Solid oral dosage form comprising antibody for sustained release in lower gastrointestinal tract

Abstract

The present invention relates to a solid oral dosage form for sustained release in the lower gastrointestinal tract comprising an antibody or a functional fragment thereof in a depot layer (2) covering an inert core unit (1), a sustained release layer (3) covering the depot layer and a delayed release layer (4) covering the sustained release layer, preferably prepared by pharmaceutical stratification; an oral multiparticulate drug delivery system comprising a plurality of such solid oral dosage forms; and the use of the solid oral dosage form in targeted topical treatment in the lower gastrointestinal tract of a patient.

Description

TECHNICAL FIELD

[0001] The present invention relates to a solid oral dosage form for sustained release in the lower gastrointestinal tract, comprising an antibody or a functional fragment thereof specific for tumor necrosis factor alpha (TNFa) in a reservoir layer (2) covering an inert core unit (1), a sustained release layer (3) covering the reservoir layer and a delayed release layer (4) covering the sustained release layer, preferably prepared by drug layering; an oral multiparticulate drug delivery system comprising a plurality of the solid oral dosage form; and the use of the solid oral dosage form in targeted local treatment of a patient's lower gastrointestinal tract. BACKGROUND

[0002] Solid dosage forms such as pellets, microtablets, tablets, granules, capsules or tablets and the like are widely used in the pharmaceutical industry. They usually comprise 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 occupation, ease of handling and improved stability. Furthermore, tablets or capsules provide the most widely used dosage unit for administering a drug to a patient in a non-invasive manner. For small molecule drugs, there is a long-standing practice of preparing solid dosage forms. On the other hand, although antibodies and functional fragments thereof are being used more and more widely as active ingredients in therapeutic or diagnostic applications, it is more challenging to formulate them into solid dosage forms.

[0003] As an alternative to systemic treatment, the use of solid dosage forms intended for oral administration and targeting a part of the gastrointestinal (GI) tract has many potential advantages and has therefore become an interesting alternative in recent years, as it allows to achieve a targeted local treatment of a disease symptom in a part of the gastrointestinal tract, such as immune checkpoint inhibitor (ICPI)-induced colitis, ICPI-induced small intestinal colitis, ICPI-induced diarrhea, inflammatory bowel disease (IBD), colorectal cancer, diarrhea or microbial infection. However, this targeted local treatment using solid dosage forms of antibodies and functional fragments of antibodies in the gastrointestinal tract faces various challenges.

[0004] Colitis is a disorder characterized by inflammation of the large intestine / colon. Enteritis is a disorder characterized by inflammation of the small intestine. Small bowel colitis 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 characterizing ICP inhibitor-induced colitis include diarrhea, abdominal pain, nausea, cramping, bloody or mucous stools or a change in bowel habits, fever, abdominal distension, intractable constipation, and constipation (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 characterizing ICP inhibitor-induced small bowel colitis include the symptoms listed above for ICP inhibitor-induced colitis.

[0005] For ICPI-induced colitis, ICPI-induced small bowel colitis, and ICPI-induced diarrhea, it is important that the patient can be treated for ICPI-induced colitis, ICPI-induced small bowel colitis, or ICPI-induced diarrhea with an antibody or functional antibody fragment while still being treated for cancer with an ICPI via the intravenous route. This requires an alternative route of administration, on the one hand to allow for parallel intravenous cancer treatment (e.g., the standard therapy for treating severe ICPI-induced colitis or ICPI-induced small bowel colitis with an anti-TNFa specific antibody currently involves systemic administration of the anti-TNFa antibody via intravenous infusion on a regular basis, which requires interruption of ICPI treatment), and on the other hand to ensure that targeted local delivery is achieved to reduce systemic exposure of the antibody and the potential side effects resulting therefrom to an absolute minimum. While this is beneficial for all patients, it is particularly important for patients with ICPI-induced colitis, ICPI-induced small bowel colitis, or ICPI-induced diarrhea who are already heavily burdened by cancer therapy.

[0006] A problem associated with solid oral dosage forms comprising antibodies and functional fragments of antibodies is that the size of antibodies and antibody fragments, compared to small drug molecules, greatly influences the release behavior when combined with functional coatings, such as sustained release coatings and / or delayed release coatings.

[0007] Targeted release of a therapeutic antibody or a functional fragment thereof from a solid dosage form in a specific part of the gastrointestinal tract within a defined time window is particularly desirable for lower gastrointestinal tract diseases, in particular ICPI-induced colitis, ICPI-induced small intestinal colitis, ICPI-induced diarrhea and IBD. However, targeted release of an antibody or a functional fragment thereof from a solid dosage form in a specific part of the gastrointestinal tract within a defined time window can also be very challenging.

[0008] Therefore, there is a need for a solid oral dosage form comprising a therapeutic antibody or a functional fragment thereof, preferably specific for tumor necrosis factor alpha (TNFa), for release in a defined part of the gastrointestinal tract, in particular the lower gastrointestinal tract, thereby ensuring targeted release within a defined time window. SUMMARY

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

[0010] The inventors have surprisingly found that relying on the sustained release layer alone does not provide consistent results with respect to the sustained release of the antibody from the reservoir layer. Surprisingly, only in combination with the final outer delayed release layer a consistent and sufficiently high release rate is achieved (e.g. about 80% of the antibody is released within 26 hours in a release test). This is surprising as the delayed release layer should only prevent drug release until the pH trigger condition occurs. Therefore, the final solid oral dosage form found by the inventors works due to the combined effect of the layers and the combination of carefully selected and calibrated components in the different layers enabling the targeted release of the antibody or a functional fragment thereof in the desired manner. It has been found that an advantageous release profile can be obtained when the delayed release layer comprises an anionic polymer and the sustained release layer comprises a cationic polymer. Furthermore, the formulation of the present invention proved to be stable for 12 months. Surprisingly, even after one year of storage at 25°C / 60% RH the antibody activity remained stable.

[0011] The solid oral dosage form of the present application prevents the release of the antibody or functional fragment thereof before the target site in the gastrointestinal (Gl) tract of the patient. Thus, the solid oral dosage form advantageously ensures a controlled release and sustained release from the solid oral dosage form starting in the lower part of the gastrointestinal tract, particularly preferably in the terminal ileum or ileocolonic region, and within a well-defined time period, e.g. over the course of a day, ensuring that a major portion of the antibody or functional fragment thereof is released from the solid oral dosage form in the target region of the gastrointestinal tract and before its passage through the anus. Thus, the solid oral dosage form ensures that the optimal amount of the antibody or functional fragment thereof in active form can be released from the solid oral dosage form in a controlled manner. The solid oral dosage form is preferably prepared by drug layering using a carefully selected combination of excipients to ensure a rapid and easy preparation of the solid oral dosage form while maintaining the stability and activity of the antibody or functional fragment thereof.

[0012] Thus, the present application provides a novel solid oral dosage form comprising an antibody or functional fragment thereof, preferably specific for TNFα, as active agent in a reservoir layer (2) covering an inert core unit (1), a sustained release layer (3) covering the reservoir layer and a delayed release layer (4) covering the sustained release layer, thereby ensuring that the solid oral dosage form is capable of starting at a defined location in the lower gastrointestinal tract, achieving a carefully calibrated delayed release and sustained release. The present application relates to the subject matter defined in items 1 to 131 below: [1] A solid oral dosage form, the solid oral dosage form comprising: i) an inert core unit (1); ii) a reservoir layer (2) covering the inert core unit (1) and comprising an antibody or functional fragment thereof as active agent; and optionally a stabilizer, a buffer and / or a polymeric binder; iii) a sustained release layer (3) covering the reservoir layer (2) and comprising at least one cationic polymer; and optionally a plasticizer and / or an anti-tacking agent; and iv) a delayed release layer (4) covering the sustained release layer (3) and comprising at least one anionic polymer and optionally a plasticizer.

[0013] [2] A solid oral dosage form, the solid oral dosage form comprising: i) an inert core unit (1); ii) a reservoir layer (2) covering the inert core unit (1) and comprising an antibody or functional fragment thereof as active agent; a stabilizer; a buffer; and a polymeric binder; iii) a sustained release layer (3) covering the reservoir layer (2) and comprising at least one cationic polymer; a plasticizer; and an anti-tacking agent; and iv) a delayed release layer (4) covering the sustained release layer (3) and comprising at least one anionic polymer and a plasticizer.

[0014] [3] The solid dosage form according to item 1 or 2, wherein the at least one anionic polymer is selected from the group consisting of: a polymer comprising carboxylic acid groups; 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.

[0015] [4] The solid dosage form according to any one of items 1 to 3, wherein the at least one cationic polymer is selected from the group consisting of: chitosan; cellulose; ammonio methacrylate copolymer; poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1 :2:0.1; poly(2-methacryloyl-N,N-dimethylaminoethyl ester); poly-L-lysine; polyaziridine; poly(amidoamine).

[0016] [5] A solid oral dosage form, comprising: i) an inert core unit (1); ii) a reservoir layer (2) covering the inert core unit (1) and comprising as active agent an antibody or a functional fragment thereof, preferably specific for tumor necrosis factor alpha (TNFa); a stabilizer, preferably sucrose; a buffer; and a polymeric binder, preferably hydroxypropylmethylcellulose (HPMC); iii) a sustained release layer (3) covering reservoir layer (2) and comprising ammonio methacrylate copolymer, preferably poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1 :2:0.1; a plasticizer; and an anti-tacking agent; and iv) a delayed release layer (4) covering the 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 combinations thereof, preferably poly(methacrylic acid-methyl methacrylate) 1 :2; an anti-tacking agent, preferably glycerol monostearate (GMS); and a plasticizer, preferably triethyl citrate (TEC).

[0017] [6] The solid oral dosage form according to any one of the preceding items, wherein the solid oral dosage form is a spheroid, a granule, a bead, a sphere, a microsphere, a tablet or a microtablet, preferably a spheroid.

[0018] [7] The solid oral dosage form according to any one of the preceding items, which is gastro-resistant.

[0019] [8] The solid oral dosage form according to any one of the preceding items, which is used for targeted release of the antibody or functional fragment thereof starting in the terminal ileum, in the ileocolic region, in the ascending colon, or in the transverse colon, preferably in the terminal ileum, in the ileocolic region, or in the ascending colon, more preferably in the terminal ileum or in the ileocolic region.

[0020] [9] The solid oral dosage form according to any one of the preceding items, which is used for targeted release of the antibody or functional fragment thereof in the terminal ileum, in the ileocolic region, in the ascending colon, in the transverse colon, and / or in the sigmoid colon.

[0021]

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

[0022]

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

[0023]

[12] The solid oral dosage form according to any one of the preceding items, wherein the inert core unit (1) comprises as a major component a monosaccharide, a disaccharide, an oligosaccharide, a polysaccharide, silicon dioxide, tartaric acid, calcium carbonate, or a combination thereof.

[0024]

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

[0025]

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

[0026]

[15] The solid oral dosage form according to any one of items 1 to 13, wherein the inert core unit (1) comprises or consists of a pellet, e.g. a spheroid, and optionally a seal coat covering the spheroid, the seal coat preferably consisting of a water-insoluble material.

[0027]

[16] The solid oral dosage form according to any one of the preceding items, wherein the inert core unit (1) comprises as a major component or as the only component a monosaccharide, a disaccharide, an oligosaccharide, a polysaccharide, silicon dioxide, tartaric acid, or a combination thereof.

[0028]

[17] The solid oral dosage form according to any one of the preceding items, wherein the inert core unit (1) is preferably a spheroid and comprises or consists of microcrystalline cellulose, sucrose, starch, mannitol, calcium carbonate, silicon dioxide, tartaric acid, lactose, carboxymethylcellulose, croscarmellose sodium or combinations thereof.

[0029]

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

[0030]

[19] The solid oral dosage form according to any one of the preceding items, wherein the inert core unit (1) is pharmaceutically inactive.

[0031]

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

[0032]

[21] The solid oral dosage form according to any one of the preceding items, wherein the inert core unit (1) is a spheroid 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, even more preferably at least 0.95.

[0033]

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

[0034]

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

[0035]

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

[0036]

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

[0037]

[26] The solid oral dosage form according to any of the preceding items, wherein the stabilizer in the reservoir layer (2) is selected from the group consisting of: 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.

[0038]

[27] The solid oral dosage form according to any of the preceding items, wherein the buffering agent (i.e. one or more buffering salts and / or free bases) in the reservoir layer (2) is selected from the group consisting of: L-histidine buffer, citrate buffer, hydroxymethylamino methane (TRIS) buffer, succinate buffer, phosphate buffer, acetate buffer or their salts, 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.

[0039]

[28] The solid oral dosage form according to any of the preceding items, wherein the buffering agent (i.e. buffering salts and / or free bases) in the reservoir layer (2) comprises or consists of: L-histidine, preferably L-histidine monohydrochloride and / or free base.

[0040]

[29] The solid oral dosage form according to any of the preceding items, wherein the polymeric binder in the reservoir layer (2) is selected from; hydroxypropyl methylcellulose (HPMC); methylcellulose (MC); polyvinylpyrrolidone (PVP); polyvinyl alcohol (PVA); hydroxypropyl cellulose (HPC); polyethylene glycol poly(vinyl alcohol) graft copolymer (e.g. Kollidon VA 64®); and combinations thereof; preferably HPMC or MC; more preferably HPMC. ® IR); and combinations thereof; preferably HPMC or MC; more preferably HPMC.

[0041]

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

[0042]

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

[0043]

[32] The solid oral dosage form according to any one of the preceding items, wherein the reservoir layer (2) comprises an anti-tacking agent.

[0044]

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

[0045]

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

[0046]

[35] The solid oral dosage form according to any one of the preceding items, wherein the reservoir layer (2) comprises a surfactant, preferably a non-ionic surfactant.

[0047]

[36] The solid oral 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.

[0048]

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

[0049]

[38] The solid oral dosage form according to any one of the preceding items, wherein the reservoir layer (2) comprises or consists of: as active agent, preferably an antibody or a functional fragment thereof having specificity for TNFa; sucrose; L-histidine (salts and / or free base), preferably L-histidine monohydrochloride and / or free base; hypromellose (HPMC), preferably hypromellose 2910 2.6 mPas to 3.6 mPas; mesoporous silica; polysorbate 80 and residual water.

[0050]

[39] The solid oral dosage form according to any of the preceding items, wherein the solid oral dosage form comprises 0.05 to 30 weight-%, preferably 0.1 to 25 weight-%, more preferably 0.1 to 20 weight-%, even more preferably 0.2 to 20 weight-%, even more preferably 0.2 to 15 weight-%, even more preferably 0.5 to 12 weight-%, even more preferably 0.5 to 10 weight-%, even more preferably 0.8 to 12 weight-%, even more preferably 8 to 12 weight-%, even more preferably 8 to 10 weight-%, for example about 9.5 weight-% of the antibody or functional fragment thereof preferably specific for TNFa.

[0051]

[40] The solid oral dosage form according to any of the preceding items, wherein the reservoir layer (2) comprises: 0.2 to 75 weight-% of the antibody or functional fragment thereof, 0.5 to 65 weight-% of the binder, 2 to 80 weight-% of the sucrose, 0.1 to 10 weight-% of L-histidine (salt and / or free base) and optionally 0.05 to 10 weight-% of further buffer, 0.2 to 15 weight-% of the anti-tacking agent, 0.01 to 1 weight-% of the surfactant and / or up to 10 weight-% of water, relative to the total weight of the reservoir layer; preferably 1 to 45 weight-% of the antibody or functional fragment thereof, 2 to 35 weight-% of the binder, 10 to 70 weight-% of the sucrose, 0.2 to 5 weight-% of L-histidine and optionally 0.1 to 4 weight-% of further buffer, 1 to 5 weight-% of the anti-tacking agent, 0.05 to 0.5 weight-% of the surfactant and / or up to 7 weight-% of water, relative to the total weight of the reservoir layer; more preferably 10 to 35 weight-% of the antibody or functional fragment thereof, 10 to 30 weight-% of the binder, 30 to 60 weight-% of the sucrose, 0.3 to 4 weight-% of L-histidine and optionally 0.2 to 3 weight-% of further buffer, 1.5 to 3 weight-% of the anti-tacking agent, 0.1 to 0.3 weight-% of the surfactant and / or up to 6 weight-% of water, relative to the total weight of the reservoir layer; even more preferably 25 to 35 weight-% of the antibody or functional fragment thereof, 15 to 25 weight-% of the binder, 40 to 55 weight-% of the sucrose, 0.4 to 3 weight-% of L-histidine and optionally 0.5 to 2.5 weight-% of further buffer, 1.5 to 2.5 weight-% of the anti-tacking agent, 0.2 to 0.3 weight-% of the surfactant and / or up to 5 weight-% of water, relative to the total weight of the reservoir layer.

[0052]

[41] A solid oral dosage form according to any one of the preceding items, wherein the solid oral dosage form comprises or is composed of the following: a) In this inert core unit (1), microcrystalline cellulose; and / or b) In this reservoir layer (2), preferably an antibody or its functional fragment that is specific to TNFα; sucrose; L-histidine, preferably L-histidine monohydrochloride and / or free base; hydroxypropyl methylcellulose (HPMC), preferably hydroxypropyl methylcellulose 29102.6 mPas to 3.6 mPas; mesoporous silica and / or polysorbate 80; and / or c) In this sustained-release layer (3), 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) In this delayed-release layer (4), poly(methyl methacrylate) 1:2, TEC, polysorbate 80 and / or glyceryl monostearate (GMS); and / or e) Residual water in the inert core unit and / or any layer.

[0053]

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

[0054]

[43] A solid oral dosage form according to any one of the preceding items, wherein the inert core unit comprises 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, even more preferably 25% to 30% by weight, relative to the total weight of the solid oral dosage form.

[0055]

[44] The solid oral dosage form according to any of the preceding items, wherein the reservoir layer (2) comprises 0.05 to 30 wt% of the antibody or functional fragment thereof, 0.03 to 30 wt% of the binder, 0.1 to 40 wt% of the sucrose, 0.005 to 5 wt% of L-histidine (salt and / or free base) and optionally 0.001 to 5 wt% of further buffering agents, 0.005 to 8 wt% of the anti-tacking agent and / or 0.0005 to 2 wt% of the surfactant; preferably 0.1 to 20 wt% of the antibody or functional fragment thereof, 0.1 to 25 wt% of the binder, 0.5 to 35 wt% of the sucrose, 0.01 to 3 wt% of L-histidine and optionally 0.01 to 3 wt% of further buffering agents, 0.01 to 5 wt% of the anti-tacking agent and / or 0.001 to 1 wt% of the surfactant; more preferably 0.5 to 20 wt% of the antibody or functional fragment thereof, 0.5 to 15 wt% of the binder, 1 to 25 wt% of the sucrose, 0.05 to 2 wt% of L-histidine and optionally 0.05 to 1.5 wt% of further buffering agents, 0.05 to 1.5 wt% of the anti-tacking agent and / or 0.005 to 0.3 wt% of the surfactant; even more preferably 2 to 20 wt% of the antibody or functional fragment thereof, 5 to 15 wt% of the binder, 10 to 25 wt% of the sucrose, 0.1 to 2 wt% of L-histidine and optionally 0.5 to 1.5 wt% of further buffering agents, 0.5 to 1.5 wt% of the anti-tacking agent and / or 0.05 to 0.3 wt% of the surfactant; even more preferably 8 to 12 wt% of the antibody or functional fragment thereof, 6 to 8 wt% of the binder (preferably hydroxypropyl methylcellulose (HPMC)), 15 to 18 wt% of the sucrose, 0.15 to 1 wt% of L-histidine and optionally 0.6 to 0.9 wt% of further buffering agents, 0.6 to 0.8 wt% of the anti-tacking agent (preferably mesoporous silicon dioxide) and / or 0.05 to 0.1 wt% of the surfactant (preferably polysorbate 80) relative to the total weight of the solid oral dosage form.

[0056]

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

[0057]

[46] The solid oral dosage form according to any of the preceding items, wherein the delayed release layer (4) comprises 10 to 40 wt.-%, relative to the total weight of the solid oral dosage form, of poly(methacrylic acid-methyl methacrylate) 1 :2, 0.5 to 10 wt.-% of a plasticizer, 0.1 to 3.5 wt.-% of a surfactant and / or 0.5 to 10 wt.-% of an anti-tacking agent (preferably glycerol monostearate (GMS)); preferably 15 to 35 wt.-% of poly(methacrylic acid-methyl methacrylate) 1 :2, 1 to 5 wt.-% of a plasticizer, 0.2 to 2 wt.-% of a surfactant and / or 1 to 5 wt.-% of an anti-tacking agent (preferably glycerol monostearate (GMS)); more preferably 18 to 30 wt.-% of poly(methacrylic acid-methyl methacrylate) 1 :2, 1.5 to 3 wt.-% of a plasticizer, 0.5 to 1.3 wt.-% of a surfactant and / or 1.5 to 3 wt.-% of an anti-tacking agent (preferably glycerol monostearate (GMS)); even more preferably 21 to 26 wt.-% of poly(methacrylic acid-methyl methacrylate) 1 :2, 2.0 to 2.6 wt.-% of a plasticizer, 0.7 to 1.1 wt.-% of a surfactant and / or 2.0 to 2.6 wt.-% of an anti-tacking agent (preferably glycerol monostearate (GMS)).

[0058]

[47] The solid oral dosage form according to any of the preceding items, comprising at most 7 wt.-%, preferably at most 6 wt.-%, more preferably at most 5 wt.-%, e.g. 5 wt.-% of water, relative to the total weight of the solid oral dosage form, in the inert core unit and / or any layer.

[0059]

[48] The solid oral dosage form according to any one of items 1 to 41, wherein the solid oral dosage form comprises or consists of, relative to the total weight of the solid oral dosage form: a) in the inert core unit (1), 5 to 75% by weight, preferably 15 to 65% by weight, more preferably 20 to 60% by weight, even more preferably 25 to 30% by weight, of microcrystalline cellulose; and / or b) in the reservoir layer (2), 0.05 to 30% by weight of the antibody or functional fragment thereof, 0.03 to 30% by weight of the 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 the anti-tacking agent and / or 0.0005 to 2% by weight of the surfactant; preferably 0.1 to 20% by weight of the antibody or functional fragment thereof, 0.1 to 25% by weight of the 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 buffering agents, 0.01 to 5% by weight of the anti-tacking agent and / or 0.001 to 1% by weight of the surfactant; more preferably 0.5 to 20% by weight of the antibody or functional fragment thereof, 0.5 to 15% by weight of the binder, 1 to 25% by weight of sucrose, 0.05 to 2% by weight of L-histidine and optionally 0.05 to 1.5% by weight of other buffering agents, 0.05 to 1.5% by weight of the anti-tacking agent and / or 0.005 to 0.3% by weight of the surfactant; even more preferably 2 to 20% by weight of the antibody or functional fragment thereof, 5 to 15% by weight of the binder, 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 buffering agents, 0.5 to 1.5% by weight of the anti-tacking agent and / or 0.05 to 0.3% by weight of the surfactant; even more preferably 8 to 12% by weight of the antibody or functional fragment thereof, 6 to 8% by weight of the binder (preferably hydroxypropyl methylcellulose (HPMC)), 15 to 18% by weight of sucrose, 0.15 to 1% by weight of L-histidine and optionally 0.6 to 0.9% by weight of other buffering agents, 0.6 to 0.8% by weight of mesoporous silica and / or 0.05 to 0.1% by weight of polysorbate 80; and / or c) In the sustained-release layer (3), 1% to 10% by weight of ammonium methacrylate copolymer, 0.1% to 5% by weight of plasticizer and / or 0.05% to 7% by weight of anti-sticking agent; preferably 3% to 6% by weight of ammonium methacrylate copolymer, 0.2% to 2% by weight of plasticizer and / or 0.1% to 3% by weight of anti-sticking agent; more preferably 3.3% to 4.5% by weight of ammonium methacrylate copolymer, 0.5% to 1.5% by weight of plasticizer and / or 0.2% to 1% by weight of anti-sticking agent; even more preferably 3.6% to 4.2% by weight of poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1:2:0.1 (e.g., Eudragit). ® RS 30D), 0.6% to 1% triethyl citrate (TEC) and / or 0.3% to 0.5% mesoporous silica; and / or d) In the delayed release layer (4), there are 10% to 40% by weight of poly(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-sticking agent (preferably glyceryl monostearate (GMS)); preferably 15% to 35% by weight of poly(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-sticking agent (preferably glyceryl monostearate (GMS)). More preferably, 18% to 30% by weight of poly(methyl methacrylate) 1:2, 1.5% to 3% by weight of plasticizer, 0.5% to 1.3% by weight of surfactant and / or 1.5% to 3% by weight of anti-sticking agent (preferably glyceryl monostearate (GMS)); even more preferably, 21% to 26% by weight of poly(methyl methacrylate) 1:2, 2.0% to 2.6% by weight of plasticizer, 0.7% to 1.1% by weight of surfactant and / or 2.0% to 2.6% by weight of glyceryl monostearate (GMS); and / or e) up to 5% by weight, for example 5% by weight, of water in the inert core unit and / or any layer.

[0060]

[49] The solid oral dosage form according to any one of the preceding items, wherein the sustained-release layer (3) contains no other sustained-release polymers other than ammonium methacrylate copolymer; preferably poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1:2:0.1; poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1:2:0.2 (e.g., Eudragit)® RL 30D); or a combination thereof, and preferably does not contain other release- retarding polymers.

[0061]

[50] The solid oral dosage form according to any one of the preceding items, wherein the release- retarding layer (3) comprises poly(ethyl acrylate-methyl methacrylate- trimethylammonium ethyl methacrylate chloride) 1 :2:0.1, and preferably does not contain other release-retarding polymers.

[0062]

[51] The solid oral dosage form according to any one of the preceding items, wherein the plasticizer in the release-retarding 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).

[0063]

[52] The solid oral dosage form according to any one of the preceding items, wherein the anti-tacking agent in the release-retarding layer (3) is mesoporous silica, colloidal silica, stearic acid, magnesium stearate, glycerol monostearate (GMS), or talc, preferably mesoporous silica.

[0064]

[53] The solid oral dosage form according to any one of the preceding items, wherein the solid oral dosage form comprises 0.5 to 15 weight %, preferably 1 to 10 weight %, more preferably 3 to 5 weight %, even more preferably 3.5 to 4.5 weight %, even more preferably 3.8 to 4.1 weight %, for example 4 weight % of the ammonio methacrylate copolymer, preferably poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1 :2:0.1.

[0065]

[54] The solid oral dosage form according to any one of the preceding items, wherein the release-retarding layer (3) comprises 60 to 90 weight %, preferably 65 to 85 weight %, more preferably 70 to 80 weight %, even more preferably 72 to 78 weight % of the ammonio methacrylate copolymer, preferably poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1 :2:0.1, relative to the total weight of solids (i.e. not including water) in the release-retarding layer (3).

[0066]

[55] The solid oral dosage form according to any one of the preceding items, wherein the release-retarding layer (3) comprises 2 to 40 weight %, preferably 5 to 30 weight %, more preferably 15 to 25 weight %, even more preferably 17 to 23 weight %, even more preferably 20 weight % of the plasticizer, relative to the total weight of the ammonio methacrylate copolymer in the release-retarding layer (3).

[0067]

[56] The solid oral dosage form according to any of the preceding items, wherein the sustained release layer (3) comprises 1 to 30 weight %, preferably 2 to 25 weight %, more preferably 5 to 15 weight %, even more preferably 8 to 12 weight %, even more preferably 10 weight % of an anti-tacking agent relative to the total weight of the ammonium methacrylate copolymer in the sustained release layer (3).

[0068]

[57] The solid oral dosage form according to any of the preceding items, wherein the sustained release coating comprises 5 to 25 weight %, preferably 10 to 20 weight %, more preferably 12 to 18 weight %, even more preferably 13 to 17 weight %, even more preferably 14 to 15 weight % of a plasticizer relative to the total weight of solids (i.e. not including water) in the sustained release layer (3).

[0069]

[58] The solid oral dosage form according to any of the preceding items, wherein the sustained release coating comprises 5 to 12 weight %, preferably 6 to 9 weight %, more preferably 6 to 8.5 weight %, even more preferably 6.5 to 8.0 weight %, even more preferably 6.9 to 7.8 weight %, even more preferably 7.0 to 7.5 weight % of an anti-tacking agent relative to the total weight of solids (i.e. not including water) in the sustained release layer (3).

[0070]

[59] The solid oral dosage form according to any of the preceding items, wherein the sustained release layer (3) does not comprise a coalescence enhancer.

[0071]

[60] The solid oral dosage form according to any of items 1 to 58, wherein the sustained release layer (3) comprises a coalescence enhancer.

[0072]

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

[0073]

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

[0074]

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

[0075]

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

[0076]

[65] The solid oral dosage form according to any of the preceding items, wherein the delayed release layer (4) does not comprise a polymer that is not an enteric polymer.

[0077]

[66] The solid oral dosage form according to any of the preceding items, wherein the delayed release layer (4) does not contain other delayed release polymers in addition to 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.

[0078]

[67] The solid oral dosage form according to any 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.

[0079]

[68] The solid oral dosage form according to any 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).

[0080]

[69] The solid oral dosage form according to any of the preceding items, wherein the anti-tacking 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).

[0081]

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

[0082]

[71] The solid oral 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.

[0083]

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

[0084]

[73] The solid oral dosage form of any of the preceding items, wherein the delayed release layer (4) does not comprise a coalescence enhancer.

[0085]

[74] The solid oral dosage form of any of the preceding items, wherein the solid oral dosage form comprises 5 to 40 weight %, preferably 10 to 40 weight %, more preferably 10 to 35 weight %, even more preferably 15 to 35 weight %, even more preferably 15 to 30 weight %, even more preferably 18 to 30 weight %, even more preferably 20 to 30 weight %, for example 22 to 25 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).

[0086]

[75] The solid oral dosage form of any of the preceding items, wherein the delayed release layer (4) comprises 65 to 95 weight %, preferably 70 to 90 weight %, more preferably 75 to 85 weight %, for example about 80 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) relative to the total weight of solids (i.e. not including solvents) in the delayed release layer (4).

[0087]

[76] The solid oral dosage form of any of the preceding items, wherein the delayed release layer (4) comprises 1 to 30 weight %, preferably 2 to 25 weight %, more preferably 5 to 15 weight %, even more preferably 8 to 12 weight %, even more preferably 10 weight % of plasticizer relative to the total weight of delayed release polymers in the delayed release layer (4).

[0088]

[77] The solid oral dosage form of any of the preceding items, wherein the delayed release layer (4) comprises 1 to 30 weight %, preferably 2 to 25 weight %, more preferably 5 to 15 weight %, even more preferably 8 to 12 weight %, even more preferably 10 weight % of anti-tacking agent relative to the total weight of delayed release polymers in the delayed release layer (4).

[0089]

[78] The solid oral dosage form according to any of the preceding items, wherein the delayed release layer (4) comprises 0.1 to 15 weight %, preferably 0.5 to 10 weight %, more preferably 1 to 6 weight %, even more preferably 2 to 5 weight %, even more preferably 3 to 4.5 weight %, even more preferably 3.5 to 4 weight %, even more preferably about 3 to 3.2 weight % of surfactant relative to the total weight of delayed release polymer in the delayed release layer (4).

[0090]

[79] The solid oral dosage form according to any of the preceding items, wherein the delayed release layer (4) comprises 1 to 25 weight %, preferably 4 to 15 weight %, more preferably 5 to 12 weight %, even more preferably 6 to 10 weight %, even more preferably 7 to 9 weight %, even more preferably about 8 weight % of plasticizer relative to the total weight of solids (i.e. not including solvent) in the delayed release layer (4).

[0091]

[80] The solid oral dosage form according to any of the preceding items, wherein the delayed release layer (4) comprises 1 to 25 weight %, preferably 4 to 15 weight %, more preferably 5 to 12 weight %, even more preferably 6 to 10 weight %, even more preferably 7 to 9 weight %, even more preferably about 8 weight %, even more preferably about 7.5 weight % of anti-tacking agent relative to the total weight of solids (i.e. not including solvent) in the delayed release layer (4).

[0092]

[81] The solid oral dosage form according to any of the preceding items, wherein the delayed release layer (4) comprises 0.1 to 15 weight %, preferably 0.5 to 10 weight %, more preferably 1 to 5 weight %, even more preferably 2 to 4 weight %, even more preferably 2.5 to 3.5 weight %, even more preferably 3 to 3.5 weight %, even more preferably about 3 to 3.2 weight % of surfactant relative to the total weight of solids (i.e. not including solvent) in the delayed release layer (4).

[0093]

[82] The solid oral dosage form according to any of the preceding items, wherein the solid dosage form comprises 7 mg / cm 2 to 13 mg / cm 2 , preferably 8 mg / cm 2 to 12 mg / cm 2 , more preferably 9 mg / cm 2 to 11.5 mg / cm 2 , even more preferably about 9.5 mg / cm 2 or about 11.50 mg / cm2 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).

[0094]

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

[0095]

[84] The solid oral dosage form according to any one of the preceding items, wherein the solid oral dosage form comprises an amount of the antibody or functional fragment thereof that allows for administration of a therapeutically effective dose of the antibody or functional fragment thereof in a single unit dose.

[0096]

[85] The solid oral dosage form according to any one of the preceding items, wherein the solid oral dosage form (relative to the total weight of the solid oral dosage form) comprises or consists of: a) in the inert core unit (1 ), 57.5 to 58.2 wt.% microcrystalline cellulose; preferably 57.65 to 58.05 wt.% microcrystalline cellulose (e.g. cellets 700); b) in the reservoir layer (2), 0.65 to 0.95 wt.% antibody or functional fragment thereof, 0.44 to 74 wt.% hydroxypropyl methylcellulose (HPMC) (e.g. Pharmacoat 603), 1.24 to 1.60 wt.% sucrose, 0.06 to 0.10 wt.% L-histidine (e.g. L-histidine and / or L-histidine HCL buffer salt solid), 0.04 to 0.08 wt.% mesoporous silica (e.g. Syloid 244FP having an average particle size of 3.4 to 3.6 pm and / or an average pore volume of 1.58 to 1.62 cm 3 / g), and 0.006 to 0.014 wt.% polysorbate 80; preferably 0.75 to 0.85 wt.% antibody or functional fragment thereof, 0.54 to 64 wt.% hydroxypropyl methylcellulose (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 buffer salt solid), 0.05 to 0.07 wt.% mesoporous silica (e.g. Syloid 244FP having an average particle size of 3.4 to 3.6 pm and / or an average pore volume of 1.58 to 1.62 cm 3 / g), and 0.006 to 0.014 wt.% polysorbate 80; preferably 0.75 to 0.85 wt.% antibody or functional fragment thereof, 0.54 to 64 wt.% hydroxypropyl methylcellulose (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 buffer salt solid), 0.05 to 0.07 wt.% mesoporous silica (e.g. Syloid 244FP having an average particle size of 3.4 to 3.6 pm and / or an average pore volume of 1.58 to 1.62 cm 3 / g), and 0.006 to 0.014 wt.% polysorbate 80; preferably 0.75 to 0.85 wt.% antibody or functional fragment thereof, 0.54 to 64 wt.% hydroxypropyl methylcellulose (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 buffer salt solid), 0.05 to 0.07 wt.% mesoporous silica (e.g. Syloid 244FP having an average particle size of 3.4 to 3.6 pm and / or an average pore volume of 1.58 to 1.62 cm 3an average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g., Syloid 244FP); preferably 3.9 weight % to 4.1 weight % of poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1 :2:0.1 (e.g., Eudragit® RS PO), 0.75 weight % to 0.85 weight % of triethyl citrate (TEC), and 0.35 weight % to 0.45 weight % of mesoporous silica (e.g., having an average particle size of 3.4 pm to 3.6 pm and / or an average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g., Syloid 244FP); c) in the sustained release layer (3), 3.8 weight % to 4.2 weight % of poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1 :2:0.1 (e.g., Eudragit® L30D-55), 0.65 weight % to 0.95 weight % of triethyl citrate (TEC), and 0.30 weight % to 0.50 weight % of mesoporous silica (e.g., having an average particle size of 3.4 pm to 3.6 pm and / or an average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g., Syloid 244FP); ® RS solids), 0.65 weight % to 0.95 weight % of triethyl citrate (TEC), and 0.30 weight % to 0.50 weight % of mesoporous silica (e.g., having an average particle size of 3.4 pm to 3.6 pm and / or an average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g., Syloid 244FP); 3 RS solids), 0.65 weight % to 0.95 weight % of triethyl citrate (TEC), and 0.30 weight % to 0.50 weight % of mesoporous silica (e.g., having an average particle size of 3.4 pm to 3.6 pm and / or an average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g., Syloid 244FP); 3 RS solids), 0.65 weight % to 0.95 weight % of triethyl citrate (TEC), and 0.30 weight % to 0.50 weight % of mesoporous silica (e.g., having an average particle size of 3.4 pm to 3.6 pm and / or an average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g., Syloid 244FP); ® RS solids), 0.65 weight % to 0.95 weight % of triethyl citrate (TEC), and 0.30 weight % to 0.50 weight % of mesoporous silica (e.g., having an average particle size of 3.4 pm to 3.6 pm and / or an average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g., Syloid 244FP); 3 RS solids), 0.65 weight % to 0.95 weight % of triethyl citrate (TEC), and 0.30 weight % to 0.50 weight % of mesoporous silica (e.g., having an average particle size of 3.4 pm to 3.6 pm and / or an average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g., Syloid 244FP); 3 RS solids), 0.65 weight % to 0.95 weight % of triethyl citrate (TEC), and 0.30 weight % to 0.50 weight % of mesoporous silica (e.g., having an average particle size of 3.4 pm to 3.6 pm and / or an average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g., Syloid 244FP); d) in the delayed release layer (4), 23.1 weight % to 23.7 weight % of poly(methacrylic acid-methyl methacrylate) 1 :2 (e.g., Eudragit® S100 solids), 2.19 weight % to 2.49 weight % of triethyl citrate (TEC), 0.79 weight % to 1.09 weight % of polysorbate 80, and 2.19 weight % to 2.49 weight % of glyceryl monostearate (GMS); preferably 23.25 weight % to 23.55 weight % of poly(methacrylic acid-methyl methacrylate) 1 :2 (e.g., Eudragit® S100 solids), 2.29 weight % to 2.39 weight % of triethyl citrate (TEC), 0.89 weight % to 0.99 weight % of polysorbate 80, and 2.29 weight % to 2.39 weight % of glyceryl monostearate (GMS); ® RS solids), 0.65 weight % to 0.95 weight % of triethyl citrate (TEC), and 0.30 weight % to 0.50 weight % of mesoporous silica (e.g., having an average particle size of 3.4 pm to 3.6 pm and / or an average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g., Syloid 244FP); ® RS solids), 0.65 weight % to 0.95 weight % of triethyl citrate (TEC), and 0.30 weight % to 0.50 weight % of mesoporous silica (e.g., having an average particle size of 3.4 pm to 3.6 pm and / or an average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g., Syloid 244FP); e) 4.7 weight % to 5.3 weight % of water in the inert core unit and / or any layer; preferably 4.9 weight % to 5.1 weight % of water.

[0097]

[86] The solid oral dosage form of any one of items 1 to 84, wherein the solid oral dosage form comprises or consists of, relative to the total weight of the solid oral dosage form: 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 (e.g. cellets 700); b) in the reservoir layer (2), 9.23 to 9.73% by weight of the antibody or functional fragment thereof, 6.7 to 7.1% by weight of hypromellose (HPMC) (e.g. Pharmacoat 603), 16.62 to 17.12% by weight of sucrose, 0.79 to 1.09% by weight of L-histidine (e.g. L-histidine and / or L-histidine HCL buffer salt solid), 0.54 to 0.84% by weight of mesoporous silica (e.g. Syloid 244FP having an average particle size of 3.4 to 3.6 pm and / or an average pore volume of 1.58 to 1.62 cm3 / g) and 0.06 to 0.10% by weight of polysorbate 80; preferably 9.38 to 9.58% by weight of the antibody or functional fragment thereof, 6.8 to 7.0% by weight of hypromellose (HPMC) (e.g. Pharmacoat 603), 16.72 to 17.02% by weight of sucrose, 0.89 to 0.99% by weight of L-histidine (e.g. L-histidine and / or L-histidine HCL buffer salt solid), 0.64 to 0.74% by weight of mesoporous silica (e.g. Syloid 244FP having an average particle size of 3.4 to 3.6 pm and / or an average pore volume of 1.58 to 1.62 cm3 / g) and 0.07 to 0.09% by weight of polysorbate 80; 3 3 3 3 c) in the sustained release layer (3), 3.74 to 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 to 0.94% by weight of triethyl citrate (TEC) and 0.29 to 0.49% by weight of mesoporous silica (e.g. Syloid 244FP having an average particle size of 3.4 to 3.6 pm and / or an average pore volume of 1.58 to 1.62 cm3 / g); ® 3 3 ​​​​​​poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1 :2:0.1 (e.g., Eudragit® L30D-55) at 3.84% to 4.04% by weight; preferably 3.94% to 4.04% by weight of poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1 :2:0.1 (e.g., Eudragit® L30D-55) at 3.94% to 4.04% by weight; and / or ® RS solid), 0.74% to 0.84% by weight of triethyl citrate (TEC), and 0.34% to 0.44% by weight of mesoporous silica (e.g., Syloid® W6 with an average particle size of 3.4 pm to 3.6 pm and / or an average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g., Syloid 244FP); preferably 0.74% to 0.84% by weight of triethyl citrate (TEC) and 0.34% to 0.44% by weight of mesoporous silica (e.g., Syloid® W6 with an average particle size of 3.4 pm to 3.6 pm and / or an average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g., Syloid 244FP). 3 1.62 cm3 / g to 1.72 cm3 / g, e.g., Syloid 244FP); preferably 0.74% to 0.84% by weight of triethyl citrate (TEC) and 0.34% to 0.44% by weight of mesoporous silica (e.g., Syloid® W6 with an average particle size of 3.4 pm to 3.6 pm and / or an average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g., Syloid 244FP). 3 1.62 cm3 / g to 1.72 cm3 / g, e.g., Syloid 244FP); preferably 0.74% to 0.84% by weight of triethyl citrate (TEC) and 0.34% to 0.44% by weight of mesoporous silica (e.g., Syloid® W6 with an average particle size of 3.4 pm to 3.6 pm and / or an average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g., Syloid 244FP). d) in the delayed release layer (4), 22.63% to 23.23% by weight of poly(methacrylic acid-methyl methacrylate) 1 :2 (e.g., Eudragit® S 100 solid), 2.14% to 2.44% by weight of triethyl citrate (TEC), 0.77% to 0.107% by weight of polysorbate 80, and 2.14% to 2.44% by weight of glyceryl monostearate (GMS); preferably 22.78% to 23.08% by weight of poly(methacrylic acid-methyl methacrylate) 1 :2 (e.g., Eudragit® S 100 solid), 2.14% to 2.44% by weight of triethyl citrate (TEC), 0.77% to 0.107% by weight of polysorbate 80, and 2.14% to 2.44% by weight of glyceryl monostearate (GMS). ® S 100 solid), 2.14% to 2.44% by weight of triethyl citrate (TEC), 0.77% to 0.107% by weight of polysorbate 80, and 2.14% to 2.44% by weight of glyceryl monostearate (GMS); preferably 22.78% to 23.08% by weight of poly(methacrylic acid-methyl methacrylate) 1 :2 (e.g., Eudragit® S 100 solid), 2.14% to 2.44% by weight of triethyl citrate (TEC), 0.77% to 0.107% by weight of polysorbate 80, and 2.14% to 2.44% by weight of glyceryl monostearate (GMS). ® S 100 solid), 2.14% to 2.44% by weight of triethyl citrate (TEC), 0.77% to 0.107% by weight of polysorbate 80, and 2.14% to 2.44% by weight of glyceryl monostearate (GMS); preferably 22.78% to 23.08% by weight of poly(methacrylic acid-methyl methacrylate) 1 :2 (e.g., Eudragit® S 100 solid), 2.14% to 2.44% by weight of triethyl citrate (TEC), 0.77% to 0.107% by weight of polysorbate 80, and 2.14% to 2.44% by weight of glyceryl monostearate (GMS). e) 4.03% to 4.63% by weight of water in the inert core unit and / or any layer; preferably 4.23% to 4.43% by weight of water.

[0098]

[87] The solid oral dosage form of any one of items 1 to 84, wherein the solid oral dosage form comprises or consists of: 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 this reservoir layer (2), there are 9.0% to 9.5% by weight of antibody or its functional fragment, 6.54% to 6.94% by weight of hydroxypropyl methylcellulose (HPMC) (e.g., Pharmacoat 603), 16.23% to 16.73% by weight of sucrose, 0.76% to 1.06% by weight of L-histidine (e.g., L-histidine and / or L-histidine HCl buffer salt solids), and 0.52% to 0.82% by weight of mesoporous silica (e.g., having an average particle size of 3.4 μm to 3.6 μm and / or 1.58 cm). 3 / g to 1.62cm 3 The composition includes: an average pore volume of / g (e.g., Syloid 244FP); 0.06 wt% to 0.10 wt% of polysorbate 80; preferably 9.16 wt% to 9.36 wt% of antibody or its functional fragment; 6.64 wt% to 6.84 wt% of hydroxypropyl methylcellulose (HPMC) (e.g., Pharmacoat 603); 16.33 wt% to 16.63 wt% of sucrose; 0.86 wt% to 0.96 wt% of L-histidine (e.g., L-histidine and / or L-histidine HCl buffer salt solids); and 0.62 wt% to 0.72 wt% of mesoporous silica (e.g., having an average particle size of 3.4 μm to 3.6 μm and / or 1.58 cm⁻¹). 3 / g to 1.62cm 3 / g average pore volume, e.g., Syloid 244FP) and 0.07 wt% to 0.09 wt% polysorbate 80; c) In the sustained-release layer (3), 3.6% to 4.0% by weight of poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1:2:0.1 (e.g., Eudragit) ® RS solids), 0.61 wt% to 0.91 wt% triethyl citrate (TEC), and 0.28 wt% to 0.48 wt% mesoporous silica (e.g., with an average particle size of 3.4 μm to 3.6 μm and / or 1.58 cm⁻¹). 3 / g to 1.62cm 3 / g average pore volume, e.g., Syloid 244FP); preferably 3.7 wt% to 3.9 wt% of poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1:2:0.1 (e.g., Eudragit). ® RS solids), 0.71 wt% to 0.81 wt% triethyl citrate (TEC), and 0.33 wt% to 0.43 wt% mesoporous silica (e.g., having an average particle size of 3.4 μm to 3.6 μm and / or 1.58 cm⁻¹). 3 / g to 1.62 cm3 / g 3 an average pore volume of 0.1 to 1.62 cm3 / g, for example Syloid 244FP); d) in the delay release layer (4), 24.5 to 25.1 wt% of poly(methacrylic acid-methyl methacrylate) 1 :2 (e.g. Eudragit® S100 solids), 2.33 to 2.63 wt% of triethyl citrate (TEC), 0.85 to 1.15 wt% of polysorbate 80, and 2.33 to 2.63 wt% of glyceryl monostearate (GMS); 24.65 to 24.95 wt% of poly(methacrylic acid-methyl methacrylate) 1 :2 (e.g. Eudragit® S100 solids), 2.43 to 2.53 wt% of triethyl citrate (TEC), 0.94 to 1.04 wt% of polysorbate 80, and 2.43 to 2.53 wt% of glyceryl monostearate (GMS); and / or ® S100 solids), 2.33 to 2.63 wt% of triethyl citrate (TEC), 0.85 to 1.15 wt% of polysorbate 80, and 2.33 to 2.63 wt% of glyceryl monostearate (GMS); 24.65 to 24.95 wt% of poly(methacrylic acid-methyl methacrylate) 1 :2 (e.g. Eudragit® S100 solids), 2.43 to 2.53 wt% of triethyl citrate (TEC), 0.94 to 1.04 wt% of polysorbate 80, and 2.43 to 2.53 wt% of glyceryl monostearate (GMS); and / or ® S100 solids), 2.33 to 2.63 wt% of triethyl citrate (TEC), 0.85 to 1.15 wt% of polysorbate 80, and 2.33 to 2.63 wt% of glyceryl monostearate (GMS); 24.65 to 24.95 wt% of poly(methacrylic acid-methyl methacrylate) 1 :2 (e.g. Eudragit® S100 solids), 2.43 to 2.53 wt% of triethyl citrate (TEC), 0.94 to 1.04 wt% of polysorbate 80, and 2.43 to 2.53 wt% of glyceryl monostearate (GMS); and / or e) 4.65 to 5.25 wt% of water in the inert core unit and / or any layer; preferably 4.85 to 5.05 wt% of water.

[0099]

[88] The solid oral dosage form of any one of items 1 to 84, wherein the solid oral dosage form comprises or consists of: a) in the inert core unit (1), 25.06 to 25.66 wt% of microcrystalline cellulose; preferably 25.21 to 25.51 wt% of microcrystalline cellulose (e.g. cellets 700); b) in the reservoir layer (2), 8.76 to 9.26 wt% of the antibody or functional fragment thereof, 6.38 to 6.78 wt% of hypromellose (HPMC) (e.g. Pharmacoat 603), 15.57 to 16.17 wt% of sucrose, 0.73 to 1.03 wt% of L-histidine (e.g. L-histidine and / or L-histidine HCL buffer salt solid), 0.51 to 0.81 wt% of mesoporous silica (e.g., having an average particle size of 3.4 to 3.6 pm and / or an average pore volume of 0.1 to 1.62 cm3 / g, for example Syloid 244FP); 3 / g to 1.62 cm3 / g 3average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g. Syloid 244FP) and 0.07 wt% to 0.09 wt% of polysorbate 80; 3 average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g. Syloid 244FP) and 0.07 wt% to 0.09 wt% of polysorbate 80; 3 average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g. Syloid 244FP) and 0.07 wt% to 0.09 wt% of polysorbate 80; c) in the sustained release layer (3), 3.48 wt% to 3.88 wt% of poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1 :2:0.1 (e.g. Eudragit® RS PO), 0.59 wt% to 0.89 wt% of triethyl citrate (TEC) and 0.27 wt% to 0.47 wt% of mesoporous silica (e.g. having an average particle size of 3.4 pm to 3.6 pm and / or an average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g. Syloid 244FP); ® average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g. Syloid 244FP) and 0.07 wt% to 0.09 wt% of polysorbate 80; 3 average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g. Syloid 244FP) and 0.07 wt% to 0.09 wt% of polysorbate 80; 3 average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g. Syloid 244FP) and 0.07 wt% to 0.09 wt% of polysorbate 80; ® average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g. Syloid 244FP) and 0.07 wt% to 0.09 wt% of polysorbate 80; 3 average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g. Syloid 244FP) and 0.07 wt% to 0.09 wt% of polysorbate 80; 3 average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g. Syloid 244FP) and 0.07 wt% to 0.09 wt% of polysorbate 80; d) in the delayed release layer (4), 25.41 wt% to 26.01 wt% of poly(methacrylic acid-methyl methacrylate) 1 :2 (e.g. Eudragit® L30D-55), 0.83 wt% to 0.93 wt% of L-histidine (e.g. L-histidine and / or L-histidine HCL buffer salt solids), 0.61 wt% to 0.71 wt% of mesoporous silica (e.g. having an average particle size of 3.4 pm to 3.6 pm and / or an average pore volume of 1.58 cm3 / g to 1.62 cm3 / g, e.g. Syloid 244FP) and 0.07 wt% to 0.09 wt% of polysorbate 80; ®S100 solids), 2.42 wt% to 2.72 wt% triethyl citrate (TEC), 0.88 wt% to 1.18 wt% polysorbate 80 and 2.42 wt% to 2.72 wt% glyceryl monostearate (GMS); 25.56 wt% to 25.86 wt% poly(methyl methacrylate) 1:2 (e.g., Eudragit) ® S100 solids), 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 glyceryl monostearate (GMS); and / or e) 4.60% to 5.2% water in the inert core unit and / or any layer; preferably 4.80% to 5.00% water.

[0100]

[89] A solid oral 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 biantibody, a triantibody, a tetraantibody, an Fc fusion protein, or a microantibody.

[0101]

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

[0102]

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

[0103]

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

[0104]

[93] The solid oral dosage form of item 92, wherein the antibody or functional fragment thereof specific for TNFa is an anti-TNFa antibody.

[0105]

[94] The solid oral dosage form of any of the preceding items, wherein the antibody or functional fragment thereof is an anti-TNFa antibody or functional fragment thereof having a TNFa binding domain comprising: (i) a V L domain, the V L domain comprises a CDR1 region having an amino acid sequence as set forth in SEQ ID NO: 1, a CDR2 region having an amino acid sequence as set forth in SEQ ID NO: 2, and a CDR3 region having an amino acid sequence as set forth in SEQ ID NO: 3; and / or (ii) a V H domain, the V H domain comprises a CDR1 region having an amino acid sequence as set forth in SEQ ID NO: 4, a CDR2 region having an amino acid sequence as set forth in SEQ ID NO: 5, and a CDR3 region having an amino acid sequence as set forth in SEQ ID NO: 6.

[0106]

[95] The solid oral dosage form of any of the preceding items, wherein the antibody or functional fragment thereof is an anti-TNFa antibody or functional fragment thereof having a TNFa binding domain comprising or consisting of: (i) a V L domain, the V L domain has an amino acid sequence identical to an amino acid sequence as set forth in SEQ ID NO: 8; and / or (ii) a V H domain, the V H domain has an amino acid sequence identical to an amino acid sequence as set forth in SEQ ID NO: 7.

[0107]

[96] The solid oral dosage form of any of items 1 to 93, wherein the antibody or functional fragment thereof is an anti-TNFa antibody or functional fragment thereof having a TNFa binding domain comprising: (i) a V L domain, the V L domain comprises a CDR1 region having an amino acid sequence as set forth in SEQ ID NO: 9, a CDR2 region having an amino acid sequence as set forth in SEQ ID NO: 10, and a CDR3 region having an amino acid sequence as set forth in SEQ ID NO: 11; and / or (ii) a V H domain, the V HThe domain comprises a CDR1 region having an amino acid sequence as set forth in SEQ ID NO: 12, a CDR2 region having an amino acid sequence as set forth in SEQ ID NO: 13, and a CDR3 region having an amino acid sequence as set forth in SEQ ID NO: 14.

[0108]

[97] The solid oral dosage form according to any one of items 1 to 93, wherein the antibody or functional fragment thereof is an anti-TNFa antibody or functional fragment thereof having a TNF a binding domain comprising or consisting of: (i) a V L domain having an amino acid sequence identical to that as set forth in SEQ ID NO: 16 or SEQ ID NO: 17; and / or (ii) a V L domain having an amino acid sequence identical to that as set forth in SEQ ID NO: 15. H domain having an amino acid sequence identical to that as set forth in SEQ ID NO: 16 or SEQ ID NO: 17; and / or (ii) a V H domain having an amino acid sequence identical to that as set forth in SEQ ID NO: 15.

[0109]

[98] The solid oral dosage form according to any one of items 1 to 93, wherein the antibody or functional fragment thereof is an anti-TNFa antibody comprising an Fc region having an amino acid sequence identical to or consisting of that as set forth 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.

[0110]

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

[0111]

[100] The solid oral dosage form according to any one of items 1 to 93, wherein the antibody or functional fragment thereof is an anti-TNFa antibody comprising or consisting of: (i) a light chain having an amino acid sequence identical to or consisting of that as set forth in SEQ ID NO: 24 or SEQ ID NO: 25; and (ii) a heavy chain having an amino acid sequence identical to or consisting of that as set forth in SEQ ID NO: 27.

[0112]

[101] The solid oral dosage form of any one of items 1 to 93, wherein the antibody or functional fragment thereof is an anti-TNFa antibody comprising or consisting of: (i) a light chain having an amino acid sequence identical to or consisting of the amino acid sequence as set forth in SEQ ID NO: 23; and (ii) a heavy chain having an amino acid sequence identical to or consisting of the amino acid sequence as set forth in SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 30.

[0113]

[102] The solid oral dosage form of any one of items 1 to 93, wherein the antibody or functional fragment thereof is an anti-TNFa antibody comprising or consisting of: (i) a light chain having an amino acid sequence identical to or consisting of the amino acid sequence as set forth in SEQ ID NO: 24 or SEQ ID NO: 25; and (ii) a heavy chain having an amino acid sequence identical to or consisting of the amino acid sequence as set forth in SEQ ID NO: 31 or SEQ ID NO: 32 or SEQ ID NO: 33.

[0114]

[103] The solid oral dosage form of any one of items 1 to 93, wherein the antibody or functional fragment thereof is an anti-TNFa antibody comprising or consisting of: (i) a light chain having an amino acid sequence identical to or consisting of the amino acid sequence as set forth in SEQ ID NO: 23; and (ii) a heavy chain having an amino acid sequence identical to or consisting of the amino acid sequence as set forth in SEQ ID NO: 34.

[0115]

[104] The solid oral dosage form of any one of items 1 to 93, wherein the antibody or functional fragment thereof is an anti-TNFa antibody comprising or consisting of: (i) a light chain having an amino acid sequence identical to or consisting of the amino acid sequence as set forth in SEQ ID NO: 24 or SEQ ID NO: 25; and (ii) a heavy chain having an amino acid sequence identical to or consisting of the amino acid sequence as set forth in SEQ ID NO: 35.

[0116]

[105] The solid oral dosage form of any one of items 1 to 91, wherein the antibody or functional fragment thereof is selected from the group consisting of: infliximab, adalimumab, etanercept, certolizumab pegol, golimumab, visilizumab, ediralizumab, anifrolumab, canakinumab, tocilizumab, ustekinumab, natalizumab, rilonacept, brodalumab, vedolizumab, and functional fragments thereof.

[0117]

[106] The solid oral dosage form according to any one of items 1 to 92, wherein the anti-TNFa antibody or functional fragment thereof is selected from the group consisting of infliximab, adalimumab, etanercept, certolizumab pegol and golimumab or functional fragments thereof.

[0118]

[107] The solid oral dosage form according to any one of the preceding items, allowing the antibody or functional fragment thereof to be released 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, most preferably at least 24 hours, when the solid oral dosage form is continuously immersed in an aqueous solution having a pH of 6.5 to 7.5, preferably about 6.8, under continuous stirring.

[0119]

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

[0120]

[109] The solid oral dosage form according to any one of the preceding items, wherein the water content in the solid oral dosage form 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, relative to the total weight of the solid oral dosage form.

[0121]

[110] The solid oral dosage form according to any one of the preceding items, wherein the fraction of the total content of the antibody or functional fragment thereof present in the solid oral dosage form as dimers and other aggregates is no more than 15%, preferably 12%, more preferably 10%, even more preferably 8%, even more preferably 7%, even more preferably 5%, even more preferably 3%.

[0122]

[111] The solid oral dosage form according to any one of the preceding items, wherein the fraction of the total content of the antibody or functional fragment thereof present in the solid oral dosage form as fragments of the full-length antibody or functional fragment thereof is no more than 15%, preferably 12%, more preferably 10%, even more preferably 8%, even more preferably 7%, even more preferably 5%, even more preferably 3%.

[0123]

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

[0124]

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

[0125]

[114] The solid oral dosage form according to any one of the preceding items, wherein the sustained release layer (3) has a fixed average thickness of 5 pm to 50 pm, preferably 10 pm to 45 pm, more preferably 15 pm to 35 pm, even more preferably 18 pm to 30 pm, even more preferably 20 pm to 30 pm, for example 24 pm or 25 pm; preferably, the thickness of the reservoir layer (2) and / or the amount of antibody or functional fragment thereof in the reservoir layer (2) is not considered.

[0126]

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

[0127]

[116] The solid oral dosage form according to any one of the preceding items, wherein the average thickness of the sustained release layer (3) is constant without considering the amount of antibody or functional fragment thereof in the solid oral dosage form and / or the thickness of the reservoir layer.

[0128]

[117] The solid oral dosage form according to any one of items 1 to 116 for the targeted local treatment of a gastrointestinal disease, preferably immune checkpoint inhibitor (ICPI)-induced colitis, ICPI-induced enterocolitis, ICPI-induced diarrhea, IBD, colorectal cancer, small intestine cancer, celiac disease, gastrointestinal infection (e.g. Clostridium difficile infection), more preferably ICPI-induced colitis, ICPI-induced enterocolitis, ICPI-induced diarrhea or IBD.

[0129]

[118] The solid oral dosage form for use according to item 117, wherein the gastrointestinal disease is IBD, preferably Crohn’s disease or ulcerative colitis.

[0130]

[119] The solid oral dosage form for use according to item 117, wherein the gastrointestinal disease is ICPI-induced colitis, ICPI-induced small bowel colitis, or ICPI-induced diarrhea, preferably ICPI-induced colitis.

[0131]

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

[0132]

[121] An oral multiparticulate drug delivery system comprising a plurality of solid oral dosage forms according to any one of items 1 to 116, preferably wherein the oral multiparticulate drug delivery system is a sachet / stick pack, a straw device (XStraw ® ), a capsule, or a tablet / minitablet, more preferably a capsule; preferably, wherein the oral multiparticulate drug delivery system comprises a total amount of the antibody or functional fragment thereof suitable for oral administration to a human patient.

[0133]

[122] An oral multiparticulate drug delivery system comprising a plurality of solid oral dosage forms according to any one of items 1 to 116, wherein each solid oral dosage form unit preferably has a predetermined axis and a predetermined cross-sectional profile, wherein at least 80% by number, preferably 90%, more preferably 95% of those solid oral dosage forms have a median aspect ratio of 0.7 to 1.7, the aspect ratio being defined as the length of the solid oral dosage form along the predetermined axis divided by the smallest cross-sectional dimension.

[0134]

[123] The oral multiparticulate drug delivery system according to item 121 or 122, wherein the median aspect ratio is higher than 0.8, preferably higher than 0.9, and lower than 1.6, preferably lower than 1.5, more preferably 1.4, even more preferably lower than 1.3, even more preferably lower than 1.2, most preferably about 1.

[0135]

[124] The oral multiparticulate drug delivery system according to any one of items 121 to 123, which allows for a 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%, even more preferably at least 98% of the antibody or functional fragment thereof from the solid oral dosage form.

[0136]

[125] The oral multi-particulate drug delivery system according to any one of items 121 to 124, which allows for 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%, even more preferably at least 98% of the antibody or functional fragment thereof from the solid oral 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 of continuous stirring (sustained release) by continuously immersing the solid oral dosage form in an aqueous solution having a pH of 6.5 to 7, preferably a pH of about 6.8.

[0137]

[126] The oral multi-particulate drug delivery system according to any one of items 121 to 125, wherein the oral multi-particulate drug delivery system is prepared from a plurality of solid oral dosage forms by compression or encapsulation, preferably encapsulation.

[0138]

[127] A method for targeted local treatment of a gastrointestinal disease, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the solid oral dosage form according to any one of items 1 to 116 or the oral multi-particulate drug delivery system according to any one of items 121 to 126.

[0139]

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

[0140]

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

[0141]

[130] Use of the solid dosage form according to any one of items 1 to 116 for the manufacture of a medicament for the treatment of a gastrointestinal disease.

[0142]

[131] The use according to item 130, wherein the gastrointestinal disease is IBD, preferably Crohn’s disease or ulcerative colitis. BRIEF DESCRIPTION OF DRAWINGS

[0143] Figure 1 : Multilayer solid oral dosage form of the present invention, comprising: an inert core unit (1); a reservoir layer (2) comprising an antibody or functional fragment thereof; a sustained release layer (3); and a delayed release layer (4).

[0144] Figure 2 : graphical representation of the oral multiparticulate drug delivery system comprising multiple layers of solid oral dosage forms; description of the different layers in the individual solid oral dosage form; and scanning electron microscope (SEM) image of the final individual solid oral dosage form.

[0145] Figure 3 : (A) Drug loading confirmation (by Bradford assay) of the drug coated intermediate (comprising inert core and reservoir layer) of Example 1 after 1 hour incubation in pH 6.8 phosphate buffer. (B) Dissolution kinetics of the Eudragit® RS coated intermediate of Example 1 (comprising inert core unit, reservoir layer and sustained release layer) in pH 6.8 phosphate buffer (by Bradford assay). ® : (A) Drug loading confirmation (by Bradford assay) of the drug coated intermediate (comprising inert core and reservoir layer) of Example 1 after 1 hour incubation in pH 6.8 phosphate buffer. (B) Dissolution kinetics of the Eudragit® RS coated intermediate of Example 1 (comprising inert core unit, reservoir layer and sustained release layer) in pH 6.8 phosphate buffer (by Bradford assay). ® : Dissolution kinetics of the Eudragit® S coated final formulation [i.e. the intermediate of Example 1 coated with a delayed release layer as in (B)].

[0146] Figure 4 : Dissolution kinetics of Example 2 and Example 3 evaluated using dissolution assay.

[0147] Figure 5 : Scanning electron microscope (SEM) image of the cross section of the Eudragit® RS intermediate formulation (comprising inert core unit, reservoir layer and sustained release layer) with lower drug loading. ® : Scanning electron microscope (SEM) image of the cross section of the Eudragit® RS intermediate formulation (comprising inert core unit, reservoir layer and sustained release layer) with lower drug loading.

[0148] Figure 6 : Scanning electron microscope (SEM) image of the cross section of the Eudragit® RS intermediate formulation (comprising inert core unit, reservoir layer and sustained release layer) with lower drug loading. ® : Scanning electron microscope (SEM) image of the cross section of the Eudragit® RS intermediate formulation (comprising inert core unit, reservoir layer and sustained release layer) with lower drug loading. DETAILED DESCRIPTION

[0149] The present invention relates to a novel solid oral dosage form comprising: i) an inert core unit (1); ii) a reservoir layer (2) covering the inert core unit (1) and comprising as active agent an antibody or a functional fragment thereof, preferably specific for tumor necrosis factor alpha (TNFa); a stabilizer, preferably sucrose; a buffer; and a polymeric binder, preferably hydroxypropyl methylcellulose (HPMC); iii) a sustained release layer (3) covering the reservoir layer (2) and comprising ammonio methacrylate copolymer, preferably poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1:2:0.1; a plasticizer; and an anti-tacking agent; and iv) a delayed release layer (4) covering the 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-tacking agent, preferably glycerol monostearate (GMS); and a plasticizer, preferably triethyl citrate (TEC).

[0150] As used herein, the term "solid oral dosage form" can be understood as equivalent to "solid oral pharmaceutical dosage form" or "pharmaceutical composition formulated as a solid oral dosage form", which is suitable for oral administration and includes, for example, pellets, beads, spheroids, microspheres, tablets, micro-tablets, etc. In one embodiment of the present invention, the solid oral dosage form is a pellet, a spheroid, a microsphere, a bead, a granule, a tablet or a micro-tablet. In a preferred embodiment of the present invention, the solid oral dosage form is a pellet. The size of the solid oral dosage form is not particularly limited and can be characterized by a maximum diameter of 100 pm to 4000 pm, preferably 300 pm to 3000 pm, more preferably 500 pm to 2500 pm, even more preferably 700 pm to 2000 pm, for example about 1200 pm to 1600 pm.

[0151] The various solid oral dosage forms of the present invention can be combined into a single unit formulation in the form of an "oral multi-particulate drug delivery system", also known as "oral multi-particulate dosage form". The oral multi-particulate drug delivery system can be, for example, in the form of a hard gelatin capsule, a tablet, a sachet, a caplet or a pill.

[0152] As used herein, the term "inert core unit" is known to the skilled person. As used herein, the term "inert core unit" can be understood to mean an inert pellet, micro-tablet, tablet, granule, core, bead, microsphere or spheroid, which consists of one or more soluble or insoluble inert materials, etc., all of which are pharmacologically inactive and do not interact with the active ingredient in the solid oral dosage form, i.e. the antibody or functional fragment thereof.

[0153] The inert core unit can optionally be seal-coated, for example for increasing the strength of the core to withstand mechanical pressure during processing.

[0154] As used herein, the term "inert" preferably means that the inert core unit (1) (including all its ingredients) is pharmacologically inactive and does not interact with the antibody or functional fragment thereof in the reservoir layer (2). This preferably means that the inert core unit (1) does not contain any active ingredients and does not reduce the stability and activity of the antibody or functional fragment thereof in the reservoir layer (2) during the preparation, storage and subsequent administration and dissolution of the solid oral dosage form.

[0155] As used herein, the term "about" indicates that a value or range of values for a given quantity can include within 10% of the stated value or range, or optionally within 5% of the value or range, or within 1% of the value or range in some embodiments. Generally, "weight%" as used herein means weight percent of a substance relative to the total weight of the solid oral dosage form. In some cases, "weight%" can mean weight percent of a substance relative to the weight of a particular layer of the solid oral dosage form.

[0156] The inert core unit (1) can be an inert pellet, a microtablet, a tablet, a granule, a core, a bead, a microsphere, or a spheroid, for example prepared from one excipient or a mixture of excipients, for example by tableting or extrusion-spheronization. In a preferred embodiment, the inert core unit (1) is a pellet. For example, the pellet can comprise or consist of a water-insoluble or water-swellable material and / or can have a uniform composition. In one embodiment of the present application, the inert core unit (1) comprises as a main component a monosaccharide, a disaccharide, an oligosaccharide, a polysaccharide, silicon dioxide, tartaric acid, calcium carbonate, or a combination thereof. In another embodiment, the inert core unit (1) consists of a monosaccharide, a disaccharide, an oligosaccharide, a polysaccharide, silicon dioxide, tartaric acid, calcium carbonate, or a combination thereof.

[0157] In one embodiment of the present application, the inert core unit (1) (e.g. a spheroid) comprises or consists of microcrystalline cellulose, sucrose, starch, mannitol, calcium carbonate, silicon dioxide, tartaric acid, lactose or a combination thereof, preferably microcrystalline cellulose. In another embodiment, the inert core unit (1) (e.g. a spheroid) comprises as a main component microcrystalline cellulose, sucrose, starch, mannitol, calcium carbonate, silicon dioxide, tartaric acid, lactose or a combination thereof, preferably microcrystalline cellulose. In the present context, "main component" means that the inert core unit (1) comprises at least 50 wt.%, preferably at least 70 wt.%, more preferably at least 90 wt.%, even more preferably at least 95 wt.% of said component. As used in the context of the above-mentioned inert core units, "wt.%" means weight percent of the substance with respect to the weight of the inert core unit (1).

[0158] In one embodiment, the inert core unit (1) is a spheroid. The spheroid can have a median particle size of 50 pm to 5000 pm, preferably 100 pm to 3000 pm, more preferably 200 pm to 2000 pm, even more preferably 300 pm to 1500 pm, even more preferably 400 pm to 1400 pm, even more preferably 700 pm to 1400 pm, even more preferably 500 pm to 1000 pm, most preferably 500 pm to 700 pm, 600 pm to 800 pm, or 700 pm to 1000 pm. In another embodiment, the inert core unit (1) is a spheroid having a particle size distribution such that at least 85% of the spheroids have a particle size of 50 pm to 3000 pm, preferably 100 pm to 1500 pm, more preferably 350 pm to 1400 pm, even more preferably 500 pm to 1400 pm, even more preferably 700 pm to 1400 pm, even more preferably 500 pm to 1000 pm, for example 500 pm to 700 pm, or 700 pm to 1000 pm. According to one preferred embodiment of the present application, the inert core unit (1) is a spheroid having a particle size distribution such that at least 85% of the spheroids have a particle size of 700 pm to 1400 pm, preferably 700 pm to 1000 pm.

[0159] The shape of the inert core unit (1) (preferably a spheroid) is not particularly limited. In one embodiment, the inert core unit (1) is a spheroid 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, even more preferably at least 0.95. In one preferred embodiment, the inert core unit (1) is a spheroid comprising or consisting of spherules. As used herein, the term "spherules" preferably means particles having a sphericity of at least 0.8. For example, the spheroid can comprise or consist of spherules, the spheroid preferably consisting of a water-insoluble or water-swellable material and / or having a uniform composition.

[0160] The pellets or spheres can be coated with a coating deposited on the sphere, for example a seal coating, which seal coating preferably consists of a water-insoluble material. According to one embodiment, the inert core unit (1) comprises or consists of a pellet (e.g. sphere) and optionally a seal coating covering the sphere, which seal coating consists of a water-insoluble material.

[0161] The pellets (or spheres) can consist of microcrystalline cellulose, sucrose, starch, mannitol, calcium carbonate, silicon dioxide, tartaric acid, lactose or combinations thereof. In a preferred embodiment, the inert core unit (1) is a pellet (e.g. sphere) and consists of microcrystalline cellulose, sucrose, starch, mannitol, calcium carbonate, silicon dioxide, tartaric acid, lactose or combinations thereof. In a preferred embodiment, the inert core unit (1) is a pellet, preferably in the form of a sphere, and consists of microcrystalline cellulose. Examples of commercially available inert core units include CELLETS® ® (Sanaq AG) and SUGLETS® ® sugar spheres (Colorcon ® Ldt).

[0162] The solid oral dosage form comprises a reservoir layer (2) covering the inert core unit (1) and comprising as active agent an antibody or functional fragment thereof; a stabilizer; a buffer; and a polymeric binder. As used herein, the term “reservoir layer” refers to a coating or layer which comprises at least one active agent in the form of an antibody or functional fragment thereof and which covers the inert core unit.

[0163] As used herein, in the context of a “layer” of the solid oral dosage form of the present application, the term “cover” or “covering” means that the layer is on top of the inert core unit or layer being covered, such that there are no other layers in between (i.e. between the covering layer and the inert core unit or layer being covered), or such that there is one or more additional layers in between, preferably such that there are no other layers in between. Preferably, the layers of the solid oral dosage form of the present application continuously cover the inert core unit or layer being covered, such that there are no gaps in the covering layer. This is particularly relevant for the sustained release layer and the delayed release layer, the integrity of which can otherwise be compromised.

[0164] Preferably, the reservoir layer (2) is on top of the inert core unit (1), such that there are no other layers in between (i.e. between the reservoir layer and the inert core unit). Preferably, the reservoir layer (2) of the solid oral dosage form of the present application continuously covers the inert core unit (1), such that there are no gaps in the reservoir layer.

[0165] The particular layer can be separated from the inert core unit or other layers of the solid oral dosage form which have been applied separately by its unique physico-chemical properties. Thus, the reservoir layer (2), the sustained release layer (3) and / or the delayed release layer (4) can be separated from the inert core unit and other layers which have been applied separately after application of the reservoir layer by its unique physico-chemical properties.

[0166] According to one embodiment of the present application, the reservoir layer (2) of the solid oral dosage form of the present application has an average thickness of 1 pm to 300 pm, preferably 2 pm to 200 pm, more preferably 5 pm to 200 pm, even more preferably 10 pm to 200 pm, for example 100 pm to 200 pm, or 150 pm.

[0167] According to another embodiment of the present application, the sustained release layer (3) has an average thickness of 5 pm to 50 pm, preferably 10 pm to 45 pm, more preferably 15 pm to 35 pm, even more preferably 18 pm to 30 pm, even more preferably 20 pm to 30 pm, for example about 24 pm or 25 pm. According to another embodiment of the present application, the thickness of the sustained release layer (3) is constant and does not depend on the amount of active agent and / or the thickness of the reservoir layer (2). According to another embodiment, the sustained release layer (3) has a fixed average thickness of 5 pm to 50 pm, preferably 10 pm to 45 pm, more preferably 15 pm to 35 pm, even more preferably 18 pm to 30 pm, even more preferably 20 pm to 30 pm, for example 24 pm or 25 pm; preferably, the thickness of the sustained release layer (3) is constant irrespective of the thickness of the reservoir layer (2) and / or the amount of antibody or functional fragment thereof in the reservoir layer (2).

[0168] According to one preferred embodiment of the present application, the delayed release layer (4) has an average thickness of 10 pm to 300 pm, preferably 50 pm to 180 pm, more preferably 60 pm to 160 pm, even more preferably 80 pm to 150 pm, even more preferably 90 pm to 130 pm, even more preferably 95 pm to 120 pm, for example 105 pm or 120 pm.

[0169] According to one specific embodiment of the present application, the solid oral dosage form according to any one of the above-mentioned embodiments, the average thickness of the sustained release layer (3) is constant irrespective of the amount of antibody or functional fragment thereof in the solid oral dosage form and / or the thickness of the reservoir layer.

[0170] The thickness of a layer can be determined using a scanning electron microscope (SEM) based on 10, or 15, or 20, or 30, or 50 different measurement points in the layer.

[0171] In the context of the present invention, the term "antibody" refers to "immunoglobulin" (Ig), which is defined as a protein belonging to the IgG, IgM, IgE, IgA or IgD class (or any subclass thereof) and includes all conventionally known antibodies and functional fragments thereof. The antibody or functional fragment thereof used in the present invention is an active agent, i.e. the antibody or functional fragment thereof is incorporated into the solid oral dosage form because the antibody or functional fragment thereof has pharmacological activity in a patient.

[0172] In the context of the present invention, a "functional fragment" of an antibody / immunoglobulin is defined as an antigen-binding fragment or other derivative of a parent antibody that substantially retains the properties of such parent antibody. An "antigen-binding fragment" of an antibody / immunoglobulin is defined as a fragment that retains the antigen-binding region (e.g. the variable region of an 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, CDR-2 and / or CDR-3 regions. The "antigen-binding fragment" according to the present invention includes the domains of F(ab')2 fragments and Fab fragments. The "functional fragment" of 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 domains can be engineered to minimize or completely eliminate the intermolecular disulfide bond interaction that occurs between the CH1 domain and the CL domain. The antibody or functional fragment thereof used in the present invention can be part of a bifunctional construct or a multifunctional construct.

[0173] Fab fragments can be obtained as purified digestion products after digestion of an antibody with a cysteine protease such as papain (EC 3.4.22.2). F(ab')2 fragments can be obtained as purified digestion products after digestion of an antibody with pepsin (EC 3.4.23.1) or IdeS (immunoglobulin-degrading enzyme from Streptococcus pyogenes; EC 3.4.22). Fab' fragments can be obtained from F(ab')2 fragments under mild reducing conditions, whereby two Fab' fragments are produced from each F(ab')2 molecule. scFv is a single-chain Fv fragment, in which the variable light ("VL") domain and the variable heavy ("VH") domain are connected by a peptide bridge.

[0174] A "diabody" is a dimer that consists of two fragments, each of which has a variable region (hereinafter referred to as a diabody-forming fragment) connected together by a linker or the like, and generally contains two VLs and two VHs. The diabody-forming fragments include those consisting of VL and VH, VL and VL, VH and VH, etc., preferably VH and VL. In the diabody-forming fragments, the linker connecting the variable regions is not particularly limited, but is preferably short enough to avoid formation of non-covalent bonds between the variable regions in the same fragment. The length of such a linker can be appropriately determined by one skilled in the art, but 2 to 14 amino acids, preferably 3 to 9 amino acids, in particular 4 to 6 amino acids, are generally used. In this case, the VL and VH encoded on the same fragment are connected by a linker that is short enough to avoid formation of non-covalent bonds between the VL and VH on the same chain, and to avoid formation of a single-chain variable region fragment, so that a dimer can be formed with another fragment. The dimer can be formed by covalent or non-covalent bonds between the diabody-forming fragments or both.

[0175] In addition, the diabody-forming fragments can be connected by a linker or the like to form a single-chain diabody (sc(Fv)2). By connecting the diabody-forming fragments using a long linker having about 15 to 20 amino acids, non-covalent bonds can be formed between the diabody-forming fragments present on the same chain, thereby forming a dimer. Based on the same principle as the preparation of diabodies, a polymeric antibody, such as a trimer or a tetramer, can also be prepared by connecting three or more diabody-forming fragments.

[0176] In one embodiment, the functional fragment in the solid oral dosage form of the present application is a Fab fragment, a F(ab')2 fragment, a Fab' fragment, a scFv, a dsFv, a VHH, a diabody, a triabody, a tetrabody, a Fc fusion protein, or a minibody. The preferred functional fragment used in the present application is a Fab fragment, a F(ab')2 fragment, a Fab' fragment, a scFv, and a diabody.

[0177] The antibody or functional fragment thereof used in the solid oral dosage form of the present application is not particularly limited. In one embodiment, the antibody or functional fragment thereof is an antibody. In another embodiment of the present application, the antibody or functional fragment thereof is a functional fragment as defined above. The antibody or functional fragment thereof can also comprise one or more modifications, for example in the form of added or substituted residues, which improve stability, specificity, or targeting. These modifications can include any such modifications known in the art.

[0178] The antigen against which the antibody or functional fragment is directed (i.e. the immunogen, peptide, protein or other molecular structure to which the antibody or functional fragment thereof is capable of specifically binding) is not limited. In the context herein, the terms "specific for", "specific binding" or "specific binding" are known to the skilled person. In its most general form (and when no explicit reference is made) "specific for" or "specific binding" refers to the ability of the antibody or functional fragment thereof to distinguish the target of interest from an unrelated biological molecule (e.g. an antibody specific for human TNFa is capable of distinguishing human TNFa from an unrelated biological molecule), as determined, for example, according to specific assay methods known in the art. Such methods include, but are not limited to, Western Blot and Enzyme-Linked Immunosorbent Assay (ELISA) tests. For example, a standard ELISA assay can be performed. Typically, the determination of binding specificity is not performed by using a single reference biological molecule, but rather using a panel of about three to five unrelated biological molecules (such as milk powder, BSA, transferrin, etc.).

[0179] In one embodiment of the application, the antibody or functional fragment thereof is suitable for the treatment of an inflammatory condition in the gastrointestinal tract, such as immune checkpoint inhibitor (ICPI)-induced colitis, ICPI-induced small intestinal colitis, ICPI-induced diarrhea or inflammatory bowel disease (IBD, e.g. Crohn's disease or ulcerative colitis). In another embodiment of the application, the antibody or functional fragment thereof is suitable for local treatment in the (distal) ileum and / or large intestine of the gastrointestinal tract of a patient, in particular at the mucosal site.

[0180] In another embodiment of the application, the antibody or functional fragment thereof is selected from the group consisting of an antibody specific for tumor necrosis factor alpha (TNFa) and functional fragments thereof, an antibody specific for alpha4beta7 integrin and functional fragments thereof, an antibody specific for CD3, CD4 or CD20 and functional fragments thereof, an antibody specific for interleukin 6 (IL-6), interleukin 12 (IL-12), interleukin 13 (IL-13), interleukin 23 (IL-23) or their receptors and functional fragments thereof, an antibody specific for CXCL10 / IP-10 and functional fragments thereof, and an antibody specific for the p40 protein subunit and functional fragments thereof. In yet another embodiment of the application, the antibody or functional fragment thereof is selected from the group consisting of infliximab, adalimumab, etanercept, certolizumab pegol, golimumab, visilizumab, ediralizumab, anifrolumab, canakinumab, tocilizumab, ustekinumab, natalizumab, rilonacept, risankizumab, vedolizumab and functional fragments thereof.

[0181] In a preferred embodiment of the solid oral dosage form of the application, the antibody or functional fragment thereof is an antibody or functional fragment thereof specific for tumor necrosis factor alpha (TNFa) (i.e. an anti-TNFa antibody or functional fragment thereof). The antibody or functional fragment thereof specific for TNFa is not particularly limited. In one embodiment, the antibody or functional fragment thereof specific for TNFa is an antibody. In another embodiment, the antibody or functional fragment thereof specific for TNFa is a functional fragment as defined above. The antibody or functional fragment thereof specific for TNFa can also comprise one or more modifications, e.g. in the form of added or substituted residues, which improve stability, specificity or targeting. These modifications can include any such modifications known in the art.

[0182] As used herein, the terms "anti-TNFa antibody", "TNFa antibody" and "antibody specific for TNFa" are used interchangeably and preferably mean that the anti-TNFa antibody is capable of specifically binding to TNFa, i.e. it preferably refers to the ability of the antibody to specifically bind to TNFa (more preferably human TNFa) (e.g. identifiable by UniProt identifier P01375). In the context herein, the term "specific for", "specific binding" or "binding specific" is known to the person skilled in the art (see above). In one embodiment, "binding specific" in the context of TNFa refers in particular to the ability of the antibody or fragment to discriminate between human TNFa and human TNFp.

[0183] In one embodiment of the application, the anti-TNFa antibody or functional fragment thereof is suitable for the treatment of immune checkpoint inhibitor (ICPI)-induced colitis, ICPI-induced small intestinal colitis, ICPI-induced diarrhea and / or inflammatory bowel disease (IBD), e.g. Crohn's disease or ulcerative colitis. In another embodiment of the application, the antibody or functional fragment thereof is suitable for local treatment in the ileum (preferably the terminal ileum) or the large intestine of the gastrointestinal tract of the patient, in particular at the mucosal site. In a preferred embodiment of the application, the anti-TNFa antibody or functional fragment thereof is an afucosylated antibody, meaning that it does not contain a core fucose.

[0184] Several monoclonal antibodies against TNFα (i.e., those specific to TNFα) have been described in the prior art. Meager et al. (Hybridoma, 6,305-311, 1987) described a mouse monoclonal antibody against recombinant TNFα. Fendly et al. (Hybridoma, 6,359-370, 1987) described the use of a mouse monoclonal antibody against recombinant TNFα in identifying neutralizing epitopes on TNF. Furthermore, recombinant antibodies specific to TNFα, including CDR transplantation antibodies, are disclosed in International Patent Application WO 92 / 11383. US Patent No. 5,919,452 discloses anti-TNFα chimeric antibodies and their use in treating pathologies associated with the presence of TNFα. Other anti-TNFα antibodies have been disclosed in Stephens et al. (Immunology, 85,668-674, 1995), GB-A-2 246 570, GB-A-2 297 145, US 8,673,310, US 2014 / 0193400, EP2 390 267 B1, US 8,293,235, US 8,697,074, WO 2009 / 155723 A2 and WO 2006 / 131013 A2.

[0185] Currently approved anti-TNFα antibodies include (i) infliximab, a chimeric IgG anti-human monoclonal antibody (Remicade). ® (ii) Etanercept, a TNFR2 dimer fusion protein containing IgG1 Fc (Enbrel) ® (iii) Adalimumab, a fully human monoclonal antibody (mAb) (Humira) ® (iv) Citrullumab, 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 a functional fragment thereof is selected from: infliximab, adalimumab, etanercept, pegylated cetrusumab, and golimumab, or functional fragments thereof.

[0186] In a preferred embodiment of the present invention, the antibody or a functional fragment thereof is an anti-TNFα antibody or a functional fragment thereof having a TNFα-binding domain, the TNFα-binding domain comprising: (i) V L Structural domain, the V Lthe V H domain, the V H domain comprises a CDR1 region having an amino acid sequence as set forth in SEQ ID NO: 4, a CDR2 region having an amino acid sequence as set forth in SEQ ID NO: 5, and a CDR3 region having an amino acid sequence as set forth in SEQ ID NO: 6.

[0187] In another preferred embodiment of the application, the antibody or functional fragment thereof is an anti-TNFa antibody or functional fragment thereof having a TNFa binding domain comprising or consisting of: (i) a V L domain, the V L domain has an amino acid sequence identical to or consisting of an amino acid sequence as set forth in SEQ ID NO: 8; and / or (ii) a V H domain, the V H domain has an amino acid sequence identical to or consisting of an amino acid sequence as set forth in SEQ ID NO: 7.

[0188] In another preferred embodiment of the application, the antibody or functional fragment thereof is an anti-TNFa antibody or functional fragment thereof having a TNFa binding domain comprising: (i) a V L domain, the V L domain comprises a CDR1 region having an amino acid sequence as set forth in SEQ ID NO: 9, a CDR2 region having an amino acid sequence as set forth in SEQ ID NO: 10, and a CDR3 region having an amino acid sequence as set forth in SEQ ID NO: 11; and / or (ii) a V H domain, the V H domain comprises a CDR1 region having an amino acid sequence as set forth in SEQ ID NO: 12, a CDR2 region having an amino acid sequence as set forth in SEQ ID NO: 13, and a CDR3 region having an amino acid sequence as set forth in SEQ ID NO: 14.

[0189] In another preferred embodiment of the application, the antibody or functional fragment thereof is an anti-TNFa antibody or functional fragment thereof having a TNFa binding domain comprising or consisting of: (i) a V L domain, the V Lthe V H domain has an amino acid sequence which is identical to or consists of the amino acid sequence as set forth in SEQ ID NO: 16 or SEQ ID NO: 17; and / or (ii) V H the domain has an amino acid sequence which is identical to or consists of the amino acid sequence as set forth in SEQ ID NO: 15.

[0190] In yet another preferred embodiment of the present application, the antibody or functional fragment thereof is an anti-TNFa antibody comprising an Fc region having or consisting of an amino acid sequence which is identical to or consists of the amino acid sequence as set forth 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.

[0191] In yet another preferred embodiment of the present application, the antibody or functional fragment thereof is an anti-TNFa antibody comprising or consisting of (i) a light chain having or consisting of an amino acid sequence which is identical to or consists of the amino acid sequence as set forth in SEQ ID NO: 23; and (ii) a heavy chain having or consisting of an amino acid sequence which is identical to or consists of the amino acid sequence as set forth in SEQ ID NO: 26.

[0192] In yet another preferred embodiment of the present application, the antibody or functional fragment thereof is an anti-TNFa antibody comprising or consisting of (i) a light chain having or consisting of an amino acid sequence which is identical to or consists of the amino acid sequence as set forth in SEQ ID NO: 24 or SEQ ID NO: 25; and (ii) a heavy chain having or consisting of an amino acid sequence which is identical to or consists of the amino acid sequence as set forth in SEQ ID NO: 27.

[0193] In yet another preferred embodiment of the present application, the antibody or functional fragment thereof is an anti-TNFa antibody comprising or consisting of (i) a light chain having or consisting of an amino acid sequence which is identical to or consists of the amino acid sequence as set forth in SEQ ID NO: 23; and (ii) a heavy chain having or consisting of an amino acid sequence which is identical to or consists of the amino acid sequence as set forth in SEQ ID NO: 28, SEQ ID NO: 29 or SEQ ID NO: 30.

[0194] In yet another preferred embodiment of the present application, the antibody or functional fragment thereof is an anti-TNFa antibody comprising or consisting of: (i) a light chain having an amino acid sequence identical to or consisting of the amino acid sequence set forth in SEQ ID NO: 24 or SEQ ID NO: 25; and (ii) a heavy chain having an amino acid sequence identical to or consisting of the amino acid sequence set forth in SEQ ID NO: 31, SEQ ID NO: 32, or SEQ ID NO: 33.

[0195] In yet another preferred embodiment of the present application, the antibody or functional fragment thereof is an anti-TNFa antibody comprising or consisting of: (i) a light chain having an amino acid sequence identical to or consisting of the amino acid sequence set forth in SEQ ID NO: 23; and (ii) a heavy chain having an amino acid sequence identical to or consisting of the amino acid sequence set forth in SEQ ID NO: 34.

[0196] In yet another preferred embodiment of the present application, the antibody or functional fragment thereof is an anti-TNFa antibody comprising or consisting of: (i) a light chain having an amino acid sequence identical to or consisting of the amino acid sequence set forth in SEQ ID NO: 24 or SEQ ID NO: 25; and (ii) a heavy chain having an amino acid sequence identical to or consisting of the amino acid sequence set forth in SEQ ID NO: 35.

[0197] The amount of antibody or functional fragment thereof is not particularly limited. Preferably, the reservoir layer (2) comprises an amount of antibody or functional fragment thereof which allows for the administration of a therapeutically effective dose of the antibody or functional fragment thereof in a single unit dose, e.g. in the form of a multi-particulate drug delivery system comprising a plurality of the solid oral dosage form according to the application. In one embodiment, the reservoir layer (2) comprises 0.2 to 75 wt.-%, preferably 1 to 45 wt.-%, more preferably 10 to 35 wt.-%, even more preferably 20 to 35 wt.-%, even more preferably 25 to 35 wt.-%, of the antibody or functional fragment thereof, preferably specific for TNF alpha, relative to the total weight of solids, i.e. not comprising a solvent, preferably water, in the reservoir layer (2). According to another preferred embodiment, the solid oral dosage form according to the application comprises 0.05 to 30 wt.-%, preferably 0.1 to 25 wt.-%, more preferably 0.1 to 20 wt.-%, even more preferably 0.2 to 20 wt.-%, even more preferably 0.2 to 15 wt.-%, even more preferably 0.5 to 12 wt.-%, even more preferably 0.5 to 10 wt.-%, even more preferably 0.8 to 12 wt.-%, even more preferably 8 to 12 wt.-%, even more preferably 8 to 10 wt.-%, e.g. about 9 wt.-%, or about 9.25 wt.-%, or about 9.5 wt.-%, of the antibody or functional fragment thereof, preferably specific for TNF alpha.

[0198] In one embodiment of the application, the solid oral dosage form according to the application comprises an amount of antibody or functional fragment thereof which allows for the oral administration of a therapeutically effective dose of the antibody or functional fragment thereof in a single unit dose, e.g. in the form of a tablet or preferably a capsule comprising a plurality of the solid oral dosage form, e.g. in the form of a plurality of pellets. A "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 can vary depending on the different antibodies or functional fragments thereof and / or depending on the individual patient, but can be determined by the person skilled in the art.

[0199] The reservoir layer (2) comprises a stabilizer. The nature of the stabilizer is not particularly limited, and the stabilizer includes all stabilizers that ensure the stability and activity of the antibody and functional fragments thereof (e.g., the antibody and functional fragments thereof specific to TNFa) while not impairing the integrity of the reservoir layer (2). In one embodiment of the present application, the stabilizer is selected from the group consisting of sucrose, maltose, lactose, trehalose, glycerol, maltitol, isomaltitol, mannitol, sorbitol, xylitol, and combinations thereof, preferably sucrose, maltose, lactose, glycerol, maltitol, isomaltitol, and combinations thereof. According to one preferred embodiment, the stabilizer in the reservoir layer (2) is sucrose. The amount of the stabilizer in the reservoir layer (2) is not particularly limited, as long as it ensures the stability of the low and high concentrations of the antibody or functional fragments thereof while not impairing the integrity of the reservoir layer. In one embodiment of the present application, the reservoir layer (2) comprises 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, even more preferably about 40 to 55% by weight of the stabilizer (preferably sucrose) with respect to the total weight of the solids (i.e., not including the solvent, preferably water) in the reservoir layer (2). In another embodiment, the weight ratio of the antibody or functional fragments thereof 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.

[0200] The reservoir layer (2) comprises a buffer. The nature of the buffer is not particularly limited, and the buffer includes all buffers that ensure the stability and activity of the antibody and functional fragments thereof while not impairing the integrity of the reservoir layer (2). In one embodiment of the present application, the buffer (i.e., one or more buffer salts and / or free bases) in the reservoir layer (2) is selected from the group consisting of L-histidine buffer, citrate buffer, hydroxymethylamino methane (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. According to one preferred embodiment, the buffer (i.e., buffer salts and / or free bases) in the reservoir layer (2) comprises or consists of L-histidine, preferably L-histidine monohydrochloride and / or free base.

[0201] The buffering agent can be present in the reservoir layer (2) in any amount that ensures the stability and activity of the antibody and functional fragments thereof during and after the preparation of the solid oral dosage form, while not compromising the integrity of the reservoir layer (2). In one embodiment of the application, the reservoir layer (2) comprises 0.1 to 10 wt%, preferably 0.2 to 6 wt%, more preferably 0.3 to 5 wt%, more preferably 0.5 to 4.5 wt%, even more preferably 1 to 4 wt%, more preferably about 2 to 3.5 wt% of the buffering agent relative to the total weight of solids (i.e. not including solvent, preferably water) in the reservoir layer (2). In another embodiment of the application, the reservoir layer (2) comprises 0.1 to 10 wt%, preferably 0.2 to 5 wt%, more preferably 0.3 to 4 wt%, even more preferably 0.35 to 3.5 wt%, more preferably about 0.4 to 3 wt% of L-histidine salt and / or free base, and optionally 0.3 to 6 wt%, preferably 0.5 to 4 wt%, more preferably 1 to 3.5 wt%, even more preferably 1.5 to 3 wt%, more preferably about 1.5 to 3.5 wt% of other buffering salts relative to the total weight of solids (i.e. not including solvent, preferably water) in the reservoir layer (2). In another embodiment, the weight ratio of the antibody or functional fragment thereof to the buffering agent (preferably L-histidine buffering agent (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 functional fragment thereof to the L-histidine buffering agent 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 functional fragment thereof to the other buffering agent is 25:1 to 5:1, preferably 16:1 to 10:1, more preferably 14:1 to 12:1.

[0202] Polymeric binders (also referred to herein as "binders") suitable for use in the reservoir layer (2) of the solid oral dosage form of the application comprise hydroxypropyl methylcellulose (HPMC); methylcellulose (MC); polyvinylpyrrolidone (PVP); hydroxypropylcellulose (HPC); polyethylene glycol poly(vinyl alcohol) graft copolymer (e.g. Kollidon VA 64®); polyethylene glycol; polyethylene oxide; starch; maltodextrin; gelatin; and mixtures thereof. In one embodiment of the application, the reservoir layer (2) comprises 0.1 to 10 wt%, preferably 0.2 to 6 wt%, more preferably 0.3 to 5 wt%, more preferably 0.5 to 4.5 wt%, even more preferably 1 to 4 wt%, more preferably about 2 to 3.5 wt% of a polymeric binder relative to the total weight of solids (i.e. not including solvent, preferably water) in the reservoir layer (2). In another embodiment of the application, the reservoir layer (2) comprises 0.1 to 10 wt%, preferably 0.2 to 5 wt%, more preferably 0.3 to 4 wt%, even more preferably 0.35 to 3.5 wt%, more preferably about 0.4 to 3 wt% of a polymeric binder relative to the total weight of solids (i.e. not including solvent, preferably water) in the reservoir layer (2). In another embodiment, the weight ratio of the antibody or functional fragment thereof to the polymeric binder 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 functional fragment thereof to the polymeric binder is 100:1 to 20:1, preferably 80:1 to 40:1, more preferably 60:1 to 50:1. ®IR); and combinations thereof; preferably hypromellose or MC. In a preferred embodiment of the application, the polymeric binder in the reservoir layer (2) of the solid oral dosage form is hypromellose. Hypromellose is also known as hydroxypropyl methylcellulose (HPMC) and is available in different degrees of substitution (DS), molar substitution (MS) and viscosity. According to a preferred embodiment of the application, the polymeric binder in the reservoir layer (2) is hypromellose 2910, preferably hypromellose 2910 2.6 mPas to 3.6 mPas, more preferably hypromellose 2910 3 mPas.

[0203] The amount of polymeric binder in the reservoir layer (2) is not particularly limited as long as a stable reservoir layer can be easily formed. In one embodiment of the application, the reservoir layer (2) comprises 0.5% to 65% by weight, preferably 2% to 35% by weight, more preferably 10% to 30% by weight, even more preferably 15% to 25% by weight, for example about 20% by weight of the polymeric binder (preferably hypromellose) relative to the total weight of solids (i.e. not including solvents, preferably water) in the reservoir layer (2). In another embodiment, the weight ratio of the antibody or functional fragment thereof to the polymeric 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.

[0204] Preferably, the polymeric binder in the reservoir layer (2) is suitable for immediate release drug coating. Thus, the reservoir layer (2) without any additional layer (i.e. a sustained release layer and a delayed release layer) results in an immediate release of the antibody or functional fragment thereof from the dosage form. As used herein, the term "immediate release" is intended to describe a reservoir layer wherein more than 60%, preferably more than 70%, more preferably more than 80%, even more preferably more than 90%, most preferably 95% of the antibody or functional fragment thereof is released from the reservoir layer (2) after 2 hours, preferably after 1 hour, even more preferably after 0.5 hours of exposure to an aqueous environment. The term "aqueous environment" as used in the context of the present application can refer to a solution or suspension of which the majority is water. This includes intestinal fluid.

[0205] To measure the amount of antibody or functional fragment thereof released from the reservoir layer (2) as the outermost coating of a solid dosage form into an aqueous solution, the reservoir layer (drug layer) deposited on an inert core can be immersed in a defined volume of the aqueous, preferably buffered, solution under continuous stirring of the aqueous, preferably buffered, solution for a defined period of time, and the resulting concentration of at least one antibody or functional fragment thereof in the aqueous solution can be determined and compared to the initial amount applied during layering, taking into account the process efficiency and weight gain. Similarly, the release from a solid dosage form with additional coatings (e.g. sustained release and / or delayed release coatings) deposited on the reservoir layer (2) can be determined. Means to determine the antibody concentration in an aqueous solution are known in the art and include, for example, measuring the absorbance at 280 nm or using a colorimetric, reagent-based protein assay such as the Bradford assay or an ELISA.

[0206] According to one embodiment of the present application, the reservoir layer (2) of the solid oral dosage form of the present application comprises an anti-tacking agent. The anti-tacking agent useful in the reservoir layer (2) is not particularly limited. In one embodiment of the present application, the anti-tacking agent in the reservoir layer (2) is selected from the group consisting of colloidal silicon dioxide, mesoporous silicon dioxide, glycerol monostearate (GMS), stearic acid, magnesium stearate, and talc, preferably mesoporous silicon dioxide or GMS, more preferably mesoporous silicon dioxide. The amount of anti-tacking agent in the reservoir layer (2) is not particularly limited. In one embodiment of the present application, the reservoir layer (2) comprises 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 anti-tacking agent relative to the total weight of solids (i.e. not including solvents, preferably water) in the reservoir layer (2). In another embodiment, the weight ratio of the anti-tacking agent to the polymeric binder (e.g. hypromellose) in the reservoir layer (2) is 1 : 15 to 1 : 5, preferably 1 : 12 to 1 : 8, for example about 1 : 10.

[0207] According to one preferred embodiment of the present application, the anti-tacking agent in the reservoir layer (2) is mesoporous silicon dioxide, preferably mesoporous silicon dioxide having an average particle size of 1 pm to 10 pm, preferably 2 pm to 5 pm, more preferably 3 pm to 4 pm, even more preferably about 3.5 pm and / or an average pore volume of 1.50 cm 3 / g to 1.70 cm 3 / g, preferably 1.55 cm 3 / g to 1.65 cm 3 / g, more preferably 1.58 cm 3 / g to 1.62 cm 3 / g, even more preferably about 1.60 cm 3 / g.

[0208] According to another embodiment, the reservoir layer (2) of the solid oral dosage form of the present application does not comprise a plasticizer. According to another embodiment, the reservoir layer (2) of the solid oral dosage form of the present application comprises a coalescence enhancer, such as propylene glycol monolaurate (e.g. Lauroglycol ™ 90).

[0209] According to yet another embodiment of the present application, the reservoir layer (2) of the solid oral dosage form of the present application comprises a surfactant. The surfactant in the reservoir layer (2) is not particularly limited, however preferably, the surfactant is a non-ionic surfactant. According to one embodiment of the present application, the surfactant in the reservoir 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.

[0210] According to one preferred embodiment of the solid oral dosage form, the surfactant in the reservoir layer (2) is polysorbate 20, 28, 40, 60, 65, 80, 81 and 85. In a particularly preferred embodiment, the surfactant in the reservoir layer (2) is polysorbate 80. In one embodiment of the present application, the reservoir layer (2) comprises 0.01 to 2 wt%, preferably 0.02 to 1 wt%, more preferably 0.03 to 0.8 wt%, even more preferably 0.05 to 0.5 wt%, even more preferably 0.1 to 0.3 wt%, even more preferably 0.2 to 0.3 wt% of the surfactant relative to the total weight of solids (i.e. not comprising solvents, preferably water) in the reservoir layer (2).

[0211] The reservoir layer (2) can optionally comprise at least one additional excipient. As used herein, the term "excipient" refers to a non-therapeutic agent added to a formulation to provide, for example, a desired consistency, viscosity or stabilizing effect. According to one embodiment of the present application, the at least one additional excipient is selected from pharmaceutically acceptable excipients, such as antioxidants, humectants, protective colloids, dyes, protease inhibitors, and combinations thereof. In another embodiment, the reservoir layer (2) does not comprise any additional excipient.

[0212] According to one preferred embodiment of the present application, the reservoir layer (2) of the solid oral dosage form of the present application comprises or consists of an antibody or a functional fragment thereof, e.g. specific for TNFa, as active agent; a stabilizer, preferably sucrose; a buffer, preferably L-histidine, more preferably L-histidine monohydrochloride and / or free base; a polymeric binder, preferably hydroxypropyl methylcellulose (HPMC), more preferably hydroxypropyl methylcellulose 2910 2.6 mPas to 3.6 mPas; an anti-tacking agent, preferably mesoporous silicon dioxide; a surfactant, preferably polysorbate 80; optionally an additional buffer, such as citrate-TRIS; and optionally a residual solvent (preferably water). According to another preferred embodiment of the present application, the reservoir layer (2) of the solid oral dosage form of the present application comprises or consists of an antibody or a functional fragment thereof, e.g. specific for TNFa, as active agent; sucrose; L-histidine, preferably L-histidine monohydrochloride, and / or L-histidine free base; hydroxypropyl methylcellulose (HPMC), preferably hydroxypropyl methylcellulose 2910 2.6 mPas to 3.6 mPas; mesoporous silicon dioxide; polysorbate 80; and optionally residual water.

[0213] According to another preferred embodiment of the present application, the reservoir layer (2) of the solid oral dosage form of the present application comprises or consists of 0.2 to 75% by weight of the antibody or functional fragment thereof, 0.5 to 65% by weight of the 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 further buffer, 0.2 to 15% by weight of the anti-tacking agent, 0.01 to 1% by weight of the surfactant and / or up to 10% by weight of water, relative to the total weight of the reservoir layer; preferably 1 to 45% by weight of the antibody or functional fragment thereof, 2 to 35% by weight of the binder, 10 to 70% by weight of sucrose, 0.2 to 2% by weight of L-histidine, 0.5 to 4% by weight of further buffer, 1 to 5% by weight of the anti-tacking agent, 0.05 to 0.5% by weight of the surfactant and / or up to 7% by weight of water, relative to the total weight of the reservoir layer; more preferably 10 to 35% by weight of the antibody or functional fragment thereof, 10 to 30% by weight of the binder, 30 to 60% by weight of sucrose, 0.3 to 0.8% by weight of L-histidine, 1.5 to 3% by weight of further buffer, 1.5 to 3% by weight of the anti-tacking agent, 0.1 to 0.3% by weight of the surfactant and / or up to 6% by weight of water, relative to the total weight of the reservoir layer; even more preferably 25 to 35% by weight of the antibody or functional fragment thereof, 15 to 25% by weight of the binder, 40 to 55% by weight of sucrose, 0.4 to 0.6% by weight of L-histidine, 1.5 to 2.5% by weight of further buffer, 1.5 to 2.5% by weight of the anti-tacking agent, 0.2 to 0.3% by weight of the surfactant and / or up to 5% by weight of water, relative to the total weight of the reservoir layer (2).

[0214] In the solid oral dosage form of the present application, the reservoir layer (2) can be deposited on the inert core unit (1) by drug layering, preferably using spray coating, more preferably fluidized bed spray coating. Drug layering using solution / suspension layering allows the preparation of solid dosage forms with a uniform size distribution and a smooth surface morphology. Solution / suspension layering (or coating) involves the deposition of 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, for example an inert core (sucrose or microcrystalline cellulose spheres, etc.) suspended in the fluidized bed of a fluidized bed spray coater. Methods for drug layering of a layer containing an antibody or functional fragment as active ingredient on an inert core are known in the art. Such methods can be found, for example, in WO 2019 / 057562. Methods for applying a functional coating, for example by fluidized bed spray coating, are disclosed, for example, in WO 2004 / 062577, EP 1 684 729, WO 2005 / 046561 or WO 2005 / 115340.

[0215] The reservoir layer (2) can be applied on the inert core unit using spray coating. For example, a fluidized bed spray coater or a pan coater can be used. According to one preferred embodiment, a fluidized bed spray coater is used. The use of fluidized bed spray coaters for spraying inert core units is known in the art. If the parameters and conditions employed are strictly controlled during the spraying process, it is advantageous for the at least one antibody or functional fragment thereof contained in the solid oral dosage form prepared by the method of the present application. Fluidized bed spray coaters available for use are not particularly limited. Fluidized bed spray coaters are known in the art and include, for example, fluidized bed apparatus developed and commercialized by the GEA Group, Glatt GmbH, Freund-Vector Corporation and Inora Pharmaceutical Machinery Corporation. A bottom spray fluidized bed spray coater can be used to spray the reservoir layer coating liquid containing the antibody or functional fragment thereof onto the inert core unit. Alternatively, a top spray fluidized bed spray coater can be used to spray the reservoir layer coating liquid onto the inert core unit.

[0216] It is understood that whenever in the present disclosure reference is made to the dissolution or recovery of an antibody or functional fragment thereof from a solid dosage form / multiparticulate drug delivery system, e.g. in the above and below sections, e.g. by continuous immersion of the solid dosage form / multiparticulate drug delivery system under continuous (constant) stirring into an aqueous (buffered) solution, the following standard test setting, or a related standard test setting known to the skilled person, can be used: The release of at least one antibody or functional fragment thereof can be assessed using a standard dissolution apparatus I (basket method), II (paddle method), III (reciprocating cylinder method) or apparatus IV (flow-through cell method), wherein the buffer (i.e. the aqueous buffered solution) is equilibrated at 37°C. The volume of the buffer used for the dissolution test can be adjusted, e.g. using a mini-vessel in apparatus I or II, to reduce the volume required and to make it more physiologically relevant. The antibody or functional fragment thereof released during the dissolution process can be quantitatively determined offline by an ELISA method.

[0217] The solid oral dosage form of the present application comprises a sustained release layer (3) covering the reservoir layer (2) and comprising a methacrylic acid ammonium ester copolymer, preferably poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1 :2:0.1 ; a plasticizer; and an anti-tacking agent. The term "sustained release" is known in the art. As used herein, the term "sustained release" can be used to describe the continuous release of an antibody or functional fragment thereof from a solid oral dosage form over several hours, e.g. at a constant or almost constant release rate, e.g. 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 a solid oral dosage form in a suitable aqueous environment over several hours, preferably at an almost constant release rate. According to another embodiment, the term "sustained release" is used to describe the release of an antibody or functional fragment thereof from a solid oral dosage form such that during prolonged time exposure in an aqueous environment (e.g. over at least 6 hours, preferably at least 10 hours, more preferably at least 14 hours, even more preferably at least 18 hours, e.g. at least 24 hours), the majority of the antibody or functional fragment thereof is released from the solid oral dosage form.

[0218] As used in the context herein, the term "cover" or "covering" is to be understood as defined above. Preferably, the sustained release layer (3) is on top of the covered reservoir layer (2) such that there is no other layer in between (i.e. between the sustained release layer and the reservoir layer). Preferably, the sustained release layer of the solid oral dosage form of the present application continuously covers the reservoir layer such that there is no gap in the sustained release layer (3).

[0219] The term "ammonio methacrylate copolymer" is known in the art. For example, the term "ammonio methacrylate copolymer" can refer to poly(ethyl acrylate-methyl methacrylate-trimethylammonio ethyl methacrylate chloride) (also referred to as poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonio ethyl methacrylate chloride)). In a preferred embodiment, the ammonio methacrylate copolymer is selected from the group consisting of poly(ethyl acrylate-methyl methacrylate-trimethylammonio ethyl methacrylate chloride) 1 :2:0.1 (also referred to as ammonio methacrylate copolymer type B, or as poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonio ethyl methacrylate chloride) 1 :2:0.1, or as poly[ethyl acrylate-co-2-methylprop-2-enoic acid methyl ester-co-N,N,N-trimethyl-2-[(2-methylprop-2-enoyl)oxy]ethan-1 -ammonium chloride] 1 :2:0.1, or as Eudragit® RS PO, or as Eudragit® RL PO, or as Eudragit® RL 30D, or combinations thereof. ® RS, such as commercially available Eudragit® RS 30D); poly(ethyl acrylate-methyl methacrylate-trimethylammonio ethyl methacrylate chloride) 1 :2:0.2 (also referred to as ammonio methacrylate copolymer type A, or as poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonio ethyl methacrylate chloride) 1 :2:0.2, or as poly[ethyl acrylate-co-2-methylprop-2-enoic acid methyl ester-co-N,N,N-trimethyl-2-[(2-methylprop-2-enoyl)oxy]ethan-1 -ammonium chloride] 1 :2:0.2, or as Eudragit® RS PO, or as Eudragit® RL PO, or as Eudragit® RL 30D, or combinations thereof. ® RS, such as commercially available Eudragit® RS 30D); poly(ethyl acrylate-methyl methacrylate-trimethylammonio ethyl methacrylate chloride) 1 :2:0.2 (also referred to as ammonio methacrylate copolymer type A, or as poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonio ethyl methacrylate chloride) 1 :2:0.2, or as poly[ethyl acrylate-co-2-methylprop-2-enoic acid methyl ester-co-N,N,N-trimethyl-2-[(2-methylprop-2-enoyl)oxy]ethan-1 -ammonium chloride] 1 :2:0.2, or as Eudragit® RS PO, or as Eudragit® RL PO, or as Eudragit® RL 30D, or combinations thereof. ® RS, such as commercially available Eudragit® RS 30D); poly(ethyl acrylate-methyl methacrylate-trimethylammonio ethyl methacrylate chloride) 1 :2:0.2 (also referred to as ammonio methacrylate copolymer type A, or as poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonio ethyl methacrylate chloride) 1 :2:0.2, or as poly[ethyl acrylate-co-2-methylprop-2-enoic acid methyl ester-co-N,N,N-trimethyl-2-[(2-methylprop-2-enoyl)oxy]ethan-1 -ammonium chloride] 1 :2:0.2, or as Eudragit® RS PO, or as Eudragit® RL PO, or as Eudragit® RL 30D, or combinations thereof. ® RS, such as commercially available Eudragit® RS 30D); poly(ethyl acrylate-methyl methacrylate-trimethylammonio ethyl methacrylate chloride) 1 :2:0.2 (also referred to as ammonio methacrylate copolymer type A, or as poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonio ethyl methacrylate chloride) 1 :2:0.2, or as poly[ethyl acrylate-co-2-methylprop-2-enoic acid methyl ester-co-N,N,N-trimethyl-2-[(2-methylprop-2-enoyl)oxy]ethan-1 -ammonium chloride] 1 :2:0.2, or as Eudragit® RS PO, or as Eudragit® RL PO, or as Eudragit® RL 30D, or combinations thereof.

[0220] According to a preferred embodiment, the solid oral dosage form of the present application does not contain other release retarding polymers in addition to the ammonio methacrylate copolymer. According to another preferred embodiment, the solid oral dosage form of the present application comprises poly(ethyl acrylate-methyl methacrylate-trimethylammonio ethyl methacrylate chloride) 1 :2:0.1; poly(ethyl acrylate-methyl methacrylate-trimethylammonio ethyl methacrylate chloride) 1 :2:0.2; or combinations thereof, and preferably does not contain other release retarding polymers. According to another preferred embodiment of the present application, the release retarding layer (3) does not contain other release retarding polymers (preferably does not contain other polymers) in addition to poly(ethyl acrylate-methyl methacrylate-trimethylammonio ethyl methacrylate chloride) 1 :2:0.1; poly(ethyl acrylate-methyl methacrylate-trimethylammonio ethyl methacrylate chloride) 1 :2:0.2 (such as Eudragit® RS PO, or Eudragit® RL PO, or Eudragit® RL 30D); or combinations thereof. ® RS, such as commercially available Eudragit® RS 30D); poly(ethyl acrylate-methyl methacrylate-trimethylammonio ethyl methacrylate chloride) 1 :2:0.2 (also referred to as ammonio methacrylate copolymer type A, or as poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonio ethyl methacrylate chloride) 1 :2:0.2, or as poly[ethyl acrylate-co-2-methylprop-2-enoic acid methyl ester-co-N,N,N-trimethyl-2-[(2-methylprop-2-enoyl)oxy]ethan-1 -ammonium chloride] 1 :2:0.2, or as Eudragit® RS PO, or as Eudragit® RL PO, or as Eudragit® RL 30D, or combinations thereof.

[0221] According to one particularly preferred embodiment of the present application, the sustained release layer (3) comprises poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1 :2:0.1 and preferably no other sustained release polymer. According to another particularly preferred embodiment of the present application, the sustained release layer (3) comprises poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1 :2:0.1 and preferably no other polymer.

[0222] 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 application is triethyl citrate (TEC).

[0223] The anti-tacking agent in the sustained release layer (3) is not particularly limited. The anti-tacking agent in the sustained release layer (3) can be selected from, for example, mesoporous silica, colloidal silica, stearic acid, magnesium stearate, glycerol monostearate (GMS), and talc. Preferably, the anti-tacking agent in the sustained release layer (3) of the oral dosage form of the present application is mesoporous silica, preferably the mesoporous silica has an average particle size of 1 pm to 10 pm, preferably 2 pm to 5 pm, more preferably about 3 pm to 4 pm, even more preferably 3.5 pm, and / or an average pore volume of 1.50 cm3 / g to 1.70 cm3 / g, preferably 1.55 cm3 / g to 1.65 cm3 / g, more preferably 1.58 cm3 / g to 1.62 cm3 / g, and even more preferably about 1.60 cm3 / g. 3 3 3 3 3 3 3

[0224] ​​​​​​​The amount of ammonio methacrylate copolymer in the sustained release layer (3) is not particularly limited. According to one embodiment, the solid oral dosage form of the present application comprises 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 ammonio methacrylate copolymer (preferably poly(ethyl acrylate-methyl methacrylate-trimethylammonio ethyl methacrylate chloride) 1 :2:0.1). According to another embodiment of the present application, the sustained release layer (3) comprises 60 to 90% by weight, preferably 65 to 85% by weight, more preferably 70 to 80% by weight, even more preferably 72 to 78% by weight of ammonio methacrylate copolymer (preferably poly(ethyl acrylate-methyl methacrylate-trimethylammonio ethyl methacrylate chloride) 1 :2:0.1) relative to the total weight of solids (i.e. not including solvent, preferably water) in the sustained release layer (3).

[0225] The amount of plasticizer in the sustained release layer (3) is not particularly limited. According to one embodiment of the present application, the sustained release layer (3) comprises 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, even more preferably 20% by weight of plasticizer relative to the total weight of ammonio methacrylate copolymer in the sustained release layer (3). According to another embodiment of the present application, the sustained release coating comprises 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 relative to the total weight of solids (i.e. not including solvent, preferably water) in the sustained release layer (3).

[0226] The amount of anti-tacking agent in the sustained release layer (3) is not particularly limited. According to one embodiment of the present application, the sustained release layer (3) comprises 1 to 30 wt.%, preferably 2 to 25 wt.%, more preferably 5 to 15 wt.%, even more preferably 8 to 12 wt.%, even more preferably 10 wt.% of the anti-tacking agent relative to the total weight of the ammonio methacrylate ester copolymer in the sustained release layer (3). According to another embodiment of the present application, the sustained release coating comprises 2 to 15 wt.%, preferably 5 to 12 wt.%, more preferably 6 to 9 wt.%, even more preferably 6 to 9 wt.%, even more preferably 6.5 to 8.5 wt.%, even more preferably 7 to 8 wt.%, even more preferably about 7.5 wt.% of the anti-tacking agent relative to the total weight of solids (i.e. not including solvent, preferably water) in the sustained release layer (3).

[0227] The sustained release layer (3) can comprise or not comprise a coalescence enhancer. According to one preferred embodiment of the present application, the sustained release layer (3) does not comprise a coalescence enhancer. According to another embodiment of the present application, the sustained release layer (3) comprises a coalescence enhancer, such as propylene glycol monolaurate (e.g. Lauroglycol ™ 90).

[0228] According to one preferred embodiment, the sustained release layer (3) consists of: ammonio methacrylate ester copolymer (preferably poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1 :2:0.1), plasticizer (preferably TEC) and anti-tacking agent (preferably mesoporous silica), and optionally residual solvent (preferably water).

[0229] According to one specific embodiment, the weight of the sustained release layer (3) relative to the combined weight of the inert core unit (1) and the reservoir layer (2) is 4 to 8 wt.%, preferably 5 to 7 wt.%, more preferably about 6 wt.%.

[0230] The sustained release layer (3) can be applied to the inert core unit (1) covered (coated) with the reservoir layer (2) using a drug layering. According to one preferred embodiment, the sustained release layer (3) of the solid oral dosage form of the present application can be deposited on the reservoir layer (2) by drug layering (preferably using spray coating, more preferably fluidized bed spray coating). Methods for drug layering of a sustained layer on a reservoir layer containing an antibody or functional fragment as active ingredient and covering an inert core are known in the art. Such methods can be found for example in WO 2019 / 057562. According to one specific embodiment, after the sustained release coating by drug layering and subsequent drying, but before the application of any further layer, the weight of the solid oral dosage form is increased by 4 to 8 wt.%, preferably 5 to 7 wt.%, more preferably about 6 wt.%.

[0231] Finally, the solid oral dosage form of the present application comprises a delayed release layer (4) covering the 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-tacking agent, preferably glycerol monostearate (GMS); a plasticizer, preferably triethyl citrate (TEC); and preferably a surfactant.

[0232] The term "delayed release" is known in the art. In the sense meant by the present application, a delayed release layer is a layer / coating which functions to prevent the release of the antibody or functional fragment thereof from the solid oral dosage form prior to a specific event, preferably in a pH-triggered fashion in solution. For example, the delayed release layer can be designed to concentrate the delivery of the antibody or functional fragment thereof entirely in the large intestine, starting in the caecum, through the ascending, transverse and descending colon, and ending in the sigmoid colon. Alternatively, for example, the delayed release coating can be designed to start the delivery of the antibody or functional fragment thereof in the ileum, and end the release in the sigmoid colon.

[0233] As used herein in the context, the term "cover" or "covering" is to be understood as defined above. Preferably, the delayed release layer (4) is on top of the covered sustained release layer (3) such that there is no other layer in between (i.e. between the delayed release layer and the delayed release layer). Preferably, the delayed release layer of the solid oral dosage form of the present application continuously covers the sustained release layer such that there is no gap in the delayed release layer.

[0234] The solid oral dosage form of the present application is for oral administration and comprises a delayed release layer as an outer layer (coating the delayed release layer / being coated with the delayed release layer) which prevents the release of the composition preferably before the terminal ileum or before the ileocolonic region, alternatively before the ascending colon or before the transverse colon of the gastrointestinal tract. The ileocolonic region is the region in the gastrointestinal tract where the small intestine merges with the large intestine. The large intestine is the penultimate part of the gastrointestinal tract and can be further subdivided into the caecum, the colon and the rectum. The colon is further subdivided into the ascending colon, the transverse colon, the descending colon and the sigmoid colon. The terminal ileum is the penultimate part of the small intestine and directly adjacent to the caecum.

[0235] The method of applying the delayed release layer is not particularly limited as long as it does not affect the stability and activity of the at least one antibody or functional fragment thereof in the reservoir layer coating. Methods for applying a delayed release coating are known in the art. In one embodiment of the present application, the delayed release coating is applied by spray coating, preferably fluidized bed spray coating, e.g. as described above.

[0236] 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 as poly(methacrylic acid-co-methyl methacrylate) 1 :2, or as Eudragit® L 30 D-55 (Evonik). ® 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 as Eudragit® S 100 (Evonik). ® FS. Poly(methacrylic acid-methyl methacrylate) 1 :1 is also known as methacrylic acid-methyl methacrylate copolymer (1 :1 ), or as poly(methacrylic acid-co-methyl methacrylate) 1 :1, or as Eudragit® FS 30 D (Evonik). ® L.

[0237] According to one embodiment, the delayed release layer (4) does not comprise a polymer which is not an enteric polymer. The term "enteric polymer" is known in the art and can refer to a polymer which does not dissolve in the stomach environment. According to another embodiment of the present application, the delayed release layer (4) does not contain other delayed release polymers in addition to 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 application, the delayed release layer (4) comprises poly(methacrylic acid-methyl methacrylate) 1 :2 and preferably does not contain other delayed release polymers.

[0238] According to one embodiment of the present application, the solid oral dosage form comprises 5 to 40 weight %, preferably 10 to 40 weight %, more preferably 10 to 35 weight %, even more preferably 15 to 35 weight %, even more preferably 15 to 30 weight %, even more preferably 18 to 30 weight %, even more preferably 20 to 30 weight %, even more preferably 21 to 26 weight %, for example about 22 to 25 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 combinations thereof (preferably poly(methacrylic acid-methyl methacrylate) 1 :2). According to another embodiment of the present application, the delayed release layer (4) comprises 50 to 97 weight %, preferably 65 to 95 weight %, more preferably 70 to 90 weight %, even more preferably 75 to 85 weight %, for example about 80 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 combinations thereof (preferably poly(methacrylic acid-methyl methacrylate) 1 :2) relative to the total weight of solids (i.e. not including residual solvents, such as ethanol and / or water) in the delayed release layer (4).

[0239] According to another embodiment of the present application, the solid dosage form (in the delayed release layer) comprises 7 mg / cm 2 to 12 mg / cm 2 , preferably 8 mg / cm 2 to 11 mg / cm 2 , more preferably 9 mg / cm 2 to 10 mg / cm 2 , even more preferably about 9.5 mg / cm 2 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 combinations thereof (preferably poly(methacrylic acid-methyl methacrylate) 1 :2).

[0240] The plasticizer in the delayed release layer (4) is not particularly limited. The plasticizer in the delayed release layer (4) can 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 application, the delayed release layer (4) comprises 1 to 30 wt%, preferably 2 to 25 wt%, more preferably 5 to 15 wt%, even more preferably 8 to 12 wt%, even more preferably about 10 wt% of the plasticizer relative to the total weight of the delayed release polymer in the delayed release layer (4). According to another embodiment of the present application, the delayed release layer (4) comprises 1 to 25 wt%, preferably 4 to 15 wt%, more preferably 5 to 12 wt%, even more preferably 6 to 10 wt%, even more preferably 7 to 9 wt%, even more preferably about 8 wt% of the plasticizer relative to the total weight of the solids (i.e., not including residual solvents, such as ethanol and / or water) in the delayed release layer (4).

[0241] The anti-tacking agent in the delayed release layer (4) is not particularly limited. The anti-tacking agent in the delayed release layer (4) can be selected from, for example, mesoporous silica, colloidal silica, stearic acid, magnesium stearate, glycerol monostearate (GMS), or talc. Preferably, the anti-tacking agent in the delayed release layer (4) is glycerol monostearate (GMS). According to one embodiment of the present application, the delayed release layer (4) comprises 1 to 30 wt%, preferably 2 to 25 wt%, more preferably 5 to 15 wt%, even more preferably 8 to 12 wt%, even more preferably about 10 wt% of the anti-tacking agent relative to the total weight of the delayed release polymer in the delayed release layer (4). According to another embodiment of the present application, the delayed release layer (4) comprises 1 to 20 wt%, preferably 4 to 15 wt%, more preferably 5 to 12 wt%, even more preferably 6 to 10 wt%, even more preferably 7 to 9 wt%, even more preferably about 8 wt% of the anti-tacking agent relative to the total weight of the solids (i.e., not including residual solvents, such as ethanol and / or water) in the delayed release layer (4).

[0242] The delayed release layer (4) of the solid oral dosage form of the present application can optionally further comprise a surfactant. The surfactant in the delayed release layer (4) is not particularly limited, however preferably the surfactant is a non-ionic surfactant. The solid oral dosage form in the delayed release layer (4) can comprise a surfactant 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.

[0243] According to a preferred embodiment of the present application, 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 application, the delayed release layer (4) comprises 0.1 to 15 wt%, preferably 0.5 to 10 wt%, more preferably 1 to 6 wt%, even more preferably 2 to 5 wt%, even more preferably 3 to 4.5 wt%, even more preferably 3.5 to 4 wt%, even more preferably about 4% of a surfactant relative to the total weight of the delayed release polymer in the delayed release layer (4). According to another embodiment of the present application, the delayed release layer (4) comprises 0.1 to 15 wt%, preferably 0.5 to 10 wt%, more preferably 1 to 5 wt%, even more preferably 2 to 4 wt%, even more preferably 2.5 to 3.5 wt%, even more preferably 3 to 3.5 wt%, even more preferably about 3 to 3.2 wt% of a surfactant relative to the total weight of the solids (i.e. not including solvent) in the delayed release layer (4).

[0244] According to a preferred embodiment of the solid oral dosage form of the present application, the delayed release layer (4) consists 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 combinations thereof (preferably poly(methacrylic acid-methyl methacrylate) 1 :2); an anti-tacking agent (preferably glycerol monostearate (GMS)); a plasticizer (preferably triethyl citrate (TEC)); a surfactant (preferably polysorbate 80) and optionally residual solvent (e.g. ethanol and / or water).

[0245] In one embodiment of the present application, the residual solvent content (e.g., residual solvent (preferably water) content after preparation of the solid oral dosage form) of the solid oral dosage form is less than 15 wt.%, preferably less than 10 wt.%, more preferably less than 8 wt.%, even more preferably less than 7%, even more preferably not more than 5%, e.g., about 5%, or alternatively not more than about 4 wt.% or not more than about 3 wt.% relative to the total weight of the solid oral dosage form. In another embodiment of the present application, the residual water content of the solid oral dosage form is less than 15 wt.%, preferably less than 10 wt.%, more preferably less than 8 wt.%, even more preferably less than 7%, even more preferably not more than 5%, e.g., about 5%, or alternatively not more than about 4 wt.%, or not more than about 3 wt.%, or not more than about 2 wt.% relative to the total weight of the solid oral dosage form.

[0246] In a preferred embodiment of the present application, the solid oral dosage form comprises or consists of a) in the inert core unit, microcrystalline cellulose; and / or b) in the reservoir layer, e.g., an antibody or functional fragment thereof specific for TNFa, sucrose, L-histidine (preferably L-histidine monohydrochloride and / or free base), hydroxypropyl methylcellulose (HPMC) (preferably hydroxypropyl methylcellulose 2910 2.6 mPas to 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 glyceryl monostearate (GMS); and / or e) residual water in the inert core unit and / or any layer.

[0247] In one preferred embodiment of the solid oral dosage form of the present application, the inert core unit comprises 5 wt.% to 75 wt.%, preferably 15 wt.% to 65 wt.%, more preferably 15 wt.% to 60 wt.%, even more preferably 20 wt.% to 60 wt.%, even more preferably 25 wt.% to 30 wt.% of microcrystalline cellulose relative to the total weight of the solid oral dosage form.

[0248] In another preferred embodiment of the solid oral dosage form of the application, the reservoir layer (2) comprises 0.05 to 30% by weight of the antibody or functional fragment thereof, 0.03 to 30% by weight of the 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 further buffering agents, 0.005 to 8% by weight of the anti-tacking agent and / or 0.0005 to 2% by weight of the surfactant; preferably 0.1 to 20% by weight of the antibody or functional fragment thereof, 0.1 to 25% by weight of the 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 further buffering agents, 0.01 to 5% by weight of the anti-tacking agent and / or 0.001 to 1% by weight of the surfactant; more preferably 0.5 to 20% by weight of the antibody or functional fragment thereof, 0.5 to 15% by weight of the binder, 1 to 25% by weight of sucrose, 0.05 to 2% by weight of L-histidine and optionally 0.05 to 1.5% by weight of further buffering agents, 0.05 to 1.5% by weight of the anti-tacking agent and / or 0.005 to 0.3% by weight of the surfactant; even more preferably 2 to 20% by weight of the antibody or functional fragment thereof, 5 to 15% by weight of the binder, 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 further buffering agents, 0.5 to 1.5% by weight of the anti-tacking agent and / or 0.05 to 0.3% by weight of the surfactant; even more preferably 8 to 12% by weight of the antibody or functional fragment thereof, 6 to 8% by weight of the binder, 15 to 18% by weight of sucrose, 0.15 to 1% by weight of L-histidine and optionally 0.6 to 0.9% by weight of further buffering agents, 0.6 to 0.8% by weight of the anti-tacking agent (preferably mesoporous silicon dioxide) and / or 0.05 to 0.1% by weight of the surfactant (preferably polysorbate 80) relative to the total weight of the solid oral dosage form.

[0249] In another preferred embodiment of the solid oral dosage form of the present application, the sustained release layer (3) comprises 1 to 10% by weight of ammonio methacrylate copolymer, 0.1 to 5% by weight of plasticizer and / or 0.05 to 7% by weight of anti-tacking agent, relative to the total weight of the solid oral dosage form; preferably 3 to 6% by weight of ammonio methacrylate copolymer, 0.2 to 2% by weight of plasticizer and / or 0.1 to 3% by weight of anti-tacking agent; more preferably 3.3 to 4.5% by weight of ammonio methacrylate copolymer, 0.5 to 1.5% by weight of plasticizer and / or 0.2 to 1% by weight of anti-tacking agent; even more preferably 3.6 to 4.2% by weight of poly(ethyl acrylate-methyl methacrylate-trimethylammonio ethyl methacrylate chloride) 1:2:0.1 (e.g. Eudragit® RS 30D), 0.6 to 1% by weight of plasticizer (preferably triethyl citrate (TEC)) and / or 0.3 to 0.5% by weight of anti-tacking agent. ® RS 30D), 0.6 to 1% by weight of plasticizer (preferably triethyl citrate (TEC)) and / or 0.3 to 0.5% by weight of anti-tacking agent.

[0250] In another preferred embodiment of the solid oral dosage form of the present application, the delayed release layer (4) comprises 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-tacking agent (preferably glycerol monostearate (GMS)), relative to the total weight of the solid oral dosage form; 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-tacking agent (preferably glycerol monostearate (GMS)); more preferably 18 to 30% by weight of poly(methacrylic acid-methyl methacrylate) 1:2, 1.5 to 3% by weight of plasticizer, 0.5 to 1.3% by weight of surfactant and / or 1.5 to 3% by weight of anti-tacking agent (preferably glycerol monostearate (GMS)); even more preferably 21 to 26% by weight of poly(methacrylic acid-methyl methacrylate) 1:2, 2.0 to 2.6% by weight of plasticizer, 0.7 to 1.1% by weight of surfactant and / or 2.0 to 2.6% by weight of anti-tacking agent (preferably glycerol monostearate (GMS)).

[0251] In another preferred embodiment of the application, the solid oral dosage form comprises at most 8 wt%, at most 7 wt%, or at most 6 wt%, or at most 5.5 wt%, preferably at most 5 wt%, for example about 5 wt%, or 4.5 wt%, or 4 wt%, or 3 wt%, of water relative to the total weight of the solid oral dosage form in the inert core unit and / or in any layer.

[0252] In yet another preferred embodiment of the present application, the solid oral dosage form comprises, or consists of, a) in the inert core unit, 5 to 75%, preferably 15 to 65%, more preferably 20 to 60%, even more preferably 25 to 30% by weight of microcrystalline cellulose; and / or b) in the reservoir layer, 0.05 to 30% by weight of the antibody or functional fragment thereof, 0.03 to 30% by weight of a 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 further buffering agents, 0.005 to 10% by weight of an anti-tacking agent and / or 0.0005 to 2% by weight of a surfactant; preferably 0.1 to 20% by weight of the 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 3% by weight of L-histidine and optionally 0.01 to 3% by weight of further buffering agents, 0.01 to 5% by weight of an anti-tacking agent and / or 0.001 to 1% by weight of a surfactant; more preferably 0.5 to 20% by weight of the antibody or functional fragment thereof, 0.5 to 15% by weight of a binder, 1 to 25% by weight of sucrose, 0.05 to 2% by weight of L-histidine and optionally 0.05 to 1.5% by weight of further buffering agents, 0.05 to 1.5% by weight of an anti-tacking agent and / or 0.005 to 0.3% by weight of a surfactant; even more preferably 2 to 20% by weight of the antibody or functional fragment thereof, 5 to 15% by weight of a binder, 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 further buffering agents, 0.5 to 1.5% by weight of an anti-tacking agent and / or 0.05 to 0.3% by weight of a surfactant; even more preferably 8 to 12% by weight of the antibody or functional fragment thereof, 6 to 8% by weight of a binder, 15 to 18% by weight of sucrose, 0.15 to 1% by weight of L-histidine and optionally 0.6 to 0.9% by weight of further buffering agents, 0.6 to 0.8% by weight of mesoporous silica and / or 0.05 to 0.1% by weight of polysorbate 80; and / or c) in the sustained release layer, 1 to 10% by weight of ammonio methacrylate copolymer, 0.1 to 5% by weight of a plasticizer and / or 0.05 to 7% by weight of an anti-tacking agent; preferably 3 to 6% by weight of ammonio methacrylate copolymer, 0.2 to 2% by weight of a plasticizer and / or 0.1 to 3% by weight of an anti-tacking agent; more preferably 3.3 to 4.5% by weight of ammonium methacrylate copolymer, 0.5 to 1.5% by weight of plasticizer and / or 0.2 to 1% by weight of anti-tacking agent; preferably 3.6 to 4.2% by weight of poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl 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 mesoporous silica; and / or d) in the delayed release layer, 10 to 40% by weight of poly(methacrylic acid-methyl methacrylate) 1 :2, 0.5 to 5% by weight of plasticizer, 0.1 to 3.5% by weight of surfactant and / or 0.5 to 8% by weight of glycerol monostearate (GMS); preferably 15 to 35% by weight of poly(methacrylic acid-methyl methacrylate) 1 :2, 1 to 4% by weight of plasticizer, 0.2 to 2% by weight of surfactant and / or 1 to 5% by weight of glycerol monostearate (GMS); more preferably 18 to 30% by weight of poly(methacrylic acid-methyl methacrylate) 1 :2, 1.5 to 3% by weight of plasticizer, 0.5 to 1.3% by weight of surfactant and / or 1.5 to 3% by weight of glycerol monostearate (GMS); even more preferably 21 to 26% by weight of poly(methacrylic acid-methyl methacrylate) 1 :2, 2.0 to 2.6% by weight of plasticizer, 0.7 to 1.1% by weight of surfactant (e.g. polysorbate 80) and / or 2.0 to 2.6% by weight of glycerol monostearate (GMS); and / or e) up to 5.5% by weight or up to 5% by weight, e.g. 5% by weight, of water in the inert core unit and / or any layer.

[0253] The activity and stability of the antibody or functional fragment thereof, e.g. an anti-TNFa antibody or functional fragment thereof, in the solid oral dosage form of the present application is high. The stability and activity of the antibody or fragment thereof can be estimated, for example, by determining the fraction of the antibody or functional fragment thereof present as a dimer and other aggregates. According to one embodiment of the present application, the fraction of the total content of the antibody or functional fragment thereof present in the solid oral dosage form as a dimer and other aggregates is not more than 15%, preferably 12%, more preferably 10%, even more preferably 8%, even more preferably 7%, even more preferably 5%, for example 3%. Methods of determining the fraction of a polypeptide present as a dimer and other aggregates are known in the art and include, for example, size exclusion chromatography (SEC). According to another embodiment, the fraction of the total content of the antibody or functional fragment thereof present in the solid oral dosage form as a fragment of a full-length antibody or functional fragment thereof is not more than 15%, preferably 12%, more preferably 10%, even more preferably 8%, even more preferably 7%, even more preferably 5%, for example 3%.

[0254] The solid oral dosage form of the present application is preferably gastro-resistant. According to one embodiment of the present application, the solid oral dosage form of the present application is used for targeted release of the antibody or functional fragment thereof starting in the terminal ileum, in the ileocolic region, in the ascending colon, or in the transverse colon, preferably in the terminal ileum, in the ileocolic region, or in the ascending colon, more preferably in the terminal ileum or in the ileocolic region. According to another embodiment of the present application, the solid oral dosage form of the present application is used for targeted release of the antibody or functional fragment thereof in the terminal ileum, in the ileocolic region, in the ascending colon, in the transverse colon, in the descending colon, and / or in the sigmoid colon. According to yet another embodiment of the present application, the solid oral dosage form of the present application is used for targeted sustained release of the antibody or functional fragment thereof starting in the terminal ileum and continuing at least through the descending colon, preferably the sigmoid colon.

[0255] The solid oral dosage form of the present application is suitable for targeted sustained release in the lower gastrointestinal tract. Preferably, the solid oral dosage form of the present application does not release any relevant amount of the antibody or functional fragment thereof (e.g., releases less than 1 wt%, or less than 0.5 wt%, or less than 0.1 wt% of the total antibody or functional fragment thereof loading) upon immersion in an aqueous solution at pH 6.0 under continuous stirring (e.g., for 2 hours). According to one embodiment of the present application, the solid oral dosage form according to any one of the above embodiments allows for a sustained release of the antibody or 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, most preferably at least 24 hours, upon continuous immersion of the solid oral dosage form in an aqueous solution having a pH of 6.5 to 7.5, preferably a pH of about 6.8, under continuous stirring. According to another embodiment of the present application, at least 80%, preferably at least 90%, 95% or 98%, of the antibody or fragment thereof in the solid oral dosage form is released within 4 hours to 30 hours, preferably 8 hours to 28 hours, more preferably 16 hours to 26 hours, even more preferably 24 hours, preferably with a substantially constant release rate, upon continuous immersion of the solid oral dosage form according to any one of the above embodiments in an aqueous solution having a pH of 6.5 to 7.5, preferably a pH of 6.5 to 7.0, more preferably a pH of 6.8, under continuous stirring.

[0256] In another aspect, the present application relates to a solid oral dosage form as defined in any of the above embodiments for use in the treatment of a disease in the gastrointestinal tract, preferably in the ileum (preferably terminal ileum), ileocolonic region, ascending colon, transverse colon, descending colon and / or sigmoid colon of a patient, preferably a human patient. Such diseases include for example immune checkpoint inhibitor (ICPI)-induced colitis, ICPI-induced small bowel colitis, ICPI-induced diarrhea, IBD, cancer (such as colorectal cancer or small bowel cancer), celiac disease, infections of the small bowel and colon (such as Clostridium difficile infection) and diarrhea. In a preferred embodiment of the present application, the solid oral dosage form of the present application is for use in the treatment of ICPI-induced colitis, ICPI-induced small bowel colitis or ICPI-induced diarrhea, preferably ICPI-induced colitis. In another preferred embodiment of the present application, the solid oral dosage form of the present application is for use in the treatment of IBD, for example Crohn’s disease or ulcerative colitis.

[0257] In another aspect, the present application relates to an oral multi-particulate drug delivery system comprising a plurality of solid oral dosage forms as described in any of the above embodiments, preferably wherein the oral multi-particulate drug delivery system is a sachet / stick pack, a straw device (xStraw ® ), a capsule or a tablet / minitablet, more preferably a capsule; preferably wherein the oral multi-particulate drug delivery system comprises a total amount of the antibody or functional fragment thereof suitable for oral administration to a human patient.

[0258] According to another embodiment, the oral multi-particulate drug delivery system of the present application comprises a plurality of solid oral dosage forms according to any one of the above embodiments, wherein each solid oral dosage form preferably has a predetermined axis and a predetermined cross-sectional profile, wherein at least 80% by number, preferably 90%, more preferably 95% of those solid oral dosage forms have a median aspect ratio of from 0.7 to 1.7, which aspect ratio is defined as the length of the solid oral dosage form along the predetermined axis divided by the smallest cross-sectional dimension. According to another embodiment, the median aspect ratio is higher than 0.8, preferably higher than 0.9, and lower than 1.6, preferably lower than 1.5, more preferably 1.4, even more preferably lower than 1.3, even more preferably lower than 1.2, most preferably about 1. For further details regarding the aspect ratio, the predetermined axis, the predetermined cross-sectional profile and the span (including definitions and embodiments), reference is made to the disclosure of EP 2 512 453. It is understood that the above definitions and embodiments regarding the aspect ratio and the span of the solid oral dosage form equally apply to the solid oral dosage forms of the present application according to any one of the above embodiments. Further embodiments of the oral multi-particulate drug delivery system can be found in EP 2 512 453 and are applicable to the present application, whether these embodiments are disclosed in EP 2 512 453 as relating to spheronized / non-spheronized solid dosage forms or not.

[0259] According to yet another embodiment of the present application, the oral multi-particulate drug delivery system of the present application allows for a 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%, even more preferably at least 98% of the antibody or functional fragment thereof from the solid oral dosage form.

[0260] According to yet another embodiment of the present application, the oral multi-particulate drug delivery system of the present application allows for a 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%, even more preferably at least 98% of the antibody or functional fragment thereof from the solid oral 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 of continuous immersion of the solid oral dosage form into an aqueous solution having a pH of from 6.5 to 7, preferably a pH of about 6.8, under continuous stirring (sustained release).

[0261] According to yet another embodiment of the present application, the oral multi-particulate drug delivery system of the present application is prepared from a plurality of solid oral dosage forms by compression or encapsulation, preferably encapsulation.

[0262] In another aspect, the present application relates to the use of the solid oral dosage form of any one of the above-mentioned embodiments for the preparation of a medicament for the treatment of a gastrointestinal disease. The medicament can comprise the oral multiparticulate drug delivery system of any one of the above-mentioned embodiments. According to one embodiment, the gastrointestinal disease is immune checkpoint inhibitor (ICPI)-induced colitis, ICPI-induced small bowel colitis, ICPI-induced diarrhea, or IBD, such as Crohn’s disease or ulcerative colitis.

[0263] In yet another aspect, the present application relates to a method for targeted local treatment of a gastrointestinal disease, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the solid oral dosage form according to any one of the above-mentioned embodiments or the oral multiparticulate drug delivery system according to any one of the above-mentioned embodiments. The patient is preferably a human patient. According to one embodiment, the method is for the treatment of a gastrointestinal disease in the ileum (preferably the terminal ileum), ileocolonic region, ascending colon, transverse colon, descending colon, and / or sigmoid colon of the patient. According to a further embodiment of the method, the gastrointestinal disease is inflammatory bowel disease (IBD), such as Crohn’s disease or ulcerative colitis. According to one preferred embodiment of the method, the gastrointestinal disease is immune checkpoint inhibitor (ICPI)-induced colitis, ICPI-induced small bowel colitis, or ICPI-induced diarrhea, preferably ICPI-induced colitis.

[0264] Table 1 : Sequence Summary of Sequence Listing .

[0265]

[0266]

[0267] Examples Materials and Methods Applied in the Examples 1 Manufacturing Process 1.1 Drug layering Drug loaded multi-particulate pellets were prepared by layering (depositing) the reservoir layer solution containing anti-TNFa antibody onto the starting cellet cores in a Mini-Glatt fluid bed (Glatt GmbH, Binzen, Germany) equipped with a Wurster column (bottom spray evaluation). To prepare the reservoir layer formulation, hydroxypropyl methylcellulose (HPMC) was slowly added to a histidine buffer solution (pH 5.5) under paddle stirring homogenization conditions until the HPMC solids were completely dissolved into the buffer media. Thereafter, Syloid 244 FP was slowly added and dispersed in the HPMC-pH 5.5 histidine buffer media by paddle stirring. The resulting HPMC coating dispersion was then blended with the desired mass of anti-TNF antibody drug substance (DS) which was available as a buffered solution in pH 5.5 histidine buffer also containing sucrose as a stabilizer and polysorbate 80 as a surfactant. The anti-TNF-a antibody coating formulation was layered onto the inert cellets ® ) to achieve the desired loading at an inlet air temperature of 38°C to 44°C and a product temperature of 31°C to 35°C. The antibody layered pellets were dried in a drying cabinet with air circulation at 40°C for 20 hours to 24 hours.

[0268] 1.2 Sustained release coating A ready-to-use Eudragit RS30D aqueous dispersion containing 30% Eudragit ® RS solids was used for the sustained release coating of the antibody layered pellets. Prior to the coating step with Eudragit RS, the 30% polymer dispersion was homogenized and transferred through a sieve into a glass beaker to prevent particle agglomeration. Purified water was added followed by triethyl citrate (plasticizer) and homogenized for 15 minutes by magnetic stirring. Thereafter, Syloid 244 FP (anti-tacking agent) was added and the target concentration of the final Eudragit RS dispersion was set to 20% total solids. The final aqueous coating dispersion of Eudragit RS was sprayed onto the anti-TNF-a antibody drug layered pellets (cellets) using the Micro-kit of the Glatt fluid bed with bottom spray, an inlet air temperature of 29°C to 31°C and a product temperature of 26°C to 28°C. After completion of the spraying of the Eudragit RS coating formulation, a Syloid 244 FP aqueous suspension was sprayed to reduce the stickiness of the pellets. After this step, a post-coating heat treatment (in-process solidification) was performed in the fluid bed equipment at an inlet air temperature of 52°C to 55°C for 30 minutes to achieve a target product temperature of 45°C to 46°C while spraying water to create a humid environment.

[0269] 1.3 Delayed release coating The anti-TNF-α antibody sustained-release spheres (coated with Eudragit RS) were further coated with Eudragit S as a delayed-release polymer. Eudragit S was then coated at room temperature with magnetic stirring. ® Eudragit S coating formulation was prepared by completely dissolving the S polymer in 96% ethanol. Triethyl citrate was added to the organic (ethanol) solution and homogenized by magnetic stirring. As a next step, polysorbate 80 (Tween 80) was dissolved in purified water by magnetic stirring, followed by the addition of GMS to prepare an aqueous emulsion of glyceryl monostearate (GMS) (used as an anti-sticking agent). The mixture was then heated to 75°C under continuous magnetic stirring and held at this temperature for 15 minutes to obtain a homogeneous emulsion. Subsequently, the GMS emulsion was 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 coating formulation. The coating process was carried out using a Glatt fluidized bed micro-kit with bottom spray, an inlet air temperature of 27°C to 32°C, and a product temperature of 26.0°C to 29°C. After spraying the target amount of Eudragit S polymer, a pre-drying step following coating is performed at 40°C for 30 minutes in a fluidized bed apparatus. The drying process continues for 2 to 4 hours at 40°C in a drying oven with air circulation.

[0270] 2 Dissolution Method 2.1 Dissolution assay Dissolved at 37°C with stirring at 75 rpm.

[0271] medium: a) 0.1N HCl; b) Potassium phosphate buffer containing sodium chloride, pH 6.0. The salts were mixed such that the ionic strength of the medium was equal to that of the biologically relevant Hanks buffer (HMFadda and AW Basit, J. Drug Del. Sci. Tech. 2005; 15(4): 273-280).

[0272] Procedure: One dose unit was added to each container and stirred in 0.1N HCl for 2 hours, followed by dissolution in medium b) for 2 hours. The pH of the dissolution medium was then set to pH 6.8. To obtain a chromatogram, the samples were analyzed by HPLC, and total protein was quantified using the Bradford method detailed below.

[0273] 2.2 useBradford Measured antibody release Dissolution testing of anti-TNFa antibody layered pellets and sustained release coated pellets was performed in phosphate buffer at pH 6.8 by means of rotational mixing. Briefly, pellets were weighed in 5 mL cryotubes to which 4 mL of phosphate buffer at pH 6.8 was added. The tubes were then placed in a benchtop rotation device to rotate at 15 rpm. The amount of coated pellets used per tube was calculated in order to produce a theoretical 0.8 mg / mL antibody drug substance (DS) concentration in the buffer at 100% release, taking into account the theoretical antibody loading. At defined time points (15 min; 30 min; 1 h; 2 h; 4 h; 6 h and 24 h), 100 pL of supernatant was sampled. The samples were then centrifuged at 3000 rpm for 5 min and the supernatant was used for further analysis. The volume of sample taken was not replaced with fresh buffer during the course of the experiment.

[0274] Total protein quantification was performed by colorimetry following the Bradford method with Coomassie Plus assay (Thermo Scientific). Quantification was performed using a standard calibration curve freshly prepared in 10 mM phosphate buffer at pH 6.8. The calibration curve was established with standard TNFa antibody at 0.03 mg / mL to 1.0 mg / mL.

[0275] Results Formulation of Multilayer Solid Oral Dosage Forms for Delayed Release and Sustained Release A drug product was developed comprising an anti-TNFa antibody as a multiparticulate formulation, adopting a multi-layered coating design, using cellets ® As inert core unit, the inert core unit was coated with a reservoir layer formulation comprising an anti-TNFa antibody (whole antibody fraction) as active ingredient, sucrose (stabilizer), histidine / histidine HC1 (buffer) and Pharmacoat 603 (hydroxypropyl methylcellulose) as film forming polymer (polymeric binder). Anti-TNFa antibody layered cellets ® were further coated with an inner layer comprising Eudragit ® RS (sustained release polymer) and an outer layer of Eudragit ® S (delayed release polymer). Different layers were applied by means of drug layering using fluidized bed spray coating.

[0276] Therefore, the following multi-layered pellet design was defined during formulation development: - Inert core unit (cellets ® ); - Anti-TNFα antibody reservoir layer (hydroxypropyl methylcellulose as film-forming polymer; aqueous); - Sustained-release layer (Eudragit) ® RS as a film-forming polymer; aqueous); and - Delayed release layer (Eudragit) ® S is a film-forming polymer; organic.

[0277] The resulting multilayer solid oral dosage form is shown in Figure 1 and Figure 2 middle. Figure 5 SEM images of the cross-section of the final drug product are shown. The final drug product has the following components in each layer, as shown in Table 2 below.

[0278] Table 2: Ingredients in the Coated Spheroid Layer

[0279] During drug product development, solid dosage forms were formulated with different loadings of anti-TNFα antibodies in the reservoir layer, and different functional coatings in solid oral dosage forms were explored.

[0280] One method for generating multi-particle formulations with different antibody loadings involves using the same reservoir coating formulation (e.g., the same concentration of anti-TNFα antibody and excipients in the reservoir coating formulation) for drug products with different antibody loadings in a multi-particle solid oral dosage form, and adjusting the application amount during coating to achieve the desired anti-TNFα antibody loading. This method results in a thinner reservoir layer at lower drug loadings compared to a thicker layer corresponding to higher drug loadings. (Eudragit is included.) ® RS (inner coating) and Eudragit ® The other functional coating layers of S (outer coating) remain unchanged and are unrelated to the target level of anti-TNFα antibody loading expected after drug stratification.

[0281] By applying a reservoir coating formulation until the target loading level (target loading level of anti-TNFα antibody) is reached, cells loaded with anti-TNFα antibody are obtained. ® 100% recovery of anti-TNFα antibody can be confirmed from globules containing a reservoir layer but without a sustained-release or delayed-release layer (by Bradford assay) (see example). Figure 3 (A), Example 1 Drug Layering Intermediate).

[0282] Next, Eudragit will be applied by spraying. ® The continuous coating of RS is applied to the top of the reservoir layer. (via Eudragit) ®SEM analysis of the RS intermediate confirmed that Eudragit ® the quality and uniformity of the coating of the RS layer, wherein Figure 5 Results are shown for the lower drug load case, Figure 6 Results are shown for the higher drug load case.

[0283] As a final step, a Eudragit ® S based delayed release layer was applied on top of the extended release layer.

[0284] Upon evaluation of the anti-TNFa antibody loaded embodiments comprising the extended release layer, it was surprisingly found that the drug levels released from the anti-TNFa antibody layered cellets ® further coated with a Eudragit ® RS based extended release layer, but not yet comprising a Eudragit ® S delayed release layer, were not stable. In some cases, the drug release within 24 to 26 hours was only about 12% in the release test simulating the gastro-intestinal environment as described above (B in Figure 3 ).

[0285] However, surprisingly, upon application of the final outer delayed release layer comprising Eudragit ® S (Example 1 final product), the drug release continued to increase in the release test to a level which is of commercial interest for an expensive drug product and exhibited a consistent and sufficiently high release rate (about 80% antibody released within 26 hours in the release test, see (C in Figure 3 and (D in Figure 4 ). This was surprising, as the delayed release layer should only prevent drug release until the pH trigger condition occurs.

[0286] These findings indicate that the anti-TNFa antibody multi-layer coating system as proposed by the inventors is not only driven by the separate properties of the excipients used in the different coating layers or by the separate properties of the functional polymers, but also by a combined effect of the entire formulation, resulting in a drug delivery system suitable for targeted release of the large antibody moiety. Thus, these surprising results indicate (without being bound to any particular theory) that the final solid oral dosage form as found by the inventors containing the antibody (e.g., Example 1 final product) is able to function due to a combined effect of the components in the different layers, enabling the release of the large antibody moiety in the desired manner. Figure 1

[0287] Exemplary compositions of the final solid oral dosage form having a layer structure as shown in Figure 1 Table 3 / Table 4 and Table 5 / Table 6, respectively. ​

[0288] For the final (multilayer) combination of an anti-TNFa antibody reservoir layer and a functional polymer layer, as for example assessed from using a dissolution assay Figure 3 (C) and Figure 4 As can be seen in Table 2, the release rate after 2 hours at pH 6.0 was 0%. At pH 6.8, a slow release started after 1 hour to 2.5 hours. After 26 hours, about 80% of the antibody had been released.

[0289] Finally, the final (multilayer) combination of an anti-TNFa antibody reservoir layer and a functional polymer layer, as proposed by the inventors, as shown in Figure 2 prevented early (and undesired) drug release in a medium simulating the gastric acid environment (0.1 N HCI, 2 hours of action) and also no drug release during passage through the upper small intestine (no release in pH 6.0 buffer for 2 hours of action) and allowed a slow release of the antibody in a medium at pH 6.8 or higher, thus simulating the pH conditions in the ileum, enabling the drug release to start as intended and to proceed in a sustained manner along the intestinal tract.

[0290] Table 3: Composition of Example 1 (percent values are relative to the total weight of the final composition of Example 1 Weight Percent of Each Ingredient

[0291] Table 4: Composition of Example 1 (percent values are relative to the total weight of the final composition of Example 1 Weight Percent of Each Ingredient in Each Layer )

[0292] Table 5: Composition of Examples 2, 3, and 4 (weight percent of each ingredient is relative to the total weight of the final composition of Examples 2, 3, and 4, respectively) Table 6: Composition of Examples 2, 3, and 4 (weight percent of each ingredient in each layer is relative to the total weight of the final composition of Examples 2, 3, and 4, respectively)

[0293] Stability Testing Exemplary Potency Assay

[0294] Results The formulation according to Example 4 was stored at 2°C to 8°C or 25°C / 60% RH for 12 months. At different time points, the potency of the antibody in the formulation was tested by determining the relative potency of the anti-TNFa antibody (relative to the nominal antibody content) using a cell-based assay suitable for antibodies.

[0295] ​ : A549 cells were seeded prior to assay. A gradient dilution of the analyte was incubated with a constant dose of TNF alpha. After allowing the analyte-TNF alpha complex to form, the A549 cells were then stimulated with the mixture and the stimulation was eliminated by fixing the cells with paraformaldehyde. The phosphorylated NF-kappa B S536 was labeled by sequentially staining the cells with a phospho-specific NF-kappa B S536 antibody and a HRP-labeled detection antibody. The amount of HRP was detected by its conversion of a chemiluminescent substrate and the generation of a luminescent signal that can be captured by a dedicated instrument.

[0296] ​ :

[0297] It can be seen that the antibody maintains its activity over a period of at least 12 months under both conditions of 2°C to 8°C and 25°C / 60% RH. The stability under 25°C conditions is very significant and surprising for an antibody drug.

Claims

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

2. A solid oral dosage form comprising: i) an inert core unit (1); ii) a reservoir layer (2) covering the inert core unit (1) and comprising as active agent an antibody or a functional fragment thereof; a stabilizer; a buffer; and a polymeric binder; iii) a sustained release layer (3) covering the reservoir layer (2) and comprising at least one cationic polymer; a plasticizer; and an anti-tacking agent; and iv) a delayed release layer (4) covering the sustained release layer (3) and comprising at least one anionic polymer and a plasticizer.

3. The solid dosage form according to claim 1 or 2, wherein the at least one anionic polymer is selected from the group consisting of: a polymer comprising carboxylic acid groups; 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 dosage form 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; ammonio methacrylate copolymer; poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1:2:0.1; poly(2-methacryloyl-N,N-dimethylaminoethyl methacrylate); poly-L-lysine; polyaziridine; poly(amidoamine).

5. A solid oral dosage form comprising: i) an inert core unit (1); ii) a reservoir layer (2) covering the inert core unit (1) and comprising as active agent an antibody or a functional fragment thereof; a stabilizer; a buffer; and a polymeric binder; iii) a sustained release layer (3) covering the reservoir layer (2) and comprising ammonio methacrylate copolymer; a plasticizer; and an anti-tacking agent; and iv) a delayed release layer (4) covering the sustained release layer (3) and comprising poly(methacrylic acid-methyl methacrylate) 1:2, poly(methacrylic acid-methyl methacrylate) 1:1 or a combination thereof; an anti-tacking agent; and a plasticizer.

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

7. The solid oral dosage form according to any one of the preceding claims, wherein the inert core unit (1) is an inert spheroid comprising or consisting of microcrystalline cellulose.

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

9. The solid oral dosage form according to any one of the preceding claims, wherein the buffering agent in the reservoir layer (2) is selected from the group consisting of: L-histidine buffer, citrate buffer, hydroxymethylamino methane (TRIS) buffer, succinate buffer, phosphate buffer, acetate buffer, and combinations thereof.

10. The solid oral dosage form according to any one of the preceding claims, wherein the stabilizer in the reservoir layer (2) is sucrose; and / or the buffering agent is L-histidine or a salt thereof; and / or the polymeric binder in the reservoir layer (2) is hydroxypropyl methylcellulose (HPMC).

11. The solid oral dosage form according to any one of the preceding claims, wherein the reservoir layer (2) comprises an anti-tacking agent and / or a surfactant.

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

13. The solid oral dosage form according to any one of the preceding claims, wherein the sustained release layer (3) comprises poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1:2:0.1, and is free of other sustained release polymers.

14. The solid oral dosage form according to any one of the preceding claims, wherein the plasticizer in the sustained release layer (3) is triethyl citrate (TEC); and / or the anti-tacking agent is mesoporous silica.

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

16. The solid oral dosage form according to any one of the preceding claims, wherein the delayed release layer (4) comprises poly(methacrylic acid-methyl methacrylate) 1:2, and is free of other delayed release polymers.

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

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

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

20. The solid oral dosage form according to any one of the preceding claims, wherein the inert core unit comprises 15% to 60% by weight of microcrystalline cellulose relative to the total weight of the solid oral dosage form.

21. The solid oral dosage form according to any one of the preceding claims, wherein the reservoir layer (2) comprises 0.1% to 20% by weight of the 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 further buffering agents, 0.01% to 5% by weight of an anti-tacking agent and / or 0.001% to 1% by weight of polysorbate 80 relative to the total weight of the solid oral dosage form.

22. The solid oral dosage form according to any one of the preceding claims, wherein the sustained release layer (3) comprises 3% to 6% by weight of ammonio methacrylate copolymer, 0.2% to 2% by weight of a plasticizer and / or 0.1% to 3% by weight of an anti-tacking agent relative to the total weight of the solid oral dosage form.

23. The solid oral dosage form according to any one of the preceding claims, 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 glyceryl monostearate (GMS) relative to the total weight of the solid oral dosage form.

24. The solid oral dosage form according to any one of the preceding claims, comprising at most 5% by weight of water relative to the total weight of the solid oral dosage form in the inert core unit and / or any layer.

25. The solid oral dosage form according to any one of the preceding claims, wherein the solid oral dosage form comprises or consists of: a) in the inert core unit (1), 57.65% to 58.05% by weight of microcrystalline cellulose; b) in the reservoir layer (2), 0.75% to 0.85% by weight of the antibody or functional fragment thereof, 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) in the extended release layer (4), 23.25 to 23.55 wt% of poly(methacrylic acid-methyl methacrylate) 1 :2, 2.29 to 2.39 wt% triethyl citrate (TEC), 0.89 to 0.99 wt% polysorbate 80, and 2.29 to 2.39 wt% glyceryl monostearate (GMS); and d) in the extended release layer (4), 23.25 to 23.55 wt% of poly(methacrylic acid-methyl methacrylate) 1 :2, 2.29 to 2.39 wt% triethyl citrate (TEC), 0.89 to 0.99 wt% polysorbate 80, and 2.29 to 2.39 wt% glyceryl monostearate (GMS); and e) 4.9 to 5.1 wt% water in the inert core unit and / or any layer.

26. The solid oral dosage form of any one of the preceding claims, wherein the solid oral dosage form comprises or consists of: a) in the inert core unit (1), 57.85 wt% microcrystalline cellulose; b) in the reservoir layer (2), 0.80 wt% anti-TNFa antibody or functional fragment thereof, 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) in the extended release layer (4), 23.25 to 23.55 wt% of poly(methacrylic acid-methyl methacrylate) 1 :2, 2.29 to 2.39 wt% triethyl citrate (TEC), 0.89 to 0.99 wt% polysorbate 80, and 2.29 to 2.39 wt% glyceryl monostearate (GMS); and d) in the extended release layer (4), 23.25 to 23.55 wt% of poly(methacrylic acid-methyl methacrylate) 1 :2, 2.29 to 2.39 wt% triethyl citrate (TEC), 0.89 to 0.99 wt% polysorbate 80, and 2.29 to 2.39 wt% glyceryl monostearate (GMS); and e) 4.9 to 5.1 wt% water in the inert core unit and / or any layer.

27. The solid oral dosage form of any one of claims 1 to 24, wherein the solid oral dosage form comprises or consists of: a) in the inert core unit (1), 27.0 to 27.3 wt% microcrystalline cellulose; b) in the reservoir layer (2), 9.38 to 9.58 wt% antibody or functional fragment thereof, 6.8 to 7.0 wt% hypromellose (HPMC), 16.72 to 17.02 wt% sucrose, 0.89 to 0.99 wt% L-histidine, 0.64 to 0.74 wt% mesoporous silica, and 0.07 to 0.09 wt% polysorbate 80; c) in the extended release layer (4), 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 glyceryl monostearate (GMS); and d) in the extended release layer (4), 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 glyceryl monostearate (GMS); and e) 4.23 to 4.43% by weight of water in the inert core unit and / or any layer.

28. The solid oral dosage form of any one of claims 1 to 24, wherein the solid oral dosage form comprises or consists of: a) in the inert core unit (1), 27.16% by weight of microcrystalline cellulose; b) in the reservoir layer (2), 9.48% by weight of an anti-TNFa antibody or functional fragment thereof, 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) in the extended release layer (4), 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 glyceryl monostearate (GMS); and d) in the extended release layer (4), 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 glyceryl monostearate (GMS); and e) 4.33% by weight of water in the inert core unit and / or any layer.

29. The solid oral dosage form of any one of claims 1 to 24, wherein the solid oral dosage form comprises or consists of: a) in the inert core unit (1), 25.07 to 25.37% by weight of microcrystalline cellulose; b) in the reservoir layer (2), 9.16 to 9.36% by weight of an antibody or functional fragment thereof, 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) in the extended release layer (4), 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 glyceryl monostearate (GMS); and d) in the extended release layer (4), 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 glyceryl monostearate (GMS); and e) 4.33% by weight of water in the inert core unit and / or any layer. c) in the extended release layer (4), 24.65 to 24.95 wt% of poly(methacrylic acid-methyl methacrylate) 1 :2, 2.43 to 2.53 wt% of triethyl citrate (TEC), 0.94 to 1.04 wt% of polysorbate 80, and 2.43 to 2.53 wt% of glyceryl monostearate (GMS); and d) in the extended release layer (4), 24.65 to 24.95 wt% of poly(methacrylic acid-methyl methacrylate) 1 :2, 2.43 to 2.53 wt% of triethyl citrate (TEC), 0.94 to 1.04 wt% of polysorbate 80, and 2.43 to 2.53 wt% of glyceryl monostearate (GMS); and e) 4.85 to 5.05 wt% of water in the inert core unit and / or any layer.

30. The solid oral dosage form of any one of claims 1 to 24, wherein the solid oral dosage form comprises or consists of: a) in the inert core unit (1), 25.22 wt% of microcrystalline cellulose; b) in the reservoir layer (2), 9.26 wt% of an anti-TNFa antibody or functional fragment thereof, 6.74 wt% of hypromellose (HPMC), 16.48 wt% of sucrose, 0.91 wt% of L-histidine, 0.67 wt% of mesoporous silica, and 0.08 wt% of polysorbate 80; c) in the extended release layer (4), 24.65 to 24.95 wt% of poly(methacrylic acid-methyl methacrylate) 1 :2, 2.43 to 2.53 wt% of triethyl citrate (TEC), 0.94 to 1.04 wt% of polysorbate 80, and 2.43 to 2.53 wt% of glyceryl monostearate (GMS); and d) in the extended release layer (4), 24.65 to 24.95 wt% of poly(methacrylic acid-methyl methacrylate) 1 :2, 2.43 to 2.53 wt% of triethyl citrate (TEC), 0.94 to 1.04 wt% of polysorbate 80, and 2.43 to 2.53 wt% of glyceryl monostearate (GMS); and e) 4.85 to 5.05 wt% of water in the inert core unit and / or any layer.

31. The solid oral dosage form of any one of claims 1 to 24, wherein the solid oral dosage form comprises or consists of: a) in the inert core unit (1), 25.21 to 25.51 wt% of microcrystalline cellulose; b) in the reservoir layer (2), 8.91 to 9.11 wt% of an antibody or functional fragment thereof, 6.48 to 6.68 wt% of hypromellose (HPMC), 15.72 to 16.02 wt% of sucrose, 0.83 to 0.93 wt% of L-histidine, 0.61 to 0.71 wt% of mesoporous silica, and 0.07 to 0.09 wt% of polysorbate 80; c) in the extended release layer (4), 24.65 to 24.95 wt% of poly(methacrylic acid-methyl methacrylate) 1 :2, 2.43 to 2.53 wt% of triethyl citrate (TEC), 0.94 to 1.04 wt% of polysorbate 80, and 2.43 to 2.53 wt% of glyceryl monostearate (GMS); and d) in the extended release layer (4), 24.65 to 24.95 wt% of poly(methacrylic acid-methyl methacrylate) 1 :2, 2.43 to 2.53 wt% of triethyl citrate (TEC), 0.94 to 1.04 wt% of polysorbate 80, and 2.43 to 2.53 wt% of glyceryl monostearate (GMS); and e) 4.85 to 5.05 wt% of water in the inert core unit and / or any layer. c) in the sustained release layer (3), 3.58 to 3.78 wt.% of poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1 :2:0.1, 0.69 to 0.79 wt.% of triethyl citrate (TEC), and 0.32 to 0.42 wt.% of mesoporous silica; d) in the delayed release layer (4), 25.56 to 25.86 wt.% of poly(methacrylic acid-methyl methacrylate) 1 :2, 2.52 to 2.62 wt.% of triethyl citrate (TEC), 0.98 to 1.08 wt.% of polysorbate 80, and 2.52 to 2.62 wt.% of glyceryl monostearate (GMS); and e) 4.80 to 5.00 wt.% of water in the inert core unit and / or any layer.

32. The solid oral dosage form according to any one of claims 1 to 24, wherein the solid oral dosage form comprises or consists of: a) in the inert core unit (1), 25.36 wt.% of microcrystalline cellulose; b) in the reservoir layer (2), 9.01 wt.% of an anti-TNFa antibody or functional fragment thereof, 6.58 wt.% of hypromellose (HPMC), 15.87 wt.% of sucrose, 0.88 wt.% of L-histidine, 0.66 wt.% of mesoporous silica, and 0.08 wt.% of polysorbate 80; c) in the sustained release layer (3), 3.68 wt.% of poly(ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride) 1 :2:0.1, 0.74 wt.% of triethyl citrate (TEC), and 0.37 wt.% of mesoporous silica; d) in the delayed release layer (4), 25.71 wt.% of poly(methacrylic acid-methyl methacrylate) 1 :2, 2.57 wt.% of triethyl citrate (TEC), 1.03 wt.% of polysorbate 80, and 2.57 wt.% of glyceryl monostearate (GMS); and e) 4.90 wt.% of water in the inert core unit and / or any layer.

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

34. The solid oral dosage form of claim 33, wherein the antibody or functional fragment thereof specific for TNFa is an anti-TNFa antibody or functional fragment thereof having a TNFa binding domain comprising: (i) a V L domain comprising a CDR1 region having an amino acid sequence as set forth in SEQ ID NO: 1, a CDR2 region having an amino acid sequence as set forth in SEQ ID NO: 2, and a CDR3 region having an amino acid sequence as set forth in SEQ ID NO: 3; and / or (ii) a V L domain comprising a CDR1 region having an amino acid sequence as set forth in SEQ ID NO: 4, a CDR2 region having an amino acid sequence as set forth in SEQ ID NO: 5, and a CDR3 region having an amino acid sequence as set forth in SEQ ID NO:

6. H H domain comprising a CDR1 region having an amino acid sequence as set forth in SEQ ID NO: 4, a CDR2 region having an amino acid sequence as set forth in SEQ ID NO: 5, and a CDR3 region having an amino acid sequence as set forth in SEQ ID NO: 6.​ 35. The solid oral dosage form of claim 33, wherein the antibody or functional fragment thereof specific for TNFa is an anti-TNFa antibody or functional fragment thereof having a TNFa binding domain comprising or consisting of: (i)V L Structural domain, the V L The domain has an amino acid sequence consistent with the amino acid sequence shown in SEQ ID NO:8; and / or (ii) V H Structural domain, the V H The domain has an amino acid sequence that is consistent with the amino acid sequence shown in SEQ ID NO:

7.

36. The solid oral dosage form of claim 33, wherein the antibody or functional fragment thereof specific for TNFa is an anti-TNFa antibody comprising an Fc region having or consisting of: an amino acid sequence identical to the amino acid sequence set forth as 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.

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

38. The solid oral dosage form according to any one of the preceding claims for use in targeted local treatment of immune checkpoint inhibitor (ICPI)-induced colitis, ICPI-induced small bowel colitis, ICPI-induced diarrhea, or inflammatory bowel disease (IBD).

39. An oral multi-particulate drug delivery system comprising a plurality of solid oral dosage forms according to any one of the preceding claims.

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

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

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

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