Methods for treating tnfα-related diseases

Abstract

This invention relates to a method for subcutaneously administering antibodies that bind to TNF-α (anti-TNF-α antibodies) to treat TNF-α-related diseases. The treatment methods, compositions, reagent sets, or uses according to this invention shorten administration time and patient hospitalization time, thereby improving patient convenience and quality of life. This offers the advantage of increased patient satisfaction.

Description

Technical Field

[0001] The present application relates to methods for treating TNF-α-related diseases by subcutaneous administration of antibodies that bind to TNF-α (anti-TNF-α antibodies). Prior Art

[0002] Tumor necrosis factor-alpha (TNF-α) is a cell signaling protein (cytokine) involved in systemic inflammation and is a cytokine that mediates the acute phase response. TNF-α has been implicated in a variety of diseases and conditions, including sepsis, infection, autoimmune disease, and transplant rejection. TNF-α stimulates immune responses and causes many clinical problems associated with autoimmune disorders such as rheumatoid arthritis, ankylosing spondylitis, ulcerative colitis, adult Crohn's disease, childhood Crohn's disease, psoriasis, and psoriatic arthritis. TNF-α inhibitors can be used to treat these disorders.

[0003] Infliximab is a type of chimeric monoclonal antibody that can be used as a TNF-α inhibitor. Currently available infliximab products include Remsima, Remicade, Renflexis, etc. However, these products are all provided in the form of freeze-dried powders, which are reconstituted and diluted, and the dosing regimen and dosage are selected according to various diseases for intravenous injection.

[0004] However, the above intravenous administration method requires patients to go to the hospital for medical treatment, which takes 2 to 4 hours including waiting time, causing considerable burden and inconvenience to daily life. In addition, there is a problem that the person who administers the drug is limited to those who have received medical education.

[0005] Therefore, subcutaneous (SC) administration is recommended as an alternative route of administration. SC administration can be self-injected by trained patients and can shorten the administration time from 30 to 90 minutes with traditional techniques to 2 to 5 minutes.

[0006] The commercially available formulations that have been developed are not only for intravenous administration but also for subcutaneous administration, such as Rituxan (Rituximab), Simponi (Golimumab), Herceptin (Trastuzumab), Actemra (Tocilizumab), and Xolair (Omalizumab), but no infliximab formulations for subcutaneous injection have been reported.

[0007] Subcutaneous administration requires a stable liquid formulation containing a high concentration of antibody, and its clinical efficacy and safety should be demonstrated.

[0008] The applicant has demonstrated the efficacy and stability of an infliximab formulation for subcutaneous administration, which is comparable to traditional intravenous formulations, thus completing a subcutaneous administration regimen that improves patient convenience and quality of life. Summary of the Invention Problems to be Solved by the Invention

[0009] An object of the present invention is to provide a treatment method that includes subcutaneously administering to an individual a pharmaceutical composition containing an anti-TNF-α antibody or an antigen-binding fragment thereof for treating TNF-α-related diseases.

[0010] Another object of the present invention is to provide a pharmaceutical composition for treating diseases treatable with an anti-TNF-α antibody, the pharmaceutical composition containing an anti-TNF-α antibody or an antigen-binding fragment thereof and being subcutaneously administered to an individual.

[0011] Yet another object of the present invention is to provide a kit that includes: a pharmaceutical composition containing an anti-TNF-α antibody or an antigen-binding fragment thereof; and instructions indicating subcutaneously administering the pharmaceutical composition to an individual for treating diseases treatable with an anti-TNF-α antibody.

[0012] Still another object of the present invention is to provide the use of an anti-TNF-α antibody or an antigen-binding fragment thereof for manufacturing a drug that is subcutaneously administered to an individual for treating diseases treatable with an anti-TNF-α antibody. Means for Solving the Problems

[0013] The present invention provides a method for treating diseases treatable with an anti-TNF-α antibody, the method including the step of subcutaneously administering to an individual a pharmaceutical composition containing an anti-TNF-α antibody or an antigen-binding fragment thereof.

[0014] The present invention also provides a pharmaceutical composition for treating diseases treatable with an anti-TNF-α antibody, the pharmaceutical composition containing an anti-TNF-α antibody or an antigen-binding fragment thereof and being subcutaneously administered to an individual.

[0015] The present invention also provides a reagent kit comprising: (a) a pharmaceutical composition containing an anti-TNF-α antibody or an antigen-binding fragment thereof and a pharmaceutically acceptable carrier; and (b) instructions for subcutaneously administering the pharmaceutical composition to an individual to treat a disease that can be treated with the anti-TNF-α antibody.

[0016] The present invention also provides the use of an anti-TNF-α antibody or an antigen-binding fragment thereof for preparing a pharmaceutical composition, wherein the pharmaceutical composition is subcutaneously administered to an individual to treat a disease that can be treated with an anti-TNF-α antibody.

[0017] In a specific example of the present invention, the anti-TNF-α antibody may include one or more antibodies selected from the group consisting of infliximab, adalimumab, certolizumab pegol, golimumab and biosimilars thereof.

[0018] In one embodiment of the present invention, the anti-TNF-α antibody may be infliximab.

[0019] In one embodiment of the present invention, the anti-TNF-α antibody may include a chimeric human-mouse IgG monoclonal antibody.

[0020] In one specific example of the present invention, the anti-TNF-α antibody may include: a light chain variable region, which includes a CDR1 domain comprising an amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising an amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising an amino acid sequence of SEQ ID NO: 3; and a heavy chain variable region, which includes a CDR1 domain comprising an amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising an amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising an amino acid sequence of SEQ ID NO: 6.

[0021] In one embodiment of the present invention, the anti-TNF-α antibody may include: a light chain variable region including the amino acid sequence of SEQ ID NO: 7; and a heavy chain variable region including the amino acid sequence of SEQ ID NO: 8.

[0022] In one embodiment of the present invention, the anti-TNF-α antibody may include: a light chain including the amino acid sequence of SEQ ID NO: 9; and a heavy chain including the amino acid sequence of SEQ ID NO: 10.

[0023] In one embodiment of the present invention, the composition may include: a surfactant, a sugar or a derivative thereof; and a buffer including acetate or histidine.

[0024] In one embodiment of the present invention, the composition may include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 or a mixture thereof as a surfactant.

[0025] In one embodiment of the present invention, the concentration of the surfactant in the composition can be 0.02 to 0.1% (w / v).

[0026] In one embodiment of the present invention, the composition may include sorbitol, mannitol, trehalose, sucrose or a mixture thereof as sugar or its derivatives.

[0027] In one embodiment of the present invention, the concentration of sugar or its derivative in the composition can be 1 to 10% (w / v).

[0028] In one embodiment of the present invention, the composition may include acetate as a buffer.

[0029] In one embodiment of the present invention, the concentration of the buffer in the composition can be 1 to 50 mM.

[0030] In one embodiment of the present invention, the composition may have a pH of 4.0 to 5.5.

[0031] In one embodiment of the present invention, the composition may include: (A) 90 to 180 mg / ml of an anti-TNF-α antibody or an antigen-binding fragment thereof; (B) 0.02 to 0.1% (w / v) of polysorbate; (C) 1 to 10% (w / v) of sorbitol; and (D) 1 to 50 mM of a buffer including acetate or histidine.

[0032] In one embodiment of the present invention, the composition may not contain aspartic acid, lysine, arginine or a mixture thereof.

[0033] In one embodiment of the present invention, the composition may not contain NaCl, KCl, NaF, KBr, NaBr, Na2SO4, NaSCN, K2SO4 or a mixture thereof.

[0034] In one embodiment of the present invention, the composition may not contain a chimeric agent.

[0035] In one embodiment of the present invention, the composition may have a viscosity of 0.5 cp to 10.0 cp after being stored at a temperature of 40°C ± 2°C for 1 month, or may have a viscosity of 0.5 cp to 5.0 cp after being stored at a temperature of 5°C ± 3°C for 6 months.

[0036] In one embodiment of the present invention, the composition may not be subjected to a reconstitution step, a dilution step, or both before use.

[0037] In one embodiment of the present invention, the composition can be filled into a pre-filled syringe or an automatic injector before administration to a subject.

[0038] In one embodiment of the present invention, the individual may include a mammal.

[0039] In one embodiment of the present invention, the individual may include a human.

[0040] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof can be administered at a dose of 60 to 300 mg.

[0041] In one embodiment of the invention, the antibody or antigen-binding fragment thereof can be administered at a dose of 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290 or 300 mg.

[0042] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof can be administered at a dose of 90 to 180 mg.

[0043] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof can be administered at a dose of 120 to 240 mg.

[0044] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof can be administered at a dose of 80 to 100 mg, 110 to 130 mg, 170 to 190 mg, or 230 to 250 mg.

[0045] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof can be administered at a dose of 90 mg, 120 mg, 180 mg or 240 mg.

[0046] In one embodiment of the present invention, when the patient weighs less than 80 kg, the antibody or antigen-binding fragment thereof can be administered at a dose of 90 to 180 mg, and when the patient weighs more than 80 kg, it can be administered at a dose of 190 to 270 mg.

[0047] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof can be administered at intervals of 1 to 8 weeks.

[0048] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof can be administered at intervals of 1, 2, 3, 4, 5, 6, 7 or 8 weeks.

[0049] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof can be administered at intervals of 2 or 4 weeks.

[0050] In one embodiment of the present invention, the diseases that can be treated with anti-TNF-α antibodies may include rheumatoid arthritis, ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis and ankylosing spondylitis.

[0051] In one embodiment of the present invention, a patient who is to receive an anti-TNF-α antibody may exhibit one or more characteristics selected from the following: a) Patients who have had an inadequate response to disease-modifying antirheumatic drugs (DMARDs) including methotrexate; b) Patients who have not been treated with methotrexate or other DMARDs before; c) Patients present with elevated serological markers associated with severe, predominantly axial symptoms and inflammation that do not respond adequately to conventional treatments; d) Patients who have not responded to, have contraindications to, or are intolerant to methotrexate, cyclosporine, or systemic therapy including psoralen ultraviolet A therapy (PUVA); e) patients who have an inadequate response to, intolerance to, or contraindications to treatment with corticosteroids, 6-mercaptopurine, azathioprine, or immunosuppressants; and f) Patients who have not responded to conventional treatment including antibiotics, excretion or immunosuppressive therapy.

[0052] In a specific example of the present invention, the patient can be a patient who has been intravenously administered an anti-TNF-α antibody or an antigen-binding fragment thereof at least once before subcutaneous administration.

[0053] In a specific example of the present invention, the patient can be a patient who has been intravenously administered an anti-TNF-α antibody or an antigen-binding fragment thereof at a dose of 1 to 10 mg / kg each time before subcutaneous administration.

[0054] In a specific example of the present invention, the first subcutaneous administration can be carried out 2 to 8 weeks after the last intravenous administration.

[0055] In a specific example of the present invention, the first subcutaneous administration can be carried out 4 weeks after the last intravenous administration.

[0056] In a specific example of the present invention, the composition containing an anti-TNF-α antibody or an antigen-binding fragment thereof can be administered simultaneously with, before, or after administering one or more antibodies selected from the group consisting of infliximab, adalimumab, certolizumab, golimumab, and their biosimilars.

[0057] In a specific example of the present invention, the composition containing an anti-TNF-α antibody or an antigen-binding fragment thereof can be administered simultaneously with, before, or after administering methotrexate, lefluromide, sulfasalazine, hydroxychloroquine, or a mixture thereof.

[0058] In a specific example of the present invention, a patient after subcutaneous administration may exhibit one or more characteristics selected from the following: a) The DAS28 (Disease Activity Score 28) is reduced by at least 2.0; and b) The CDAI (Crohn's Disease Activity Index) is reduced by at least 70. Effect of the Invention

[0059] The treatment method, composition, reagent kit, or use according to the present invention makes it possible to subcutaneously administer an anti-TNF-α antibody or an antigen-binding fragment thereof to treat anti-TNF-α-related diseases. In addition, the treatment method, composition, reagent kit, or use according to the present invention shortens the dosing time and the patient's hospitalization time, thereby improving the convenience of the patient and the patient's quality of life. This provides the advantage of improving patient satisfaction.

[0060] In addition, a method of treatment, composition, reagent set or use according to the present invention is added as a new infliximab treatment regimen, as a result of which patients who have been given intravenous infliximab and medical staff will not be burdened or rejected by the change in medication. Simple diagram description

[0061] Figure 1 shows the design of a clinical trial of subcutaneous infliximab in patients with rheumatoid arthritis (RA).

[0062] Figure 2 shows the design of a clinical trial of subcutaneous administration of infliximab in patients with Crohn's disease (CD). Implementation

[0063] The present invention relates to a method for treating a disease treatable by an anti-TNF-α antibody, comprising the step of subcutaneously administering a pharmaceutical composition containing an anti-TNF-α antibody or an antigen-binding fragment thereof to an individual.

[0064] In order to facilitate understanding of the present invention, the terms used in the present invention are defined as follows.

[0065] "TNF-α" refers to a human cytokine that exists in a 17 kD secreted form and a 26 kD membrane-bound form, the biologically active form of which is a trimer composed of non-covalently bound 17 kD molecules. The structure of TNF-α is further described in, for example, Pennica, D., et al. (1984) Nature 312:724-729; Davis, JM, et al. (1987) Biochemistry 26:1322-1326; and Jones, EY, et al. (1989) Nature 338:225-228.

[0066] The term "antibody" refers to an immunoglobulin molecule composed of four polypeptide chains, two heavy chains and two light chains interconnected by disulfide bonds. Other naturally occurring antibodies with altered structures, such as camelid antibodies, are also included in this definition. Each heavy chain consists of a heavy chain variable region and a heavy chain constant region. The heavy chain constant region consists of three domains (CH1, CH2, and CH3). Each light chain consists of a light chain variable region and a light chain constant region. The light chain constant region consists of one domain (CL). The heavy and light chain variable regions can be further subdivided into highly variable regions, called complementarity determining regions (CDRs), interspersed with more conserved regions, called framework regions (FRs). Each heavy and light chain variable region consists of three CDRs and four FRs, arranged from amino terminus to carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0067] The term "antigen-binding fragment" refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. Examples of antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv, etc.

[0068] The term "biosimilar" refers to a biological product that is highly similar to an FDA-approved biological product (reference drug) and has no clinically meaningful differences from the reference product in terms of pharmacokinetics, safety, and efficacy.

[0069] The term "administering" refers to administering a substance (eg, an anti-TNF-α antibody) for the purpose of obtaining treatment (eg, a TNF-α-related disease).

[0070] The term "TNF-α-associated disease" refers to local and / or systemic physiological diseases in which anti-TNF-α is the primary mediator leading to disease manifestations. The terms "TNF-α-associated disease", "disease treatable with anti-TNF-α" and "disease to which TNF-α activity is detrimental" are used interchangeably herein.

[0071] The term "subject" includes all human and non-human animals. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, cats, rabbits and ferrets; rodents such as mice, rats and guinea pigs; birds such as chickens; amphibians and reptiles. In a preferred embodiment, the subject is a mammal such as a non-human primate, sheep, dog, cat, rabbit, ferret or rodent. In a more preferred embodiment, the subject is a human. The terms "subject", "patient" and "subject" are used interchangeably herein.

[0072] The term "IC50" refers to the concentration of an inhibitor that is effective in inhibiting the biological outcome of interest, e.g., neutralizing a cytotoxic activity.

[0073] The term "kit" refers to a packaged product comprising components for administering an anti-TNF-α antibody of the invention for treating a TNF-α-related disease. The kit preferably comprises a box or container containing the kit components. The box or container is labeled or has a Food and Drug Administration-approved regimen. The box or container contains the components of the invention in a plastic, polyethylene, polypropylene, ethylene or propylene container. The container may be a tube or bottle with a lid. The kit may also include instructions for administering the anti-TNF-α antibody.

[0074] Various aspects of the present invention will be described in further detail. [- Anti-TNF-α Antibodies or Antigen-binding Fragments thereof of the Present Invention] In one embodiment of the present invention, the pharmaceutical preparation may include polyclonal antibodies, monoclonal antibodies, recombinant antibodies, single-chain antibodies, hybrid antibodies, chimeric antibodies, humanized antibodies or fragments thereof as antibodies. The term "chimeric antibody" refers to an antibody comprising heavy chain and light chain variable region sequences from one species and heavy chain and light chain constant region sequences from another species. In one embodiment of the present invention, the pharmaceutical preparation may contain chimeric human-mouse IgG monoclonal antibodies as antibodies. Chimeric human-mouse IgG monoclonal antibodies are composed of mouse heavy chain and light chain variable regions and human heavy chain and light chain constant regions. Chimeric human-mouse IgG monoclonal antibodies can be produced by methods known in the art. For example, infliximab can be produced according to the method described in US Patent No. 6,284,471.

[0075] In one embodiment of the present invention, the pharmaceutical preparation may contain an antibody that binds to TNF-α or an epitope of TNF-α as an antibody. The antibody that binds to TNF-α or an epitope of TNF-α may include infliximab, adalimumab, certolizumab pegol, golimumab or a biosimilar thereof. In one embodiment of the present invention, the antibody may include infliximab.

[0076] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof (A) may include: a light chain variable region including a CDR1 domain comprising an amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising an amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising an amino acid sequence of SEQ ID NO: 3; and a heavy chain variable region including a CDR1 domain comprising an amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising an amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising an amino acid sequence of SEQ ID NO: 6.

[0077] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof (A) may include: a light chain variable region having an amino acid sequence of SEQ ID NO: 7; and a heavy chain variable region having an amino acid sequence of SEQ ID NO: 8.

[0078] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof (A) may include: a light chain having an amino acid sequence of SEQ ID NO: 9; and a heavy chain having an amino acid sequence of SEQ ID NO: 10. [- Composition containing the anti-TNF-α antibody or antigen-binding fragment thereof of the present invention]

[0079] As used herein, the terms "composition containing the anti-TNF-α antibody or antigen-binding fragment thereof of the present invention" and "stable liquid pharmaceutical formulation" are used interchangeably.

[0080] The stable liquid pharmaceutical formulation according to the present invention contains: (A) an antibody or an antigen-binding fragment thereof; (B) a surfactant; (C) a sugar or a derivative thereof; and (D) a buffer.

[0081] As used herein, the term "free of" means that the preparation does not contain the corresponding ingredient at all. In addition, the term means that the preparation does not substantially contain the corresponding ingredient, that is, contains the corresponding ingredient in an amount that does not affect the activity of the antibody and the stability and viscosity of the liquid pharmaceutical preparation. For example, the term means that the preparation contains the corresponding ingredient in an amount of 0% to 1% (w / v), 0 to 1 ppm (w / v) or 0 to 1 ppb (w / v) based on the total weight of the liquid pharmaceutical preparation. [(A) Antibody or antigen-binding fragment thereof]

[0082] The concentration of the antibody or its antigen-binding fragment can be freely controlled within a range that does not substantially adversely affect the stability and viscosity of the stable liquid pharmaceutical preparation according to the present invention. In one embodiment of the present invention, the concentration of the antibody or its antigen-binding fragment can be 10 to 200 mg / ml. In another embodiment of the present invention, the concentration of the antibody or its antigen-binding fragment can be 50 to 200 mg / ml. In yet another embodiment of the present invention, the concentration of the antibody or its antigen-binding fragment can be 80 to 150 mg / ml. In yet another embodiment of the present invention, the concentration of the antibody or its antigen-binding fragment can be 90 to 145 mg / ml. In yet another embodiment of the present invention, the concentration of the antibody or its antigen-binding fragment can be 110 to 130 mg / ml. If the concentration of the antibody or its antigen-binding fragment is within the above range, the high content of the antibody or its antigen-binding fragment can increase the freedom of dosage and administration cycle, and the pharmaceutical preparation can exhibit excellent long-term stability and low viscosity. [(B) Surfactant]

[0083] Examples of surfactants include, but are not limited to, polyoxyethylene sorbitan fatty acid esters (e.g., polysorbate), polyoxyethylene alkyl ethers (e.g., Brij), alkyl, phenol polyoxyethylene ethyl ethers (e.g., Triton-X), polyoxyethylene-polyoxypropylene copolymers (e.g., Poloxamer, Pluronic), sodium dodecyl sulfate (SDS), and the like.

[0084] In one embodiment of the present invention, the surfactant may include polyoxyethyl sorbitan fatty acid ester (polysorbate). Polysorbate may include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a mixture of two or more thereof. In one embodiment of the present invention, polysorbate may include polysorbate 20, polysorbate 80, or a mixture thereof. In another embodiment of the present invention, polysorbate may include polysorbate 80.

[0085] In one embodiment of the present invention, the concentration of the surfactant can be freely controlled within a range that does not substantially adversely affect the stability and viscosity of the stable liquid pharmaceutical preparation according to the present invention. For example, the concentration of the surfactant can be 0.001% to 5% (w / v), 0.01 to 1% (w / v), or 0.02 to 0.1% (w / v). If the concentration of the surfactant is within the above range, the pharmaceutical composition can exhibit excellent long-term stability and low viscosity. [(C) sugar or its derivatives]

[0086] Sugars may include monosaccharides, disaccharides, oligosaccharides, polysaccharides, or mixtures of two or more thereof. Examples of monosaccharides include, but are not limited to, glucose, fructose, galactose, and the like. Examples of disaccharides include, but are not limited to, sucrose, lactose, maltose, trehalose, and the like. Examples of oligosaccharides include, but are not limited to, fructooligosaccharides, galacto-oligosaccharides, manno-oligosaccharides, and the like. Examples of polysaccharides include, but are not limited to, starch, glycogen, cellulose, chitin, pectin, and the like.

[0087] Sugar derivatives may include sugar alcohols, sugar acids, or mixtures thereof. Examples of sugar alcohols include, but are not limited to, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, trehalitol, iditol, inositol, volemitol, bartitol, maltitol, lactitol, maltotriitol, maltotetraitol, polyglycitol, etc. Examples of sugar acids include, but are not limited to, aldonic acids (glyceric acid, etc.), ketonic acids (neuramic acid, etc.), carbonyl sugar acids (glucuronic acid, etc.), aldaric acids (tartaric acid, etc.), etc.

[0088] In one embodiment of the present invention, the sugar or its derivative (C) may include sorbitol, mannitol, trehalose, sucrose or a mixture of two or more thereof.

[0089] In one embodiment of the present invention, the concentration of sugar or its derivative can be freely controlled within a range that does not substantially adversely affect the stability and viscosity of the stable liquid pharmaceutical preparation according to the present invention. For example, the concentration of sugar or its derivative can be 0.1 to 30% (w / v), 1 to 20% (w / v) or 1 to 10% (w / v). If the concentration of sugar or its derivative can be within this range, the pharmaceutical composition can exhibit excellent long-term stability and low viscosity. [(D) Buffer]

[0090] The buffer used in the present invention is a neutralizing substance that minimizes pH changes caused by acids or bases. Examples of buffers include phosphates, acetates, succinates, gluconates, glutamate, citrates, histidines, etc. In a specific example of the present invention, the buffer may include acetate or histidine. If the buffer includes both acetate and histidine, the stability of the pharmaceutical preparation may be reduced.

[0091] In one embodiment of the present invention, the buffer may include acetate. Examples of acetate include, but are not limited to, sodium acetate, zinc acetate, aluminum acetate, ammonium acetate, potassium acetate, etc. For pH adjustment, the buffer may further include an acid, such as acetic acid. When the buffer includes acetate, pH adjustment and stability may be optimal.

[0092] In one embodiment of the present invention, the buffer may include histidine. When the buffer includes histidine, it may include histidine salts, such as histidine chloride, histidine acetate, histidine phosphate, histidine sulfate, etc. For pH adjustment, the buffer may include an acid, such as hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, etc.

[0093] In one embodiment of the present invention, the stable liquid pharmaceutical formulation may not contain citrate, phosphate, or a mixture thereof.

[0094] In one embodiment of the present invention, the concentration of the buffer (or the anion of the buffer) can be freely controlled within a range that does not substantially adversely affect the stability and viscosity of the stable liquid pharmaceutical preparation according to the present invention. For example, the concentration of the buffer or its anion can be 1 to 50 mM, 5 to 30 mM, or 10 to 25 mM. If the concentration of the buffer or its anion is within this range, the pharmaceutical composition can exhibit excellent long-term stability and low viscosity. [(E)pH]

[0095] In one embodiment of the present invention, the pH value of the stable liquid pharmaceutical composition can be 4.0 to 5.5 or 4.7 to 5.3. If the pH is within this range, the pharmaceutical composition can exhibit excellent long-term stability and low viscosity. The pH value of the pharmaceutical preparation can be adjusted using a buffer. In other words, if the pharmaceutical preparation contains a certain amount of a buffer, a pH value within the above range can be displayed without using a separate pH adjuster. If citrate, phosphate or a mixture thereof is used as a buffer, it is difficult to display a pH value within the above range. If the pharmaceutical preparation further contains an acid (e.g., hydrochloric acid) or a base (e.g., sodium hydroxide) as a separate pH adjuster, the stability of the antibody may be reduced. [(F) Other components]

[0096] In one embodiment of the present invention, the stable liquid pharmaceutical formulation may not contain aspartic acid, lysine, arginine or a mixture thereof. If the stable liquid pharmaceutical formulation contains these amino acids, it may become solid. In one embodiment of the present invention, the stable liquid pharmaceutical formulation may contain one or more amino acids excluding the above three amino acids. In this case, the stable liquid pharmaceutical formulation may contain 5% (w / v) or less of one or more amino acids, for example, 0.001 to 5% (w / v), 0.001 to 1% (w / v), 0.01 to 5% (w / v), 0.01 to 1% (w / v), 0.1 to 5% (w / v) or 0.1 to 1% (w / v).

[0097] In another embodiment of the present invention, the stable liquid pharmaceutical formulation may contain taurine. In this case, it may contain 5% (w / v) or less taurine, for example, 0.001 to 5% (w / v), 0.001 to 1% (w / v), 0.01 to 5% (w / v), 0.01 to 1% (w / v), 0.1 to 5% (w / v) or 0.1 to 1% (w / v).

[0098] In one embodiment of the present invention, the stable liquid drug formulation may not contain metal salts, such as NaCl, KCl, NaF, KBr, NaBr, Na2SO4, NaSCN, K2SO4, etc. If the stable liquid drug formulation contains these metal salts, precipitation of the formulation may occur, and the formulation may gel and may have poor stability.

[0099] In one embodiment of the present invention, the stable liquid pharmaceutical formulation may not contain an intercalating agent (e.g., EDTA). If the pharmaceutical formulation contains an intercalating agent, its oxidation rate may increase.

[0100] In one embodiment of the present invention, the stable liquid pharmaceutical preparation may not contain a preservative. Examples of preservatives include octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, hydroxychloroaniline, benzethonium chloride, phenol, butyl alcohol, benzyl alcohol, alkyl parabens, catechol, resorcinol, cyclohexanol, 3-pentanol, m-cresol, etc. If the pharmaceutical preparation contains a preservative, the preservative may not improve the stability of the pharmaceutical preparation.

[0101] In one embodiment of the present invention, the stable liquid pharmaceutical preparation of the present invention may further contain additives known in the art, which do not have a substantial adverse effect on the activity of the antibody and the stability and low viscosity of the preparation. For example, the pharmaceutical preparation may further contain an aqueous carrier, an antioxidant, or a mixture of two or more thereof. An aqueous carrier is a pharmaceutically acceptable (safe and non-toxic when administered to humans) carrier and is suitable for the preparation of a liquid pharmaceutical preparation. Examples of aqueous carriers include, but are not limited to, sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), sterile saline, Ringer's solution, aqueous glucose solution, etc. Examples of antioxidants include, but are not limited to, ascorbic acid, etc. [(G) "Stable" liquid pharmaceutical preparations]

[0102] The term "stable" in the "stable" liquid pharmaceutical formulation of the present invention means that the antibody according to the present invention substantially maintains its physical stability and / or chemical stability and / or biological activity during production and / or storage. Various analytical techniques for measuring protein stability are readily available in the art.

[0103] Physical stability can be assessed by methods known in the art, including measuring the apparent optical attenuation (absorbance or optical density) of a sample. This optical attenuation measurement is related to the turbidity of the formulation. In addition, for physical stability, the content of high molecular weight components, the content of low molecular weight components, the amount of intact protein, the number of subvisible particles, etc. can be measured.

[0104] Chemical stability can be assessed, for example, by detecting and quantifying chemically altered forms of the antibody. Chemical stability includes charge changes (e.g., occurring as a result of deamidation or oxidation), which can be assessed, for example, by ion exchange chromatography. For chemical stability, charge variants (acidic or basic peaks) can be measured.

[0105] Biological activity can be assessed by methods known in the art. For example, antigen binding affinity can be measured by ELISA.

[0106] In one embodiment of the present invention, the liquid pharmaceutical formulation can remain stable for a long time.

[0107] In one embodiment of the present invention, the term "stable" liquid pharmaceutical formulation refers to a liquid pharmaceutical formulation that meets one or more of the following criteria. [Turbidity]

[0108] - a liquid pharmaceutical preparation having an absorbance A600 of 0 to 0.0300 or 0 to 0.0700 measured by a spectrophotometer after storage at a temperature of 40°C ± 2°C for 4 weeks;

[0109] - Liquid pharmaceutical preparations having an absorbance A600 of 0 to 0.0300 or 0 to 0.0700 as measured by a spectrophotometer after storage at a temperature of 40°C ± 2°C and a relative humidity of 75 ± 5% for 4 weeks; [Content of main components] (main peak)

[0110] - a liquid pharmaceutical preparation in which the content of the main component is between 98% and 100% as measured by SE-HPLC after storage at 40°C ± 2°C for 4 weeks;

[0111] - Liquid pharmaceutical preparations with a content of 98% to 100% of the main components measured by SE-HPLC after storage at a temperature of 40°C ± 2°C and a relative humidity of 75 ± 5% for 4 weeks; [Content of high molecular weight components] (Peak with earlier retention time than the main peak (intact IgG))

[0112] - liquid pharmaceutical preparations in which the content of high molecular weight components measured by SE-HPLC is between 0 and 1.00% after storage at a temperature of 5°C ± 3°C for 12 months;

[0113] - Liquid pharmaceutical preparations in which the content of high molecular weight components measured by SE-HPLC is between 0 and 1.00% after storage at 5°C ± 3°C under sealed conditions for 12 months; [Content of low molecular weight components] (Peak with a later retention time than the main peak (intact IgG))

[0114] - liquid pharmaceutical preparations in which the content of low molecular weight components measured by SE-HPLC is between 0 and 0.40% after storage at a temperature of 5°C ± 3°C for 12 months;

[0115] - Liquid pharmaceutical preparations in which the content of low molecular weight components measured by SE-HPLC is 0 to 0.40% after storage at 5°C ± 3°C under sealed conditions for 12 months; [Complete immunoglobulin G content]

[0116] - a liquid pharmaceutical preparation in which the intact immunoglobulin G content (intact IgG%) measured by non-reducing CE-SDS is between 94.0% and 100% after storage at 5°C ± 3°C for 12 months;

[0117] - Liquid pharmaceutical preparations in which the content of intact immunoglobulin G (intact IgG%) measured by non-reducing CE-SDS is between 94.0% and 100% after storage at 5°C ± 3°C under sealed conditions for 12 months;

[0118] - a liquid pharmaceutical preparation in which the intact immunoglobulin G content (intact IgG%) measured by non-reducing CE-SDS is between 94.0% and 100% after storage at 40°C ± 2°C for 4 weeks;

[0119] - Liquid pharmaceutical preparations in which the content of intact immunoglobulin G (intact IgG%) measured by non-reducing CE-SDS is between 94.0% and 100% after storage at a temperature of 40°C ± 2°C and a relative humidity of 75 ± 5% for 4 weeks; [Complete heavy and light chain content]

[0120] - a liquid drug product in which the content of intact heavy and light chains (intact HC+LC%) is between 99.0% and 100% as measured by non-reducing CE-SDS after storage at 5°C±3°C for 12 months;

[0121] - Liquid drug preparations in which the content of intact heavy and light chains (intact HC+LC%) measured by non-reducing CE-SDS is between 99.0% and 100% after storage at 5°C±3°C under sealed conditions for 12 months;

[0122] - a liquid drug product having a content of intact heavy and light chains (intact HC+LC%) of 98.0% to 100% as measured by non-reducing CE-SDS after storage at 40°C ± 2°C for 4 weeks;

[0123] - After storage at 40℃±2℃ under sealed conditions for 4 weeks, the content of intact heavy chain and light chain (intact HC+LC%) of liquid drug preparation is 98.0% to 100% as measured by non-reducing CE-SDS; [Number of subvisible particles]

[0124] - After storage at 5℃±3℃ for 12 months, sub-visible particles ( 10.00μm, <400.00μm) of liquid pharmaceutical preparations with a number of 0 to 1000 measured by HIAC;

[0125] - After storage at 5℃±3℃ in a sealed container for 12 months, the sub-visible particles ( 10.00μm, <400.00μm) of liquid pharmaceutical preparations with a number of 0 to 1000 measured by HIAC;

[0126] - After storage at 40℃±2℃ for 4 weeks, sub-visible particles ( 1.00μm, <100.00μm) with a number of 0 to 30,000 as measured by MFI;

[0127] - After being stored in a sealed container at a temperature of 40℃±2℃ and a relative humidity of 75±5% for 4 weeks, the sub-visible particles ( 1.00μm, <100.00μm) with a number of 0 to 30,000 as measured by MFI;

[0128] - After storage at 40℃±2℃ for 4 weeks, sub-visible particles ( 10.00μm, <100.00μm) of a liquid pharmaceutical preparation having a number of 0 to 200 as measured by MFI;

[0129] - After being stored in a sealed container at a temperature of 40℃±2℃ and a relative humidity of 75±5% for 4 weeks, the sub-visible particles ( 10.00μm, <100.00μm) of a liquid pharmaceutical preparation having a number of 0 to 200 as measured by MFI;

[0130] - After storage at 40℃±2℃ for 6 weeks, sub-visible particles ( 10.00μm, <100.00μm) of a liquid pharmaceutical preparation having a number of 0 to 500 as measured by MFI;

[0131] - After 6 weeks of storage at 40℃±2℃ and 75±5% relative humidity in a sealed container, the sub-visible particles ( 10.00μm, <100.00μm) of a liquid pharmaceutical preparation having a number of 0 to 500 as measured by MFI; [Oxidation rate]

[0132] - liquid pharmaceutical preparations in which the oxidation rate of Met 255 of the heavy chain measured by LC-MS is between 0% and 2.5% after storage at a temperature of 40°C ± 2°C for 4 weeks;

[0133] - Liquid pharmaceutical preparations in which the oxidation rate of Met 255 of the heavy chain measured by LC-MS is between 0% and 2.5% after storage at a temperature of 40°C ± 2°C and a relative humidity of 75 ± 5% for 4 weeks; [Charge variant]

[0134] - Liquid pharmaceutical preparations showing an acidic peak of 20% to 35% as measured by IEC-HPLC after storage at 40°C ± 2°C for 4 weeks;

[0135] - Liquid pharmaceutical preparations showing an acidic peak of 20% to 35% as measured by IEC-HPLC after storage at a temperature of 40°C ± 2°C and a relative humidity of 75 ± 5% for 4 weeks;

[0136] - Liquid pharmaceutical preparations showing a basic peak of 33% to 40% as measured by IEC-HPLC after storage at 40°C ± 2°C for 4 weeks;

[0137] - Liquid pharmaceutical preparations that show a basic peak of 33% to 40% as measured by IEC-HPLC after storage at a temperature of 40°C ± 2°C and a relative humidity of 75 ± 5% for 4 weeks; [TNF-α binding affinity]

[0138] - a liquid pharmaceutical preparation having a TNF-α binding affinity of 80% to 120% as measured by ELISA after storage at 5°C ± 3°C for 12 months; and

[0139] - Liquid pharmaceutical preparations with 80% to 120% TNF-α binding affinity as measured by ELISA after storage at 5°C ± 3°C for 12 months.

[0140] In one embodiment of the present invention, the pharmaceutical preparation may have a viscosity of 0.5 cp to 10.0 cp measured after storage at a temperature of 40°C ± 2°C for 1 month. In another embodiment of the present invention, the pharmaceutical preparation may have a viscosity of 0.5 cp to 5.0 cp measured after storage at a temperature of 5°C ± 3°C for 6 months. [(H) Method for preparing a stable liquid pharmaceutical preparation]

[0141] The stable liquid pharmaceutical preparation of the present invention can be prepared using any known method without limitation to a specific method. For example, a stable liquid pharmaceutical preparation can be prepared by adding a buffer to a solution containing a surfactant and a sugar or a derivative thereof, adjusting the pH of the solution, and then adding an antibody to the mixed solution. Alternatively, a liquid pharmaceutical preparation can be prepared by preparing a solution containing certain excipients in the final step of a purification process and then adding the remaining components to the solution. For example, a liquid pharmaceutical preparation can be prepared by preparing a solution containing an antibody, a buffer, and a sugar or a derivative thereof, and then adding a surfactant to the solution.

[0142] Furthermore, the method of preparing the formulation may or may not include a freeze-drying step.

[0143] When the preparation method does not include a freeze-drying step, for example, the liquid pharmaceutical preparation prepared according to the present invention can be sterilized and then immediately placed in a closed container.

[0144] When the preparation method includes a freeze-drying step, for example, the liquid pharmaceutical preparation prepared according to the present invention may be freeze-dried or freeze-dried and stored, and then the components removed or modified by freeze-drying and / or storage may be supplemented or replaced to prepare the liquid pharmaceutical preparation according to the present invention. Alternatively, only the components of the liquid pharmaceutical preparation of the present invention, excluding the components that may be removed or modified by freeze-drying and / or storage, are freeze-dried or freeze-dried and stored, and then the excluded components may be added thereto to prepare the liquid pharmaceutical preparation according to the present invention.

[0145] The Korean Patent Application No. 10-2017-0081814 previously filed by the applicant is incorporated herein by reference. [- Methods for treating diseases that can be treated with the anti-TNF-α antibody of the present invention]

[0146] The present invention provides a method for treating a disease that can be treated with anti-TNF-α, which comprises the step of subcutaneously administering a pharmaceutical composition containing an anti-TNF-α antibody or an antigen-binding fragment thereof to an individual.

[0147] In one embodiment of the present invention, the antibody may include infliximab, adalimumab, certolizumab pegol, golimumab or their biosimilars.

[0148] In one embodiment of the present invention, the antibody may include infliximab.

[0149] In one embodiment of the present invention, the antibody may include a chimeric human-mouse IgG monoclonal antibody.

[0150] In one embodiment of the present invention, the antibody or its antigen-binding fragment may include: a light chain variable region, which includes a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3; and a heavy chain variable region, which includes a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 6.

[0151] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may include: a light chain variable region having an amino acid sequence of SEQ ID NO:7; and a heavy chain variable region having an amino acid sequence of SEQ ID NO:8.

[0152] In one embodiment of the present invention, the antibody may include: a light chain having an amino acid sequence of SEQ ID NO: 9; and a heavy chain having an amino acid sequence of SEQ ID NO: 10.

[0153] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof (A) may be contained in a concentration of 10 to 200 mg / ml.

[0154] The present invention also provides a method for treating a disease that can be treated with anti-TNF-α, which comprises subcutaneously administering to a subject a pharmaceutical composition containing (A) an anti-TNF-α antibody or an antigen-binding fragment thereof; (B) a surfactant; (C) a sugar or a derivative thereof; and (D) a buffer.

[0155] In one embodiment of the present invention, the surfactant (B) may include polysorbate, poloxamer or a mixture thereof.

[0156] In one embodiment of the present invention, the surfactant (B) may include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 or a mixture of two or more thereof.

[0157] In one embodiment of the present invention, the surfactant (B) may include polysorbate 80.

[0158] In one embodiment of the present invention, the surfactant (B) may be contained in a concentration of 0.02 to 0.1% (w / v).

[0159] In a specific example of the present invention, the sugar (C) may include monosaccharides, disaccharides, oligosaccharides, polysaccharides or a mixture of two or more thereof, and the sugar derivative (C) may include sugar alcohols, sugar acids or a mixture thereof.

[0160] In one embodiment of the present invention, the sugar or its derivative (C) may include sorbitol, mannitol, trehalose, sucrose or a mixture of two or more thereof.

[0161] In one embodiment of the present invention, the sugar or its derivative (C) may be contained in a concentration of 1 to 10% (w / v).

[0162] In one embodiment of the present invention, the buffer (D) may include acetate or histidine.

[0163] In one embodiment of the present invention, the buffer (D) may have a concentration of 1 to 50 mM.

[0164] In one embodiment of the present invention, the stable liquid pharmaceutical formulation may have a pH of 4.0 to 5.5.

[0165] In one embodiment of the present invention, the stable liquid pharmaceutical formulation may not contain aspartic acid, lysine, arginine or a mixture thereof.

[0166] In one embodiment of the present invention, the stable liquid pharmaceutical preparation may not contain NaCl, KCl, NaF, KBr, NaBr, Na2SO4, NaSCN, K2SO4 or a mixture thereof.

[0167] In one embodiment of the present invention, the stable liquid pharmaceutical formulation may not contain a chimeric agent.

[0168] In one embodiment of the present invention, the stable liquid pharmaceutical formulation may be free of preservatives.

[0169] In one embodiment of the present invention, the stable liquid pharmaceutical preparation may further contain an aqueous carrier, an antioxidant or a mixture of two or more thereof.

[0170] In one embodiment of the present invention, the stable liquid pharmaceutical preparation may have a viscosity of 0.5 cp to 10.0 cp measured after storage at a temperature of 40°C ± 2°C for 1 month, or may have a viscosity of 0.5 cp to 5.0 cp measured after storage at a temperature of 5°C ± 3°C for 6 months.

[0171] In one embodiment of the present invention, the stable liquid pharmaceutical formulation may contain: (A) an antibody or an antigen-binding fragment thereof, comprising: a light chain variable region comprising a CDR1 domain comprising an amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising an amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising an amino acid sequence of SEQ ID NO: 3; and a heavy chain variable region comprising a CDR1 domain comprising an amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising an amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising an amino acid sequence of SEQ ID NO: 6; (B) a surfactant; (C) a sugar or a derivative thereof; and (D) a buffer comprising acetate or histidine.

[0172] In one embodiment of the present invention, a stable liquid pharmaceutical formulation may contain: (A) 90 to 180 mg / ml of an antibody or an antigen-binding fragment thereof, comprising: a light chain variable region comprising a CDR1 domain comprising an amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising an amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising an amino acid sequence of SEQ ID NO: 3; and a heavy chain variable region comprising a CDR1 domain comprising an amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising an amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising an amino acid sequence of SEQ ID NO: 6; (B) 0.02 to 0.1% (w / v) of a surfactant; (C) 1 to 10% (w / v) of a sugar or a derivative thereof; and (D) 1 to 50 mM of a buffer comprising acetate or histidine.

[0173] In one embodiment of the present invention, the stable liquid pharmaceutical formulation can be administered subcutaneously.

[0174] In one embodiment of the present invention, the stable liquid pharmaceutical formulation may not require a reconstitution step, a dilution step, or both prior to use.

[0175] In one embodiment of the present invention, the stable liquid drug formulation can be filled in a pre-filled syringe before use.

[0176] In one embodiment of the present invention, the pre-filled syringe may be contained in an auto-injector prior to use. [Diseases that can be treated with anti-TNF-α antibodies]

[0177] In one embodiment of the present invention, the disease that can be treated with an anti-TNF-α antibody is selected from the group consisting of: rheumatoid arthritis, ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, neonatal hemolytic disease, inflammatory bowel disease, multiple sclerosis, prevention of organ transplant rejection, non-Hodgkin's lymphoma, metastatic cancer, retinopathy of prematurity, ovarian cancer, gastric cancer, head and neck cancer, osteoporosis, paroxysmal nocturnal hemoglobinuria, invasive candidiasis, breast cancer, melanoma, chronic lymphocytic leukemia, acute myeloid leukemia, renal cell carcinoma, colorectal cancer, asthma, nasopharyngeal carcinoma, hemorrhagic shock, Staphylococcus aureus infection and follicular lymphoma.

[0178] In one embodiment of the present invention, the disease that can be treated with an anti-TNF-α antibody can be a disease that can be treated with infliximab via intravenous administration.

[0179] In one embodiment of the present invention, the disease that can be treated with anti-TNF-α antibodies can be rheumatoid arthritis, ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis or ankylosing spondylitis, which can be treated by intravenous administration of infliximab.

[0180] In one embodiment of the present invention, the individual to be administered the anti-TNF-α antibody is a patient who has had an inadequate response to a disease-modifying antirheumatic drug (DMARD) containing methotrexate.

[0181] In one embodiment of the present invention, the individual to be administered the anti-TNF-α antibody is a patient who has not been previously treated with methotrexate or other DMARDs.

[0182] In one embodiment of the present invention, the individual to be administered the anti-TNF-α antibody is a patient who exhibits elevated serological markers associated with severe axial-predominant symptoms and inflammation that are inadequately responsive to conventional treatments.

[0183] In one embodiment of the present invention, the subject to be administered the anti-TNF-α antibody is a patient who has not responded to, has a contraindication to, or is intolerant to methotrexate, cyclosporine, or systemic therapy including psoralen ultraviolet A therapy (PUVA).

[0184] In one embodiment of the present invention, the individual to be administered the anti-TNF-α antibody is a patient who has an insufficient response to, is intolerant of, or has contraindications to treatment with corticosteroids, 6-mercaptopurine, azathioprine, or immunosuppressants.

[0185] In one embodiment of the invention, the subject to be administered an anti-TNF-α antibody is a patient who has not responded to conventional therapy including antibiotics, excretion or immunosuppressive therapy. [Dosage and dosing interval]

[0186] In one embodiment of the present invention, the anti-TNF-α antibody or antigen-binding fragment thereof can be administered at a dose of 60 to 300 mg. Specifically, it can be administered at a dose of 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290 or 300 mg.

[0187] In one embodiment of the present invention, the anti-TNF-α antibody or antigen-binding fragment thereof can be administered at a dose of 90 to 180 mg. In another embodiment, the anti-TNF-α antibody or antigen-binding fragment thereof can be administered at a dose of 120 to 240 mg. In yet another embodiment, the anti-TNF-α antibody or antigen-binding fragment thereof can be administered at a dose of 120 to 240 mg.

[0188] In one embodiment of the present invention, when the patient weighs less than 80 kg, the anti-TNF-α antibody or its antigen-binding fragment can be administered at a dose of 90 to 180 mg, and when the patient weighs more than 80 kg, it can be administered at a dose of 190 to 270 mg.

[0189] In one embodiment of the present invention, the anti-TNF-α antibody or antigen-binding fragment thereof can be administered at intervals of 1 to 8 weeks. Specifically, the administration can be performed at intervals of 1 week, 1.5 weeks, 2 weeks, 2.5 weeks, 3 weeks, 3.5 weeks, 4 weeks, 4.5 weeks, 5 weeks, 5.5 weeks, 6 weeks, 6.5 weeks, 7 weeks, 7.5 weeks or 8 weeks.

[0190] In another embodiment of the present invention, the anti-TNF-α antibody or antigen-binding fragment thereof can be administered at intervals of 2 to 4 weeks. [Pre-drug administration]

[0191] The step of subcutaneously administering the anti-TNF-α antibody or the antigen-binding fragment thereof may include the step of intravenously administering the anti-TNF-α antibody or the antigen-binding fragment thereof.

[0192] In one embodiment of the present invention, before the step of subcutaneous administration, there may be a step of intravenously administering an anti-TNF-α antibody or an antigen-binding fragment thereof at a dose of 1 to 10 mg / kg. Specifically, there is a step of intravenously administering an anti-TNF-α antibody or an antigen-binding fragment thereof at a dose of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg / kg.

[0193] In another embodiment of the present invention, before the step of subcutaneous administration, there may be a step of intravenously administering an anti-TNF-α antibody or an antigen-binding fragment thereof at a dose of 2 to 8 mg / kg. In yet another embodiment of the present invention, before the step of subcutaneous administration, there may be a step of intravenously administering an anti-TNF-α antibody or an antigen-binding fragment thereof at a dose of 3 to 5 mg / kg.

[0194] In a specific example of the present invention, before the step of subcutaneous administration, the step of intravenous administration of anti-TNF-α antibody or antigen-binding fragment thereof at intervals of 1 to 8 weeks may be included. Specifically, the step of intravenous administration of anti-TNF-α antibody or antigen-binding fragment thereof at intervals of 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 weeks may be included.

[0195] In another embodiment of the present invention, before the step of subcutaneous administration, there may be a step of intravenously administering an anti-TNF-α antibody or an antigen-binding fragment thereof at an interval of 2 to 4 weeks.

[0196] In one embodiment of the present invention, before the step of subcutaneous administration, the step of intravenous administration of anti-TNF-α antibody or antigen-binding fragment thereof may be included, and the time interval between the last intravenous administration and the first subcutaneous administration is 1 to 8 weeks. Specifically, the step of intravenous administration of anti-TNF-α antibody or antigen-binding fragment thereof may be included at intervals of 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 weeks.

[0197] In another embodiment of the present invention, before the subcutaneous administration step, there may be a step of intravenous administration of an anti-TNF-α antibody or an antigen-binding fragment thereof, and the time interval between the last intravenous administration and the first subcutaneous administration is 2 to 4 weeks. [Co-administration]

[0198] Other biological agents or chemotherapeutic agents can be administered together with the anti-TNF-α antibodies or antigen-binding fragments thereof of the invention.

[0199] The above administration is performed simultaneously with, before or after administration of the anti-TNF-α antibody or the antigen-binding fragment thereof.

[0200] In one embodiment of the present invention, the co-administered biological agent may include etanercept, infliximab, adalimumab, certolizumab pegol, golimumab, or a combination thereof.

[0201] In one embodiment of the present invention, the co-administered chemotherapeutic agent may include a disease-modifying antirheumatic drug (DMARD).

[0202] In one embodiment of the present invention, the co-administered chemotherapeutic agent may include methotrexate, leflunomide, sulfasalazine, hydroxychloroquine or a mixture thereof. [- product]

[0203] The present invention also provides a product, including: a stable liquid drug preparation; and a container for storing the stable liquid drug preparation in a sealed state.

[0204] The stable liquid pharmaceutical formulation is as described above.

[0205] In one embodiment of the present invention, the container may be formed of materials such as glass, polymer (plastic), metal, etc., but not limited thereto. In one embodiment of the present invention, the container is a bottle, a vial, a medicine box, a syringe (pre-filled syringe, automatic syringe) or a tube, but not limited thereto. In one embodiment of the present invention, the container may be a glass or polymer vial, or a glass or polymer pre-filled syringe.

[0206] The specific product forms of the above-mentioned vials, cartridges, prefilled syringes or automatic syringes, and the methods of filling the stable liquid drug preparations into the vials, cartridges, prefilled syringes or automatic syringes can be obtained or implemented at any time by any skilled person in the technical field involved in the present invention. For example, U.S. Patent Nos. 4,861,335 and 6,331,174, etc. disclose specific product forms and filling methods of prefilled syringes. For example, U.S. Patent Nos. 5,085,642 and 5,681,291, etc. disclose specific product forms and assembly methods of automatic syringes. The above-mentioned vials, cartridges, prefilled syringes or automatic syringes used in the present invention can be commercially available products, or they can be products manufactured separately in consideration of the physical properties of the stable liquid drug preparation, the range of the preparation to be administered, the dosage of the preparation, etc.

[0207] In one embodiment of the present invention, the interior of the container shall not be coated with silicone oil. If silicone oil is coated, the stability of the preparation may be reduced. The container may be a single-dose container or a multi-dose container.

[0208] In one embodiment of the present invention, the product may further include instructions for providing a method of using the stable liquid pharmaceutical formulation, a method of storing the formulation, or both. The method of using the formulation includes a method of treating a disease in which TNF-α activity acts as a deleterious factor, and may include a route of administration, a dosage of the formulation, and a time point of administration.

[0209] In one embodiment of the present invention, the product may include other necessary instruments (e.g., needles, syringes, etc.) from a commercial point of view and a user point of view. [[Example]]

[0210] Hereinafter, the present invention will be described with reference to examples. However, it should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. [Example 1. Safety and therapeutic efficacy evaluation of subcutaneous administration of infliximab in patients with rheumatoid arthritis (RA)]

[0211] This clinical trial of infliximab is a randomized, multicenter, parallel-group, phase I / III trial designed to evaluate the efficacy, pharmacokinetics, and safety of subcutaneous infliximab (hereinafter referred to as infliximab SC) and intravenous infliximab (hereinafter referred to as infliximab IV) in combination with methotrexate (MTX) and folic acid in the treatment of patients with active rheumatoid arthritis who have not had an adequate response to at least 3 months of MTX administration. This clinical trial consists of two parts.

[0212] Part I was designed to find the optimal dose of infliximab SC, where the optimal dose of infliximab SC relative to 3 mg / kg infliximab IV in the first 30 weeks was determined by the area under the steady-state concentration-time curve between weeks 22 and 30. In Part I, the clinical trial period was up to 65 weeks, including the period from screening (up to 3 weeks) to the end-of-study visit.

[0213] Part 2 was designed to demonstrate non-inferiority of infliximab SC to infliximab IV. Thus, infliximab SC was non-inferior to infliximab IV in terms of efficacy as determined by clinical response based on change from baseline Disease Activity Score using 28 joint counts (DAS 28; Disease Activity Assessment in 28 Joints) (C-reactive protein, CRP) at Week 22. In the Part 2 setting, the dose and dosing interval of infliximab SC was set at 120 mg every two weeks. [Part 1]

[0214] Patients are eligible to participate in this clinical trial if they meet all of the following criteria: * Patients with active disease were defined as having 6 or more swollen joints (28 evaluated), 6 or more tender joints (28 evaluated), and a serum CRP concentration >0.6 mg / dL at screening; and * Patients who have completed oral or parenteral methotrexate 12.5 to 25 mg / week for at least 3 months and have been stable on methotrexate 12.5 to 25 mg / week for at least 4 weeks before the first dose of study drug (Day 0).

[0215] Patients are not eligible to participate in this clinical trial if they meet any of the following criteria: * Patients who have previously received biologic agents for the treatment of RA and / or TNF-α inhibitors for the treatment of other diseases; and * Patients with known hypersensitivity to any excipient of infliximab or any other mouse and / or human protein, or to immunoglobulin products.

[0216] This clinical trial consists of three clinical trial periods: screening period; treatment period; and end-of-study visit. Screening was conducted between 21 days and 1 day before the initial administration of the study drug, during which the patient's study eligibility was assessed. All examinations included hepatitis B, hepatitis C, and human immunodeficiency virus (HIV-1 and HIV-2) infection, urine and serum pregnancy tests for women of childbearing potential, as well as rheumatoid factor, anti-cyclic citrullinated peptide, 12-lead ECG, clinical laboratory tests, etc. At the same time, interferon-γ release assay (IGRA) and chest X-ray examinations were also performed to exclude patients with tuberculosis (TB).

[0217] All patients enrolled in the clinical trial were given infliximab IV at Week 0 and Week 2, respectively. In addition, folic acid was given to patients in combination with MTX and study medication to minimize and prevent adverse events related to MTX side effects, and they were reminded to take the maintenance dose of MTX from the start to the end of the clinical trial. In addition, at the discretion of the investigator, patients were eligible to take the following premedications 30 to 60 minutes before the start of study medication to prevent their allergic reaction to the study medication: such as, but not limited to, antihistamines (equivalent doses of 2 to 4 mg chlorpheniramine), hydrocortisone, acetaminophen, and / or non-sedating antihistamines (equivalent doses of 10 mg cetirizine).

[0218] Those who had received two full doses of study drug and who had no safety concerns at the investigator's discretion were randomized to infliximab SC or infliximab IV at week 6 / day 42 before dosing. This randomization to study drug was stratified by country, week 2 serum CRP concentration (same or less than 0.6 mg / dL, or greater than 0.6 mg / dL), and week 6 body weight (same or less than 70 kg, or greater than 70 kg). A total of 50 patients with active RA were included, of whom 48 were randomized in a 1:1:1:1 ratio to the four clinical trial groups, with study drug administration continuing until week 54 (Table 1).

[0219]

[0220] Those assigned to Group 1 were given an additional 7 doses of infliximab IV at Week 6 and every 8 weeks thereafter (Weeks 14, 22, 30, 38, 46, and 54). Those assigned to Groups 2, 3, and 4 were initially given infliximab SC at Week 6 and then additional doses of infliximab SC every 2 weeks until Week 54. When the optimal dose was determined after dose survey, the initially assigned dose for all patients in Groups 2, 3, and 4 was adjusted to the optimal dose. Thereafter, additional SC injections were given at the optimal dose until Week 54. Infliximab SC was injected into patients at each visit (Weeks 6, 8, 10, 14, 22, 24, 26, 28, 30, 38, 46, and 54) by a healthcare professional at the study site. However, on all other weeks (Weeks 12, 16, 18, 20, 32, 34, 36, 40, 42, 44, 48, 50, and 52), patients were allowed to self-inject SC infliximab if the investigators deemed it appropriate after training the patients in the proper injection technique.

[0221] Patients visited the study site at pre-determined intervals for clinical assessments and blood sampling. At each visit, patients were asked questions about adverse events and concomitant medications, and clinical signs and symptoms of TB were monitored. Primary pharmacokinetic endpoints were assessed during the maintenance phase between weeks 22 and 30, and secondary pharmacokinetic endpoints were assessed during the treatment period until week 54, with blood sampling and analysis and assessments of efficacy, PD, and safety at the time points specified on the assessment form.

[0222] The end-of-study visit occurred 8 weeks after the last dose was received, or at the end of the maintenance phase, or earlier if the patient withdrew from the study. Every effort was made to complete all end-of-study assessments at the 8-week time point following the patient's last dose. [Part 2]

[0223] Part 2 was initiated based on the Data Safety Monitoring Board's review of the PK modeling report data containing PK, efficacy, PD, and safety data, which were determined during the first 30 weeks of Part 1.

[0224] The second part consists of 3 clinical trial periods, including screening; a double-blind period during the maintenance phase until week 30, followed by a 24-week open-label treatment period (dose loading phase and maintenance phase); and end of study. Screening was performed between day 42 and day 0 before the initial administration of study drug, and then the patients' study eligibility was evaluated. All examinations included hepatitis B, hepatitis C and human immunodeficiency virus (HIV-1 and HIV-2) infection, urine and serum pregnancy tests for women of childbearing potential, as well as rheumatoid factor, anti-cyclic citrullinated peptide, 12-lead ECG, clinical laboratory tests, etc. At the same time, interferon-γ release assay (IGRA) and chest X-ray examination were also performed to exclude patients with tuberculosis (TB).

[0225] All patients enrolled in the clinical trial were given a single dose of infliximab IV at Week 0 and Week 2, respectively. In addition, folic acid was given to patients in combination with MTX and study medication to minimize and prevent adverse events related to MTX side effects, and they were reminded to take a maintenance dose of MTX from the start to the end of the clinical trial. In addition, at the discretion of the investigator, patients were eligible to take the following premedications 30 to 60 minutes before the start of study medication to prevent their allergic reaction to the study medication: such as, but not limited to, antihistamines (equivalent doses of 2 to 4 mg chlorpheniramine), hydrocortisone, acetaminophen, and / or non-sedating antihistamines (equivalent doses of 10 mg cilitoril).

[0226] Those who had received two full doses of study drug and who had no safety concerns at the investigator's discretion were randomized to receive infliximab SC with placebo IV or infliximab IV with placebo SC via prefilled syringe (PFS) at week 6 / day 42 before dosing (PFS). This randomization to study drug was stratified by country, week 2 serum CRP concentration (same or less than 0.6 mg / dL, or greater than 0.6 mg / dL), and week 6 body weight (same or less than 100 kg, or greater than 100 kg). At least 218 patients with active RA were randomized in a 1:1 ratio to 2 clinical trial groups, with study drug administration continuing until week 54. Blinding was maintained until week 30 using a double dummy design (Table 2).

[0227]

[0228] Those assigned to Group 1 received an additional 3 doses of infliximab IV at Week 6 and then every 8 weeks (Weeks 14 and 22) until Week 22, while placebo SC was given at Week 6 and then every 2 weeks until Week 28. Thereafter, infliximab IV was switched to infliximab SC (PFS) at Week 30. Thereafter, infliximab SC (PFS) was given until Week 54. Those assigned to Group 2 initially received infliximab SC (PFS) at Week 6 and then every 2 weeks until Week 54, while placebo IV was given at Weeks 6, 14, and 22.

[0229] Infliximab SC (placebo SC in the double-blind period) was injected into patients by healthcare professionals at each visit (Weeks 6, 14, 22, 24 to 28 (those who went for PK assessments), 30, 38, 46, and 54) at the study site. However, at all other weeks (Weeks 8, 10, 12, 16, 18, 20, 24 to 28 (those who did not go for PK assessments), 32, 34, 36, 40, 42, 44, 48, 50, and 52), patients were allowed to self-inject infliximab SC (placebo SC in the double-blind period) if deemed appropriate by the investigator after training the patients in the proper injection technique.

[0230] In some countries, infliximab SC was self-administered every two weeks via autoinjector (AI) starting from week 46. The usability of infliximab SC (AI) was assessed by the Self-Injection Assessment Questionnaire (SIAQ), the Self-Injection Assessment Checklist, and the Potential Hazards Checklist before and after self-administration of infliximab SC.

[0231] In the case of Part II, each type of clinical assessment, blood sampling, and study visit was performed in the same manner as indicated in Part I and at the time points specified in the assessment form.

[0232] [result] [1-1. Safety assessment] [Summary of Adverse Events] Safety assessments were conducted on the secondary endpoints of Part I, i.e., immunogenicity, allergic reaction monitoring (including delayed allergic reaction monitoring), vital sign measurements (including blood pressure, heart and respiratory rate, body temperature), body weight, interferon-γ release assay (IGRA), chest X-ray, hepatitis B, hepatitis C and human immunodeficiency virus (HIV-1, HIV-2) infection status, comments on physical examination, 12-lead ECG, adverse events (hereinafter referred to as AEs) (including "serious adverse events" (hereinafter referred to as SAEs)), adverse events of special interest (infusion-related reactions / hypersensitivity reactions / anaphylactic reactions [administration-related reactions], delayed allergic reactions, injection site reactions, infections and malignancies), signs and symptoms of TB, clinical laboratory analysis, pregnancy test, prior and concomitant medications, local pain using a 10-cm visual analogue scale (VAS), etc.

[0233] Cumulative safety data included adverse events (and serious adverse events) reported until the end of the study, regardless of their relevance to clinical medications, and Table 3 presents an overall summary of AEs reported after treatment during the maintenance phase (weeks 6 to 54). Overall, 109 treatment-emergent AEs (hereafter referred to as TEAEs) were reported in 33 patients (68.8%) - 9 patients (69.2%) from the IV group (group 1) and 24 patients (68.6%) from the total SC group (groups 2, 3, and 4), respectively, indicating that the proportion in the total SC group was similar to that in the IV group. Moreover, most TEAEs showed an intensity of grade 1 or 2, and among all TEAEs, AEs reported in a total of 23 patients (47.9%) were considered to be related to the study medication.

[0234] Treatment-emergent SAEs (TESAEs) were reported in a total of 6 patients (12.5%) - 1 patient (7.7%) from the IV group (Group 1) and 5 patients (14.3%) from the SC groups (Groups 2 and 4). In the SC group, no TESAEs were reported in Group 3. TESAEs were grade 2 or 3 in intensity and were considered to be related to study drug in 2 patients (16.7%) reported in Group 4. In addition, 1 patient (9.1%) in Group 2 at 30 weeks post-dosing and 2 patients (16.7%) in Group 3 at 30 and 32 weeks post-dosing, respectively, discontinued study drug dosing because the investigators determined it to be a major medical event among all TESAEs.

[0235] Among the TEAEs classified as administration-related reactions (ARR), infusion-related reactions, hypersensitivity, or anaphylactic reactions were reported in a total of 4 patients (8.3%) - 1 patient (7.7%) from the IV group (Group 1) and 3 patients (8.6%) from the SC group (Groups 2 and 3). Among the TEAEs classified as ARR, no infusion-related reactions, hypersensitivity, or anaphylactic reactions were reported in Group 4 of the SC group. As infliximab ARR is associated with anti-drug antibodies (hereafter referred to as ADA) (Remsima SmPC 2017), the presence of ADA was evaluated in patients who showed ARR. A total of 2 patients (1 patient each from Group 1 and Group 2) had positive results for ADA and neutralizing antibodies (hereafter referred to as NAb). One patient in Group 2 received two doses of infliximab IV during the loading phase, at Weeks 0 and 2, followed by two doses of infliximab SC at Weeks 6 and 8. ARR was reported at Weeks 6 and 8, and positive responses to ADA and NAb were confirmed at Week 6 and at the end-of-study visit (performed within 10 weeks after the Week 8 visit). One patient in Group 1 reported an ARR at Week 38, and positive responses to ADA and NAb were confirmed at Weeks 30 and 38 and at the end-of-study visit (performed within 10 weeks after the Week 38 visit).

[0236] TEAEs classified as injection site reactions were reported in 5 patients (14.3%) in the total SC group (Groups 2, 3, and 4), all of which were grade 1 or 2 in intensity. No TEAEs classified as injection site reactions were reported in the IV group (Group 1). Patients who showed injection site reactions were also evaluated for the presence of ADA, and 1 of the 5 patients (Group 2) had positive results for ADA and NAB at the Week 6 visit, the day before the TEAE classified as an injection site reaction occurred.

[0237] Treatment-emergent AEs classified as infections were reported in 5 patients (38.5%) in the IV group (Group 1) and 13 patients (37.1%) in the total SC group (Groups 2 to 4), respectively.

[0238] TEAEs leading to study drug discontinuation were reported in 6 patients (17.1%) in the SC groups (groups 2, 3, and 4), with the reported AEs being antiphospholipid syndrome, injection site reactions, ARR, tuberculosis, and latent tuberculosis. In the IV group, no TEAEs classified as infections were reported.

[0239] No deaths were reported during the study period.

[0240]

[0241] [Immunogenicity] Overall, during the study period, the proportion of patients with positive ADA results in the SC group was low, and most patients had negative ADA test results at week 54. Moreover, the ADA positivity rate showed a decreasing trend with the increase of infliximab SC dose. The number of patients with positive ADA results at week 54 was 9 (69.2%), 4 (36.4%), 2 (16.7%), and 2 (16.7%) from group 1 to group 4, respectively (Table 4).

[0242]

[0243] [Local pain assessment using visual analog scale] The VAS range is 0 to 100 mm, with higher scores indicating more severe pain. At the first SC injection (week 6), slightly higher local pain (VAS) was observed in the SC groups (Groups 2, 3, and 4) compared with the IV group (Group 1), however, with repeated injections of infliximab SC, local pain gradually decreased, and the SC groups (Groups 2, 3, and 4) reported lower levels of pain compared with the IV group (Group 1). Among the SC groups, the average local pain in the SC180 mg group was slightly higher than that in the other SC groups due to receiving 2 SC injections at one time, but the pain level in the SC180 mg group tended to be lower than that in the IV group (Group 1) (Table 5).

[0244]

[0245] [1-2. Evaluation of therapeutic efficacy] [Disease activity measured by DAS28] Results of the secondary efficacy endpoints of DAS28 (C-reactive protein; CRP) and DAS28 (erythrocyte sedimentation rate; ESR) compared with baseline at weeks 2, 6, 14, 22, 30, and 54 indicated no significant differences between the 3 different doses of infliximab SC and infliximab IV, confirming that actual values ​​tended to decrease over time.

[0246] The actual values ​​and changes from baseline in disease activity measured by DAS28 are summarized in Table 6 (CRP) and Table 7 (ESR). In each group, the mean disease activity scores measured by DAS 28 decreased from baseline at Weeks 2, 6, 14, 22, 30, and 54. From Week 22, there was a trend for slightly lower DAS (CRP) scores in the SC group than in the IV group, and from Week 30, there was a trend for slightly lower DAS 28 (ESR) scores in the SC group than in the IV group, which was consistent with the higher trough concentrations in the SC group.

[0247]

[0248]

[0249] [EULAR reaction] The proportion of patients with a good or moderate response, as defined by the EULAR (European League Against Rheumatism) response criteria using DAS28 (CRP), was similar in the groups during the study period (Table 8). The results of the EULAR response criteria using the DAS28 (ESR) response were also similar in the groups during the study period (Table 9).

[0250]

[0251]

[0252] [Proportion of patients achieving clinical response based on ACR20] From Week 14 to Week 54, the proportion of patients achieving clinical response based on ACR20 (American College of Rheumatology 20% improvement) was similar in the IV group (Group 1) and the SC group (Groups 2, 3, and 4) (Table 10).

[0253]

[0254] [Example 2. Establishment of a model for subcutaneous administration of infliximab to RA patients] [Construction of PK-PD model] A pharmacokinetic-pharmacodynamic (PK-PD) model of subcutaneous (SC) infliximab was established and integrated with a quantitative pharmacokinetic (PK) model to simulate not only the PK of future dosing doses and regimens, but also the efficacy and safety of SC infliximab. The PK-PD model was based on data from IV infliximab administration in healthy volunteers, patients with ankylosing spondylitis (AS), rheumatoid arthritis (RA), and Crohn's disease (CD), and data from SC infliximab administration in CD patients, RA patients, and healthy volunteers (Clinicaltrials.gov identifiers NCT 01220518, NCT 01217086, and NCT 02096861).

[0255] The PK-PD model constructed based on the data can be used to simulate the results of subcutaneous administration of infliximab in patients with indications for infliximab (RA, ulcerative colitis (UC), CD, plaque psoriasis, psoriatic arthritis, or ankylosing spondylitis).

[0256] PK-PD modeling analysis was performed via a nonlinear mixed effects modeling approach. Data analysis started with a one-compartment model, proportional elimination including a proportional error model, and then the final model was performed via a two-compartment model with linear elimination from the central compartment. All pharmacokinetic models varied by clearance (CL) and volume of distribution.

[0257] For the final PK model, profiles were predicted in such a way that the parameters related to the clinical trials of infliximab for each estimated value of the area under the concentration-time curve (AUCtau) and the lowest concentration before the next study drug dose (Ctrough) were applicable to each actual dose, use and route of administration, where the data were summarized descriptively with median values ​​and 90% confidence intervals. In addition, additional simulations were performed to evaluate the effect of various body weights for fixed doses, uses and routes of administration. PK-PD modeling and subcutaneous dose simulations were performed using NONMEM v7.2.

[0258] SC dosage regimen for RA patient modeling

[0259] The pharmacokinetic aspects, from which efficacy and safety were predicted, were predicted based on the following simulation scheme and then compared with the use of infliximab IV infusions, where maintenance doses of 3 mg / kg were given at 8-week intervals (Table 11):

[0260]

[0261] [Estimates of infliximab SC doses and infliximab exposure parameters for patients with RA at various body weights]

[0262] The infliximab SC dose and exposure pharmacokinetic parameters (AUCτ, Ctrough and Cmax) were simulated, and the body weight range of 50 to 130 kg was divided into 10 kg units. The Ctrough and AUCτ estimates of infliximab SC exposure for various body weights showed correlation with the drug dose (Table 12).

[0263]

[0264] [Example 3. Safety and therapeutic efficacy evaluation of subcutaneous administration of infliximab in patients with CD or UC] This infliximab clinical trial is an open-label, randomized, multicenter, parallel-group, phase I trial designed to evaluate the pharmacokinetics, efficacy, and safety of infliximab SC and infliximab IV in patients with active CD or active UC until week 54. This clinical trial consists of two parts.

[0265] Part I was designed to find the optimal dose of infliximab SC in CD patients, where the optimal dose of infliximab SC equivalent to 5 mg / kg infliximab IV in the first 30 weeks was determined by the area under the steady-state concentration-time curve (AUCτ) between weeks 22 and 30. In the case of Part I, the clinical trial period was up to 65 weeks, including the period from screening (up to 3 weeks) to the end-of-study visit.

[0266] Part II was designed to seek to determine whether infliximab SC was pharmacokinetically non-inferior to infliximab IV in patients with CD or UC, as demonstrated by pre-dose concentrations (Ctrough) at week 22. In Part II, based on the pharmacokinetic, pharmacodynamic, and safety data from the first 30 weeks of Part I, the optimal dose and dosing interval of infliximab SC equivalent to 5 mg / kg infliximab IV was determined as follows: ●For patients weighing less than 80 kg: 120 mg of infliximab SC every 2 weeks; and ●For patients weighing 80 kg or more: Administer 240 mg of infliximab SC every 2 weeks.

[0267] [Part 1] Patients are eligible to participate in this clinical trial if they meet all of the following criteria: * Patients with Crohn's disease and a CDAI score of 220 to 450; * Patients who have had Crohn's disease for at least 3 months before the first dose of study drug (Day 0); and * Patients who have been treated for active Crohn's disease and have not responded despite a complete and adequate course of corticosteroids and / or immunosuppressants; or who are intolerant to or have contraindications to such therapy.

[0268] Patients are not eligible to participate in this clinical trial if they meet any of the following criteria: * Patients who have previously received biologic agents for the treatment of Crohn's disease or ulcerative colitis and / or TNF-α (tumor necrosis factor-α) inhibitors for the treatment of other diseases; and * Patients with hypersensitivity to any excipient of infliximab or any other mouse and / or human protein, or patients with hypersensitivity to immunoglobulin products; * Patients with active intestinal and bladder, retroperitoneal, enterocutaneous and enterovaginal fistulas within 6 months before the first dose of study drug (Day 0). Intestinal fistulas without clinically significant symptoms and anal fistulas without defecation problems were allowed at the discretion of the investigator; and * Patients who underwent more than 3 small bowel resections before the first dose of study drug (Day 0).

[0269] This clinical trial consists of 3 clinical trial periods: screening period; treatment period; and end-of-study visit. Screening was conducted between 21 days and 1 day before the initial administration of the study drug, during which the patient's study eligibility was assessed. All examinations were performed, including hepatitis B, hepatitis C, and human immunodeficiency virus (HIV-1 and HIV-2) infection, urine and serum pregnancy tests for women of childbearing potential, as well as colonoscopy, CRP, 12-lead ECG, clinical laboratory tests, etc. At the same time, interferon-γ release assay (IGRA) and chest X-ray were also performed to exclude patients with tuberculosis (TB).

[0270] Patients who met all inclusion criteria and did not meet any exclusion criteria at Week 0 / Day 0 were enrolled in the clinical trial, where all participating patients received a single dose of infliximab IV twice at Week 0 and Week 2. In addition, at the discretion of the investigator, patients were eligible to take the following premedications 30 to 60 minutes before the start of study drug administration to prevent their allergic reaction to the study drug: such as, but not limited to, antihistamines (equivalent doses of 2 to 4 mg chlorpheniramine), hydrocortisone, acetaminophen, and / or non-sedating antihistamines (equivalent doses of 10 mg cilitoril).

[0271] Patients who had received two full doses of study drug and who had no safety concerns at the investigator's discretion were randomized to either infliximab SC or infliximab IV at week 6 / day 42 before dosing. This randomization to study drug was based on region (European or non-European), current treatment with azathioprine (AZA) or 6-mercaptopurine (6-MP) or methotrexate (MTX) (using or not), clinical response by CDAI-70 at week 6, and body weight at week 6 (equal to or less than 70 kg, or more than 70 kg). A total of 45 patients with active RA were enrolled, of whom 44 were randomized in a 1:1:1:1 ratio to the four clinical trial groups, with study drug administration continuing until week 54 (Table 13).

[0272]

[0273] Those assigned to Group 1 were given an additional 7 doses of infliximab IV at Week 6 and every 8 weeks thereafter (Weeks 14, 22, 30, 38, 46, and 54). Those assigned to Groups 2, 3, and 4 were initially given infliximab SC at Week 6 and then additional doses of infliximab SC every 2 weeks until Week 54. When the optimal dose was determined after the dose survey, the initially assigned dose for all patients in Groups 2, 3, and 4 was adjusted to the optimal dose. Thereafter, additional SC injections were given at the optimal dose until Week 54. Infliximab SC was injected into patients at each visit (Weeks 6, 8, 10, 14, 22, 24, 26, 28, 30, 38, 46, and 54) by a healthcare professional at the study site. However, on all other weeks (Weeks 12, 16, 18, 20, 32, 34, 36, 40, 42, 44, 48, 50, and 52), patients were allowed to self-inject SC infliximab if the investigators deemed it appropriate after training the patients in the proper injection technique.

[0274] Patients visited the study site at pre-determined intervals for clinical assessments and blood sampling. At each visit, patients were asked questions about adverse events and concomitant medications, and clinical signs and symptoms of TB were monitored. Primary pharmacokinetic endpoints were assessed during the maintenance phase between weeks 22 and 30, and secondary pharmacokinetic endpoints were assessed during the treatment period until week 54, with blood sampling and analysis and assessments of efficacy, PD, and safety at the time points specified on the assessment form.

[0275] The end-of-study visit will be conducted within 8 weeks after the maintenance phase. However, when patients discontinue the clinical trial, it will be conducted within 8 weeks after the last dosing time point. If there is a patient withdrawal, all clinical trial procedures will be conducted on the day of withdrawal or the next day, with every effort made to complete all end-of-study assessments at the 8-week time point after the last dosing of the patient. [Part 2]

[0276] Part 2 will begin based on the Data Safety Monitoring Board's review of the PK modeling report data containing PK, efficacy, PD, and safety data determined during the initial 30 weeks of Part 1.

[0277] Patients are eligible to participate in the second part of this clinical trial if they meet all of the following criteria: In case of active CD patients - * Patients with Crohn's disease and a CDAI score of 220 to 450; * Patients who have had Crohn's disease for at least 3 months before the first dose of study drug (Day 0); and * Patients who have been treated for active Crohn's disease and have not responded despite a complete and adequate course of corticosteroids and / or immunosuppressants; or who are intolerant to or have contraindications to such therapy. * Patients who meet at least one of the following criteria: - Serum C-reactive protein (CRP) concentration greater than 0.5 mg / dL; - Fecal calprotectin greater than 100 μg / g; and - Patients with ileo-colonic CD with a colonoscopy (SES-CD) score of 6 or more, or patients with ileo-colonic CD with at least 4 or more such scores and at least 1 ulceration score.

[0278] If it is the case of patients with active UC- * Patients with active ulcerative colitis, as defined by the Mayo total score, should have a positive endoscopy score at screening. 2 indicates evidence of active endoscopic colitis, between 6 and 12 points; * Patients who had ulcerative colitis for at least 3 months before the first dose of study drug (Day 0); and * Patients who have been treated for active ulcerative colitis and have not responded despite conventional therapy consisting of corticosteroids alone or in combination with 6-MP or AZA and 5-ASA-containing drugs; or who are intolerant to or have contraindications to such therapy.

[0279] Patients are not eligible to participate in the second part of the clinical trial if they meet any of the following criteria: * Patients who have previously received biologic agents for the treatment of CD or UC and / or TNF-α inhibitors for the treatment of other diseases; and * Patients with hypersensitivity to any excipient of infliximab or any other mouse and / or human protein, or patients with hypersensitivity to immunoglobulin products; * Patients with active intestinal and bladder, retroperitoneal, enterocutaneous and enterovaginal fistulas within 6 months before the first dose of study drug (Day 0). Intestinal fistulas without clinically significant symptoms and anal fistulas without defecation problems were allowed at the discretion of the investigator; and * Patients who had undergone more than 3 small bowel resections before the first dose of study drug (Day 0); and * Patients who have taken medications containing corticosteroids or 5-ASA administered rectally for the treatment of ulcerative colitis within 2 weeks prior to screening.

[0280] The second part consists of 3 clinical trial periods: screening period; treatment period; and end-of-study visit. Screening was conducted between 42 days and 0 days before the initial administration of the study drug, during which the patients' study eligibility was assessed. All examinations were performed, including hepatitis B, hepatitis C, and human immunodeficiency virus (HIV-1 and HIV-2) infection, urine and serum pregnancy tests for women of childbearing potential, as well as colonoscopy (CD patients), flexible proctosigmoidoscopy (UC patients), CRP, 12-lead ECG, clinical laboratory tests, etc. At the same time, interferon-γ release assay (IGRA) and chest X-ray were also performed to exclude patients with tuberculosis (TB).

[0281] Patients who met all inclusion criteria and did not meet any exclusion criteria at Week 0 / Day 0 were enrolled in the clinical trial, where all participating patients received a single dose of infliximab IV twice at Week 0 and Week 2. In addition, at the discretion of the investigator, patients were eligible to take the following premedications 30 to 60 minutes before the start of study drug administration to prevent their allergic reaction to the study drug: such as, but not limited to, antihistamines (equivalent doses of 2 to 4 mg chlorpheniramine), hydrocortisone, acetaminophen, and / or non-sedating antihistamines (equivalent doses of 10 mg cilitoril).

[0282] Patients who had received two full doses of study drug and who had no safety concerns at the investigator's discretion were randomized to either infliximab SC or infliximab IV at week 6 / day 42 prior to dosing. This randomization to study drug was stratified by current treatment with azathioprine or 6-mercaptopurine or MTX, disease (CD or UC), clinical response by CDAI-70 for CD or by partial Mayo score for UC at week 6, and body weight at week 6 (less than 80 kg, or more than 80 kg). A minimum of 130 patients with active CD or active UC were randomized in a 1:1 ratio to the two clinical trial groups, with study drug administration continuing until week 54 (Table 14).

[0283]

[0284] Those assigned to Group 1 received additional IV infliximab at Week 6 and every 8 weeks thereafter (Weeks 14 and 22) until Week 22. Thereafter, IV infliximab was switched to SC infliximab from Week 30. The SC dose was determined based on the Week 30 body weight. This dose was given every 2 weeks until Week 54. For those assigned to Group 2, the SC infliximab dose was determined based on the Week 6 body weight and was given every 2 weeks from Week 6 to Week 54. After Week 30, dose increases were allowed at the discretion of the investigator. SC infliximab was injected into the patient by a healthcare professional at each visit (Weeks 6, 14, 22, 24, 26, 28, 30, 38, 46, and 54) at the study site. However, on all other weeks, patients were allowed to self-inject SC infliximab if the investigator deemed it appropriate after training the patient in proper injection technique.

[0285] The primary pharmacokinetic endpoint was assessed at week 22, and secondary pharmacokinetic endpoints were assessed during the maintenance phase between weeks 22 and 30 and during the treatment period until week 54. Blood sampling and analysis, as well as assessments of efficacy, PD, and safety were performed at the time points specified on the assessment form.

[0286] The end-of-study visit will be conducted within 2 weeks after the end of the maintenance phase. However, when a patient discontinues the clinical trial after SC dosing, it will be conducted within 2 weeks after the last dosing time point. However, when a patient discontinues the clinical trial after IV dosing, it will be conducted within 8 weeks after the last dosing time point. If there is a patient withdrawal, all clinical trial procedures will be conducted on the day of withdrawal or the next day, with every effort made to complete all end-of-study assessments at the scheduled time point after the last dosing of the patient.

[0287] In the case of Part II, various types of clinical assessments, blood sampling, and study visits were performed in the same manner as indicated in Part I and at the time points specified in the assessment form.

[0288] result 3-1. Safety assessment [Summary of Adverse Events] Safety assessments were conducted on the secondary endpoints of Part I, i.e., immunogenicity, allergic reaction monitoring (including delayed allergic reaction monitoring), vital sign measurements (including blood pressure, heart and respiratory rate, and temperature), body weight, interferon-γ release assay (IGRA), chest X-ray, hepatitis B, hepatitis C, and human immunodeficiency virus (HIV-1, HIV-2) infection status, comments on physical examination, 12-lead ECG, adverse events (hereinafter referred to as AEs) (including "serious adverse events" (hereinafter referred to as SAEs)), adverse events of special interest (infusion-related reactions / hypersensitivity reactions / anaphylactic reactions [administration-related reactions], delayed allergic reactions, injection site reactions, infections, and malignancies), signs and symptoms of TB, clinical laboratory analysis, pregnancy test, prior and concomitant medications, and local pain using a 100-mm visual analog scale (VAS).

[0289] Cumulative safety data included AEs up to Week 30, with Table 15 presenting an overall summary of AEs reported following treatment during the maintenance phase (Weeks 6 to 30).

[0290] Overall, 70 TEAEs were reported in 28 patients (63.6%) - 8 patients (69.2%) from the IV group (Group 1) and 20 patients (64.56%) from the SC group (Groups 2 to 4), indicating similar proportions between the two groups. Moreover, most TEAEs showed an intensity of Grade 1 or 2. Among all TEAEs, AEs reported in 9 patients (20.5%) were considered to be related to study drug.

[0291] Treatment-emergent serious AEs (hereafter referred to as TESAEs) were reported in 8 patients (18.2%) - 2 patients (15.4%) from the IV group (Group 1) and 6 patients (19.4%) from the total SC group (Groups 2 to 4). All TESAEs were considered to be related to the study drug.

[0292] Among the TEAEs classified as ARR, infusion-related reactions, hypersensitivity, or anaphylactic reactions were reported in 1 patient in the IV group (Group 1) (on the day of drug treatment at week 30) and in 1 patient in the SC group (Group 4) (2 days after drug treatment at week 6). Since infliximab administration-related reactions are associated with anti-drug antibodies (ADA) (Remsima SmPC 2017), the presence of ADA was evaluated in patients who showed administration-related reactions. There was only 1 patient (IV group (Group 1)) with positive results for ADA and neutralizing antibodies (NAb), in which the patient received drug treatment with IV drugs in the maintenance phase after the dose loading period, i.e., weeks 6 and 14, and then was confirmed to be ADA positive from week 22, and then reported an administration-related reaction at week 30.

[0293] TEAEs classified as injection site reactions were reported in 4 patients (12.9%) in the SC groups (groups 2 to 4), all of which were grade 1 or 2 in intensity. Even patients who showed injection site reactions were evaluated for the presence of ADA, with 2 of the 4 patients having positive results for ADA and NAb during the clinical trial.

[0294] TEAEs classified as infections were reported in 2 (15.4%) patients in the IV group (Group 1) and in 7 (22.6%) patients in the SC groups (Groups 2 to 4).

[0295] TEAEs leading to study drug discontinuation were reported in 1 patient (7.7%) in Group IV (Group 1) and 4 patients (12.9%) in Group SC (Groups 2 to 4), with only 1 patient in Group 3 discontinuing study drug due to a TEAE considered to be related to study drug, which was Grade 1 potential TB.

[0296] Two deaths were reported during the clinical trial (one in each of Group 1 and Group 3). One patient in Group IV (Group 1) died at home due to sudden cardiac death one month after the end of medication at Week 6, which was not reported to be related to the study medication. This patient had comorbidities of hypertension and chronic heart failure. In Group SC (Group 3), one patient died at home due to sudden death on the evening after medication at Week 30, which was not reported to be related to the study medication. This patient had comorbidities of chronic aortic calcification, diabetes, obesity, and metabolic syndrome.

[0297] [Immunogenicity]

[0298] Overall, the proportion of patients with positive ADA results was low in the SC group, and most patients tested ADA negative at week 30. The number of patients with positive ADA results at week 30 was 8 (61.5%), 0 (0.0%), 3 (25.0%), and 1 (12.57%) in groups 1 to 4, respectively (Table 16).

[0299] [Use visual analogue scale (VAS) to assess local pain]

[0300] The VAS ranged from 0 to 100 mm, with higher scores indicating more severe pain. In Groups 3 and 4, where two injections had to be given at each visit, slightly higher levels of localized pain were observed than in the other groups. Overall, low levels of localized pain (mean the same or less than 21.05 mm) were observed in all groups (Table 17).

[0301]

[0302] [3-2. Evaluation of therapeutic efficacy] [Disease activity measured by CDAI] Analysis of the CDAI (Crohn's Disease Activity Index) scores at weeks 2, 6, 14, 22, and 30 compared with baseline as a secondary efficacy endpoint confirmed that the actual values ​​in each group tended to decrease over time. At week 6, the proportion of patients responding to the CDAI-70 standard, one of the stratified random variables, was slightly higher in group 2 than in the other groups, so more attention needs to be paid to the interpretation of the efficacy results.

[0303] Table 18 summarizes the actual values ​​of disease activity measured by CDAI and the values ​​changed from baseline.

[0304]

[0305] [Response assessment according to CDAI-70 and CDAI-100 response criteria] Based on the CDAI score, the proportion of patients who responded to the CDAI-70 response criteria (patients whose CDAI score decreased by 70 points or more from baseline) showed similar levels among the treatment groups (Table 19). The proportion of patients who responded to the CDAI-100 response criteria (patients whose CDAI score decreased by 100 points or more from baseline) also showed similar levels among the treatment groups (Table 20).

[0306]

[0307]

[0308]

Table 20

[0309] [Clinical remission assessment] The proportion of patients who achieved clinical remission (patients with CDAI absolute score less than 150 points) was similar between treatment groups. During the drug maintenance phase (weeks 6 to 30), a relatively high proportion of patients who achieved clinical remission was observed in group 2, but 6 patients (54.5%) in group 2 achieved clinical remission at week 6, and most of these patients maintained clinical remission until week 30 (Table 21).

[0310]

[0311] [Example 4. Establishment of a model for subcutaneous administration of infliximab to CD patients] [Construction of PK-PD model] The PK-PD model construction was performed in the same manner as shown in Example 2.

[0312] [SC dosage regimen for CD patient modeling] The pharmacokinetic aspects, from which efficacy and safety were also predicted, were predicted based on the following simulation scheme and then evaluated in comparison with the use of infliximab IV infusions, where maintenance doses of 5 mg / kg were administered at 8-week intervals (Table 22):

[0313]

[0314] [Estimates of infliximab SC doses and infliximab exposure parameters for CD patients of various body weights] The pharmacokinetic parameters of infliximab SC dose and exposure were simulated, and the body weight range of 50 to 130 kg was divided into 10 kg units. The estimated values ​​of the minimum concentration (Ctrough) before the next dose of study drug and the area under the concentration-time curve (AUCτ) of SC exposure were shown to be correlated with the drug dose (Table 23).

[0315]

Claims

1. The use of a pharmaceutical composition comprising infliximab in the preparation of a medicament for treating rheumatoid arthritis, wherein, Infliximab is administered subcutaneously to patients at 120 mg doses every 2 weeks, provided that the patient has received at least one intravenous dose of infliximab prior to the subcutaneous administration and that the first subcutaneous administration is performed 4 weeks after the last intravenous administration.

2. The use as described in claim 1, wherein, Infliximab is administered in combination with disease-modifying antirheumatic drugs (DMARDs).

3. The use as described in claim 2, wherein, The disease-modifying antirheumatic drugs (DMARDs) are selected from the group consisting of methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine.

4. The use as described in claim 1, wherein, This patient had previously received infliximab intravenously at doses ranging from 1 to 10 mg / kg per administration.

5. The use as described in claim 1, wherein, After subcutaneous administration to patients, infliximab was maintained at the lowest possible blood concentration (Ctrough) of 3 to 16 μg / mL.

6. The use as described in claim 1, wherein, After subcutaneous administration to patients, infliximab was maintained at the lowest possible blood concentration (Ctrough) of 9 to 32 μg / mL.

7. The use as described in claim 1, wherein, Patients who received subcutaneous administration showed a decrease of at least 2.0 in DAS28 (Disease Activity Assessment of 28 Joints).

8. The use as described in claim 1, wherein, Prior to subcutaneous administration, patients must possess one or more of the following characteristics: a) patients with an inadequate response to disease-modifying antirheumatic drugs (DMARDs) including methotrexate; b) patients who have not previously been treated with methotrexate or other DMARDs; c) patients exhibiting elevated serological markers associated with severe axial predominant symptoms and inflammation that do not respond adequately to conventional treatment; or d) patients who are unresponsive to, have contraindications to, or are intolerant of systemic therapy with methotrexate.

9. The use as described in claim 1, wherein, Prior to subcutaneous administration, the patient must have one or more of the following characteristics: a) inadequate response, intolerance, or contraindications to treatment with corticosteroids, 6-mercaptopurine, azathioprine, or immunosuppressants; or b) unresponsive to conventional treatments including antibiotics, elimination therapy, or immunosuppressive therapy.

10. The use as described in claim 1, wherein, The composition containing infliximab contains: (A) 90 to 180 mg / ml of infliximab; (B) 0.02 to 0.1% (w / v) of polysorbate; (C) 1 to 10% (w / v) of sorbitol; and (D) 1 to 50 mM of a buffer including acetate.

11. The use as described in claim 1, wherein, The composition containing infliximab is filled in a pre-filled syringe or auto-injector before being administered to the patient.

12. A reagent kit, comprising: (a) Pharmaceutical compositions containing infliximab; (b) Instructions to administer the pharmaceutical composition subcutaneously at 120 mg doses every 2 weeks to treat patients with rheumatoid arthritis, wherein the patient has received at least one intravenous dose of infliximab prior to the subcutaneous administration and the first subcutaneous administration is performed 4 weeks after the last intravenous administration.

Images