Oral solid dosage form containing antibodies for sustained release in the lower gastrointestinal tract

Abstract

The present invention relates to an oral solid dosage form for sustained release in the lower gastrointestinal tract, comprising an inert core unit (1) covered by a depot layer (2), a sustained-release layer (3) covering the depot layer, and a delayed-release layer (4) covering the sustained-release layer, preferably prepared by drug layering; an oral multiparticle drug delivery system comprising multiple oral solid dosage forms; and the use of oral solid dosage forms in targeted local treatment in the lower gastrointestinal tract of patients.

Description

[Technical Field]

[0001] The present invention relates to an oral solid dosage form for sustained release in the lower gastrointestinal tract, comprising an inert core unit (1) covered by a depot layer (2), a sustained-release layer (3) covering the depot layer, and a delayed-release layer (4) covering the sustained-release layer, containing an antibody or functional fragment thereof specific to tumor necrosis factor alpha (TNFα), preferably prepared by drug layering; an oral multiparticle drug delivery system comprising multiple oral solid dosage forms; and the use of oral solid dosage forms in targeted local treatment in the lower gastrointestinal tract of patients. [Background technology]

[0002] Solid dosage forms, such as pellets, minitablets, tablets, granules, capsules, or tablets, are widely used in the pharmaceutical industry. They typically contain at least one active ingredient, as well as one or more carriers and other excipients. Advantages of such solid dosage forms include less storage space, easier handling, and improved stability. Furthermore, tablets or capsules provide the most widely used unit of administration for non-invasively administering drugs to patients. For small molecule drugs, there are long-established practices for preparing solid dosage forms. On the other hand, while antibodies and their functional fragments continue to be increasingly used as active ingredients in therapeutic or diagnostic applications, formulation into solid dosage forms is more challenging.

[0003] As an alternative to systemic therapy, the use of solid dosage forms intended for oral administration and targeting a portion of the gastrointestinal (GI) tract has many potential advantages and has therefore become an interesting alternative in recent years, enabling targeted local treatment of symptoms of diseases in a portion of the GI tract, such as immune checkpoint inhibitor (ICPI)-induced colitis, ICPI-induced enteritis, ICPI-induced diarrhea, inflammatory bowel disease (IBD), colorectal cancer, diarrhea, or microbial infections. However, the use of antibodies and functional fragments of antibodies in solid dosage forms for such targeted local treatment in the GI tract faces various challenges.

[0004] Colitis is a disorder characterized by inflammation of the large intestine / colon. Enteritis is defined as a disorder characterized by inflammation of the small intestine. Enteritis is a disorder characterized by inflammation of both the small intestine and the large intestine / colon, i.e., a combination of enteritis and colitis. Symptoms characteristic of ICP inhibitor-induced colitis include diarrhea, abdominal pain, nausea, cramps, blood or mucus in the stool or changes in bowel habits, fever, abdominal distension, constipation and bowel movements (Brahmer et al., Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology (ASCO) Practice Guideline, J Clin Oncol. (2018) 10;36(17):1714-1768). Symptoms characteristic of ICP inhibitor-induced enteritis include the symptoms listed above for ICP inhibitor-induced colitis.

[0005] Regarding ICPI-induced colitis, ICPI-induced enteritis, and ICPI-induced diarrhea, it is important that patients may be treated for ICPI-induced colitis, ICPI-induced enteritis, or ICPI-induced diarrhea with antibodies or functional antibody fragments while undergoing cancer treatment with ICPI via an intravenous route. This requires an alternative route of administration both to enable parallel intravenous cancer treatment (for example, the current standard therapy for treating severe ICPI-induced colitis or ICPI-induced enteritis using anti-TNFα-specific antibodies involves periodic systemic administration of anti-TNFα antibodies via intravenous infusion, which requires interruption of ICPI treatment) and to ensure targeted local delivery to minimize systemic exposure to the antibody and the potential side effects that may result therefrom. While this is beneficial for all patients, it is particularly important for patients with ICPI-induced colitis, ICPI-induced enteritis, or ICPI-induced diarrhea who are already severely burdened by cancer treatment.

[0006] A problem associated with oral solid dosage forms containing antibodies and functional antibody fragments is the size of the antibodies and antibody fragments compared to small drug molecules, which can significantly affect their release behavior when combined with functional coatings such as sustained-release coatings and / or delayed-release coatings.

[0007] Targeted release of therapeutic antibodies or functional fragments thereof from solid dosage forms into specific portions of the GI tubule over a defined time frame is particularly desirable for diseases of the lower GI tubule, especially ICPI-induced colitis, ICPI-induced enteritis, ICPI-induced diarrhea, and IBD. However, targeted release of antibodies or functional fragments thereof from solid dosage forms into specific portions of the GI tubule over a defined time frame can also be extremely difficult.

[0008] Therefore, there is a need for an oral solid dosage form containing a therapeutic antibody or functional fragment thereof, preferably specific to tumor necrosis factor alpha (TNFα), for release in a defined portion of the GI tubule, particularly the lower GI tubule, that ensures targeted release over a defined time frame. [Overview of the project]

[0009] After testing various solid dosage form designs, excipients, manufacturing methods, and processing conditions, the inventors have found a favorable oral solid dosage form containing, as an active ingredient, an antibody or functional fragment thereof, preferably specific to tumor necrosis factor alpha (TNFα). The oral solid dosage form of the present invention comprises an inactive core unit (1), a depot layer (2) containing the antibody or functional fragment thereof, a sustained-release layer (3), and a delayed-release layer (4). The components and composition of the depot layer, sustained-release layer, and delayed-release layer are carefully selected to ensure a desired release profile of the antibody or functional fragment thereof after oral administration.

[0010] The inventors unexpectedly found that the sustained-release layer alone does not provide consistent results with respect to the sustained-release of antibodies from the depot layer. Surprisingly, consistent and sufficiently high release rates (e.g., about 80% of the antibody is released within 26 hours in the release test) were achieved only when combined with the final outer delayed-release layer. This is surprising since the delayed-release layer is thought to only prevent drug release until the pH trigger. Thus, the final oral solid formulation found by the inventors functions by the combined effect of the layers and carefully selected and calibrated components in different layers, enabling the targeted release of an antibody or a functional fragment thereof in a desired manner. It has been found that a preferred release profile can be obtained when the delayed-release layer contains an anionic polymer and the sustained-release layer contains a cationic polymer. Also, the formulations of the present invention have been shown to be stable for 12 months. Unexpectedly, the antibody activity was stable even after storage at 25°C / 60% RH for 1 year.

[0011] The oral solid formulation of the present invention prevents the release of an antibody or a functional fragment thereof before reaching the target site in the gastrointestinal (GI) tract of the patient. Thereby, the oral solid formulation advantageously ensures controlled sustained release from the oral solid formulation in the lower part of the GI tract, particularly preferably starting in the terminal ileum or the ileocolonic region and ensuring the release of most of the antibody or a functional fragment thereof from the oral solid formulation in the target region of the GI tract over a clearly defined period, e.g., throughout the day, and then being excreted via the anus. Thus, the oral solid formulation ensures that the optimal amount of the active form of the antibody or a functional fragment thereof can be released from the oral solid formulation in a controlled manner. The oral solid formulation is preferably prepared by drug layering using a carefully selected combination of excipients that ensure the rapid and easy preparation of the oral solid formulation while maintaining the stability and activity of the antibody or a functional fragment thereof.

[0012] Therefore, the present invention provides a novel oral solid preparation comprising, in an inert core unit (1)-coating depot layer (2), a sustained-release layer (3) coating the depot layer, and a delayed-release layer (4) coating the sustained-release layer, an antibody or a functional fragment thereof as an active agent, preferably specific for TNFα, thereby ensuring carefully calibrated delayed release and sustained release from an oral solid preparation that starts at a defined position in the lower GI tract. The present invention relates to the subject matter defined in the following items 1 to 131: [1] An oral solid preparation comprising: i) an inert core unit (1); and ii) a depot layer (2) coating the inert core unit (1) and containing an antibody or a functional fragment thereof as an active agent, optionally containing a stabilizer, a buffer, and / or a polymeric binder; and iii) a sustained-release layer (3) coating the depot layer (2) and containing at least one cationic polymer, optionally containing a plasticizer and / or an anti-tack agent; and iv) a delayed-release layer (4) coating the sustained-release layer (3) and containing at least one anionic polymer, optionally containing a plasticizer. [2] An oral solid preparation comprising: i) an inert core unit (1); and ii) a depot layer (2) coating the inert core unit (1) and containing an antibody or a functional fragment thereof as an active agent, a stabilizer, a buffer, and a polymeric binder; and iii) a sustained-release layer (3) coating the depot layer (2) and containing at least one cationic polymer, a plasticizer, and an anti-tack agent; and iv) a delayed-release layer (4) coating the sustained-release layer (3) and containing at least one anionic polymer and a plasticizer. [3] A solid dosage form according to item 1 or 2, wherein at least one anionic polymer is selected from the group consisting of polymers containing a carboxylic acid group; poly(methacrylic acid, methyl methacrylate) 1:1; poly(methacrylic acid, ethyl acrylate) 1:1; poly(methacrylic acid, methyl methacrylate) 1:2; poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1; carboxymethylcellulose; and combinations thereof. [4] A solid dosage form according to any one of items 1 to 3, wherein at least one cationic polymer is selected from the group consisting of chitosan; cellulose; ammonia methacrylate copolymer; poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1; poly(2-N,N-dimethylaminoethyl methacrylate); poly-L-lysine; polyethyleneimine; and poly(amidoamine). [5] Oral solid dosage form, i) Inert core unit (1), ii) A depot layer (2) coating the inert core unit (1) and comprising an antibody or functional fragment thereof, preferably specific to tumor necrosis factor alpha (TNFα), as an active agent; a stabilizer, preferably sucrose; a buffer; and a polymer binder, preferably hypromellose (HPMC), iii) A sustained-release layer (3) covering the depot layer (2) and comprising an ammonia methacrylate copolymer, preferably poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1; a plasticizer; and an anti-tack agent, iv) An oral solid dosage form comprising: a sustained-release layer (3) coated with a delayed-release layer (4) comprising poly(methacrylic acid, methyl methacrylate) 1:2, poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1, poly(methacrylic acid, methyl methacrylate) 1:1, or a combination thereof, preferably poly(methacrylic acid, methyl methacrylate) 1:2; an anti-tack agent, preferably glycerol monostearate (GMS); and a plasticizer, preferably triethyl citrate (TEC). [6] The oral solid dosage form according to any one of the preceding items, wherein the oral solid dosage form is a pellet, granule, bead, sphere, minisphere, tablet or minitablet, preferably a pellet. [7] An oral solid dosage form that is acid-resistant, as described in any one of the preceding items. [8] An oral solid dosage form according to any one of the preceding items, for targeted release of an antibody or a functional fragment thereof, which begins in the terminal ileum, ileocolonic region, ascending colon, or transverse colon, preferably the terminal ileum, ileocolonic region, or ascending colon, more preferably the terminal ileum or ileocolonic region. [9] An oral solid dosage form according to any one of the preceding items, for targeted release of an antibody or functional fragment thereof in the terminal ileum, ileocolon, ascending colon, transverse colon, and / or sigmoid colon.

[10] An oral solid dosage form according to any one of the preceding items, for targeted sustained release of an antibody or functional fragment thereof, which begins in the terminal ileum and continues at least through the sigmoid colon.

[11] The oral solid dosage form according to any one of the preceding items, wherein the inert core unit (1) is an inert pellet, mini tablet, tablet, granule, core, bead, mini sphere or sphere, preferably a pellet.

[12] An oral solid dosage form according to any one of the preceding items, wherein the inactive core unit (1) mainly contains a monosaccharide, disaccharide, oligosaccharide, polysaccharide, silica, tartaric acid, calcium carbonate, or a combination thereof.

[13] An oral solid dosage form according to any one of the preceding items, wherein the inactive core unit (1) consists of a monosaccharide, disaccharide, oligosaccharide, polysaccharide, silica, tartaric acid, calcium carbonate, or a combination thereof.

[14] An oral solid dosage form according to any one of the preceding items, wherein the inert core unit (1) is preferably a pellet comprising or consisting of spheres; is made of a water-insoluble or water-swellable material; and / or has a homogeneous composition.

[15] An oral solid dosage form according to any one of items 1 to 13, wherein the inert core unit (1) comprises or consists of pellets, for example spheres, and optionally a sealing coating covering the spheres, the sealing coating preferably consisting of a water-insoluble material.

[16] An oral solid dosage form according to any one of the preceding items, wherein the inactive core unit (1) contains a monosaccharide, disaccharide, oligosaccharide, polysaccharide, silica, tartaric acid, or a combination thereof as the main or sole component.

[17] An oral solid dosage form according to any one of the preceding items, wherein the inert core unit (1) is preferably a pellet and comprises or consists of microcrystalline cellulose, sucrose, starch, mannitol, calcium carbonate, silica, tartaric acid, lactose, carboxymethylcellulose, cross-linked carboxymethylcellulose sodium, or a combination thereof.

[18] An oral solid dosage form according to any one of the preceding items, wherein the inert core unit (1) contains or consists of microcrystalline cellulose.

[19] An oral solid dosage form described in any one of the preceding items, wherein the inactive core unit (1) is pharmaceutically inactive.

[20] An oral solid dosage form according to any one of the preceding items, wherein the inactive core unit (1) does not contain an active agent.

[21] The oral solid dosage form according to any one of the preceding items, wherein the inert core unit (1) is a pellet having a sphericity of at least 0.6, preferably at least 0.7, more preferably at least 0.8, even more preferably at least 0.9, and even more preferably at least 0.95.

[22] An oral solid dosage form according to any one of the preceding items, wherein the inert core unit (1) is a pellet having a median particle size of 50 to 5000 μm, preferably 100 to 3000 μm, more preferably 200 to 2000 μm, even more preferably 300 to 1500 μm, even more preferably 400 to 1400 μm, even more preferably 700 to 1400 μm, even more preferably 500 to 1000 μm, most preferably 500 to 700 μm, 600 to 800 μm, or 700 to 1000 μm.

[23] The oral solid dosage form according to any one of the preceding items, wherein the inert core unit (1) is a pellet having a particle size distribution such that at least 85% of the pellets have a particle size of 50 to 3000 μm, preferably 100 to 1500 μm, more preferably 350 to 1400 μm, even more preferably 500 to 1400 μm, even more preferably 700 to 1400 μm, even more preferably 500 to 1000 μm, for example 500 to 700 μm or 700 to 1000 μm.

[24] The oral solid dosage form according to any one of the preceding items, wherein the inert core unit (1) is a pellet having a particle size distribution such that at least 85% of the pellets have a particle size of 700 to 1400 μm, preferably 700 to 1000 μm.

[25] The oral solid dosage form according to any one of the preceding items, wherein the depot layer (2) is deposited on an inert core unit (1) by drug layering, preferably using spray coating, more preferably using fluid bed spray coating.

[26] An oral solid dosage form according to any one of the preceding items, wherein the stabilizer in the depot layer (2) is selected from sucrose, maltose, lactose, trehalose, glycerol, maltitol, isomalt, mannitol, sorbitol, xylitol and combinations thereof, preferably sucrose, maltose, lactose, glycerol, maltitol, isomalt and combinations thereof, more preferably sucrose.

[27] An oral solid dosage form according to any one of the preceding items, wherein the buffer in the depot layer (2) (i.e., one or more buffer salts and / or free bases) is selected from the group consisting of L-histidine buffer, citrate buffer, hydroxymethylaminomethane (TRIS) buffer, succinate buffer, phosphate buffer, acetate buffer, or salts thereof, and combinations thereof; preferably L-histidine buffer, citrate buffer, TRIS buffer, and combinations thereof; more preferably L-histidine buffer, citrate-TRIS buffer, and combinations thereof.

[28] The oral solid dosage form according to any one of the above items, wherein the buffer in the depot layer (2) (i.e., buffer salt and / or free base) contains or consists of L-histidine, preferably L-histidine monohydrochloride and / or a free base.

[29] An oral solid dosage form according to any one of the preceding items, wherein the polymer binder in the depot layer (2) is hypromellose (HPMC); methylcellulose (MC); polyvinylpyrrolidone (PVP); polyvinyl alcohol (PVA); hydroxypropylcellulose (HPC); macrogol poly(vinyl alcohol) grafted copolymer (e.g., Kollidon® IR); and combinations thereof; preferably HPMC or MC; more preferably selected from HPMC.

[30] The oral solid dosage form according to any one of the preceding items, wherein the polymer binder in the depot layer (2) is suitable for immediate-release drug coating.

[31] An oral solid dosage form according to any one of the preceding items, wherein the polymer binder in the depot layer (2) is hypromellose (HPMC); preferably hypromellose 2910, more preferably hypromellose 2910 2.6 to 3.6 mPas, and even more preferably hypromellose 2910 3 mPas.

[32] An oral solid dosage form according to any one of the preceding items, wherein the depot layer (2) contains an anti-sticking agent.

[33] The oral solid formulation according to item 32, wherein the anti-tack agent is selected from mesoporous silica, colloidal silicon dioxide, stearic acid, magnesium stearate, glycerol monostearate (GMS), and talc, preferably mesoporous silica.

[34] An oral solid dosage form according to any one of the preceding items, wherein the depot layer (2) contains a coalescence enhancer.

[35] An oral solid dosage form according to any one of the preceding items, wherein the depot layer (2) contains a surfactant, preferably a nonionic surfactant.

[36] The oral solid dosage form according to item 35, wherein the surfactant is selected from the group consisting of polysorbate 20, polysorbate 28, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, poloxamer 124, poloxamer 181, poloxamer 188, poloxamer 237, poloxamer 331, poloxamer 338 and poloxamer 407, and combinations thereof.

[37] The oral solid dosage form according to item 35, wherein the surfactant is polysorbate 20, 28, 40, 60, 65, 80, 81 and 85; preferably polysorbate 80.

[38] An oral solid dosage form according to any one of the preceding items, wherein the depot layer (2) contains or consists of, as an active agent, an antibody or functional fragment thereof that is preferably specific to TNFα, sucrose, L-histidine (salt and / or free base), preferably L-histidine monohydrochloride and / or free base, hypromellose (HPMC), preferably hypromellose 2910 2.6-3.6 mPas, mesoporous silica, polysorbate 80, and residual water.

[39] An oral solid dosage form according to any one of the preceding items, comprising 0.05 to 30% by weight, preferably 0.1 to 25% by weight, more preferably 0.1 to 20% by weight, even more preferably 0.2 to 20% by weight, even more preferably 0.2 to 15% by weight, even more preferably 0.5 to 12% by weight, even more preferably 0.5 to 10% by weight, even more preferably 0.8 to 12% by weight, even more preferably 8 to 12% by weight, even more preferably 8 to 10% by weight, for example about 9.5% by weight, an antibody or functional fragment thereof that is preferably specific to TNFα.

[40] The depot layer (2) comprises, with respect to the total weight of the depot layer, 0.2 to 75% by weight of antibody or its functional fragment, 0.5 to 65% by weight of binder, 2 to 80% by weight of sucrose, 0.1 to 10% by weight of L-histidine (salt and / or free base), and optionally 0.05 to 10% by weight of other buffers, 0.2 to 15% by weight of anti-tack agents, 0.01 to 1% by weight of surfactants, and / or up to 10% by weight of water; preferably, with respect to the total weight of the depot layer, 1 to 45% by weight of antibody or its functional fragment, 2 to 35% by weight of binder, 10 to 70% by weight of sucrose, 0.2 to 5% by weight of L-histidine, and optionally 0.1 to 4% by weight of other buffers, 1 to 5% by weight of anti-tack agents, 0.05 to 0.5% by weight of surfactants, and / or up to 7% by weight of water; more preferably More preferably, an oral solid dosage form according to any one of the preceding items, comprising, relative to the total weight of the depot layer, 10 to 35% by weight of an antibody or functional fragment thereof, 10 to 30% by weight of a binder, 30 to 60% by weight of sucrose, 0.3 to 4% by weight of L-histidine, and optionally 0.2 to 3% by weight of another buffer, 1.5 to 3% by weight of an anti-tack agent, 0.1 to 0.3% by weight of a surfactant, and / or up to 6% by weight of water; more preferably, relative to the total weight of the depot layer, 25 to 35% by weight of an antibody or functional fragment thereof, 15 to 25% by weight of a binder, 40 to 55% by weight of sucrose, 0.4 to 3% by weight of L-histidine, and optionally 0.5 to 2.5% by weight of another buffer, 1.5 to 2.5% by weight of an anti-tack agent, 0.2 to 0.3% by weight of a surfactant, and / or up to 5% by weight of water.

[41] Oral solid dosage forms, a) Microcrystalline cellulose in the inert core unit (1); and / or b) The depot layer (2) preferably contains an antibody specific to TNFα or a functional fragment thereof, sucrose, L-histidine, preferably L-histidine monohydrochloride and / or free base, hypromellose (HPMC), preferably hypromellose 2910 2.6~3.6 mPas, mesoporous silica, and / or polysorbate 80; and / or c) The sustained-release layer (3 contains poly(ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride) 1:2:0.1 (e.g., Eudragit® RS 30D), triethyl citrate (TEC) and / or mesoporous silica; and / or d) The delayed-release layer (4) contains poly(methacrylic acid, methyl methacrylate) 1:2, TEC, polysorbate 80, and / or glycerol monostearate (GMS); and / or e) An oral solid dosage form according to any one of the preceding items, comprising or consisting of an inert core unit and / or residual water in either layer.

[42] The oral solid dosage form according to any one of the preceding items, wherein the inert core unit (1) is a pellet having a particle size distribution such that at least 85% of the pellets have a particle size of 700 to 1400 μm, preferably 700 to 1000 μm.

[43] The oral solid dosage form according to any one of the preceding items, wherein the inert core unit contains 5 to 75% by weight, preferably 15 to 65% by weight, more preferably 15 to 60% by weight, even more preferably 20 to 60% by weight, and even more preferably 25 to 30% by weight of microcrystalline cellulose, based on the total weight of the oral solid dosage form.

[44] The depot layer (2) comprises, with respect to the total weight of the oral solid dosage form, 0.05 to 30% by weight of antibody or functional fragment thereof, 0.03 to 30% by weight of binder, 0.1 to 40% by weight of sucrose, 0.005 to 5% by weight of L-histidine (salt and / or free base), and optionally 0.001 to 5% by weight of other buffering agents, 0.005 to 8% by weight of anti-tack agents, and / or 0.0005 to 2% by weight of surfactant; preferably 0.1 to 20% by weight of antibody or functional fragment thereof. Fragments, 0.1-25% by weight of a binder, 0.5-35% by weight of sucrose, 0.01-3% by weight of L-histidine, and optionally 0.01-3% by weight of other buffers, 0.01-5% by weight of an anti-tackifying agent, and / or 0.001-1% by weight of a surfactant; more preferably 0.5-20% by weight of an antibody or its functional fragment, 0.5-15% by weight of a binder, 1-25% by weight of sucrose, 0.05-2% by weight of L-histidine, and optionally 0.05-1.5% by weight of % by weight of other buffers, 0.05 to 1.5% by weight of anti-tackifiers, and / or 0.005 to 0.3% by weight of surfactants; more preferably 2 to 20% by weight of antibodies or functional fragments thereof, 5 to 15% by weight of binders, 10 to 25% by weight of sucrose, 0.1 to 2% by weight of L-histidine, and optionally 0.5 to 1.5% by weight of other buffers, 0.5 to 1.5% by weight of anti-tackifiers, and / or 0.05 to 0.3% by weight of surfactants; more preferably 8 to 12% by weight An oral solid dosage form according to any one of the preceding items, comprising % antibody or a functional fragment thereof, 6-8% by weight of a binder (preferably hypromellose (HPMC)), 15-18% by weight of sucrose, 0.15-1% by weight of L-histidine, and optionally 0.6-0.9% by weight of another buffer, 0.6-0.8% by weight of an anti-tackifying agent (preferably mesoporous silica), and / or 0.05-0.1% by weight of a surfactant (preferably polysorbate 80).

[45] The sustained-release layer (3) comprises, with respect to the total weight of the oral solid dosage form, 1 to 10% by weight of ammonia methacrylate copolymer, 0.1 to 5% by weight of a plasticizer, and / or 0.05 to 7% by weight of an anti-tack agent; preferably 3 to 6% by weight of ammonia methacrylate copolymer, 0.2 to 2% by weight of a plasticizer, and / or 0.1 to 3% by weight of an anti-tack agent; more preferably 3.3 to 4.5% by weight of ammonia methacrylate copolymer, 0.5 to 1.5% by weight of a plasticizer, and / or 0.2 to 1% by weight of an anti-tack agent; even more preferably 3.6 to 4.2% by weight of poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 (e.g., Eudragit® RS 30D) An oral solid dosage form according to any one of the preceding items, comprising 0.6 to 1% by weight of a plasticizer (preferably triethyl citrate (TEC)) and / or 0.3 to 0.5% by weight of an anti-tackifying agent.

[46] The delayed-release layer (4) consists of 10-40% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 0.5-10% by weight of plasticizer, 0.1-3.5% by weight of surfactant, and / or 0.5-10% by weight of anti-tack agent (preferably glycerol monostearate (GMS)) relative to the total weight of the oral solid dosage form; preferably 15-35% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 1-5% by weight of plasticizer, 0.2-2% by weight of surfactant, and / or 1-5% by weight of anti-tack agent (preferably glycerol monostearate (GMS)); more preferably 1 An oral solid dosage form according to any one of the preceding items, comprising 8-30% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 1.5-3% by weight of a plasticizer, 0.5-1.3% by weight of a surfactant, and / or 1.5-3% by weight of an anti-tack agent (preferably glycerol monostearate (GMS)); more preferably 21-26% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 2.0-2.6% by weight of a plasticizer, 0.7-1.1% by weight of a surfactant, and / or 2.0-2.6% by weight of an anti-tack agent (preferably glycerol monostearate (GMS)).

[47] An oral solid dosage form according to any one of the preceding items, comprising up to 7% by weight, preferably up to 6% by weight, more preferably up to 5% by weight, for example 5% by weight of water in an inert core unit and / or any of the layers, relative to the total weight of the oral solid dosage form.

[48] ​​Oral solid dosage form (relative to the total weight of the oral solid dosage form) a) Microcrystalline cellulose in the inert core unit (1) in an amount of 5 to 75% by weight, preferably 15 to 65% by weight, more preferably 20 to 60% by weight, and even more preferably 25 to 30% by weight; and / or b) The depot layer (2) contains 0.05 to 30% by weight of antibody or its functional fragment, 0.03 to 30% by weight of binder, 0.1 to 40% by weight of sucrose, 0.005 to 5% by weight of L-histidine (salt and / or free base), and optionally 0.001 to 5% by weight of other buffers, 0.005 to 8% by weight of anti-tackener, and / or 0.0005 to 2% by weight of surfactant; preferably 0.1 to 20% by weight of antibody or its functional Functional fragment, 0.1-25% by weight of binder, 0.5-35% by weight of sucrose, 0.01-3% by weight of L-histidine, and optionally 0.01-3% by weight of other buffers, 0.01-5% by weight of anti-tackifiers, and / or 0.001-1% by weight of surfactant; more preferably 0.5-20% by weight of antibody or functional fragment thereof, 0.5-15% by weight of binder, 1-25% by weight of sucrose, 0.05-2% by weight of L-histidine, and And optionally 0.05 to 1.5% by weight of other buffers, 0.05 to 1.5% by weight of anti-tack agents, and / or 0.005 to 0.3% by weight of surfactants; more preferably 2 to 20% by weight of antibodies or functional fragments thereof, 5 to 15% by weight of binders, 10 to 25% by weight of sucrose, 0.1 to 2% by weight of L-histidine, and optionally 0.5 to 1.5% by weight of other buffers, 0.5 to 1.5% by weight of anti-tack agents, and / or 0 0.05-0.3 wt% surfactant; more preferably 8-12 wt% antibody or functional fragment thereof, 6-8 wt% binder (preferably hypromellose (HPMC)), 15-18 wt% sucrose, 0.15-1 wt% L-histidine and optionally 0.6-0.9 wt% other buffer, 0.6-0.8 wt% mesoporous silica, and / or 0.05-0.1 wt% polysorbate 80; and / or c) The sustained-release layer (3) contains 1 to 10% by weight of ammonia methacrylate copolymer, 0.1 to 5% by weight of a plasticizer, and / or 0.05 to 7% by weight of an anti-tack agent; preferably 3 to 6% by weight of ammonia methacrylate copolymer, 0.2 to 2% by weight of a plasticizer, and / or 0.1 to 3% by weight of an anti-tack agent; more preferably 3.3 to 4.5% by weight of ammonia methacrylate copolymer, 0.5 to 1.5% by weight of a plasticizer, and / or 0.2 to 1% by weight of an anti-tack agent; even more preferably 3.6 to 4.2% by weight of poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 (e.g., Eudragit® RS 30D), 0.6 to 1% by weight of triethyl citrate (TEC) and / or 0.3 to 0.5% by weight of mesoporous silica; and / or d) In the delayed release layer (4), 10-40% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 0.5-10% by weight of plasticizer, 0.1-3.5% by weight of surfactant, and / or 0.5-10% by weight of anti-tack agent (preferably glycerol monostearate (GMS)); preferably 15-35% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 1-5% by weight of plasticizer, 0.2-2% by weight of surfactant, and / or 1-5% by weight of anti-tack agent (preferably glycerol monostearate (GMS)). More preferably 18-30% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 1.5-3% by weight of plasticizer, 0.5-1.3% by weight of surfactant, and / or 1.5-3% by weight of anti-tack agent (preferably glycerol monostearate (GMS)); even more preferably 21-26% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 2.0-2.6% by weight of plasticizer, 0.7-1.1% by weight of surfactant, and / or 2.0-2.6% by weight of glycerol monostearate (GMS)); and / or e) An oral solid dosage form according to any one of items 1 to 41, comprising or consisting of up to 5% by weight, for example, 5% by weight of water, in an inert core unit and / or any of the layers.

[49] An oral solid dosage form according to any one of the preceding items, wherein the sustained-release layer (3) contains no other sustained-release polymers other than ammonia methacrylate copolymer; preferably poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1; poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 (e.g., Eudragit® RL 30D); or a combination thereof, preferably without other sustained-release polymers.

[50] An oral solid dosage form according to any one of the preceding items, wherein the sustained-release layer (3) comprises another sustained-release polymer in a ratio of poly(ethyl acrylate, methyl methacrylate, trimethylammoniumethyl methacrylate chloride) 1:2:0.1, preferably without other sustained-release polymers.

[51] An oral solid dosage form according to any one of the preceding items, wherein the plasticizer in the sustained-release layer (3) is triethyl citrate (TEC), polyethylene glycol, acetyl triethyl citrate, butyl citrate, polysorbate, polypropylene glycol, dibutyl sebacate (DBS), or a combination thereof, preferably triethyl citrate (TEC).

[52] An oral solid preparation according to any one of the preceding items, wherein the anti-tack agent in the sustained-release layer (3) is mesoporous silica, colloidal silicon dioxide, stearic acid, magnesium stearate, glycerol monostearate (GMS), or talc, preferably mesoporous silica.

[53] An oral solid dosage form according to any one of the preceding items, comprising 0.5 to 15% by weight, preferably 1 to 10% by weight, more preferably 3 to 5% by weight, even more preferably 3.5 to 4.5% by weight, even more preferably 3.8 to 4.1% by weight, for example 4% by weight of an ammonia methacrylate copolymer, preferably poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1.

[54] An oral solid dosage form according to any one of the preceding items, wherein the sustained-release layer (3) contains 60 to 90% by weight, preferably 65 to 85% by weight, more preferably 70 to 80% by weight, and even more preferably 72 to 78% by weight of an ammonia methacrylate copolymer, preferably poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1, based on the total weight of the solid (i.e., water-free) in the sustained-release layer (3).

[55] An oral solid dosage form according to any one of the preceding items, wherein the sustained-release layer (3) contains 2 to 40% by weight, preferably 5 to 30% by weight, more preferably 15 to 25% by weight, even more preferably 17 to 23% by weight, and even more preferably 20% by weight of a plasticizer based on the total weight of the ammonia methacrylate copolymer in the sustained-release layer (3).

[56] An oral solid dosage form according to any one of the preceding items, wherein the sustained-release layer (3) contains 1 to 30% by weight, preferably 2 to 25% by weight, more preferably 5 to 15% by weight, even more preferably 8 to 12% by weight, and even more preferably 10% by weight of an anti-tack agent based on the total weight of the ammonia methacrylate copolymer in the sustained-release layer (3).

[57] An oral solid dosage form according to any one of the preceding items, wherein the sustained-release coating contains 5 to 25% by weight, preferably 10 to 20% by weight, more preferably 12 to 18% by weight, even more preferably 13 to 17% by weight, and even more preferably 14 to 15% by weight of a plasticizer, based on the total weight of the solid in the sustained-release layer (3) (i.e., excluding water).

[58] An oral solid formulation according to any one of the preceding items, wherein the sustained-release coating contains 5 to 12% by weight, preferably 6 to 9% by weight, more preferably 6 to 8.5% by weight, even more preferably 6.5 to 8.0% by weight, even more preferably 6.9 to 7.8% by weight, and even more preferably 7.0 to 7.5% by weight of an anti-tackifying agent, based on the total weight of the solid in the sustained-release layer (3) (i.e., excluding water).

[59] An oral solid dosage form according to any one of the preceding items, wherein the sustained-release layer (3) does not contain a fusion promoter.

[60] An oral solid dosage form according to any one of items 1 to 58, wherein the sustained-release layer (3) contains a fusion promoter.

[61] The oral solid dosage form according to item 60, wherein the fusion accelerator is propylene glycol monolaurate (e.g., Lauroglycol® 90).

[62] The oral solid dosage form according to any one of the preceding items, wherein the weight of the sustained-release layer (3) relative to the total weight of the inert core unit (1) and the depot layer (2) is 4 to 8% by weight, preferably 5 to 7% by weight, and more preferably about 6% by weight.

[63] The oral solid dosage form according to any one of the preceding items, wherein the sustained-release layer (3) is applied by spray coating, preferably by fluid bed spray coating.

[64] The oral solid dosage form according to item 63, wherein the weight increase of the oral solid dosage form after sustained-release coating and drying, but before application of any further layer, is 4-8% by weight, preferably 5-7% by weight, more preferably about 6% by weight.

[65] An oral solid dosage form according to any one of the preceding items, wherein the delayed-release layer (4) does not contain a polymer other than an enteric-coated polymer.

[66] An oral solid dosage form according to any one of the preceding items, wherein the delayed-release layer (4) does not contain any other delayed-release polymers, except for poly(methacrylic acid, methyl methacrylate) 1:2, poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1, poly(methacrylic acid, methyl methacrylate) 1:1, or any combination thereof.

[67] An oral solid dosage form according to any one of the preceding items, wherein the delayed-release layer (4) comprises poly(methacrylic acid, methyl methacrylate) 1:2 and preferably does not contain other delayed-release polymers.

[68] The oral solid dosage form according to any one of the preceding items, wherein the plasticizer in the delayed-release layer (4) is triethyl citrate (TEC), polyethylene glycol, acetyl triethyl citrate, butyl citrate, polypropylene glycol, dibutyl sebacate (DBS), or a combination thereof, preferably triethyl citrate (TEC).

[69] An oral solid preparation according to any one of the preceding items, wherein the anti-tack agent in the delayed-release layer (4) is mesoporous silica, colloidal silicon dioxide, stearic acid, magnesium stearate, glycerol monostearate (GMS), or talc, preferably glycerol monostearate (GMS).

[70] An oral solid dosage form according to any one of the preceding items, wherein the delayed-release layer (4) comprises a surfactant, preferably a nonionic surfactant.

[71] The oral solid dosage form according to item 66, wherein the surfactant is selected from the group consisting of polysorbate 20, polysorbate 28, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, poloxamer 124, poloxamer 181, poloxamer 188, poloxamer 237, poloxamer 331, poloxamer 338 and poloxamer 407, and combinations thereof.

[72] The oral solid dosage form according to item 70, wherein the surfactant is polysorbate 20, 28, 40, 60, 65, 80, 81 and 85; preferably polysorbate 80.

[73] An oral solid dosage form according to any one of the preceding items, wherein the delayed-release layer (4) does not contain a fusion promoter.

[74] An oral solid dosage form according to any one of the preceding items, comprising 5-40% by weight, preferably 10-40% by weight, more preferably 10-35% by weight, even more preferably 15-35% by weight, even more preferably 15-30% by weight, even more preferably 18-30% by weight, even more preferably 20-30% by weight, for example 22-25% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1, poly(methacrylic acid, methyl methacrylate) 1:1, or a combination thereof (preferably poly(methacrylic acid, methyl methacrylate) 1:2).

[75] An oral solid dosage form according to any one of the preceding items, wherein the delayed-release layer (4) contains 65 to 95% by weight, preferably 70 to 90% by weight, more preferably 75 to 85% by weight, for example about 80% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1, poly(methacrylic acid, methyl methacrylate) 1:1, or a combination thereof (preferably poly(methacrylic acid, methyl methacrylate) 1:2), based on the total weight of the solid in the delayed-release layer (4) (i.e., without the solvent).

[76] An oral solid dosage form according to any one of the preceding items, wherein the delayed-release layer (4) contains 1 to 30% by weight, preferably 2 to 25% by weight, more preferably 5 to 15% by weight, even more preferably 8 to 12% by weight, and even more preferably 10% by weight of a plasticizer, based on the total weight of the delayed-release polymer in the delayed-release layer (4).

[77] An oral solid dosage form according to any one of the preceding items, wherein the delayed-release layer (4) contains 1 to 30% by weight, preferably 2 to 25% by weight, more preferably 5 to 15% by weight, even more preferably 8 to 12% by weight, and even more preferably 10% by weight of an anti-tack agent, based on the total weight of the delayed-release polymer in the delayed-release layer (4).

[78] An oral solid dosage form according to any one of the preceding items, wherein the delayed-release layer (4) contains 0.1 to 15% by weight, preferably 0.5 to 10% by weight, more preferably 1 to 6% by weight, even more preferably 2 to 5% by weight, even more preferably 3 to 4.5% by weight, and even more preferably 3.5 to 4% by weight of a surfactant, based on the total weight of the delayed-release polymer in the delayed-release layer (4).

[79] An oral solid dosage form according to any one of the preceding items, wherein the delayed-release layer (4) contains 1 to 25% by weight, preferably 4 to 15% by weight, more preferably 5 to 12% by weight, even more preferably 6 to 10% by weight, even more preferably 7 to 9% by weight, and even more preferably about 8% by weight of a plasticizer, based on the total weight of the solid in the delayed-release layer (4) (i.e., without the solvent).

[80] An oral solid preparation according to any one of the preceding items, wherein the delayed-release layer (4) contains 1 to 25% by weight, preferably 4 to 15% by weight, more preferably 5 to 12% by weight, even more preferably 6 to 10% by weight, even more preferably 7 to 9% by weight, even more preferably about 8% by weight, and even more preferably about 7.5% by weight of an anti-tack agent, based on the total weight of the solid in the delayed-release layer (4) (i.e., without the solvent).

[81] An oral solid dosage form according to any one of the preceding items, wherein the delayed-release layer (4) contains 0.1 to 15% by weight, preferably 0.5 to 10% by weight, more preferably 1 to 5% by weight, even more preferably 2 to 4% by weight, even more preferably 2.5 to 3.5% by weight, even more preferably 3 to 3.5% by weight, and even more preferably about 3 to 3.2% by weight of a surfactant, based on the total weight of the solid in the delayed-release layer (4) (i.e., without the solvent).

[82] The solid dosage form contains 7-13 mg / cm³ in the delayed-release layer (4). 2 Preferably 8-12 mg / cm³ 2 More preferably 9-11.5 mg / cm³ 2 More preferably, about 9.5 mg / cm³ 2 , or approximately 11.50 mg / cm³ 2 An oral solid preparation according to any one of the preceding items, comprising poly(methacrylic acid, methyl methacrylate) 1:2, poly(methacrylic acid, methyl methacrylate) 1:2, poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1, poly(methacrylic acid, methyl methacrylate) 1:1, or a combination thereof (preferably poly(methacrylic acid, methyl methacrylate) 1:2).

[83] The oral solid dosage form according to any one of the preceding items, wherein the delayed-release layer (4) is applied by spray coating, preferably by fluid bed spray coating.

[84] An oral solid dosage form according to any one of the preceding items, comprising an amount of antibody or functional fragment thereof that enables administration of a therapeutically effective amount of antibody or functional fragment thereof as a single unit dose.

[85] Oral solid dosage forms (relative to the total weight of oral solid dosage forms), a) In the inert core unit (1), 57.5 to 58.2% by weight of microcrystalline cellulose; preferably 57.65 to 58.05% by weight of microcrystalline cellulose (e.g., Cellets 700); (b) In the depot layer (2), 0.65-0.95% by weight of antibody or its functional fragment, 0.44-74% by weight of hypromellose HPMC (e.g., Pharmacoat 603), 1.24-1.60% by weight of sucrose, 0.06-0.10% by weight of L-histidine (e.g., L-histidine and / or L-histidine HCl buffered solid), and 0.04-0.08% by weight of mesoporous silica (e.g., average particle size of 3.4-3.6 μm and / or 1.58-1.62 cm²). 3 A polysorbate 80 having an average pore volume of 3.4 to 3.6 μm and / or 1.58 to 1.62 cm², e.g., Syloid 244 FP), and 0.006 to 0.014 wt% polysorbate 80; preferably 0.75 to 0.85 wt% antibody or its functional fragment, 0.54 to 64 wt% hypromellose (HPMC) (e.g., Pharmacoat 603), 1.34 to 1.50 wt% sucrose, 0.07 to 0.09 wt% L-histidine (e.g., L-histidine and / or L-histidine HCl buffered solid), and 0.05 to 0.07 wt% mesoporous silica (e.g., average particle size of 3.4 to 3.6 μm and / or 1.58 to 1.62 cm²). 3 Polysorbate 80 having an average pore volume of 244 FP (e.g., Syloid 244 FP), and 0.008-0.012 wt%; c) The sustained-release layer (3) contains 3.8-4.2% by weight of poly(ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride) 1:2:0.1 (e.g., Eudragit® RS solid), 0.65-0.95% by weight of triethyl citrate (TEC), and 0.30-0.50% by weight of mesoporous silica (e.g., average particle size of 3.4-3.6 μm and / or 1.58-1.62 cm²). 3having an average pore volume of, for example, Syloid 244 FP); preferably 3.9 to 4.1% by weight of poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 (for example, Eudragit® RS solid), 0.75 to 0.85% by weight of triethyl citrate (TEC) and 0.35 to 0.45% by weight of mesoporous silica (for example, having an average particle size of 3.4 to 3.6 μm and / or an average pore volume of 1.58 to 1.62 cm 3 having an average pore volume of, for example, Syloid 244 FP); d) in the delayed release layer (4), 23.1 to 23.7% by weight of poly(methacrylic acid, methyl methacrylate) 1:2 (for example, Eudragit® S100 solid), 2.19 to 2.49% by weight of triethyl citrate (TEC), 0.79 to 1.09% by weight of polysorbate 80, and 2.19 to 2.49% by weight of glyceryl monostearate (GMS); preferably 23.25 to 23.55% by weight of poly(methacrylic acid, methyl methacrylate) 1:2 (for example, Eudragit® S100 solid), 2.29 to 2.39% by weight of triethyl citrate (TEC), 0.89 to 0.99% by weight of polysorbate 80, and 2.29 to 2.39% by weight of glyceryl monostearate (GMS); and / or e) an oral solid preparation according to any one of the preceding items, comprising or consisting of 4.7% to 5.3% by weight of water, preferably 4.9% to 5.1% by weight of water, in the inert core unit and / or in any of the layers.

[86] The oral solid preparation is (relative to the total weight of the oral solid preparation), a) in the inert core unit (1), 26.85 to 27.45% by weight of microcrystalline cellulose; preferably 27.0 to 27.3% by weight of microcrystalline cellulose (for example, cellets 700); (b) In the depot layer (2), 9.23-9.73% by weight of antibody or its functional fragment, 6.7-7.1% by weight of hypromellose HPMC (e.g., Pharmacoat 603), 16.62-17.12% by weight of sucrose, 0.79-1.09% by weight of L-histidine (e.g., L-histidine and / or L-histidine HCl buffered solid), and 0.54-0.84% ​​by weight of mesoporous silica (e.g., average particle size of 3.4-3.6 μm and / or 1.58-1.62 cm²). 3 A polysorbate having an average pore volume of / g (e.g., Syloid 244 FP), and 0.06-0.10 wt% polysorbate 80; preferably 9.38-9.58 wt% antibody or its functional fragment, 6.8-7.0 wt% hypromellose (HPMC) (e.g., Pharmacoat 603), 16.72-17.02 wt% sucrose, 0.89-0.99 wt% L-histidine (e.g., L-histidine and / or L-histidine HCl buffered solid), and 0.64-0.74 wt% mesoporous silica (e.g., average particle size of 3.4-3.6 μm and / or 1.58-1.62 cm²). 3 Polysorbate 80 having an average pore volume of 244 FP (e.g., Syloid 244 FP), and 0.07-0.09 wt% of polysorbate 80; c) The sustained-release layer (3) contains 3.74-4.14% by weight of poly(ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride) 1:2:0.1 (e.g., Eudragit® RS solid), 0.64-0.94% by weight of triethyl citrate (TEC), and 0.29-0.49% by weight of mesoporous silica (e.g., average particle size of 3.4-3.6 μm and / or 1.58-1.62 cm²). 3 A porosity having an average pore volume of / g, for example, Syloid 244 FP); preferably 3.84-4.04 wt% poly(ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride) 1:2:0.1 (e.g., Eudragit® RS solid), 0.74-0.84 wt% triethyl citrate (TEC), and 0.34-0.44 wt% mesoporous silica (e.g., average particle size of 3.4-3.6 μm and / or 1.58-1.62 cm²).3 Having an average pore volume of / g, e.g., Syloid 244 FP); d) The delayed-release layer (4) contains 22.63-23.23% by weight of poly(methacrylic acid, methyl methacrylate) 1:2 (e.g., Eudragit® S100 solid), 2.14-2.44% by weight of triethyl citrate (TEC), 0.77-0.107% by weight of polysorbate 80, and 2.14-2.44% by weight of glycerol monostearate (GMS); preferably 22.78-23.08% by weight of poly(methacrylic acid, methyl methacrylate) 1:2 (e.g., Eudragit® S100 solid), 2.24-2.34% by weight of triethyl citrate (TEC), 0.87-0.97% by weight of polysorbate 80, and 2.24-2.34% by weight of glycerol monostearate (GMS); and / or e) An oral solid dosage form according to any one of items 1 to 84, comprising or consisting of 4.03% to 4.63% by weight of water, preferably 4.23% to 4.43% by weight of water, in an inert core unit and / or any of the layers.

[87] Oral solid dosage forms (relative to the total weight of oral solid dosage forms), a) In the inert core unit (1), 24.92 to 25.52% by weight of microcrystalline cellulose; preferably 25.07 to 25.37% by weight of microcrystalline cellulose (e.g., Cellets 700); (b) In the depot layer (2), 9.0-9.5% by weight of antibody or its functional fragment, 6.54-6.94% by weight of hypromellose HPMC (e.g., Pharmacoat 603), 16.23-16.73% by weight of sucrose, 0.76-1.06% by weight of L-histidine (e.g., L-histidine and / or L-histidine HCl buffered solid), and 0.52-0.82% by weight of mesoporous silica (e.g., average particle size of 3.4-3.6 μm and / or 1.58-1.62 cm²). 3A polysorbate 80 having an average pore volume of 3.4 to 3.6 μm and / or 1.58 to 1.62 cm², e.g., Syloid 244 FP), and 0.06 to 0.10 wt% polysorbate 80; preferably 9.16 to 9.36 wt% antibody or functional fragment thereof, 6.64 to 6.84 wt% hypromellose (HPMC) (e.g., Pharmacoat 603), 16.33 to 16.63 wt% sucrose, 0.86 to 0.96 wt% L-histidine (e.g., L-histidine and / or L-histidine HCl buffered solid), and 0.62 to 0.72 wt% mesoporous silica (e.g., with an average particle size of 3.4 to 3.6 μm and / or 1.58 to 1.62 cm²). 3 Polysorbate 80 having an average pore volume of 244 FP (e.g., Syloid 244 FP), and 0.07-0.09 wt% of polysorbate 80; c) The sustained-release layer (3) contains 3.6-4.0% by weight of poly(ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride) 1:2:0.1 (e.g., Eudragit® RS solid), 0.61-0.91% by weight of triethyl citrate (TEC), and 0.28-0.48% by weight of mesoporous silica (e.g., average particle size of 3.4-3.6 μm and / or 1.58-1.62 cm²). 3 A porosity having an average pore volume of / g, for example, Syloid 244 FP); preferably 3.7-3.9 wt% poly(ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride) 1:2:0.1 (e.g., Eudragit® RS solid), 0.71-0.81 wt% triethyl citrate (TEC), and 0.33-0.43 wt% mesoporous silica (e.g., average particle size of 3.4-3.6 μm and / or 1.58-1.62 cm²). 3 Having an average pore volume of / g, e.g., Syloid 244 FP); d) In the delayed-release layer (4), 24.5-25.1% by weight of poly(methacrylic acid, methyl methacrylate) 1:2 (e.g., Eudragit® S100 solid), 2.33-2.63% by weight of triethyl citrate (TEC), 0.85-1.15% by weight of polysorbate 80, and 2.33-2.63% by weight of glycerol monostearate (GMS); 24.65-24.95% by weight of poly(methacrylic acid, methyl methacrylate) 1:2 (e.g., Eudragit® S100 solid), 2.43-2.53% by weight of triethyl citrate (TEC), 0.94-1.04% by weight of polysorbate 80, and 2.43-2.53% by weight of glycerol monostearate (GMS); and / or e) An oral solid dosage form according to any one of items 1 to 84, comprising or consisting of 4.65% to 5.25% by weight of water, preferably 4.85% to 5.05% by weight of water, in an inert core unit and / or any of the layers.

[88] Oral solid dosage forms (relative to the total weight of oral solid dosage forms), a) In the inert core unit (1), 25.06 to 25.66% by weight of microcrystalline cellulose; preferably 25.21 to 25.51% by weight of microcrystalline cellulose (e.g., Cellets 700); (b) In the depot layer (2), 8.76–9.26% by weight of antibody or its functional fragment, 6.38–6.78% by weight of hypromellose HPMC (e.g., Pharmacoat 603), 15.57–16.17% by weight of sucrose, 0.73–1.03% by weight of L-histidine (e.g., L-histidine and / or L-histidine HCl buffered solid), and 0.51–0.81% by weight of mesoporous silica (e.g., average particle size of 3.4–3.6 μm and / or 1.58–1.62 cm²). 3A polysorbate having an average pore volume of / g (e.g., Syloid 244 FP), and 0.06-0.10 wt% polysorbate 80; preferably 8.91-9.11 wt% antibody or its functional fragment, 6.48-6.68 wt% hypromellose (HPMC) (e.g., Pharmacoat 603), 15.72-16.02 wt% sucrose, 0.83-0.93 wt% L-histidine (e.g., L-histidine and / or L-histidine HCl buffered solid), and 0.61-0.71 wt% mesoporous silica (e.g., average particle size of 3.4-3.6 μm and / or 1.58-1.62 cm²). 3 Polysorbate 80 having an average pore volume of 244 FP (e.g., Syloid 244 FP), and 0.07-0.09 wt% of polysorbate 80; c) The sustained-release layer (3) contains 3.48-3.88% by weight of poly(ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride) 1:2:0.1 (e.g., Eudragit® RS Solid), 0.59-0.89% by weight of triethyl citrate (TEC), and 0.27-0.47% by weight of mesoporous silica (e.g., average particle size of 3.4-3.6 μm and / or 1.58-1.62 cm²). 3 Having an average pore volume of / g, for example, Syloid 244 FP); preferably 3.58-3.78 wt% poly(ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride) 1:2:0.1 (e.g., Eudragit® RS Solid), 0.69-0.79 wt% triethyl citrate (TEC), and 0.32-0.42 wt% mesoporous silica (e.g., with an average particle size of 3.4-3.6 μm and / or 1.58-1.62 cm²). 3 Having an average pore volume of / g, e.g., Syloid 244 FP); d) In the delayed-release layer (4), 25.41-26.01% by weight of poly(methacrylic acid, methyl methacrylate) 1:2 (e.g., Eudragit® S100 solid), 2.42-2.72% by weight of triethyl citrate (TEC), 0.88-1.18% by weight of polysorbate 80, and 2.42-2.72% by weight of glycerol monostearate (GMS); 25.56-25.86% by weight of poly(methacrylic acid, methyl methacrylate) 1:2 (e.g., Eudragit® S100 solid), 2.52-2.62% by weight of triethyl citrate (TEC), 0.98-1.08% by weight of polysorbate 80, and 2.52-2.62% by weight of glycerol monostearate (GMS); and / or e) An oral solid dosage form according to any one of items 1 to 84, comprising or consisting of 4.60% to 5.2% by weight of water, preferably 4.80% to 5.00% by weight of water, in an inert core unit and / or any of the layers.

[89] An oral solid dosage form according to any one of the preceding items, wherein the functional antibody fragment is a Fab fragment, an F(ab')2 fragment, a Fab' fragment, scFv, dsFv, VHH, a diabody, a triabody, a tetrabody, an Fc fusion protein, or a minibody.

[90] An oral solid dosage form according to any one of the preceding items, wherein the antibody or functional fragment thereof is selected from an antibody and functional fragment thereof that is specific to tumor necrosis factor alpha (TNFα), an antibody and functional fragment thereof that is specific to α4β7 integrin, an antibody and functional fragment thereof that is specific to CD3, CD4 or CD20, an antibody and functional fragment thereof that is specific to interleukin 6 (IL-6), interleukin 12 (IL-12), interleukin 13 (IL-13), interleukin 23 (IL-23) or their receptors, an antibody and functional fragment thereof that is specific to CXCL10 / IP-10, and an antibody and functional fragment thereof that is specific to the p40 protein subunit.

[91] An oral solid dosage form according to any one of the preceding items, wherein the antibody or functional fragment thereof is suitable for use in the treatment of immune checkpoint inhibitor (ICPI)-induced colitis, ICPI-induced enteritis, ICPI-induced diarrhea and / or inflammatory bowel disease (IBD) such as Crohn's disease or ulcerative colitis.

[92] An oral solid dosage form according to any one of the preceding items, wherein the antibody or functional fragment thereof is an antibody or functional fragment thereof that is specific to tumor necrosis factor alpha (TNFα).

[93] An oral solid dosage form according to item 92, wherein the antibody or functional fragment thereof is specific to TNFα and is an anti-TNFα antibody.

[94] The antibody or functional fragment thereof comprises (i) a CDR1 region having the amino acid sequence shown in SEQ ID NO: 1, a CDR2 region having the amino acid sequence shown in SEQ ID NO: 2, and a CDR3 region having the amino acid sequence shown in SEQ ID NO: 3. L A domain, and / or (ii) a V including a CDR1 region having the amino acid sequence shown in SEQ ID NO: 4, a CDR2 region having the amino acid sequence shown in SEQ ID NO: 5, and a CDR3 region having the amino acid sequence shown in SEQ ID NO: 6. H An oral solid dosage form according to any one of the preceding items, which is an anti-TNFα antibody or a functional fragment thereof having a TNFα-binding domain including a domain.

[95] The antibody or functional fragment thereof has an amino acid sequence that follows the amino acid sequence shown in SEQ ID NO: 8. L V having a domain and / or (ii) an amino acid sequence according to the amino acid sequence shown in Sequence ID No. 7 H An oral solid dosage form according to any one of the preceding items, which is an anti-TNFα antibody or a functional fragment thereof having a TNFα-binding domain including or consisting of a domain.

[96] The antibody or functional fragment thereof comprises (i) a CDR1 region having the amino acid sequence shown in SEQ ID NO: 9, a CDR2 region having the amino acid sequence shown in SEQ ID NO: 10, and a CDR3 region having the amino acid sequence shown in SEQ ID NO: 11. LA domain, and / or (ii) a V including a CDR1 region having the amino acid sequence shown in SEQ ID NO: 12, a CDR2 region having the amino acid sequence shown in SEQ ID NO: 13, and a CDR3 region having the amino acid sequence shown in SEQ ID NO: 14. H An oral solid dosage form according to any one of items 1 to 93, which is an anti-TNFα antibody or a functional fragment thereof having a TNFα-binding domain including a domain.

[97] The antibody or functional fragment thereof has an amino acid sequence that follows the amino acid sequence shown in SEQ ID NO: 16 or SEQ ID NO: 17. L V having a domain and / or (ii) an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 15 H An oral solid dosage form according to any one of items 1 to 93, which is an anti-TNFα antibody or functional fragment thereof having a TNFα-binding domain including or consisting of a domain.

[98] An oral solid dosage form according to any one of items 1 to 93, wherein the antibody or functional fragment thereof is an anti-TNFα antibody having an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, or SEQ ID NO: 22, preferably SEQ ID NO: 18, or comprising an Fc region thereof.

[99] An oral solid dosage form according to any one of items 1 to 93, wherein the antibody or functional fragment thereof is an anti-TNFα antibody comprising (i) a light chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 23, and (ii) a heavy chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 26.

[0100] An oral solid dosage form according to any one of items 1 to 93, wherein the antibody or functional fragment thereof is an anti-TNFα antibody comprising (i) a light chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 24 or SEQ ID NO: 25, and (ii) a heavy chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 27.

[0101] An oral solid dosage form according to any one of items 1 to 93, wherein the antibody or functional fragment thereof is an anti-TNFα antibody comprising (i) a light chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 23, and (ii) a heavy chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 30.

[0102] An oral solid dosage form according to any one of items 1 to 93, wherein the antibody or functional fragment thereof is an anti-TNFα antibody comprising (i) a light chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 24 or SEQ ID NO: 25, and (ii) a heavy chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 31, SEQ ID NO: 32, or SEQ ID NO: 33.

[0103] An oral solid dosage form according to any one of items 1 to 93, wherein the antibody or functional fragment thereof is an anti-TNFα antibody comprising (i) a light chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 23, and (ii) a heavy chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 34.

[0104] An oral solid dosage form according to any one of items 1 to 93, wherein the antibody or functional fragment thereof is an anti-TNFα antibody comprising (i) a light chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 24 or SEQ ID NO: 25, and (ii) a heavy chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 35.

[0105] An oral solid dosage form according to any one of items 1 to 91, wherein the antibody or functional fragment thereof is selected from infliximab, adalimumab, etanercept, certolizumab pegol, golimumab, vizilizumab, erderumab, abrimab, canakinumab, tocilizumab, ustekinumab, natalizumab, etrolizumab, priliximab, vedolizumab, and functional fragments thereof.

[0106] An oral solid dosage form according to any one of items 1 to 92, wherein the anti-TNFα antibody or functional fragment thereof is selected from infliximab, adalimumab, etanercept, certolizumab pegol, and golimumab or functional fragment thereof.

[0107] An oral solid dosage form according to any one of the preceding items, which allows for sustained release of an antibody or a functional fragment thereof over a period of at least 5 hours, preferably at least 10 hours, more preferably at least 12 hours, even more preferably at least 15 hours, even more preferably at least 20 hours, and most preferably at least 24 hours, when the oral solid dosage form is continuously immersed in an aqueous solution with continuous stirring at a pH of 6.5 to 7.5, preferably about 6.8.

[0108] An oral solid preparation according to any one of the preceding items, wherein, when the oral solid preparation is continuously immersed in an aqueous solution with a pH of 6.5 to 7.5, preferably 6.5 to 7.0, more preferably 6.8, under continuous stirring, sustained release is achieved of at least 60%, preferably at least 80%, more preferably at least 90% of the antibody or functional fragment thereof in the oral solid preparation, over a period of 4 to 30 hours, preferably 8 to 28 hours, more preferably 16 to 26 hours, and even more preferably 24 hours, preferably at a substantially constant release rate.

[0109] An oral solid preparation according to any one of the preceding items, wherein the water content in the oral solid preparation is less than 10% by weight, preferably less than 8% by weight, more preferably less than 5% by weight, or less than 3% by weight, less than 1.5% by weight, or less than 1% by weight, based on the total weight of the oral solid preparation.

[0110] An oral solid dosage form according to any one of the preceding items, wherein the total content of antibodies or functional fragments thereof present as dimers and other aggregates in the oral solid dosage form does not exceed 15%, preferably 12%, more preferably 10%, even more preferably 8%, even more preferably 7%, even more preferably 5%, and even more preferably 3%.

[0111] An oral solid dosage form according to any one of the preceding items, wherein the total content of antibodies or functional fragments present in the oral solid dosage form as full-length antibodies or fragments thereof does not exceed 15%, preferably 12%, more preferably 10%, even more preferably 8%, even more preferably 7%, even more preferably 5%, and even more preferably 3%.

[0112] An oral solid dosage form according to any one of the preceding items, wherein the depot layer (2) has an average thickness of 1 to 300 μm, preferably 2 to 200 μm, more preferably 5 to 200 μm, and even more preferably 10 to 200 μm, for example, 100 to 200 μm, or 150 μm.

[0113] An oral solid dosage form according to any one of the preceding items, wherein the sustained-release layer (3) has an average thickness of 5 to 50 μm, preferably 10 to 45 μm, more preferably 15 to 35 μm, even more preferably 18 to 30 μm, and even more preferably 20 to 30 μm, for example, 24 or 25 μm.

[0114] An oral solid dosage form according to any one of the preceding items, wherein the sustained-release layer (3) preferably has a fixed average thickness of 5 to 50 μm, preferably 10 to 45 μm, more preferably 15 to 35 μm, even more preferably 18 to 30 μm, even more preferably 20 to 30 μm, for example 24 or 25 μm, regardless of the thickness of the depot layer (2) and / or the amount of antibody or functional fragment thereof in the depot layer (2).

[0115] An oral solid dosage form according to any one of the preceding items, wherein the delayed-release layer (4) has an average thickness of 10 to 300 μm, preferably 50 to 180 μm, more preferably 60 to 160 μm, even more preferably 80 to 150 μm, even more preferably 90 to 130 μm, even more preferably 95 to 120 μm, for example 105 or 120 μm.

[0116] An oral solid preparation according to any one of the preceding items, wherein the average thickness of the sustained-release layer (3) is constant regardless of the amount of antibody or its functional fragment in the oral solid preparation and / or the thickness of the depot layer.

[0117] An oral solid dosage form according to any one of items 1 to 116, for use in targeted topical treatment of gastrointestinal disorders, preferably immune checkpoint inhibitor (ICPI)-induced colitis, ICPI-induced enteritis, ICPI-induced diarrhea, IBD, colorectal cancer, small intestine cancer, celiac disease, gastrointestinal infections (e.g., Clostridium difficile infection), more preferably ICPI-induced colitis, ICPI-induced enteritis, ICPI-induced diarrhea, or IBD.

[0118] An oral solid dosage form for use as described in item 117, wherein the gastrointestinal disorder is IBD, preferably Crohn's disease or ulcerative colitis.

[0119] An oral solid formulation for use as described in item 117, wherein the gastrointestinal disorder is ICPI-induced colitis, ICPI-induced enteritis, or ICPI-induced diarrhea, preferably ICPI-induced colitis.

[0120] An oral solid dosage form according to any one of items 117 to 119, for use in targeted local therapy in the terminal ileum, ileocolon region, ascending colon, transverse colon, descending colon and / or sigmoid colon of a patient, preferably a human patient.

[0121] An oral multiparticle drug delivery system comprising an oral solid dosage form as described in any one of items 1 to 116, wherein the oral multiparticle drug delivery system is preferably a sachet / stick pack, a straw device (XStraw®), a capsule, or a tablet / mini tablet, more preferably a capsule; and preferably an oral multiparticle drug delivery system comprising a total amount of an antibody or functional fragment thereof suitable for oral administration to a human patient.

[0122] An oral multiparticle drug delivery system comprising an oral solid dosage form as described in any one of items 1 to 116, wherein each oral solid dosage form unit preferably has a predetermined axis and a predetermined cross-sectional profile, and at least 80%, preferably 90%, and more preferably 95% of the number of such oral solid dosage forms have a central aspect ratio of 0.7 to 1.7, the aspect ratio being defined as the length of the oral solid dosage form along the predetermined axis divided by the minimum cross-sectional dimension.

[0123] An oral multiparticle drug delivery system according to item 121 or 122, wherein the median aspect ratio is greater than 0.8, preferably greater than 0.9, and less than 1.6, preferably less than 1.5, more preferably 1.4, even more preferably less than 1.3, even more preferably less than 1.2, and most preferably about 1.

[0124] An oral multiparticle drug delivery system according to any one of items 121 to 123, enabling the recovery of at least 60%, preferably at least 80%, more preferably at least 85%, even more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, and even more preferably at least 98% of an antibody or functional fragment thereof from an oral solid dosage form.

[0125] An oral multiparticle drug delivery system according to any one of items 121 to 124, enabling the recovery of at least 60%, preferably at least 80%, more preferably at least 85%, even more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, and even more preferably at least 98% of the antibody or functional fragment thereof from the oral solid dosage form within 4 hours, or 6 hours, or 8 hours, or 10 hours, or 12 hours, or 14 hours, or 16 hours, or 18 hours, or 20 hours, or 22 hours, or 24 hours, or 26 hours, or 28 hours, or 30 hours, under continuous stirring of the oral solid dosage form (sustained release) at a pH of 6.5 to 7, preferably at about 6.8.

[0126] An oral multiparticle drug delivery system according to any one of items 121 to 125, wherein the oral multiparticle drug delivery system is prepared from a plurality of oral solid dosage forms by compression or encapsulation, preferably by encapsulation.

[0127] A method for targeted local treatment of gastrointestinal disorders, comprising administering to a patient in need an oral solid dosage form described in any one of items 1 to 116 or an oral multiparticle drug delivery system described in any one of items 121 to 126 in a pharmaceutically effective amount.

[0128] The method according to item 127, wherein the gastrointestinal disorder is immune checkpoint inhibitor (ICPI)-induced colitis, ICPI-induced enteritis, ICPI-induced diarrhea, or inflammatory bowel disease (IBD).

[0129] The method according to item 127 or 128, wherein the patient is a human patient and, optionally, an oral solid dosage form or an oral multiparticle drug delivery system is administered orally every 24 to 48 hours, preferably every 24 hours.

[0130] Use of any one of items 1 to 116 in the preparation of a drug for the treatment of gastrointestinal disorders.

[0131] Use as described in item 130, where the gastrointestinal disorder is IBD, preferably Crohn's disease or ulcerative colitis. [Brief explanation of the drawing]

[0013] [Figure 1] The multilayer oral solid dosage form of the present invention comprises an inactive core unit (1); a depot layer (2) containing an antibody or a functional fragment thereof; a sustained-release layer (3); and a delayed-release layer (4). [Figure 2] This figure shows an oral multiparticle drug delivery system including a multilayer oral solid dosage form; an explanation of the different layers in a single oral solid dosage form; and a scanning electron microscope (SEM) image of the final single oral solid dosage form. [Figure 3](A) Confirmation of drug load (Bradford assay) of the drug-coated intermediate (including the inactive core and depot layer) of Example 1 after incubation for 1 hour in pH 6.8 phosphate buffer. (B) Dissolution kinetics (Bradford assay) of the Eudragit® RS intermediate (including the inactive core unit, depot layer and sustained-release layer) of Example 1 in pH 6.8 phosphate buffer. (C) Dissolution kinetics of the final formulation coated with Eudragit® S of Example 1 [i.e., the intermediate of Example 1 (B) coated with the delayed-release layer], evaluated using a dissolution assay. [Figure 4] The elution dynamics of Examples 2 and 3 were evaluated using an elution assay. [Figure 5] This is a scanning electron microscope (SEM) image of a cross-section of an Eudragit® RS intermediate formulation (including the inactive core unit, depot layer, and sustained-release layer) with a lower drug load. [Figure 6] This is a scanning electron microscope (SEM) image of a cross-section of the Eudragit® RS intermediate formulation (including the inactive core unit, depot layer, and sustained-release layer) which has a higher drug load. [Modes for carrying out the invention]

[0014] The present invention relates to i) an inert core unit (1); ii) a depot layer (2) coating the inert core unit (1) and comprising an antibody or functional fragment thereof, preferably specific to tumor necrosis factor alpha (TNFα) as an active agent; a stabilizer, preferably sucrose; a buffer; and a polymer binder, preferably hypromellose (HPMC); and iii) a depot layer (2) coating the depot layer (2) and comprising an ammonia methacrylate copolymer, preferably poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1; and a plasticizer. The present invention relates to a novel oral solid dosage form comprising: iv) a sustained-release layer (3) containing an anti-tack agent and an anti-tack agent; and a delayed-release layer (4) coating the sustained-release layer (3) and containing poly(methacrylic acid, methyl methacrylate) 1:2, poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1, poly(methacrylic acid, methyl methacrylate) 1:1, or a combination thereof, preferably poly(methacrylic acid, methyl methacrylate) 1:2; an anti-tack agent, preferably glycerol monostearate (GMS); and a plasticizer, preferably triethyl citrate (TEC).

[0015] As used herein, the term “oral solid dosage form” may be understood to be equivalent to “solid oral pharmaceutical dosage form” or “pharmaceutical composition formulated as an oral solid dosage form,” which is suitable for oral administration and includes, for example, pellets, beads, spheres, minispheres, tablets, minitablets, etc. In one embodiment of the present invention, the oral solid dosage form is a pellet, sphere, minisphere, bead, granule, tablet, or minitablet. In a preferred embodiment of the present invention, the oral solid dosage form is a pellet. The size of the oral solid dosage form is not particularly limited and may be characterized by a maximum diameter of 100 to 4000 μm, preferably 300 to 3000 μm, more preferably 500 to 2500 μm, and even more preferably 700 to 2000 μm, for example, about 1200 to 1600 μm.

[0016] Multiple oral solid dosage forms of the present invention can be combined into a single unit formulation in the form of an "oral multiparticle drug delivery system," also known as an "oral multiparticle dosage form." The oral multiparticle drug delivery system may be in the form of, for example, hard gelatin capsules, tablets, sachets, caplets, or pills.

[0017] The term “inactive core unit” as used herein is known to those skilled in the art. The term “inactive core unit” as used herein can be understood to mean an inactive pellet, minitablet, tablet, granule, core, bead, minisphere, or sphere consisting of one or more soluble or insoluble inactive materials, etc., that are all pharmacologically inactive and do not interact with the active ingredient in an oral solid dosage form, i.e., an antibody or its functional fragment.

[0018] The inert core unit may optionally be sealed with a coating to increase the core's strength, for example, to withstand mechanical pressure during machining.

[0019] As used herein, the term “inactive” preferably means that the inactive core unit (1), containing all of its components, is pharmacologically inactive and does not interact with the antibody or its functional fragment in the depot layer (2). This preferably means that the inactive core unit (1) does not contain any active ingredients and does not reduce the stability and activity of the antibody or its functional fragment in the depot layer (2) during the preparation, storage, and subsequent administration and dissolution of the oral solid dosage form.

[0020] As used herein, the term “about” indicates that a given quantity’s value or range may include quantities within 10% of the stated value or range, or optionally within 5% of the value or range, or, in some embodiments, within 1% of the value or range. Generally, unless otherwise specified, “weight %” as used herein refers to a weight percentage of a substance relative to the total weight of an oral solid dosage form. In some cases where indicated, “weight %” may refer to a weight percentage of a substance relative to the weight of a particular layer of an oral solid dosage form.

[0021] The inert core unit (1) may be an inert pellet, mini-tablet, tablet, granule, core, bead, mini-sphere, or sphere, prepared, for example, from one excipient or a mixture thereof by compression or extrusion-spheronization. In a preferred embodiment, the inert core unit (1) is a pellet. The pellet may contain, or consist of, a water-insoluble or water-swellable material, and / or have a homogeneous composition. In one embodiment, the inert core unit (1) mainly comprises a monosaccharide, disaccharide, oligosaccharide, polysaccharide, silica, tartaric acid, calcium carbonate, or a combination thereof. In another embodiment, the inert core unit (1) consists of a monosaccharide, disaccharide, oligosaccharide, polysaccharide, silica, tartaric acid, calcium carbonate, or a combination thereof.

[0022] In certain embodiments of the present invention, the inert core unit (1), for example, a pellet, contains or comprises microcrystalline cellulose, sucrose, starch, mannitol, calcium carbonate, silica, tartaric acid, lactose, or a combination thereof, preferably microcrystalline cellulose. In further embodiments, the inert core unit (1), for example, a pellet, contains microcrystalline cellulose, sucrose, starch, mannitol, calcium carbonate, silica, tartaric acid, lactose, or a combination thereof, preferably microcrystalline cellulose, as a main component. In this context, “main component” refers to the inert core unit (1) containing at least 50% by weight, preferably at least 70% by weight, more preferably at least 90% by weight, and even more preferably at least 95% by weight of the component. When used in the context of the above inert core unit, “weight%” refers to the weight percentage of the substance relative to the weight of the inert core unit (1).

[0023] In one embodiment, the inert core unit (1) is a pellet. The pellet may have a median particle size of 50 to 5000 μm, preferably 100 to 3000 μm, more preferably 200 to 2000 μm, even more preferably 300 to 1500 μm, even more preferably 400 to 1400 μm, even more preferably 700 to 1400 μm, even more preferably 500 to 1000 μm, most preferably 500 to 700 μm, 600 to 800 μm, or 700 to 1000 μm. In another embodiment, the inert core unit (1) is a pellet having a particle size distribution such that at least 85% of the pellets have a particle size of 50 to 3000 μm, preferably 100 to 1500 μm, more preferably 350 to 1400 μm, even more preferably 500 to 1400 μm, even more preferably 700 to 1400 μm, and even more preferably 500 to 1000 μm, for example, 500 to 700 μm or 700 to 1000 μm. According to a preferred embodiment of the present invention, the inert core unit (1) is a pellet having a particle size distribution such that at least 85% of the pellets have a particle size of 700 to 1400 μm, preferably 700 to 1000 μm.

[0024] The shape of the inert core unit (1), preferably the pellet, is not particularly limited. In one embodiment, the inert core unit (1) is a pellet having a sphericity of at least 0.6, preferably at least 0.7, more preferably at least 0.8, even more preferably at least 0.9, and even more preferably at least 0.95. In a preferred embodiment, the inert core unit (1) is a pellet containing or consisting of spheres. As used herein, the term “sphere” refers preferably to a particle having a sphericity of at least 0.8. The pellet may contain or consist of spheres, for example, preferably made of a water-insoluble or water-swellable material and / or having a uniform composition.

[0025] The pellets or spheres may be coated with a coating deposited on the spheres, for example, a seal coating, which preferably consists of a water-insoluble material. According to one embodiment, the inert core unit (1) includes or consists of pellets, for example spheres, and optionally a seal coating covering the spheres, the seal coating consisting of a water-insoluble material.

[0026] The pellets (or spheres) may consist of microcrystalline cellulose, sucrose, starch, mannitol, calcium carbonate, silica, tartaric acid, lactose, or a combination thereof. In a preferred embodiment, the inert core unit (1) is a pellet, for example, a sphere, and consists of microcrystalline cellulose, sucrose, starch, mannitol, calcium carbonate, silica, tartaric acid, lactose, or a combination thereof. In a preferred embodiment, the inert core unit (1) is in the form of a pellet, preferably a sphere, and consists of microcrystalline cellulose. Examples of commercially available inert core units include CELLETS® (Pharmatrans-Sanaq AG) and SUGLETS® (Colorcon® Ltd).

[0027] An oral solid dosage form comprises a depot layer (2) that coats an inactive core unit (1) and contains an antibody or a functional fragment thereof as an active agent, a stabilizer, a buffer, and a polymer binder. As used herein, the term “depot layer” refers to a coating or coat that covers the inactive core unit and contains at least one active agent in the form of an antibody or a functional fragment thereof.

[0028] In the context of the “layers” of the oral solid dosage forms of the present invention, the terms “coating” or “to coat” as used herein mean that the layer is positioned on the inert core unit or layer to be coated, without any other layers in between (i.e., between the coating layer and the inert core unit or layer to be coated), or with one or more additional layers in between, preferably without any other layers. Preferably, the layers of the oral solid dosage forms of the present invention continuously coat the inert core unit or layer to be coated, resulting in no gaps in the coating layer. This may be particularly relevant to sustained-release and delayed-release layers, as otherwise the integrity of these layers may be compromised.

[0029] Preferably, the depot layer (2) is positioned on the inert core unit (1) so that no other layer is present in between (i.e., between the depot layer and the inert core unit). Preferably, the depot layer (2) of the oral solid dosage form of the present invention continuously covers the inert core unit (1) so that there are no gaps in the depot layer.

[0030] Certain layers can be separated from the inert core unit or further layers of the oral solid dosage form that are applied separately, due to their different physicochemical properties. Thus, the depot layer (2), sustained-release layer (3), and / or delayed-release layer (4) can be separated from the inert core unit and further layers that are applied separately, after the depot layer has been applied, due to their unique physicochemical properties.

[0031] According to one embodiment of the present invention, the depot layer (2) of the oral solid dosage form of the present invention has an average thickness of 1 to 300 μm, preferably 2 to 200 μm, more preferably 5 to 200 μm, and even more preferably 10 to 200 μm, for example, 100 to 200 μm, or 150 μm.

[0032] According to another embodiment of the present invention, the sustained-release layer (3) has an average thickness of 5 to 50 μm, preferably 10 to 45 μm, more preferably 15 to 35 μm, even more preferably 18 to 30 μm, even more preferably 20 to 30 μm, for example about 24 or 25 μm. According to another embodiment of the present invention, the thickness of the sustained-release layer (3) is constant and independent of the amount of active agent and / or the thickness of the depot layer (2). According to another embodiment, the sustained-release layer (3) preferably has a fixed average thickness of 5 to 50 μm, preferably 10 to 45 μm, more preferably 15 to 35 μm, even more preferably 18 to 30 μm, even more preferably 20 to 30 μm, for example 24 or 25 μm, regardless of the thickness of the depot layer (2) and / or the amount of antibody or its functional fragment in the depot layer (2).

[0033] According to a preferred embodiment of the present invention, the delayed emission layer (4) has an average thickness of 10 to 300 μm, preferably 50 to 180 μm, more preferably 60 to 160 μm, even more preferably 80 to 150 μm, even more preferably 90 to 130 μm, and even more preferably 95 to 120 μm, for example, 105 or 120 μm.

[0034] In specific embodiments of the present invention, or according to any of the above embodiments, the average thickness of the sustained-release layer (3) is constant regardless of the amount of antibody or its functional fragment in the oral solid formulation and / or the thickness of the depot layer.

[0035] The thickness of the layer can be determined, for example, using scanning electron microscopy (SEM) based on 10, 15, 20, 30, or 50 different measurement points within the layer.

[0036] In the context of the present invention, the term “antibody” refers to “immunoglobulin” (Ig), defined as a protein belonging to class IgG, IgM, IgE, IgA, or IgD (or any subclass thereof), and includes all conventionally known antibodies and their functional fragments. The antibodies or their functional fragments used in the present invention are active agents, i.e., the antibodies or their functional fragments are incorporated into an oral solid dosage form for the pharmacological activity of the antibodies or their functional fragments in a patient.

[0037] In the context of the present invention, an “antibody / immunoglobulin” “functional fragment” is defined as an antigen-binding fragment or other derivative of a parent antibody that essentially maintains the properties of the parent antibody. An “antibody / immunoglobulin” “antigen-binding fragment” is defined as a fragment that holds an antigen-binding region (e.g., the variable region of IgG). The “antigen-binding region” of an antibody is typically found in one or more hypervariable regions of the antibody, i.e., the CDR-1, -2, and / or -3 regions. An “antigen-binding fragment” according to the present invention includes domains of F(ab')2 fragments and Fab fragments. An “antibody / functional fragment” according to the present invention includes Fab fragments, F(ab')2 fragments, Fab' fragments, scFv, dsFv, VHH, diabodies, triabodies, tetrabodies, Fc fusion proteins, and minibodies. The F(ab')2 or Fab domain may be manipulated to minimize or completely eliminate intermolecular disulfide interactions that occur between the CH1 and CL domains. The antibody or its functional fragment used in the present invention may be part of a bifunctional or multifunctional construct.

[0038] Fab fragments can be obtained as purified digest products after digestion of antibodies with a cysteine ​​proteinase such as papain (EC 3.4.22.2). F(ab')2 fragments can be obtained as purified digest products after digestion of antibodies with pepsin (EC 3.4.23.1) or IdeS (an immunoglobulin-degrading enzyme derived from Streptococcus pyogenes; EC 3.4.22). Fab' fragments can be obtained from F(ab')2 fragments under mild reducing conditions, thereby producing two Fab' fragments from each F(ab')2 molecule. scFv is a single-chain Fv fragment in which a variable light chain ("VL") domain and a variable heavy chain ("VH") domain are linked by a peptide crosslink.

[0039] A "diabody" is a dimer (hereinafter referred to as a dibody-forming fragment) formed by linking two fragments having variable regions via a linker or the like, and typically contains two VLs and two VHs. Examples of dibody-forming fragments include those consisting of VL and VH, VL and VL, VH and VH, and preferably VH and VL. In a dibody-forming fragment, the linker connecting the variable regions is not particularly limited, but preferably it is short enough to avoid non-covalent bonds between variable regions within the same fragment. The length of such a linker can be appropriately determined by those skilled in the art, but usually 2 to 14 amino acids, preferably 3 to 9 amino acids, and particularly 4 to 6 amino acids are used. In this case, the VL and VH encoded on the same fragment are linked via a linker short enough to avoid non-covalent bonds between VL and VH on the same chain and to avoid the formation of a single-chain variable region fragment, and as a result, a dimer with another fragment may be formed. The dimer may be formed via covalent bonds, non-covalent bonds, or both between the dibody-forming fragments.

[0040] Furthermore, single-chain diabodies (sc(Fv)2) can be formed by linking diabodies via linkers or other means. By linking diabodies using long linkers of approximately 15-20 amino acids, non-covalent bonds can be formed between diabodies on the same chain, thereby forming dimers. Polymerized antibodies, such as trimers or tetramers, can also be prepared based on the same principle as preparing diabodies by linking three or more diabodies.

[0041] In one embodiment, the functional fragment in the oral solid dosage form of the present invention is a Fab fragment, an F(ab')2 fragment, a Fab' fragment, scFv, dsFv, VHH, a diabody, a triabody, a tetrabody, an Fc fusion protein, or a minibody. Preferred functional fragments used in the present invention are a Fab fragment, an F(ab')2 fragment, a Fab' fragment, scFv, and a diabody.

[0042] The antibody or functional fragment thereof used in the oral solid dosage form of the present invention is not particularly limited. In one embodiment, the antibody or functional fragment thereof is an antibody. In another embodiment of the present invention, the antibody or functional fragment thereof is a functional fragment as defined above. The antibody or functional fragment thereof may further include one or more modifications, for example, in the form of added or substituted residues, that improve stability, specificity, or targeting. These may include any such modifications known in the art.

[0043] The antigen to which the antibody or functional fragment is directed, i.e., the immunogen, peptide, protein, or other molecular structure to which the antibody or its functional fragment can specifically bind, is not limited. The terms “specific to,” “specifically bind,” or “specifically bind” in this context are known to those skilled in the art. In its most common form (and where no defined reference is mentioned), “specific to” or “specifically bind” refers to the ability of the antibody or its functional fragment to distinguish between biomolecules unrelated to the target of interest (for example, for an antibody specific to human TNFα, the ability to distinguish between biomolecules unrelated to human TNFα), as determined, for example, by specificity assay methods known in the art. Such methods include, but are not limited to, Western blotting and enzyme-linked immunosorbent assay (ELISA) tests. For example, a standard ELISA assay can be performed. Typically, the determination of binding specificity is performed by using a set of about 3 to 5 unrelated biomolecules, such as powdered milk, BSA, or transferrin, rather than a single reference biomolecule.

[0044] In one embodiment of the present invention, an antibody or functional fragment thereof is suitable for use in the treatment of inflammatory conditions in the GI tract, such as immune checkpoint inhibitor (ICPI)-induced colitis, ICPI-induced enteritis, ICPI-induced diarrhea, or inflammatory bowel disease (IBD, e.g., Crohn's disease or ulcerative colitis). In a further embodiment of the present invention, an antibody or functional fragment thereof is suitable for use in local treatment of the ileum (terminal) and / or colon of the patient's gastrointestinal tract, particularly in the mucosa.

[0045] In further embodiments of the present invention, the antibody or functional fragment thereof is selected from antibodies and functional fragments specific to tumor necrosis factor alpha (TNFα), antibodies and functional fragments specific to α4β7 integrin, antibodies and functional fragments specific to CD3, CD4, or CD20, antibodies and functional fragments specific to interleukin 6 (IL-6), interleukin 12 (IL-12), interleukin 13 (IL-13), interleukin 23 (IL-23) or their receptors, antibodies and functional fragments specific to CXCL10 / IP-10, and antibodies and functional fragments specific to the p40 protein subunit. In yet another embodiment of the present invention, an antibody or functional fragment thereof is selected from infliximab, adalimumab, etanercept, certolizumab pegol, golimumab, vizilizumab, erderumab, abrimab, canakinumab, tocilizumab, ustekinumab, natalizumab, etrolizumab, priliximab, vedolizumab, and functional fragments thereof.

[0046] In preferred embodiments of the oral solid dosage form of the present invention, the antibody or functional fragment thereof is an antibody or functional fragment thereof that is specific to tumor necrosis factor alpha (TNFα) (i.e., an anti-TNFα antibody or functional fragment thereof). The antibody or functional fragment thereof that is specific to TNFα is not particularly limited. In one embodiment, the antibody or functional fragment thereof that is specific to TNFα is an antibody. In another embodiment, the antibody or functional fragment thereof that is specific to TNFα is a functional fragment as defined above. The antibody or functional fragment thereof that is specific to TNFα may further include one or more modifications in the form of added or substituted residues that improve stability, specificity, or targeting. These may include any such modifications known in the art.

[0047] As used herein, the terms “anti-TNFα antibody,” “TNFα antibody,” and “TNFα-specific antibody” are interchangeable and preferably mean that the anti-TNFα antibody can specifically bind to TNFα, i.e., preferably specifically bind to TNFα, more preferably specifically to human TNFα (identifiable by, for example, uniport identifier P01375). The terms “specific to,” “specifically bind,” or “specific binding” in this context are known to those skilled in the art (see above). In one embodiment, “specific binding” in the context of TNFα refers, in particular, to the ability of an antibody or fragment to distinguish between human TNFα and human TNFβ.

[0048] In one embodiment of the present invention, an anti-TNFα antibody or a functional fragment thereof is suitable for use in the treatment of immune checkpoint inhibitor (ICPI)-induced colitis, ICPI-induced enteritis, ICPI-induced diarrhea, and / or inflammatory bowel disease (IBD), such as Crohn's disease or ulcerative colitis. In another embodiment of the present invention, the antibody or a functional fragment thereof is suitable for use in topical treatment of the ileum (preferably the terminal ileum) or colon of the patient's gastrointestinal tract, particularly in the mucosa. In a preferred embodiment of the present invention, the anti-TNFα antibody or a functional fragment thereof is a defucosylated antibody, meaning that it lacks core fucose.

[0049] Several monoclonal antibodies against TNFα (specific to TNFα) have been described in the prior art. Meager et al. (Hybridoma, 6, 305-311, 1987) describe a mouse monoclonal antibody against recombinant TNFα. Fendly et al. (Hybridoma, 6, 359-370, 1987) describe the use of a mouse monoclonal antibody against recombinant TNFα in characterizing neutralizing epitopes on TNF. Furthermore, international patent application WO92 / 11383 discloses recombinant antibodies, including a CDR-transplant antibody specific to TNFα. U.S. Patent No. 5,919,452 discloses anti-TNFα chimeric antibodies and their use in the treatment of conditions associated with the presence of TNFα. For further information on anti-TNFα antibodies, see Stephens et al. (Immunology, 85, 668-674, 1995), UK Patent A-2 246 570, UK Patent A-2 297 145, US Patent No. 8,673,310, US Patent Publication 2014 / 0193400, European Patent No. 2 390 267 B1, US Patent No. 8,293,235, US Patent No. 8,697,074, International Publication 2009 / 155723 A2, and International Publication 2006 / 131013 A2.

[0050] Currently approved anti-TNFα antibodies include (i) infliximab, a chimeric IgG anti-human monoclonal antibody (Remicade®); (ii) etanercept, a TNFR2 dimer fusion protein with IgG1 Fc (Enbrel®); (iii) adalimumab, a fully human monoclonal antibody (mAb) (Humira®); (iv) certolizumab, a PEGylated Fab fragment (Cimzia®); and (v) golimumab, a human IgG1K monoclonal antibody (Simponi®). Furthermore, various biosimilars are under development. Therefore, in some embodiments of the present invention, the anti-TNFα antibody or its functional fragment is selected from infliximab, adalimumab, etanercept, certolizumab pegol, and golimumab or its functional fragment.

[0051] In a preferred embodiment of the present invention, the antibody or functional fragment thereof comprises (i) a CDR1 region having the amino acid sequence shown in SEQ ID NO: 1, a CDR2 region having the amino acid sequence shown in SEQ ID NO: 2, and a CDR3 region having the amino acid sequence shown in SEQ ID NO: 3. L A domain, and / or (ii) a V including a CDR1 region having the amino acid sequence shown in SEQ ID NO: 4, a CDR2 region having the amino acid sequence shown in SEQ ID NO: 5, and a CDR3 region having the amino acid sequence shown in SEQ ID NO: 6. H This is an anti-TNFα antibody or a functional fragment thereof having a TNFα-binding domain that includes a domain.

[0052] In another preferred embodiment of the present invention, the antibody or functional fragment thereof (i) has an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 8 or consists of V L (ii) a domain and / or a V having an amino acid sequence according to the amino acid sequence shown in Sequence ID No. 7 H An anti-TNFα antibody or functional fragment thereof having a TNFα-binding domain that includes or consists of a domain.

[0053] In yet another preferred embodiment of the present invention, the antibody or functional fragment thereof comprises (i) a CDR1 region having the amino acid sequence shown in SEQ ID NO: 9, a CDR2 region having the amino acid sequence shown in SEQ ID NO: 10, and a CDR3 region having the amino acid sequence shown in SEQ ID NO: 11. L A domain, and / or (ii) a V including a CDR1 region having the amino acid sequence shown in SEQ ID NO: 12, a CDR2 region having the amino acid sequence shown in SEQ ID NO: 13, and a CDR3 region having the amino acid sequence shown in SEQ ID NO: 14. H This is an anti-TNFα antibody or a functional fragment thereof having a TNFα-binding domain that includes a domain.

[0054] In yet another preferred embodiment of the present invention, the antibody or functional fragment thereof (i) has an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 16 or SEQ ID NO: 17, or consists of the same VL (ii) a domain and / or a V having an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 15 H An anti-TNFα antibody or functional fragment thereof having a TNFα-binding domain that includes or consists of a domain.

[0055] In yet another preferred embodiment of the present invention, the antibody or functional fragment thereof is an anti-TNFα antibody having an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, or SEQ ID NO: 22, preferably SEQ ID NO: 18, or comprising an Fc region thereof.

[0056] In yet another preferred embodiment of the present invention, the antibody or functional fragment thereof is an anti-TNFα antibody comprising (i) a light chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 23, and (ii) a heavy chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 26.

[0057] In yet another preferred embodiment of the present invention, the antibody or functional fragment thereof is an anti-TNFα antibody comprising (i) a light chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 24 or SEQ ID NO: 25, and (ii) a heavy chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 27.

[0058] In yet another preferred embodiment of the present invention, the antibody or functional fragment thereof is an anti-TNFα antibody comprising (i) a light chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 23, and (ii) a heavy chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 30.

[0059] In yet another preferred embodiment of the present invention, the antibody or functional fragment thereof is an anti-TNFα antibody comprising (i) a light chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 24 or SEQ ID NO: 25, and (ii) a heavy chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 31, SEQ ID NO: 32, or SEQ ID NO: 33.

[0060] In yet another preferred embodiment of the present invention, the antibody or functional fragment thereof is an anti-TNFα antibody comprising (i) a light chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 23, and (ii) a heavy chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 34.

[0061] In yet another preferred embodiment of the present invention, the antibody or functional fragment thereof is an anti-TNFα antibody comprising (i) a light chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 24 or SEQ ID NO: 25, and (ii) a heavy chain having or comprising an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 35.

[0062] The amount of antibody or functional fragment thereof is not particularly limited. Preferably, the depot layer (2) contains an amount of antibody or functional fragment thereof that allows for the administration of a therapeutically effective dose of antibody or functional fragment thereof as a single unit dose (for example, in the form of a multiparticle drug delivery system comprising multiple oral solid dosage forms of the present invention). In one embodiment, the depot layer (2) contains 0.2 to 75% by weight, preferably 1 to 45% by weight, more preferably 10 to 35% by weight, even more preferably 20 to 35% by weight, and even more preferably 25 to 35% by weight of antibody or functional fragment thereof, preferably TNFα-specific, based on the total weight of the solid in the depot layer (2) (i.e., excluding the solvent, preferably water). According to another preferred embodiment, the oral solid dosage form of the present invention contains 0.05 to 30% by weight, preferably 0.1 to 25% by weight, more preferably 0.1 to 20% by weight, even more preferably 0.2 to 20% by weight, even more preferably 0.2 to 15% by weight, even more preferably 0.5 to 12% by weight, even more preferably 0.5 to 10% by weight, even more preferably 0.8 to 12% by weight, even more preferably 8 to 12% by weight, even more preferably 8 to 10% by weight, for example about 9% by weight, or about 9.25% by weight, or about 9.5% by weight, an antibody or functional fragment thereof that is preferably specific to TNFα.

[0063] In one embodiment of the present invention, the oral solid dosage form of the present invention is, for example, in the form of a tablet comprising multiple oral solid dosage forms or preferably in the form of a capsule (e.g., in the form of multiple pellets), and contains, as a single unit dose, an amount of antibody or functional fragment that enables oral administration of a therapeutically effective dose of antibody or functional fragment thereof. The “therapeutically effective dose” is the amount of at least one antibody or functional fragment thereof required to provide the desired therapeutic effect. The exact amount may vary depending on different antibodies or functional fragments and / or individual patients, but can be determined by those skilled in the art.

[0064] The depot layer (2) contains a stabilizer. The properties of the stabilizer are not particularly limited and include all stabilizers that ensure the stability and activity of antibodies and their functional fragments, such as antibodies and their functional fragments that are specific to TNFα, while not impairing the integrity of the depot layer (2). In one embodiment of the present invention, the stabilizer is selected from sucrose, maltose, lactose, trehalose, glycerol, maltitol, isomalt, mannitol, sorbitol, xylitol, and combinations thereof, preferably selected from sucrose, maltose, lactose, glycerol, maltitol, isomalt, and combinations thereof. According to a preferred embodiment, the stabilizer in the depot layer (2) is sucrose. The amount of stabilizer in the depot layer (2) is not particularly limited, as long as it ensures the stability of low and high concentrations of antibodies or their functional fragments without impairing the integrity of the depot layer. In one embodiment of the present invention, the depot layer (2) contains 2 to 80% by weight, preferably 10 to 75% by weight, more preferably 20 to 70% by weight, even more preferably 30 to 60% by weight, even more preferably 35 to 60% by weight, and even more preferably about 40 to 55% by weight of a stabilizer (preferably sucrose) based on the total weight of solids in the depot layer (i.e., excluding the solvent, preferably water). In another embodiment, the weight ratio of the antibody or its functional fragment to the stabilizer (e.g., sucrose) is 1:2 to 1:1.5, preferably 1:9 to 1:1.7, for example, about 1:1.77.

[0065] The depot layer (2) contains a buffer. The properties of the buffer are not particularly limited and include all buffers that ensure the stability and activity of the antibody and its functional fragments without impairing the integrity of the depot layer (2). In one embodiment of the present invention, the buffer in the depot layer (2) (i.e., one or more buffer salts and / or free bases) is selected from the group consisting of L-histidine buffers, citrate buffers, hydroxymethylaminomethane (TRIS) buffers, succinate buffers, phosphate buffers, acetate buffers, or salts thereof, and combinations thereof; preferably L-histidine buffers, citrate buffers, TRIS buffers, and combinations thereof; more preferably L-histidine buffers, citrate-TRIS buffers, and combinations thereof. According to a preferred embodiment, the buffer in the depot layer (2) (i.e., buffer salts and / or free bases) contains or consists of L-histidine, preferably L-histidine monohydrochloride and / or free bases.

[0066] The buffer may be present in the depot layer (2) in any amount that ensures the stability and activity of the antibody and its functional fragments during and after the preparation of the oral solid dosage form without impairing the integrity of the depot layer (2). In one embodiment of the present invention, the depot layer (2) contains 0.1 to 10% by weight, preferably 0.2 to 6% by weight, more preferably 0.3 to 5% by weight, more preferably 0.5 to 4.5% by weight, even more preferably 1 to 4% by weight, and more preferably about 2 to 3.5% by weight of the buffer, based on the total weight of the solids in the depot layer (2) (i.e., excluding the solvent, preferably water). In further embodiments of the present invention, the depot layer (2) contains 0.1 to 10% by weight, preferably 0.2 to 5% by weight, more preferably 0.3 to 4% by weight, even more preferably 0.35 to 3.5% by weight, and more preferably about 0.4 to 3% by weight of L-histidine salt and / or free base, based on the total weight of solids in the depot layer (i.e., excluding the solvent, preferably water), and optionally 0.3 to 6% by weight, preferably 0.5 to 4% by weight, more preferably 1 to 3.5% by weight, even more preferably 1.5 to 3% by weight, and more preferably about 1.5 to 3.5% by weight of other buffer salts. In another embodiment, the weight ratio of the antibody or functional fragment thereof to the buffer, preferably L-histidine buffer (salt and / or free base), is 100:1 to 1:1, preferably 50:1 to 3:1, more preferably 30:1 to 5:1; even more preferably 15:1 to 7:1; for example, about 10:1. In another embodiment, the weight ratio of the antibody or its functional fragment to the L-histidine buffer is 100:1 to 20:1, preferably 80:1 to 40:1, more preferably 60:1 to 50:1, and optionally, the weight ratio of the antibody or its functional fragment to the other buffer is 25:1 to 5:1, preferably 16:1 to 10:1, more preferably 14:1 to 12:1.

[0067] Suitable polymer binders (also referred to herein as “binders”) for the depot layer (2) of the oral solid dosage form of the present invention include hypromellose (HPMC); methylcellulose (MC); polyvinylpyrrolidone (PVP); hydroxypropylcellulose (HPC); macrogol poly(vinyl alcohol) graft copolymer (e.g., Kollidon® IR); and combinations thereof; preferably containing hypromellose or MC. In a preferred embodiment of the present invention, the polymer binder in the depot layer (2) of the oral solid dosage form is hypromellose. Hypromellose is also known as hydroxypropylmethylcellulose (HPMC) and is available in different degrees of substitution (DS), molar substitution (MS), and viscosity. According to a preferred embodiment of the present invention, the polymer binder in the depot layer (2) is hypromellose 2910, preferably hypromellose 2910 2.6-3.6 mPas, more preferably hypromellose 2910 3 mPas.

[0068] The amount of polymer binder in the depot layer (2) is not particularly limited, as long as a stable depot layer can be easily formed. In one embodiment of the present invention, the depot layer (2) contains 0.5 to 65% by weight, preferably 2 to 35% by weight, more preferably 10 to 30% by weight, and even more preferably 15 to 25% by weight, for example about 20% by weight of polymer binder (preferably hypromellose), based on the total weight of solids in the depot layer (i.e., excluding the solvent, preferably water). In another embodiment, the weight ratio of the antibody or its functional fragment to the polymer binder (e.g., hypromellose) is 1.2:1 to 1:1.5, preferably 1.3:1 to 1:1.4, for example about 1.35:1.

[0069] Preferably, the polymer binder in the depot layer (2) is suitable for immediate-release drug coating. Therefore, the depot layer (2) allows for the immediate release of the antibody or its functional fragment from the dosage form without the need for any additional layers (i.e., sustained-release and delayed-release layers). As used herein, the term “immediate release” means that more than 60%, preferably more than 70%, more preferably more than 80%, even more preferably more than 90%, and most preferably 95% of the antibody or its functional fragment is released from the depot layer (2) 2 hours, preferably 1 hour, and even more preferably 0.5 hours after exposure to an aqueous environment. As used in the context of this invention, the term “aqueous environment” may refer to a solution or suspension that is predominantly water. This includes intestinal fluid.

[0070] To measure the amount of antibody or its functional fragment released into an aqueous solution from a depot layer (2) as the outermost coating of a solid dosage form, the depot layer (drug layer) deposited on an inert core can be immersed in a specified volume of aqueous solution (preferably buffered) for a specified period under continuous stirring of the aqueous solution (preferably buffered), and the resulting concentration of at least one antibody or its functional fragment in the aqueous solution can be determined and compared to the initial amount applied during the layering process, taking into account process efficiency and weight increase. Similarly, the release from solid dosage forms having additional coatings deposited on the depot layer (2), such as sustained-release coatings and / or delayed-release coatings, can be determined. Means for determining the antibody concentration in an aqueous solution are known in the art and include, for example, measuring absorbance at 280 nm, using reagent-based protein assays of colorimetric analysis such as the Bradford assay, or by ELISA.

[0071] According to one embodiment of the present invention, the depot layer (2) of the oral solid dosage form of the present invention contains an anti-tack agent. The anti-tack agent that can be used in the depot layer (2) is not particularly limited. In one embodiment of the present invention, the anti-tack agent in the depot layer (2) is selected from colloidal silicon dioxide, mesoporous silica, glycerol monostearate (GMS), stearic acid, magnesium stearate, and talc, preferably mesoporous silica or GMS, more preferably mesoporous silica. The amount of anti-tack agent in the depot layer (2) is not particularly limited. In one embodiment of the present invention, the depot layer (2) contains 0.2 to 15% by weight, preferably 0.5 to 10% by weight, more preferably 1 to 5% by weight, even more preferably 1.5 to 3% by weight, even more preferably 1.5 to 2.5% by weight, for example about 2% by weight, of the total weight of the solid in the depot layer (2) (i.e., excluding the solvent, preferably water). In another embodiment, the weight ratio of the anti-tack agent to the polymer binder (e.g., hypromellose) in the depot layer (2) is 1:15 to 1:5, preferably 1:12 to 1:8, for example, about 1:10.

[0072] According to a preferred embodiment of the present invention, the anti-tack agent in the depot layer (2) is mesoporous silica, preferably with an average particle size of 1 to 10 μm, preferably 2 to 5 μm, more preferably 3 to 4 μm, and even more preferably about 3.5 μm, and / or 1.50 to 1.70 cm². 3 / g, preferably 1.55-1.65cm 3 / g, more preferably 1.58~1.62cm 3 / g, more preferably about 1.60cm 3 This is a mesoporous silica with an average pore volume of / g.

[0073] According to a further embodiment, the depot layer (2) of the oral solid dosage form of the present invention does not contain a plasticizer. According to another embodiment, the depot layer (2) of the oral solid dosage form of the present invention contains a fusion accelerator, such as propylene glycol monolaurate (e.g., Lauroglycol® 90).

[0074] According to yet another embodiment of the present invention, the depot layer (2) of the oral solid dosage form of the present invention contains a surfactant. The surfactant in the depot layer (2) is not particularly limited, but is preferably a nonionic surfactant. According to one embodiment of the present invention, the surfactant in the depot layer (2) is selected from the group consisting of polysorbate 20, polysorbate 28, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, poloxamer 124, poloxamer 181, poloxamer 188, poloxamer 237, poloxamer 331, poloxamer 338 and poloxamer 407, and combinations thereof.

[0075] In a preferred embodiment of the oral solid dosage form, the surfactant in the depot layer (2) is polysorbate 20, 28, 40, 60, 65, 80, 81, and 85. In a particularly preferred embodiment, the surfactant in the depot layer (2) is polysorbate 80. In one embodiment of the present invention, the depot layer (2) contains 0.01 to 2% by weight, preferably 0.02 to 1% by weight, more preferably 0.03 to 0.8% by weight, even more preferably 0.05 to 0.5% by weight, even more preferably 0.1 to 0.3% by weight, and even more preferably 0.2 to 0.3% by weight of surfactant, based on the total weight of the solid in the depot layer (2) (i.e., excluding the solvent, preferably water).

[0076] The depot layer (2) may optionally contain at least one further excipient. As used herein, the term “excipient” refers to, for example, a non-therapeutic agent added to the formulation to provide a desired consistency, viscosity, or stabilizing effect. According to one embodiment of the present invention, the at least one further excipient is selected from pharmaceutically acceptable excipients such as antioxidants, wetting agents, protective colloids, dyes, protease inhibitors, and combinations thereof. In another embodiment, the depot layer (2) does not contain any further excipient.

[0077] According to a preferred embodiment of the present invention, the depot layer (2) of the oral solid dosage form of the present invention comprises or consists of the following: an active agent, for example, an antibody or functional fragment thereof, specific to TNFα; a stabilizer, preferably sucrose; a buffer, preferably L-histidine, more preferably L-histidine monohydrochloride and / or a free base; a polymer binder, preferably hypromellose (HPMC), more preferably hypromellose 2910 2.6-3.6 mPas; an anti-tackifying agent, preferably mesoporous silica; a surfactant, preferably polysorbate 80; optionally a further buffer such as citrate-TRIS; and optionally a residual solvent (preferably water). According to another preferred embodiment of the present invention, the depot layer (2) of the oral solid dosage form of the present invention comprises, for example, an antibody or functional fragment thereof, specific to TNFα, as an active agent; sucrose; L-histidine, preferably L-histidine monohydrochloride, and / or L-histidine free base; hypromellose (HPMC), preferably hypromellose 2910 2.6-3.6 mPas; mesoporous silica; polysorbate 80; and optionally residual water.

[0078] According to another preferred embodiment of the present invention, the depot layer (2) of the oral solid dosage form of the present invention comprises, relative to the total weight of the depot layer, 0.2 to 75% by weight of antibody or functional fragment thereof, 0.5 to 65% by weight of binder, 2 to 80% by weight of sucrose, 0.1 to 5% by weight of L-histidine (salt and / or free base), 0.1 to 10% by weight of other buffering agents, 0.2 to 15% by weight of anti-tackifying agents, 0.01 to 1% by weight of surfactant, and / or up to 10% by weight of water; preferably, relative to the total weight of the depot layer, 1 to 45% by weight of antibody or functional fragment thereof, 2 to 35% by weight of binder, 10 to 70% by weight of sucrose, 0.2 to 2% by weight of L-histidine, 0.5 to 4% by weight of other buffering agents, 1 to 5% by weight of anti-tackifying agents, 0.05 to 0.5% by weight of surfactant, and / or most A maximum of 7% by weight of water; more preferably, 10-35% by weight of antibody or its functional fragment, 10-30% by weight of binder, 30-60% by weight of sucrose, 0.3-0.8% by weight of L-histidine, 1.5-3% by weight of other buffers, 1.5-3% by weight of anti-tack agents, 0.1-0.3% by weight of surfactants, and / or up to 6% by weight of water, relative to the total weight of the depot layer; even more preferably, 25-35% by weight of antibody or its functional fragment, 15-25% by weight of binder, 40-55% by weight of sucrose, 0.4-0.6% by weight of L-histidine, 1.5-2.5% by weight of other buffers, 1.5-2.5% by weight of anti-tack agents, 0.2-0.3% by weight of surfactants, and / or up to 5% by weight of water, relative to the total weight of the depot layer (2).

[0079] In the solid oral dosage form of the present invention, the depot layer (2) can be deposited on an inert core unit (1) by drug layering, preferably using spray coating, more preferably using fluidized bed spray coating. Drug layering using solution / suspension layering allows for the preparation of solid dosage forms having a uniform size distribution and a smooth surface morphology. Solution / suspension layering (or coating) involves depositing a substance dissolved or dispersed in a solvent onto the surface of a substrate. An example of spray coating is fluidized bed spray coating / air suspension coating. In fluidized bed spray coating, one or more substances are dissolved or dispersed in a liquid carrier in the form of a solvent. This solution or dispersion is then sprayed onto a substrate suspended in a fluidized bed of a fluidized bed spray coater, for example, an inert core (such as sucrose or microcrystalline cellulose spheres). Methods for drug layering a layer containing an antibody or functional fragment as an active ingredient on an inert core are known in the art. Such methods can be found, for example, in International Publication No. 2019 / 057562. For example, methods for applying functional coatings by fluidized bed spray coating are disclosed in, for example, International Publication No. 2004 / 062577, European Patent No. 1684729, International Publication No. 2005 / 046561, or International Publication No. 2005 / 115340.

[0080] The inert core unit may be coated with a depot layer (2) using spray coating. For example, a fluidized bed spray coater or a pan coater can be used. According to a preferred embodiment, a fluidized bed spray coater is used. The use of a fluidized bed spray coater for spray coating an inert core unit is known in the art. For at least one antibody or functional fragment thereof in the oral solid dosage form prepared by the method of the present invention, it is beneficial that the parameters and conditions used during spray coating are carefully controlled. The fluidized bed spray coater that can be used is not particularly limited. Fluidized bed spray coaters are known in the art and include, for example, fluidized bed devices developed and commercialized by GEA Group, Glatt GmbH, Freund-Vector Corporation and Inora Pharmaceutical Machinery Co. The depot layer coating solution containing the antibody or functional fragment thereof may be sprayed onto the inert core unit using a bottom-spray fluidized bed spray coater. Alternatively, the depot layer coating solution may be sprayed onto the inert core unit using a top-spray fluidized bed spray coater.

[0081] Throughout this disclosure, whenever referring to the elution of a solid dosage form / multiparticle drug delivery system (such as in the immediate and immediate segments) or the recovery of antibodies or functional fragments thereof by continuous immersion of the solid dosage form / multiparticle drug delivery system in an aqueous (buffered) solution under continuous (constant) agitation, it should be understood that, for example, the following standard test setup, or any relevant standard test setup known to those skilled in the art, may be used: the release of at least one antibody or functional fragment thereof can be evaluated using a standard elution device I (basket), II (paddle), III (reciprocating cylinder), or IV (flow-through cell), where the buffer (i.e., aqueous buffer) is equilibrated at 37°C. The volume of buffer used in the elution test can be adapted to be more biorelevant, for example, by using a minivessel in device I or II, allowing for a reduction in the required volume. The release of antibodies or functional fragments during elution can be quantified offline by ELISA.

[0082] The oral solid dosage form of the present invention comprises a depot layer (2) coated with a sustained-release layer (3) comprising an ammonia methacrylate copolymer, preferably poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1; a plasticizer; and an anti-tackifier. The term “sustained-release” is known in the art. As used herein, the term “sustained-release” may be used to describe the continuous release of an antibody or functional fragment thereof from an oral solid dosage form over several hours, for example, at a constant or substantially constant release rate, when immersed in an aqueous (buffered) solution under continuous stirring. According to one embodiment, the term “sustained-release” is used to describe the continuous release of an antibody or functional fragment thereof from an oral solid dosage form over several hours in a suitable aqueous environment, preferably at a substantially constant release rate. In another embodiment, the term “sustained-release” is used to describe the release of an antibody or functional fragment from an oral solid dosage form such that a substantial fraction of the antibody or functional fragment is released from the oral solid dosage form after being exposed to an aqueous environment for an extended period, for example, at least 6 hours, preferably at least 10 hours, more preferably at least 14 hours, even more preferably at least 18 hours, for example at least 24 hours.

[0083] The terms “coating” or “to coat” as used in this context should be understood as defined above. Preferably, the sustained-release layer (3) is positioned on top of the coated depot layer (2) so as not to have any other layers in between (i.e., between the sustained-release layer and the depot layer). Preferably, the sustained-release layer of the oral solid dosage form of the present invention continuously coats the depot layer so as to leave no gaps in the sustained-release layer (3).

[0084] The term "ammonia methacrylate copolymer" is known in the art. For example, the term "ammonia methacrylate copolymer" may refer to poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) (also known as poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride)). In preferred embodiments, the ammonia methacrylate copolymer is poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 (as ammonia methacrylate copolymer type B), or poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1, or poly[ethylpropenoate-co-methyl2-methylpropa-2-enoate-co-N,N,N-trimethyl-2-[(2-methylpropa-2-enoyl)oxy]ethane-1-aminium chloride] 1:2:0.1, or Eudragit® RS, for example, Eudragit® RS Commercially available as 30D; poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 (as ammonia methacrylate copolymer type A), or poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2, or poly[ethylpropenoate-co-methyl2-methylpropa-2-enoate-co-N,N,N-trimethyl-2-[(2-methylpropa-2-enoyl)oxy]ethane-1-aminium chloride] 1:2:0.2, or Eudragit® RL, for example, commercially available as Eudragit® RL 30D); or selected from a combination thereof.

[0085] According to a preferred embodiment, the oral solid dosage form of the present invention does not contain any other sustained-release polymers other than ammoniace methacrylate copolymer. According to another preferred embodiment, the oral solid dosage form of the present invention comprises poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1; poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2; or a combination thereof, and preferably does not contain any other sustained-release polymers. According to another preferred embodiment of the present invention, the sustained-release layer (3) does not contain any other sustained-release polymers other than poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1; poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 (e.g., Eudragit® RL 30D); or a combination thereof (preferably does not contain any other polymers).

[0086] According to a particularly preferred embodiment of the present invention, the sustained-release layer (3) comprises poly(ethyl acrylate, methyl methacrylate, trimethylammoniumethyl methacrylate chloride) 1:2:0.1 and preferably does not contain other sustained-release polymers. According to another particularly preferred embodiment of the present invention, the sustained-release layer (3) comprises poly(ethyl acrylate, methyl methacrylate, trimethylammoniumethyl methacrylate chloride) 1:2:0.1 and preferably does not contain other polymers.

[0087] The plasticizer in the sustained-release layer (3) is not particularly limited. The plasticizer in the sustained-release layer (3) can be selected from, for example, triethyl citrate (TEC), polyethylene glycol, acetyl triethyl citrate, butyl citrate, polysorbate, polypropylene glycol, dibutyl sebacate (DBS), and combinations thereof. Preferably, the plasticizer in the sustained-release layer (3) of the oral dosage form of the present invention is triethyl citrate (TEC).

[0088] The anti-tack agent in the sustained-release layer (3) is not particularly limited. The anti-tack agent in the sustained-release layer (3) can be selected from, for example, mesoporous silica, colloidal silicon dioxide, stearic acid, magnesium stearate, glycerol monostearate (GMS), and talc. Preferably, the anti-tack agent in the sustained-release layer (3) of the oral dosage form of the present invention is mesoporous silica. Preferably, the mesoporous silica has an average particle size of 1 to 10 μm, preferably 2 to 5 μm, more preferably about 3 to 4 μm, and even more preferably 3.5 μm, and / or 1.50 to 1.70 cm². 3 / g, preferably 1.55-1.65cm 3 / g, more preferably 1.58~1.62cm 3 / g, more preferably about 1.60cm 3 It has an average pore volume per gram.

[0089] The amount of ammonia methacrylate copolymer in the sustained-release layer (3) is not particularly limited. According to one embodiment, the oral solid dosage form of the present invention contains 0.2 to 25% by weight, preferably 0.5 to 15% by weight, more preferably 1 to 10% by weight, even more preferably 3 to 5% by weight, even more preferably 3.5 to 4.5% by weight, even more preferably 3.8 to 4.1% by weight, for example 4% by weight of ammonia methacrylate copolymer (preferably poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1). According to another embodiment of the present invention, the sustained-release layer (3) contains 60 to 90% by weight, preferably 65 to 85% by weight, more preferably 70 to 80% by weight, and even more preferably 72 to 78% by weight of an ammonia methacrylate copolymer (preferably poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1) based on the total weight of the solids in the sustained-release layer (3) (i.e., excluding the solvent, preferably water).

[0090] The amount of plasticizer in the sustained-release layer (3) is not particularly limited. According to one embodiment of the present invention, the sustained-release layer (3) contains 2 to 40% by weight, preferably 5 to 30% by weight, more preferably 15 to 25% by weight, even more preferably 17 to 23% by weight, and even more preferably 20% by weight of plasticizer, based on the total weight of the ammonia methacrylate copolymer in the sustained-release layer (3). According to another embodiment of the present invention, the sustained-release coating contains 2 to 30% by weight, preferably 5 to 25% by weight, more preferably 10 to 20% by weight, even more preferably 12 to 18% by weight, even more preferably 13 to 17% by weight, even more preferably 14 to 16% by weight, or 15 to 16% by weight of plasticizer, based on the total weight of the solid in the sustained-release layer (3) (i.e., excluding the solvent, preferably water).

[0091] The amount of anti-tack agent in the sustained-release layer (3) is not particularly limited. According to one embodiment of the present invention, the sustained-release layer (3) contains 1 to 30% by weight, preferably 2 to 25% by weight, more preferably 5 to 15% by weight, even more preferably 8 to 12% by weight, and even more preferably 10% by weight of anti-tack agent based on the total weight of the ammonia methacrylate copolymer in the sustained-release layer (3). According to another embodiment of the present invention, the sustained-release coating contains 2 to 15% by weight, preferably 5 to 12% by weight, more preferably 6 to 9% by weight, even more preferably 6 to 9% by weight, even more preferably 6.5 to 8.5% by weight, even more preferably 7 to 8% by weight, and even more preferably about 7.5% by weight of anti-tack agent based on the total weight of the solid in the sustained-release layer (3) (i.e., excluding the solvent, preferably water).

[0092] The sustained-release layer (3) may or may not contain a fusion accelerator. According to a preferred embodiment of the present invention, the sustained-release layer (3) does not contain a fusion accelerator. According to another embodiment of the present invention, the sustained-release layer (3) contains a fusion accelerator, for example, propylene glycol monolaurate (e.g., Lauroglycol® 90).

[0093] In a preferred embodiment, the sustained-release layer (3) comprises an ammonia methacrylate copolymer (preferably poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1), a plasticizer (preferably TEC), an anti-tack agent (preferably mesoporous silica), and optionally a residual solvent (preferably water).

[0094] In a specific embodiment, the weight of the sustained-release layer (3) relative to the total weight of the inert core unit (1) and the depot layer (2) is 4-8% by weight, preferably 5-7% by weight, and more preferably about 6% by weight.

[0095] The sustained-release layer (3) can be applied to an inert core unit (1) coated with a depot layer (2) using drug layering. According to a preferred embodiment, the sustained-release layer (3) of the oral solid dosage form of the present invention can be deposited on the depot layer (2) by drug layering, preferably using spray coating, more preferably using fluidized bed spray coating. Methods of drug layering a sustained-release layer onto a depot layer coating an inert core, containing an antibody or functional fragment as the active ingredient, are known in the art. Such methods can be found, for example, in International Publication No. 2019 / 057562. According to a specific embodiment, the weight increase of the oral solid dosage form after drug layering and subsequent drying for sustained-release coating, but before application of any further layers, is 4-8% by weight, preferably 5-7% by weight, more preferably about 6% by weight.

[0096] Finally, the oral solid dosage form of the present invention comprises a delayed-release layer (4) covering a sustained-release layer (3) and comprising poly(methacrylic acid, methyl methacrylate) 1:2, poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1, poly(methacrylic acid, methyl methacrylate) 1:1, or a combination thereof, preferably poly(methacrylic acid, methyl methacrylate) 1:2; an anti-tack agent, preferably glycerol monostearate (GMS); a plasticizer, preferably triethyl citrate (TEC); and preferably a surfactant.

[0097] The term “delayed release” is known in the art. Within the scope of the present invention, a delayed release layer is a layer / coating that prevents the release of an antibody or its functional fragment from an oral solid dosage form until a specific event occurs, preferably in the form of a pH trigger in solution. For example, a delayed release layer may be designed to focus on the delivery of an antibody or its functional fragment throughout the entire large intestine, starting in the cecum and continuing through the ascending colon, transverse colon, and descending colon, ending in the sigmoid colon. Alternatively, for example, a delayed release coating may be designed to initiate the delivery of an antibody or its functional fragment in the ileum and terminate the release in the sigmoid colon.

[0098] The terms “coating” or “to coat” as used in this context should be understood as defined above. Preferably, the delayed-release layer (4) is positioned on top of the coated sustained-release layer (3) so as not to have any other layers in between (i.e., between the delayed-release layers). Preferably, the delayed-release layer of the oral solid dosage form of the present invention continuously coats the sustained-release layer so as to have no gaps in the delayed-release layer.

[0099] The oral solid dosage form of the present invention is for oral administration and preferably includes (coated with) a delayed-release layer as an outer layer to prevent the release of the composition anterior to the terminal ileum, or anterior to the ileocolonic region, or anterior to the ascending colon or transverse colon. The ileocolonic region is the region of the gastrointestinal tract where the small intestine merges with the large intestine. The large intestine is the second to last part of the gastrointestinal tract and can be further subdivided into the cecum, colon, and rectum. The colon can be further subdivided into the ascending colon, transverse colon, descending colon, and sigmoid colon. The terminal ileum is the second to last part of the small intestine and is directly adjacent to the cecum.

[0100] The approach for applying the delayed-release layer is not particularly limited, as long as it does not affect the stability and activity of at least one antibody or its functional fragment in the depot layer coating. Methods for applying delayed-release coatings are known in the art. In one embodiment of the present invention, the delayed-release coating is applied, for example, by spray coating, preferably fluidized bed spray coating, as described above.

[0101] The delayed-release polymer in the delayed-release layer (4) is selected from poly(methacrylic acid, methyl methacrylate) 1:2, poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1, poly(methacrylic acid, methyl methacrylate) 1:1, or a combination thereof. Poly(methacrylic acid, methyl methacrylate) 1:2 is also known as methacrylic acid-methyl methacrylate copolymer (1:2), or poly(methacrylic acid-co-methyl methacrylate) 1:2, or Eudragit® S. Poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1 is also known as poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1, or Eudragit® FS. Poly(methacrylic acid, methyl methacrylate) 1:1 is also known as methacrylic acid-methyl methacrylate copolymer (1:1), poly(methacrylic acid-co-methyl methacrylate) 1:1, or Eudragit® L.

[0102] According to one embodiment, the delayed-release layer (4) does not contain polymers other than enteric-coated polymers. The term "enteric-coated polymer" is known in the art and may refer to polymers that do not dissolve in the gastric environment. According to another embodiment of the present invention, the delayed-release layer (4) does not contain any other delayed-release polymers other than poly(methacrylic acid, methyl methacrylate) 1:2, poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1, poly(methacrylic acid, methyl methacrylate) 1:1, or a combination thereof. According to a preferred embodiment of the present invention, the delayed-release layer (4) comprises poly(methacrylic acid, methyl methacrylate) 1:2 and preferably does not contain any other delayed-release polymers.

[0103] According to one embodiment of the present invention, the oral solid dosage form contains 5 to 40% by weight, preferably 10 to 40% by weight, more preferably 10 to 35% by weight, even more preferably 15 to 35% by weight, even more preferably 15 to 30% by weight, even more preferably 18 to 30% by weight, even more preferably 20 to 30% by weight, even more preferably 21 to 26% by weight, for example, about 22 to 25% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1, poly(methacrylic acid, methyl methacrylate) 1:1, or a combination thereof (preferably poly(methacrylic acid, methyl methacrylate) 1:2). According to another embodiment of the present invention, the delayed-release layer (4) contains 50 to 97% by weight, preferably 65 to 95% by weight, more preferably 70 to 90% by weight, and even more preferably 75 to 85% by weight, for example about 80% by weight, of poly(methacrylic acid, methyl methacrylate) 1:2, poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1, poly(methacrylic acid, methyl methacrylate) 1:1, or a combination thereof (preferably poly(methacrylic acid, methyl methacrylate) 1:2), based on the total weight of the solids in the delayed-release layer (4) (i.e., excluding residual solvents, such as ethanol and / or water).

[0104] According to another embodiment of the present invention, the solid dosage form (in the delayed-release layer) is 7-12 mg / cm³. 2 Preferably 8-11 mg / cm³2 More preferably 9-10 mg / cm³ 2 More preferably, about 9.5 mg / cm³ 2 This includes poly(methacrylic acid, methyl methacrylate) 1:2, poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1, poly(methacrylic acid, methyl methacrylate) 1:1, or combinations thereof (preferably poly(methacrylic acid, methyl methacrylate) 1:2).

[0105] The plasticizer in the delayed-release layer (4) is not particularly limited. The plasticizer in the delayed-release layer (4) may be selected from, for example, triethyl citrate (TEC), polyethylene glycol, acetyl triethyl citrate, butyl citrate, polysorbate, polypropylene glycol, dibutyl sebacate (DBS), or a combination thereof. Preferably, the plasticizer in the delayed-release layer (4) is triethyl citrate (TEC). According to one embodiment of the present invention, the delayed-release layer (4) contains 1 to 30% by weight, preferably 2 to 25% by weight, more preferably 5 to 15% by weight, even more preferably 8 to 12% by weight, and even more preferably about 10% by weight of plasticizer, based on the total weight of the delayed-release polymer in the delayed-release layer (4). According to another embodiment of the present invention, the delayed release layer (4) contains 1 to 25% by weight, preferably 4 to 15% by weight, more preferably 5 to 12% by weight, even more preferably 6 to 10% by weight, even more preferably 7 to 9% by weight, and even more preferably about 8% by weight of a plasticizer, based on the total weight of the solid in the delayed release layer (4) (i.e., excluding the residual solvent, e.g., ethanol and / or water).

[0106] The anti-tack agent in the delayed-release layer (4) is not particularly limited. The anti-tack agent in the delayed-release layer (4) can be selected from, for example, mesoporous silica, colloidal silicon dioxide, stearic acid, magnesium stearate, glycerol monostearate (GMS), and talc. Preferably, the anti-tack agent in the delayed-release layer (4) is glycerol monostearate (GMS). According to one embodiment of the present invention, the delayed-release layer (4) contains 1 to 30% by weight, preferably 2 to 25% by weight, more preferably 5 to 15% by weight, even more preferably 8 to 12% by weight, and even more preferably about 10% by weight of the anti-tack agent based on the total weight of the delayed-release polymer in the delayed-release layer (4). According to another embodiment of the present invention, the delayed-release layer (4) contains 1 to 20% by weight, preferably 4 to 15% by weight, more preferably 5 to 12% by weight, even more preferably 6 to 10% by weight, even more preferably 7 to 9% by weight, and even more preferably about 8% by weight of an anti-tack agent based on the total weight of the solid in the delayed-release layer (4) (i.e., excluding residual solvents, such as ethanol and / or water).

[0107] The delayed-release layer (4) of the oral solid dosage form of the present invention may optionally further contain a surfactant. The surfactant in the delayed-release layer (4) is not particularly limited, but is preferably a nonionic surfactant. The oral solid dosage form may contain a surfactant in the delayed-release layer (4) selected from the group consisting of polysorbate 20, polysorbate 28, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, poloxamer 124, poloxamer 181, poloxamer 188, poloxamer 237, poloxamer 331, poloxamer 338 and poloxamer 407, and combinations thereof.

[0108] According to a preferred embodiment of the present invention, the surfactant in the delayed-release layer (4) is polysorbate 20, 28, 40, 60, 65, 80, 81, and 85, preferably polysorbate 80. According to one embodiment of the present invention, the delayed-release layer (4) contains 0.1 to 15% by weight, preferably 0.5 to 10% by weight, more preferably 1 to 6% by weight, even more preferably 2 to 5% by weight, even more preferably 3 to 4.5% by weight, even more preferably 3.5 to 4% by weight, and even more preferably about 4% by weight of surfactant, based on the total weight of the delayed-release polymer in the delayed-release layer (4). According to another embodiment of the present invention, the delayed-release layer (4) contains 0.1 to 15% by weight, preferably 0.5 to 10% by weight, more preferably 1 to 5% by weight, even more preferably 2 to 4% by weight, even more preferably 2.5 to 3.5% by weight, even more preferably 3 to 3.5% by weight, and even more preferably about 3 to 3.2% by weight of surfactant, based on the total weight of the solid in the delayed-release layer (4) (i.e., without solvent).

[0109] According to a preferred embodiment of the oral solid dosage form of the present invention, the delayed-release layer (4) comprises poly(methacrylic acid, methyl methacrylate) 1:2, poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1, poly(methacrylic acid, methyl methacrylate) 1:1, or a combination thereof (preferably poly(methacrylic acid, methyl methacrylate) 1:2); an anti-tackifying agent (preferably glycerol monostearate (GMS)); a plasticizer (preferably triethyl citrate (TEC)); a surfactant (preferably polysorbate 80); and optionally a residual solvent (e.g., ethanol and / or water).

[0110] In one embodiment of the present invention, the residual solvent content of the oral solid dosage form (for example, the residual solvent after preparation of the oral solid dosage form, preferably water content) is less than 15% by weight, preferably less than 10% by weight, more preferably less than 8% by weight, even more preferably less than 7%, even more preferably less than 6%, and even more preferably 5% or less, for example about 5%, or alternatively about 4% or less by weight or about 3% or less by weight, based on the total weight of the oral solid dosage form. In another embodiment of the present invention, the residual water content of the oral solid dosage form is less than 15% by weight, preferably less than 10% by weight, more preferably less than 8% by weight, even more preferably less than 7%, even more preferably 5% or less, for example about 5%, or alternatively about 4% or less by weight, or about 3% or less by weight, or about 2% or less by weight, based on the total weight of the oral solid dosage form.

[0111] In a preferred embodiment of the present invention, the oral solid dosage form comprises: a) microcrystalline cellulose in an inert core unit; and / or b) an antibody or functional fragment thereof, sucrose, L-histidine, preferably L-histidine monohydrochloride and / or free base, hypromellose (HPMC), preferably hypromellose 2910 in a depot layer, for example, TNFα-specific antibodies or functional fragments thereof. 2.6~3.6 mPas, mesoporous silica, and / or polysorbate 80; and / or c) in the sustained-release layer, poly(ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride) 1:2:0.1, triethyl citrate (TEC), and / or mesoporous silica; and / or d) in the delayed-release layer, poly(methacrylic acid, methyl methacrylate) 1:2, TEC, polysorbate 80, and / or glycerol monostearate (GMS); and / or e) inert core unit and / or residual water in any of the layers, or comprising these.

[0112] In preferred embodiments of the oral solid dosage form of the present invention, the inert core unit contains 5 to 75% by weight, preferably 15 to 65% by weight, more preferably 15 to 60% by weight, even more preferably 20 to 60% by weight, and even more preferably 25 to 30% by weight, based on the total weight of the oral solid dosage form.

[0113] In another preferred embodiment of the oral solid dosage form of the present invention, the depot layer (2) comprises, with respect to the total weight of the oral solid dosage form, 0.05 to 30% by weight of antibody or functional fragment thereof, 0.03 to 30% by weight of binder, 0.1 to 40% by weight of sucrose, 0.005 to 5% by weight of L-histidine (salt and / or free base), and optionally 0.001 to 5% by weight of other buffering agents, 0.005 to 8% by weight of anti-tackifying agents, and / or 0.0005 to 2% by weight of surfactant. Agent; preferably 0.1 to 20% by weight of antibody or functional fragment thereof, 0.1 to 25% by weight of binder, 0.5 to 35% by weight of sucrose, 0.01 to 3% by weight of L-histidine, and optionally 0.01 to 3% by weight of other buffer, 0.01 to 5% by weight of anti-tackifying agent, and / or 0.001 to 1% by weight of surfactant; more preferably 0.5 to 20% by weight of antibody or functional fragment thereof, 0.5 to 15% by weight of binder, 1 to 25% by weight of sucrose, 0.0 5-2% by weight of L-histidine, and optionally 0.05-1.5% by weight of other buffers, 0.05-1.5% by weight of anti-tack agents, and / or 0.005-0.3% by weight of surfactants; more preferably 2-20% by weight of antibody or functional fragment thereof, 5-15% by weight of binder, 10-25% by weight of sucrose, 0.1-2% by weight of L-histidine, and optionally 0.5-1.5% by weight of other buffers, 0.5-1.5% by weight of anti-tack agents, and The mixture comprises / or 0.05 to 0.3 wt% of a surfactant; more preferably 8 to 12 wt% of an antibody or a functional fragment thereof, 6 to 8 wt% of a binder, 15 to 18 wt% of sucrose, 0.15 to 1 wt% of L-histidine, and optionally 0.6 to 0.9 wt% of another buffer, 0.6 to 0.8 wt% of an anti-tack agent (preferably mesoporous silica), and / or 0.05 to 0.1 wt% of a surfactant (preferably polysorbate 80).

[0114] In another preferred embodiment of the oral solid dosage form of the present invention, the sustained-release layer (3) comprises, with respect to the total weight of the oral solid dosage form, 1 to 10% by weight of ammonia methacrylate copolymer, 0.1 to 5% by weight of a plasticizer, and / or 0.05 to 7% by weight of an anti-tack agent; preferably 3 to 6% by weight of ammonia methacrylate copolymer, 0.2 to 2% by weight of a plasticizer, and / or 0.1 to 3% by weight of an anti-tack agent; more preferably 3.3 to 4.5% by weight of ammonia methacrylate copolymer, 0.5 to 1.5% by weight of a plasticizer, and / or 0.2 to 1% by weight of an anti-tack agent; even more preferably 3.6 to 4.2% by weight of poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 (e.g., Eudragit® RS 30D) comprises 0.6 to 1% by weight of a plasticizer (preferably triethyl citrate (TEC)) and / or 0.3 to 0.5% by weight of an anti-tack agent.

[0115] In another preferred embodiment of the oral solid dosage form of the present invention, the delayed-release layer (4) comprises, with respect to the total weight of the oral solid dosage form, 10 to 40% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 0.5 to 10% by weight of plasticizer, 0.1 to 3.5% by weight of surfactant, and / or 0.5 to 10% by weight of anti-tack agent (preferably glycerol monostearate (GMS)); preferably 15 to 35% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 1 to 5% by weight of plasticizer, 0.2 to 2% by weight of surfactant, and / or 1 to 5% by weight of anti-tack agent (preferably monostearate). The mixture comprises glycerol monostearate (GMS); more preferably 18-30% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 1.5-3% by weight of a plasticizer, 0.5-1.3% by weight of a surfactant, and / or 1.5-3% by weight of an anti-tack agent (preferably glycerol monostearate (GMS)); even more preferably 21-26% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 2.0-2.6% by weight of a plasticizer, 0.7-1.1% by weight of a surfactant, and / or 2.0-2.6% by weight of an anti-tack agent (preferably glycerol monostearate (GMS)).

[0116] In another preferred embodiment of the present invention, the oral solid dosage form contains, in the inert core unit and / or any of the layers, up to 8% by weight, up to 7% by weight, or up to 6% by weight, or up to 5.5% by weight, preferably up to 5% by weight, for example, about 5, or 4.5, or 4, or 3% by weight of water, relative to the total weight of the oral solid dosage form.

[0117] In yet another preferred embodiment of the present invention, the oral solid dosage form comprises, with respect to the total weight of the oral solid dosage form, a) 5 to 75% by weight, preferably 15 to 65% by weight, more preferably 20 to 60% by weight, and even more preferably 25 to 30% by weight of microcrystalline cellulose in the inert core unit; and / or b) 0.05 to 30% by weight of antibody or functional fragment thereof, 0.03 to 30% by weight of binder, 0.1 to 40% by weight of sucrose, 0.005 to 5% by weight of L-histidine (salt and / or free base), and optionally 0.001 to 5% by weight of other buffering agents, 0 0.005-10% by weight of an anti-tack agent and / or 0.0005-2% by weight of a surfactant; preferably 0.1-20% by weight of an antibody or functional fragment thereof, 0.1-25% by weight of a binder, 0.5-35% by weight of sucrose, 0.01-3% by weight of L-histidine, and optionally 0.01-3% by weight of another buffer, 0.01-5% by weight of an anti-tack agent and / or 0.001-1% by weight of a surfactant; more preferably 0.5-20% by weight of an antibody or functional fragment thereof, 0.5-15% by weight of a binder, 1-25% by weight of sucrose, and 0.05-2% by weight of L-histidine Also optionally 0.05 to 1.5 wt% of other buffers, 0.05 to 1.5 wt% of anti-tack agents, and / or 0.005 to 0.3 wt% of surfactants; more preferably 2 to 20 wt% of antibody or a functional fragment thereof, 5 to 15 wt% of binders, 10 to 25 wt% of sucrose, 0.1 to 2 wt% of L-histidine and optionally 0.5 to 1.5 wt% of other buffers, 0.5 to 1.5 wt% of anti-tack agents, and / or 0.05 to 0.3 wt% of surfactants; more preferably 8 to 12 wt% of antibody or a functional fragment thereof, 6 to 8 wt% of binders, 15 to 18 c) a sustained-release layer containing 1 to 10% by weight of ammonia methacrylate copolymer, 0.1 to 2% by weight of plasticizer, and / or 0.05 to 0.1% by weight of polysorbate 80; and / or c) a sustained-release layer containing 1 to 10% by weight of ammonia methacrylate copolymer, 0.1 to 5% by weight of plasticizer, and / or 0.05 to 7% by weight of anti-tack agent; preferably 3 to 6% by weight of ammonia methacrylate copolymer, 0.2 to 2% by weight of plasticizer, and / or 0.1 to 3% by weight of anti-tack agent; more preferably 3.3 to 4.5% by weight of ammonia methacrylate copolymer, 0.5 to 1.5% by weight of a plasticizer, and / or 0.2 to 1% by weight of an anti-tack agent; preferably 3.6 to 4.2% by weight of poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1, 0.6 to 1% by weight of triethyl citrate (TEC), and / or 0.3 to 0.5% by weight of mesopropyl alcohol. Silica; and / or d) In the delayed release layer, 10-40% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 0.5-5% by weight of plasticizer, 0.1-3.5% by weight of surfactant, and / or 0.5-8% by weight of glycerol monostearate (GMS); preferably 15-35% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 1-4% by weight of plasticizer, and 0.2-2% by weight % surfactant and / or 1-5% by weight glycerol monostearate (GMS); more preferably 18-30% by weight poly(methacrylic acid, methyl methacrylate) 1:2, 1.5-3% by weight plasticizer, 0.5-1.3% by weight surfactant, and / or 1.5-3% by weight glycerol monostearate (GMS); even more preferably 21-26% by weight poly(methacrylic acid, methyl methacrylate) 1:2, 2.0-2.6% by weight plasticizer, 0.7-1.1% by weight surfactant (e.g., polysorbate 80), and / or 2.0-2.6% by weight glycerol monostearate (GMS); and / or e) inert core units and / or any of the layers containing or comprising up to 5.5% by weight, or up to 5% by weight, for example, 5% by weight water.

[0118] The antibody or its functional fragment in the oral solid dosage form of the present invention, for example, the anti-TNFα antibody or its functional fragment, exhibits high activity and stability. The stability and activity of the antibody or its fragment can be estimated, for example, by determining the fraction of the antibody or its functional fragment present as dimers and other aggregates. According to one embodiment of the present invention, the total content of the antibody or its functional fragment present in the oral solid dosage form as dimers and other aggregates does not exceed 15%, preferably 12%, more preferably 10%, even more preferably 8%, even more preferably 7%, even more preferably 5%, for example, 3%. Methods for determining the fraction of polypeptide present as dimers and other aggregates are known in the art and include, for example, size exclusion chromatography (SEC). According to another embodiment, the total content of the antibody or its functional fragment present in the oral solid dosage form as fragments of a full-length antibody or its functional fragment does not exceed 15%, preferably 12%, more preferably 10%, even more preferably 8%, even more preferably 7%, even more preferably 5%, for example, 3%.

[0119] The oral solid dosage form of the present invention is preferably acid-resistant. According to one embodiment of the present invention, the oral solid dosage form of the present invention is for targeted release of an antibody or functional fragment thereof, starting in the terminal ileum, ileocolon region, ascending colon, or transverse colon, preferably the terminal ileum, ileocolon region, or ascending colon, more preferably the terminal ileum or ileocolon region. According to another embodiment of the present invention, the oral solid dosage form of the present invention is for targeted release of an antibody or functional fragment thereof in the terminal ileum, ileocolon region, ascending colon, transverse colon, descending colon, and / or sigmoid colon. According to yet another embodiment of the present invention, the oral solid dosage form of the present invention is for targeted sustained release of an antibody or functional fragment thereof, starting in the terminal ileum and continuing at least through the descending colon, preferably the sigmoid colon.

[0120] The oral solid dosage form of the present invention is suitable for targeted sustained release in the lower GI tube. Preferably, when the oral solid dosage form of the present invention is immersed in an aqueous solution at pH 6.0 under continuous stirring (e.g., for 2 hours), it does not release a corresponding amount of antibody or its functional fragment (e.g., it releases less than 1% by weight, less than 0.5% by weight, or less than 0.1% by weight of the total antibody or its functional fragment). According to one embodiment of the present invention, when the oral solid dosage form of the present invention is continuously immersed in an aqueous solution at pH 6.5 to 7.5, preferably about 6.8, with continuous stirring, it enables sustained release of antibody or its functional fragment for a period of at least 5 hours, preferably at least 10 hours, more preferably at least 12 hours, even more preferably at least 15 hours, even more preferably at least 20 hours, and most preferably at least 24 hours. According to another embodiment of the present invention, when an oral solid dosage form according to any of the above embodiments is continuously immersed in an aqueous solution of pH 6.5 to 7.5, preferably pH 6.5 to 7.0, more preferably pH 6.8, under continuous stirring, a sustained release of at least 80%, preferably at least 90%, 95%, or 98% of the antibody or fragment thereof in the oral solid dosage form is achieved, preferably at a substantially constant release rate, over a period of 4 to 30 hours, preferably 8 to 28 hours, more preferably 16 to 26 hours, and even more preferably 24 hours.

[0121] In further embodiments, the present invention relates to oral solid dosage forms as defined in any of the above embodiments for use in the treatment of diseases in patients, preferably human patients, in the gastrointestinal tract, preferably the intestine (preferably the terminal ileum), ileocolonic region, ascending colon, transverse colon, descending colon and / or sigmoid colon. Such diseases include, for example, immune checkpoint inhibitor (ICPI)-induced colitis, ICPI-induced enteritis, ICPI-induced diarrhea, IBD, cancer (e.g., colorectal cancer or small intestinal cancer), celiac disease, infections of the small and colon (e.g., Clostridium difficile infection), and diarrhea. In a preferred embodiment of the present invention, the oral solid dosage form of the present invention is for use in the treatment of ICPI-induced colitis, ICPI-induced enteritis, or ICPI-induced diarrhea, preferably ICPI-induced colitis. In another preferred embodiment of the present invention, the oral solid dosage form of the present invention is for use in the treatment of IBD, for example, Crohn's disease or ulcerative colitis.

[0122] In another embodiment, the present invention relates to an oral multiparticle drug delivery system comprising a plurality of oral solid dosage forms of any of the embodiments described above, preferably the oral multiparticle drug delivery system being a sachet / stick pack, a straw device (xStraw®), a capsule, or a tablet / minitablet, more preferably a capsule, and preferably the oral multiparticle drug delivery system comprising a total amount of an antibody or functional fragment thereof suitable for oral administration to a human patient.

[0123] According to further embodiments, the oral multiparticle drug delivery system of the present invention comprises a plurality of oral solid dosage forms of any of the above embodiments, each oral solid dosage form preferably having a predetermined axis and a predetermined cross-sectional profile, and at least 80%, preferably 90%, and more preferably 95% of the number of such oral solid dosage forms have a median aspect ratio of 0.7 to 1.7, where the aspect ratio is defined as the length of the oral solid dosage form along the predetermined axis divided by the minimum cross-sectional dimension. According to another embodiment, the median aspect ratio is greater than 0.8, preferably greater than 0.9, and less than 1.6, preferably less than 1.5, more preferably less than 1.4, even more preferably less than 1.3, even more preferably less than 1.2, and most preferably about 1. For further details regarding aspect ratio, predetermined axis, predetermined cross-sectional profile, and span (including definitions and embodiments), please refer to the disclosure of European Patent No. 2512453. It should be understood that the above definitions and embodiments regarding the aspect ratio and span of oral solid dosage forms apply equally to the oral solid dosage forms of the present invention according to any one of the above embodiments. Further embodiments of oral multiparticle drug delivery systems can be found in EP 2 512 453, and these embodiments are applicable to the present invention regardless of whether they are disclosed in EP 2 512 453 as referring to spheroidized / non-spheroidized solid dosage forms.

[0124] According to yet another embodiment of the present invention, the oral multiparticle drug delivery system of the present invention enables the recovery of at least 60%, preferably at least 80%, more preferably at least 85%, even more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, and even more preferably at least 98% of the antibody or its functional fragment from an oral solid dosage form.

[0125] According to yet another embodiment of the present invention, the oral multiparticle drug delivery system of the present invention enables the recovery of at least 60%, preferably at least 80%, more preferably at least 85%, even more preferably at least 93%, even more preferably at least 95%, even more preferably at least 97%, and even more preferably at least 98% of the antibody or functional fragment thereof from the oral solid dosage form within 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 26 hours, 28 hours, or 30 hours, by continuously immersing the oral solid dosage form in an aqueous solution (sustained release) at a pH of 6.5 to 7, preferably at about 6.8, under continuous stirring.

[0126] According to yet another embodiment of the present invention, the oral multiparticle drug delivery system of the present invention is prepared from a plurality of oral solid dosage forms by compression or encapsulation, preferably by encapsulation.

[0127] In further embodiments, the present invention relates to the use of oral solid dosage forms described in any of the above embodiments in the preparation of pharmaceuticals for the treatment of gastrointestinal disorders. The pharmaceuticals may include oral multiparticle drug delivery systems described in any of the above embodiments. According to one embodiment, the gastrointestinal disorder is immune checkpoint inhibitor (ICPI)-induced colitis, ICPI-induced enteritis, ICPI-induced diarrhea, or IBD (e.g., Crohn's disease or ulcerative colitis).

[0128] In further embodiments, the present invention relates to a method for targeted local treatment of gastrointestinal disorders, comprising administering to a patient in need an oral solid dosage form or an oral multiparticle drug delivery system of any of the above embodiments in a pharmaceutically effective amount. The patient is preferably a human patient. According to one embodiment, the method of the present invention is for the treatment of GI disorders in the ileum (preferably the terminal ileum), ileocolonic region, ascending colon, transverse colon, descending colon and / or sigmoid colon. According to another embodiment of the method, the gastrointestinal disorder is inflammatory bowel disease (IBD), such as Crohn's disease or ulcerative colitis. According to a preferred embodiment of the method, the gastrointestinal disorder is immune checkpoint inhibitor (ICPI)-induced colitis, ICPI-induced enteritis, or ICPI-induced diarrhea, preferably ICPI-induced colitis.

[0129] [Table 1] [Examples]

[0130] Materials and methods applied in the examples 1 Manufacturing process 1.1 Drug Layering Drug-filled multiparticle pellets were prepared by layering a depot layer solution containing anti-TNFα antibody onto starting cellet seeds in a Mini-Glatt fluidized bed (Glatt GmbH, Binzen, Germany) equipped with a Wurster column (bottom spray evaluation). For the preparation of the depot layer formulation, hydroxypropyl methylcellulose (HPMC) was slowly added to histidine buffer solution (pH 5.5) under paddle stirring homogenization until the HPMC solid was completely dissolved in the buffer medium. Then, Syloid 244 FP was slowly added and dispersed in HPMC-pH 5.5 histidine buffer medium by paddle stirring. The resulting HPMC-coated dispersion was then blended with the required mass of anti-TNF antibody drug substance (DS). This is available as a buffer solution in pH 5.5 histidine buffer and further contains sucrose as a stabilizer and polysorbate 80 as a surfactant. The anti-TNF-α antibody-coated formulation was layered on an inert pellet (cellets®), and the desired filling was achieved with an inlet air temperature of 38-44°C and a product temperature of 31-35°C. The antibody-layered pellets were dried in a drying oven with air circulation at 40°C for 20-24 hours.

[0131] 1.2 Slow-release coatings A ready-to-use aqueous dispersion of Eudragit RS30D, containing 30% Eudragit® RS solids, was used for sustained-release coating on antibody cellets. Prior to the Eudragit RS coating process, the 30% polymer dispersion was homogenized and transferred to a beaker glass through a sieve to prevent particle aggregation. Purified water was added, followed by triethyl citrate (plasticizer), and homogenized by magnetic stirring for 15 minutes. Subsequently, Syloid 244 FP (anti-tackifier) ​​was added to set the final Eudragit RS dispersion to a target concentration of 20% total solids. The final aqueous coating dispersion of Eudragit RS was sprayed onto anti-TNF-α antibody cellets by bottom spray using a Glatt fluidized bed Micro-kit at an inlet air temperature of 29–31°C and a product temperature of 26–28°C. After the spraying of the Eudragit RS coating formulation was complete, a Syloid 244 FP aqueous suspension was sprayed to reduce the stickiness of the pellets. Following this step, post-coating heat treatment (in-process curing) was performed in a fluidized bed apparatus for 30 minutes at an inlet air temperature of 52-55°C, while creating a humid environment by spraying water, until the target product temperature reached 45-46°C.

[0132] 1.3 Delayed emission coating A sustained-release pellet of anti-TNF-α antibody (coated with Eudragit RS) was further coated with Eudragit S as a delayed-release polymer. The Eudragit S coated formulation was prepared by completely dissolving the Eudragit® S polymer in 96% ethanol at room temperature with magnetic stirring. Triethyl citrate was added to the organic (ethanol) solution and homogenized by magnetic stirring. In the next step, a glycerol monostearate (GMS) aqueous emulsion (used as an anti-tack agent) was prepared by dissolving polysorbate 80 (Tween 80) in purified water with magnetic stirring, followed by the addition of GMS. The mixture was then heated to 75°C with continuous magnetic stirring and maintained at this temperature for 15 minutes to obtain a homogeneous emulsion. The GMS emulsion was then cooled to room temperature under continuous magnetic stirring. The GMS emulsion was slowly added to the Eudragit S organic solution to obtain the final Eudragit S coated formulation. The coating process was performed by bottom spray using a Glatt fluidized bed Micro-kit, with an inlet air temperature of 27–32°C and a product temperature of 26.0–29°C. After spraying the target amount of Eudragit S polymer, a post-coating pre-drying step was carried out in the fluidized bed apparatus at 40°C for 30 minutes. The drying process was continued for 2–4 hours in a drying oven with air circulation at 40°C.

[0133] 2 Elution method 2.1 Elution assay Elution occurred at 37°C with a stirring speed of 75 rpm.

[0134] Medium: a) 0.1N HCl; b) Potassium phosphate buffer containing sodium chloride, pH 6.0. The salts were mixed so that the ionic strength of the medium was equal to that of the biocompatible Hanks buffer (HMFadda, and AWBasit, J. Drug Del. Sci. Tech. 2005;15(4):273-280).

[0135] Procedure: One dose unit was placed in each container and stirred in 0.1N HCl for 2 hours, followed by elution in medium b) for 2 hours. The pH of the elution medium was then set to pH 6.8. To obtain profiles, the samples were analyzed by HPLC, and total protein was quantified using the Bradford method detailed below.

[0136] 2.2 Antibody release using the Bradford assay method Elution of anti-TNFα antibody layered pellets and sustained-release coated pellets was performed by rotational mixing in phosphate buffer pH 6.8. Briefly, the pellets were weighed into 5 mL cryotubes, to which 4 mL of phosphate buffer pH 6.8 was added. The tubes were then rotated at 15 rpm in a benchtop rotary apparatus. The amount of coated pellet used per tube was calculated to obtain a theoretical antibody drug substance (DS) concentration of 0.8 mg / mL in the buffer at 100% release, taking into account the theoretical antibody loading. 100 μL of supernatant was sampled at specified time points (15 min; 30 min; 1 hour; 2 hours; 4 hours; 6 hours and 24 hours). The samples were then centrifuged at 3000 rpm for 5 minutes, and the supernatant was used for further analysis. During the experiment, the volume of collected samples was not replaced with fresh buffer.

[0137] Total protein quantification was performed by colorimetric analysis according to the Bradford method using the Coomassie Plus assay (Thermo Scientific). Quantification was performed using a newly created standard calibration curve in 10 mM phosphate buffer pH 6.8. Calibration curves were created using anti-TNFα antibody standards ranging from 0.03 to 1.0 mg / mL.

[0138] result Composition of multilayer oral solid dosage forms for delayed and sustained release We developed a drug product containing anti-TNFα antibody as a multi-particle formulation with a multilayer coating concept, using cellets® as an inert core unit coated with a depot layer formulation containing anti-TNFα antibody (complete antibody portion) as the active ingredient, sucrose (stabilizer), histidine / histidine HCl (buffer), and Pharmacoat 603 (hypromellose) as a film-forming polymer (polymer binder). The cellets® having the anti-TNFα antibody layer was further coated with an inner layer containing Eudragit® RS (sustained-release polymer) and an outer layer of Eudragit® S (delayed-release polymer). Different layers were applied by drug layering using fluidized bed spray coating.

[0139] Therefore, the following multilayer pellet design was defined during formulation development. - Inert core unit (cellets(registered trademark)); - Anti-TNFα antibody depot layer (hypromellose as film-forming polymer; aqueous); - Sustained-release layer (Eudragit® RS as a film-forming polymer; aqueous); and - Delayed release layer (Eudragit® S as a film-forming polymer; organic).

[0140] The obtained multilayer oral solid dosage forms are shown in Figures 1 and 2. Figure 5 shows an SEM image of a cross-section of the final formulation. The final formulation contained the following components in each layer, as shown in Table 2 below.

[0141] [Table 2]

[0142] During formulation development, solid dosage forms were formulated using different loadings of anti-TNFα antibody in the depot layer, and different functional coatings in oral solid dosage forms were investigated.

[0143] One approach to producing multiparticles with different antibody loadings is to use the same depot layer formulation composition (e.g., the same concentrations of anti-TNFα antibody and excipients in the depot layer coating formulation) for oral solid dosage forms in the multiparticles, and adjust the amount required for the intended anti-TNFα antibody loading during coating. Such an approach results in thinner depot layers for lower loadings compared to thicker layers for higher drug loadings. Other functional coating layers, including Eudragit® RS (inner coating) and Eudragit® S (outer coating), both remained unchanged after drug layering, regardless of the target level of the intended anti-TNFα antibody loading.

[0144] Cellets loaded with anti-TNFα antibody were prepared by applying a depot layer coating formulation until the target loading amount (of anti-TNFα antibody) was achieved. 100% recovery of anti-TNFα antibody was confirmed from the anti-TNFα antibody-loaded pellet, which included a depot layer but did not contain a sustained-release or delayed-release layer (Bradford assay) (see Figure 3A for the drug layering intermediate in Example 1, for example).

[0145] Next, a sustained-release coating based on Eudragit®RS was applied to the depot layer by spray coating. The quality and uniformity of the Eudragit®RS coating were confirmed by SEM analysis of the Eudragit®RS intermediate, shown in Figure 5 for lower drug loads and in Figure 6 for higher drug loads.

[0146] As the final step, a delayed-release layer based on Eudragit® S was applied to the sustained-release layer by spray coating.

[0147] During evaluation of examples filled with anti-TNFα antibodies containing a sustained-release layer, it was found that the level of drug released from layered cellets containing anti-TNFα antibodies that were further coated with a sustained-release layer containing Eudragit®RS but did not yet contain the Eudragit®S delayed-release layer was unreliable. Unexpectedly, in some cases, only about 12% drug release was achieved within 24-26 hours in release tests simulating the above-mentioned GI environment (Figure 3B).

[0148] However, surprisingly, after applying the final outer delayed-release layer containing Eudragit® S (final in Example 1), the amount of drug released consistently increased to a level of interest for the commercial use of the expensive formulation in the release test, exhibiting a consistently high release rate (approximately 80% of the antibody was released within 26 hours in the release test (see Figures 3C and 4)). This was surprising, as the delayed-release layer is thought to only prevent drug release until the pH trigger.

[0149] These findings suggest that the anti-TNFα antibody multilayer coating system proposed by the inventors is not driven solely by the isolated properties of the excipients used in different coating layers or by the isolated properties of the functional polymers, but rather by the combined effect of the entire formulation, resulting in a drug delivery system suitable for the targeted release of a large antibody moiety. Therefore, these unexpected results suggest that the antibody-containing final oral solid dosage form (e.g., Figure 1) discovered by the inventors (without being bound by any particular theory) functions due to the combined effect of components in different layers that enables the release of a large antibody moiety in the desired manner.

[0150] Exemplary compositions of final oral solid dosage forms having a layered structure as shown in Figure 1 are shown in Tables 3 / 4 and 5 / 6 below.

[0151] Regarding the final (multilayer) combination of the anti-TNFα antibody depot layer and the functional polymer layer, as is evident from Figures 3C and 4, which were evaluated using an elution assay, 0% release occurred after 2 hours at pH 6.0. Sustained release began after 1 to 2.5 hours at pH 6.8. After 26 hours, approximately 80% of the antibody had been released.

[0152] Ultimately, the final (multilayer) combination of the anti-TNFα antibody depot layer and the functional polymer layer proposed by the inventors, as shown in Figure 2, prevented premature (and undesirable) drug release in a medium simulating the acidic environment of the stomach (2 hours in 0.1N HCl), as well as release during passage through the upper small intestine (no release for 2 hours in buffer pH 6.0), and enabled sustained release of the antibody in a medium of pH 6.8 or higher, simulating the pH conditions of the ileum where drug release is expected to begin and continue in a sustained-release manner along the intestine.

[0153] [Table 3]

[0154] [Table 4]

[0155] [Table 5]

[0156] [Table 6]

[0157] Stability testing The formulations from Example 4 were stored for 12 months at either 2–8°C or 25°C / 60%RH. At various time points, the potency of the antibodies in the formulations was tested by determining the relative potency (relative to the nominal antibody content) of the anti-TNFα antibody using antibody-adapted cell-based assays.

[0158] Exemplary titer assay: A549 cells are seeded before the assay. A series of analyte dilutions are incubated with a fixed amount of TNFα. After enabling the formation of the analyte-TNFα complex, the A549 cells are subsequently stimulated with the mixture, and this stimulation is eliminated by fixing the cells with paraformaldehyde. Phosphorylated NF-κB S536 is labeled by sequential staining of cells using a phosphorus-specific NF-κB S536 antibody and an HRP-labeled detection antibody. The amount of HRP is detected by the conversion of the chemiluminescent substrate by HRP and the generation of a luminescence signal that can be captured by specialized equipment.

[0159] [Table 7]

[0160] As can be seen from the figure, the antibody retains its activity for at least 12 months at both 2-8°C and 25°C / 60%RH. The stability at 25°C is particularly noteworthy and surprising for an antibody drug.

Claims

1. Oral solid dosage form, i) Inert core unit (1), ii) A depot layer (2) that coats the inert core unit (1) and contains an antibody or a functional fragment thereof as an active agent, and optionally contains a stabilizer, a buffer and / or a polymer binder, iii) A sustained-release layer (3) covering the depot layer (2) and comprising at least one cationic polymer, and optionally comprising a plasticizer and / or an anti-tack agent, iv) an oral solid dosage form comprising: a delayed-release layer (4) covering the sustained-release layer (3), comprising at least one anionic polymer and optionally comprising a plasticizer;

2. Oral solid dosage form, i) Inert core unit (1) and ii) A depot layer (2) that coats the inert core unit (1) and contains an antibody or a functional fragment thereof as an active agent, a stabilizer, a buffer, and a polymer binder, iii) A sustained-release layer (3) covering the depot layer (2) and comprising at least one cationic polymer, a plasticizer, and an anti-tack agent, iv) an oral solid dosage form comprising: a delayed-release layer (4) covering the sustained-release layer (3) and containing at least one anionic polymer and a plasticizer.

3. The solid preparation according to claim 1 or 2, wherein the at least one anionic polymer is selected from the group consisting of polymers containing a carboxylic acid group, poly(methacrylic acid, methyl methacrylate) 1:1, poly(methacrylic acid, ethyl acrylate) 1:1, poly(methacrylic acid, methyl methacrylate) 1:2, poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1, carboxymethylcellulose, and combinations thereof.

4. The solid preparation according to any one of claims 1 to 3, wherein the at least one cationic polymer is selected from the group consisting of chitosan, cellulose, ammonia methacrylate copolymer, poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1, poly(2-N,N-dimethylaminoethyl methacrylate), poly-L-lysine, polyethyleneimine, and poly(amidoamine).

5. Oral solid dosage form, i) Inert core unit (1), ii) A depot layer (2) that coats the inert core unit (1) and contains an antibody or a functional fragment thereof as an active agent, a stabilizer, a buffer, and a polymer binder, iii) A sustained-release layer (3) covering the depot layer (2) and containing an ammonia methacrylate copolymer, a plasticizer, and an anti-tack agent, iv) An oral solid dosage form comprising: a delayed-release layer (4) coating the sustained-release layer (3) and containing poly(methacrylic acid, methyl methacrylate) 1:2, poly(methacrylic acid, methyl methacrylate) 1:1, or a combination thereof, an anti-tack agent, and a plasticizer.

6. The solid dosage form according to any one of claims 1 to 5, wherein the sustained-release layer does not contain an anionic polymer and / or the delayed-release layer does not contain a cationic polymer.

7. The oral solid preparation according to any one of claims 1 to 6, wherein the inert core unit (1) contains or is an inert pellet made of microcrystalline cellulose.

8. The oral solid dosage form according to any one of claims 1 to 7, wherein the stabilizer in the depot layer (2) is selected from sucrose, maltose, lactose, trehalose, glycerol, maltitol, isomalt, mannitol, sorbitol, xylitol, and combinations thereof, preferably sucrose.

9. The oral solid dosage form according to any one of claims 1 to 8, wherein the buffer in the depot layer (2) is selected from the group consisting of L-histidine buffer, citrate buffer, hydroxymethylaminomethane (TRIS) buffer, succinate buffer, phosphate buffer, acetate buffer, and combinations thereof.

10. An oral solid dosage form according to any one of claims 1 to 9, wherein in the depot layer (2), the stabilizer is sucrose; and / or the buffer is L-histidine or a salt thereof; and / or the polymer binder in the depot layer (2) is hypromellose (HPMC).

11. The oral solid preparation according to any one of claims 1 to 10, wherein the depot layer (2) comprises an anti-tack agent and / or a surfactant.

12. The oral solid preparation according to claim 11, wherein the anti-tack agent is mesoporous silica and / or the surfactant is polysorbate 80.

13. The oral solid dosage form according to any one of claims 1 to 12, wherein the sustained-release layer (3) contains poly(ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride) in a ratio of 1:2:0.1 and does not contain any other sustained-release polymers.

14. The oral solid preparation according to any one of claims 1 to 13, wherein in the sustained-release layer (3), the plasticizer is triethyl citrate (TEC) and / or the anti-tack agent is mesoporous silica.

15. The oral solid dosage form according to any one of claims 1 to 14, wherein in the delayed-release layer (4), the plasticizer is triethyl citrate (TEC) and / or the anti-tack agent is glycerol monostearate (GMS).

16. The oral solid dosage form according to any one of claims 1 to 15, wherein the delayed-release layer (4) comprises poly(methacrylic acid, methyl methacrylate) 1:2 and does not contain other delayed-release polymers.

17. The oral solid dosage form according to any one of claims 1 to 16, wherein the delayed-release layer (4) contains a surfactant.

18. The oral solid preparation according to claim 17, wherein the surfactant in the delayed-release layer (4) is polysorbate 80.

19. The oral solid dosage form according to any one of claims 1 to 18, wherein the inert core unit (1) is a pellet having a particle size distribution such that at least 85% of the pellets have a particle size of 700 to 1400 μm.

20. The oral solid preparation according to any one of claims 1 to 19, wherein the inert core unit contains 15 to 60% by weight of microcrystalline cellulose relative to the total weight of the oral solid preparation.

21. The oral solid dosage form according to any one of claims 1 to 20, wherein the depot layer (2) comprises, with respect to the total weight of the oral solid dosage form, 0.1 to 20% by weight of an antibody or functional fragment thereof, 0.1 to 25% by weight of a binder, 0.5 to 35% by weight of sucrose, 0.01 to 2% by weight of L-histidine, and optionally 0.01 to 3% by weight of another buffer, 0.01 to 5% by weight of an anti-tack agent, and / or 0.001 to 1% by weight of polysorbate 80.

22. The oral solid preparation according to any one of claims 1 to 21, wherein the sustained-release layer (3) comprises 3 to 6% by weight of ammonia methacrylate copolymer, 0.2 to 2% by weight of a plasticizer, and / or 0.1 to 3% by weight of an anti-tack agent, based on the total weight of the oral solid preparation.

23. The oral solid dosage form according to any one of claims 1 to 22, wherein the delayed-release layer (4) comprises 15 to 35% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 1 to 4% by weight of a plasticizer, 0.2 to 2% by weight of a surfactant, and / or 1 to 5% by weight of glycerol monostearate (GMS) based on the total weight of the oral solid dosage form.

24. The oral solid preparation according to any one of claims 1 to 23, wherein the inert core unit and / or any of the layers contain up to 5% by weight of water relative to the total weight of the oral solid preparation.

25. The aforementioned oral solid preparation is a) The inert core unit (1) contains 57.65 to 58.05% by weight of microcrystalline cellulose, b) The depot layer (2) contains 0.75 to 0.85% by weight of antibody or its functional fragment, 0.54 to 64% by weight of hypromellose (HPMC), 1.34 to 1.50% by weight of sucrose, 0.07 to 0.09% by weight of L-histidine, 0.05 to 0.07% by weight of mesoporous silica, and 0.008 to 0.012% by weight of polysorbate 80, c) The sustained-release layer (3) contains 3.9 to 4.1% by weight of poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1, 0.75 to 0.85% by weight of triethyl citrate (TEC), and 0.35 to 0.45% by weight of mesoporous silica, d) The delayed release layer (4) contains 23.25 to 23.55% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 2.29 to 2.39% by weight of triethyl citrate (TEC), 0.89 to 0.99% by weight of polysorbate 80, and 2.29 to 2.39% by weight of glycerol monostearate (GMS), e) The oral solid dosage form according to any one of claims 1 to 24, comprising or consisting of 4.9% to 5.1% by weight of water in the inert core unit and / or any of the layers.

26. The aforementioned oral solid preparation is a) The inert core unit (1) contains 57.85% by weight of microcrystalline cellulose, b) The depot layer (2) contains 0.80 wt% anti-TNFα antibody or its functional fragment, 0.59 wt% hypromellose (HPMC), 1.42 wt% sucrose, 0.08 wt% L-histidine, 0.06 wt% mesoporous silica, and 0.01 wt% polysorbate 80, c) The sustained-release layer (3) contains 4.00% by weight of poly(ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride) 1:2:0.1, 0.80% by weight of triethyl citrate (TEC), and 0.40% by weight of mesoporous silica, d) The delayed-release layer (4) contains 23.40% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 2.34% by weight of triethyl citrate (TEC), 0.94% by weight of polysorbate 80, and 2.34% by weight of glycerol monostearate (GMS), e) The oral solid dosage form according to any one of claims 1 to 25, comprising or consisting of 4.99% by weight of water in the inert core unit and / or any of the layers.

27. The aforementioned oral solid preparation is a) The inert core unit (1) contains 27.0 to 27.3% by weight of microcrystalline cellulose, b) The depot layer (2) contains 9.38 to 9.58% by weight of antibody or its functional fragment, 6.8 to 7.0% by weight of hypromellose (HPMC), 16.72 to 17.02% by weight of sucrose, 0.89 to 0.99% by weight of L-histidine, 0.64 to 0.74% by weight of mesoporous silica, and 0.07 to 0.09% by weight of polysorbate 80, c) The sustained-release layer (3) contains 3.84 to 4.04% by weight of poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1, 0.74 to 0.84% ​​by weight of triethyl citrate (TEC), and 0.34 to 0.44% by weight of mesoporous silica, d) The delayed-release layer (4) contains 22.78 to 23.08% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 2.24 to 2.34% by weight of triethyl citrate (TEC), 0.87 to 0.97% by weight of polysorbate 80, and 2.24 to 2.34% by weight of glycerol monostearate (GMS), e) The oral solid dosage form according to any one of claims 1 to 24, comprising or consisting of 4.23% to 4.43% by weight of water in the inert core unit and / or any of the layers.

28. The aforementioned oral solid preparation is a) The inert core unit (1) contains 27.16% by weight of microcrystalline cellulose, b) The depot layer (2) contains 9.48% by weight of anti-TNFα antibody or its functional fragment, 6.90% by weight of hypromellose (HPMC), 16.87% by weight of sucrose, 0.94% by weight of L-histidine, 0.69% by weight of mesoporous silica, and 0.08% by weight of polysorbate 80, c) The sustained-release layer (3) contains 3.94% by weight of poly(ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride) 1:2:0.1, 0.79% by weight of triethyl citrate (TEC), and 0.39% by weight of mesoporous silica, d) The delayed-release layer (4) contains 22.93% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 2.29% by weight of triethyl citrate (TEC), 0.92% by weight of polysorbate 80, and 2.29% by weight of glycerol monostearate (GMS), e) The oral solid dosage form according to any one of claims 1 to 24, comprising or consisting of 4.33% by weight of water in the inert core unit and / or any of the layers.

29. The aforementioned oral solid preparation is a) The inert core unit (1) contains 25.07 to 25.37% by weight of microcrystalline cellulose, b) The depot layer (2) contains 9.16 to 9.36% by weight of antibody or its functional fragment, 6.64 to 6.84% by weight of hypromellose (HPMC), 16.33 to 16.63% by weight of sucrose, 0.86 to 0.96% by weight of L-histidine, 0.62 to 0.72% by weight of mesoporous silica, and 0.07 to 0.09% by weight of polysorbate 80, c) The sustained-release layer (3) contains 3.7 to 3.9% by weight of poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1, 0.71 to 0.81% by weight of triethyl citrate (TEC), and 0.33 to 0.43% by weight of mesoporous silica, d) The delayed release layer (4) contains 24.65 to 24.95% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 2.43 to 2.53% by weight of triethyl citrate (TEC), 0.94 to 1.04% by weight of polysorbate 80, and 2.43 to 2.53% by weight of glycerol monostearate (GMS), e) The oral solid dosage form according to any one of claims 1 to 24, comprising or consisting of 4.85% to 5.05% by weight of water in the inert core unit and / or any of the layers.

30. The aforementioned oral solid preparation is a) The inert core unit (1) contains 25.22% by weight of microcrystalline cellulose, b) The depot layer (2) contains 9.26% by weight of anti-TNFα antibody or its functional fragment, 6.74% by weight of hypromellose (HPMC), 16.48% by weight of sucrose, 0.91% by weight of L-histidine, 0.67% by weight of mesoporous silica, and 0.08% by weight of polysorbate 80, c) The sustained-release layer (3) contains 3.80% by weight of poly(ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride) 1:2:0.1, 0.76% by weight of triethyl citrate (TEC), and 0.38% by weight of mesoporous silica, d) The delayed-release layer (4) contains 24.80% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 2.48% by weight of triethyl citrate (TEC), 0.99% by weight of polysorbate 80, and 2.48% by weight of glycerol monostearate (GMS), e) The oral solid dosage form according to any one of claims 1 to 24, comprising or consisting of 4.95% by weight of water in the inert core unit and / or any of the layers.

31. The aforementioned oral solid preparation is a) The inert core unit (1) contains 25.21 to 25.51% by weight of microcrystalline cellulose, b) The depot layer (2) contains 8.91 to 9.11% by weight of antibody or its functional fragment, 6.48 to 6.68% by weight of hypromellose (HPMC), 15.72 to 16.02% by weight of sucrose, 0.83 to 0.93% by weight of L-histidine, 0.61 to 0.71% by weight of mesoporous silica, and 0.07 to 0.09% by weight of polysorbate 80, c) The sustained-release layer (3) contains 3.58 to 3.78% by weight of poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1, 0.69 to 0.79% by weight of triethyl citrate (TEC), and 0.32 to 0.42% by weight of mesoporous silica, d) The delayed release layer (4) contains 25.56 to 25.86% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 2.52 to 2.62% by weight of triethyl citrate (TEC), 0.98 to 1.08% by weight of polysorbate 80, and 2.52 to 2.62% by weight of glycerol monostearate (GMS), e) The oral solid preparation according to any one of claims 1 to 24, comprising or consisting of 4.80% to 5.00% by weight of water in the inert core unit and / or any of the layers.

32. The aforementioned oral solid preparation is a) The inert core unit (1) contains 25.36% by weight of microcrystalline cellulose, b) The depot layer (2) contains 9.01% by weight of anti-TNFα antibody or its functional fragment, 6.58% by weight of hypromellose (HPMC), 15.87% by weight of sucrose, 0.88% by weight of L-histidine, 0.66% by weight of mesoporous silica, and 0.08% by weight of polysorbate 80, c) The sustained-release layer (3) contains 3.68% by weight of poly(ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride) 1:2:0.1, 0.74% by weight of triethyl citrate (TEC), and 0.37% by weight of mesoporous silica, d) The delayed-release layer (4) contains 25.71% by weight of poly(methacrylic acid, methyl methacrylate) 1:2, 2.57% by weight of triethyl citrate (TEC), 1.03% by weight of polysorbate 80, and 2.57% by weight of glycerol monostearate (GMS), e) The oral solid dosage form according to any one of claims 1 to 24, comprising or consisting of 4.90% by weight of water in the inert core unit and / or any of the layers.

33. The oral solid dosage form according to any one of claims 1 to 32, wherein the antibody or functional fragment thereof is an antibody or functional fragment thereof specific to tumor necrosis factor alpha (TNFα).

34. The antibody or functional fragment thereof that is specific to TNFα includes (i) a CDR1 region having the amino acid sequence shown in SEQ ID NO: 1, a CDR2 region having the amino acid sequence shown in SEQ ID NO: 2, and a CDR3 region having the amino acid sequence shown in SEQ ID NO:

3. Ｌ A domain and / or (ii) a V having a CDR1 region having the amino acid sequence shown in SEQ ID NO: 4, a CDR2 region having the amino acid sequence shown in SEQ ID NO: 5, and a CDR3 region having the amino acid sequence shown in SEQ ID NO:

6. Ｈ The oral solid dosage form according to claim 33, which is an anti-TNFα antibody or a functional fragment thereof having a TNFα-binding domain including a domain.

35. The antibody or functional fragment thereof that is specific to TNFα (i) has an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 8 Ｌ V having a domain and / or (ii) an amino acid sequence according to the amino acid sequence shown in Sequence ID No. 7 Ｈ The oral solid dosage form according to claim 33, which is an anti-TNFα antibody or a functional fragment thereof having a TNFα-binding domain comprising or consisting of a domain.

36. The oral solid dosage form according to claim 33, wherein the antibody or functional fragment thereof that is specific to TNFα is an anti-TNFα antibody having an amino acid sequence according to the amino acid sequence shown in SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, or SEQ ID NO: 22, preferably SEQ ID NO: 18, or comprising an Fc region consisting thereof.

37. The oral solid dosage form according to any one of claims 1 to 36, wherein the oral solid dosage form is prepared by drug layering using spray coating.

38. An oral solid dosage form according to any one of claims 1 to 37, for use in targeted topical treatment of immune checkpoint inhibitor (ICPI)-induced colitis, ICPI-induced enteritis, ICPI-induced diarrhea, or inflammatory bowel disease (IBD).

39. An oral multiparticle drug delivery system comprising a plurality of oral solid dosage forms according to any one of claims 1 to 38.

40. The oral multiparticle drug delivery system according to claim 39, wherein the oral multiparticle drug delivery system is a capsule.

41. A method for targeted local treatment of gastrointestinal disease, comprising administering to a patient in need thereof an oral solid dosage form according to any one of claims 1 to 37 or an oral multiparticle drug delivery system according to claim 39 or 40 in a pharmaceutically effective amount.

42. The method according to claim 41, wherein the gastrointestinal disorder is immune checkpoint inhibitor (ICPI)-induced colitis, ICPI-induced enteritis, ICPI-induced diarrhea, or inflammatory bowel disease (IBD).

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