TABLETTENFORMULIERUNGEN AUS (+)-2-[1-(3-ETHOXY-4-METHOXYPHENYL)-2-METHYLSULFONYLETHYL]-4-ACETYLAMINOISOINDOLIN-1,3-DION

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 61 / 840,210, filed June 27, 2013 and U.S. Provisional Application No. 61 / 835,667, filed June 17, 2013.1. Field

[0002] Provided herein are oral dosage forms of apremilast, i.e., (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, as defined in the claims. Oral dosage forms for use intherapeutic methods are also provided herein, as defined in the claims.2. Background

[0003] Tumor necrosis factor alpha, (TNF-α) is a cytokine that is released primarily by mononuclear phagocytes in response to immunostimulators. TNF-α is capable of enhancing most cellular processes, such as differentiation, recruitment, proliferation, and proteolytic degradation. At low levels, TNF-α confers protection against infective agents, tumors, and tissue damage. But TNF-α also has a role in many diseases. When administered to mammals or humans, TNF-α causes or aggravates inflammation, fever, cardiovascular effects, hemorrhage, coagulation, and acute phase responses similar to those seen during acute infections and shock states. Enhanced or unregulated TNF-α production has been implicated in a number of diseases and medical conditions, for example, cancers, such as solid tumors and blood born tumors; heart disease, such as congestive heart failure; and viral, genetic, inflammatory, allergic, and autoimmune diseases.

[0004] Adenosine 3',5'-cyclic monophosphate (cAMP) also plays a role in many diseases and conditions, such as but not limited to asthma and inflammation, and other conditions (Lowe and Cheng, Drugs of the Future, 17(9), 799-807, 1992). It has been shown that the elevation of cAMP in inflammatory leukocytes inhibits their activation and the subsequent release of inflammatory mediators, including TNF-α and NF-κB. Increased levels of cAMP also leads to the relaxation of airway smooth muscle.

[0005] It is believed that the primary cellular mechanism for the inactivation of cAMP is the breakdown of cAMP by a family of isoenzymes referred to as cyclic nucleotide phosphodiesterases (PDE) (Beavo and Reitsnyder, Trends in Pharm., 11, 150-155, 1990). There are eleven known PDE families. It is recognized, for example, that the inhibition of PDE type IV is particularly effective in both the inhibition of inflammatory mediator release and the relaxation of airway smooth muscle (Verghese, et al., Journal of Pharmacology and Experimental Therapeutics, 272(3), 1313-1320, 1995). Thus, compounds that inhibit PDE4 (PDE IV) specifically, may inhibit inflammation and aid the relaxation of airway smooth muscle with a minimum of unwanted side effects, such as cardiovascular or anti-platelet effects. Currently used PDE4 inhibitors lack the selective action at acceptable therapeutic doses.

[0006] Cancer is a particularly devastating disease, and increases in blood TNF-α levels are implicated in the risk of and the spreading of cancer. Normally, in healthy subjects, cancer cells fail to survive in the circulatory system, one of the reasons being that the lining of blood vessels acts as a barrier to tumor-cell extravasation. But increased levels of cytokines have been shown to substantially increase the adhesion of cancer cells to endothelium in vitro. One explanation is that cytokines, such as TNF-α, stimulate the biosynthesis and expression of a cell surface receptors called ELAM-1 (endothelial leukocyte adhesion molecule). ELAM-1 is a member of a family of calcium-dependent cell adhesion receptors, known as LEC-CAMs, which includes LECAM-1 and GMP-140. During an inflammatory response, ELAM-1 on endothelial cells functions as a "homing receptor" for leukocytes. Recently, ELAM-1 on endothelial cells was shown to mediate the increased adhesion of colon cancer cells to endothelium treated with cytokines (Rice et al., 1989, Science 246:1303-1306).

[0007] Inflammatory diseases such as arthritis, related arthritic conditions (e.g., osteoarthritis and rheumatoid arthritis), inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), sepsis, psoriasis, atopic dermatitis, contact dermatitis, and chronic obstructive pulmonary disease, chronic inflammatory pulmonary diseases are also prevalent and problematic ailments. TNF-α plays a central role in the inflammatory response and the administration of their antagonists block chronic and acute responses in animal models of inflammatory disease.

[0008] Enhanced or unregulated TNF-α production has been implicated in viral, genetic, inflammatory, allergic, and autoimmune diseases. Examples of such diseases include but are not limited to: HIV; hepatitis; adult respiratory distress syndrome; bone-resorption diseases; chronic obstructive pulmonary diseases; chronic pulmonary inflammatory diseases; asthma, dermatitis; cystic fibrosis; septic shock; sepsis; endotoxic shock; hemodynamic shock; sepsis syndrome; post ischemic reperfusion injury; meningitis; psoriasis; fibrotic disease; cachexia; graft rejection; auto-immune disease; rheumatoid spondylitis; arthritic conditions, such as rheumatoid arthritis and osteoarthritis; osteoporosis; Crohn's disease; ulcerative colitis; inflammatory-bowel disease; multiple sclerosis; systemic lupus erythrematosus; ENL in leprosy; radiation damage; asthma; and hyperoxic alveolar injury. Tracey et al., 1987, Nature 330:662-664 and Hinshaw et al., 1990, Circ. Shock 30:279-292 (endotoxic shock); Dezube et al., 1990, Lancet, 335:662 (cachexia ); Millar et al., 1989, Lancet 2:712-714 and Ferrai-Baliviera et al., 1989, Arch. Surg. 124:1400-1405 (adult respiratory distress syndrome); Bertolini et al., 1986, Nature 319:516-518, Johnson et al.,1989, Endocrinology 124:1424-1427, Holler et al., 1990, Blood 75:1011-1016, and Grau et al., 1989, N. Engl. J. Med. 320:1586-1591 (bone resorption diseases); Pignet et al., 1990, Nature, 344:245-247, Bissonnette et al., 1989, Inflammation 13:329-339 and Baughman et al., 1990, J. Lab. Clin. Med. 115:36-42 (chronic pulmonary inflammatory diseases); Elliot et al., 1995, Int. J. Pharmac. 17:141-145 (rheumatoid arthritis); von Dullemen et al., 1995, Gastroenterology, 109:129-135 (Crohn's disease); Duh et al., 1989, Proc. Nat. Acad. Sci. 86:5974-5978, Poll et al., 1990, Proc. Nat. Acad. Sci. 87:782-785, Monto et al., 1990, Blood 79:2670, Clouse et al., 1989, J. Immunol. 142, 431-438, Poll et al., 1992, AIDS Res. Hum. Retrovirus, 191-197, Poli et al. 1990, Proc. Natl. Acad. Sci. 87:782-784, Folks et al., 1989, PNAS 86:2365-2368 (HIV and opportunistic infections resulting from HIV).

[0009] Pharmaceutical compounds that can block the activity or inhibit the production of certain cytokines, including TNF-α, may be beneficial therapeutics. Many small-molecule inhibitors have demonstrated an ability to treat or prevent inflammatory diseases implicated by TNF-α (for a review, see Lowe, 1998 Exp. Opin. Ther. Patents 8:1309-1332). One such class of molecules are the substituted phenethylsulfones described in United States Patent No. 6,020,358.

[0010] Due to its diversified pharmacological properties, apremilast is useful in treating, preventing, and / or managing various diseases or disorders. Thus, a need exists as to dosage forms of apremilast having advantageous physical and pharmaceutical properties, such as those suitable for once per day dosing. WO 2012 / 083017 A2 describes "controlled release oral dosage forms of poorly soluble drugs, methods of making the dosage forms, and methods of their use for the treatment of various diseases and / or disorders".3. Summary

[0011] Provided herein are pharmaceutical dosage forms comprising the (+) enantiomer of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione (apremilast), or a pharmaceutically acceptable salt thereof.

[0012] Without being limited by theory, it is thought that the dosage forms provided herein are suitable for once daily dosing of apremilast and also result in reduced gastrointestinal adverse effects relative to dosing regimens comprising more than one dose per day.

[0013] Further provided herein are pharmaceutical dosage forms of the (+) enantiomer of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione for treating, managing or preventing diseases or disorders ameliorated by the inhibition of TNF-α production in mammals. In certain embodiments, this treatment includes the reduction or avoidance of adverse effects. Such diseases or disorders include, but are not limited to, cancers, including, but not limited to cancer of the head, thyroid, neck, eye, skin, mouth, throat, esophagus, chest, bone, blood, bone marrow, lung, colon, sigmoid, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, brain, intestine, heart, adrenal, subcutaneous tissue, lymph nodes, heart, and combinations thereof. Specific cancers that can be treated include multiple myeloma, malignant melanoma, malignant glioma, leukemia and solid tumors.

[0014] Further provided herein are pharmaceutical dosage forms of the (+) enantiomer of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione for treatment or prevention of heart disease, including, but not limited to congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction.

[0015] Further provided herein are pharmaceutical dosage forms of the (+) enantiomer of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione for treating diseases or disorders ameliorated by the inhibition of PDE4. For example, provided herein are pharmaceutical dosage forms for treating or preventing viral, genetic, inflammatory, allergic, and autoimmune diseases. Examples of such diseases include, but are not limited to: HIV; hepatitis; adult respiratory distress syndrome; bone-resorption diseases; chronic obstructive pulmonary diseases; chronic pulmonary inflammatory diseases; dermatitis; inflammatory skin disease, atopic dermatitis, cystic fibrosis; septic shock; sepsis; endotoxic shock; hemodynamic shock; sepsis syndrome; post ischemic reperfusion injury; meningitis; psoriasis; fibrotic disease; cachexia; graft rejection including graft versus host disease; auto-immune disease; rheumatoid spondylitis; arthritic conditions, such as psoriatic arthritis, rheumatoid arthritis and osteoarthritis; osteoporosis; Crohn's disease; ulcerative colitis; inflammatory-bowel disease; multiple sclerosis; systemic lupus erythrematosus; erythema nodosum leprosum (ENL) in leprosy; radiation damage; asthma; and hyperoxic alveolar injury.

[0016] Pharmaceutical dosage forms of the (+) enantiomer of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione are also useful in the treatment or prevention of microbial infections or the symptoms of microbial infections including, but not limited to, bacterial infections, fungal infections, malaria, mycobacterial infection, and opportunistic infections resulting from HIV.4. Brief Description Of The Figures

[0017] FIG 1: Process flow diagram for the manufacture of apremilast modified released (MR) tablet. FIG 2: Process flow diagram for the manufacture of apremilast immediate release (IR) minitablets coated with modified release coat. FIG 3: Process flow diagram for the manufacture of apremilast matrix minitablets coated with modified release coat. FIG. 4: Dissolution profile for Formulation E. FIG. 5: Dissolution profile for Formulation F. FIG. 6: Dissolution profile for Formulation G. FIG. 7: Dissolution profile for Formulation H. FIG. 8: Dissolution profile for Formulation I. 5. Definitions

[0018] As used herein, term "apremilast" refers to an enantiomerically pure form of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione. In one embodiment, the apremilast is what comes off of an HPLC column at about 25.4 minutes when that column is a 150 mm x 4.6 mm Ultron Chiral ES-OVS chiral HPLC column (Agilent Technology), the eluent is 15:85 ethanol: 20 mM KH 2 PO 4 at pH 3.5, and the observation wavelength is 240 nm. The 1< H NMR spectrum of apremilast is substantially as follows: δ(CDCl 3 ):1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84-5.90 (dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H). The 13< C NMR spectrum of apremilast is substantially as follows δ(DMSO-d 6 ): 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48. Apremilast dissolved in methanol also rotates plane polarized light in the (+) direction.

[0019] Without being limited by theory, apremilast is believed to be S-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione}, which has the following structure:

[0020] As used herein, the term "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.

[0021] As used herein, term "Compound A" refers to apremilast, or a pharmaceutically acceptable salt, stereoisomer, prodrug, solvate, hydrate, clathrate, isotopologue, metabolite or solid form thereof.

[0022] As used herein, the term "patient" refers to a mammal, particularly a human.

[0023] As used herein and unless otherwise specified, a sample or composition that is "substantially free" of one or more other solid forms and / or other chemical compounds means that the composition contains, in particular embodiments, less than about 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.75%, 0.5%, 0.25% or 0.1% percent by weight of one or more other solid forms and / or other chemical compounds.

[0024] As used herein and unless otherwise indicated, the term "stereomerically pure" means a composition that comprises one stereoisomer of a compound and is substantially 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 diastereomers of the compound. A typical stereomerically 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, more preferably greater than about 90 percent by weight of one stereoisomer of the compound and less than about 10 percent by weight of the other stereoisomers of the compound, even more preferably greater than about 95 percent by weight of one stereoisomer of the compound and less than about 5 percent by weight of the other stereoisomers of the compound, even more preferably greater than about 97 percent by weight of one stereoisomer of the compound and less than about 3 percent by weight of the other stereoisomers of the compound, and most preferably greater than about 99 percent by weight of one stereoisomer of the compound and less than about 1 percent by weight of the other stereoisomers of the compound.

[0025] As used herein and unless otherwise indicated, the term "enantiomerically pure" means a stereomerically pure composition of a compound having one chiral center.

[0026] As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt(s)," as used herein includes, but is not limited to, salts of acidic or basic moieties of apremilast. Basic moieties are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions. Suitable organic acids include, but are not limited to, maleic, fumaric, benzoic, ascorbic, succinic, acetic, formic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, oleic, tannic, aspartic, stearic, palmitic, glycolic, glutamic, gluconic, glucaronic, saccharic, isonicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, benzenesulfonic acids, or pamoic (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate) acids. Suitable inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, or nitric acids. Compounds that include 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 and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, or iron salts.

[0027] 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-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.

[0028] As used herein and unless otherwise indicated, the term "prodrug" means a derivative of a compound that can hydrolyze, 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 apremilast 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 apremilast that include -NO, -NO 2 , -ONO, or -ONO 2 moieties.

[0029] 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, 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, aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

[0030] 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, 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.

[0031] As used herein and unless otherwise indicated, the term "biohydrolyzable 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, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound. Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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%, or 5% of the specified dose, amount, or weight percent is encompassed.

[0036] 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 remains solubilized for a specified amount of time and does not significantly degrade or aggregate or become otherwise modified (e.g., as determined, for example, by HPLC). In some embodiments, about 70 percent or greater, about 80 percent or greater or about 90 percent or greater of the compound remains solubilized after the specified period.

[0037] As used herein, term "adverse effects" includes, but is not limited to gastrointestinal, renal and hepatic toxicities, leukopenia, increases in bleeding times due to, e.g., thrombocytopenia, and prolongation of gestation, nausea, vomiting, somnolence, asthenia, dizziness, teratogenicity, extra-pyramidal symptoms, akathisia, cardiotoxicity including cardiovascular disturbances, inflammation, male sexual dysfunction, and elevated serum liver enzyme levels. The term "gastrointestinal toxicities" includes but is not limited to gastric and intestinal ulcerations and erosions. The term "renal toxicities" includes but is not limited to such conditions as papillary necrosis and chronic interstitial nephritis.

[0038] As used herein and unless otherwise indicated, the phrases "reduce or avoid adverse effects" and "reducing or avoiding adverse effects" mean the reduction of the severity of one or more adverse effects as defined herein.

[0039] The phrases "therapeutically effective amount", "prophylactically effective amount" and "therapeutically or prophylactically effective amount," as used herein encompasses the above described dosage amounts and dose frequency schedules. Different therapeutically effective amounts may be applicable for different diseases and conditions, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to treat or prevent such disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with racemic 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione are also encompassed by the above described dosage amounts and dose frequency schedules.

[0040] As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease or disorder, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0041] The term "composition" as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amounts, if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant that the diluent, excipient or carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0042] It should be noted that if there is a discrepancy between a depicted structure and a name given that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.6. Detailed Description

[0043] Provided herein are oral dosage forms of Compound A, as defined in the claims. The dosage forms are suitable for oral administration to a patient. In embodiments, the dosage forms provided herein exhibit advantageous physical and / or pharmacological properties. Such properties include, but are not limited to, ease of assay, content uniformity, flow properties for manufacture, dissolution and bioavailability, and stability. In certain embodiments, the dosage forms provided herein have a shelf life of at least about 12 months, at least about 24 months, or at least about 36 months without refrigeration.

[0044] In certain embodiments, the pharmaceutical compositions and dosage forms provided herein are designed to release Compound A throughout the gastrointestinal tract. In certain embodiments, the compositions and dosage forms are designed to allow for pH-dependent release of Compound A in the gastrointestinal tract. In certain embodiments, the compositions and dosage forms are designed to allow for pH-independent release of Compound A in the gastrointestinal tract.

[0045] In certain embodiments, the pharmaceutical compositions and dosage forms provided herein are tailored to provide once a day dosing option in order to enhance patient compliance and to reduce or eliminate peaks and troughs associated with twice a day dosing.

[0046] Also provided herein are oral dosage forms for use in methods of treating, managing, and / or preventing a disease or condition, which comprises administering to a patient in need thereof a pharmaceutical composition or a dosage form provided herein.

[0047] In certain embodiments, the pharmaceutical dosage forms provided herein are capsules. In certain embodiments, the pharmaceutical dosage forms provided herein are tablets.

[0048] In certain embodiments, the pharmaceutical dosage forms provided herein are multiparticulate formulations. In certain embodiments, the multiparticulate formulations comprise discrete units. In certain embodiments, the multiparticulates are minitabs or minitablets.

[0049] In one embodiment, the dosage form is suitable for administration in a size 4 or larger capsule.6.1 Oral Dosage Forms

[0050] In embodiments, the invention relates to oral dosage forms comprising first, second, and third component dosage forms, as defined in the claims (e.g., as described below).6.1.1 Formulation A

[0051] Diluents include, but are not limited to, lactose (e.g., lactose monohydrate (FAST FLO ®< 316)), cellulose (e.g., microcrystalline cellulose, such as AVICEL ®< PH 101 and AVICEL ®< PH 102). 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. In yet another embodiment, the diluent is cellulose. In yet another embodiment, the diluent is microcrystalline cellulose. In yet another embodiment, the diluent is AVICEL ®< PH 101. In still another embodiment, the diluent is AVICEL ®< PH 102). The oral dosage forms as defined in the claims comprise lactose monohydrate and microcrystalline cellulose.

[0052] Surfactants include, but are not limited to, organosulfate (e.g., sodium lauryl sulfate). In one embodiment, the surfactant is sodium lauryl sulfate. The oral dosage forms as defined in the claims comprise sodium lauryl sulfate.

[0053] Disintegrants include, but are not limited to, carboxymethyl cellulose (e.g., croscarmellose sodium, such as AC-DI-SOL ®< ). In one embodiment, the disintegrant is carboxymethyl cellulose. In another embodiment, the disintegrant is croscarmellose sodium. In still another embodiment, the disintegrant is AC-DI-SOL ®< . The oral dosage forms as defined in the claims comprise carboxymethyl cellulose.

[0054] Glidants include, but are not limited to fumed silica (e.g., silicon oxide, such as colloidal silicon dioxide). In one embodiment, the gilant is fumed silica. In another embodiment, the gilant is silicon oxide. In another embodiment, the gilant is colloidal silicon dioxide. The oral dosage forms as defined in the claims comprise colloidal silicon dioxide.

[0055] Lubricants include, but are not limited to, magnesium stearate (e.g., magnesium stearate, vegetable source). In one embodiment, the lubricant is magnesium stearate. In another embodiment, the lubricant is magnesium stearate, vegetable source. The oral dosage forms as defined in the claims comprise magnesium stearate.

[0056] Coats include, but are not limited to, Opadry (e.g., Opadry clear). In one embodiment, the coat is Opadry. In another embodiment, the coat is Opadry clear. The oral dosage forms as defined in the claims comprise Opadry.

[0057] In one embodiment, provided herein is a pharmaceutical composition comprising 10-30% by weight of Compound A, 40-50% by weight of lactose monohydrate, 20-30% by weight of microcrystalline cellulose, 1-5% by weight of sodium lauryl sulfate, 1-5% by weight of carboxymethyl cellulose, 1-5% by weight of colloidal silicon dioxide, 0.1-2% by weight of magnesium stearate and 1-5% by weight of Opadry.

[0058] In one embodiment, provided herein is a pharmaceutical composition comprising about 19% by weight of Compound A, about 43% by weight of lactose monohydrate, about 25% by weight of microcrystalline cellulose, about 3% by weight of sodium lauryl sulfate, about 3% by weight of carboxymethyl cellulose, about 2% by weight of colloidal silicon dioxide, about 1% by weight of magnesium stearate and about 4% by weight of Opadry.

[0059] In one embodiment, provided herein is a pharmaceutical composition comprising about 19.23% by weight of Compound A, about 43.44% by weight of lactose monohydrate, about 25.03% by weight of microcrystalline cellulose, about 2.90% by weight of sodium lauryl sulfate, about 2.90% by weight of carboxymethyl cellulose, about 1.95% by weight of colloidal silicon dioxide, about 0.72% by weight of magnesium stearate and about 3.85% by weight of Opadry.

[0060] In one embodiment, provided herein is a pharmaceutical composition comprising 10-30% by weight of Compound A, 40-50% by weight of lactose monohydrate, 20-30% by weight of microcrystalline cellulose, 1-5% by weight of sodium lauryl sulfate, 1-5% by weight of croscarmellose sodium, 1-5% by weight of colloidal silicon dioxide, 0.1-2% by weight of magnesium stearate and 1-5% by weight of Opadry.

[0061] In one embodiment, provided herein is a pharmaceutical composition comprising about 19% by weight of Compound A, about 43% by weight of lactose monohydrate, about 25% by weight of microcrystalline cellulose, about 3% by weight of sodium lauryl sulfate, about 3% by weight of croscarmellose sodium, about 2% by weight of colloidal silicon dioxide, about 1% by weight of magnesium stearate and about 4% by weight of Opadry.

[0062] In one embodiment, provided herein is a pharmaceutical composition comprising about 19.23% by weight of Compound A, about 43.44% by weight of lactose monohydrate, about 25.03% by weight of microcrystalline cellulose, about 2.90% by weight of sodium lauryl sulfate, about 2.90% by weight of croscarmellose sodium, about 1.95% by weight of colloidal silicon dioxide, about 0.72% by weight of magnesium stearate and about 3.85% by weight of Opadry.

[0063] In one embodiment, provided herein is a pharmaceutical composition comprising 10-30% by weight of Compound A, 40-50% by weight of FAST FLO ®< 316, 20-30% by weight of AVICEL ®< PH 101 or AVICEL ®< PH 102, 1-5% by weight of sodium lauryl sulfate, 1-5% by weight of AC DI SOL ®< , 1-5% by weight of colloidal silicon dioxide, 0.1-2% by weight of magnesium stearate vegetable source and 1-5% by weight of Opadry clear.

[0064] In one embodiment, provided herein is a pharmaceutical composition comprising about 19.23% by weight of Compound A, about 43.44% by weight of FAST FLO ®< 316, about 25.03% by weight of AVICEL ®< PH 101 or AVICEL ®< PH 102, about 2.90% by weight of sodium lauryl sulfate, about 2.90% by weight of AC-DI-SOL ®< , about 1.95% by weight of colloidal silicon dioxide, about 0.72% by weight of magnesium stearate vegetable source and about 3.85% by weight of Opadry clear.

[0065] In certain embodiments, the weight of a pharmaceutical composition is about 5-15 mg and comprises about 0.5-3 mg Compound A, about 1-5 mg lactose monohydrate, about 1-5 mg microcrystalline cellulose, about 0.1-1 mg sodium lauryl sulfate, about 0.1-1 mg carboxymethyl cellulose, about 0.05-0.5 mg colloidal silicon dioxide, about 0.01-0.3 mg magnesium stearate and about 0.1-0.5 mg Opadry.

[0066] In certain embodiments, the weight of a pharmaceutical composition is about 7.8 mg and comprises about 1.5 mg Compound A, about 3.388 mg lactose monohydrate, about 1.952 mg microcrystalline cellulose, about 0.226 mg sodium lauryl sulfate, about 0.226 mg carboxymethyl cellulose, about 0.152 mg colloidal silicon dioxide, about 0.056 mg magnesium stearate and about 0.300 mg Opadry.

[0067] In certain embodiments, the weight of a pharmaceutical composition is 5-15 mg and comprises 0.5-3 mg Compound A, 1-5 mg lactose monohydrate, 1-5 mg microcrystalline cellulose, 0.1-1 mg sodium lauryl sulfate, 0.1-1 mg croscarmellose sodium, 0.05-0.5 mg colloidal silicon dioxide, 0.01-0.3 mg magnesium stearate and 0.1-0.5 mg Opadry.

[0068] In certain embodiments, the weight of a pharmaceutical composition is about 7.8 mg and comprises about 1.5 mg Compound A, about 3.388 mg lactose monohydrate, about 1.952 mg microcrystalline cellulose, about 0.226 mg sodium lauryl sulfate, about 0.226 mg croscarmellose sodium, about 0.152 mg colloidal silicon dioxide, about 0.056 mg magnesium stearate and about 0.300 mg Opadry.

[0069] In certain embodiments, the weight of a pharmaceutical composition is 5-15 mg and comprises 0.5-3 mg Compound A, 1-5 mg FAST FLO ®< 316, 1-5 mg AVICEL ®< PH 101 or AVICEL ®< PH 102, 0.1-1 mg sodium lauryl sulfate, 0.1-1 mg AC DI SOL ®< , 0.05-0.5 mg colloidal silicon dioxide, 0.01-0.3 mg magnesium stearate vegetable source and 0.1-0.5 mg Opadry clear.

[0070] In certain embodiments, the weight of a pharmaceutical composition is about 7.8 mg and comprises about 1.5 mg Compound A, about 3.388 mg FAST FLO ®< 316, about 1.952 mg AVICEL ®< PH 101 or AVICEL ®< PH 102, about 0.226 mg sodium lauryl sulfate, about 0.226 mg AC DI SOL ®< , about 0.152 mg colloidal silicon dioxide, about 0.056 mg magnesium stearate vegetable source and about 0.300 mg Opadry clear.6.1.2 Formulation B

[0071] Diluents include, but are not limited to, lactose (e.g., lactose monohydrate (FAST FLO ®< 316)), cellulose (e.g., microcrystalline cellulose, such as AVICEL ®< PH 101 and AVICEL ®< PH 102). 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. In yet another embodiment, the diluent is cellulose. In yet another embodiment, the diluent is microcrystalline cellulose. In yet another embodiment, the diluent is AVICEL ®< PH 101. In still another embodiment, the diluent is AVICEL ®< PH 102). The oral dosage forms as defined in the claims comprise lactose monohydrate and microcrystalline cellulose.

[0072] Surfactants include, but are not limited to, organosulfate (e.g., sodium lauryl sulfate). In one embodiment, the surfactant is sodium lauryl sulfate. The oral dosage forms as defined in the claims comprise sodium lauryl sulfate.

[0073] Disintegrants include, but are not limited to, carboxymethyl cellulose (e.g., croscarmellose sodium, such as AC-DI-SOL ®< ). In one embodiment, the disintegrant is carboxymethyl cellulose. In another embodiment, the disintegrant is croscarmellose sodium. In still another embodiment, the disintegrant is AC-DI-SOL ®< . The oral dosage forms as defined in the claims comprise carboxymethyl cellulose.

[0074] Glidants include, but are not limited to fumed silica (e.g., silicon oxide, such as colloidal silicon dioxide). In one embodiment, the gilant is silicon oxide. In another embodiment, the gilant is colloidal silicon dioxide. The oral dosage forms as defined in the claims comprise colloidal silicon dioxide.

[0075] Lubricants include, but are not limited to, magnesium stearate (e.g., magnesium stearate, vegetable source). In one embodiment, the lubricant is magnesium stearate. In another embodiment, the lubricant is magnesium stearate, vegetable source. The oral dosage forms as defined in the claims comprise magnesium stearate.

[0076] Polymers include, but are not limited to, poly(methacrylic acid, ethyl acrylate) (e.g., poly(methacrylic acid, ethyl acrylate) white). In one embodiment, the modified-release coat is poly(methacrylic acid, ethyl acrylate). In another embodiment, the modified-release coat is poly(methacrylic acid, ethyl acrylate) white. In another embodiment, the modified-release coat is poly(methacrylic acid, ethyl acrylate, 1:1) white. The oral dosage forms as defined in the claims comprise poly(methacrylic acid, ethyl acrylate).

[0077] Plasticizers include, but are not limited to, triethyl citrate. In one embodiment, the plasticizer is triethyl citrate. The oral dosage forms as defined in the claims comprise triethyl citrate.

[0078] Coats include, but are not limited to, Opadry (e.g., Opadry clear). In one embodiment, the coat is Opadry. In another embodiment, the coat is Opadry clear. The oral dosage forms as defined in the claims comprise Opadry.

[0079] In one embodiment, provided herein is a pharmaceutical composition comprising 5-30% by weight of Compound A, 15-45% by weight of lactose monohydrate, 5-30% by weight of microcrystalline cellulose, 1-5% by weight of sodium lauryl sulfate, 1-5% by weight of carboxymethyl cellulose, 0.5-5% by weight of colloidal silicon dioxide, 0.1-2% by weight of magnesium stearate, 10-50% by weight of poly(methacrylic acid, ethyl acrylate), about 1-10% by weight of triethyl citrate and about 1-10% by weight of Opadry.

[0080] In one embodiment, provided herein is a pharmaceutical composition comprising about 13% by weight of Compound A, about 30% by weight of lactose monohydrate, about 17% by weight of microcrystalline cellulose, about 2% by weight of sodium lauryl sulfate, about 2% by weight of carboxymethyl cellulose, about 1% by weight of colloidal silicon dioxide, about 1% by weight of magnesium stearate, about 25% by weight of poly(methacrylic acid, ethyl acrylate), about 3% by weight of triethyl citrate and about 6% by weight of Opadry.

[0081] In one embodiment, provided herein is a pharmaceutical composition comprising about 13.33% by weight of Compound A, about 30.12% by weight of lactose monohydrate, about 17.35% by weight of microcrystalline cellulose, about 2.01% by weight of sodium lauryl sulfate, about 2.01% by weight of carboxymethyl cellulose, about 1.35% by weight of colloidal silicon dioxide, about 0.50% by weight of magnesium stearate, about 25.21% by weight of poly(methacrylic acid, ethyl acrylate), about 2.52% by weight of triethyl citrate and about 5.58% by weight of Opadry.

[0082] In one embodiment, provided herein is a pharmaceutical composition form comprising 5-30% by weight of Compound A, 15-45% by weight of lactose monohydrate, 5-30% by weight of microcrystalline cellulose, 1-5% by weight of sodium lauryl sulfate, 1-5% by weight of croscarmellose sodium, 0.5-5% by weight of colloidal silicon dioxide, 0.1-2% by weight of magnesium stearate, 10-50% by weight of poly(methacrylic acid, ethyl acrylate), 1-10% by weight of triethyl citrate and 1-10% by weight of Opadry.

[0083] In one embodiment, provided herein is a pharmaceutical composition comprising about 13% by weight of Compound A, about 30% by weight of lactose monohydrate, about 17% by weight of microcrystalline cellulose, about 2% by weight of sodium lauryl sulfate, about 2% by weight of croscarmellose sodium, about 1% by weight of colloidal silicon dioxide, about 1% by weight of magnesium stearate, about 25% by weight of poly(methacrylic acid, ethyl acrylate), about 3% by weight of triethyl citrate and about 6% by weight of Opadry.

[0084] In one embodiment, provided herein is a pharmaceutical composition comprising about 13.33% by weight of Compound A, about 30.12% by weight of lactose monohydrate, about 17.35% by weight of microcrystalline cellulose, about 2.01% by weight of sodium lauryl sulfate, about 2.01% by weight of croscarmellose sodium, about 1.35% by weight of colloidal silicon dioxide, about 0.50% by weight of magnesium stearate, about 25.21% by weight of poly(methacrylic acid, ethyl acrylate), about 2.52% by weight of triethyl citrate and about 5.58% by weight of Opadry.

[0085] In one embodiment, provided herein is a pharmaceutical composition comprising 5-30% by weight of Compound A, 15-45% by weight of FAST FLO ®< 316, 5-30% by weight of AVICEL ®< PH 101 or AVICEL ®< PH 102, 1-5% by weight of sodium lauryl sulfate, 1-5% by weight of AC DI SOL ®< , 0.5-5% by weight of colloidal silicon dioxide, 0.1-2% by weight of magnesium stearate vegetable source, 10-50% by weight of poly(methacrylic acid, ethyl acrylate) white, 1-10% by weight of triethyl citrate and about 1-10% by weight of Opadry clear.

[0086] In one embodiment, provided herein is a pharmaceutical composition comprising about 13.33% by weight of Compound A, about 30.12% by weight of FAST FLO ®< 316, about 17.35% by weight of AVICEL ®< PH 101 or AVICEL ®< PH 102, about 2.01% by weight of sodium lauryl sulfate, about 2.01% by weight of AC-DI-SOL ®< , about 1.35% by weight of colloidal silicon dioxide, about 0.50% by weight of magnesium stearate vegetable source, about 25.21% by weight of poly(methacrylic acid, ethyl acrylate) white, about 2.52% by weight of triethyl citrate and about 5.58% by weight of Opadry clear.

[0087] In certain embodiments, the weight of a pharmaceutical composition is about 5-20 mg and comprises about 0.5-3 mg Compound A, about 1-5 mg lactose monohydrate, about 1-5 mg microcrystalline cellulose, about 0.1-1 mg sodium lauryl sulfate, about 0.1-1 mg carboxymethyl cellulose, about 0.05-0.5 mg colloidal silicon dioxide, about 0.01-0.3 mg magnesium stearate, about 1-5 mg poly(methacrylic acid, ethyl acrylate), about 0.1-1 mg triethyl citrate and about 0.1-1 mg Opadry.

[0088] In certain embodiments, the weight of a pharmaceutical composition is about 11.248 mg and comprises about 1.5 mg Compound A, about 3.388 mg lactose monohydrate, about 1.952 mg microcrystalline cellulose, about 0.226 mg sodium lauryl sulfate, about 0.226 mg carboxymethyl cellulose, about 0.152 mg colloidal silicon dioxide, about 0.056 mg magnesium stearate, about 2.836 mg poly(methacrylic acid, ethyl acrylate), about 0.284 mg triethyl citrate and about 0.628 mg Opadry.

[0089] In certain embodiments, the weight of a pharmaceutical composition is 5-20 mg and comprises 0.5-3 mg Compound A, 1-5 mg lactose monohydrate, 1-5 mg microcrystalline cellulose, 0.1-1 mg sodium lauryl sulfate, 0.1-1 mg croscarmellose sodium, 0.05-0.5 mg colloidal silicon dioxide, 0.01-0.3 mg magnesium stearate, 1-5 mg poly(methacrylic acid, ethyl acrylate), 0.1-1 mg triethyl citrate and 0.1-1 mg Opadry.

[0090] In certain embodiments, the weight of a pharmaceutical composition is about 11.248 mg and comprises about 1.5 mg Compound A, about 3.388 mg lactose monohydrate, about 1.952 mg microcrystalline cellulose, about 0.226 mg sodium lauryl sulfate, about 0.226 mg croscarmellose sodium, about 0.152 mg colloidal silicon dioxide, about 0.056 mg magnesium stearate, about 2.836 mg poly(methacrylic acid, ethyl acrylate), about 0.284 mg triethyl citrate and about 0.628 mg Opadry.

[0091] In certain embodiments, the weight of a pharmaceutical composition is 5-20 mg and comprises 0.5-3 mg Compound A, 1-5 mg FAST FLO ®< 316, 1-5 mg AVICEL ®< PH 101 or AVICEL ®< PH 102, 0.1-1 mg sodium lauryl sulfate, 0.1-1 mg AC DI SOL ®< , 0.05-0.5 mg colloidal silicon dioxide, 0.01-0.3 mg magnesium stearate vegetable source, 1-5 mg poly(methacrylic acid, ethyl acrylate) white, 0.1-1 mg triethyl citrate and 0.1-1 mg Opadry clear.

[0092] In certain embodiments, the weight of a pharmaceutical composition is about 11.248 mg and comprises about 1.5 mg Compound A, about 3.388 mg FAST FLO ®< 316, about 1.952 mg AVICEL ®< PH 101 or AVICEL ®< PH 102, about 0.226 mg sodium lauryl sulfate, about 0.226 mg AC DI SOL ®< , about 0.152 mg colloidal silicon dioxide, about 0.056 mg magnesium stearate vegetable source, about 2.836 mg poly(methacrylic acid, ethyl acrylate), about 0.284 mg triethyl citrate and about 0.628 mg Opadry clear.6.1.3 Formulation C

[0093] Diluents include, but are not limited to, lactose (e.g., lactose monohydrate (FAST FLO ®< 316)), cellulose (e.g., microcrystalline cellulose, such as AVICEL ®< PH 101 and AVICEL ®< PH 102). 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. In yet another embodiment, the diluent is cellulose. In yet another embodiment, the diluent is microcrystalline cellulose. In yet another embodiment, the diluent is AVICEL ®< PH 101. In still another embodiment, the diluent is AVICEL ®< PH 102). The oral dosage forms as defined in the claims comprise lactose monohydrate and microcrystalline cellulose.

[0094] Surfactants include, but are not limited to, organosulfate (e.g., sodium lauryl sulfate). In one embodiment, the surfactant is sodium lauryl sulfate. The oral dosage forms as defined in the claims comprise sodium lauryl sulfate.

[0095] Disintegrants include, but are not limited to, carboxymethyl cellulose (e.g., croscarmellose sodium, such as AC-DI-SOL ®< ). In one embodiment, the disintegrant is carboxymethyl cellulose. In another embodiment, the disintegrant is croscarmellose sodium. In still another embodiment, the disintegrant is AC-DI-SOL ®< . The oral dosage forms as defined in the claims comprise carboxymethyl cellulose.

[0096] Glidants include, but are not limited to fumed silica (e.g., silicon oxide, such as colloidal silicon dioxide). In one embodiment, the gilant is silicon oxide. In another embodiment, the gilant is colloidal silicon dioxide. The oral dosage forms as defined in the claims comprise colloidal silicon dioxide.

[0097] In certain embodiments, the lubricants include, but are not limited to, magnesium stearate (e.g., magnesium stearate, vegetable source). In one embodiment, the lubricant is magnesium stearate. In another embodiment, the lubricant is magnesium stearate, vegetable source. The oral dosage forms as defined in the claims comprise magnesium stearate.

[0098] Polymers include, but are not limited to, poly(methyl acrylate, methyl methacrylate, methacrylic acid). In one embodiment, the polymer is poly(methyl acrylate, methyl methacrylate, methacrylic acid). In another embodiment, the polymer is poly(methyl acrylate, methyl methacrylate, methacrylic acid, 7:3:1). The oral dosage forms as defined in the claims comprise poly(methyl acrylate, methyl methacrylate, methacrylic acid).

[0099] Plasticizers include, but are not limited to and triethyl citrate. In one embodiment, the plasticizer is triethyl citrate. The oral dosage forms as defined in the claims comprise triethyl citrate.

[0100] In one embodiment, the modified-release coat is poly(methyl acrylate, methyl methacrylate, methacrylic acid). In another embodiment, the modified-release coat is poly(methyl acrylate, methyl methacrylate, methacrylic acid, 7:3:1). The oral dosage forms as defined in the claims comprise poly(methyl acrylate, methyl methacrylate, methacrylic acid).

[0101] Coats include, but are not limited to, Opadry (e.g., Opadry clear). In one embodiment, the coat is Opadry. In another embodiment, the coat is Opadry clear. The oral dosage forms as defined in the claims comprise Opadry.

[0102] In one embodiment, provided herein is a pharmaceutical composition comprising 5-30% by weight of Compound A, 15-50% by weight of lactose monohydrate, 5-40% by weight of microcrystalline cellulose, 1-5% by weight of sodium lauryl sulfate, 1-5% by weight of carboxymethyl cellulose, 0.5-5% by weight of colloidal silicon dioxide, 0.1-2% by weight of magnesium stearate, 1-10% by weight of poly(methyl acrylate, methyl methacrylate, methacrylic acid), 0.1-5% by weight of triethyl citrate and 1-10% by weight of Opadry.

[0103] In one embodiment, provided herein is a pharmaceutical composition comprising about 18% by weight of Compound A, about 41% by weight of lactose monohydrate, about 24% by weight of microcrystalline cellulose, about 3% by weight of sodium lauryl sulfate, about 3% by weight of carboxymethyl cellulose, about 2% by weight of colloidal silicon dioxide, about 1% by weight of magnesium stearate, about 5% by weight of poly(methyl acrylate, methyl methacrylate, methacrylic acid), about 1% by weight of triethyl citrate and about 4% by weight of Opadry.

[0104] In one embodiment, provided herein is a pharmaceutical composition comprising about 18.14% by weight of Compound A, about 40.98% by weight of lactose monohydrate, about 23.61% by weight of microcrystalline cellulose, about 2.73% by weight of sodium lauryl sulfate, about 2.73% by weight of carboxymethyl cellulose, about 1.84% by weight of colloidal silicon dioxide, about 0.68% by weight of magnesium stearate, about 5.09% by weight of poly(methyl acrylate, methyl methacrylate, methacrylic acid), about 0.57% by weight of triethyl citrate and about 3.63% by weight of Opadry.

[0105] In one embodiment, provided herein is a pharmaceutical composition comprising 5-30% by weight of Compound A, 15-50% by weight of lactose monohydrate, 5-40% by weight of microcrystalline cellulose, 1-5% by weight of sodium lauryl sulfate, 1-5% by weight of croscarmellose sodium, 0.5-5% by weight of colloidal silicon dioxide, 0.1-2% by weight of magnesium stearate, 1-10% by weight of poly(methyl acrylate, methyl methacrylate, methacrylic acid), 0.1-5% by weight of triethyl citrate and 1-10% by weight of Opadry.

[0106] In one embodiment, provided herein is a pharmaceutical composition comprising about 18% by weight of Compound A, about 41% by weight of lactose monohydrate, about 24% by weight of microcrystalline cellulose, about 3% by weight of sodium lauryl sulfate, about 3% by weight of croscarmellose sodium, about 2% by weight of colloidal silicon dioxide, about 1% by weight of magnesium stearate, about 5% by weight of poly(methyl acrylate, methyl methacrylate, methacrylic acid), about 1% by weight of triethyl citrate and about 4% by weight of Opadry.

[0107] In one embodiment, provided herein is a pharmaceutical composition comprising about 18.14% by weight of Compound A, about 40.98% by weight of lactose monohydrate, about 23.61% by weight of microcrystalline cellulose, about 2.73% by weight of sodium lauryl sulfate, about 2.73% by weight of croscarmellose sodium, about 1.84% by weight of colloidal silicon dioxide, about 0.68% by weight of magnesium stearate, about 5.09% by weight of poly(methyl acrylate, methyl methacrylate, methacrylic acid), about 0.57% by weight of triethyl citrate and about 3.63% by weight of Opadry.

[0108] In one embodiment, provided herein is a pharmaceutical composition comprising 5-30% by weight of Compound A, 15-50% by weight of FAST FLO ®< 316, 5-40% by weight of AVICEL ®< PH 101 or AVICEL ®< PH 102, 1-5% by weight of sodium lauryl sulfate, 1-5% by weight of AC DI SOL ®< , 0.5-5% by weight of colloidal silicon dioxide, 0.1-2% by weight of magnesium stearate vegetable source, 1-10% by weight of poly(methyl acrylate, methyl methacrylate, methacrylic acid), 0.1-5% by weight of triethyl citrate and 1-10% by weight of Opadry clear.

[0109] In one embodiment, provided herein is a pharmaceutical composition comprising about 18.14% by weight of Compound A, about 40.98% by weight of FAST FLO ®< 316, about 23.61% by weight of AVICEL ®< PH 101 or AVICEL ®< PH 102, about 2.73% by weight of sodium lauryl sulfate, about 2.73% by weight of AC-DI-SOL ®< , about 1.84% by weight of colloidal silicon dioxide, about 0.68% by weight of magnesium stearate vegetable source, about 5.09% by weight of poly(methyl acrylate, methyl methacrylate, methacrylic acid), about 0.57% by weight of triethyl citrate and about 3.63% by weight of Opadry clear.

[0110] In certain embodiments, the weight of a pharmaceutical composition is about 5-20 mg and comprises about 0.5-3 mg Compound A, about 1-5 mg lactose monohydrate, about 1-5 mg microcrystalline cellulose, about 0.1-1 mg sodium lauryl sulfate, about 0.1-1 mg carboxymethyl cellulose, about 0.05-0.5 mg colloidal silicon dioxide, about 0.01-0.3 mg magnesium stearate, about 0.1-5 mg poly(methyl acrylate, methyl methacrylate, methacrylic acid), about 0.01-1 mg triethyl citrate and about 0.1-1 mg Opadry.

[0111] In certain embodiments, the weight of a pharmaceutical composition is about 8.268 mg and comprises about 1.5 mg Compound A, about 3.388 mg lactose monohydrate, about 1.952 mg microcrystalline cellulose, about 0.226 mg sodium lauryl, about 0.226 mg carboxymethyl cellulose, about 0.152 mg colloidal silicon dioxide, about 0.056 mg magnesium stearate, about 0.421 mg poly(methyl acrylate, methyl methacrylate, methacrylic acid), about 0.047 mg triethyl citrate and about 0.300 mg Opadry.

[0112] In certain embodiments, the weight of a pharmaceutical composition is 5-20 mg and comprises 0.5-3 mg Compound A, 1-5 mg lactose monohydrate, 1-5 mg microcrystalline cellulose, 0.1-1 mg sodium lauryl sulfate, 0.1-1 mg croscarmellose sodium, 0.05-0.5 mg colloidal silicon dioxide, 0.01-0.3 mg magnesium stearate, 0.1-5 mg poly(methyl acrylate, methyl methacrylate, methacrylic acid), 0.01-1 mg triethyl citrate and 0.1-1 mg Opadry.

[0113] In certain embodiments, the weight of a pharmaceutical composition is about 8.268 mg and comprises about 1.5 mg Compound A, about 3.388 mg lactose monohydrate, about 1.952 mg microcrystalline cellulose, about 0.226 mg sodium lauryl sulfate, about 0.226 mg croscarmellose sodium, about 0.152 mg colloidal silicon dioxide, about 0.056 mg magnesium stearate, about 0.421 mg poly(methyl acrylate, methyl methacrylate, methacrylic acid), about 0.047 mg triethyl citrate and about 0.300 mg Opadry.

[0114] In certain embodiments, the weight of a pharmaceutical composition is 5-20 mg and comprises 0.5-3 mg Compound A, 1-5 mg FAST FLO ®< 316, 1-5 mg AVICEL ®< PH 101 or AVICEL ®< PH 102, 0.1-1 mg sodium lauryl sulfate, 0.1-1 mg AC DI SOL ®< , 0.05-0.5 mg colloidal silicon dioxide, 0.01-0.3 mg magnesium stearate vegetable source, 0.1-5 mg poly(methyl acrylate, methyl methacrylate, methacrylic acid), 0.01-1 mg triethyl citrate and 0.1-1 mg Opadry clear.

[0115] In certain embodiments, the weight of a pharmaceutical composition is about 8.268 mg and comprises about 1.5 mg Compound A, about 3.388 mg FAST FLO ®< 316, about 1.952 mg AVICEL ®< PH 101 or AVICEL ®< PH 102, about 0.226 mg sodium lauryl sulfate, about 0.226 mg AC DI SOL ®< , about 0.152 mg colloidal silicon dioxide, about 0.056 mg magnesium stearate vegetable source, about 0.421 mg poly(methyl acrylate, methyl methacrylate, methacrylic acid), about 0.047 mg triethyl citrate and about 0.300 mg Opadry clear.6.1.4 Formulation D

[0116] Diluents include, but are not limited to, starch (e.g., pregelatinized starch), cellulose (e.g., microcrystalline cellulose, such as AVICEL ®< PH 101 and AVICEL ®< PH 102). In one embodiment, the diluent is starch. In another embodiment, the diluent is pregelatinized starch. In yet another embodiment, the diluent is cellulose. In yet another embodiment, the diluent is microcrystalline cellulose. In yet another embodiment, the diluent is AVICEL ®< PH 101. In still another embodiment, the diluent is AVICEL ®< PH 102. The oral dosage forms as defined in the claims comprise starch and microcrystalline cellulose.

[0117] Surfactants include, but are not limited to, organosulfate (e.g., sodium lauryl sulfate). In one embodiment, the surfactant is sodium lauryl sulfate. The oral dosage forms as defined in the claims comprise sodium lauryl sulfate.

[0118] Glidants include, but are not limited to fumed silica (e.g., silicon oxide, such as colloidal silicon dioxide). In one embodiment, the gilant is silicon oxide. In another embodiment, the gilant is colloidal silicon dioxide. The oral dosage forms as defined in the claims comprise colloidal silicon dioxide.

[0119] Lubricants include, but are not limited to, magnesium stearate (e.g., magnesium stearate, vegetable source). In one embodiment, the lubricant is magnesium stearate. In another embodiment, the lubricant is magnesium stearate, vegetable source. The oral dosage forms as defined in the claims comprise magnesium stearate.

[0120] Polymers include, but are not limited to, polyethylene oxide and ethylcellulose (e.g., ethylcellulose clear). In one embodiment, the polymer is polyethylene oxide. In another embodiments, the polymer is ethylcellulose. In another embodiments, the polymer is ethylcellulose clear. The oral dosage forms as defined in the claims comprise polyethylene oxide.

[0121] Pore formers include, but are not limited to, Opadry (e.g., Opadry clear). In one embodiment, the pore former is Opadry. In another embodiment, the pore former is Opadry clear. The oral dosage forms as defined in the claims comprise Opadry.

[0122] Coats include, but are not limited to, Opadry (e.g., Opadry clear). In one embodiment, the coat is Opadry. In one embodiment, the coat is Opadry. In another embodiment, the coat is Opadry clear. The oral dosage forms as defined in the claims comprise Opadry.

[0123] In one embodiment, the modified-release coat is ethylcellulose. In another embodiment, the modified-release coat is ethylcellulose clear. The oral dosage forms as defined in the claims comprise ethylcellulose.

[0124] In one embodiment, provided herein is a pharmaceutical composition comprising 5-30% by weight of Compound A, 5-50% by weight of starch, 5-40% by weight of microcrystalline cellulose, 1-5% by weight of sodium lauryl sulfate, 0.5-5% by weight of colloidal silicon dioxide, 0.1-2% by weight of magnesium stearate, 10-50% by weight of polyethylene oxide, 1-10% by weight of ethylcellulose, 1-10% by weight of Opadry as pore former and about 1-10% by weight of Opadry as coat.

[0125] In one embodiment, provided herein is a pharmaceutical composition comprising about 17% by weight of Compound A, about 13% by weight of starch, about 26% by weight of microcrystalline cellulose, about 3% by weight of sodium lauryl sulfate, about 2% by weight of colloidal silicon dioxide, about 0.5% by weight of magnesium stearate, about 26% by weight of polyethylene oxide, about 6% by weight of ethylcellulose, about 3% by weight of Opadry as pore former and about 6% by weight of Opadry as coat.

[0126] In one embodiment, provided herein is a pharmaceutical composition comprising about 17.25% by weight of Compound A, about 12.97% by weight of starch, about 25.51% by weight of microcrystalline cellulose, about 2.60% by weight of sodium lauryl sulfate, about 1.72% by weight of colloidal silicon dioxide, about 0.44% by weight of magnesium stearate, about 25.94% by weight of polyethylene oxide, about 6.49% by weight of ethylcellulose, about 2.91% by weight of Opadry as pore former and about 6.37% by weight of Opadry as coat.

[0127] In one embodiment, provided herein is a pharmaceutical composition comprising 5-30% by weight of Compound A, 5-50% by weight of pregelatinized starch, 5-40% by weight of microcrystalline cellulose, 1-5% by weight of sodium lauryl sulfate, 0.5-5% by weight of colloidal silicon dioxide, 0.1-2% by weight of magnesium stearate, 10-50% by weight of polyethylene oxide, 1-10% by weight of ethylcellulose, 1-10% by weight of Opadry as pore former and 1-10% by weight of Opadry as coat.

[0128] In one embodiment, provided herein is a pharmaceutical composition comprising about 17% by weight of Compound A, about 13% by weight of pregelatinized starch, about 26% by weight of microcrystalline cellulose, about 3% by weight of sodium lauryl sulfate, about 2% by weight of colloidal silicon dioxide, about 0.5% by weight of magnesium stearate, about 26% by weight of polyethylene oxide, about 6% by weight of ethylcellulose, about 3% by weight of Opadry as pore former and about 6% by weight of Opadry as coat.

[0129] In one embodiment, provided herein is a pharmaceutical composition comprising about 17.25% by weight of Compound A, about 12.97% by weight of pregelatinized starch, about 25.51% by weight of microcrystalline cellulose, about 2.60% by weight of sodium lauryl sulfate, about 1.72% by weight of colloidal silicon dioxide, about 0.44% by weight of magnesium stearate, about 25.94% by weight of polyethylene oxide, about 6.49% by weight of ethylcellulose, about 2.91% by weight of Opadry as pore former and about 6.37% by weight of Opadry as coat.

[0130] In one embodiment, provided herein is a pharmaceutical composition comprising 5-30% by weight of Compound A, 5-50% by weight of pregelatinized starch, 5-40% by weight of AVICEL ®< PH 101 or AVICEL ®< PH 102, 1-5% by weight of sodium lauryl sulfate, 0.5-5% by weight of colloidal silicon dioxide, 0.1-2% by weight of magnesium stearate, 10-50% by weight of polyethylene oxide, 1-10% by weight of ethylcellulose clear, 1-10% by weight of Opadry clear as pore former and 1-10% by weight of Opadry clear as coat.

[0131] In one embodiment, provided herein is a pharmaceutical composition comprising about 17.25% by weight of Compound A, about 12.97% by weight of pregelatinized starch, about 25.51% by weight of AVICEL ®< PH 101 or AVICEL ®< PH 102, about 2.60% by weight of sodium lauryl sulfate, about 1.72% by weight of colloidal silicon dioxide, about 0.44% by weight of magnesium stearate, about 25.94% by weight of polyethylene oxide, about 6.49% by weight of ethylcellulose clear, about 2.91% by weight of Opadry clear as pore former and about 6.37% by weight of Opadry clear as coat.

[0132] In certain embodiments, the weight of a pharmaceutical composition is 5-20 mg and comprises 0.5-3 mg Compound A, 1-5 mg starch, 1-5 mg microcrystalline cellulose, 0.1-1 mg sodium lauryl sulfate, 0.05-0.5 mg colloidal silicon dioxide, 0.01-0.3 mg magnesium stearate, 0.1-5 mg polyethylene oxide, 0.1-1 mg ethylcellulose, 0.1-1 mg Opadry as pore former and 0.1-1 mg Opadry as coat.

[0133] In certain embodiments, the weight of a pharmaceutical composition is about 8.696 mg and comprises about 1.5 mg Compound A, about 1.128 mg starch, about 2.218 mg microcrystalline cellulose, about 0.226 mg sodium lauryl sulfate, about 0.150 mg colloidal silicon dioxide, about 0.038 mg magnesium stearate, about 2.256 mg polyethylene oxide, about 0.564 mg ethylcellulose, about 0.253 mg Opadry as pore former and about 0.554 mg Opadry as coat.

[0134] In certain embodiments, the weight of a pharmaceutical composition is 5-20 mg and comprises 0.5-3 mg Compound A, 1-5 mg pregelatinized starch, 1-5 mg microcrystalline cellulose, 0.1-1 mg sodium lauryl sulfate, 0.05-0.5 mg colloidal silicon dioxide, 0.01-0.3 mg magnesium stearate, 0.01-0.3 mg polyethylene oxide, 0.1-1 mg ethylcellulose, 0.1-1 mg Opadry as pore former and 0.1-1 mg Opadry as coat.

[0135] In certain embodiments, the weight of a pharmaceutical composition is about 8.696 mg and comprises about 1.5 mg Compound A, about 1.128 mg pregelatinized starch, about 2.218 mg microcrystalline cellulose, about 0.226 mg sodium lauryl sulfate, about 0.150 mg colloidal silicon dioxide, about 0.038 mg magnesium stearate, about 2.256 mg polyethylene oxide, about 0.564 mg ethylcellulose, about 0.253 mg Opadry as pore former and about 0.554 mg Opadry as coat.

[0136] In certain embodiments, the weight of a pharmaceutical composition is about 5-20 mg and comprises 0.5-3 mg Compound A, 1-5 mg pregelatinized starch, 1-5 mg AVICEL ®< PH 101 or AVICEL ®< PH 102, 0.1-1 mg sodium lauryl sulfate, 0.05-0.5 mg colloidal silicon dioxide, 0.01-0.3 mg magnesium stearate, 0.1-5 mg polyethylene oxide, 0.1-1 mg ethylcellulose clear, 0.1-1 mg Opadry clear as pore former and 0.1-1 mg Opadry clear as coat.

[0137] In certain embodiments, the weight of a pharmaceutical composition is about 8.696 mg and comprises about 1.5 mg Compound A, about 1.128 mg pregelatinized starch, about 2.218 mg AVICEL ®< PH 101 or AVICEL ®< PH 102, about 0.226 mg sodium lauryl sulfate, about 0.150 mg colloidal silicon dioxide, about 0.038 mg magnesium stearate, about 2.256 mg polyethylene oxide, about 0.564 mg ethylcellulose clear, about 0.253 mg Opadry clear as pore former and about 0.554 mg Opadry clear as coat.6.1.7 Oral Dosage Forms of the Invention

[0138] In one embodiment, provided herein is a pharmaceutical composition comprising Formulations A, B and C, as defined by the claims, wherein A, B, and C are as defined above.

[0139] Provided herein is an oral dosage form comprising about 20-60% by weight of a first component dosage form as defined in the claims (e.g., Formulation A described above), about 10-30% by weight of a second component dosage form as defined in the claims (e.g., Formulation B described above) and about 30-60% by weight of a third component dosage form as defined in the claims (e.g., Formulation C described above).

[0140] In one embodiment, provided herein is a pharmaceutical composition comprising about 34.03% by weight of a first component dosage form as defined in the claims (e.g., Formulation A as described above), about 20.98% by weight of a second component dosage form as defined in the claims (e.g., Formulation B as described above) and about 44.99% by weight of a third component dosage form as defined in the claims (e.g., Formulation C as described above).

[0141] In certain embodiments, provided herein are oral dosage forms weighing about 429 mg. In one embodiment, the oral dosage form comprises about 146 mg of a first component dosage form as defined in the claims (e.g., Formulation A as described above), about 90 mg of a second component dosage form as defined in the claims (e.g., Formulation B as described above) and about 193 mg of a third component dosage form as defined in the claims (e.g., Formulation C as described above).

[0142] Provided herein are oral dosage forms comprising about 20-60% by weight of a first component dosage form, about 10-30% by weight of a second component dosage form and about 30-60% by weight of a third component dosage form, wherein the first component dosage form comprises about 10-30% by weight of Compound A, about 40-50% by weight of lactose monohydrate, about 20-30% by weight of microcrystalline cellulose, about 1-5% by weight of sodium lauryl sulfate, about 1-5% by weight of carboxymethyl cellulose, about 1-5% by weight of colloidal silicon dioxide, about 0.1-2% by weight of magnesium stearate and about 1-5% by weight of Opadry; wherein the second component dosage form comprises about 5-30% by weight of Compound A, about 15-45% by weight of lactose monohydrate, about 5-30% by weight of microcrystalline cellulose, about 1-5% by weight of sodium lauryl sulfate, about 1-5% by weight of carboxymethyl cellulose, about 0.5-5% by weight of colloidal silicon dioxide, about 0.1-2% by weight of magnesium stearate, about 10-50% by weight of poly(methacrylic acid, ethyl acrylate), about 1-10% by weight of triethyl citrate and about 1-10% by weight of Opadry; and wherein the third component dosage form comprises about 5-30% by weight of Compound A, about 15-50% by weight of lactose monohydrate, about 5-40% by weight of microcrystalline cellulose, about 1-5% by weight of sodium lauryl sulfate, about 1-5% by weight of carboxymethyl cellulose, about 0.5-5% by weight of colloidal silicon dioxide, about 0.1-2% by weight of magnesium stearate, about 1-10% by weight of poly(methyl acrylate, methyl methacrylate, methacrylic acid), about 0.1-5% by weight of triethyl citrate and about 1-10% by weight of Opadry.

[0143] In certain embodiments, the oral dosage forms are capsules.

[0144] In one embodiment, provided herein is a capsule oral dosage form suitable for administration in a size 4 or larger capsule.

[0145] In one embodiment, the oral dosage form is a multiparticulate formulation comprising discrete units (e.g., multiparticulates, minitabs or minitablets) of the first, second, and third component dosage forms (e.g., Formulations, A, B, and C as described above).

[0146] In certain embodiments, the oral dosage forms provide pH-dependent release of Compound A (see, e.g., FIG. 6).

[0147] Without being limited by theory, the amount of each component dosage form (e.g., the first, second, and third component dosage forms) that comprises pharmaceutical compositions of the oral dosage form can dictate the pH-release profile.6.1.8 Other Oral Dosage Forms of the Invention

[0148] In one embodiment, provided herein is a pharmaceutical composition comprising Formulations A, C and D, as defined in the claims, wherein A, C, and D are as defined above.

[0149] In one embodiment, provided herein is a pharmaceutical composition comprising about 24.82% by weight of Formulation A, about 13.13% by weight of Formulation C and about 62.05% by weight of Formulation D.

[0150] In certain embodiments, provided herein are oral dosage forms comprising about 20-60% by weight of a first component dosage form, about 10-30% by weight of a second component dosage form and about 30-60% by weight of a third component dosage form, wherein the first component dosage form comprises about 10-30% by weight of Compound A, about 40-50% by weight of lactose monohydrate, about 20-30% by weight of microcrystalline cellulose, about 1-5% by weight of sodium lauryl sulfate, about 1-5% by weight of carboxymethyl cellulose, about 1-5% by weight of colloidal silicon dioxide, about 0.1-2% by weight of magnesium stearate and about 1-5% by weight of Opadry; wherein the second component dosage form comprises about 5-30% by weight of Compound A, about 15-50% by weight of lactose monohydrate, about 5-40% by weight of microcrystalline cellulose, about 1-5% by weight of sodium lauryl sulfate, about 1-5% by weight of carboxymethyl cellulose, about 0.5-5% by weight of colloidal silicon dioxide, about 0.1-2% by weight of magnesium stearate, about 1-10% by weight of poly(methyl acrylate, methyl methacrylate, methacrylic acid), about 0.1-5% by weight of triethyl citrate and about 1-10% by weight of Opadry; and wherein the third component dosage form comprises about 5-30% by weight of Compound A, about 5-50% by weight of starch, about 5-40% by weight of microcrystalline cellulose, about 1-5% by weight of sodium lauryl sulfate, about 0.5-5% by weight of colloidal silicon dioxide, about 0.1-2% by weight of magnesium stearate, about 10-50% by weight of polyethylene oxide, about 1-10% by weight of ethylcellulose, about 1-10% by weight of Opadry as pore former and about 1-10% by weight of Opadry as coat.

[0151] In certain embodiments, the oral dosage forms are capsule dosage forms.

[0152] In one embodiment, provided herein is a capsule dosage form suitable for administration in a size 4 or larger capsule.

[0153] In one embodiment, Formulation H is a multiparticulate formulation comprising discrete units (e.g., multiparticulates, minitabs or minitablets) of Formulations A, C and D.

[0154] In certain embodiments, the pharmaceutical compositions comprising Formulation H provide pH-dependent release of Compound A (see, e.g., FIG. 7).

[0155] Without being limited by theory, the amount of each component dosage form (e.g., Formulations A, C and D) that comprises pharmaceutical compositions of Formulation H can dictate the pH-release profile.6.2 Second Active Agents

[0156] In certain embodiments, provided herein are oral dosage forms of Compound A as defined in the claims, which may further comprise one or more secondary active ingredients. Certain combinations may work synergistically in the treatment of particular types diseases or disorders, and conditions and symptoms associated with such diseases or disorders. In certain embodiments, Compound A can also work to alleviate adverse effects associated with certain second active agents, and vice versa.

[0157] Specific second active compounds that can be contained in the formulations and dosage forms provided herein vary depending on the specific indication to be treated, prevented or managed.

[0158] For instance, for the treatment, prevention or management of cancer, second active agents include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alfa 2a; interferon alfa 2b; interferon alfa n1 ; interferon alfa n3; interferon beta I a; interferon gamma I b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride. Other anti cancer drugs include, but are not limited to: 20 epi 1,25 dihydroxyvitamin D3; 5 ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti dorsalizing morphogenetic protein 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara CDP DL PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL 2; capecitabine; carboxamide amino triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro 5 azacytidine; dihydrotaxol, 9 ; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin like growth factor 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4 ; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N acetyldinaline; N substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6 benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis acridone; prostaglandin J2; proteasome inhibitors; protein A based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

[0159] Additional embodiments of the second active compounds include, but not limited to: adalimumab, alefacept, azathioprine, certolizumab pegol, corticosteroids, cyclosporin, cyclosporine, diclofenac, efalizumab, etanercept, etodolac, golimumab, ibuprofen, indomethacin, infliximab, leflunomide, methotrexate, naproxen, nonsteroidal anti-inflammatory drugs, Opioid analgesics, phenylbutazone, retinoids, sulfasalazine, taclonex scalp, the biologics etanercept, tocilizumab, and ustekinumab.

[0160] Examples of such additional therapeutic agents include, but are not limited to: antihistamines including, but not limited to, ethanolamines, ethylenediamines, piperazines, and phenothiazines; antinflammatory drugs; NSAIDS, including, but not limited to, aspirin, salicylates, acetominophen, indomethacin, sulindac, etodolac, fenamates, tolmetin, ketorolac, diclofenac, ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, piroxicam, meloxicam, pyrazolon derivatives; and steriods including, but not limited to, cortical steroids, adrenocortical steroids, anti-inflammatory drugs, antihistamines and decongestants.6.3 Process For Making Dosage Forms

[0161] Dosage forms of the invention can be prepared by any of the methods of pharmacy, but all 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 excipients 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.

[0162] A dosage form of the invention can be prepared by compression or molding, optionally 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 as above 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. Encapsulation of the dosage forms provided herein can be done using capsules of methylcellulose, calcium alginate, or gelatin.

[0163] The active ingredients and excipients can be directly blended and loaded into, for example, a capsule, or compressed directly into tablets. A direct-blended dosage form may be more advantageous than a compacted (e.g., roller-compacted) dosage form in certain instances, since direct-blending can reduce or eliminate the harmful health effects that may be caused by airborne particles of ingredients during the manufacture using compaction process.

[0164] Direct blend formulations may be advantageous in certain instances because they require only one blending step, that 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.

[0165] 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 excipients 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. Therefore, disclosed 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.

[0166] Disclosed herein are methods for preparing a composition provided herein, comprising: (i) weighing out the desired amount of Compound A and the desired amount of excipients; (ii) mixing or blending Compound A and the excipients; (iii) passing the mixture of Compound A and excipients through a screen; (iv) mixing or blending Compound A and the excipients after passage through the screen; (v) weighing out the desired amount of lubricating agents; (vi) passing the lubricating agents through a screen; (vii) mixing or blending Compound A the excipients and the lubricating agents; (viii) compressing the mixture of Compound A, the excipients and the lubricating agents; and (ix) coating the compressed mixture of Compound A, the excipients and the lubricating agents with a coating agent. In one instance, the excipient is lactose monohydrate. In another instance, the excipient is croscarmellose sodium. In yet another instance, the excipient is microcrystalline cellulose. In one instance, the screen is 18 mesh screen. In another instance, the screen is 1000 µm screen. In one instance, the screen is 30 mesh screen. In another instance, the screen is 600 µm screen. In one instance, the lubricating agent is stearic acid. In another instance, the lubricating agent is magnesium stearate. In one instance, the coating agent is Opadry clear. In another instance, the coating agent is Opadry pink. In another instance, the coating agent is Opadry yellow. In another instance, the coating agent is Opadry beige. In one instance, the mixture of Compound A, the excipients and the lubricating agents is compressed into a tablet form.

[0167] Disclosed herein are methods for preparing a composition provided herein, comprising: (i) weighing out the desired amount of Compound A and the desired amount of excipients (such as lactose monohydrate, croscarmellose sodium and microcrystalline cellulose); (ii) passing the excipients through a screen (such as an 18 mesh or 1000 µm screen); (iii) mixing or blending Compound A and the excipients; (iv) passing the mixture of Compound A and excipients through a screen; (v) mixing or blending Compound A and the excipients; (vi) weighing out the desired amount of lubricating agents; (vii) passing the lubricating agents through a screen; (viii) mixing or blending Compound A, the excipients and the lubricating agents; (ix) compressing the mixture of Compound A, the excipients and the lubricating agents; and (x) coating the compressed mixture of Compound A, the excipients and the lubricating agents with a coating agent. In one instance, the screen is 18 mesh screen. In another instance, the screen is 1000 µm screen. In one instance, the screen is 30 mesh screen. In another instance, the screen is 600 µm screen. In one instance, the mixing or blending speed is 26 revolutions per minute. In one instance, the mixing or blending process lasts for 20 minutes. In one instance, the mixture of Compound A, the excipients and the lubricating agents is compressed into a tablet form. In one instance, the coating agent is Opadry clear. In another instance, the coating agent is Opadry pink. In another instance, the coating agent is Opadry yellow. In ther instance, the coating agent is Opadry beige.6.3.1 Screening

[0168] theThe process for making the pharmaceutical compositions can include the screening of the active ingredient and the excipient(s). In one instance, the active ingredient is passed through a screen having openings of about 200 microns to about 750 microns. In another instance, the active ingredient is passed through a screen with openings of about 200 microns to about 400 microns. In one instance, the active ingredient is passed through a screen having openings of about 300 to qbout 400 microns. Depending on the excipient(s) used, the screen openings vary. For example, disintegrants and binders are passed through openings of about 430 microns to about 750 microns, from about 600 microns to about 720 microns, or about 710 microns. Lubricants are typically passed through smaller openings, e.g., about 150 microns to about 250 microns screen. In one instance, the lubricant is passed through a screen opening of about 210 microns.6.3.2 Pre-Blending

[0169] After the ingredients are screened, the excipient and active ingredient are mixed in a diffusion mixer. In one instance, the mixing time is from about 1 minute to about 50 minutes, from about 5 minutes to about 45 minutes, from about 10 minutes to about 40 minutes, or from about 10 minutes to about 25 minutes. In another instance, the mixing time is about 15 minutes.

[0170] When more than one excipients are used, the excipients may be admixed in a tumble blender for about 1 minute to about 20 minutes, or for about 5 minutes to about 10 minutes, prior to mixing with the active ingredient.6.3.3 Roller Compaction

[0171] In one instance, the pre-blend may optionally be passed through a roller compactor with a hammer mill attached at the discharge of the compactor.6.3.4 Final Blend

[0172] When a lubricant, e.g., magnesium stearate, vegetable source, is used, the lubricant is mixed with the pre-blend at the end of the process to complete the pharmaceutical composition. This additional mixing is from about 1 minute to about 10 minutes, or from about 3 minutes to about 5 minutes.6.3.5 Encapsulation

[0173] The formulation mixture is then encapsulated into the desired size capsule shell using, for example, a capsule filling machine or a rotary tablet press.6.4 Kits

[0174] Described herein are kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a patient.

[0175] Kits may comprise an oral dosage form of the invention, and a unit dosage form of a second active ingredient. Examples of second active ingredients include, but are not limited to, those listed herein.

[0176] Kits can further comprise devices that are used to administer the active ingredient(s). Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers.

[0177] Kit can further comprise pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injecti'n, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lacta'ed Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, com oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.6.5 Dissolution Profile

[0178] In certain embodiments, tablets or capsules of the invention comprising Compound A have a dissolution profile wherein about 100% of Compound A is released in about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours in water, diluted HCl aqueous solution or other aqueous buffer solutions of about pH 1 to about pH 10 (e.g., about pH 3), with or without surfactant, with a paddle speed of 50 rpm or 75 rpm, or with a basket speed of 100 rpm or 150 rpm.

[0179] In certain embodiments, tablets or capsules of the invention comprising Compound A have a dissolution profile wherein about 50% of Compound A is released in about 2-4 hours in an aqueous solution of about pH 4.5 with a basket speed of 150 rpm.

[0180] In certain embodiments, tablets or capsules of the invention comprising Compound A have a dissolution profile wherein about 50% of Compound A is released in about 1-3 hours in an aqueous solution of about pH 4.5 with a basket speed of 150 rpm.

[0181] In certain embodiments, tablets or capsules of the invention comprising Compound A have a dissolution profile wherein about 50% of Compound A is released in about 1-2 hours in an aqueous solution of about pH 4.5 with a basket speed of 150 rpm.

[0182] In certain embodiments, tablets or capsules of the invention comprising Compound A have a dissolution profile wherein about 50% of Compound A is released in about 1-3 hours in an aqueous solution of about pH 4.5 with a basket speed of 150 rpm.

[0183] In certain embodiments, tablets or capsules of the invention comprising Compound A have a dissolution profile wherein about 50% of Compound A is released in about 5-7 hours in an aqueous solution of about pH 4.5 with a paddle speed of 75 rpm.6.6 Methods of Treatment, Prevention, and Management

[0184] The invention also provides oral dosage forms for use in methods of treating, preventing, and / or managing certain diseases, as defined in the claims. The methods may comprise administration of an effective amount of the oral dosage form to a patient having said disease.

[0185] Examples of diseases or disorders that the oral dosage forms of the invention are useful for treating, preventing or managing include, but are not limited to: heart disease, such as congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction; solid tumors, including but not limited to, sarcoma, carcinomas, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, Kaposi's sarcoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma, and retinoblastoma; and blood-born tumors including but not limited to, acute lymphoblastic leukemia "ALL", acute lymphoblastic B cell leukemia, acute lymphoblastic T cell leukemia, acute myeloblastic leukemia "AML", acute promyelocytic leukemia "APL", acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocyctic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia "CML", chronic lymphocytic leukemia "CLL", hairy cell leukemia, multiple myeloma and acute and chronic leukemias, for example, lymphoblastic, myelogenous, lymphocytic, and myelocytic leukemias.

[0186] Specific methods provided herein further comprise the administration of an additional therapeutic agent (i.e., a therapeutic agent other than apremilast). Examples of additional therapeutic agents include, but are not limited to, those listed herein.

[0187] Further provided herein are methods of treating or preventing diseases or disorders ameliorated by the inhibition of PDE4 in a patient which comprise administering to a patient in need of such treatment or prevention a therapeutically effective amount of stereomerically pure apremilast, or a pharmaceutically acceptable prodrug, metabolite, polymorph, salt, solvate, hydrate, or clathrate thereof. Disorders ameliorated by the inhibition of PDE4 include, but are not limited to, asthma, inflammation, chronic or acute obstructive pulmonary disease, chronic or acute pulmonary inflammatory disease, inflammatory bowel disease, Crohn's Disease, ankylosing spondylitis, Behcet's Disease, colitis, ulcerative colitis and arthritis (including psoriatic arthritis) or inflammation due to reperfusion. In a preferred embodiment, the disease or disorder to be treated or prevented is chronic obstructive pulmonary disease.

[0188] Specific methods provided herein can further comprise the administration of an additional therapeutic agent such as, but not limited to, anti-inflammatory drugs, antihistamines and decongestants. Examples of such additional therapeutic agents include, but are not limited to: antihistamines including, but not limited to, ethanolamines, ethylenediamines, piperazines, and phenothiazines; antinflammatory drugs; NSAIDS, including, but not limited to, aspirin, salicylates, acetominophen, indomethacin, sulindac, etodolac, fenamates, tolmetin, ketorolac, diclofenac, ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, piroxicam, meloxicam, pyrazolon derivatives; and steriods including, but not limited to, cortical steroids and adrenocortical steroids.

[0189] Specific methods provided herein can avoid or reduce drug-drug interactions and other adverse effects associated with agents used in the treatment of such disorders, including racemic substituted phenylethylsulfones. Without being limited by any theory, stereomerically pure apremilast may further provide an overall improved therapeutic effectiveness, or therapeutic index, over racemic 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione. For example, a smaller amount of the drug may in some circumstances be administered to attain the same level of effectiveness.

[0190] In certain embodiments, the active compound (i.e., apremilast) may be used in the treatment or prevention of a wide range of diseases and conditions. The magnitude of a prophylactic or therapeutic dose of a particular active ingredient in the acute or chronic management of a disease or condition will vary, however, 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 1000 mg per day, given as a single once-a-day dose preferably as divided doses throughout a day. More specifically, the daily dose is administered twice daily in equally divided doses. Specifically, a daily dose range should 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, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, and 200 mg dosage forms. In managing the patient, the therapy should be initiated at a lower dose, perhaps about 1 mg to about 25 mg, and increased if necessary up to about 200 mg to about 1000 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.

[0191] 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.7. Examples

[0192] 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. The invention is defined by the claims. Any examples falling outside the scope of the claims are provided for reference.7.1 Example 1

[0193] Table 1 provides a dosage formulation for a 1.5 mg strength apremilast single unit dose immediate release (IR) minitablet that was prepared (Formulation A). Table 1: Composition of IR Minitablets (Formulation A)Component Function mg / tablet ApremilastActive ingredient1.500Lactose monohydrateDiluent3.388Microcrystalline celluloseDiluent1.952Sodium lauryl sulfateSurfactant0.226Croscarmellose sodiumDisintegrant0.226Colloidal silicon dioxideGlidant0.152Magnesium stearate, Vegetable sourceLubricant0.056Total uncoated minitablet weight 7.500Opadry clearCoat0.300Water purified*Total 7.800* Removed during processing 7.2 Example 2

[0194] Table 2 provides a dosage formulation for a 1.5 mg strength apremilast single unit dose modified released (MR) minitablet coated with poly(methacrylic acid, ethyl acrylate, 1:1) that was prepared (Formulation B). Table 2: Composition of MR Minitablets Coated with Poly(methacrylic acid, ethyl acrylate, 1:1) (Formulation B)Component Function mg / tablet ApremilastActive ingredient1.500Lactose monohydrateDiluent3.388Microcrystalline celluloseDiluent1.952Sodium lauryl sulfateSurfactant0.226Croscarmellose sodiumDisintegrant0.226Colloidal silicon dioxideGlidant0.152Magnesium stearate, Vegetable sourceLubricant0.056Total uncoated minitablet weight7.500Opadry clearCoat0.300Water purified*Total seal coated minitablet weight 7.800Poly(methacrylic acid, ethyl acrylate) whitePolymer / Modified release coat2.836Triethyl citratePlasticizer0.284Water purified*Total poly(methacrylic acid, ethyl acrylate) coated minitab 10.920Opadry clearCoat0.328Water purified *Total 11.248* Removed during processing 7.3 Example 3

[0195] Table 3 provides a dosage formulation for a 1.5 mg strength apremilast single unit dose modified released (MR) minitablet coated with poly(methyl acrylate, methyl methacrylate, methacrylic acid, 7:3:1) that was prepared (Formulation C). Table 3: Composition of MR Minitablets Coated with Poly(methyl acrylate, methyl methacrylate, methacrylic acid, 7:3:1) (Formulation C)Component Function mg / tablet ApremilastActive ingredient1.500Lactose monohydrateDiluent3.388Microcrystalline celluloseDiluent1.952Sodium lauryl sulfateSurfactant0.226Croscarmellose sodiumDisintegrant0.226Colloidal silicon dioxideGlidant0.152Magnesium stearate, Vegetable sourceLubricant0.056Total uncoated minitablet weight 7.500Opadry clearCoat0.300Water purified*Total seal coated minitablet weight 7.800Poly(methyl acrylate, methyl methacrylate, methacrylic acid)Polymer / Modified release coat0.421Triethyl citratePlasticizer0.047Water purified*Total 8.268* Removed during processing 7.4 Example 4

[0196] Table 4 provides a dosage formulation for a 1.5 mg strength apremilast single unit dose modified released (MR) matrix minitablet coated with ethylcellulose that was prepared (Formulation D). Table 4: Composition of MR Matrix Minitablets Coated with Ethylcellulose (Formulation D)Component Function mg / tablet ApremilastActive ingredient1.500Microcrystalline celluloseDiluent2.218Polyethylene oxidePolymer / Modified release component2.256Pregelatinized starchDiluent1.128Sodium lauryl sulfateSurfactant0.226Colloidal silicon dioxideGlidant0.150Magnesium stearate, Vegetable sourceLubricant0.038Total uncoated minitablet weight 7.516Opadry clearCoat0.301Water purified*Total seal coated minitablet weight 7.817Ethylcellulose clearPolymer / Modified release coat0.564Opadry clearPore former0.062Water purified*Total ethylcellulose coated minitab 8.443Opadry clearCoat0.253Water purified*Total 8.696* Removed during processing 7.5 Reference Example 5

[0197] Table 5 provides a dosage formulation for a 75 mg strength apremilast single dose MR unit in a size #0 capsule that was prepared (Formulation E). Table 5: Composition of Apremilast (or Compound A) 75 mg MR Capsules (Formulation E)Minitablet population E IR Minitablet (A)0 mgMR Minitablet coated with Poly(methacrylic acid, ethyl acrylate, 1:1) (B)0 mgMR Minitablet coated with Poly(methyl acrylate, methyl methacrylate, methacrylic acid, 7:3:1) (C)0 mgMR Matrix Minitablets Coated with Ethylcellulose (D)434 mgSize 0 White Gelatin Capsule1 unit

[0198] Dissolution profile is provided in FIG. 4. The dissolution profile of Formulation E is measured in an aqueous solution with 0.5%wt sodium lauryl sulfate with a basket speed of 150 rpm. The pH of the aqueous solution is 4.5 for 6 hours after the measurement starts, and then adjusted to 7.4.7.6 Reference Example 6

[0199] Table 6 provides a dosage formulation for a 75 mg strength apremilast single dose MR unit in a size #0 capsule that was prepared (Formulation F). Table 6: Composition of Apremilast (or Compound A) 75 mg MR Capsules (Formulation F)Minitablet population F IR Minitablet (A)78 mgMR Minitablet coated with Poly(methacrylic acid, ethyl acrylate, 1:1) (B)0 mgMR Minitablet coated with Poly(methyl acrylate, methyl methacrylate, methacrylic acid, 7:3:1) (C)0 mgMR Matrix Minitablets Coated with Ethylcellulose (D)347 mgSize 0 White Gelatin Capsule1 unit

[0200] Dissolution profile is provided in FIG. 5. The dissolution profile of Formulation F is measured in an aqueous solution with 0.5%wt sodium lauryl sulfate with a basket speed of 150 rpm. The pH of the aqueous solution is 4.5 for 6 hours after the measurement starts, and then adjusted to 7.4.7.7 Example 7

[0201] Table 7 provides a dosage formulation for a 75 mg strength apremilast single dose MR unit in a size #0 capsule that was prepared (Formulation G). Table 7: Composition of Apremilast (or Compound A) 75 mg MR Capsules (Formulation G)Minitablet population G IR Minitablet (A)146 mgMR Minitablet coated with Poly(methacrylic acid, ethyl acrylate, 1:1) (B)90 mgMR Minitablet coated with Poly(methyl acrylate, methyl methacrylate, methacrylic acid, 7:3:1) (C)193 mgMR Matrix Minitablets Coated with Ethylcellulose (D)0 mgSize 0 White Gelatin Capsule1 unit

[0202] Dissolution profile is provided in FIG. 6. The dissolution profile of Formulation G is measured in an aqueous solution with 0.5%wt sodium lauryl sulfate with a basket speed of 150 rpm. The pH of the aqueous solution is 4.5 for 2 hours after the measurement starts, and then adjusted to 7.4. The dissolution profile of Formulation G indicates a pH dependent release process.7.8 Example 8

[0203] Table 8 provides a dosage formulation for a 75 mg strength apremilast single dose MR unit in a size #0 capsule that was prepared (Formulation H). Table 8: Composition of Apremilast (or Compound A) 75 mg MR Capsules (Formulation H)Minitablet population H IR Minitablet (A)104 mgMR Minitablet coated with Poly(methacrylic acid, ethyl acrylate, 1:1) (B)0 mgMR Minitablet coated with Poly(methyl acrylate, methyl methacrylate, methacrylic acid, 7:3:1) (C)55 mgMR Matrix Minitablets Coated with Ethylcellulose (D)260 mgSize 0 White Gelatin Capsule1 unit

[0204] Dissolution profile is provided in FIG. 7. The dissolution profile of Formulation H is measured in an aqueous solution with 0.5%wt sodium lauryl sulfate with a basket speed of 150 rpm. The pH of the aqueous solution is 4.5 for 6 hours after the measurement starts, and then adjusted to 7.4. The dissolution profile of Formulation H indicates a pH dependent release process.7.9 Reference Example 9

[0205] Table 9 provides a dosage formulation for a 75 mg strength apremilast single unit dose modified release (MR) tablet that was prepared (Formulation I). Table 9: Composition of 75 mg Apremilast MR Tablets (Formulation I)Component Function Quality Standard mg / tablet Batch Formula ApremilastActive ingredientIn-house75.0450.0Microcrystalline celluloseDiluentNF147.5885.0Pregelatinized starchDiluentNF100.0600.0Polyethylene oxidePolymer / Modified release componentNF150.0900.0Sodium lauryl sulfateSurfactantNF15.090.0Colloidal silicon dioxideGlidantNF10.060.0Magnesium stearate, Vegetable sourceLubricantNF2.515.0Total 500.03000.0

[0206] Dissolution profile is provided in FIG. 8. The dissolution profile of Formulation I is measured in an aqueous solution with 0.3%wt sodium lauryl sulfate with a paddle speed of 75 rpm. The pH of the aqueous solution is 4.5.7.10 Reference Example 10

[0207] Table 10 provides dosage formulations for single dose MR units in a size #0 capsule with 80 mg strength apremilast (Formulations J, K, L, M). Table 10: Composition of Apremilast (or Compound A) MR Capsules (Formulations J, K, L, M)Minitablet population J K L M IR Minitablet (A)156 mg156 mg0 mg208 mgMR Matrix Minitablets with or without ethylcellulose coate (D)289.2 mg250 mg400 mg231.4 mgSize 0 White Gelatin Capsule1 unit1 unit1 unit1 unitApremilast strength80 mg80 mg80 mg80 mg 7.11 Reference Example 11

[0208] As described in FIG. 1, a manufacturing process for the 75 mg apremilast modified release (MR) tablet comprises steps of: (1) loading microcrystalline cellulose, apremilast drug substance, polyethylene oxide, pregelatinized starch, sodium lauryl sulfate and silicon dioxide in a blender and blending; (2) screening the blend from step 1, loading the screened blend in the blender and blending; (3) screening magnesium stearate, loading the screened magnesium stearate and the blend in the blender from step 2 and blending; and (4) compressing the blend from step 3 to tablets.7.12 Reference Example 12

[0209] As described in FIG. 2, a manufacturing process for apremilast immediate release (IR) minitablets coated with modified release coat comprises steps of: (1) screening apremilast drug substance, lactose monohydrate, microcrystalline cellulose, sodium lauryl sulfate, croscarmellose sodium, and colloidal silicon dioxide, loading the screened mixture in a blender and blending; (2) screening the blend from step 1, loading the screened mixture in the blender and blending; (3) screening magnesium stearate, loading the screened magnesium stearate and the blender from step 2 in the blender and blending; (4) compressing the blender from step 3 to minitablets; (5) seal coating the minitablets from step 4 with Opadry; and (6) coating the seal coated minitablets from step 5 with poly(methacrylic acid, ethyl acrylate) and / or poly(methyl acrylate, methyl methacrylate, methacrylic acid).7.13 Reference Example 13

[0210] As described in FIG. 3, a manufacturing process for apremilast modified released (MR) matrix minitablets coated with modified release coat comprises steps of: (1) screening apremilast drug substance, microcrystalline cellulose, polyethylene oxide, pregelatinized starch, sodium lauryl sulfate, and colloidal silicon dioxide, loading the screened mixture in a blender and blending; (2) screening the blend from step 1, loading the screened blend in a blender and blending; (3) screening magnesium stearate, load the screened magnesium stearate and the blender from step 2 and blending; (4) compressing the blend from step 3 to minitablets; (5) seal coating the minitablets from step 4 with Opadry; and (6) coating the coated minitablets from step 5 with ethylcellulose.7.14 Reference Example 14

[0211] A manufacturing process for a apremilast MR formulation for administration in a capsule comprises: 1) mixing different amount of minitablets provided herein; and (2) encapsulating the mixture from step 1 into a size 1 or larger capsule.

Claims

1. An oral dosage form comprising 20-60% by weight of a first component dosage form, 10-30% by weight of a second component dosage form and 30-60% by weight of a third component dosage form, wherein the first component dosage form comprises 10-30% by weight of apremilast, or a pharmaceutically acceptable salt thereof, 40-50% by weight of lactose monohydrate, 20-30% by weight of microcrystalline cellulose, 1-5% by weight of sodium lauryl sulfate, 1-5% by weight of carboxymethyl cellulose, 1-5% by weight of colloidal silicon dioxide, and 0.1-2% by weight of magnesium stearate and 1-5% by weight of Opadry; wherein the second component dosage form comprises 5-30% by weight of apremilast, or a pharmaceutically acceptable salt thereof, 15-45% by weight of lactose monohydrate, 5-30% by weight of microcrystalline cellulose, 1-5% by weight of sodium lauryl sulfate, 1-5% by weight of carboxymethyl cellulose, 0.5-5% by weight of colloidal silicon dioxide, 0.1-2% by weight of magnesium stearate, 10-50% by weight of poly(methacrylic acid, ethyl acrylate), 1-10% by weight of triethyl citrate and 1-10% by weight of Opadry; and wherein the third component dosage form comprises 5-30% by weight of apremilast, or a pharmaceutically acceptable salt thereof, 15-50% by weight of lactose monohydrate, 5-40% by weight of microcrystalline cellulose, 1-5% by weight of sodium lauryl sulfate, 1-5% by weight of carboxymethyl cellulose, 0.5-5% by weight of colloidal silicon dioxide, 0.1-2% by weight of magnesium stearate, 1-10% by weight of poly(methyl acrylate, methyl methacrylate, methacrylic acid), 0.1-5% by weight of triethyl citrate and 1-10% by weight of Opadry.

2. An oral dosage form comprising 20-60% by weight of a first component dosage form, 10-30% by weight of a second component dosage form and 30-60% by weight of a third component dosage form, wherein the first component dosage form comprises 10-30% by weight of apremilast, or a pharmaceutically acceptable salt thereof, 40-50% by weight of lactose monohydrate, 20-30% by weight of microcrystalline cellulose, 1-5% by weight of sodium lauryl sulfate, 1-5% by weight of carboxymethyl cellulose, 1-5% by weight of colloidal silicon dioxide, 0.1-2% by weight of magnesium stearate and 1-5% by weight of Opadry; wherein the second component dosage form comprises 5-30% by weight of apremilast, or a pharmaceutically acceptable salt thereof, 15-50% by weight of lactose monohydrate, 5-40% by weight of microcrystalline cellulose, 1-5% by weight of sodium lauryl sulfate, 1-5% by weight of carboxymethyl cellulose, 0.5-5% by weight of colloidal silicon dioxide, 0.1-2% by weight of magnesium stearate, 1-10% by weight of poly(methyl acrylate, methyl methacrylate, methacrylic acid), 0.1-5% by weight of triethyl citrate and 1-10% by weight of Opadry; and wherein the third component dosage form comprises 5-30% by weight of apremilast, or a pharmaceutically acceptable salt thereof, 5-50% by weight of starch, 5-40% by weight of microcrystalline cellulose, 1-5% by weight of sodium lauryl sulfate, 0.5-5% by weight of colloidal silicon dioxide, 0.1-2% by weight of magnesium stearate, 10-50% by weight of polyethylene oxide, 1-10% by weight of ethylcellulose, 1-10% by weight of Opadry as pore former and 1-10% by weight of Opadry as coating.

3. The oral dosage form according to claim 1, wherein the first component dosage form comprises 19% by weight of apremilast, or a pharmaceutically acceptable salt thereof, 43% by weight of lactose monohydrate, 25% by weight of microcrystalline cellulose, 3% by weight of sodium lauryl sulfate, 3% by weight of croscarmellose sodium, 2% by weight of colloidal silicon dioxide, 1% by weight of magnesium stearate and 4% by weight of Opadry.

4. The oral dosage form according to claim 1 or 3, wherein the second component dosage form comprises 13% by weight of apremilast, or a pharmaceutically acceptable salt thereof, 30% by weight of lactose monohydrate, 17% by weight of microcrystalline cellulose, 2% by weight of sodium lauryl sulfate, 2% by weight of croscarmellose sodium, 1% by weight of colloidal silicon dioxide, 1% by weight of magnesium stearate, 25% by weight of poly(methacrylic acid, ethyl acrylate), 3% by weight of triethyl citrate and 6% by weight of Opadry.

5. The oral dosage form according to any one of claims 1, 3, or 4, wherein the third component dosage form comprises 18% by weight of apremilast, or a pharmaceutically acceptable salt thereof, 41% by weight of lactose monohydrate, 24% by weight of microcrystalline cellulose, 3% by weight of sodium lauryl sulfate, 3% by weight of croscarmellose sodium, 2% by weight of colloidal silicon dioxide, 1% by weight of magnesium stearate, 5% by weight of poly(methyl acrylate, methyl methacrylate, methacrylic acid), 1% by weight of triethyl citrate and 4% by weight of Opadry.

6. The oral dosage form according to any one of claims 1 or 3-5, wherein the oral dosage form comprises 34.03% by weight of the first component dosage form; 20.98% by weight of the second component dosage form; and 44.99% by weight of the third component dosage form.

7. The oral dosage form according to claim 2, wherein the first component dosage form comprises 19% by weight of apremilast, or a pharmaceutically acceptable salt thereof, 43% by weight of lactose monohydrate, 25% by weight of microcrystalline cellulose, 3% by weight of sodium lauryl sulfate, 3% by weight of croscarmellose sodium, 2% by weight of colloidal silicon dioxide, 1% by weight of magnesium stearate and 4% by weight of Opadry.

8. The oral dosage form according to claim 2 or 7, wherein the second component dosage form comprises 18% by weight of apremilast, or a pharmaceutically acceptable salt thereof, 41% by weight of lactose monohydrate, 24% by weight of microcrystalline cellulose, 3% by weight of sodium lauryl sulfate, 3% by weight of croscarmellose sodium, 2% by weight of colloidal silicon dioxide, 1% by weight of magnesium stearate, 5% by weight of poly(methyl acrylate, methyl methacrylate, methacrylic acid), 1% by weight of triethyl citrate and 4% by weight of Opadry.

9. The oral dosage form according to any one of claims 2, 7, or 8, wherein the third component dosage form comprises 17% by weight of apremilast, or a pharmaceutically acceptable salt thereof, 13% by weight of pregelatinized starch, 26% by weight of microcrystalline cellulose, 3% by weight of sodium lauryl sulfate, 2% by weight of colloidal silicon dioxide, 0.5% by weight of magnesium stearate, 26% by weight of polyethylene oxide, 6% by weight of ethylcellulose, 3% by weight of Opadry as pore former and 6% by weight of Opadry as coat.

10. The oral dosage form according to any one of claims 2 or 7-9, wherein the oral dosage form comprises 24.82% by weight of the first component dosage form; 13.13% by weight of the second component dosage form; and 62.05% by weight of the third component dosage form.

11. The oral dosage form according to any one of claims 1 to 10, wherein the oral dosage form is in the form of tablets and / or capsules.

12. The oral dosage form according to claim 11, wherein the oral dosage form is a capsule.

13. The oral dosage form according to any one of claims 1 to 12 for use in a method for treating, preventing or managing a viral, genetic, inflammatory, allergic or autoimmune disease, wherein the method comprises administering to a patient having a viral, genetic, inflammatory, allergic or autoimmune disease said oral dosage form.