Apremilast Formulations

Abstract

Provided herein is an oral dosage form comprising: a) a core tablet comprising: (i) a drug layer comprising apremilast and hypromellose acetate succinate (HPMCAS) in an amorphous solid dispersion; and (ii) a swellable layer comprising one or more swellable polymers; and b) a coating layer disposed on the core tablet, wherein the oral dosage form surface comprises at least one drug release orifice. The disclosed oral dosage form provides a once-daily administration of apremilast and is suitable for treating diseases or disorders ameliorated by inhibiting phosphodiesterase subtype IV (PDE4).

Description

[Background technology]

[0001] Apremilast is a phosphodiesterase subtype IV ("PDE4") inhibitor that is approved worldwide for the treatment of various diseases associated with inflammation. For example, in the United States, Apremilast is approved for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy, for the treatment of adult patients with active psoriatic arthritis, and for the treatment of adult patients with oral ulcers associated with Behcet's disease. Apremilast is the first and remains the only orally administered PDE4 inhibitor approved for the treatment of these inflammatory diseases. The recommended dosage for adult patients with active PsA and psoriasis is 30 mg orally twice daily (BID) after a 5-day titration intended to relieve gastrointestinal (GI) symptoms associated with initial treatment. Summary of the Invention [Problem to be solved by the invention]

[0002] The goal of developing a drug is to provide a dosage form that allows for maintaining a constant amount or concentration of drug in the body of a clinically or therapeutically relevant subject. In some cases, this may not be achieved by conventional fast disintegrating tablets, as these tablets release the active ingredient contained therein all at once.

[0003] In view of the above, there remains a need for oral dosage forms of apremilast that provide clinically desirable drug exposure. [Means for solving the problem]

[0004] The present disclosure provides an oral dosage form comprising a core tablet comprising: (i) a drug layer comprising apremilast and hypromellose acetate succinate (HPMCAS) in an amorphous solid dispersion; and (ii) a swellable layer comprising one or more swellable polymers; and a coating layer disposed on the core tablet, wherein the oral dosage form surface comprises at least one drug release orifice.

[0005] The present disclosure further relates to a drug layer comprising: (i) 8-11% by weight of apremilast, based on the total weight of the core tablet, 8-11% by weight of hypromellose acetate succinate (HPMCAS), based on the total weight of the core tablet, 2-7% by weight of mannitol, based on the total weight of the core tablet, 40-45% by weight of polyethylene oxide, based on the total weight of the core tablet, 0.1-0.5% by weight of magnesium stearate, based on the total weight of the core tablet, and 0.1-0.5% by weight of colloidal silicon dioxide, based on the total weight of the core tablet, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) ) An oral dosage form is provided, comprising: a core tablet comprising a swellable layer comprising 18 to 25% by weight of polyethylene oxide based on the total weight of the core tablet, 7 to 10% by weight of microcrystalline cellulose based on the total weight of the core tablet, 1.5 to 3.5% by weight of sodium chloride based on the total weight of the core tablet, 0.01 to 0.2% by weight of iron oxide based on the total weight of the core tablet, and 0.05 to 0.3% by weight of magnesium stearate based on the total weight of the core tablet; and a coating layer disposed on the core tablet and comprising cellulose acetate and polyethylene glycol, wherein the surface of the oral dosage form comprises at least one drug release orifice.

[0006] The present disclosure also provides a drug layer comprising: (i) 10-15% by weight of apremilast, based on the total weight of the core tablet; 10-15% by weight of hypromellose acetate succinate (HPMCAS), based on the total weight of the core tablet; 30-40% by weight of polyethylene oxide, based on the total weight of the core tablet; 2-8% by weight of sodium chloride, based on the total weight of the core tablet; 0.1-0.5% by weight of magnesium stearate, based on the total weight of the core tablet; and 0.1-0.5% by weight of colloidal silicon dioxide, based on the total weight of the core tablet, wherein the apremilast and HPMCAS are in a solid dispersion; ii) providing an oral dosage form comprising: a core tablet comprising a swellable layer comprising 18-25% by weight of polyethylene oxide based on the total weight of the core tablet, 7.5-10.0% by weight of microcrystalline cellulose based on the total weight of the core tablet, 2-4% by weight of sodium chloride based on the total weight of the core tablet, 0.01-0.1% by weight of iron oxide based on the total weight of the core tablet, and 0.05-0.3% by weight of magnesium stearate based on the total weight of the core tablet; and a coating layer disposed on the core tablet and comprising cellulose acetate and polyethylene glycol, wherein the surface of the oral dosage form comprises at least one drug release orifice. [Brief description of the drawings]

[0007] [Figure 1] FIG. 1 shows the dissolution profiles of tablets 6 to 10. [Diagram 2] FIG. 1 shows the dissolution profiles of tablets 1 to 5. [Diagram 3] FIG. 1 shows the dissolution profiles of tablet core 5 uncoated or with CA or PEG coating. [Figure 4] FIG. 1 shows the dissolution profiles of tablets 10 to 12. [Diagram 5] FIG. 1 shows the mean (±SD) apremilast plasma concentration-time profile. [Figure 6]FIG. 1 shows apremilast plasma concentrations over 24 hours for 75 mg tablet 21 once daily (open circles) compared to 30 mg immediate release formulation twice daily (closed circles) and 75 mg gastrokinetic (GR) tablet once daily (closed diamonds). [Figure 7] FIG. 1 shows apremilast plasma concentrations over a 5 day period for 75 mg tablet 21 once daily (open circles) compared to 30 mg immediate release formulation twice daily (closed circles) and 75 mg gastrokinetic (GR) tablet once daily (closed diamonds). [Figure 8] FIG. 1 shows the dissolution of core tablet compositions 7-1 to 7-6. [Figure 9] FIG. 1 shows the dissolution of core tablet compositions 7-7 to 7-12. [Figure 10A] FIG. 1 shows the decrease in dissolution of core tablet compositions 7-8 after various storage conditions. [Figure 10B] FIG. 1 shows the increase in crystallinity of core tablet compositions 7-8 after various storage conditions. [Figure 11A] FIG. 1 shows the dissolution of core tablet compositions 7-12 after various storage conditions. [Figure 11B] FIG. 1 shows a comparison of crystallinity in core tablet compositions 7-8 and 7-12 after various storage conditions. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Provided herein is an oral dosage form suitable for providing apremilast once-daily (QD) administration.In some embodiments, the disclosed oral dosage form is administered under fed conditions.

[0009] The oral dosage form disclosed herein comprises a core tablet, a coating layer disposed on the core tablet, and at least one drug release orifice. In some embodiments, the oral dosage form further comprises a subcoat layer between the core tablet and the coating layer.

[0010] Core Tablet The core tablet of the disclosed oral dosage form comprises i) a drug layer comprising apremilast and hypromellose acetate succinate (HPMCAS) in an amorphous solid dispersion, and ii) a swellable layer comprising one or more swellable polymers.

[0011] Drug Layer The drug layer contains an appropriate amount of apremilast. Desirably, the drug layer contains an amount of apremilast suitable to provide a once-daily delivery / administration of apremilast. If the oral dosage form contains too little apremilast, the dosage form will not deliver a clinically relevant amount of apremilast and will not be effective when administered QD. Conversely, if the oral dosage form contains too much apremilast, the dosage form will be inefficient in its use of apremilast and will be overly expensive. Furthermore, if there is too much or too little apremilast, the bioequivalence of the dosage form and / or the flux and release of apremilast from the dosage form may be negatively affected. In some embodiments, the apremilast is present in an amount of 6-15% by weight of the core tablet. Some examples of contemplated amounts of apremilast include, but are not limited to, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13 1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, and 16.0% by weight. In some embodiments, apremilast is present in an amount of 8-11% by weight of the core tablet. In various embodiments, apremilast is present in an amount of 9.6% by weight of the core tablet, 10.2% by weight of the core tablet, or 12.5% ​​by weight of the core tablet.

[0012] In some embodiments, in combination with other embodiments above or below, the oral dosage form contains a total of 25-100 mg of apremilast (e.g., 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78 In some embodiments, in combination with other embodiments described above or below, the oral dosage form comprises 25-30 mg apremilast or 50-100 mg apremilast (e.g., 50-60 mg or 65-85 mg apremilast). In various embodiments, in combination with other embodiments described above or below, the oral dosage form comprises 70, 75 or 80 mg apremilast. In some embodiments, the oral dosage form comprises 27.5 mg of apremilast, 55 mg of apremilast, 75 mg of apremilast, or 100 mg of apremilast.

[0013] In addition to apremilast, the drug layer also includes HPMCAS. As used herein, HPMCAS refers to a family of cellulose derivatives that can have (1) two types of ether substituents, methyl and / or 2-hydroxypropyl, and (2) two types of ester substituents, acetyl and / or succinyl. HPMCAS is also known by the chemical name O-(2-hydroxypropyl)-O-methylcellulose acetate succinate. The degree of substitution of each of the four general types just mentioned can be varied over a wide range to affect the chemical and physical properties of the polymer. This versatility of HPMCAS allows its structure to be optimized to obtain good performance with a particular drug of interest. HPMCAS can be synthesized or purchased commercially. Three commercially available HPMCAS are Shin-EtsuAQOAT®-LF, Shin-EtsuAQOAT®-MF, and Shin-EtsuAQOAT®-HF. All three of these polymers are manufactured by Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan). In some embodiments, the HPMCAS is an L grade (e.g., HPMCAS-LF or HPMCAS-LG or HPMCAS-LMP), where it is understood that the L, M, and H grades of HPMCAS differ in acetyl and succinoyl content. The L, M, and H grades also refer to the pH at which the polymer dissolves (L=low pH≧5.5, M=medium pH≧6.0, and H=high pH≧6.5). The LF, LG, and LMP grades refer to different average particle sizes (F is cohesive fine powder-5 μm, MP is medium particle size-200 μm, and G is free flowing granule-1000 μm).

[0014] HPMCAS may have any suitable molecular weight. In some embodiments, the average weight average molecular weight range of HPMCAS is 10,000 to 1 million daltons (e.g., 10,000 to 400,000 daltons or 55,000 to 115,000 daltons as determined using a polyethylene oxide standard). It should be noted that molecular weights may be given herein as daltons (Da) or g / mol, which are used interchangeably throughout. The molecular weight range may also vary based on the degree of substitution (e.g., the amount of acetyl and / or succinyl groups present). For example, in various embodiments, in conjunction with other embodiments described above or below, the average weight average molecular weight of HPMCAS is about 15,000 to 20,000 daltons, e.g., 15,000, 16,000, 17,000, 18,000, 19,000, or 20,000 daltons. In some embodiments, the average weight average molecular weight of HPMCAS is 17,700, 17,900, 18,800, 18,900, 20,400, or 21,200 Daltons. In some embodiments, along with other embodiments above or below, the number average molecular weight is about 13,000 Daltons.

[0015] The drug layer contains an appropriate amount of HPMCAS. If the drug layer contains too little or too much HPMCAS, the amorphous solid dispersion may not have the desired release characteristics. In some embodiments, HPMCAS is 6-15% by weight of the core tablet (e.g., 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9 or 15.0% by weight. In some embodiments, HPMCAS is present in an amount of 8-11% by weight of the core tablet. In various embodiments, HPMCAS is present in an amount of 9.6% by weight of the core tablet, 10.2% by weight of the core tablet, or 12.5% ​​by weight of the core tablet.

[0016] In some embodiments, in combination with other embodiments above or below, the oral dosage form comprises a total amount of 25-100 mg of HPMCAS (e.g., 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78 In some embodiments, in conjunction with other embodiments above or below, the oral dosage form comprises 65-85 mg of HPMCAS. In various embodiments, in conjunction with other embodiments above or below, the oral dosage form comprises 25-30 mg of HPMCAS or 50-100 mg of HPMCAS (e.g., 50-60 mg or 65-85 mg of HPMCAS). In various embodiments, in combination with other embodiments described above or below, the oral dosage form contains 70, 75, or 80 mg of HPMCAS. In some embodiments, the oral dosage form contains 27.5 mg of HPMCAS, 55 mg of HPMCAS, 75 mg of HPMCAS, or 100 mg of HPMCAS.

[0017] In various embodiments, apremilast and HPMCAS are present in the core tablet in a weight ratio of 40:60 to 60:40. For example, in some embodiments, the apremilast:HPMCAS weight ratio in the core tablet is 40:60, 41:59, 42:58, 43:57, 44:56, 45:55, 46:56, 47:53, 48:52, 49:51, 50:50, 51:49, 52:48, 53:47, 54:46, 55:45, 56:44, 57:43, 58:42, 59:41, or 60:40. In some embodiments, apremilast and HPMCAS are present in the core tablet in a weight ratio of 45:55 to 55:45. In various embodiments, apremilast and HPMCAS are present in the core tablet in a weight ratio of 48:52 to 52:48. In some embodiments, apremilast and HPMCAS are present in the core tablet in a weight ratio of 50:50.

[0018] Amorphous Solid Dispersions Apremilast and HPMCAS are present in the core tablet as amorphous solid dispersion.Without wishing to be bound by any particular theory, it is believed that the amorphous solid dispersion provides improved bioavailability of apremilast due to, for example, 1) improved drug dispersion, thereby preventing or slowing the rate of crystallization in solid state; 2) improved in vivo dissolution, thereby allowing drug release in the gastrointestinal tract; and 3) inhibiting precipitation or crystallization of aqueous-dissolved drug.It has been found that a small amount (e.g., 1.5% by weight or less) of crystalline apremilast can cause slower dissolution of solid dispersion, so apremilast needs to remain amorphous in the compositions disclosed herein.

[0019] In some embodiments, the amorphous solid dispersion is spray dried, as described above or in conjunction with other embodiments below. It has been found that spray-dried solid dispersions (SDDs) of apremilast in HPMCAS unexpectedly provide good solubility and improved ease of formulation. As will be understood, spray drying refers to a process that involves breaking a liquid mixture into small droplets (atomization) and rapidly removing the solvent from the mixture in a vessel where there is a strong driving force to evaporate the solvent from the droplets. A strong driving force for solvent evaporation is generally provided by maintaining the partial pressure of the solvent in the spray drying apparatus well below the vapor pressure of the solvent at the temperature of the dried droplets. This is accomplished by (1) maintaining the pressure in the spray drying apparatus at a partial vacuum (e.g., 0.01-0.50 atm), (2) mixing the droplets with a warm drying gas, or (3) both. For example, a solution of drug and HPMCAS in acetone can be suitably spray dried by spraying the solution at a temperature of 50°C (the vapor pressure of acetone at 50°C is approximately 0.8 atm) into a chamber maintained at a total pressure of 0.01-0.2 atm by connecting the outlet to a vacuum pump. Alternatively, the acetone solution can be sprayed into a chamber where it is mixed with nitrogen or other inert gas at a temperature of 80-180°C and a pressure of 1.0-1.2 atm.

[0020] In general, the temperature and flow rate of the drying gas are selected so that by the time the HPMCAS / drug solution droplets reach the walls of the device, they are sufficiently dry that they are essentially solid, so that they form a fine powder and do not adhere to the walls of the device. The actual length of time to achieve this level of drying depends on the size of the droplets. Droplet sizes generally range from 1 μm to 500 μm in diameter, with 5 μm to 100 μm being more typical. The large surface-to-volume ratio of the droplets and the large driving force for solvent evaporation result in actual drying times of a few seconds or less. This rapid drying is important for the particles to maintain a uniform, homogeneous composition instead of separating into a drug-rich phase and a polymer-rich phase. Such dispersions with homogeneous composition can be considered solid solutions and can be supersaturated in the drug. Such homogeneous dispersions are preferred in that the maximum supersaturation concentration (MSSC) values ​​obtained when large amounts of drug are administered can be higher for such dispersions compared to dispersions in which at least a portion of the drug is present as a drug-rich amorphous or crystalline phase. The solidification time should be less than 20 seconds, preferably less than 5 seconds, more preferably less than 2 seconds. In general, to achieve this rapid solidification of the drug / polymer solution, the size of the droplets formed during the spray drying process is preferably less than 100 μm in diameter, preferably less than 50 μm in diameter, more preferably less than 25 μm in diameter. The resulting solid particles thus formed are generally less than 100 μm in diameter, preferably less than 50 μm in diameter, more preferably less than 25 μm in diameter.

[0021] After solidification, the solid powder is allowed to remain in the spray drying chamber for 5-50 seconds to allow further evaporation of the solvent from the solid powder. The final solvent content of the solid dispersion when it exits the dryer should be low in order to reduce the mobility of the drug molecules in the dispersion, thereby improving its stability. In general, the residual solvent content of the dispersion should be less than 10% by weight, preferably less than 2% by weight.

[0022] The dispersion can then be post-processed and prepared for administration using methods known in the art, such as roller compaction, fluidized bed agglomeration, or spray coating. Spray-drying processes and spray-drying equipment are generally described, for example, in Chemical Engineershun Handbook, Sixth Edition (R.H.Perry, D.W.Green, J.O.Maroney, eds.) McGraw-Hill Book Co. 1984, pages 20-54 to 20-57. Further details regarding spray-drying processes and equipment are discussed by Marshall ("Atomization and Spray-Drying," Chem.Eng.Prog.Monogr.Series,50

[1954] 2).

[0023] In some embodiments, the solution spray dried to form the HPMCAS / apremilast dispersion contains only apremilast and HPMCAS in the solvent. In some embodiments, the ratio of apremilast to HPMCAS in the solution is 0.2-1.2 to 1-100 or 0.4-1.2 to 1-20. In some embodiments, the ratio of apremilast to HPMCAS in the spray-dried solution is 1.2-0.8:1. Solvents suitable for spray drying can be any organic compound in which apremilast and HPMCAS are mutually soluble. Also, the solvent is preferably volatile with a boiling point of 150° C. or less. In some embodiments, the solvent includes alcohols such as methanol, ethanol, n-propanol, isopropanol, and butanol; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate and propyl acetate; and various other solvents such as acetonitrile, methylene chloride, toluene, and 1,1,1-trichloroethane. Low volatility solvents such as dimethylacetamide or dimethylsulfoxide can also be used. Mixtures of solvents can also be used, as can mixtures with water, so long as the polymer and HPMCAS are sufficiently soluble to make the spray drying process practical. In some embodiments, the solvent comprises acetone.

[0024] In some embodiments, the spray-dried solution and the resulting dispersion may also contain various excipients / additives that aid in the stability, dissolution, tableting or processing of the dispersion, as described herein. In some embodiments, examples of such additives include: surfactants, pH control substances (e.g., acids, bases, buffers), diluents / fillers, disintegrants, lubricants, or binders. Such excipients / additives, if present, can be added directly to the spray-dried solution such that the additives are dissolved or suspended in the solution as a slurry. Alternatively, such additives can be added after the spray-drying process to aid in the formation of the final dosage form.

[0025] Water-soluble polymers In some embodiments, the drug layer comprises a water-soluble polymer. The water-soluble polymer in the drug layer, when present, is any suitable water-soluble polymer. Suitable water-soluble polymers include, for example, polyethylene oxide, and combinations thereof. In various embodiments, the water-soluble polymer is polyethylene oxide.

[0026] The water-soluble polymer in the drug layer has an appropriate molecular weight. For example, in embodiments where the water-soluble polymer in the drug layer is polyethylene oxide (PEO), the polyethylene oxide has an average molecular weight of 200,000 Da or more. In some embodiments, the polyethylene oxide has an average molecular weight of 200,000 Da to 300,000 Da (e.g., 200,000 and / or 300,000 Da) and / or 600,000 Da. Some embodiments have been found to exhibit improved stability where the drug layer comprises a polyethylene oxide having two or more average molecular weights (e.g., a mixture of polyethylene oxides). For example, in embodiments where the drug layer comprises a mixture of polyethylene oxides with molecular weights of 200,000 Da and 300,000 Da, the amount of crystalline apremilast formed during some stability tests (e.g., accelerated stability tests) is less than embodiments that comprise only one low molecular weight polyethylene oxide (e.g., a molecular weight of 200,000 Da). In some cases, the polyethylene oxide is a 1:1 mixture by weight of 200 kDa PEO to 300 kDa PEO. In some cases, the polyethylene oxide is a 20:80 mixture by weight of 200 kDa PEO to 300 kDa PEO. In some cases, the polyethylene oxide is a 300 kDa PEO. Certain embodiments including high molecular weight polyethylene oxide (e.g., a molecular weight of at least 300,000 Da) and further including an osmotic agent (e.g., sodium chloride) in the drug layer may provide improved dissolution, lag time (e.g., reduced lag time) and stability.

[0027] Exemplary polyethylene oxides suitable for the drug layer are the POLYOX WSR family of PEOs available from Dupont (Midland, Mich.), including POLYOX® WSR N80, POLYOX® WSR N750, and POLYOX® WSR 205. POLYOX® WSR N80 (available from Dupont; Midland, Mich.) has the following physical properties: MW of 200,000 Da; viscosity of 65-115 cP; silicon dioxide content of 0.8-3.0 wt.%; particle size at 10 mesh: 100 min; particle size at 20 mesh: 96-100 min; POLYOX® WSRN750 (available from Dupont; Midland, Mich.) has the following physical properties: MW of 200,000 Da; viscosity of 65-115 cP; silicon dioxide content of 0.8-3.0 wt.%; particle size at 10 mesh: 100 min; particle size at 20 mesh: 96-100 min. POLYOX® WSR205 (available from Dupont; Midland, MI) has the following physical properties: MW of 300,000 Da; viscosity of 600-1,200 cP; silicon dioxide content of 0.8-3.0 wt%; 10 mesh particle size: 100 min; 20 mesh particle size: 96-100 min.

[0028] The water-soluble polymer is present in a suitable amount. For example, in some embodiments, the water-soluble polymer is present in an amount of 30-55% by weight of the core tablet (e.g., 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55% by weight of the core tablet). In some embodiments, the water-soluble polymer is present in an amount of 30-55, 35-50, 35-45, 35-40, 40-55, 40-50, 45-55, or 45-50% by weight of the core tablet. In some embodiments, in conjunction with other embodiments described above or below, the water-soluble polymer (e.g., polyethylene oxide) is present in 34.3% by weight of the core tablet, 35% by weight of the core tablet, 37.6% by weight of the core tablet, or 42.7% by weight of the core tablet. In various embodiments, in conjunction with other embodiments described above or below, the water soluble polymer and apremilast are present in the drug layer in a weight ratio of 2 to 6 to 1. For example, in various embodiments, the weight ratio of water soluble polymer to apremilast in the drug layer is 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.0 to 1. In some embodiments, along with other embodiments above or below, the weight ratio of water soluble polymer to apremilast in the drug layer is 2.7, 2.8, 3.0, 3.7, 4.2, or 5.1 to 1.

[0029] In some embodiments, the oral dosage form comprises 100 mg or more of polyethylene oxide in the drug layer, e.g., 105, 110, 115, 120 or 125 mg of polyethylene oxide in the drug layer. In some embodiments, the oral dosage form comprises 200 mg or more of polyethylene oxide in the drug layer, e.g., 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285 or 290 mg of polyethylene oxide in the drug layer. In some embodiments, the oral dosage form comprises 300 mg or more of polyethylene oxide in the drug layer, e.g., 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355 or 360 mg of polyethylene oxide in the drug layer. In some embodiments, in combination with other embodiments above or below, the oral dosage forms disclosed herein contain 115.6 mg, 206 mg, 230.9 mg, 274.6 mg, 301.4 mg, 307.2 mg, 314.8 mg, 332.8 mg, or 358.4 mg of polyethylene oxide in the drug layer.

[0030] Diluents, Lubricants and Glidants In some embodiments, in conjunction with other embodiments above or below, the drug layer comprises a diluent. The diluent can be extragranular (EG) and / or intragranular (IG). In some embodiments, the diluent is intragranular (IG). In some embodiments, the drug layer comprises intragranular and extragranular diluents. The diluent is present in any suitable amount. In some embodiments, in conjunction with other embodiments above or below, the diluent is present in an amount of 2-7% by weight of the core tablet (e.g., 2, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, or 7.0% by weight of the core tablet). In some embodiments, the diluent is present in 3.0% by weight of the core tablet or 4.8% by weight of the core tablet.

[0031] Non-limiting examples of diluents include lactose, sucrose, glucose, mannitol, sorbitol, calcium phosphate, calcium carbonate, microcrystalline cellulose and cellulose. An exemplary suitable diluent in the drug layer is mannitol. In embodiments in which the diluent comprises mannitol, the drug layer typically comprises 5-60 mg of mannitol (e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mg of mannitol). For example, in various embodiments, in combination with other embodiments described above or below, the drug layer comprises 8.1 mg, 16.2 mg, 22.1 mg, 25.0 mg, 48.0 mg, 52.0 mg, or 56.0 mg of mannitol. In some embodiments, the drug layer comprises 12.3 mg mannitol (IG) and 9.8 mg mannitol (EG), 9.0 mg mannitol (IG) and 7.2 mg mannitol (EG), 4.5 mg mannitol (IG) and 3.6 mg mannitol (EG), or 25 mg mannitol (IG) and 25 mg mannitol (EG). In some embodiments, the drug layer comprises 50 mg mannitol (EG). In some embodiments that include both IG mannitol and EG mannitol, 55-57% of the total mannitol present is intragranular and 43-45% of the total mannitol present is extragranular.

[0032] In some embodiments, in conjunction with other embodiments described above or below, the drug layer comprises a lubricant. The lubricant can be extragranular (EG) and / or intragranular (IG). In some embodiments, the lubricant is intragranular (IG). In some embodiments, the drug layer comprises an intragranular and extragranular lubricant. The lubricant is present in any suitable amount. In some embodiments, in conjunction with other embodiments described above or below, by way of example, the lubricant is present in an amount of 0.05 to 0.50% by weight of the core tablet (e.g., 0.05, 0.10, 0.15, 0.2, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50% by weight of the core tablet). In some embodiments, in conjunction with other embodiments described above or below, the lubricant (e.g., magnesium stearate) is present in an amount of 0.25%, 0.31%, 0.33%, or 0.37% by weight of the core tablet.

[0033] Examples of lubricants include magnesium stearate, talc, starch, and cellulose. An exemplary suitable lubricant is magnesium stearate. In embodiments in which the lubricant comprises magnesium stearate, the drug layer typically comprises 1-5 mg of magnesium stearate (e.g., 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg of magnesium stearate). For example, in various embodiments, in combination with other embodiments described above or below, the drug layer comprises 1.0, 1.7, 2.0, 2.4, 2.5, 2.6, 2.7, or 2.8 mg of magnesium stearate. In some embodiments, the drug layer comprises 0.5, 0.9, 1.0, 1.2, 1.3, or 1.4 mg of magnesium stearate (IG) and 0.5, 1.0, 1.2, 1.3, or 1.4 mg of magnesium stearate (EG).

[0034] In some embodiments, in conjunction with other embodiments above or below, the drug layer comprises a glidant. In some embodiments, the glidant is extragranular. The glidant is present in any suitable amount. In some embodiments, in conjunction with other embodiments above or below, by way of example, the glidant is present in an amount of 0.05-0.50% by weight of the core tablet (e.g., 0.05, 0.10, 0.15, 0.2, 0.25, 0.30, 0.35, 0.40, 0.45 or 0.50% by weight of the core tablet). In some embodiments, in conjunction with other embodiments above or below, the glidant (e.g., colloidal silicon dioxide) is present in an amount of 0.25%, 0.33%, 0.34% or 0.37% by weight of the core tablet.

[0035] Glidants include silica, magnesium stearate, and talc. An exemplary suitable glidant is silicon dioxide (e.g., colloidal silicon dioxide). In embodiments in which the glidant comprises silicon dioxide, the drug layer typically comprises 0.5-5 mg of silicon dioxide (e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg of silicon dioxide). For example, in various embodiments, in combination with other embodiments described above or below, the drug layer comprises 0.9, 1.8, 2.0, 2.4, 2.5, 2.6, 2.7, or 2.8 mg of silicon dioxide.

[0036] In some embodiments, the drug layer of the disclosed oral dosage form further comprises an osmotic agent. When present, the osmotic agent of the drug layer can be any suitable osmotic agent. Non-limiting examples of osmotic agents include sugar and sodium chloride. In some embodiments, as well as other embodiments described above or below, the osmotic agent of the drug layer comprises sodium chloride. The osmotic agent of the drug layer is present in any suitable amount. In some embodiments, as well as other embodiments described above or below, the drug layer comprises 2-12% by weight of an osmotic agent (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12% by weight of an osmotic agent). In some embodiments, the drug layer comprises 5%, 7.7%, or 10% by weight of an osmotic agent (e.g., sodium chloride). Depending on the dosage strength of the dosage form, the drug layer comprises 15-60 mg of an osmotic agent (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 mg of an osmotic agent). In some embodiments, the drug layer comprises 18.0, 26.7, 40, or 53.3 mg of an osmotic agent (e.g., sodium chloride). In some embodiments, the osmotic agent (e.g., sodium chloride) of the drug layer is present in an amount of 3-8% by weight of the core tablet (e.g., 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0% by weight of the core tablet. In some embodiments, the osmotic agent (eg, sodium chloride) in the drug layer is present in an amount of 3.3%, 5.1%, or 6.7% by weight of the core tablet.

[0037] swellable layer The swellable layer comprises one or more swellable polymers. Thus, the swellable layer expands when contacted with water, which expansion creates pressure that results in drug release from the drug layer through at least one drug release orifice of the dosage form. In some embodiments, in conjunction with other embodiments above or below, the drug layer and the swellable layer are present in the core tablet in a weight ratio of 2:1.

[0038] The swellable polymer can be any suitable swellable polymer. In some embodiments, the swellable polymer comprises polyethylene oxide. An exemplary suitable polyethylene oxide for the swellable layer is, for example, POLYOX® WSR coagulant (commercially available from Dupont; Midland, MI), which has the following physical properties: MW of 5,000,000 Da; viscosity: 5500-7500 cP; and silicon dioxide 0.8-3.0 wt.%. The polyethylene oxide of the swellable layer typically has a higher molecular weight (e.g., 5,000,000 Da) than the polyethylene oxide of the drug layer.

[0039] The swellable polymer is present in any suitable amount. Typically, the swellable polymer is present in an amount of 50-70% by weight of the swellable layer (e.g., polyethylene oxide) (e.g., 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70% by weight of the swellable layer). In some embodiments, as well as other embodiments above or below, the swellable polymer is present in an amount of 50-70%, 55-70%, or 55-65% by weight of the swellable layer. In some embodiments, the swellable polymer is present in 64.8%, 64.9%, or 65% by weight of the swellable layer. Depending on the dosage strength of the dosage form, the swellable polymer is present in the swellable layer in an amount of 50-75 mg, 100-130 mg, 150-200 mg. In some embodiments, the swellable polymer (e.g., polyethylene oxide) is present in the swellable layer in an amount of 58.6 mg, 117.0 mg, 129.8 mg, 159.6 mg, or 173.1 mg. In some embodiments, the swellable polymer (e.g., polyethylene oxide) is present in an amount of 15-25% by weight of the core tablet (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25% by weight of the core tablet). In some embodiments, the swellable polymer comprises 21.6% or 22% by weight of the core tablet.

[0040] In some embodiments, the swellable layer further comprises one or more of an osmotic agent, a diluent, a lubricant, and a colorant.

[0041] The osmotic agent of the swellable layer can be any suitable osmotic agent described herein. Non-limiting examples of osmotic agents include sugars and sodium chloride. In some embodiments, as well as other embodiments described above or below, the osmotic agent comprises sodium chloride. The osmotic agent is present in any suitable amount. In some embodiments, as well as other embodiments described above or below, the swellable layer comprises 5-15% by weight of an osmotic agent (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% by weight of an osmotic agent). In some embodiments, the swellable layer comprises 5-10%, 5-7%, 8-12%, or 8-10% by weight of an osmotic agent. In some embodiments, the swellable layer comprises 8.4%, 8.5%, 8.6%, 9.1%, or 9.8% by weight of an osmotic agent. Depending on the dosage strength of the dosage form, the swellable layer comprises 5-25 mg of an osmotic agent (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mg of an osmotic agent). In some embodiments, the swellable layer comprises 7.8 mg, 15.5 mg, 17.2 mg, 20.6 mg, 21.1 mg, 22.4 mg, 22.9 mg, or 24.1 mg of an osmotic agent (e.g., sodium chloride). In some embodiments, the osmotic agent (e.g., sodium chloride) is present in an amount of 1.5-3.5% by weight of the total core tablet (e.g., 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or 3.5% by weight of the core tablet). In some embodiments, the osmotic agent (e.g., sodium chloride) is present in an amount of 2.80, 2.85, 2.90, or 2.95% by weight of the core tablet.

[0042] The diluent of the swellable layer can be any suitable diluent described herein. An exemplary suitable diluent in the swellable layer is microcrystalline cellulose. In some embodiments, as well as other embodiments above or below, the diluent comprises microcrystalline cellulose. The diluent is present in any suitable amount. In some embodiments, the diluent (e.g., microcrystalline cellulose) is present in an amount of 20-35% by weight of the swellable layer (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35% by weight). In some embodiments, the diluent is present in an amount of 25.2%, 25.8%, 27.3%, or 29.4% by weight of the swellable layer. In some embodiments, the diluent is present in an amount of 7-10% by weight of the core tablet (e.g., 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0% by weight of the core tablet).

[0043] The lubricant in the swellable layer may be any suitable lubricant as described herein. An exemplary suitable lubricant in the swellable layer is magnesium stearate. The lubricant is present in any suitable amount. In some embodiments, the lubricant is present in an amount of 0.3-1% by weight of the swellable layer (e.g., 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0% by weight of the swellable layer). In some embodiments, as well as other embodiments above or below, the lubricant is present in an amount of 0.5% or 0.6% by weight of the swellable layer. In some embodiments, as well as other embodiments above or below, as examples, the lubricant in the swellable layer is present in an amount of 0.05-0.50% by weight of the core tablet (e.g., 0.05, 0.10, 0.15, 0.2, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50% by weight of the core tablet). Depending on the dosage strength of the dosage form, in various embodiments the swellable layer comprises 0.5, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 mg of magnesium stearate.

[0044] The colorant can be any suitable colorant. An exemplary suitable colorant is iron(III) oxide. The colorant is present in any suitable amount. In some embodiments, as well as other embodiments described above or below, by way of example, the colorant (e.g., iron(III) oxide) of the swellable layer is present in an amount of 0.05-0.50% by weight of the core tablet (e.g., 0.05, 0.10, 0.15, 0.2, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50% by weight of the core tablet). In some embodiments, the colorant is present in an amount of 0.05, 0.06, 0.07, 0.08, 0.09, or 0.10% by weight of the core tablet. In various embodiments, as well as other embodiments described above or below, the swellable layer comprises 0.2 mg, 0.4 mg, or 0.5 mg of colorant (e.g., iron(III) oxide).

[0045] Coating Layer The oral dosage forms disclosed herein include a coating layer disposed on the core tablet. In some embodiments, the coating layer is present in an amount of 6.5-8.5% by weight based on the total oral dosage form weight. In some embodiments, the coating layer is present in an amount of 7.5% by weight based on the total oral dosage form weight. In some embodiments, the coating layer includes cellulose acetate (CA) and polyethylene glycol (PEG). In various embodiments, the PEG has an average molecular weight of 3,000-4,000 Da, e.g., 3,000-3,700 Da or 3,350 Da.

[0046] The cellulose acetate and PEG are present in any suitable amount. In some embodiments, the coating layer comprises 10-80 mg of CA (e.g., 10, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 mg CA). In some embodiments, the coating layer comprises 15.2, 30.3, 36.3, 37.4, 40.3, 41.3, 49.6, 72.0, and 74.9 mg of CA. In some embodiments, in combination with other embodiments above or below, the coating layer comprises 3.8, 7.6, 9.1, 9.4, 10.1, 10.3, 12.4, 18.0, or 18.7 mg of PEG. In some embodiments, the CA and PEG are present in a CA:PEG weight ratio of 3.5 to 4.5:1. For example, in some embodiments, the weight ratio of CA to PEG in the coating layer is 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5. In some embodiments, the CA and PEG are present in a CA:PEG weight ratio of 4:1.

[0047] Subcoat layer In some embodiments, the disclosed oral dosage forms further comprise a subcoat layer between the core tablet and the coating layer. In some embodiments, the subcoat layer comprises hydroxypropyl methylcellulose (HPMC).

[0048] The subcoat layer, when present, is present in any suitable amount. In some embodiments, the subcoat layer is present in an amount of 2-4% by weight of the oral dosage form (e.g., 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0% by weight of the oral dosage form). In some embodiments, the subcoat layer is present in an amount of 2.3% by weight of the oral dosage form. In some embodiments, the subcoat layer is present in an amount of 3.4% by weight of the oral dosage form.

[0049] In some embodiments, the coating layer further comprises a color coat layer. The color coat layer comprises one or more suitable colorants. An exemplary suitable colorant is Opadry® II colorant, commercially available from Colorcon, Inc. (Harleysville, PA). The color coat layer is present in a suitable amount. In some embodiments, the color coat layer is present in an amount of 3-5% (3.0, 3.5, 4.0, 4.5, 5.0%) by weight of the oral dosage form. In some embodiments, the color coat layer is present in an amount of 3.4% by weight of the oral dosage form.

[0050] Drug Release Orifice The oral dosage forms disclosed herein include at least one drug release orifice. In some embodiments, the drug release orifice is made by drilling the oral dosage form. Typically, the drug release orifice ranges in size from 600 μm to 1.5 mm. In some embodiments, the oral dosage form is drilled using a 900 μm drill. In some embodiments, the oral dosage form is drilled using a 1600 μm drill. In some embodiments, the drug release orifice has a size of 1.2 mm.

[0051] In some embodiments, the present disclosure provides a drug layer comprising: (i) 8-11% by weight of apremilast based on the total weight of the core tablet; 8-11% by weight of hypromellose acetate succinate (HPMCAS) based on the total weight of the core tablet; 2-7% by weight of mannitol based on the total weight of the core tablet; 40-45% by weight of polyethylene oxide based on the total weight of the core tablet; 0.1-0.5% by weight of magnesium stearate based on the total weight of the core tablet; and 0.1-0.5% by weight of colloidal silicon dioxide based on the total weight of the core tablet, wherein the apremilast and HPMCAS are in a solid dispersion; layer, (ii) a swellable layer comprising 18-25% by weight of polyethylene oxide based on the total weight of the core tablet, 7-10% by weight of microcrystalline cellulose based on the total weight of the core tablet, 1.5-3.5% by weight of sodium chloride based on the total weight of the core tablet, 0.01-0.2% by weight of iron oxide based on the total weight of the core tablet, and 0.05-0.3% by weight of magnesium stearate based on the total weight of the core tablet; and a coating layer disposed on the core tablet and comprising cellulose acetate and polyethylene glycol, wherein the surface of the oral dosage form comprises at least one drug release orifice.

[0052] In some embodiments, the disclosure provides an oral dosage form comprising: (i) a core tablet comprising a drug layer comprising 75 mg of apremilast, 75 mg of hypromellose acetate succinate (HPMCAS), 22.1 mg of mannitol, 314.8 mg of polyethylene oxide, 2.4 mg of magnesium stearate, and 2.5 mg of colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 159.6 mg of polyethylene oxide, 63.4 mg of microcrystalline cellulose, 21.1 mg of sodium chloride, 0.5 mg of iron oxide, and 1.2 mg of magnesium stearate; and a coating layer disposed on the core tablet comprising cellulose acetate and polyethylene glycol, wherein the oral dosage form surface comprises at least one drug release orifice.

[0053] In some embodiments, the disclosure provides an oral dosage form comprising: (i) a core tablet comprising a drug layer comprising 55 mg of apremilast, 55 mg of hypromellose acetate succinate (HPMCAS), 16.2 mg of mannitol, 230.9 mg of polyethylene oxide, 1.7 mg of magnesium stearate, and 1.8 mg of colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 117 mg of polyethylene oxide, 46.5 mg of microcrystalline cellulose, 15.5 mg of sodium chloride, 0.4 mg of iron oxide, and 0.9 mg of magnesium stearate; and a coating layer disposed on the core tablet comprising cellulose acetate and polyethylene glycol, wherein the oral dosage form surface comprises at least one drug release orifice.

[0054] In some embodiments, the disclosure provides an oral dosage form comprising: (i) a core tablet comprising a drug layer comprising 27.5 mg of apremilast, 27.5 mg of hypromellose acetate succinate (HPMCAS), 8.1 mg of mannitol, 115.6 mg of polyethylene oxide, 1.0 mg of magnesium stearate, and 0.9 mg of colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 58.6 mg of polyethylene oxide, 23.3 mg of microcrystalline cellulose, 7.8 mg of sodium chloride, 0.2 mg of iron oxide, and 0.5 mg of magnesium stearate; and a coating layer disposed on the core tablet comprising cellulose acetate and polyethylene glycol, wherein the oral dosage form surface comprises at least one drug release orifice.

[0055] In some embodiments, the present disclosure provides a drug layer comprising: (i) 10-15% by weight of apremilast based on the total weight of the core tablet; 10-15% by weight of hypromellose acetate succinate (HPMCAS) based on the total weight of the core tablet; 30-40% by weight of polyethylene oxide based on the total weight of the core tablet; 2-8% by weight of sodium chloride based on the total weight of the core tablet; 0.1-0.5% by weight of magnesium stearate based on the total weight of the core tablet; and 0.1-0.5% by weight of colloidal silicon dioxide based on the total weight of the core tablet, wherein the apremilast and HPMCAS are in a solid dispersion; layer, (ii) a swellable layer comprising 18-25% by weight of polyethylene oxide based on the total weight of the core tablet, 7.5-10.0% by weight of microcrystalline cellulose based on the total weight of the core tablet, 2-4% by weight of sodium chloride based on the total weight of the core tablet, 0.01-0.1% by weight of iron oxide based on the total weight of the core tablet, and 0.05-0.3% by weight of magnesium stearate based on the total weight of the core tablet, and a coating layer disposed on the core tablet and comprising cellulose acetate and polyethylene glycol, wherein the surface of the oral dosage form comprises at least one drug release orifice.

[0056] In some embodiments, the disclosure provides an oral dosage form comprising: (i) a core tablet comprising a drug layer comprising 100 mg of apremilast, 100 mg of hypromellose acetate succinate (HPMCAS), 301.4 mg of polyethylene oxide, 26.7 mg of sodium chloride, 2.6 mg of magnesium stearate, and 2.7 mg of colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 173.1 mg of polyethylene oxide, 68.8 mg of microcrystalline cellulose, 22.9 mg of sodium chloride, 0.5 mg of iron oxide, and 1.3 mg of magnesium stearate; and a coating layer disposed on the core tablet comprising cellulose acetate and polyethylene glycol, wherein the oral dosage form surface comprises at least one drug release orifice.

[0057] In some embodiments, the disclosure provides an oral dosage form comprising: (i) a core tablet comprising a drug layer comprising 100 mg of apremilast, 100 mg of hypromellose acetate succinate (HPMCAS), 274.6 mg of polyethylene oxide, 53.3 mg of sodium chloride, 2.6 mg of magnesium stearate, and 2.7 mg of colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 173.1 mg of polyethylene oxide, 68.8 mg of microcrystalline cellulose, 22.9 mg of sodium chloride, 0.5 mg of iron oxide, and 1.3 mg of magnesium stearate; and a coating layer disposed on the core tablet comprising cellulose acetate and polyethylene glycol, wherein the oral dosage form surface comprises at least one drug release orifice.

[0058] In some embodiments, the present disclosure provides an oral dosage form comprising: a) a core tablet comprising: (i) a drug layer comprising 60 mg apremilast, 60 mg hypromellose acetate succinate (HPMCAS), 48 mg mannitol, 307.2 mg polyethylene oxide, 2.4 mg magnesium stearate, and 2.4 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 155.8 mg polyethylene oxide, 61.9 mg microcrystalline cellulose, 20.6 mg sodium chloride, 0.5 mg iron oxide, and 1.2 mg magnesium stearate; and b) a coating layer comprising 37.4 mg CA and 9.4 mg PEG, wherein the oral drug dosage form comprises at least one drug release orifice as described herein.

[0059] In some embodiments, the disclosure provides an oral dosage form comprising: a) a core tablet comprising: (i) a drug layer comprising 60 mg apremilast, 60 mg hypromellose acetate succinate (HPMCAS), 48 mg mannitol, 307.2 mg polyethylene oxide, 2.4 mg magnesium stearate, and 2.4 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 155.8 mg polyethylene oxide, 61.9 mg microcrystalline cellulose, 20.6 mg sodium chloride, 0.5 mg iron oxide, and 1.2 mg magnesium stearate; and b) a coating layer comprising 72.0 mg CA and 18.0 mg PEG, wherein the oral drug dosage form comprises at least one drug release orifice as described herein.

[0060] In some embodiments, the disclosure provides an oral dosage form comprising: a) a core tablet comprising: (i) a drug layer comprising 65 mg apremilast, 65 mg hypromellose acetate succinate (HPMCAS), 52 mg mannitol, 332.8 mg polyethylene oxide, 2.6 mg magnesium stearate, and 2.6 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 168.7 mg polyethylene oxide, 67.1 mg microcrystalline cellulose, 22.4 mg sodium chloride, 0.5 mg iron oxide, and 1.3 mg magnesium stearate; and b) a coating layer comprising 37.4 mg CA and 9.4 mg PEG, wherein the oral drug dosage form comprises at least one drug release orifice as described herein.

[0061] In some embodiments, the disclosure provides an oral dosage form comprising: a) a core tablet comprising: (i) a drug layer comprising 65 mg apremilast, 65 mg hypromellose acetate succinate (HPMCAS), 52 mg mannitol, 332.8 mg polyethylene oxide, 2.6 mg magnesium stearate, and 2.6 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 168.7 mg polyethylene oxide, 67.1 mg microcrystalline cellulose, 22.4 mg sodium chloride, 0.5 mg iron oxide, and 1.3 mg magnesium stearate; and b) a coating layer comprising 74.9 mg CA and 18.7 mg PEG, wherein the oral drug dosage form comprises at least one drug release orifice as described herein.

[0062] In some embodiments, the disclosure provides an oral dosage form comprising: a) a core tablet comprising: (i) a drug layer comprising 70 mg apremilast, 70 mg hypromellose acetate succinate (HPMCAS), 56 mg mannitol, 358.4 mg polyethylene oxide, 2.8 mg magnesium stearate, and 2.8 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 181.7 mg polyethylene oxide, 72.3 mg microcrystalline cellulose, 24.1 mg sodium chloride, 0.5 mg iron oxide, and 1.4 mg magnesium stearate; and b) a coating layer comprising 40.3 mg CA and 10.1 mg PEG, wherein the oral drug dosage form comprises at least one drug release orifice as described herein.

[0063] In some embodiments, the present disclosure provides an oral dosage form comprising: a) a core tablet comprising: (i) a drug layer comprising 75 mg apremilast, 75 mg hypromellose acetate succinate (HPMCAS), 22.1 mg mannitol, 314.8 mg polyethylene oxide, 2.4 mg magnesium stearate, and 2.5 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 159.6 mg polyethylene oxide, 63.4 mg microcrystalline cellulose, 21.1 mg sodium chloride, 0.5 mg iron oxide, and 1.2 mg magnesium stearate; b) a subcoat layer comprising 18.4 mg HPMC; and c) a coating layer comprising 36.3 mg CA and 9.1 mg PEG, wherein the oral drug dosage form comprises at least one drug release orifice as described herein.

[0064] In some embodiments, the present disclosure provides an oral dosage form comprising: a) a core tablet comprising: (i) a drug layer comprising 75 mg apremilast, 75 mg hypromellose acetate succinate (HPMCAS), 22.1 mg mannitol, 314.8 mg polyethylene oxide, 2.4 mg magnesium stearate, and 2.5 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 159.6 mg polyethylene oxide, 63.4 mg microcrystalline cellulose, 21.1 mg sodium chloride, 0.5 mg iron oxide, and 1.2 mg magnesium stearate; b) a subcoat layer comprising 18.4 mg HPMC; and c) a coating layer comprising 49.6 mg CA and 12.4 mg PEG, wherein the oral drug dosage form comprises at least one drug release orifice as described herein.

[0065] In some embodiments, the disclosure provides an oral dosage form comprising: a) a core tablet comprising: (i) a drug layer comprising 75 mg apremilast, 75 mg hypromellose acetate succinate (HPMCAS), 22.1 mg mannitol, 314.8 mg polyethylene oxide, 2.4 mg magnesium stearate, and 2.5 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 159.6 mg polyethylene oxide, 63.4 mg microcrystalline cellulose, 21.1 mg sodium chloride, 0.5 mg iron oxide, and 1.2 mg magnesium stearate; and b) a coating layer comprising 41.3 mg CA and 10.3 mg PEG, further comprising 27.6 mg colorant, wherein the oral drug dosage form comprises at least one drug release orifice as described herein.

[0066] In some embodiments, the disclosure provides an oral dosage form comprising: a) a core tablet comprising: (i) a drug layer comprising 75 mg apremilast, 75 mg hypromellose acetate succinate (HPMCAS), 22.1 mg mannitol, 314.8 mg polyethylene oxide, 2.4 mg magnesium stearate, and 2.5 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 159.6 mg polyethylene oxide, 63.4 mg microcrystalline cellulose, 21.1 mg sodium chloride, 0.5 mg iron oxide, and 1.2 mg magnesium stearate; and b) a coating layer comprising 41.3 mg CA and 10.3 mg PEG, further comprising 27.6 mg colorant, wherein the oral drug dosage form comprises at least one drug release orifice as described herein.

[0067] In some embodiments, the present disclosure provides an oral dosage form comprising: a) a core tablet comprising: (i) a drug layer comprising 55 mg apremilast, 55 mg hypromellose acetate succinate (HPMCAS), 16.2 mg mannitol, 230.9 mg polyethylene oxide, 1.7 mg magnesium stearate, and 1.8 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 117 mg polyethylene oxide, 46.5 mg microcrystalline cellulose, 15.5 mg sodium chloride, 0.4 mg iron oxide, and 0.9 mg magnesium stearate; and b) a coating layer comprising 30.3 mg CA and 7.6 mg PEG, further comprising 20.2 mg colorant, wherein the oral drug dosage form comprises at least one drug release orifice as described herein.

[0068] In some embodiments, the present disclosure provides an oral dosage form comprising: a) a core tablet comprising: (i) a drug layer comprising 27.5 mg apremilast, 27.5 mg hypromellose acetate succinate (HPMCAS), 8.1 mg mannitol, 115.6 mg polyethylene oxide, 1 mg magnesium stearate, and 0.9 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 58.6 mg polyethylene oxide, 23.3 mg microcrystalline cellulose, 7.8 mg sodium chloride, 0.2 mg iron oxide, and 0.5 mg magnesium stearate; and b) a coating layer comprising 15.2 mg CA and 3.8 mg PEG, further comprising 10.1 mg colorant, wherein the oral drug dosage form comprises at least one drug release orifice as described herein.

[0069] In some embodiments, the disclosure provides an oral dosage form comprising: a) a core tablet comprising: (i) a drug layer comprising 100 mg apremilast, 100 mg hypromellose acetate succinate (HPMCAS), 26.7 mg sodium chloride, 150.7 mg polyethylene oxide having a MW of 300,000 Da, 150.7 mg polyethylene oxide having a MW of 200,000, 2.6 mg magnesium stearate, and 2.7 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 173.1 mg polyethylene oxide, 68.8 mg microcrystalline cellulose, 22.9 mg sodium chloride, 0.5 mg iron oxide, and 1.3 mg magnesium stearate; and b) a coating layer as described herein, wherein the oral drug dosage form comprises at least one drug release orifice as described herein.

[0070] In some embodiments, the disclosure provides an oral dosage form comprising: a) a core tablet comprising: (i) a drug layer comprising 100 mg apremilast, 100 mg hypromellose acetate succinate (HPMCAS), 53.3 mg sodium chloride, 274.6 mg polyethylene oxide with a MW of 300,000 Da, 2.6 mg magnesium stearate, and 2.7 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 173.1 mg polyethylene oxide, 68.8 mg microcrystalline cellulose, 22.9 mg sodium chloride, 0.5 mg iron oxide, and 1.3 mg magnesium stearate; and b) a coating layer as described herein, wherein the oral drug dosage form comprises at least one drug release orifice as described herein.

[0071] In some embodiments, the disclosure provides an oral dosage form comprising: a) a core tablet comprising: (i) a drug layer comprising 75 mg apremilast, 75 mg hypromellose acetate succinate (HPMCAS), 40 mg sodium chloride, 206 mg polyethylene oxide with a MW of 300,000 Da, 2 mg magnesium stearate, and 2 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 129.8 mg polyethylene oxide, 51.6 mg microcrystalline cellulose, 17.2 mg sodium chloride, 0.4 mg iron oxide, and 1 mg magnesium stearate; and b) a coating layer as described herein, wherein the oral drug dosage form comprises at least one drug release orifice as described herein.

[0072] In some embodiments, the disclosure provides an oral dosage form comprising: a) a core tablet comprising: (i) a drug layer comprising 75 mg apremilast, 75 mg hypromellose acetate succinate (HPMCAS), 40 mg sodium chloride, 274.6 mg polyethylene oxide having a MW of 300,000 Da, 2 mg magnesium stearate, 50 mg mannitol, and 2 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 173.1 mg polyethylene oxide, 68.8 mg microcrystalline cellulose, 22.9 mg sodium chloride, 0.5 mg iron oxide, and 1.3 mg magnesium stearate; and b) a coating layer as described herein, wherein the oral drug dosage form comprises at least one drug release orifice as described herein.

[0073] In some embodiments, the disclosure provides an oral dosage form comprising: a) a core tablet comprising: (i) a drug layer comprising 75 mg apremilast, 75 mg hypromellose acetate succinate (HPMCAS), 40 mg sodium chloride, 274.6 mg polyethylene oxide with a MW of 300,000 Da, 2 mg magnesium stearate, 25 mg mannitol (IG), 25 mg mannitol (EG), and 2 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 173.1 mg polyethylene oxide, 68.8 mg microcrystalline cellulose, 22.9 mg sodium chloride, 0.5 mg iron oxide, and 1.3 mg magnesium stearate; and b) a coating layer as described herein, wherein the oral drug dosage form comprises at least one drug release orifice as described herein.

[0074] Treatment The present disclosure provides a method of treating a patient suffering from a disease or disorder ameliorated by inhibiting PDE4, comprising administering to the patient under fed conditions an oral dosage form disclosed herein.

[0075] A fed subject refers to a subject who has consumed food or eaten a meal. In some embodiments, the formulation disclosed herein is administered to a fed subject 5 minutes after a meal, 10 minutes after a meal, 15 minutes after a meal, 20 minutes after a meal, 30 minutes after a meal, 40 minutes after a meal, 50 minutes after a meal, 1 hour after a meal, or 2 hours after a meal. In some cases, the formulation disclosed herein is administered to a fed subject 30 minutes after a meal. In various cases, the formulation disclosed herein is administered to a fed subject 1 hour after a meal. In some embodiments, the formulation disclosed herein is administered to a subject with food.

[0076] In some embodiments, the disease or disorder is asthma, arthritis, psoriasis, inflammation, chronic or acute obstructive pulmonary disease, chronic or acute inflammatory pulmonary disease, cutaneous lupus erythematosus, inflammatory bowel disease, Crohn's disease, Behcet's disease, hidradenitis suppurativa, or colitis. In some embodiments, the disease or disorder is arthritis. In some embodiments, the arthritis is psoriatic arthritis. In some embodiments, the disease or disorder is psoriasis. In some embodiments, the disease or disorder is colitis. In some embodiments, the colitis is ulcerative colitis. In some embodiments, the disease or disorder is Behcet's disease. In some embodiments, the disease or disorder is inflammatory bowel disease. In some embodiments, the disease or disorder is hidradenitis suppurativa.

[0077] In some embodiments, the disclosed oral dosage forms are administered after initial titration with a conventional twice-daily apremilast formulation.

[0078] In some embodiments, the disclosed methods include the following initial titration schedule: (i) 10 mg in the morning on day 1 of administration; (ii) 10 mg in the morning and 10 mg in the afternoon on day 2 of administration; (iii) 10 mg in the morning and 20 mg in the afternoon on day 3 of administration; (iv) 20 mg in the morning and 20 mg in the afternoon on day 4 of administration; (v) 20 mg in the morning and 30 mg in the afternoon on day 5 of administration; and (vi) 30 mg in the morning and 30 mg in the afternoon on days 6-14 of administration; and the disclosed oral dosage forms are administered once daily on each subsequent day of administration. In some embodiments, the oral dosage form administered on day 15 includes 27.5 mg apremilast, 55 mg apremilast, or 75 mg apremilast.

[0079] In some embodiments, the disclosed methods include the following initial titration schedule: (i) 10 mg in the morning on day 1 of dosing; (ii) 10 mg in the morning and 10 mg in the afternoon on day 2 of dosing; (iii) 10 mg in the morning and 20 mg in the afternoon on day 3 of dosing; (iv) 20 mg in the morning and 20 mg in the afternoon on day 4 of dosing; (v) 20 mg in the morning and 30 mg in the afternoon on day 5 of dosing; and (vi) 30 mg in the morning and 30 mg in the afternoon on days 6-14 of dosing; and the disclosed oral dosage form having 75 mg of apremilast once daily on the morning of day 15 and once daily on each subsequent day of dosing.

[0080] In some embodiments, the disclosed methods include the following initial titration schedules: (i) 10 mg in the morning on day 1 of administration; (ii) 10 mg in the morning and 10 mg in the afternoon on day 2 of administration; (iii) 10 mg in the morning and 20 mg in the afternoon on day 3 of administration; (iv) 20 mg in the morning and 20 mg in the afternoon on day 4 of administration; (v) 20 mg in the morning and 30 mg in the afternoon on day 5 of administration; and (vi) an oral dosage form disclosed herein having 75 mg of apremilast once daily on the morning of day 6 and thereafter.

[0081] In some embodiments, the disclosed methods include the following initial titration schedule: (i) 10 mg in the morning on day 1; (ii) 10 mg in the morning and 10 mg in the afternoon on day 2; (iii) 10 mg in the morning and 20 mg in the afternoon on day 3; (iv) an oral dosage form disclosed herein having 55 mg of apremilast once daily on the morning of day 4 and thereafter.

[0082] In some embodiments, the disclosed methods include the following initial titration schedule: (i) 10 mg in the morning on day 1 of administration; (ii) 10 mg in the morning and 10 mg in the afternoon on day 2 of administration; (iii) 10 mg in the morning and 20 mg in the afternoon on day 3 of administration; (iv) 20 mg in the morning and 20 mg in the afternoon on days 4-14; (v) an oral dosage form disclosed herein having 55 mg of apremilast once daily in the morning on day 15 and thereafter.

[0083] In some embodiments, the disclosed methods include the following initial titration schedule: (i) 10 mg in the morning on day 1; (ii) 10 mg in the morning and 10 mg in the afternoon on day 2; (iii) 10 mg in the morning and 20 mg in the afternoon on day 3; (iv) two oral dosage forms disclosed herein having 27.5 mg of apremilast (55 mg total apremilast) once daily in the morning and thereafter on day 4.

[0084] In some embodiments, the disclosed methods include the following initial titration schedule: (i) 10 mg in the morning on day 1 of administration; (ii) 10 mg in the morning and 10 mg in the afternoon on day 2 of administration; (iii) 10 mg in the morning and 20 mg in the afternoon on day 3 of administration; (iv) 20 mg in the morning and 20 mg in the afternoon on days 4-14; (v) two oral dosage forms as disclosed herein having 27.5 mg of apremilast (55 mg total apremilast) once daily on the morning of day 15 and thereafter.

[0085] Embodiment 1. a. (i) a drug layer comprising apremilast and hypromellose acetate succinate (HPMCAS) in an amorphous solid dispersion; and (ii) a swellable layer comprising one or more swellable polymers; A core tablet comprising: b. a coating layer disposed on the core tablet; 1. An oral dosage form comprising: the oral dosage form surface comprises at least one drug release orifice; Oral dosage form. 2. The oral dosage form of embodiment 1, wherein apremilast is present in an amount of 6-15% by weight of the core tablet. 3. The oral dosage form of embodiment 1 or 2, wherein the solid dispersion is spray dried. 4. The oral dosage form of any one of embodiments 1-3, wherein HPMCAS is present in an amount of 6-15% by weight of the core tablet. 5. The oral dosage form of any one of embodiments 1-4, wherein apremilast and HPMCAS are present in the core tablet in a weight ratio of 45:55 to 55:45. 6. The oral dosage form of embodiment 5, wherein apremilast and HPMCAS are present in a weight ratio of 48:52 to 52:48. 7. The oral dosage form of embodiment 5, wherein apremilast and HPMCAS are present in a 50:50 weight ratio. 8. The oral dosage form of any one of embodiments 1-7, wherein the drug layer further comprises one or more of a water soluble polymer, a diluent, an osmotic agent, and a lubricant. 9. The oral dosage form of embodiment 8, wherein the water-soluble polymer is present in an amount of 30-55% by weight of the core tablet. 10. The oral dosage form of embodiment 8 or 9, wherein the water-soluble polymer comprises polyethylene oxide. 11. The oral dosage form of embodiment 10, wherein the polyethylene oxide has an average molecular weight of 200,000 to 600,000 Da. 12. The oral dosage form of embodiment 11, wherein the drug layer comprises polyethylene oxide having an average molecular weight of 200,000 Da. 13. The oral dosage form of embodiment 11, wherein the drug layer comprises polyethylene oxide having an average molecular weight of 300,000 Da. 14. The oral dosage form of embodiment 11, wherein the drug layer comprises polyethylene oxide having an average molecular weight of 600,000 Da. 15. The oral dosage form of any one of embodiments 8-14, wherein the water-soluble polymer and apremilast are present in the drug layer in a weight ratio of 2-6:1. 16. The oral dosage form of any one of embodiments 8-15, wherein the diluent comprises mannitol. 17. The oral dosage form according to any one of embodiments 8 to 16, wherein the diluent is present in an amount of 2 to 7% by weight of the core tablet. 18. The oral dosage form of any one of embodiments 8-17, wherein the drug layer comprises an intragranular diluent and an extragranular diluent. 19. The oral dosage form of any one of embodiments 8-18, wherein the osmotic agent is present in the drug layer in an amount of 3-8% by weight of the core tablet. 20. The oral dosage form of any one of embodiments 8-19, wherein the osmotic agent in the drug layer comprises sodium chloride. 21. The oral dosage form of any one of embodiments 8-20, wherein the lubricant comprises magnesium stearate. 22. The oral dosage form of any one of embodiments 8-21, wherein the lubricant in the drug layer is present in an amount of 0.05-0.5% by weight of the core tablet. 23. The oral dosage form of any one of embodiments 1-22, wherein the drug layer further comprises an extragranular glidant, an extragranular lubricant, or both. 24. The oral dosage form of embodiment 23, wherein the extragranular glidant comprises silicon dioxide. 25. The oral dosage form of embodiment 23 or 24, wherein the extragranular lubricant comprises magnesium stearate. 26. An oral dosage form according to any one of embodiments 1-25, wherein the drug layer and the swellable layer are present in the core tablet in a weight ratio of 2:1. 27. The oral dosage form of any one of embodiments 1-26, wherein the swellable polymer comprises polyethylene oxide. 28. The oral dosage form of embodiment 27, wherein the polyethylene oxide has an average molecular weight of 5,000,000 Da. 29. The oral dosage form of any one of embodiments 1-28, wherein the swellable layer further comprises one or more of an osmotic agent, a diluent, a lubricant, and a colorant. 30. The oral dosage form of embodiment 29, wherein the osmotic agent of the swellable layer comprises sodium chloride. 31. The oral dosage form of embodiment 29 or 30, wherein the osmotic agent in the swellable layer is present in an amount of 2.5 to 3.5% by weight of the core tablet. 32. The oral dosage form of any one of embodiments 29-31, wherein the diluent of the swellable layer comprises microcrystalline cellulose. 33. The oral dosage form according to any one of embodiments 29-32, wherein the diluent in the swellable layer is present in an amount of 7-10% by weight of the core tablet. 34. The oral dosage form of any one of embodiments 29-33, wherein the lubricant of the swellable layer comprises magnesium stearate. 35. The oral dosage form according to any one of embodiments 29-34, wherein the lubricant in the swellable layer is present in an amount of 0.05-0.5% by weight of the core tablet. 36. The oral dosage form of any one of embodiments 29-35, wherein the colorant comprises iron(III) oxide. 37. The oral dosage form of any one of embodiments 29-36, wherein the colorant is present in an amount of 0.05-0.5% by weight of the core tablet. 38. The oral dosage form of any one of embodiments 1-37, wherein the coating comprises cellulose acetate and polyethylene glycol. 39. The oral dosage form of embodiment 38, wherein the cellulose acetate and polyethylene glycol are present in the coating in a weight ratio of 3.5 to 4.5:1. 40. The oral dosage form of any one of embodiments 1-39, wherein the coating comprises 6.5-8.5% by weight of the total weight of the oral dosage form. 41. The oral dosage form of embodiment 40, wherein the coating constitutes 7.5% by weight of the total weight of the oral dosage form. 42. The oral dosage form of any one of embodiments 1-41, further comprising a subcoat layer between the core tablet and the coating layer. 43. The oral dosage form of embodiment 42, wherein the subcoat layer comprises hydroxypropyl methylcellulose. 44. The oral dosage form of embodiment 42 or 43, wherein the subcoat layer is present in an amount of 2-4% by weight of the oral dosage form. 45. The oral dosage form of embodiment 44, wherein the subcoat layer is present in an amount of 2.3% by weight of the oral dosage form. 46. ​​The oral dosage form of embodiment 44, wherein the subcoat layer is present in an amount of 3.4% by weight of the oral dosage form. 47. An oral dosage form according to any one of embodiments 1-46, wherein the drug layer comprises an intragranular portion and an extragranular portion. 48. The oral dosage form according to embodiment 47, wherein the extragranular portion comprises a lubricant and a glidant. 49. The oral dosage form of embodiment 48, wherein the extragranular portion further comprises a diluent. 50. The oral dosage form of embodiment 49, wherein the lubricant comprises magnesium stearate, the glidant comprises silicon dioxide, and the diluent comprises mannitol. 51. The oral dosage form of any one of embodiments 47-50, wherein the intragranular portion comprises apremilast, HPMCAS, polyethylene oxide and mannitol, and an intragranular lubricant. 52. The oral dosage form of embodiment 51, wherein the intragranular lubricant comprises magnesium stearate. 53. An oral dosage form according to any one of embodiments 49-52, wherein mannitol is present in both the intragranular and extragranular portions. 54. The oral dosage form according to embodiment 53, wherein 55-57% of the total mannitol present is in the intragranular portion and 43-45% of the total mannitol present is in the extragranular portion. 55. The oral dosage form of any one of embodiments 47-54, wherein the swellable layer further comprises a lubricant. 56. The oral dosage form of embodiment 55, wherein the lubricant of the swellable layer comprises magnesium stearate. 57. The oral dosage form of any one of embodiments 47-56, wherein the drug layer intragranular portion comprises sodium chloride. 58. The oral dosage form of any one of embodiments 47-57, further comprising a color coat layer in an amount of 3-5% by weight of the oral dosage form. 59. The oral dosage form of embodiment 58, wherein the color coat layer is present in an amount of 3.4% by weight of the oral dosage form. 60. a. (i) a drug layer comprising 8-11% by weight of apremilast, based on the total weight of the core tablet, 8-11% by weight of hypromellose acetate succinate (HPMCAS), based on the total weight of the core tablet, 2-7% by weight of mannitol, based on the total weight of the core tablet, 40-45% by weight of polyethylene oxide having a molecular weight of 200,000 Da, based on the total weight of the core tablet, 0.1-0.5% by weight of magnesium stearate, based on the total weight of the core tablet, and 0.1-0.5% by weight of colloidal silicon dioxide, based on the total weight of the core tablet, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 18 to 25% by weight of polyethylene oxide having a molecular weight of 5,000,000 Da based on the total weight of the core tablet, 7 to 10% by weight of microcrystalline cellulose based on the total weight of the core tablet, 1.5 to 3.5% by weight of sodium chloride based on the total weight of the core tablet, 0.01 to 0.2% by weight of iron oxide based on the total weight of the core tablet, and 0.05 to 0.3% by weight of magnesium stearate based on the total weight of the core tablet. A core tablet comprising: b. a coating layer disposed on the core tablet, the coating layer comprising cellulose acetate and polyethylene glycol; wherein the oral dosage form surface comprises at least one drug release orifice. 61. a. (i) a drug layer comprising 75 mg apremilast, 75 mg hypromellose acetate succinate (HPMCAS), 22.1 mg mannitol, 314.8 mg polyethylene oxide of molecular weight 200,000 Da, 2.4 mg magnesium stearate, and 2.5 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 159.6 mg of polyethylene oxide of molecular weight 5,000,000 Da, 63.4 mg of microcrystalline cellulose, 21.1 mg of sodium chloride, 0.5 mg of iron oxide and 1.2 mg of magnesium stearate. A core tablet comprising: b. a coating layer disposed on the core tablet, the coating layer comprising cellulose acetate and polyethylene glycol; 61. The oral dosage form of embodiment 60, wherein the oral dosage form surface comprises at least one drug release orifice. 62. a. (i) a drug layer comprising 55 mg apremilast, 55 mg hypromellose acetate succinate (HPMCAS), 16.2 mg mannitol, 230.9 mg polyethylene oxide of molecular weight 200,000 Da, 1.7 mg magnesium stearate, and 1.8 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 117 mg of polyethylene oxide of molecular weight 5,000,000 Da, 46.5 mg of microcrystalline cellulose, 15.5 mg of sodium chloride, 0.4 mg of iron oxide and 0.9 mg of magnesium stearate. A core tablet comprising: b. a coating layer disposed on the core tablet, the coating layer comprising cellulose acetate and polyethylene glycol; 61. The oral dosage form of embodiment 60, wherein the oral dosage form surface comprises at least one drug release orifice. 63. a. (i) a drug layer comprising 27.5 mg apremilast, 27.5 mg hypromellose acetate succinate (HPMCAS), 8.1 mg mannitol, 115.6 mg polyethylene oxide of molecular weight 200,000 Da, 1.0 mg magnesium stearate, and 0.9 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 58.6 mg of polyethylene oxide of molecular weight 5,000,000 Da, 23.3 mg of microcrystalline cellulose, 7.8 mg of sodium chloride, 0.2 mg of iron oxide and 0.5 mg of magnesium stearate. A core tablet comprising: b. a coating layer disposed on the core tablet, the coating layer comprising cellulose acetate and polyethylene glycol; 61. The oral dosage form of embodiment 60, wherein the oral dosage form surface comprises at least one drug release orifice. 64. a. (i) a drug layer comprising 9-15% by weight of apremilast, based on the total weight of the core tablet, 10-15% by weight of hypromellose acetate succinate (HPMCAS), based on the total weight of the core tablet, 0-27% by weight of mannitol, based on the total weight of the core tablet, 30-40% by weight of polyethylene oxide having a molecular weight of 200,000-300,000 Da or a mixture thereof, based on the total weight of the core tablet, 2-8% by weight of sodium chloride, based on the total weight of the core tablet, 0.1-0.5% by weight of magnesium stearate, based on the total weight of the core tablet, and 0.1-0.5% by weight of colloidal silicon dioxide, based on the total weight of the core tablet, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 15 to 25% by weight of polyethylene oxide having a molecular weight of 5,000,000 Da based on the total weight of the core tablet, 5 to 10.0% by weight of microcrystalline cellulose based on the total weight of the core tablet, 2 to 4% by weight of sodium chloride based on the total weight of the core tablet, 0.01 to 0.1% by weight of iron oxide based on the total weight of the core tablet, and 0.05 to 0.3% by weight of magnesium stearate based on the total weight of the core tablet. A core tablet comprising: b. a coating layer disposed on the core tablet, the coating layer comprising cellulose acetate and polyethylene glycol; wherein the oral dosage form surface comprises at least one drug release orifice. 65. a. (i) a drug layer comprising 100 mg apremilast, 100 mg hypromellose acetate succinate (HPMCAS), 301.4 mg polyethylene oxide having a molecular weight of 200,000 to 300,000 Da or mixtures thereof, 26.7 mg sodium chloride, 2.6 mg magnesium stearate, and 2.7 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 173.1 mg of polyethylene oxide of molecular weight 5,000,000 Da, 68.8 mg of microcrystalline cellulose, 22.9 mg of sodium chloride, 0.5 mg of iron oxide and 1.3 mg of magnesium stearate. A core tablet comprising: b. a coating layer disposed on the core tablet, the coating layer comprising cellulose acetate and polyethylene glycol; 65. The oral dosage form of embodiment 64, wherein the oral dosage form surface comprises at least one drug release orifice. 66. a. (i) a drug layer comprising 100 mg apremilast, 100 mg hypromellose acetate succinate (HPMCAS), 274.6 mg polyethylene oxide of molecular weight 300,000 Da, 53.3 mg sodium chloride, 2.6 mg magnesium stearate, and 2.7 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 173.1 mg of polyethylene oxide of molecular weight 5,000,000 Da, 68.8 mg of microcrystalline cellulose, 22.9 mg of sodium chloride, 0.5 mg of iron oxide and 1.3 mg of magnesium stearate. A core tablet comprising: b. a coating layer disposed on the core tablet, the coating layer comprising cellulose acetate and polyethylene glycol; 65. The oral dosage form of embodiment 64, wherein the oral dosage form surface comprises at least one drug release orifice. 67. a. (i) a drug layer comprising 75 mg apremilast, 75 mg hypromellose acetate succinate (HPMCAS), 226.0 mg polyethylene oxide having a molecular weight of 200,000 to 300,000 Da or mixtures thereof, 20.0 mg sodium chloride, 2.0 mg magnesium stearate, and 2.0 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 129.8 mg of polyethylene oxide having a molecular weight of 5,000,000 Da, 51.6 mg of microcrystalline cellulose, 17.2 mg of sodium chloride, 0.4 mg of iron oxide and 1.0 mg of magnesium stearate. A core tablet comprising: b. a coating layer disposed on the core tablet, the coating layer comprising cellulose acetate and polyethylene glycol; 65. The oral dosage form of embodiment 64, wherein the oral dosage form surface comprises at least one drug release orifice. 68. a. (i) a drug layer comprising 75 mg apremilast, 75 mg hypromellose acetate succinate (HPMCAS), 206.0 mg polyethylene oxide of molecular weight 300,000 Da, 40.0 mg sodium chloride, 2.0 mg magnesium stearate, and 2.0 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 129.8 mg of polyethylene oxide having a molecular weight of 5,000,000 Da, 51.6 mg of microcrystalline cellulose, 17.2 mg of sodium chloride, 0.4 mg of iron oxide and 1.0 mg of magnesium stearate. A core tablet comprising: b. a coating layer disposed on the core tablet, the coating layer comprising cellulose acetate and polyethylene glycol; 65. The oral dosage form of embodiment 64, wherein the oral dosage form surface comprises at least one drug release orifice. 69. a. (i) a drug layer comprising 55 mg apremilast, 55 mg hypromellose acetate succinate (HPMCAS), 165.7 mg polyethylene oxide having a molecular weight of 200,000 to 300,000 Da or mixtures thereof, 14.7 mg sodium chloride, 1.4 mg magnesium stearate, and 1.5 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 95.2 mg of polyethylene oxide of molecular weight 5,000,000 Da, 37.8 mg of microcrystalline cellulose, 12.6 mg of sodium chloride, 0.3 mg of iron oxide and 0.7 mg of magnesium stearate. A core tablet comprising: b. a coating layer disposed on the core tablet, the coating layer comprising cellulose acetate and polyethylene glycol; 65. The oral dosage form of embodiment 64, wherein the oral dosage form surface comprises at least one drug release orifice. 70. a. (i) a drug layer comprising 55 mg apremilast, 55 mg hypromellose acetate succinate (HPMCAS), 151.1 mg polyethylene oxide of molecular weight 300,000 Da, 29.3 mg sodium chloride, 1.4 mg magnesium stearate, and 1.5 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 95.2 mg of polyethylene oxide of molecular weight 5,000,000 Da, 37.8 mg of microcrystalline cellulose, 12.6 mg of sodium chloride, 0.3 mg of iron oxide and 0.7 mg of magnesium stearate. A core tablet comprising: b. a coating layer disposed on the core tablet, the coating layer comprising cellulose acetate and polyethylene glycol; 65. The oral dosage form of embodiment 64, wherein the oral dosage form surface comprises at least one drug release orifice. 71. a. (i) a drug layer comprising 27.5 mg apremilast, 27.5 mg hypromellose acetate succinate (HPMCAS), 82.9 mg polyethylene oxide having a molecular weight of 200,000 to 300,000 Da or a mixture thereof, 7.3 mg sodium chloride, 0.8 mg magnesium stearate, and 0.7 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 47.6 mg of polyethylene oxide of molecular weight 5,000,000 Da, 18.9 mg of microcrystalline cellulose, 6.3 mg of sodium chloride, 0.1 mg of iron oxide and 0.4 mg of magnesium stearate. A core tablet comprising: b. a coating layer disposed on the core tablet, the coating layer comprising cellulose acetate and polyethylene glycol; 65. The oral dosage form of embodiment 64, wherein the oral dosage form surface comprises at least one drug release orifice. 72. a. (i) a drug layer comprising 27.5 mg apremilast, 27.5 mg hypromellose acetate succinate (HPMCAS), 75.5 mg polyethylene oxide having a molecular weight of 300,000 Da, 14.7 mg sodium chloride, 0.4 mg magnesium stearate, and 0.7 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) a swellable layer comprising 47.6 mg of polyethylene oxide of molecular weight 5,000,000 Da, 18.9 mg of microcrystalline cellulose, 6.3 mg of sodium chloride, 0.1 mg of iron oxide and 0.4 mg of magnesium stearate. A core tablet comprising: b. a coating layer disposed on the core tablet, the coating layer comprising cellulose acetate and polyethylene glycol; 65. The oral dosage form of embodiment 64, wherein the oral dosage form surface comprises at least one drug release orifice. 73. A method of treating a patient suffering from a disease or disorder ameliorated by inhibiting PDE4, comprising administering to the patient an oral dosage form described in any one of embodiments 1-72 once daily under fed conditions. 74. The method of embodiment 73, wherein the disease or disorder is psoriasis, psoriatic arthritis, or Behcet's disease. 75. The method of embodiment 73, wherein the disease or disorder is colitis, inflammatory bowel disease, or hidradenitis suppurativa. 76. The method of embodiment 75, wherein the disease or disorder is colitis. 77. The method of embodiment 76, wherein the colitis is ulcerative colitis. 78. The method of embodiment 75, wherein the disease or disorder is inflammatory bowel disease. 79. The method of embodiment 75, wherein the disease or disorder is hidradenitis suppurativa. EXAMPLES

[0086] The following examples further illustrate the disclosed methods of treatment but, of course, should not be construed as in any way limiting their scope.

[0087] The following abbreviations are used in the examples: SCT refers to swellable core technology, TAB refers to tablet, SDD refers to amorphous spray dried dispersion, APR refers to amorphous apremilast, HPMCAS refers to hypromellose acetate succinate, HPMC refers to hydroxypropyl methylcellulose, DL refers to drug layer, SL refers to swellable layer, CL refers to coating layer, PEO refers to polyethylene oxide, PEG refers to polyethylene glycol, Mg refers to magnesium, IG refers to intragranular, EG refers to extragranular, MCC refers to microcrystalline cellulose, NaCl refers to sodium chloride, MW refers to molecular weight, cSiO2 refers to colloidal silicon dioxide, CA refers to cellulose acetate, RR refers to release rate, SRC refers to standard round concave, SEM refers to scanning electron microscope, inWC refers to inches of water column, AUC refers to 100 μm. 0-∞ refers to the area under the plasma concentration-time curve calculated from time 0 to infinity, AUC 0-t refers to the area under the concentration-time curve calculated from time 0 to the last measurement time point, CL / F refers to the apparent clearance of the drug from plasma after extravascular administration, and C max refers to the maximum concentration observed, and C trough refers to the plasma concentration observed at the end of the dosing interval, CI refers to the confidence interval, CV% refers to the coefficient of variation, and t 1 / 2 refers to the terminal elimination half-life, and t lagrefers to the delay between the time of administration and the onset of the absorption lag time, T max is C max Vz / F refers to the time to the end of the phase, Vz / F refers to the apparent volume of distribution during the terminal phase, F rel1 refers to the relative bioavailability of each test formulation compared to the reference formulation, and F rel2 refers to the relative bioavailability of each dose-normalized test formulation compared to the dose-normalized reference formulation IR tablet, and RA refers to the accumulation rate based on the area under the 24-hour plasma concentration-time curve on days 1 and 5.

[0088] Example 1 This example demonstrates the preparation of amorphous spray-dried solid dispersions containing 48% and 52% apremilast loadings by weight, produced in batch sizes of 2 kg for each loading using a PSD-1 scale spray dryer.

[0089] Solutions were prepared at 48:52 APR:HPMCAS-LG and 52:48 APR:HPMCAS-LG at 12% total solids in acetone (Tables 1 and 2). Solutions were sprayed in order of increasing drug loading with minor cleaning between two sprays (e.g., rinsing chamber and duct works with water and detergent (e.g., alkaline detergent; CIP-100) and flushing acetone via feed pump). Drying kinetics and thermodynamics remained consistent with past 50% apremilast SDD runs. The 48% drug loading in the SDD had a wet yield of 82%, followed by 67% wet yield for the 52% drug loading SDD. Wet yields were calculated based on the introduction of 2 kg solids from the total net weight collected from the spray dryer, not including start / stop amounts and prior wet SDD sampling. The average operating conditions and wet yields for both SDD batches are listed in Table 3.

[0090] [Table 1]

[0091] [Table 2]

[0092] [Table 3]

[0093] Once all the wet SDD samples were collected, the bulk SDD from both drug loads were secondary dried using a convection tray dryer at 40° C. and 15% relative humidity (RH). The 48% APR SDD was dried for 1100 minutes and the 52% APR SDD was dried for 505 minutes. The drying yields for the 48% and 52% drug loaded SDD were 78% and 64%, respectively, based on 2 kg input solids, calculated from the total net weight collected from the tray dryer including the dry SDD sample and the wet SDD sample assuming 5% solvent loss.

[0094] The dried SDD from each drug load was then characterized for particle size distribution using laser diffraction with a Malvern Mastersizer 2000 (Malvern Panalytical; Malvern, United Kingdom). The mean particle size data are shown in Table 4. Both drug loads had the same particle size of 33 μm (D[4,3]), indicating that minor differences in composition do not affect particle size.

[0095] [Table 4]

[0096] Characterization of the SDD is summarized in Table 5 and includes residual acetone by gas chromatography (GC), crystallinity by powder X-ray diffraction (PXRD), thermal properties by modulated differential scanning calorimetry (mDSC), assay and related substances by high performance liquid chromatography (HPLC), performance by microcentrifuge dissolution, and morphology by scanning electron microscopy (SEM).

[0097] [Table 5]

[0098] As shown in Table 5, there was no significant difference in the residual acetone content of 48% and 52% APR SDD after spray drying and before secondary drying. The 52% APR SDD had slightly higher residual acetone after secondary drying due to the shorter drying time, but both batches were below the ICH limit of 5000 ppm. The 48% APR SDD was dried for 1100 minutes and the 52% APR SDD was dried for 505 minutes. Similarly, there was no measurable difference in the glass transition temperatures.

[0099] SEM analysis showed that both the 48% and 52% APR SDD consisted of smoothly disintegrated and non-disintegrated spheres with no evidence of crystallinity. The 52% APR SDD appeared to have a greater number of non-disintegrated spheres and a greater number of broken particles compared to the 48% APR SDD.

[0100] SDD Stability Test - Wet SDD Retention Time Test The PSD-1 scale spray dryer described herein was used to produce 48% and 52% drug loading (by weight) SDD. Wet SDD from each batch was stored in LDPE bags in airtight stainless steel containers and held at 27° C. for up to 30 days. At 10, 20 and 30 days, samples were removed from each batch for assay by SEM, mDSC, PXRD, HPLC and characterization by related substances, residual solvents and no-sink dissolution (microcentrifuge dissolution test).

[0101] SEM analysis showed that both the 48% and 52% APR SDD contained smooth disintegrated and non-disintegrated spheres with no evidence of fusion or crystallinity. No changes in morphology or physical state were observed after 30 days of storage prior to secondary drying. PXRD analysis showed that no crystallization occurred throughout the 30 day stability study for both the 48% and 52% APR SDD. Additionally, no morphological changes indicative of crystallization were observed within the method capabilities of the SEM analysis. DSC thermograms showed no measurable difference in the Tg of the stability samples compared to the dried SDD. Assay and related substances showed no increase in impurities over the 30 day stability hold. Similarly, microcentrifuge dissolution results showed no difference in performance over the 30 day period.

[0102] Example 2 This example illustrates a tablet dosage form according to an embodiment of the present disclosure.

[0103] Fourteen apremilast SCT dosage formulations were prepared with eight drug layers (DL) and six swellable layers (SL) as shown in Tables 6 and 7. The tablet cores were coated with a coating layer containing CA and PEG as shown in Table 8. The drug layer compositions and swellable layer compositions are shown in Tables 9 and 10.

[0104] [Table 6]

[0105] [Table 7]

[0106] [Table 8]

[0107] [Table 9]

[0108] [Table 10]

[0109] process The drug layer blend was prepared using the procedures described herein, including blending, milling, and dry granulation using roller compaction. Fill volumes were calculated assuming a pre-granulated blend density of 0.48 g / mL. Blender speeds were determined by keeping the Froude number constant at approximately 0.05 across the entire scale.

[0110] For the drug layer preblend, the following ingredients were added to a blender and blended: polyethylene oxide (e.g., PolyOx WSR-N80, MW 200 kDa), SDD, and mannitol. The preblend was then passed through a cone mill at low speed followed by blending. The lubricant (e.g., magnesium stearate) was screened (20 mesh) and added to the blender and blended. This blended mixture was then granulated using a roller compactor (see Table 11 for parameters). The resulting granulation was discharged into a container. The extragranular excipients (e.g., colloidal silicon dioxide and mannitol) were added to the blender and mixed. The extragranular excipient blend was then passed through a cone mill at low speed. The granulation and this screened extragranular blend were then combined in a blender and mixed. The lubricant (e.g., magnesium stearate) was screened (20 mesh) and added to the blender with mixing. After blending, the drug layer was discharged.

[0111] The swellable layer was prepared using a similar procedure assuming a bulk density of 0.41 g / mL to calculate the fill volume. The osmotic agent (e.g., sodium chloride) and colorant (e.g., iron oxide) were combined and blended at low speed. The sodium chloride and iron oxide mixture was then passed through a cone mill at low speed. The swellable polymer (e.g., polyethylene oxide) and diluent (e.g., microcrystalline cellulose) were added to the screened mixture and blended. The combined blended mixture was milled and blended again. The lubricant (e.g., magnesium stearate) was screened (20 mesh) and added to the blender and blended. The blended swellable layer mixture was discharged.

[0112] Roller compaction was carried out using the process parameters outlined in Table 11 with a target solids percentage of 0.65, ranging from 0.60 to 0.70.

[0113] [Table 11]

[0114] The ribbon solid fraction of each drug layer blend was in the range of 0.62-0.65. Granule particle size was measured using sieve analysis for each drug layer blend. All drug layer granulations using the same processing parameters (roll speed = 4.0 RPM, roll force = 2.0 kN / cm, roll gap = 2.0 mm, mill screen size = 1.0 mm) resulted in similar granule particle size distributions. The mean particle size was generally 75-850 μm, with populations of particles having particle sizes of, for example, 75-106 μm (less than 5% mass fraction), 106-150 μm (approximately 10% mass fraction), 150-250 μm (approximately 15% mass fraction), 250-500 μm (approximately 30% mass fraction), and 500-850 μm (approximately 37% mass fraction).

[0115] Bilayer tablet compression The final blends were compressed into 14 tablet batches using a Korsch XM12 tablet press and the process parameters are summarized in Table 12. Run times of 10-20 minutes were achieved for each formulation using four 12.0 mm SRC tooling stations. All 14 tablet batches were successfully produced with average tablet weights, thickness, and hardness ranging from 733.8-739.9 mg, 7.10-7.16 mm, and 14.0-16.3 kP, respectively. The average tablet weights, thickness, and hardness were within acceptable limits.

[0116] [Table 12]

[0117] Coating Layer Tablet cores 1-14 were coated with one of the coating compositions A-C shown in Table 13. The coating conditions are summarized in Table 14.

[0118] Tablet cores 1-12 were coated with coating composition A, tablet core 13 was coated with coating composition B, and tablet core 14 was coated with coating composition C. The target coating wet weight gain was 7.5%.

[0119] [Table 13]

[0120] [Table 14]

[0121] The coated tablets were drilled using a Phase 1 laser drill with 1.2 mm holes to provide drug release orifices and then pan-dried for approximately 15 hours.

[0122] Dissolution Test Dissolution (n=6) was performed on tablets 6-10, each with a different drug layer (DL1-5) and the same swellable layer (SL-6). The composition and dissolution metric variations of these formulations are shown in Table 15. The dissolution profiles of these formulations are shown in Figure 1. No significant differences in dissolution were observed for the five formulations. The tablets provided suitable dissolution profiles.

[0123] [Table 15]

[0124] Dissolution (n=6) was performed on tablets 1-5 with different swellable layers (SL1-5) and the same drug layer (DL-6). The variations in excipient amounts and key dissolution metrics are shown in Table 16. The dissolution profiles are shown in Figure 2. No significant differences in dissolution profiles were observed for the five formulations. The tablets provided suitable dissolution profiles.

[0125] [Table 16]

[0126] Tablet 5 was coated with three different coating solution compositions by varying the ratio of cellulose acetate to polyethylene glycol (PEG3350) to provide tablets 5, 5A, and 5B. The specific ratios tested as well as key dissolution metrics can be found in Table 17. The dissolution profiles are shown in Figure 3. No differences were observed in the dissolution profiles of the three formulations.

[0127] [Table 17]

[0128] Tablets 10-12 were made with SDDs with varying levels of apremilast relative to HPMCAS-L as outlined in Table 18, which also contains key dissolution metrics from the study. The dissolution profiles are shown in Figure 4. A slower release profile with a slight increase in residuals was observed for formulations containing SDDs with increased amounts of apremilast (52%) relative to the centerline SDD (50% apremilast). In this analysis, the dose per tablet for these formulations was not normalized to the actual amount found in their respective SDD lots, the centerline dose was assumed.

[0129] [Table 18]

[0130] Example 3 This example demonstrates oral dosage forms according to embodiments of the present disclosure.

[0131] Eight tablets (Tablets 15-22) containing the ingredients set forth in Table 19 were prepared as described herein. The drug layer of each tablet comprised apremilast and HPMCAS in a 50:50 weight ratio. Additionally, the drug layer of Tablet 15 further comprised extragranular mannitol as a diluent. Additionally, Dosage Forms 21 and 22 further comprised a subcoat layer comprising hydroxypropyl methylcellulose.

[0132] [Table 19]

[0133] Subjects were administered one of tablets 16-22 in a fed state (e.g., 30 minutes after consuming a moderate or high fat meal).

[0134] [Table 20]

[0135] Example 4 This example demonstrates oral dosage forms according to embodiments of the present disclosure.

[0136] Two 75 mg SCT QD apremilast tablets of Formulation 15 were prepared (Tablets A and B). Subjects were administered Tablet A (Treatment A) and Tablet B (Treatment B) during the study. Treatments were administered with approximately 240 mL (or 8 oz) of non-carbonated room temperature water. Subjects fasted overnight for at least 10 hours prior to each dosing period and for at least 4 hours after the morning dose. No food or drink (except water) was allowed for at least 4 hours after dosing. Water was allowed as desired, except for 1 hour before dosing and 1 hour after dosing.

[0137] Blood samples were collected at specific time points for pharmacokinetic (PK) and clinical laboratory evaluations. Safety was monitored throughout the study. Mean (±SD) apremilast plasma concentration versus time profiles are shown in Figure 5. All pharmacokinetic estimates were calculated using actual recorded blood draw times. Plasma pharmacokinetic parameters by treatment are summarized in Table 21.

[0138] [Table 21]

[0139] Following a single oral dose of a 75 mg SCT formulation of apremilast (Treatment A or Treatment B), apremilast was slowly absorbed and had a maximum plasma concentration (T max ) with maximum plasma concentrations occurring at approximately 6 and 8 hours, respectively. Exposure for Treatment B was slightly lower but appears to be comparable to that observed for Treatment A (C max : 357ng / mL vs. 382ng / mL, AUC 0-t : 5650h*ng / mL vs. 6040h*ng / mL, and AUC 0-∞ :5680h*ng / mL vs. 6080h*ng / mL). C max After achieving this, apremilast concentrations declined with a terminal elimination half-life (t 1 / 2 ) decreased.

[0140] Example 5 This example demonstrates oral dosage forms according to embodiments of the present disclosure.

[0141] Subjects were administered tablet 21 once daily during the study and compared with a 30 mg IR apremilast formulation and a 75 mg gastroretentive (GR) formulation. Treatments were administered with approximately 240 mL (or 8 oz) of noncarbonated room temperature water. On dosing days, subjects fasted for at least 8 hours before each morning meal and at least 4 hours after the morning dose. During the fasting period, water was available ad libitum (except for water given IP), except from 1 hour before dosing until 1 hour after dosing. A standard meal was administered 30 minutes prior to administration of the morning dose. The standard meal consisted of approximately 450 calories, with 25% of calories from fat. The standard meal content was equivalent to 8 oz of 1% fat milk, one large hard-boiled egg, two whole grain toast, one piece of butter (5 g), and one medium banana. The content (in terms of calories, fat, protein, and carbohydrates) and timing of lunch, dinner, and all snacks were consistent throughout the entire duration of all dosing days. Lunch, dinner, and a snack were provided approximately 4, 9, and 13 hours after the morning dose, respectively.

[0142] Blood samples were collected at specific time points for pharmacokinetic (PK) and clinical laboratory evaluations. Safety was monitored throughout the study. Mean (±SD) apremilast plasma concentration versus time profiles for both Day 1 and Day 5 are shown in Figures 6 and 7, respectively. All pharmacokinetic estimates were calculated using the actual recorded blood draw times. Plasma pharmacokinetic parameters for all subjects who completed treatment are summarized in Table 22.

[0143] [Table 22]

[0144] The median time to maximum plasma concentration (T maxApremilast was absorbed slowly, with maximum plasma concentrations (C ) occurring at approximately 6 hours (Figures 6, 7, and Table 22). max ) were similar between tablets 21 and 30 mg IR BID on Day 1, whereas C max was slightly lower for Table 21 on Day 5. Table 21 shows the C max The median delay in reaching C 0.01 and the relatively low C 0.01 based on a daily dose of 75 mg max , reflecting the sustained release effect of a typical modified release formulation (Figures 6, 7, and Table 22).

[0145] Steady-state C on day 5 max After achieving this, the apremilast concentration decreased with a terminal elimination half-life (t 1 / 2 ) was decreased by Apremilast t 1 / 2 was similar between 21 and 30 mg IR tablets BID in healthy male subjects after multiple dosing. AUC 0-24 , AUC 0-t , and AUC 0-∞ was similar between tablet 21 and 30 mg IR BID after single and multiple oral doses. The accumulation rates in Table 21 were also similar to those of 30 mg IR BID after multiple oral doses. C on day 5 after oral administration of tablet 21 trough The relative bioavailability was similar between tablet 21 and 30 mg IR BID, but the dose-normalized relative bioavailability of tablet 21 was approximately 23% lower than that of 30 mg IR BID.

[0146] The median time to maximum plasma concentration (T max Apremilast was absorbed slowly, with maximum plasma concentrations (C ) occurring at approximately 6 hours (Figures 6, 7, and Table 22). The peak plasma concentrations (C ) of apremilast for the 75 mg GR tablet were max ) is a C maxThe 75mg GR tablet had a higher C max Delay in median time to reach C based on a daily dose of 75 mg max , reflecting the sustained release effect of a typical modified release formulation (Figures 6, 7, and Table 22).

[0147] Steady-state C on day 5 max After achieving this, apremilast concentrations declined with a terminal elimination half-life (t 1 / 2 ) for apremilast t 1 / 2 was 2-3 hours longer. AUC 0-24 , AUC 0-t , and AUC 0-∞ were generally lower with the 75 mg GR tablet compared with the 30 mg IR BID after single and multiple oral doses. The accumulation rate and C on day 5 when the 75 mg GR tablet was administered were trough was less after multiple oral doses compared to 30 mg IR BID (Table 22). Both the relative bioavailability and dose-normalized relative bioavailability of the 75 mg GR tablet were lower than that of the 30 mg IR BID.

[0148] AUC for bioavailability of both the 21 mg Apremilast QD tablet formulation (Test) and the 75 mg Apremilast QD tablet formulation (Test) compared to the 30 mg IR BID Apremilast formulation (Reference) 0-24 , C max , and C trough The results of the statistical analysis are summarized in Table 23. T max The median difference analysis is summarized in Table 24.

[0149] [Table 23]

[0150] [Table 24]

[0151] After multiple oral administration of tablet 21 and GR tablet once daily for 5 days, AUC on day 5 0-24 Values ​​are the reference AUC 0-24 The C values ​​for Tablet 21 and GR Tablet on the 5th day were approximately 100% and 79%, respectively. max were 91% and 103%, respectively, of the reference formulation IR 30 mg BID (Table 23).

[0152] AUC shown in Table 23 0-24 Because the 90% CI of the geometric mean ratio was within the limits of 80% to 125%, which is the conventional bioequivalence criterion, the AUC 0-24 is considered to be comparable between the tablet 21 apremilast QD formulation and the 30 mg IR apremilast BID formulation. However, max and C trough were approximately 9% and 36% lower, respectively.

[0153] AUC of GR tablets 0-24 was approximately 21% lower compared to 30 mg IR BID. However, the C max Because the 90% CI of the geometric mean ratio was within the limits of 80% to 125%, which is the conventional bioequivalence criterion, C max The C of the GR tablet appeared to be comparable between the 75 mg GR tablet apremilast QD formulation and the 30 mg IR apremilast BID formulation. trough was approximately 40% lower compared with 30 mg IR BID.

[0154] T max Median analysis is shown in Table 24. T of Tablet 21 Apremilast QD Formulation and 75mg GR Tablet Apremilast QD Formulation max Both median T of both test formulations compared to the reference formulation were significantly delayed by a median difference of 2.5 to 3 hours when compared to the 30 mg IR apremilast BID formulation. max The median difference was statistically significant (p<0.0001).

[0155] Example 6 This example demonstrates tablet formulations and oral dosage forms according to embodiments of the present disclosure. Tablet formulations 6-1 to 6-13 were prepared containing the ingredients listed in Table 25.

[0156] [Table 25]

[0157] [Table 26]

[0158] Example 7 This example demonstrates 100 mg core tablet formulations of embodiments of the present disclosure. 100 mg core tablet formulations 7-1 to 7-6 were prepared containing the drug layer components listed in Table 26. Each of 7-1 to 7-6 contained the same swellable layer containing the following components (weight % of swellable layer): 64.9% PEO, 25.8% MCC, 8.6% NaCl, 0.2% iron(III) oxide; and 0.5% Mg stearate. Each drug layer of 7-1 to 7-6 had a total weight of 533.3 mg and the swellable layer had a weight of 266.7 mg, providing a total uncoated weight of 800 mg for each tablet core composition.

[0159] [Table 27]

[0160] Dissolution of core tablet formulations 7-1 to 7-6 was analyzed under the following conditions: Apparatus used: USP Apparatus 2 (paddle); Vessel: Low-evaporation lid 1 L dissolution vessel; Paddle stirring speed: 75 ± 2 rpm; Dissolution media temperature: 37.0 ± 0.5 °C; Sample size: 1 tablet per vessel; Dissolution media composition: 0.5% Tween® 80 in sodium acetate buffer, pH 5.5; Dissolution media volume: 900 mL; Sample volume: 1.5 mL (autosampler) or 5 mL (manual sampling).

[0161] The results are shown in Table 27 and FIG.

[0162] [Table 28]

[0163] As shown in Table 27 and Figure 8, dissolution at 24 hours increases with increasing percentage of high molecular weight PEO in the presence of osmotic agent in the drug layer. Furthermore, the lag time increases with the MW of PEO and is shorter in the presence of osmotic agent in the drug layer. Residual apremilast remaining is highest for tablet core composition 7-4 and decreases for tablet core compositions 7-5 and 7-6 with increasing high molecular weight PEO (600 kDa) fraction and osmotic agent (e.g., NaCl). An overall improvement in dissolution performance of formulations with high MW PWO in the presence of osmotic agent is observed (7-2 vs. 7-5 and 7-3 vs. 7-6).

[0164] Next, core tablet compositions 7-7 to 7-12 were prepared, each containing a drug layer shown in Table 28 and the same swellable layer as above.

[0165] [Table 29]

[0166] The dissolution of Compositions 7-7 to 7-12 was evaluated using the same conditions as above.

[0167] The results are shown in Table 29 and FIG.

[0168] [Table 30]

[0169] As shown in Table 29 and Figure 9, both the lag time and % apremilast remaining increase with increasing osmotic agent in the drug layer for compositions 7-7 through 7-9, which contain a mixture of two PEO grades. Lag time and residual apremilast decrease or remain the same with increasing osmotic agent for compositions with high MW PEO (7-10 through 7-12). Composition 7-12 showed desirable performance with minimal residual apremilast and short lag time while containing a single grade of PEO and 10% NaCl.

[0170] In general, minimization of residues during dissolution was a function of both the concentration of sodium chloride and the molecular weight of the PEO in the drug layer, with the lowest residues found in formulations containing 10% sodium chloride and the highest MW PEO (PolyOx WSR205, MW=600 kDa). Increasing the amount of sodium chloride (5% and 10% of the drug layer) decreased the lag time and increased the release rate for compositions with higher MW PEO (7-3 vs. 7-6 and 7-10 to 7-12). The shortest lag time was observed in formulations containing 10% NaCl and the lowest molecular weight PEO (PolyOx WSR N80, MW=200 kDa). The preferred formulations reduced residuals and lag time with the simplest formulations, thus formulations 7-12 had the best overall performance from both round 1 and round 2 with a lag time of 1.9 hours, 14% residuals, and using only one grade of PEO (PolyOx WSR N750 LEO) with 10% sodium chloride.

[0171] In stability studies, core tablet formulations 7-8 showed some degree of crystallinity by PXRD and decreased dissolution after 3 and 6 months at 40°C / 75% relative humidity (Figures 10A and 10B). In contrast, core tablet compositions 7-12 showed no change in crystallinity or dissolution after 6 months at 40°C / 75% RH (Figures 11A and 11B). Core tablet compositions 7-8 showed no change at 30°C / 65% RH at 3 or 6 months (Figures 10B and 11B). To ensure the sensitivity of the PXRD method to detect crystalline drug in formulation samples with respect to stability, 0.5% milled API of the SDD standard was used as a control for these measurements (Figures 10B and 11B).

[0172] No change in dissolution or crystallinity was observed for 7-8 and 7-12 at 25 °C / 60% RH and 30 °C / 65% RH, with 7-12 remaining stable under these conditions. It was determined that undissolved drug in the dissolution media in combination with residues in the tablet was responsible for the difference in % dose dissolved for the samples with poor performance (approximately 10-15% residual drug in the tablet shell is expected for this formulation) (Figure 10A). Acetonitrile (ACN) was added at the 24 hour time point and after bath homogenization to ensure complete dissolution of the residual drug in the tablet (Figures 10A and 11A).

[0173] These data demonstrate that high MW PEO in the drug layer is beneficial to ensure adequate dissolution performance at accelerated stability conditions of 30° C. / 65% RH and 40° C. / 75% RH. The presence of NaCl in the drug layer in these situations ensures adequate lag time.

[0174] The foregoing examples are merely illustrative of embodiments of the disclosed processes described herein and are not intended to limit the disclosed methods. Variations and modifications that are obvious to those skilled in the art are intended to be within the scope and spirit of the present disclosure as defined by the appended claims.

[0175] All references cited herein (e.g., publications, patent applications, and patents) are herein incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference herein and was set forth in its entirety herein.

[0176] The use of the terms "a," "an," "the," and "at least one," and similar referents with respect to the description of embodiments of the present disclosure (especially with respect to the claims below) should be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The term "at least one" following a list of one or more items (e.g., "at least one of A and B") should be construed to mean one item (A or B) selected from the listed items or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms "comprise," "have," "include," and "contain" should be construed as open-ended terms (i.e., meaning "including, but not limited to"), unless otherwise indicated herein or clearly contradicted by context. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated herein as if it were individually recited herein, unless otherwise indicated herein. All methods described herein may be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "etc.") provided herein is intended only to better illuminate embodiments of the disclosure, and does not impose limitations on the scope of the disclosure, unless otherwise claimed. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

Claims

1. a. (i) A drug layer containing apremilast and hypromellose acetate succinate (HPMCAS) in an amorphous solid dispersion; and (ii) A swelling layer containing one or more swelling polymers comprising a core tablet, and b. A coating layer disposed on the core tablet, comprising an oral dosage form, The surface of the oral dosage form includes at least one drug release orifice, an oral dosage form.

2. The oral dosage form according to claim 1, wherein the apremilast is present in an amount of 6 to 15% by weight of the core tablet.

3. The oral dosage form according to claim 1, wherein the solid dispersion is spray-dried.

4. The oral dosage form according to claim 1, wherein the HPMCAS is present in an amount of 6 to 15% by weight of the core tablet.

5. The oral dosage form according to claim 1, wherein apremilast and HPMCAS are present in a weight ratio of 45:55 to 55:45 in the core tablet.

6. The oral dosage form according to claim 1, wherein the drug layer further comprises one or more of a water-soluble polymer, a diluent, an osmotic agent, and a lubricant.

7. The oral dosage form according to claim 6, wherein the water-soluble polymer comprises polyethylene oxide.

8. The oral dosage form according to claim 7, wherein the polyethylene oxide has an average molecular weight of 200,000 to 600,000 Da.

9. The water-soluble polymer and apremilast are present in a weight ratio of 2 to 6:1 in the drug layer The oral dosage form according to claim 6.

10. The oral dosage form according to claim 1, wherein the drug layer and the swelling layer are present in a weight ratio of 2:1 in the core tablet.

11. The oral dosage form according to claim 1, wherein the swelling polymer comprises polyethylene oxide.

12. The oral dosage form according to claim 11, wherein the polyethylene oxide has an average molecular weight of 5,000,000 Da.

13. a. (i) A drug layer comprising 8 to 11% by weight of apremilast, 8 to 11% by weight of hypromellose acetate succinate (HPMCAS) based on the total weight of the core tablet, 2 to 7% by weight of mannitol based on the total weight of the core tablet, 40 to 45% by weight of polyethylene oxide having a molecular weight of 200,000 Da based on the total weight of the core tablet, 0.1 to 0.5% by weight of magnesium stearate based on the total weight of the core tablet, and 0.1 to 0.5% by weight of colloidal silicon dioxide based on the total weight of the core tablet, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) A swelling layer comprising 18 to 25% by weight of polyethylene oxide having a molecular weight of 5,000,000 Da based on the total weight of the core tablet, 7 to 10% by weight of microcrystalline cellulose based on the total weight of the core tablet, 1.5 to 3.5% by weight of sodium chloride based on the total weight of the core tablet, 0.01 to 0.2% by weight of iron oxide based on the total weight of the core tablet, and 0.05 to 0.3% by weight of magnesium stearate based on the total weight of the core tablet; A core tablet comprising; b. A coating layer disposed on the core tablet and comprising cellulose acetate and polyethylene glycol; An oral dosage form comprising, wherein the surface of the oral dosage form comprises at least one drug release orifice. [

14. ] (i) a. (i) A drug layer comprising 75 mg of apremilast, 75 mg of hypromellose acetate succinate (HPMCAS), 22.1 mg of mannitol, 314.8 mg of polyethylene oxide having a molecular weight of 200,000 Da, 2.4 mg of magnesium stearate, and 2.5 mg of colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) A swelling layer comprising 159.6 mg of polyethylene oxide having a molecular weight of 5,000,000 Da, 63.4 mg of microcrystalline cellulose, 21.1 mg of sodium chloride, 0.5 mg of iron oxide and 1.2 mg of magnesium stearate; A core tablet comprising; b. A coating layer disposed on the core tablet and comprising cellulose acetate and polyethylene glycol; An oral dosage form comprising, wherein the surface of the oral dosage form comprises at least one drug release orifice; (ii) a. ​ (i) A drug layer containing 55 mg of apremilast, 55 mg of hypromellose acetate succinate (HPMCAS), 16.2 mg of mannitol, 230.9 mg of polyethylene oxide with a molecular weight of 200,000 Da, 1.7 mg of magnesium stearate, and 1.8 mg of colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion, the drug layer; (ii) A swelling layer containing 117 mg of polyethylene oxide with a molecular weight of 5,000,000 Da, 46.5 mg of microcrystalline cellulose, 15.5 mg of sodium chloride, 0.4 mg of iron oxide, and 0.9 mg of magnesium stearate comprising a core tablet, and b. A coating layer disposed on the core tablet and containing cellulose acetate and polyethylene glycol, comprising an oral dosage form, wherein the surface of the oral dosage form contains at least one drug release orifice, the oral dosage form; iii) a. (i) A drug layer containing 27.5 mg of apremilast, 27.5 mg of hypromellose acetate succinate (HPMCAS), 8.1 mg of mannitol, 115.6 mg of polyethylene oxide with a molecular weight of 200,000 Da, 1.0 mg of magnesium stearate, and 0.9 mg of colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion, the drug layer; (ii) A swelling layer containing 58.6 mg of polyethylene oxide with a molecular weight of 5,000,000 Da, 23.3 mg of microcrystalline cellulose, 7.8 mg of sodium chloride, 0.2 mg of iron oxide, and 0.5 mg of magnesium stearate comprising a core tablet, and b. A coating layer disposed on the core tablet and containing cellulose acetate and polyethylene glycol, comprising an oral dosage form, wherein the surface of the oral dosage form contains at least one drug release orifice, the oral dosage form; iv) a. (i) 9 to 15% by weight of apremilast, 10 to 15% by weight of hypromellose acetate succinate (HPMCAS) based on the total weight of the core tablet, 0 to 27% by weight of mannitol based on the total weight of the core tablet, 30 to 40% by weight of polyethylene oxide having a molecular weight of 200,000 to 300,000 Da or a mixture thereof based on the total weight of the core tablet, 2 to 8% by weight of sodium chloride based on the total weight of the core tablet, 0.1 to 0.5% by weight of magnesium stearate based on the total weight of the core tablet , and a drug layer containing 0.1 to 0.5% by weight of colloidal silicon dioxide based on the total weight of the core tablet, wherein the apremilast and HPMCAS are in a solid dispersion, the drug layer; (ii) 15 to 25% by weight of polyethylene oxide having a molecular weight of 5,000,000 Da, 5 to 10.0% by weight of microcrystalline cellulose, 2 to 4% by weight of sodium chloride, 0.01 to 0.1% by weight of iron oxide, and 0.05 to 0.3% by weight of magnesium stearate based on the total weight of the core tablet, a swelling layer comprising a core tablet; b. A coating layer disposed on the core tablet and containing cellulose acetate and polyethylene glycol; An oral dosage form comprising, wherein the surface of the oral dosage form comprises at least one drug release orifice, the oral dosage form; v) a. (i) A drug layer containing 100 mg of apremilast, 100 mg of hypromellose acetate succinate (HPMCAS), 301.4 mg of polyethylene oxide having a molecular weight of 200,000 to 300,000 Da or a mixture thereof, 26.7 mg of sodium chloride, 2.6 mg of magnesium stearate, and 2.7 mg of colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion, the drug layer; (ii) A swelling layer containing 173.1 mg of polyethylene oxide having a molecular weight of 5,000,000 Da, 68.8 mg of microcrystalline cellulose, 22.9 mg of sodium chloride, 0.5 mg of iron oxide, and 1.3 mg of magnesium stearate comprising a core tablet; b. A coating layer disposed on the core tablet and containing cellulose acetate and polyethylene glycol; An oral dosage form comprising, wherein the surface of the oral dosage form comprises at least one drug release orifice; vi) a. (i) A drug layer comprising 100 mg of apremilast, 100 mg of hypromellose acetate succinate (HPMCAS), 274.6 mg of polyethylene oxide having a molecular weight of 300,000 Da, 53.3 mg of sodium chloride, 2.6 mg of magnesium stearate, and 2.7 mg of colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) A swelling layer comprising 173.1 mg of polyethylene oxide having a molecular weight of 5,000,000 Da, 68.8 mg of microcrystalline cellulose, 22.9 mg of sodium chloride, 0.5 mg of iron oxide, and 1.3 mg of magnesium stearate comprising a core tablet; b. A coating layer disposed on the core tablet and comprising cellulose acetate and polyethylene glycol; An oral dosage form comprising, wherein the surface of the oral dosage form comprises at least one drug release orifice; vii) a. (i) A drug layer comprising 75 mg of apremilast, 75 mg of hypromellose acetate succinate (HPMCAS), 226.0 mg of polyethylene oxide having a molecular weight of 200,000 - 300,000 Da or a mixture thereof, 20.0 mg of sodium chloride, 2.0 mg of magnesium stearate, and 2.0 mg of colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) A swelling layer comprising 129.8 mg of polyethylene oxide having a molecular weight of 5,000,000 Da, 51.6 mg of microcrystalline cellulose, 17.2 mg of sodium chloride, 0.4 mg of iron oxide, and 1.0 mg of magnesium stearate comprising a core tablet; b. A coating layer disposed on the core tablet and comprising cellulose acetate and polyethylene glycol; An oral dosage form comprising, wherein the surface of the oral dosage form comprises at least one drug release orifice; viii) a. (i) A drug layer comprising 75 mg of apremilast, 75 mg of hypromellose acetate succinate (HPMCAS), 206.0 mg of polyethylene oxide with a molecular weight of 300,000 Da, 40.0 mg of sodium chloride, 2.0 mg of magnesium stearate, and 2.0 mg of colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) A swelling layer comprising 129.8 mg of polyethylene oxide with a molecular weight of 5,000,000 Da, 51.6 mg of microcrystalline cellulose, 17.2 mg of sodium chloride, 0.4 mg of iron oxide, and 1.0 mg of magnesium stearate comprising a core tablet, and b. A coating layer disposed on the core tablet and comprising cellulose acetate and polyethylene glycol, comprising an oral dosage form, wherein the surface of the oral dosage form comprises at least one drug release orifice; ix) a. (i) A drug layer comprising 55 mg of apremilast, 55 mg of hypromellose acetate succinate (HPMCAS), 165.7 mg of polyethylene oxide with a molecular weight of 200,000 - 300,000 Da or a mixture thereof, 14.7 mg of sodium chloride, 1.4 mg of magnesium stearate, and 1.5 mg of colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) A swelling layer comprising 95.2 mg of polyethylene oxide with a molecular weight of 5,000,000 Da, 37.8 mg of microcrystalline cellulose, 12.6 mg of sodium chloride, 0.3 mg of iron oxide, and 0.7 mg of magnesium stearate comprising a core tablet, and b. A coating layer disposed on the core tablet and comprising cellulose acetate and polyethylene glycol, comprising an oral dosage form, wherein the surface of the oral dosage form comprises at least one drug release orifice; x) a. (i) A drug layer comprising 55 mg of apremilast, 55 mg of hypromellose acetate succinate (HPMCAS), 151.1 mg of polyethylene oxide with a molecular weight of 300,000 Da, 29.3 mg of sodium chloride, 1.4 mg of magnesium stearate, and 1.5 mg of colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) A swelling layer containing 95.2 mg of polyethylene oxide with a molecular weight of 5,000,000 Da, 37.8 mg of microcrystalline cellulose, 12.6 mg of sodium chloride, 0.3 mg of iron oxide, and 0.7 mg of magnesium stearate including a core tablet, and b. A coating layer disposed on the core tablet and containing cellulose acetate and polyethylene glycol and, An oral dosage form including an oral dosage form surface containing at least one drug release orifice; xi) a. (i) A drug layer containing 27.5 mg of apremilast, 27.5 mg of hypromellose acetate succinate (HPMCAS), 82.9 mg of polyethylene oxide with a molecular weight of 200,000 - 300,000 Da or a mixture thereof, 7.3 mg of sodium chloride, 0.8 mg of magnesium stearate, and 0.7 mg of colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) A swelling layer containing 47.6 mg of polyethylene oxide with a molecular weight of 5,000,000 Da, 18.9 mg of microcrystalline cellulose, 6.3 mg of sodium chloride, 0.1 mg of iron oxide, and 0.4 mg of magnesium stearate including a core tablet, and b. A coating layer disposed on the core tablet and containing cellulose acetate and polyethylene glycol and, or xii) a. (i) A drug layer containing 27.5 mg of apremilast, 27.5 mg of hypromellose acetate succinate (HPMCAS), 75.5 mg of polyethylene oxide with a molecular weight of 300,000 Da, 14.7 mg of sodium chloride, 0.4 mg of magnesium stearate, and 0.7 mg of colloidal silicon dioxide, wherein the apremilast and HPMCAS are in a solid dispersion; (ii) A swelling layer containing 47.6 mg of polyethylene oxide with a molecular weight of 5,000,000 Da, 18.9 mg of microcrystalline cellulose, 6.3 mg of sodium chloride, 0.1 mg of iron oxide, and 0.4 mg of magnesium stearate including a core tablet, and b. A coating layer disposed on the core tablet and containing cellulose acetate and polyethylene glycol An oral dosage form comprising, wherein the surface of the oral dosage form comprises at least one drug release orifice, the oral dosage form The oral preparation according to claim 13, comprising

15. An oral preparation according to any one of claims 1-14 for use in the treatment of a patient suffering from a disease or disorder improved by inhibiting PDE4, wherein the oral preparation is administered once daily to the patient under feeding conditions

16. The oral preparation according to claim 15, wherein the disease or disorder is psoriasis, psoriatic arthritis, or Behçet's disease

17. The oral preparation according to claim 15, wherein the disease or disorder is colitis, inflammatory bowel disease, or hidradenitis suppurativa

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