Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof; and a release modifying excipient.

[0008] Further provided herein is a pharmaceutical formulation for once-a-day administration of Compound A, comprising Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof; and a release modifying excipient.

[0009] Provided herein is a tablet formulation for once-a-day administration of

Compound A, comprising Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof; and a release modifying excipient.

[0010] Provided herein is a pharmaceutical formulation comprising Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof; a release modifying excipient; a diluent; a lubricant, and a glidant.

Provided herein is a pharmaceutical formulation comprising from about 1% to about 20% by weight of Compound A, or a pharmaceutically acceptable prodrug, salt, sol vate, hydrate, or clathrate thereof; from about 15% to abou t 70% by weight of a release modifying excipient; from about 10% to about 70% by weight of a diluent; from about 0.2% to about 2% of a lubricant, and from about 0.2% to about 2% of a glidant.

[0Θ12] Provided herein is a pharmaceutical formulation comprising from about 1% to about 20% by weight of Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof; from about 15% to about 50% by weight of a release modifying excipient; from about 10% to about 70% by weight of a diluent; from about 0.2% to about 2%) of a lubricant, and from about 0.2% to about 2% of a glidant.

[0013] Provided herein is a pharmaceutical formulation comprising from about 5% to about 20% by weight of Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof; from about 20% to about 50% by weight of a release modifying excipient; from about 40% to about 70% by weight of a diluent; from about 0.5% to about 2% by weight of a lubricant, and from about 0.5% to about 2% by weight of a glidant.

[0014] Provided herein is a pharmaceutical formulation comprising about 10% by weight of Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof; from about 20%) to about 50%· by weight of a release modifying excipient; from about 40% to about 70% by weigh t of a diluent; about 1 % by weight of a lubricant, and about 1%> by weight of a glidant.

[0015] Provided herein are methods of treating, managing, or preventing a disease or disorder in a subject, comprising administering to the subject a modified release formulation provided herein, in one embodiment, the disease or disorder is cancer, pain, Macular Degeneration, a skin disease, a pulmonary disorder, an asbestos-related disorder, a parasitic disease, an immunodeficiency disorder, a CN8 disorder, C S injury, atherosclerosis, a sleep disorder, hemoglobinopathy, anemia, an inflammatory disease, an autoimmune disease, a viral disease, a genetic disease, an allergic disease, a bacterial disease, an ocular neovascular disease, a choroidal neovascular disease, a retina neovascular disease, or rubeosis. In another embodiment, the disease or disorder is psoriasis, arthritis, dermatitis, acne, dermatomyositis, sarcoidosis, uveitis, rosacea, Behcet's disease, ankylosing spondylitis, or Lichen Planus. In yet another embodiment, the disease or disorder is psoriatic arthritis, rheumatoid arthritis, osteoarthritis or acute gouty arthritis,

5. DETAILED DESCRIPTION

5.1 Brief Description of the Figures

[0Θ16] FIG. 1 depicts the dissolution profiles of Compound A in tablet

Formulation I with tablet hardness of 10 kP (♦), 1 5 kP (■), and 20kP ( A ).

[0017] FIG. 2 depicts the dissolution profile of Compound A in tablet Formulation

II with tablet hardness of 15 kP (■).

[0018] FIG. 3 depicts the dissolution profiles of Compound A in tablet

Formulation III with tablet hardness of 10 kP (♦), 15 kP (■), and 20kP (A).

[0019] FIG. 4 depicts the dissolution profiles of Compound A in tablet

Formulation IV with tablet hardness of 10 kP (♦), 15 kP (■), and 20kP (A).

[0020] FIG. 5 depicts the dissolution profiles of Compound A in tablet

Formulations V (♦), VI (■), and VII (A).

[0Θ21] FIG. 6 depicts the dissolution profiles of Compound A in tablet

Formulation III in dissolution media B (♦) and C(m).

[0022] FIG. 7 depicts the dissolution profiles of Compound A in Formulation VII in dissolution media B (■) and€(♦).

[0023] FIG. 8 depicts the dissolution profiles of Compound A in tablet

Formulations VIII (■), IX (A ), X (♦), XI (·), and XII (x).

[0024] FIG. 9 depicts the dissolution profi les of Compound A in tablet

Formulation VIII (caplet (■) v. round (A)).

[0025] FIG. 10 depicts the release q-q plot of Compound A in tablet Formulation

VIII (caplet v. round).

[0Θ26] FIG. 1 1 depicts the mean-difference chart of Compound A in tablet

Formulation VIII (caplet v. round). [0027] FIG. 12 depicts the dissolution profiles of 50 mg-strength tablets of

Compound A in Formulations XI II (■), XIV (A), and XV (♦).

[0028] FIG. 13 depicts the dissolution profiles of 60 mg-strength tablets of

Compound A in Formulations XIII (■), XIV (A), and XV (♦).

[0029] FIG. 14 depicts the dissolution profiles of 65 mg-strength tablets of

Compound A in Formulations XIII (■), XIV (A), and XV (♦).

[0Θ30] FIG. 15 depicts the dissolution profiles of 75 mg-strength tablets of

Compound A in Formulations XIII (■), XIV ( A), and XV (♦).

5,2 Definitions

[0031] As used herein, the term "Compound A" refers to enantiomerically pure

(+)-2-[l -(3-ethoxy-4-methoxy-phenyl)-2-methanesu[fonyl-ethyl]-4-acetylammo- isQindoline-1 ,3-dione. Without being limited by theory, Compound A is believed to have the structure:

[0032] As used herein and unless otherwise indicated, a composition that is

"substantially free" of a compound means that the composition contains, in one embodiment, less than about 20 percent by weight, in another embodiment, less than about 10 percent by weight, in yet another embodiment, less than about 5 percent by weight, and in sti ll another embodiment, less than about 3 percent by weight of the compound ,

[0033] As used herein and unless otherwise indicated, the terms "stereomerically pure" and "enantiomerically pure" mean a composition that comprises one stereoisomer of a compound and is substanti ally free of other stereoisomers of that compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other stereoisomers (a diastereomer and enantiomer) of the compound. In one embodiment, a stereomericaily pure compound comprises greater than about 80 percent by weight of one stereoisomer of the compound and less than about 20 percent by weight of other stereoisomers of the compound. In another embodiment, a stereomericaily pure compound comprises greater than about 90 percent by weight of one stereoisomer of the compound and less than about 10 percent by weight of other stereoisomers of the compound. In yet another embodiment, a stereomericaily pure compound comprises greater than about 95 percent by weight of one stereoi somer of the compound and l ess than about 5 percent by weight of other stereoisomers of the compound. In yet another embodiment, a stereomericaily pure compound comprises greater than about 97 percent by weight of one stereoisomer of the compound and less than about 3 percent by weight of other stereoisomers of the compound . In yet another embodiment, a stereomericaily pure compound comprises greater than about 98 percent by weight of one stereoisomer of the compound and less than about 2 percent by weight of other stereoisomers of the compound, in still another embodiment, a stereomericaily pure compound comprises greater than about 99 percent by weight of one stereoisomer of the compound and less than about 1 percent by weight of other stereoisomers of the compound.

[0034] As used herein and unless otherwise specified, the term "pharmaceutically acceptable salt(s)" includes, but is not limited to, salts of acidic or basic moieties of a compound provided herein. Basic moieties are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that are suitable for preparing pharmaceutically acceptable salts of a basic compound are those that form non-toxic acid salts, i.e., salts containing pharmacological!)' acceptable anions. Suitable organic acids include, but are not limited to, maleic, flmiaric, benzoic, ascorbic, succinic, acetic, formic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, oleic, tannic, aspartic, stearic, palmitic, glycoiic, glutamic, gluconic, giucaronic, saccharic, isonicotinic, methanesuifonic, ethanesulfonic, /?~toluenesulfonic, benzenesulfonic, and pamoic {i.e., 1,1 ' -methylene-bis-(2-hydroxy-3 -naphthoic) acids. Suitable inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, and nitric acids. A compound that includes an amine moiety can form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Chemical moieties that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts are alkali metal or alkaline earth metal salts, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.

[0035] As used herein and unless otherwise specified, the term "solvate" means a compound provided herein or a salt thereof, that further includes a stoichiometric or non- stoic hiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.

[0Θ36] As used herein and unless otherwise indicated, the term "prodrug" means a derivative of a compound that can hydro iyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide the compound. Examples of prodrugs include, but are not limited to, derivatives of thalidomide that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other examples of prodrugs include derivatives of thalidomide that include -NO, -NO2, -ONO, or -ONO2 moieties.

[0037] As used herein and unless otherwise indicated, the terms "biohydrolyzable carbamate," "biohydrolyzable carbonate," "biohydrolyzable ureide," "biohydrolyzable phosphate" mean a carbamate, carbonate, ureide, or phosphate, respectively, of a compound that either; 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, and/or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

[0038] As used herein and unless otherwise indicated, the term "biohydrolyzable ester" means an ester of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, and/or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters.

[0039] As used herein and unless otherwise indicated, the term "biohydroiyzable amide" means an amide of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, and/or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound.

Examples of biohydroiyzable amides include, but are not limited to, lower alkyl amides, a-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

[0040] As used herein, and unless otherwise specified, the terms "treat," "treating" and "treatment" contemplate an action that occurs while a patient is suffering from the specified disease or disorder, which reduces the severity of the disease or disorder, or retards or slows the progression of the disease or disorder.

[0041] As used herein, and unless otherwise specified, the terms "prevent,"

"preventing" and "prevention" refer to the prevention of the onset, recurrence or spread of a disease or disorder, or of one or more symptoms thereof. The terms "prevent,"

"preventing" and "prevention" contemplate an action that occurs before a patient begins to suffer from the specified disease or disorder, which inhibits or reduces the severity of the disease or disorder.

[0042] As used herein, and unless otherwise indicated, the terms "manage,"

"managing" and "management" encompass preventing the recurrence of the specified disease or disorder in a patient who has already suffered from the disease or disorder, and/or lengthening the time that a patient who has suffered from the disease or disorder remains in remission. The terms encompass modulating the threshold, development and/or duration of the disease or disorder, or changing the way that a patient responds to the disease or disorder,

[0043] As used herein, and unless otherwise specified, the term "about," when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, means dose, amount, or weight percent that is recognized by those of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent is encompassed. Specifically, the term "about" contemplates a dose, amount, or weight percent within 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.5%, or 0.25% of the specified dose, amount, or weight percent that is encompassed.

[0044] As used herein and unless otherwise specified, the term "stable," when used in connection with a formulation or a dosage form, means that the active ingredient of the formulation or dosage form does not significantly degrade or aggregate or become otherwise modified (e.g., as determined, for example, by physical methods such as visual inspection or analytical methods such as HPLC).

53 Formulations and Dosage Forms

[0045] In one embodiment, provided herein is a modified release formulation, comprising Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof; and a release modifying excipient. In certain embodiments, the modified release formulation is suitable for once-a-day administration of Compound A.

[0046] In another embodiment, provided herein is a modified release tablet formulation, comprising Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof; and a release modifying excipient. in certain embodiments, the modified release tablet formulation is suitable for once-a-day administration of Compound A.

[0047] In yet another embodiment, provided herein is a pharmaceutical formulation for once-a-day administration of Compound A, comprising Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof; and a release modifying excipient.

[0048] in still another embodiment, provided herein is a tablet formulation for once-a-day admimstration of Compound A, comprising Compound A, or a

pharmaceutically acceptable prodnig, salt, solvate, hydrate, or clathrate thereof; and a release modifying excipient.

[0Θ49] In certain embodiments, the pharmaceutical formulations provided herein contain from about 1 to about 70%, from about 5 to about 70%, from about 1 to about 50%, from about 2 to about 25%>, from about 2 to about 20%), from about 5 to about 30%, from about 5 to about 20%, or from about 5 to about 15% by weight of Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof. In certain embodiments, the pharmaceutical formulations provided herein contam from about 5 to about 70% by weight of Compound A, or a pharmaceutical ly acceptable prodrug, salt, solvate, hydrate, or clathrate thereof. In certain embodiments, the pharmaceutical formulations provided herein contain from about 5 to about 30% by weight of Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof. In certain embodiments, the pharmaceutical formulations provided herein contain from about 5 to about 15% by weight of Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof. In certain embodiments, the pharmaceutical formulations provided herein contain about 5%, about 10%, or about 15% by weight of Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof. In certain embodiments, the pharmaceutical formulations provided herein contain about 10% by weight of Compound A, or a pharmaceutical ly acceptable prodrug, salt, solvate, hydrate, or clathrate thereof.

[0Θ50] In certain embodiments, the pharmaceutical formulations provided herein contain from about 10 to about 70%, from about 10 to about 50%, from about 15 to about 50%, or from about 20 to about 50% by weight of the release modifying excipient. In certain embodiments, the pharmaceutical formulations provided herein contain from about 10 to about 70%) by weight of the release modifying excipient. In certain embodiments, the pharmaceutical formulations provided herein contain from about 10 to about 50% by weight of the rel ease modifying excipient. In certain embodiments, the pharmaceutical formulations provided herein contam from about 15 to about 50% by weight of the release modifying excipient. In certain embodiments, the pharmaceutical formulations provided herein contam from about 20 to about 50% by weight of the release modifying excipient. In certain embodiments, the pharmaceutical formulations provided herein contain from about 20 to about 50% by weight of the release modifying excipient. In certain embodiments, the pharmaceutical formulations provided herein contain about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50%> by weight of the release modifying excipient. In certain embodiments, the pharmaceutical formulations provided herein contain about 20, about 25, about 30, about 35, about 40, or about 45%> by weight of the release modifying excipient. [0051] In certain embodiments, the release modifying excipient is a gel-forming polymer, a hydratable polymer, a water swellable polymer, or mixtures thereof. In certain embodiments, the release modifying excipient is a gel-forming polymer. In certam embodiments, the release modifying excipient is a hydratable polymer. In certain embodiments, the release modifying excipient is a water swellable polymer.

[0052] In certain embodiments, the release modifying excipient comprises hydroxyalkylcellulose, aikyiceliulose, cellulose acetate, hydroxyaikyiceliulose acetate, cellulose ether, aikyiceliulose acetate, or a mixture thereof. In certam embodiments, the release modifying excipient comprises methylcellulose, ethylcellulose, hydroxypropyi cellulose, hydroxypropyi methylcellulose (hypromellose or HPMC), hydroxypropyi ethylcellulose, methoxypropyl methylcellulose, ethoxypropyi ethylcellulose, and a mixture thereof. In certain embodiments, the release modifying excipient comprises

methylcellulose. In certain embodiments, the release modifying excipient comprises ethylcellulose. In certain embodiments, the release modifying excipient comprises hydroxypropyi cellulose, in certain embodiments, the release modifying excipient comprises hydroxypropyi methylcellulose. In certain embodiments, the release modifying excipient comprises hydroxypropyi ethylcellulose. In certain embodiments, the release modifying excipient comprises methoxypropyl methylcellulose. In certam embodiments, the release modifying excipient comprises ethoxypropyi ethylcellulose.

[0053] In certain embodiments, the release modifying excipient comprises methylcellulose and hydroxypropyi methylcellulose. In certam embodiments, the release modifying excipient is a mixture of methylcellulose and hydroxypropyi methylcellulose.

[0Θ54] In certam embodiments, the release modifying excipient comprising methylcellulose and hydroxypropyi methylcellulose contains from about 19 to about 24% by weight of methoxyi. In certain embodiments, the release modifying excipient comprising methylcellulose and hydroxypropyi methylcellulose contains from about 22 to about 24% by weight of methoxyi. In certain embodiments, the release modifying excipient comprising methylcellulose and hydroxypropyi rnethylcellulose contains from about 6 to about 12% or from about 6.5 to about 12% by weight of hydroxvpropoxyl. In certam embodiments, the release modifying excipient comprising methylcellulose and hydroxypropyi methylcellulose contains from about 7 to about 12%.» by weight of hydroxvpropoxyl. In certain embodiments, the release modifying excipient comprising methylcellulose and hydroxypropyl methyl cellulose contains from about 7.5 to about 9.5% by weight of hydroxvpropoxyi. In certain embodiments, the release modifying excipient comprising methylcellulose and hydroxypropyl methylcellulose contains from about 19 to about 24% by weight of methoxyl and from about 7 to about 12% by weight of hydroxvpropoxyi. In certain embodiments, the release modifying excipient comprising methylcellulose and hydroxypropyl methylcellulose contains from about 22 to about 24% by weight of methoxyl and from about 7,5 to about 9.5%> by weight of hydroxvpropoxyi.

[0055] In certain embodiments, the release modifying excipient has apparent viscosity ranging from about 80 to about 120 cP when tested as a 2%> solution in water at 20 °C. In certain embodiments, the release modifying excipient comprising

methylcellulose and hydroxypropyl methylcellulose has apparent viscosity ranging from about 80 to about 120 cP (2% by weight in water at 20 °C).

[0056J In certain embodiments, the release modifying excipient is METHOCEL ^lM

E5LV, METHOCEL™ E15LV, M ETHOCEL™ E50LV, MET HOC EL® K100LVCR, or a mixture thereof. In certain embodiments, the release modifying excipient is

METHOCEL* Kl 00LVCR. In certain embodiments, the release modifying excipient is a mixture of METHOCEL™ E5LV and METHOCEL® K100LVCR. In certain

embodiments, the release modifying excipient is a mixture of METHOCEL ^{1 M} E15LV and METHOCEL^® 100LVCR. In certain embodiments, the release modifying excipient is a mixture of METHOCEL™ E50LV and METHOCEL® K100LVCR.

[0057] In certain embodiments, the pharmaceutical form.ulati.ons provided herein further comprise a diluent. Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose (e.g., lactose monohydrate, such as FAST FLO® 316, and lactose anhydrous), sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. In one embodiment, the diluent is lactose. In another embodiment, the diluent is lactose monohydrate. In yet another embodiment, the diluent is FAST FLO® 316.

[0058] In certain embodiments, the pharmaceutical formulations provided herein contain from about 5 to about 95%, from about 10 to about 90%, from about. 15 to about 80%>, from about 15 to about 70%>, from about 20 to about 70%, from about 30 to about 70%, from about 40 to about 70%, or from about 50 to about 70% by weight of the diluent(s). In certain embodiments, the pharmaceutical formulations provided herein contain from about 40 to about 70% by weight of the diluent(s). In certain embodiments, the pharmaceutical formulations provided herein contain about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% by weight of the dil ent(s). In certain embodiments, the pharmaceutical formulations provided herein contain about 19%, about 39%, about 43%, about 53%, about 58%, about 59%, about 63%, or about 68% by weight of the diluent(s). In certain embodiments, the plianiiaceuticai formulations provided herein contain about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% by weight of the diluent(s). In certain embodiments, the pharmaceutical formulations provided herein contain about 43%, about 53%, about 58%, about 59%, about 63%, or about 68% by weight of the diluent(s).

[0059] in certain embodiments, the pharmaceutical formulations provided herein further comprise a lubricant. Suitable lubricants include, but are not limited to, com starch, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, glycols (e.g. , glycerol behenate and polyethylene glycol (PEG)), stearic acid, sodium lauryi sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar; starch, lycopodium, silica, and silica gels. In one embodiment, the lubricant is magnesium stearate.

[0060] In certain embodiments, the pharmaceutical formulations provided herein contain from about 0, 1 to about 10%, from about 0,2 to about 5%, from about 0,5 to about 5%, from about 0.5 to about 4%, from about 0.5 to about 3%, or from about 0.5 to about 2% by weight of the lubricant(s). In certain embodiments, the plianiiaceuticai

formulations provided herein contain about 0.1%, about 0.2%, about 0.4%, about 0.6%. about 0.8%), about 1%, about 1 ,2%, about 1.4%, about 1.6%, about 1.8%, or about 2% by weigh t of the lubricant(s). In certain embodiments, the pharmaceutical formulations provided herein contain about 1%> by weight of the lubricant(s).

[0061] in certain embodiments, the pharmaceutical formulations provided herein further comprise a glidant. Suitable glidants include, but are not limited to, silica and talc (e.g., asbestos-free talc). In certain embodiments, the glidant is silica, in certain embodiments, the glidant is colloidal silicon dioxide. In certain embodiments, the glidant is CAB-O-SIL®.

[0062] In certain embodiments, the pharmaceutical formulations provided herein contain from about 0, 1 to about 10%, from about 0,2 to about 5%, from about 0,5 to about 5%, from about 0.5 to about 4%, from about 0.5 to about 3%, or from about 0.5 to about 2% by weight of the glidant(s). In certain embodiments, the pharmaceutical formulations provided herein contain about 0.1 %, about 0.2%, about 0.4%), about 0.6%, about 0.8%, about 1%, about 1.2%, about 1 ,4%, about 1.6%, about 1.8%, or about 2% by weight of the glidant(s). in certain embodiments, the pharmaceutical formulations provided herein contain about 1% by weight of the glidant(s),

[0063] in certain embodiments, the pharmaceutical formulations provided herein further comprise a coloring agent, which can be useful in distinguishing dosage forms containing different amounts of active ingredient. Suitable coloring agents include, but are not limited to, iron oxides (e.g., red, yellow and black), and titanium dioxide.

Appropriate coloring agents may be mixed to obtain a desired color of the coating formulation. In certain embodiments, two or more coloring agents can be used in coating the formulations. In certain embodiments, the coloring agents comprise titanium dioxide and red iron oxide. In certain embodiments, the coloring agents comprise titanium dioxide, red iron oxide, and yellow iron oxide. In certain embodiments, the coloring agents comprise titanium dioxide, red iron oxide, yellow iron oxide, and black iron oxide.

[0064] in certain embodiments, the pharmaceutical formulations provided herein comprise Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof; a release modifying excipient; a diluent; a lubricant, and a glidant.

[0065] In one embodiment, the pharmaceutical formulations provided herein comprise from about 1% to about 20% by weight of Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof; from about 20% to about 50% by weight of a release modifying excipient; from about 10% to about 70% by weight of a diluent; from about 0.2% to about 2% of a lubricant, and from about 0.2% to about 2% of a glidant.

[0066] In another embodiment, the pharmaceutical formulations provided herein comprise from about 5% to about 20% by weight of Compound A, or a pharmaceutically acceptable prodrag, salt, solvate, hydrate, or clathrate thereof; from about 20% to about 50% by weight of a release modifying excipient; from about 40% to about 70% by weight of a diluent; from about 0.5%) to about 2% by weight of a lubricant, and from about 0.5% to about 2% by weight of a glidant.

[0Θ67] In yet another embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof; from about 20% to about 50% by weight of a release modifying excipient; from about 40% to about 70% by weight of a diluent; about 1% by weight of a lubricant, and about 1% by weight of a glidant,

[0068] in yet another embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A, or a pharmaceutically acceptable prodrag, salt, solvate, hydrate, or clathrate thereof; about 20, about 25, about 30, about 35, about 40, or about 45% by weight of a release modifying excipient; about 43, about 53, about 58, about 63, or about 68% by we; gin of a diluent; about 1 % by weight of a lubricant, and about 1% by weight of a glidant.

[0069] In yet another embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A, or a pharmaceutically acceptable prodrag, salt, solvate, hydrate, or clathrate thereof; from about 20% to about 50% by weight of a gel-forming polymer; from about 40% to about 70% by weight of lactose; about 1% by wei ght of magnesium stearate, and about 1% by weight of silica.

[0070] in yet another embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof; about 20, about 25, about 30, about 35, about 40, or about 45% by weight of a gel-forming polymer; about 43, about 53, about 58, about 63, or about 68%> by weight of lactose; about 1% by weight of magnesium stearate, and about 1% by weight of silica.

[0071] In yet another embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A, or a pharmaceutically acceptable prodrag, salt, solvate, hydrate, or clathrate thereof; from about 20% to about 50% by weight of a gel-forming polymer comprising hydroxyal.kyl.cell.u3.ose; from about 40% to about 70% by weight of lactose; about 1% by weight of magnesium stearate, and about 1% by weight of silica,

[0072] In yet another embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof; about 20, about 25, about 30, about 35, about 40, or about 45% by weight of a gel-forming polymer comprising

hydroxvalkylcellulose; about 43, about 53, about 58, about 63, or about 68% by weight of lactose; about 1% by weight of magnesium stearate, and about 1 % by weight of silica.

[0073] In yet another embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof; from about 20% to about 50% by weight of a gel-forming polymer comprising hydroxypropyl methylcelluiose; from about 40% to about 70% by weight of lactose monoh.yd.rate; about 1 % by weight of magnesium stearate, and about 1% by weight of colloidal silicon dioxide.

[0074] In yet another embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof; about 20, about 25, about. 30, about 35, about 40, or about 45%) by weight of a gel-forming polymer comprising hydroxypropyl methylcelluiose; about 43, about 53, about 58, about 63, or about 68% by weight of lactose; about 1% by weight of magnesium stearate, and about 1% by weight of silica.

[0075] in yet another embodiment, the pharmaceutical formulations provided herein comprise about .10% by weight of Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof; from about 20% to about 50% by weight of a gel-forming polymer comprising hydroxypropyl methylcelluiose and methylcelluiose; from about 40% to about 70% by weight of lactose monohydrate; about 1% by weight of magnesium stearate, and about 1% by weight of colloidal silicon dioxide.

[0Θ76] In yet another embodiment, the pharmaceutical formulations provided herein comprise about .10% by weight of Compound A, or a pharmaceutically acceptable prodrag, salt, solvate, hydrate, or clathrate thereof; about 20, about 25, about 30, about 35, about 40, or about 45% by weight of a gel-forming polymer comprising hydroxypropyl methylcellulose and methylceilulose; about 43, about 53, about 58, about 63, or about 68% by weight of lactose; about 1% by weigh of magnesium stearate, and about 1 % by weight of silica.

[0077] in yet another embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof; from about 20% to about 50% by weight of METHOCEL™ K100LVCR; from about 40% to about 70% by weight of FAST FLO^® 316; about 1 % by weight of magnesium stearate, and about 1% by weigh t of CAB- O-SIL^®.

[0078] in still another embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A, or a pharmaceutically acceptable prodrag, salt, solvate, hydrate, or clathrate thereof; about 20, about 25, about 30, about 35, about 40, or about 45% by weight of METHOCEL™ K1G0LVCR; about 43, about 53, about 58, about 63, or about 68% by weight of FAST FLO^® 316; about 1 % by weight of magnesium stearate, and about 1% by weight of CAB-O-SIL*.

[0079] In one embodiment, the pharmaceuticai formulations provided herein comprise about 10% by weight of Compound A; about 20% by weight of a release modifying excipient; about 68% by weight of a diluent; about 1% by weight of a lubricant, and about 1% by weight of a glidant.

[0080] In another embodiment, the pharmaceutical formulations provided herein comprise about 10% by w^reight of Compound A; about 20%) by weight of a release modifying excipient comprising hydroxyalkvlcellulose; about 68% by weight of lactose; about 1% by w^reight of magnesium stearate, and about 1 % by weight of silica.

[0081] In yet another embodiment, the pharmaceuticai formulations provided herein comprise about 10% by weight of Compound A; about 20% by weight of a release modifying excipient comprising hydroxypropyl methylceilulose; about 68% by w^reight of lactose; about 1% by weight of magnesium stearate, and about 1% by weight of silica.

[0082] in yet another embodiment, the pharmaceutical formulations provided herein comprise abou t 10% by weight of Compound A; about 20% by weight of a release modifying excipient comprising hydroxypropyl methylceilulose and methylceilulose; about 68% by weight of lactose; about 1% by weight of magnesium stearate, and about 1% by weight of silica,

[0083] In still embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A; about 20%) by weight of METHOCEL^1M K100LVCR; about 68% by weight of FAST FLO^® 316; about 1% by weight of magnesium stearate, and about 1% by weight of CAB-O-Sl L*.

10084] In one embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A; about 25% by weight of a release modifying excipient; about 63% by weight of a diluent; about 1 % by weight of a lubricant, and about 1% by weight of a glidant.

[0085] in another embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A; about 25% by weight of a release modifying excipient comprising hydroxyaikyiceliulose; about 63% by weight of lactose; about 1% by weight of magnesium stearate, and about 1% by weight of silica.

[0Θ86] In yet another embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A; about 25%> by weight of a release modifying excipient comprising hydroxypropyl methylcellulose; about 63% by weight of lactose; about 1 % by weight of magnesium stearate, and about 1% by weigh t of silica.

[0087] In yet another embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A; about 25% by weight of a release modifying excipient comprising hydroxypropyl methylceilttlose and methylcellulose; about 63%) by weight of lactose; about 1% by weight of magnesium stearate, and about 1% by weight of silica.

[0088] In still embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A; about 25% by weight of MET OCEL^{i M} K100LVCR; about 63% by weight of FAST FLO^® 316; about 1%, by weight of magnesium stearate, and about 1 % by weight of CAB-O-SIL* .

[0089] In one embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A; about 30%) by weight of a release modifying excipient; about 58% by weight of a diluent; about 1% by weight of a lubricant, and about 1% by weight of a glidant.

[0090] In another embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A; about 30%) by weight of a release modifying excipient comprising hydroxyalkvlcellulose; about 58% by weight of lactose; about 1% by weight of magnesium stearate, and about 1 % by weight of silica.

[0091] In yet another embodiment, the pharmaceiiticai formulations provided herein comprise about 10% by weight of Compound A; about 30% by weight of a release modifying excipient comprising hydroxypropyl methylcellulose; about 58% by weight of lactose; about 1% by weight of magnesium stearate, and about 1% by weight of silica.

[0092] In yet another embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A; about 30% by weight of a release modifying excipient comprising hydroxypropyl methylcellulose and methylcellulose; about 58% by weight of lactose; about 1% by weight of magnesium stearate, and about 1% by weight of silica.

[0093] In still embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A; about 30% by weight of METHOCEL™ K100LVCR; about 58% by weight of F AST FLO^® 316; about 1% by weight of

magnesium stearate, and about 1% by weight of CAB-O-SIL*.

[0094] In one embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A; about 35% by weight of a release modifying excipient; about 53% by weight of a diluent; about 1% by weight of a lubricant, and about 1% by weight of a glidant.

[0Θ95] In another embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A; about 35% by weight of a release modifying excipient comprising hydroxyalkylcellulose; about 53% by weight of lactose; about 1 % by weight of magnesium stearate, and about 1% by weight of si lica.

[0096] In yet another embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A; about 35% by weight of a release modifying excipient comprising hydroxypropyl methylcellulose; about 53% by weight of lactose; about 1% by weight of magnesium stearate, and about 1 % by weight of silica.

[0097] In yet another embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A; about 35% by weight of a release modifying excipient comprising hydroxypropyl methylcellulose and methylcellulose; about 53%> by weight of lactose; about 1% by weight of magnesium stearate, and about 1%) by weight of silica,

[0Θ98] In still embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A; about 35% by weight of M ETHOCEL™ K100LVCR; about 53%» by weight of FAST FLO® 316; about 1% by weight of magnesium stearate, and about 1% by weight of CAB-O-SIL*.

[0099] In one embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A; about 45% by weight of a release modifying excipient; about 43% by weight of a diluent; about 1% by weight of a lubricant, and about 1% by weight of a glidant.

[00100] In another embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A; about 45% by weight of a release modifying excipient comprising hydroxyalkylcellulose; about 43% by weight of lactose; about 1% by weight of magnesium stearate, and about 1 % by weight of silica.

[00101] In yet another embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A; about 45% by weight of a release modifying excipient comprising hydroxypropyl methylcellulose; about 43% by weight of lactose; about 1% by weight of magnesium stearate, and about 1% by weight of silica.

[00102] In yet another embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A; about 45% by weight of a release modifying excipient comprising hydroxypropyl methylcellulose and methylcellulose; about 43% by weight of lactose; about 1 % by weight of magnesium stearate, and about 1% by weight of silica.

[00103] In still embodiment, the pharmaceutical formulations provided herein comprise about 10% by weight of Compound A; about 45% by weight of METHOCEL^IM Kl 001, VCR; about 43% by weight of FAST FLO^® 316; about 1% by weight of magnesium stearate, and about 1% by weight of CAB-O-SIL* .

[00104] in certain embodiments, the pharmaceutical formulations provided herein are formulated as tablets, , capsules, pills, s, pellets, beads, , or granules.

[00105] In certain embodiments, the pharmaceutical formulations provided herein are formulated as modified release beads.

[00106] In certain embodiments, the pharmaceutical formulations provided herein are formulated as tablets. In certain embodiments, the tablet is in caplet shape. In certain embodiments, the tablet is round.

[00107] In certain embodiments, the tablets provided herein each contain from about 5 to about 500 mg, from about 10 to about 250 mg, from about 25 to about 100 mg, or from about 50 to about 100 mg of Compound A. In certain embodiments, the tablets pro vided herein each contain from about 50 to about 100 mg of Compound A. In certain embodiments, the tablets provided herein each contain about 50, about 55, about 60, about 65, about 70, or about 75 mg of Compound A. In certain embodiments, the tablets provided herein each contain about 50, about 60, about 65, or about 75 mg of Compound A.

[00108] In certain embodiments, the pharmaceutical formulations provided herein have an in vitro dissolution profile as shown in FIGS provided herein, when measured using a USP type 2 apparatus at 75 rpm in 900 ml, of a dissolution medium as described herein.

[00109] In certain embodiments, the pharmaceutical formulations (e.g., tablets) provided herein are optionally coated. In certain embodiments, the pharmaceutical formulations (e.g., tablets) provided herein are enteric-coated. In certain embodiments, the pharmaceutical formulations (e.g., tablets) provided herein are sugar-coated. In certain embodiments, the pharmaceutical formulations (e.g., tablets) provided herein are film- coated. In certain embodiments, the pharmaceutical formulations (e.g., tablets) provided herein comprise two layers of coating. In certain embodiments, the pharmaceutical formulations (e.g., tablets) provided herein comprise two different layers of coating. [00110] Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach, acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Suitable enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Suitable film coatings include, but are not limited to, hydroxyethyl cellulose, sodium earhoxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate.

[00111] In certain embodiments, provided herein are anhydrous pharmaceutical formulations including an active ingredient, since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5 percent) is widely accepted in the pharmaceutical arts as a means of simulating shelf- life, i.e., long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water and heat accelerate decomposition. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.

[00112] An anhydrous pharmaceutical composition should be prepared and stored such that the anhydrous nature is maintained. Accordingly, in certain embodiments, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.

[00113] In this regard, also provided herein is a method of preparing a solid pharmaceutical formulation including an active ingredient through, admixing the active ingredient and an excipient under anhydrous or low moisture/humidity conditions, wherein the ingredients are substantially free of water. The method can further include packaging the anhydrous or non-hygroscopic solid formulation under low moisture conditions. By using such conditions, the risk of contact with water is reduced and the degradation of the

99 active ingredient can be prevented or substantially reduced.

[00114] In certain embodiments, the pharmaceutical formulations provided herein exhibit advantageous physical and/or pharmacological properties. Such properties include, but are not limited to, low friability, ease of assay, content uniformity, flow properties for manufacture, dissolution and bioavailability, and/or stability.

5,4. Process for Making Dosage Forms

[0Θ115] Dosage forms provided herein can be prepared by any of the methods of pharmacy, but al l methods include the step of bringing the active ingredient into association with the excipient, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly admixing (e.g., direct blend) the active ingredient with liquid e cipients or finely divided solid excipients or both, and then, if necessary, shaping the product into the desired presentation (e.g., compaction such as roller-compaction). If desired, tablets can be coated by standard aqueous or non-aqueous techniques.

[00116] In certain embodiments, a dosage form provided herein is prepared by compression or molding, optional ly with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0 117] In certain embodiments, the active ingredients (e.g., Compound A) and excipients are directly blended and compressed directly into tablets. Direct blend formulations may be advantageous in certain instances because they require only one blending step, the blending of the active and excipients, before being processed into the final dosage form, e.g., tablet or capsule. This can reduce the production of airborne particle or dust to a minimum, while roller-compaction processes may be prone to produce dust. In roller-compaction process, the compacted material is often milled into smaller particles for further processing. The milling operation can produce significant amounts of airborne particles, since the purpose for this step in manufacturing is to reduce the materials particle size. The milled material is then blended with other ingredients prior to manufacturing the final dosage form.

[00118] For certain active ingredients, in particular for a compound with a low solubility, the active ingredient's particle size is reduced to a fine powder in order to help increase the active ingredient's rate of solubilization. The increase in the rate of solubilization is often necessary for the active ingredient to be effectively absorbed in the gastrointestinal tract. However for fine powders to be directly-blended and loaded onto capsules, the excipieiits should preferably provide certain characteristics which render the ingredients suitable for the direct-blend process. Examples of such characteristics include, but are not limited to, acceptable flow characteristics. In one embodiment, therefore, provided herein is the use of, and compositions comprising, excipients which may provide characteristics, which render the resulting mixture suitable for direct-blend process, e.g., good flow characteristics. In certain embodiments, a dry blend tablet formulation is the preferred way of making the tablets provided herein.

5.4.1. Screening

[00119] The process for making the pharmaceutical compositions provided herein includes the screening of the active ingredient and the excipient(s). In one embodiment, the active ingredient is passed through a screen ha ving openings of about 200 to about 1500 microns. In another embodiment, the active ingredient is passed through a screen with openings of about 500 to about 1200 microns. In yet another embodiment, the active ingredient is passed through a screen having openings of about 750 to about 1000 microns. Depending on the excipient(s) used, the screen openings vary. For example, dismtegrants, binders, and lubricants are passed through openings of about 200 to about 1500 microns, from about 400 to about 1200 microns, or from about 600 to about 1000 microns,

[00120] In certain embodiments, the active ingredient and a diluent (e.g., lactose monohydrate, NF) are sieved and mixed together, followed by the addition of a lubricant (e.g., HPMC 2208, NF).

5.4.2. Pre-blending

[00121] After the ingredients are screened, the excipient(s) and active ingredient are mixed in a diffusion mixer. In one embodiment, the mixing time is from about I to about 50 minutes, from about 5 to about 45 minutes, from about 10 to about 40 minutes, or from about 10 to about 25 minutes. In another embodiment, the mixing time is about 15 minutes.

[00122] When more than one excipient is used, the excipients may be admixed in a tumble blender for about 1 to about 20 minutes, or for about 5 to about 10 minutes, prior to mixing with the active ingredient.

[0Θ123] In certain embodiments, the active ingredient, a diluent (e.g., lactose monohydrate, F), and a lubricant (e.g., HPMC 2208, NF) are mixed in a blender to form a pre-blend. In certain embodiments, the pre-blend is further screened and blended.

5.4.3. Final Blend

[00124] When a lubricant, e.g., sodium stearyl fumarate and magnesium stearate, or a glidant, e.g., colloidal silicon dioxide, is used, the lubricant or glidant is mixed with the pre-blend at the end of the process to complete the pharmaceutical composition. In certain embodiments, the lubricant or glidant is sieved before adding to the pre-blend. This additional mixing is from about 1 to about 10 minutes, or from about 3 to about 5 minutes.

5.4.4. Tableting

[00125] The formulation mixture can be tableted (e.g., via compaction,

compression, or molding) into the desired size and shape tablet using, for example, a tablet press or other conventional tableting equipment and standard techniques. In certain embodiments, the blend is compressed into tablets.

5.5. Kits

[00126] Pharmaceutical packs or kits which comprise pharmaceutical compositions or dosage forms provided herein are also provided. An example of a kit comprises notice in the form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

5.6. Methods of Treatment, Prevention, and Management

1 0127] Provided herein are methods of treating, preventing, and/or managing certain diseases or disorders using the formulations, compositions, or dosage forms provided herein.

[00128] Examples of diseases or disorders include, but are not limited to, those disorders related to PDE4, TNFa, cAMP, and/or angiogenesis, including diseases or disorders such as various inflammatory diseases, pulmonary diseases, autoimmune diseases, and immunological diseases. Specific examples include, but are not limited to, inflammation and various forms thereof, cancer, disorders associated with angiogenesis, pain including, but not limited to, complex regional pain syndrome ("CRPS"), macular degeneration ("MD"), and related syndromes, skin diseases, pulmonar disorders, asbestos-related disorders, parasitic diseases, immunodeficiency disorders, CNS disorders, CNS injury, atherosclerosis and related disorders, dysfunctional sleep and related disorders, hemoglobinopathy and related disorders (e.g., anemia), tuberculosis and related disorders, PDE4/TNF related disorders, infectious diseases, and other various diseases and disorders.

[00129] In one embodiment, exemplar}' diseases or disorders include, but are not limited to, inflammatory, viral, genetic, allergic, skin, and autoimmune diseases. Specific examples include, but are not limited to, arthritis, HIV, hepatitis, acne, adult respiratory distress syndrome, bone resorption diseases, chronic pulmonary inflammatory diseases, dermatitis, dematomyositis, cystic fibrosis, Lichen Planus, septic shock, sepsis, endotoxic shock, hemodynamic shock, sepsis syndrome, post ischemic reperfusion injury, meningitis, psoriasis, fibrotic disease, cachexia, graft versus host disease, graft rejection, auto-immune disease, rheumatoid spondylitis, Behcet's disease, dermatitis, Crohn's disease, ulcerative colitis, inflammatory-bowel disease, rosacea, multiple sclerosis, systemic lupus erythrematosus, ENL in leprosy, sacoidosis, radiation damage, cancer, asthma, uveitis, and hyperoxic alveolar injury.

[0Θ130] In one embodiment, the disease is psoriasis. In one embodiment, psoriasis is plaque psoriasis.

[00131] In another embodiment, the disease is arthritis, in one embodiment, arthritis is psoriatic arthritis, rheumatoid arthritis, osteoarthritis, or acute gouty arthritis.

[00132] In yet another embodiment, the disease is ankylosing spondylitis.

[00133 In yet another embodiment, the disease is a skin disease. In one, the skin disease is acne, dermatitis, or dermatomyositis. In one embodiment, dermatitis is atopic dermatitis or contact dermatitis.

[00134] In yet another embodiment, the disease is sarcoidosis. In one embodiment, sarcoidosis is chronic cutaneous sarcoidosis.

[00135] In yet another embodiment, the disease is uveitis.

[00136] In yet another embodiment, the disease is rosacea.

[00137] In yet another embodiment, the disease is Lichen Planus.

[00138] In sti ll another embodiment, the disease is Behcet's disease.

[00139] In certain embodiments, the disease or disorder is psoriasis, psoriatic arthritis, rheumatoid arthritis, Behcet's disease, or ankylosing spondylitis.

[00140] In certain embodiments, the disease is cancer or precancerous conditions.

Examples of cancer and precancerous conditions include, but are not limited to, those described in U.S. Pat. Nos. 6,962,940 and 7,893, 101 ; the disclosure of each of which is incorporated herein by reference in its entirety.

[00141] Certain examples of cancer include, but are not limited to, cancers of the skin, such as melanoma; lymph node; breast; cervix; uterus; gastrointestinal tract; lung; ovary; prostate; colon; rectum; mouth; brain; head and neck; throat; testes; kidney;

pancreas; bone; spleen; liver; bladder; larynx; nasal passages; and AIDS-related cancers. The compositions provided herein are also useful for treating cancers of the blood and bone marrow, such as multiple myeloma and acute and chronic leukemias, for example, lymphoblastic, myelogenous, lymphocytic, and myelocytic leukemias. The compositions provided herein can be used for treating, preventing or managing either primary or metastatic tumors.

[00142 J Other cancers include, but are not limited to, advanced malignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforme, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblastic leukemia, chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma, metastatic melanoma (localized melanoma, including, but not limited to, ocular melanoma), malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillar serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans ceil histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, Waldenstrom's macroglobulmemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non- metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma. In certain embodiments, the cancer is metastatic. In certain embodiments, the cancer is refractor or resistance to chemotherapy or radiation.

[00143] In one embodiment, the diseases or disorders are various forms of leukemias such as chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, and acute myeloblastic leukemia, including leukemias that are relapsed, refractory or resistant.

[00144] The term "leukemia" refers malignant neoplasms of the blood-forming tissues. The leukemia includes, but is not limited to, chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, and acute myeloblastic leukemia. The leukemia can be relapsed, refractory or resistant to conventional therapy. The term "relapsed" refers to a situation where patients who have had a remission of leukemia after therapy have a return of leukemia cells in the marrow and a decrease in norma! blood cells. The term "refractory or resistant" refers to a circumstance where patients, even after intensive treatment, have residual leukemia ceils in their marrow.

[00145] In another embodiment, the diseases or disorders are various types of lymphomas, including Non-Hodgkin's lymphoma (NHL). The term "lymphoma" refers a heterogenous group of neoplasms arising in the reticuloendothelial and lymphatic systems. "NHL" refers to malignant monoclonal proliferation of lymphoid ceils in sites of the immune system, including lymph nodes, bone marrow, spleen, liver and gastrointestinal tract. Examples of NHL include, but are not limited to, mantle ceil lymphoma (MCL), lymphocytic lymphoma of intermediate differentiation, intermediate lymphocytic lymphoma (ILL), diffuse poorly differentiated lymphocytic lymphoma (PDL), centrocyte lymphoma, diffuse small-cleaved cell lymphoma (DSCCL), follicular lymphoma, and any type of the mantle cell lymphomas that can be seen under the microscope (nodular, diffuse, blastic and mentle zone lymphoma),

[0Θ146] Examples of skin diseases include, but are not limited to, those described in

U.S. App. Publ. No, 2005/0214328, the disclosure of which is incorporated herein by reference in its entirety. Specific examples include, but are not limited to, keratoses and related symptoms, skin diseases or disorders characterized with overgrowths of the epidermis, acne, and wrinkles.

[00147] As used herein, the term "keratosis" refers to any lesion on the epidermis marked by the presence of circumscribed overgrowths of the homy layer, including, but not limited to, actinic keratosis, seborrheic keratosis, keratoacanthoma, keratosis foliicularis (Darier disease), mverted follicular keratosis, palmoplaiitar keratoderma (PPK, keratosis palrnaris et plantaris), keratosis pilaris, and stucco keratosis. The term "actinic keratosis" also refers to senile keratosis, keratosis senilis, verruca senilis, plana senilis, solar keratosis, keratoderma or keratoma. The term "seborrheic keratosis" also refers to seborrheic wart, senile wart, or basal cell papilloma. Keratosis is characterized by one or more of the fol lowing symptoms: rough appearing, scaly, erythematous papules, plaques, spicules or nodules on exposed surfaces (e.g., face, hands, ears, neck , legs and thorax), excrescences of keratin referred to as cutaneous horns, hyperkeratosis, telangiectasias, eiastosis, pigmented lentigmes, acanthosis, parakeratosis, dyskeratoses, papi llomatosis, Superpigmentation of the basal cells, cellular atypla, mitotic figures, abnormal cell-cell adhesion, dense inflammatory infiltrates and small prevalence of squamous cel l carcinomas.

[00148] Examples of skin diseases or disorders characterized with overgrowths of the epidermis include, but are not limited to, any conditions, diseases or disorders marked by the presence of overgrowths of the epidermis, including, but not limited to, infections associated with papilloma virus, arsenical keratoses, sign of Leser-Trelat, warty dyskeratoma (WD), trichostasis spinulosa (TS), erythrokeratodermia variabilis (EKV), ichthyosis fetalis (harlequin ichthyosis), knuckle pads, cutaneous melanoacanthoma, porokeratosis, psoriasis, squamous ceil carcinoma, confluent and reticulated

papillomatosis (CRP), acrochordons, cutaneous horn, cowden disease (multiple hamartoma syndrome), dermatosis papulosa nigra (DPN), epidermal nevus syndrome (ENS), ichthyosis vulgaris, molluscimi contagiosum, prurigo nodularis, and acanthosis nigricans (AN).

[00149] As stated herein, the dosage forms provided herein may be used in the treatment or prevention of a wide range of diseases and disorders. The magnitude of a prophylactic or therapeutic dose of a particular active ingredient provided herein in the acute or chronic management of a disease or condition may vary with the nature and severity of the disease or condition and the route by which the active ingredient is administered. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient. Suitable dosing regimens can be readily selected by those skilled in the art with due consideration of such factors, in general, the recommended daily dose range for the conditions described herein lie within the range of from about 1 mg to about 1 ,000 mg per day, given as a single once-a-day dose preferably as divided doses throughout a day. Specifically, a daily dose range may be from about 5 mg to about 500 mg per day, more specifically, between about 10 mg and about 200 mg per day. Specifically, the daily dose may be administered in 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg dosage forms. In managing the patient, the therapy should be initiated at a lower dose, perhaps about I mg to about 25 mg, and increased if necessary up to about 200 mg to about 1,000 mg per day as either a single dose or divided doses, depending on the patient's global response. Alternatively, the daily- dose is from 0.01 mg/kg to 100 mg kg.

[00150] It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response. 6. EXAMPLES

[00151] Embodiments provided herein may be more fully understood by reference to the following examples. These examples are meant to be illustrative of pharmaceutical compositions and dosage forms provided herein, but are not in any way limiting.

6.1. Formulation

[00152] Compound A is a poorly soluble compound (10-15 mg/L) with pH independent solubility. Site absorption study indicated that Compound A is absorbed throughout the G I tract. Compound A was formulated as modified release tablets containing about 50 mg, 60 mg, 65 nig, and 75 mg of Compound A as an active pharmaceutical ingredient.

[00153] Tablets were produced by: (i) screening Compound A, lactose

monohydrate, and hydroxypropylmethylcellulose 2208 (METHOCEL 100LVCR) through a 18 mesh screen to form a mixture; (ii) blending the mixture in a Globepharma 4- 8 quart bin blender for 15 minutes at 26 RPM; (iii) screening the blend through a 18 mesh screen; (iv) blending the mixture again in a Globepharma 4-8 quart bin blender for 10 minutes at 26 RPM; (v) screening coilodiai silicon dioxide (if present in the formulation) and magnesium stearate; (vi) transferring the screened material from the last step to the blender in step iv, and blending the mixture for 3 minutes at 26 RPM; (vii) discharging the blend into double polyethylene bags; and (viii) compressing the final blend on Minipress II at approximately 20 PM (12000 tab/hr) to achieve: target hardness: 15 kP ± 4 kP; target weight (±5%): 500 mg for 50 mg strength, 600 mg for 60 mg strength, 650 mg for 65 mg strength, and 750 mg for 75 mg strength; and tooling; 0.2905" x 0.5805" caplet shaped for 50 and 60 mg strength and 0.3250" x 0.6500" caplet shaped for 65 and 75 mg strength,

[00154] The tablets were evaluated for tablet characteristics and dissolution. Tablet friability was measured following 100 revolutions (25 rev/min) using USP method and after extended testing for 500 revolutions. Dissolution testing was carried out using USP Apparatus II Paddle method. A disk with 16 x 16 mesh screen and overall disk diameter of 80 mm (Quality Lab. Accessories) was placed over the tablets during dissolution testing to prevent tablets from floating. Paddles had to be raised in order to accommodate for the j l disk. Dissolution testing was performed in a dissolution medium (900 mL) at 37 °C with a paddle speed of 75 RPM. The dissolution medium was (a) pH 1.2 simulated gastric fluid with 0.3% SLS (sodium lauryl sulfate) for 2 hours, followed by 14 hours in pH 6.8 phosphate buffer with 0.3% SLS; (b) pH 4.5 acetate buffer with 0.3% SLS for 16 hours; or (c) pH 6.8 phosphate buffer with 0.3% SLS for 16 hours.

[00155] Modified release tablet formulations Ϊ to IV of Compound A are summarized in Tables 1 to 4. Tablets were compressed to different hardness to evaluate the effect hardness on dissolution and it was found that dissolution was not affected by hardness of the tablets. It was observed that the formulations with higher METHOCEL™ showed poor flow characteristics and were difficult to process.

Table 1. Tablet Formulation I

Table 3. Tablet Formulation III

[00156] Modified release tablet formulations V to VII of Compound A are summarized in Tables 5 to 7, with the addition of silicon dioxide to overcome the poor flow characteristics and to improve the processability.

Table 5. Tablet Formulation V

Table 7. Tablet Formulation VII

[00157] Modified release tablet formulations VIII to XII of Compound A are summarized in Tables 8 to 12. The formulations were evaluated for their dissolution in a pH 4.5 acetate buffer with 0.3% SLS. The time to release 80 and 100% of Compound are summarized in Table 13.

Table 8. Tablet Formulation VIII

Table 9. Tablet Formulation IX

Table 12. Tablet Formulation XII

Table 13. Time to release 80-100%

Calculated by fitting the linear portion of the profile to a

zero order and using the zero order equation to determine

the time.

[00158] Modified release tablet formulations XIII to XV of Compound A are summarized in Table 14. Formulations XIII to XV were used to make 50, 60, 65, and 75 strength tablets. The time to release 80 and 100% of Compound are summarized in Table 15. Table 14. Tablet Formulations

Table 15. Time to release 80-100%

Calculated by fitting the linear portion of the profile to a zero order and using the zero order equation to determine the time.

[00159] A zero order release was observed for all the formulations. Dissolution was not affected by hardness of the tablets. Dissolution rate was mainly controlled by level of METHOCEL KIOOLVCR. Similar dissolution profile was obtained in dissolution media with different pH. Tablet geometry affected the dissolution profile. [00160] Physical characterization of the blends and tablets are summarized in Tab!

16.

Table 16. Physical characterization of blends and tablets

6.2. Clinical Evaluation A-Pharmacokinetics

I00161J Apremiiast (CC-10004), (+)-2-[l -(3-ethoxy-4-methoxy-phenyl)-2- methanesulfoiiyl-ethyi]-4-acetylamiiioisoindoiine-I,3-dioiie, is an orally available small molecule that inhibits phosphodiesterase type 4 (PDE4) and modulates multiple pro- inflarnmatory and anti-inflammatory mediators. It is under clinical development for the treatment of inflammatory autoimmune disorders, such as psoriatic arthritis (PsA), psoriasis, rheumatoid arthritis (RA), ankylosing spondylitis, and Behcet's disease (BD), that involve elevated cytokine levels. Phosphodiesterase type 4 is one of the major phosphodiesterases expressed in leukocytes. Inhibitors of PDE4 cause accumulation of intracellular cyclic adenosine monophosphate (cAMP), resulting in inhibition of proinflammatory cytokine transcription and other cellular responses such as neutrophil degranulation, chemotaxis, and adhesion to endothelial ceils,

[00162] Certain modified release formulations provided herein are evaluated in a

Phase 1 , open-label, 2-part pilot (Parts A and B) study in healthy male subjects to assess their pharmacokinetics and food effect. This is a single-center, 2-part design space study in 2 separate cohorts of healthy male subjects.

[0Θ163] Part A is a 6-period, open-label, sequential, non-randomized design, in which a single cohort of up to 16 subjects (plus any replacements) receives the following treatments in the following orders:

Period 1 : 60 mg reference formulation (one 30-mg immediate -release ("IR") oral tablet in the morning and one 30-mg 1R oral tablet in the evening on the dosing day-approximateiy 12 hours after the morning dose);

Period 2: Single oral dose of prototype 1 (60 mg/polymer level 2 (30%));

Period 3: Single oral dose of prototype 2 (50 mg/polymer level 3 (37%));

Period 4: Single oral dose of prototype 3 (50 mg/polymer level 1 (22%));

Period 5: Single oral dose of prototype 4 (75 mg/polymer level 3 (37%)); or

Period 6: Single oral dose of prototype 5 (75 mg/polymer level 1 (22%)).

[00164] In Part A, all subjects receive a different formulation during each study period but receive these treatments in the same order (i.e., all subjects have the same treatment sequence).

[00165] The morning dose in Period 1 and the doses in Periods 2 through 6 are administered in the fasted state. Food and beverages (except water) are withheld from subjects for at least 8 hours prior to the morning dose on Day 1 until at least 4 hours after the morning dose on Day 1 . The evening dose in Period 1 is administered in a partially fasted state, i.e. , food and beverages (except water) are withheld from subjects for at least 2 hours prior to the evening dose until at least 4 hours after the evening dose. During fasting periods, water is al lowed ad lib except from between 1 hour prior to dosing and 2 hours postdose (excluding any water given with study drug). All doses are administered orally wi th approximately 240 mL of non-carbonated, room-temperature water.

[00166] Screening commence up to 28 days before the first treatment administration

(Day 1 of Period 1). Subject are admitted to the clinic in the evening of the day before dosing (Day 1) of each study period. During Period 1 , subjects reside in the clinic until at least 72 hours following the Day 1 evening dose. During Periods 2 through 6, subjects reside in the clinic until at least 48 hours postdose and return to the clinic on the morning of Day 4 for PK blood sampling. There is a washout period of at least 7 days and no more than 10 days between each dosing day.

[001 7] Part B is an open-label, randomized crossover design. One of two scenarios is conducted in Part B, depending on the results from Part A. Following interim analysis of Part A results, one of the prototypes may be selected for dosing in Part B (Scenario 1). Alternatively, a decision may be made to elevate a sixth prototype in Part B (Scenario 2).

[ΘΘ168] Scenario 1 is a 2 -period, 2-sequence, open-label, randomized, crossover design. A single cohort of up to 14 subjects (plus any replacements) are randomized to one of 2 treatment sequences to receive a single oral dose of the selected prototype under both fasted (Treatment A) and fed (Treatment B) conditions. Administration of the MR formulations are scheduled to commence in the morning of Day 1 of each treatment period. The chosen prototype formulation is dosed in the fed and fasted states according to the treatment sequence as determined by the randomization schedule shown in Table 17. Table 17. Treatment Sequence-Scenario 1

[00169] Scenario 2 is a 3-period, 3-sequence, open-label, randomized, crossover design. A single cohort of up to 15 subjects (plus any replacements) are randomized to one of 3 treatment sequences to receive the following treatment across 3 study periods:

Treatment A: single oral dose of Prototype 6: fasted;

Treatment B: single oral dose of Prototype 6: fed; or

Treatment C: 60 mg reference formulation (one 30-mg IR oral tablet in th morning (fasted) and one 30-mg IR oral tablet in the evening (partially fasted) on the dosing day).

[00170] Administration of the MR formulations and the morning dose of the IR formulation are schedul ed to commence in the morning of Day 1 of the appropriate treatment period. The evening dose of IR formulation, where applicable, is scheduled to occur at approximately 12 hours after the morning dose.

[00171] The reference formulation is dosed in the fasted state. The chosen prototype formulation is dosed in the fed and fasted states according to the treatment sequence as determined by the randomization schedule shown in Table 18.

Table 18. Treatment Sequence-Scenario 2

both scenarios, all doses are administered orally with approximately 240 mL of non-carbonated, room-temperature water. For subjects dosed in the fasted state, food and beverages (except water) are withheld from subjects for at least 8 hours prior to the morning dose on Day 1 and until at least 4 hours after the morning dose on Day 1. During fasting periods, water is allowed ad lib except from between 1 hour prior to dosing and 2 hours postdose (excluding any water given with study drug). Subjects dosed in the fed state also begin the overnight fast but then consume a FDA-standardized high-fat breakfast starting 30 minutes prior to the Day I morning dose. The breakfast should be consumed over a maximum period of 25 minutes.

[00173] Subjects participating in the study period in which the reference

formulation is administered reside in the clinic until at least 72 hours following the Day 1 evening dose. For all other study periods, subjects reside in the clinic until at least 48 hours postdose and return to the clinic on the morning of Day 4 for PK blood sampling.

[00174] For both scenarios, screening commence up to 28 days before the first treatment administration (Day 1), Subjects are admitted to the clinic in the evening of the day before dosing (Day 1) of each study period. There is a washout period of at least 7 days and no more than 10 days between each dosing day.

[00175] For Part B, following database lock, the log-transformed AUC₀._t, AUC₀._∞, and C_max values are subjected to ANOVA, including terms for food status (either fasting or fed), sequence, and period as fixed effects and subject as a random effect in order to assess food effect on the selected MR formulation. The ratio of the geometric means and 90% CI is provided for the comparison of fed versus fasted. If a sixth MR formulation is required, then a separate evaluation of relative bioavailability is performed . For t_ttiax, a non- parametric analysis is used to produce a median difference between treatments and, if applicable, between food status.

[00176] All subjects who take at least one dose of apremilast are included in the safety assessments. For both parts of the study, safety assessments including clinical laboratory tests (hematology, clinical chemistry, and urinalysis), electrocardiogram (ECG) recordings, vital signs, and physical examinations (PEs) are performed at predefined times and as deemed necessary by the investigator during the study. Adverse events (AEs) and use of concomitant medications/therapies are monitored throughout the study. A final safety evaluation is performed at the follow-up visit (3 to 6 days following discharge from the clinic after completion of the final study period of the relevant part of the study). In the event that a subject withdraws consent or is discontinued from the study, an early termination (ET) visit is performed within 7 to 10 days following the day of

discontinuation

[00177] Up to 31 adult healthy male subjects between 18 and 55 years of age

(inclusive) are initially enrolled into the study: up to 16 in Part A and up to 14 (Scenario 1) or 15 (Scenario 2) in Part B.

[00178] The estimated duration of the clinical phase, from first-subject- first- visit to last-subject-last- visit, is approximately 4 months. Each subject participates in the following phases: a 28-day Screening period; 6 study periods in Part A, with washout periods of 7 to 10 days between each dosing day, or up to 3 study periods in Part B, with washout periods of 7 to 10 days between each dosing day; and a Follow-up visit 3 to 6 days following discharge from the clinic after completion of the final study period of the relevant part of the study.

[00179] For IR dosing, serial blood samples are collected before dosing (zero hour) and at 0.5, 1 , 2, 3, 5, 8, 12, 24, 36, 48, and 72 hours after morning dosing (i.e., after the first dose administered in Day 1); and at 0.5, 1, 2, 3, 5, 8, 12, 24, 36, 48, and 72 hours after evening dosing (i.e., after the second dose administered in Day 1).

[00180] For MR dosing, serial blood samples are collected before dosing (zero hour) and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.

63. Clinical Evaluation B-Treatment of Psoriasis

[00181] An open label clinical study is performed in patients with severe plaque- type psoriasis (> 15% BSA) for seven months. Certain modified release formulations provided herein are orally administered.

[00182] Skin biopsies (6 mm) are taken as baseline. Day 15 and Day 29. Psoriasis area and severity index (PASI), PGA, and body surface area (BSA) are assessed weekly during the treatment phase. Also, ANA, lymphocyte safety, and PPD are assessed at baseline and Day 29. Patients are monitored for relapse and safety, and continued laboratory assessments for follow up.

6,4. Clinical Evaluation C-Treatment of Psoriasis

[00183] A raulticenter, randomized, double-blind, placebo-controlled, parallel- group, dose-comparison study is performed to evaluate the efficacy and safety of certain modified release formulations provided herein in subjects with moderate to severe plaque- type psoriasis.

100184J This study includes a 12-week treatment phase, followed by a 4-week observational follow-up phase. The primary endpoint for this study is the proportion of subjects treated with a formulation provided herein who achieve a 75% reduction in Psoriasis Area and Severity index score ("PASI-75") at week 12/last treatment in reference to the baseline visit. Last treatment is defined as the last PASI assessment completed during the 12-week treatment phase.

[0Θ185] The examples set forth above are provided to give those of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of what is disclosed herein.

Modifications that are obvious to persons of skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited in this specification are incorporated herein by reference as if each such publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference.

Claims

What is claimed is:

A pharmaceutical formulation comprising a compound of formula (I)

or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof; and a release modifying excipient.

2. The pharmaceutical formulation of claim 1, comprising from about 5% to about 70% by w ei ght of the compound.

3. The pharmaceutical formulation of claim 1 , comprising from about 5 to about 30% by weight of the compound.

4. The pharmaceutical formulation of any of claims 1 to 3, wherein the release modifying excipient is a gel-forming polymer, a hydratable polymer, a water swellable polymer, or mixtures thereof.

5. The pharmaceutical formulation of claim 4, wherein the release modifying excipient is a gel-forming polymer.

6. The pharmaceutical formulation of claim 4 or 5, wherein the release modifying excipient comprises hydroxyalkylcellulose, alkylcellulose, cellulose acetate, hydroxyalkylceilulose acetate, cellulose ether, alkylcellulose acetate, or a mixture thereof.

7. The pharmaceutical formulation of claim 6, wherein the release modifying excipient comprises hydroxyalky 1 cell uiose .

8. The pharmaceutical formulation of claim 6 or 7, wherein the release modifying excipient comprises alkylcellulose.

9. The pharmaceutical formulation of claim 6, wherem the release modifying excipient comprises hydroxyalkylcellulose and alkylcellulose.

10. The pharmaceutical formulation of any of claims 6 to 9, wherein the hydroxyalkylcellulose is hydroxypropyl methylcellulose.

1 1 . The pharmaceutical formulation of any of claims 6 to 9, wherein the alkylcellulose is methylcellulose,

12. The pharmaceutical formulation of claim 6, wherein the release modifying excipient comprises hydroxypropyl methylcellulose and methylcellulose.

13. The pharmaceutical formulation of claim 12, wherein the release modifying excipient contains from about 19 to about 24% by weight of methoxyl.

14. The pharmaceutical formulation of claim 12 or 13, wherein the release modifying excipient contains from about 6 to about 12% by weight of hydroxypropoxyl.

15. The pharmaceutical formulation of claim 12, wherein the release modifying excipient is METHOCEL™ E5LV, ETHOCEL™ E15LV, M ETHOCEL™ E50LV, METHOCEL^® K100LVCR, or a mixture thereof.

16. The pharmaceutical formulation of claim 12, wherein the release modifying excipient is METHOCEL^® 1001. VCR.

17. The pharmaceutical formulation of any of claims 1 to 16, comprising from about 5 to about 50% by weight of the release modifying excipient.

18. The pharmaceutical formulation of claim 17, comprising from about 10 to about 50% by weight of the release modifying excipient.

19. The pharmaceutical formulation of claim 17, comprising about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50%) by weight of the release modifying excipient,

20. The pharmaceutical formulation of any of claims 1 to 19, further comprising a diluent.

21. The pharmaceutical formulation of claim 20, wherein the diluent is lactose.

22. The pharmaceutical formulation of claim 20, wherein the diluent is lactose monohydrate.

23. The pharmaceutical formulation of claim 20, wherein the diluent is FAST FLO^® 316.

24. The pharmaceutical formulation of any of claims 20 to 23, comprising from about 15 to about 70% by weight of the diluent.

25. The pharmaceutical formulation of claim 24, comprising from about 40 to about 70% by weight of the diluent.

26. The pharmaceutical formulation of claim 24, comprising about 43, about 53, about 58, about 63, or about 68% by weight of the diluent.

27. The pharmaceutical formulation of any of claims 1 to 26, further comprising a lubricant.

28. The pharmaceutical formulation of claim 27, wherein the lubricant is magnesium stearate.

29. The pharmaceutical formulation of claim 27 or 28, comprising from about 0.5 to about 2% by weight of the lubricant.

30. The pharmaceutical formulation of claim 29, comprising about 1% by weight of the lubricant.

31. The pharmaceutical formulation of any of claims 1 to 30, further comprising a glidant.

32. The pharmaceutical formulation of claim 31 , wherein the glidant is silica.

33. The pharmaceutical formulation of claim 31 , wherein the glidant is colloidal silicon dioxide.

34. The pharmaceutical formulation of claim 31 , wherein the glidant is CAB- O-S! E. ^' .

35. The pharmaceutical formulation of any of claims 31 to 34, comprising from about 0.5 to about 2% by weight of the glidant.

36. The pharmaceutical formulation of claim 35, comprising about 1% by weight of the glidant.

37. The pharmaceutical formulation of claim 1 , comprising from about 5% to about 20% by weight of the compound; from about 20% to about 50% by weight of the release modifying excipient; from about 40% to about 70% by weight of a diluent; from about 0.5%) to about 2% by weight of a lubricant, and from about 0.5% to about 2% by weight of a glidant.

38. The pharmaceutical formulation of claim 1 , comprising about 10% by weight of the compound; from about 20% to about 50%> by weight of the release modifying excipient; from about 40% to about 70% by weight of a diluent; about 1% by weight of a lubricant, and about 1 % by weight of a glidant.

39. The pharmaceutical formulation of claim 1 , comprising about 10% by weight of the compound; from about 20% to about 50% by weight of a gel-forming polymer; from about 40% to about 70% by weight of lactose; about 1 % by weight of magnesium stearate, and about 1% by weight of silica.

40. The pharmaceutical formulation of claim 1 , comprising about 10% by weight of the compound; from about 20% to about 0% by weight of a gel-forming polymer; from about 40% to about 70%) by weight of lactose; about 1% by weight of magnesium stearate, and abou t 1 % by weight of silica.

41. The pharmaceutical formulation of claim 1 , comprising about 10% by weight of the compound; about 20, about 25, about 30, about 35, about 40, or about 45%) by weight of a gel-forming polymer; about 43, about 53, about 58, about 63, or about 68%) by weight of lactose; about 1 % by weight of magnesium stearate, and about 1 % by weight of silica,

42. The pharmaceutical formulation of any of claims 1 to 41 , wherein the formulation is formulated as a unit dosage form.

43. The pharmaceutical formulation of claim 42, wherein the unit dosage form is a tablet.

44. The pharmaceutical formulation of claim 42, wherein the unit dosage form is a caplet.

45. The pharmaceuticai formulation of any of claims 42 to 44, wherein the unit dosage form comprises from about 50 to about 75 mg of the compound.

46. The pharmaceutical formulation of claim 45, wherein the unit dosage form comprises about 50, about 55, about 60, about 65, about 70, or about 75 mg of the compound.

47. The pharmaceutical formulation of any of claims 1 to 46, further comprising a coating.

48. The pharmaceutical formulation of any of claims 1 to 47, suitable for once- a-day administration of the compound.

49. A method of treating, preventi ng or managing a di sease or disorder in a subject, comprising administering to the subject the pharmaceutical formulation of any of ciaims 1 to 48, wherein the disease or disorder is psoriasis, arthritis, dermatitis, acne, demiatomyositis, sarcoidosis, uveitis, rosacea, Behcet's disease, ankylosing spondylitis, or Lichen Planus.

50. The method of claim 49, wherein the psoriasis is plaque-type psoriasis.

51. The method of claim 49, wherein the arthritis is psoriatic arthritis, rheumatoid arthritis, osteoarthritis or acute gouty arthritis.

52. The method of claim 49, wherein the dermatitis is atopic dermatitis or contact dermatitis.

53. The method of claim 49, wherein the sarcoidosis is chronic cutaneous sarcoidosis.