Stable pharmaceutical formulation

Abstract

To provide a stable pharmaceutical formulation comprising an antibody that binds to the interleukin-6 receptor.SOLUTION: A stable pharmaceutical formulation according to the present invention comprises (A) an antibody or antigen-binding fragment thereof that binds to an interleukin-6 receptor; (B) a surfactant; (C) a stabilizer; and (D) a buffer. The stable pharmaceutical formulation according to the present invention has a low viscosity even when it contains an antibody, especially at a high concentration, and has excellent long-term storage stability based on excellent stability under accelerated and severe conditions, and may be administered intravenously or subcutaneously.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a stable pharmaceutical formulation comprising an antibody that binds to the Interleukin-6 Receptor (IL-6R). [Background technology]

[0002] Interleukin 6 (IL-6) is a cytokine involved in acute inflammatory response regulation, B cell differentiation, T cell activation, bone metabolism, thrombosis, immune response, etc. Interleukin 6 (IL-6) is associated with various autoimmune diseases, inflammatory diseases, malignant tumors, etc. Such abnormal diseases can be treated by using antibodies that bind to the Interleukin 6 Receptor (IL-6R).

[0003] An antibody refers to an immunoglobulin molecule consisting of four polypeptide chains, two heavy chains and two light chains linked together by disulfide bonds. 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 are further subdivided into hypervariable regions called complementarity determining regions (CDRs) arranged with more conserved regions called framework regions (FRs). Each heavy and light chain variable region consists of three CDRs and four FRs, which are arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0004] Antibodies that bind to the Interleukin-6 Receptor are unstable proteins. These antibodies are prone to physical or chemical changes due to heat stress, light stress, etc. This can impair the stability and / or activity of the product after it is stored, especially after it is stored for a long time.

[0005] That is, pharmaceutical compositions containing physiologically active proteins such as antibodies have the problem that it is difficult to formulate them while ensuring stability so that the activity of the protein can be maintained for an appropriate period of time. Summary of the Invention [Problem to be solved by the invention]

[0006] The problem to be solved by the present invention is to provide a stable pharmaceutical preparation containing an antibody that binds to the interleukin-6 receptor.

[0007] Another problem to be solved by the present invention is to provide a vial filled with the pharmaceutical preparation.

[0008] Another problem to be solved by the present invention is to provide a cartridge filled with the pharmaceutical preparation.

[0009] Another problem to be solved by the present invention is to provide a pre-filled syringe filled with the pharmaceutical preparation.

[0010] Another problem to be solved by the present invention is to provide an auto-injector having the pre-filled syringe contained therein. [Means for solving the problem]

[0011] As a result of extensive research conducted by the present inventors to overcome the above-mentioned problems, they have developed a stable preparation containing an antibody that binds to the interleukin-6 receptor.

[0012] The present invention provides a stable pharmaceutical formulation comprising: (A) an antibody or antigen-binding fragment thereof that binds to Interleukin-6 receptor; (B) a surfactant; (C) a stabilizer which is i) an amino acid or amino acid derivative, ii) a sugar or sugar alcohol, or a mixture thereof; and (D) a buffer, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising 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 comprising 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.

[0013] In one embodiment of the present invention, the pharmaceutical preparation may be, but is not limited to, a liquid.

[0014] (A) An antibody or antigen-binding fragment thereof In the present invention, the term "antibody" refers to an immunoglobulin molecule consisting of four polypeptide chains, two heavy chains and two light chains, linked together by disulfide bonds, and may include naturally occurring antibodies with other altered structures, such as camel antibodies.

[0015] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof according to the present invention may be a polyclonal antibody, a monoclonal antibody, a recombinant antibody, a single-chain antibody, a hybrid antibody, a chimeric antibody, a humanized antibody or a fragment thereof (antigen-binding fragment), or preferably a monoclonal antibody or a fragment thereof.

[0016] In the present invention, the antibody or antigen-binding fragment thereof according to the present invention may be a humanized monoclonal antibody or a fragment thereof, most preferably a humanized immunoglobulin G (IgG) monoclonal antibody, and can be produced by methods known in the art.

[0017] In the present invention, the antigen-binding fragment includes any naturally occurring, enzymatically accessible, synthetic or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex, an example of which is Nanobodies.

[0018] In the present invention, the humanized antibody is also called a reshaped human antibody, and may be an antibody in which the complementarity determining region (CDR) of an antibody from a mammal other than a human, such as a mouse, has been transplanted into the complementarity determining region (CDR) of a human antibody, or may be produced by other commonly known gene recombination techniques.

[0019] In the present invention, the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising 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 The heavy chain variable region may comprise 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.

[0020] In the present invention, the antibody or antigen-binding fragment thereof can comprise: a light chain variable region comprising the amino acid sequence of SEQ ID NO:7; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:8.

[0021] In the present invention, the antibody or antigen-binding fragment thereof can comprise: a light chain comprising the amino acid sequence of SEQ ID NO:9; and a heavy chain comprising the amino acid sequence of SEQ ID NO:10.

[0022] In the present invention, the antibody or antigen-binding fragment thereof according to the present invention may be Tocilizumab, Sarilumab, Sapelizumab, Vobarilizumab, or a mixture thereof. Preferably, the antibody or antigen-binding fragment thereof may be Tocilizumab, Sapelizumab, Vobarilizumab, or a mixture thereof. Most preferably, the antibody or antigen-binding fragment thereof may be Tocilizumab.

[0023] In the present invention, the "Tocilizumab" may be hPM-1 described in International Publication No. WO1992-019759, the original drug substance as is well known in the art, or a biosimilar thereof.

[0024] In the present invention, the "Sarilumab" may be an interleukin-6 receptor binding antibody also known as KEVZARA® or a biosimilar thereof.

[0025] In the present invention, the "Sapelizumab" may be an interleukin-6 receptor binding antibody also known as SA-237 or Satralizumab, or a biosimilar thereof.

[0026] In the present invention, the "Vobarilizumab" is also known as ALX-0061, and may be an interleukin-6 receptor binding nanobody linked to an anti-human serum albumin nanobody or a biosimilar thereof.

[0027] In one embodiment of the present invention, the concentration of the antibody or antigen-binding fragment thereof may be 1 to 300 mg / ml, preferably 20 to 250 mg / ml, more preferably 50 to 220 mg / ml, and most preferably 100 to 200 mg / ml. When the concentration of the antibody or antigen-binding fragment thereof is within the above-mentioned range, the degree of freedom in the administration dose and administration cycle can be increased, and the antibody or antigen-binding fragment thereof has excellent long-term stability and low viscosity (1 cP to 15 cP, preferably 1 cP to 10 cP).

[0028] In another embodiment of the present invention, (A) the antibody or antigen-binding fragment thereof is contained at a high concentration of 50 mg / ml or more. For example, a formulation containing a high concentration of a monoclonal antibody (mAb) drug has different stability and colloidal properties than a formulation with a low protein concentration due to the complexity of the molecule itself and various intermolecular interactions, and as the protein concentration increases, aggregation and decomposition are promoted, making it difficult to develop a stable medical formulation. In addition, reversible self-binding occurs, which affects viscosity increase, etc., making it difficult to develop a stable formulation and to manufacture a pharmaceutical product. Despite the above-mentioned difficulties, the present inventors have Regardless, it has been confirmed through experiments that the formulation of the present invention is stable at high concentrations.

[0029] (B) Surfactant In the present invention, the term "surfactant" refers to a substance that can be used to significantly increase the water solubility of a hydrophobic or oily substance or to increase the miscibility of two substances with different hydrophobicities.

[0030] In the present invention, the surfactant according to the present invention may be, but is not limited to, polyoxyethylene sorbitan fatty acid esters (e.g., polysorbates, etc.), polyoxyethylene alkyl ethers (e.g., Brij®, etc.), alkylphenyl polyoxyethylene ethers (e.g., Triton-X, etc.), polyoxyethylene-polyoxypropylene copolymers (e.g., poloxamers, Pluronic®, etc.), sodium dodecyl sulfate (SDS), and the like.

[0031] In the present invention, the surfactant may be a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene alkyl ether, an alkylphenyl polyoxyethylene ether, a polyoxyethylene-polyoxypropylene copolymer, sodium dodecyl sulfate, or a mixture thereof. The surfactant may be preferably a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene-polyoxypropylene copolymer, or a mixture thereof, more preferably a polyoxyethylene sorbitan fatty acid ester.

[0032] In the present invention, the surfactant may be a polysorbate, a poloxamer, or a mixture thereof, preferably a polysorbate.

[0033] In the present invention, the surfactant may be polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a mixture thereof, preferably polysorbate 80.

[0034] In one embodiment of the present invention, the concentration of the surfactant can be freely adjusted within a range that does not adversely affect the stability and viscosity of the stable pharmaceutical formulation according to the present invention.

[0035] In one embodiment of the present invention, the concentration of the surfactant (B) may be 0.001 to 1% (w / v), preferably 0.005 to 0.1% (w / v), and most preferably 0.01 to 0.05% (w / v). When the concentration of the surfactant is within the above range, the composition has excellent long-term stability and low viscosity.

[0036] (C) Stabilizer In the present invention, the term "stabilizer" is a substance that is physiologically tolerated and confers stability to the formulation.

[0037] In one embodiment of the present invention, (C) the stabilizing agent may be i) an amino acid or amino acid derivative; ii) a sugar or sugar alcohol; or a mixture thereof.

[0038] In one embodiment of the present invention, the amino acid or amino acid derivative (different from histidine contained in the buffer according to the present invention) may be any one or more selected from the group consisting of threonine, methionine, arginine, proline, leucine, glycine, taurine, phenylalanine, tryptophan, glutamine, aspartate, glutamate, alanine, asparagine, serine, glycine, and tyrosine. In the present invention, the amino acid or amino acid derivative i) may be preferably any one or more selected from the group consisting of threonine, methionine, arginine, proline, leucine, glycine, and taurine.

[0039] In one embodiment of the present invention, the ii) sugar or sugar alcohol may be any one or more selected from the group consisting of sucrose, trehalose, sorbitol, glucose, fructose, galactose, xylose, maltose, lactose, xylitol, mannitol, D-maltitol, inositol, lactitol and isomalt, but is not limited thereto. In the present invention, the ii) sugar or sugar alcohol may be any one or more selected from the group consisting of sucrose, trehalose and sorbitol.

[0040] In one embodiment of the invention, the stabilizer may preferably be a mixture of threonine and methionine.

[0041] In the present invention, the concentration ratio of the mixture of threonine and methionine (ie, threonine:methionine) may be 1:1 to 10:1, preferably 1:1 to 8:1, and more preferably 1:1 to 7:1.

[0042] In the present invention, the concentration of the stabilizer can be freely adjusted within a range that does not substantially adversely affect the stability and viscosity of the pharmaceutical preparation according to the present invention.

[0043] In one embodiment of the present invention, the concentration of the amino acid or amino acid derivative may be 10 to 500 mM, preferably 30 to 450 mM, more preferably 100 to 400 mM, and most preferably 130 to 300 mM.

[0044] In one embodiment of the present invention, the concentration of the threonine may be 5 to 300 mM, preferably 100 to 250 mM, and more preferably 110 to 190 mM.

[0045] In one embodiment of the present invention, the concentration of methionine may be 5 to 200 mM, preferably 10 to 150 mM, and more preferably 30 to 110 mM.

[0046] In one embodiment of the present invention, the concentration of the sugar or sugar alcohol may be 0.1 to 30% (w / v), preferably 5 to 10% (w / v).

[0047] In the present invention, when the concentration of the stabilizer according to the present invention is within the range described in the present invention, the composition has excellent long-term stability and low viscosity.

[0048] (D) Buffer In the present invention, the term "buffer" refers to a substance that minimizes changes in pH caused by acids or alkalis.

[0049] In one embodiment of the present invention, the buffer (D) is selected from the group consisting of histidine and a salt thereof, acetic acid and a salt thereof, phosphoric acid and a salt thereof, citric acid and a salt thereof, succinic acid and a salt thereof, and glutamic acid. The buffer may be, but is not limited to, histidine or a salt thereof, 2-(N-morpholino)ethanesulfonic acid (MES) or a salt thereof, or tromethamine (Tris) or a salt thereof. ine or a salt thereof, acetic acid or a salt thereof, phosphoric acid or a salt thereof, citric acid or a salt thereof, succinic acid or a salt thereof, or a mixture thereof.

[0050] In the present invention, the buffer may more preferably be histidine or a salt thereof, or a mixture thereof.

[0051] For example, histidine salts according to the present invention can be, but are not limited to, histidine chloride, histidine acetate, histidine phosphate, histidine sulfate, and the like.

[0052] For example, acetate salts according to the present invention may be, but are not limited to, sodium acetate, zinc acetate, aluminum acetate, ammonium acetate, potassium acetate, and the like.

[0053] For example, the phosphate salt according to the present invention may be, but is not limited to, potassium phosphate, sodium phosphate, ammonium phosphate, calcium phosphate, magnesium phosphate, and the like.

[0054] For example, the citrate salt according to the present invention may be, but is not limited to, sodium citrate, calcium citrate, potassium citrate, and the like.

[0055] For example, the succinate salt according to the present invention may be, but is not limited to, sodium succinate, calcium succinate, potassium succinate, sodium sulfosuccinate, potassium sulfosuccinate, calcium sulfosuccinate, and the like.

[0056] For example, the glutamate salt according to the present invention may be, but is not limited to, sodium glutamate, potassium glutamate, ammonium glutamate, and the like.

[0057] For example, the 2-(N-morpholino)ethanesulfonic acid (MES) salt according to the present invention may be, but is not limited to, MES chloride, MES sodium, and the like.

[0058] For example, tris salts according to the present invention can be, but are not limited to, tris hydrochloride, tris acetate, tris borate, and the like.

[0059] In the present invention, the content of the buffering agent can be freely adjusted within a range that does not substantially adversely affect the stability and viscosity of the pharmaceutical preparation according to the present invention.

[0060] In one embodiment of the present invention, the content of the (D) buffering agent may be 0.1 to 50 mM, preferably 1 to 25 mM.

[0061] (E) pH In the present invention, the pH of the stable pharmaceutical formulation according to the present invention can be adjusted using buffers or pH adjusting agents to a range that optimizes therapeutic effectiveness.

[0062] In the present invention, the pH may be equal to or greater than 5 and less than 7. When the pH is within the above range, the composition has excellent long-term stability and low viscosity.

[0063] In the present invention, the term "pH adjusting agent" is a substance used to adjust the pH of a formulation.

[0064] In one embodiment of the present invention, the pharmaceutical preparation according to the present invention may further include a pH adjusting agent (acid or base). The content of the pH adjusting agent can be freely adjusted within a range that does not substantially adversely affect the stability and viscosity of the preparation.

[0065] In the present invention, the pH adjuster may be, but is not limited to, acetic acid, phosphoric acid, sodium hydroxide, sodium bicarbonate, etc.

[0066] (F) Other Ingredients In the present invention, the stable pharmaceutical preparation according to the present invention may not contain a preservative. The preservative may be a preservative commonly used in the art. For example, the preservative may be, but is not limited to, octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl alcohol, benzyl alcohol, alkyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, m-cresol, etc. Preferably, the preparation does not contain a preservative, thereby improving stability.

[0067] As used herein, the term "free" or "free" means that any component is not contained at all or is substantially free of any component, i.e., contained to the extent that it does not affect the activity of the antibody, the stability or viscosity of the pharmaceutical formulation. For example, it means that any component is contained at 1% (w / v) or less, 1 mM or less, 1 mg / ml or less, 1 ppm (w / v) or less, or 1 ppb (w / v) or less, based on the total weight of the pharmaceutical formulation.

[0068] In the present invention, the stable pharmaceutical formulation of the present invention may further include additives known in the art within the range that does not substantially adversely affect the stability and viscosity of the formulation. The additives may be, for example, an aqueous carrier, an antioxidant, or a mixture thereof. In the present invention, the aqueous carrier may be a carrier useful for the manufacture of a pharmaceutical formulation that is safe and non-toxic when administered to humans. Examples of the aqueous carrier include, but are not limited to, Sterile Water for Injection (SWFI), Bacteristetic Water for Injection (BWFI), sterile saline solution, Ringer's solution, dextrose, etc. In the present invention, the antioxidant may be, but is not limited to, ascorbic acid, etc.

[0069] (G) "Stable" pharmaceutical formulations In the present invention, the term "stable" or "stabilization" means that the component according to the present invention or a composition or formulation containing the same exhibits its physical stability, chemical stability and / or biological activity during the manufacturing process and / or during storage or preservation. A variety of analytical techniques for measuring stability in the present invention are readily available in the art.

[0070] In the present invention, the physical stability can be evaluated by methods known in the art, for example, by measuring the apparent attenuation of light (absorbance or optical density) of a sample. Such light attenuation measurement is related to the turbidity of the formulation. In addition, the content of high molecular weight components, the content of low molecular weight components, the amount of intact protein, the number of insoluble foreign particles, etc. can be measured for physical stability.

[0071] In the present invention, the chemical stability can be evaluated by methods known in the art, for example, by detecting and quantifying chemically altered forms of the antibody, such as ion exchange chemistry. The charge change can be evaluated by measuring charge variants (eg, charge changes occurring as a result of deamidation or oxidation) or charge modifications (acidic or basic peak measurements), which can be evaluated by chromatography.

[0072] In the present invention, the biological activity can be evaluated by a method known in the art, for example, by measuring antigen-binding affinity by enzyme-linked immunosorbent assay (ELISA).

[0073] In one embodiment of the present invention, the term "stable" pharmaceutical formulation means a pharmaceutical formulation that satisfies one or more of the following (G)-1 to (G)-11.

[0074] (G)-1 Turbidity - After storing at 5±3℃ for 0 days, 5 days, 10 days, 2 weeks, 3 weeks or 4 weeks, the absorbance A measured by a spectrophotometer 600 A pharmaceutical preparation having a β-amino acid value of 0 to 0.03; -The absorbance A measured by a spectrophotometer after storing the product for 0, 5, 10, 2, 3, 4 or 6 weeks under the conditions of 40±2℃, 75±5% relative humidity and sealed condition. 600 A pharmaceutical preparation having a β-amino acid value of 0 to 0.06;

[0075] (G)-2 Content of main component (Main peak%) - a pharmaceutical preparation having a content of 98%-100% of the main component as determined by SEC-HPLC after storage at a temperature of 5±3°C for 0 days, 5 days, 10 days, 2 weeks, 3 weeks or 4 weeks; - A pharmaceutical preparation having a main component content of 97%-100% as measured by SEC-HPLC after storage for 0, 5, 10, 2, 3, 4 or 6 weeks under conditions of temperature 40±2°C, relative humidity 75±5% and sealed condition;

[0076] (G)-3 Content of high molecular weight components (peak with retention time ahead of the main peak (intact IgG) (Pre-peak%)) - a pharmaceutical preparation having a content of high molecular weight components of 0-1.5% as measured by SEC-HPLC after storage at a temperature of 5±3°C for 0 days (0 week), 5 days, 10 days, 2 weeks, 3 weeks or 4 weeks; - a pharmaceutical preparation having a content of high molecular weight components of 0-2% as measured by SEC-HPLC after storage for 0, 5, 10, 2, 3, 4 or 6 weeks at a temperature of 40±2°C, a relative humidity of 75±5% and sealed conditions;

[0077] (G)-4 Content of low molecular weight components (Post Peak%) after the main peak (intact IgG) in retention time - a pharmaceutical preparation having a content of low molecular weight components between 0 and 1% as measured by SEC-HPLC after storage at a temperature of 5±3°C for 0 days (0 week), 5 days, 10 days, 2 weeks, 3 weeks or 4 weeks; - a pharmaceutical preparation having a content of low molecular weight components of 0-1.5% as measured by SEC-HPLC after storage for 0, 5, 10, 2, 3, 4 or 6 weeks at a temperature of 40±2°C, a relative humidity of 75±5% and sealed conditions;

[0078] (G)-5 Intact Immunoglobulin G Content - a pharmaceutical preparation having an intact immunoglobulin G content (Intact IgG%) of 96% to 100% as measured by non-reducing CE-SDS after storage for 0 days (0 week), 5 days, 10 days, 2 weeks, 3 weeks or 4 weeks at a temperature of 5 ± 3°C; - a pharmaceutical preparation having an intact immunoglobulin G content (Intact IgG%) of 93%-100% as measured by non-reducing CE-SDS after storage for 0, 5, 10, 2, 3, 4 or 6 weeks at a temperature of 40±2°C, a relative humidity of 75±5% and sealed conditions;

[0079] (G)-6 complete heavy and light chain content - a pharmaceutical preparation having an intact heavy and light chain content (Intact HC+LC%) of 99%-100% as measured by reduced CE-SDS after storage for 0 days (week 0), 5 days, 10 days, 2 weeks, 3 weeks or 4 weeks at a temperature of 5±3°C; - a pharmaceutical preparation having an intact heavy and light chain content (Intact HC+LC%) of 98%-100% as measured by reduced CE-SDS after storage for 0, 5, 10, 2, 3, 4 or 6 weeks at a temperature of 40±2°C, a relative humidity of 75±5% and under sealed conditions;

[0080] (G)-7 Number of insoluble foreign particles - a pharmaceutical preparation having, after storage at a temperature of 5±3°C for 0 days (0 week), 5 days, 10 days, 2 weeks, 3 weeks or 4 weeks, a number of insoluble foreign particles (10 μm ≦, <100 μm) between 0 and 1000 and a number of insoluble foreign particles (25 μm ≦, <100 μm) between 0 and 150, as measured by MFI; - pharmaceutical preparations having a number of insoluble foreign particles (10 μm ≦, <100 μm) between 0 and 2000 and a number of insoluble foreign particles (25 μm ≦, <100 μm) between 0 and 200, as measured by MFI, after storage for 0, 5, 10, 2, 3, 4 or 6 weeks under conditions of temperature 40 ± 2°C, relative humidity 75 ± 5%, and sealed condition;

[0081] (G)-8 oxidation rate - a pharmaceutical preparation having an oxidation rate of heavy chain Met106 between 0% and 6% as measured by LC-MS after storage at a temperature of 5±3°C for 0 days (0 week), 5 days, 10 days, 2 weeks, 3 weeks or 4 weeks; - a pharmaceutical preparation having an oxidation rate of heavy chain Met106 of 0%-10% as measured by LC-MS after storage for 0, 5, 10, 2, 3, 4 or 6 weeks at a temperature of 40±2°C, a relative humidity of 75±5% and sealed conditions;

[0082] (G)-9 charge variant (main peak excluding acidic or basic peaks in ion exchange chromatography) - a pharmaceutical preparation having a main peak of 60%-70% as measured by IEC-HPLC after storage at a temperature of 5±3°C for 0 days (0 week), 5 days, 10 days, 2 weeks, 3 weeks or 4 weeks; - A pharmaceutical preparation having a main peak of 40%-60% as measured by IEC-HPLC after storage for 0, 5, 10, 2, 3, 4 or 6 weeks at a temperature of 40±2°C, a relative humidity of 75±5% and sealed conditions;

[0083] (G)-10IL-6R binding affinity - a pharmaceutical preparation having an IL-6R binding affinity of 80%-120% as measured by ELISA after storage for 0, 5, 10, 2, 3, 4 or 6 weeks under conditions of a temperature of 40±2°C, a relative humidity of 75±5% and sealed;

[0084] (G)-11 viscosity - a pharmaceutical preparation having a viscosity of 1 cP to 11 cP as measured by a viscometer after storage at a temperature of 5 ± 3°C for 0 days (0 week), 5 days, 10 days, 2 weeks, 3 weeks or 4 weeks; A pharmaceutical preparation having a viscosity of 1 cP to 15 cP as measured by a viscometer after storage for 0, 5, 10, 2, 3, 4 or 6 weeks at a temperature of 40±2°C, a relative humidity of 75±5% and sealed conditions.

[0085] In one embodiment of the present invention, the viscosity of the stable pharmaceutical formulation according to the present invention may be 1-15 cP, preferably 1-10 cP.

[0086] In another embodiment of the present invention, the stable pharmaceutical formulation according to the present invention comprises (A) a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, the amino acid sequence of SEQ ID NO: 2 (B) a light chain variable region comprising 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; an antibody or antigen-binding fragment thereof comprising: (A) a light chain variable region comprising 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, 1 to 300 mg / ml; (B) a surfactant 0.001 to 1% (w / v); (C) 1 to 500 mM of an amino acid or amino acid derivative as a stabilizer; and (D) a buffering agent 0.1 to 50 mM.

[0087] In yet another embodiment of the present invention, the stable pharmaceutical formulation according to the present invention comprises (A) an antibody or antigen-binding fragment thereof comprising a light chain variable region comprising 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 comprising 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, 1 to 300 mg / ml; (B) 0.001 to 1% (w / v) of a surfactant; (C) 0.1 to 30% (w / v) of a sugar or sugar alcohol as a stabilizer; and (D) 0.1 to 50 mM of a buffer.

[0088] [product] In one embodiment of the present invention, the invention provides an article of manufacture comprising: a stable pharmaceutical formulation according to the present invention; and a container containing said stable pharmaceutical formulation in a sealed state.

[0089] The stable pharmaceutical formulation is as described herein above.

[0090] In the present invention, the container may be formed from materials such as, but not limited to, glass, polymers (eg, plastics), and metals. For example, a container according to the present invention may be, but is not limited to, a bottle, a vial, a cartridge, a syringe (e.g., a pre-filled syringe, an auto-injector, etc.), or a tube, preferably a glass or polymer vial, or a glass or polymer pre-filled syringe.

[0091] In one embodiment of the present invention, the present invention provides a vial filled with the pharmaceutical formulation according to the present invention, a cartridge filled with the pharmaceutical formulation, a pre-filled syringe filled with the pharmaceutical formulation, or an auto-injector having the pre-filled syringe contained therein.

[0092] The specific product forms of the vial, cartridge, prefilled syringe, auto-injector, etc. and the method of filling the stable pharmaceutical preparation into the vial, cartridge, prefilled syringe, auto-injector, etc. can be easily obtained or performed by a person having ordinary skill in the art to which the present invention belongs. For example, U.S. Patent Nos. 4,861,335 and 6,331,174 disclose specific product forms and filling methods of prefilled syringes. For example, U.S. Patent Nos. 5,085,642 and 5,681,291 disclose specific product forms and assembly methods of auto-injectors. In addition, the commercialized products of the vial, cartridge, prefilled syringe, auto-injector, etc. can be used as they are, or products made to order can be used in consideration of the physical properties, administration site, dosage, etc. of the stable pharmaceutical preparation.

[0093] In the present invention, the container may be a single-dose container.

[0094] In accordance with the present invention, the product of the present invention may further include instructions providing a method for use, storage, or all of the above of the stable pharmaceutical formulation, including a method for treating an Interleukin-6 receptor-related disease, a route of administration, a dosage, or a timing of administration.

[0095] In the present invention, the product may include other tools necessary from a commercial and user point of view, such as needles, syringes, etc.

[0096] [Method of manufacturing stable pharmaceutical formulations] The stable pharmaceutical preparation of the present invention can be prepared by a known method and is not limited to a specific preparation method. As an example, a pharmaceutical preparation can be prepared by adding an antibody to a solution containing a surfactant and a stabilizer while adjusting the pH while adding a buffer. As another example, a pharmaceutical preparation can be prepared by preparing a solution containing an antibody, a buffer and a stabilizer in the final step of the purification process, and then adding a surfactant to the solution.

[0097] [Method of use of stable pharmaceutical preparations] In the present invention, the stable pharmaceutical preparation according to the present invention can exhibit therapeutic effects on Interleukin-6 receptor-related diseases.

[0098] In the present invention, the interleukin-6 receptor-associated disease may be an autoimmune disease, an inflammatory disease, a malignant tumor, Still's disease, vasculitis, juvenile idiopathic arthritis, osteoarthritis, and the like. For example, the interleukin-6 receptor-associated disease includes rheumatoid arthritis (RA), adult onset Still's disease (AOSD), systemic juvenile idiopathic arthritis (sJIA), polyarticular juvenile idiopathic arthritis (pJIA), Castleman's disease (CD), giant cell arteritis (GCA), Takayasu's arteritis (TAK), systemic sclerosis (SSc), systemic sclerosis-associated interstitial lung disease (SSc-ILD), cytokine release syndrome (CRS), and the like. Syndrome (CRS), Hand Osteoarthritis, Polymyalgia Rheumatica (PMR), Antineutrophil cytoplasmic antibody associated vasculitis (ANCA-AAV), Relapsing Polychondritis (RP), Type 2 diabetes (T2D), Ankylsoing Spondylitis (AS), Axial Spondyloarthritis (axSpA), Psoriasis (Ps), Psoriatic Arthritis (PsA), Inflammatory Bowel Disease (IBD) IBD), Crohn's disease (CD), Ulcerative Colitis (UC), Thyroid ophthalmopathy (TAO), Rheumatoid arthritis-Associated Cardiovascular Disease, Acute Graft Versus Host Disease (GVHD), Non-ST segment elevation myocardial infarction (N These include, but are not limited to, on-ST-segment elevation MI (NSTEMI), Systemic Lupus Erythematosus (SLE), Schizophrenia, Uveitis, Ovarian Cancer, Neuromyelitis Optica (NMO), Glomerulonephritis (GN), Chronic Glomerulonephritis, Rectal Cancer, Pneumonia, and Lung Cancer. Preferably, the interleukin-6 receptor-associated disease may be any one or more selected from the group consisting of rheumatoid arthritis, adult Still's disease, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, Castleman's disease, giant cell arteritis, Takayasu's arteritis, systemic sclerosis, systemic sclerosis-associated interstitial lung disease, cytokine release syndrome, and polymyalgia rheumatica.

[0099] In the present invention, the stable pharmaceutical formulation according to the present invention can be used for intravenous (IV) or subcutaneous (SC) administration.

[0100] In one embodiment of the present invention, the stable pharmaceutical formulation may undergo a dilution step before use. In the present invention, the subcutaneous (SC) formulation of the present invention may be used as an intravenous (IV) formulation after a dilution step.

[0101] In one embodiment of the invention, the stable pharmaceutical formulation does not require a reconstitution step prior to use.

[0102] The concentrations of the antibody and other components in the pharmaceutical preparation are as described above, and the total volume of the pharmaceutical preparation according to the present invention may be 0.9 to 20 ml.

[0103] The dosage or timing of administration of the pharmaceutical preparation may vary depending on the type of disease, the severity and course of the disease, the patient's health and response to treatment, or the judgment of the treating physician, and is not limited to a specific dosage or timing.

[0104] [Treatment and stabilization methods] In one embodiment of the present invention, the present invention provides a method for treating an Interleukin-6 receptor-associated disease, comprising administering to a patient having an Interleukin-6 receptor-associated disease a stable pharmaceutical formulation comprising (A) an antibody or antigen-binding fragment thereof that binds to the Interleukin-6 receptor, (B) a surfactant, (C) a stabilizing agent, and (D) a buffering agent.

[0105] In another embodiment of the invention, the invention provides a method for stabilizing an antibody in a pharmaceutical formulation, comprising producing a stable pharmaceutical formulation comprising: (A) an antibody or antigen-binding fragment thereof that binds to Interleukin-6 receptor; (B) a surfactant; (C) a stabilizer; and (D) a buffer.

[0106] The stable pharmaceutical formulation is as described herein above.

[0107] The treatment method or stabilization method according to the present invention is as described above in this specification.

[0108] The features described herein can be used in combination and are within the scope of the claims. The fact that certain features are recited in mutually different dependent claims does not indicate that they cannot be used in combination. Effect of the Invention

[0109] The stable pharmaceutical formulations according to the present invention have low viscosity when containing an antibody, especially when contained at a high concentration, and have excellent long-term storage stability due to their excellent stability under accelerated and harsh conditions, and can be administered intravenously or subcutaneously. [Brief description of the drawings]

[0110] [Figure 1] 1 shows the results of measuring the contents of main components in Examples 1 to 5. [Diagram 2] 1 shows the results of measuring the content of high molecular weight components in Examples 1 to 5. [Diagram 3] 1 shows the results of measuring the content of low molecular weight components in Examples 1 to 5. [Figure 4] 1 shows the results of measuring the contents of main components in Examples 6 to 13. [Diagram 5] 1 shows the results of measuring the content of high molecular weight components in Examples 6 to 13. [Figure 6] 1 shows the results of measuring the content of low molecular weight components in Examples 6 to 13. [Figure 7] 1 shows the results of measuring the contents of main components in Examples 14 to 16. [Figure 8] 1 shows the measurement results of the content of high molecular weight components in Examples 14 to 16. [Figure 9] 1 shows the results of measuring the content of low molecular weight components in Examples 14 to 16. [Figure 10]4 shows the results of measuring the contents of main components in Examples 17 to 22. [Figure 11] 1 shows the measurement results of the content of high molecular weight components in Examples 17 to 22. [Figure 12] 1 shows the results of measuring the contents of low molecular weight components in Examples 17 to 22. [Figure 13] 4 shows the measurement results of the main component contents of Examples 23 to 27. [Figure 14] 1 shows the measurement results of the content of high molecular weight components in Examples 23 to 27. [Figure 15] 4 shows the results of measuring the content of low molecular weight components in Examples 23 to 27. [Figure 16] 4 shows the results of measuring the main component contents of Examples 25 and 28 to 30. [Figure 17] 1 shows the measurement results of the contents of high molecular weight components in Examples 25 and 28 to 30. [Figure 18] 1 shows the results of measuring the content of low molecular weight components in Examples 25 and 28 to 30. [Figure 19] 1 shows the measurement results of the charge-transformed bodies of Examples 31 and 32 and Comparative Example 1. [Figure 20] 1 shows the results of measuring IL-6R binding affinity in Examples 33 to 35 and Comparative Example 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0111] The present invention will be described in detail with reference to the following examples. The following examples are merely for illustrating the present invention, and the scope of the present invention is not limited by the following examples. The literature cited in the present invention is incorporated in the specification of the present invention by reference.

[0112] In relation to the antibody used in the following experimental examples, tocilizumab cultured and purified at Celltrion Laboratories was used. The following methods were used to measure the physical stability, chemical stability and biological activity of the pharmaceutical preparations described below.

[0113] -Turbidity The absorbance at 600 nm was measured using a UV-Vis spectrophotometer. - Content of main ingredient Size Exclusion High Performance Liquid Chromatography The content of the main component (main peak;%) was measured using SEC-HPLC. - High molecular weight component content Size Exclusion High Performance Liquid Chromatography The content of high molecular weight components (pre-peak;%) was measured using Performance Liquid Chromatography (SEC-HPLC). -Low molecular weight component content Size Exclusion High Performance Liquid Chromatography The content of low molecular weight components (post-peak;%) was measured using SEC-HPLC. -Intact IgG% The content (%) of intact immunoglobulin G was measured using non-reduced capillary electrophoresis-sodium dodecyl sulfate (NR CE-SDS). -Intact heavy and light chain content (Intact HC+LC%) The content (%) of intact heavy and light chains was determined using Reduced Capillary Electrophoresis-Sodium Dodecyl Sulfate (R CE-SDS). - Number of insoluble foreign particles (sub-visible particles) The number of insoluble foreign particles was measured using Micro Flow Imaging (MFI). -Oxidation The oxidation rate (%) of Met106 in the heavy chain was measured by peptide mapping using liquid chromatography-mass spectrometry (LC-MS). -Charge transformer The main peak (%) was measured by ion exchange chromatography-high performance liquid chromatography (IEC-HPLC). -IL-6R binding affinity Enzyme-Linked ImmunoSorbent The IL-6R binding affinity (%) was measured by ELISA (ELISA Assay). -viscosity A micro-capillary rheometer (apparent shear rate range: 10 3 ~10 5 s -1 ) device and measurements were performed in a 500 μl syringe at 25±0.1°C.

[0114] Experimental Example 1: Preparation of a pharmaceutical preparation containing an antibody that binds to the Interleukin-6 Receptor (IL-6R) Examples 1 to 37 in Table 1 below were prepared by adjusting each buffer to each pH, ​​adding a stabilizer, adding an antibody, and then adding a surfactant. The specific content of each component is as shown in Table 1 below.

[0115] [Table 1] TIFF2025024049000003.tif193170

[0116] Experimental Example 2: Comparison of Buffers The stability of Examples 1 to 5 prepared according to Experimental Example 1 was measured under initial conditions and thermally accelerated conditions, and the results are shown in Table 2 and Figures 1 to 3 below. The initial conditions were samples stored at a temperature of 5±3°C for 0 to 5 days, and the thermally accelerated conditions were samples stored at a temperature of 40±2°C and a relative humidity of 75±5% for 10 days.

[0117] [Table 2]

[0118] Under the initial conditions, all of Examples 1 to 5 had a turbidity of 0.03 or less, a main component content of 98% or more, a high molecular weight component content of 1.5% or less, a low molecular weight component content of 1% or less, and a viscosity of 1 cP to 11 cP, and were found to be pharmaceutically acceptable and stable. Among them, Examples 1 and 5 had the highest main component content of 99.57% and 99.72%, respectively, and the lowest high molecular weight component content of 0.43 and 0.28, respectively, and the Examples containing acetic acid or histidine buffer were found to be the most stable. Under the thermal acceleration conditions, all of Examples 1 to 5 had a turbidity of 0.06 or less, a main component content of 97% or more, a high molecular weight component content of 2% or less, a low molecular weight component content of 1.5% or less, and a viscosity of 1 cP to 15 cP, and were found to be pharmaceutically acceptable and stable. Among them, Example 5 had the highest main component content of 99.36% and the lowest high molecular weight component content of 0.38%, indicating that the example containing the histidine buffer had the highest stability.

[0119] Since the stability of the examples containing acetate or histidine buffers was determined to be high in Experimental Example 2, various examples containing acetate buffers were additionally tested in Experimental Example 3, and various examples containing histidine buffers were additionally tested in Experimental Example 4.

[0120] Experimental Example 3: Comparison of stabilizing agents in examples containing acetate buffer The stability of Examples 6 to 13 prepared according to Experimental Example 1 was measured under initial conditions and thermally accelerated conditions, and the results are shown in Table 3 and Figures 4 to 6. The initial conditions were samples stored at a temperature of 5±3°C for 0 days, and the thermally accelerated conditions were samples stored at a temperature of 40±2°C and a relative humidity of 75±5% for 10 days.

[0121] [Table 3]

[0122] Under the initial conditions, all of Examples 6 to 13 had a turbidity of 0.03 or less, a main component content of 98% or more, a high molecular weight component content of 1.5% or less, a low molecular weight component content of 1% or less, and a viscosity of 1 cP to 11 cP, and were found to be pharmaceutically acceptable and stable. Among them, Examples 9 and 12 had the highest main component content of 99.72% and 99.74%, respectively, and the lowest high molecular weight component content of 0.28 and 0.26, respectively, and were found to be the most stable examples containing threonine or taurine stabilizers. Under the thermal acceleration conditions, all of Examples 6 to 13 had a turbidity of 0.06 or less, a main component content of 97% or more, a high molecular weight component content of 2% or less, a low molecular weight component content of 1.5% or less, and a viscosity of 1 cP to 15 cP, and were found to be pharmaceutically acceptable and stable. Among them, Examples 9 and 12 had the highest main ingredient contents of 99.35% and 99.37%, respectively, and it was found that the examples containing threonine or taurine stabilizers had the highest stability.

[0123] In Experimental Example 3, the stability of the examples containing the threonine or taurine stabilizer was measured to be high, and based on this, various examples were additionally tested in Experimental Example 4.

[0124] Experimental Example 4: Stability studies of various examples containing histidine buffer Experimental Example 4-1. Comparison of stabilizers The stability of Examples 14 to 16 prepared according to Experimental Example 1 was measured under initial, long-term, thermal acceleration 1, and thermal acceleration 2 conditions, and the results are shown in Table 4 and Figures 7 to 9 below. The initial condition was a sample stored at 5±3°C for 0 days, the long-term condition was a sample stored at 5±3°C for 4 weeks, the thermal acceleration 1 condition was a sample stored at 40±2°C and 75±5% relative humidity for 2 weeks, and the thermal acceleration 2 condition was a sample stored at 40±2°C and 75±5% relative humidity for 4 weeks.

[0125] [Table 4] TIFF2025024049000007.tif145170

[0126] Under the initial and long-term conditions, Examples 14 to 16 had a turbidity of 0.03 or less, a content of the main component of 98% or more, a content of the high molecular weight component of 1.5% or less, and a content of the low molecular weight component of 1% or less, and the experimental results are shown in Figures 7 to 9. The number of insoluble foreign particles (10 μm ≦, <100 μm) measured by MFI was 1000 or less, the number of insoluble foreign particles (25 μm ≦, <100 μm) was 150 or less, the viscosity was 1 cP to 11 cP, the content of complete immunoglobulin G was 96% or more, the content of complete heavy and light chains was 99% or more, and the oxidation rate was 6% or less, and it was found that these were pharma- ceutical acceptable stable examples. Under the conditions of thermal acceleration 1 and 2, Examples 14 to 16 had a turbidity of 0.06 or less, a content of the main component of 97% or more, a content of the high molecular weight component of 2% or less, and a content of the low molecular weight component of 1.5% or less, and the experimental results are shown in Figures 7 to 9. And, the number of insoluble foreign particles (10μm≦,<100μm) measured by MFI is 2000 or less, the number of insoluble foreign particles (25μm≦,<100μm) is 200 or less, the viscosity is 1cP-15cP, the content of complete immunoglobulin G is 93% or more, the content of complete heavy and light chains is 98% or more, and the oxidation rate is 10% or less, and it is found to be a pharma-ceutical acceptable stable example. Therefore, the example in which taurine, threonine, a mixture of threonine and methionine is added as a stabilizer and histidine is added as a buffer is found to be a pharma-ceutical acceptable stable formulation.

[0127] Experimental Example 4-2. Comparison of stabilizer concentrations Examples 17 to 22 manufactured according to Experimental Example 1 were subjected to the initial condition, the condition of thermal acceleration 1, and the thermal acceleration The stability was measured under accelerated thermal acceleration 2 conditions, and the results are shown in Table 5 and Figures 10 to 12 below. The initial condition was a sample stored at 5±3°C for 0 days, the thermal acceleration 1 condition was a sample stored at 40±2°C and 75±5% relative humidity for 3 weeks, and the thermal acceleration 2 condition was a sample stored at 40±2°C and 75±5% relative humidity for 6 weeks.

[0128] [Table 5]

[0129] Under initial conditions, all of Examples 17 to 22 had a turbidity of 0.03 or less, a main component content of 98% or more, a high molecular weight component content of 1.5% or less, a low molecular weight component content of 1% or less, the number of insoluble foreign particles (10 μm≦, <100 μm) measured by MFI of 1,000 or less, the number of insoluble foreign particles (25 μm≦, <100 μm) of 150 or less, a content of intact immunoglobulin G of 96% or more, and a charge-transformed form (main peak%) of 60% to 70%, and were found to be pharma- ceutical acceptable and stable examples. Under the conditions of thermal acceleration 1 and 2, all of Examples 17 to 22 had a turbidity of 0.06 or less, a main component content of 97% or more, a high molecular weight component content of 2% or less, a low molecular weight component content of 1.5% or less, the number of insoluble foreign particles (10 μm≦, <100 μm) measured by MFI was 2000 or less, the number of insoluble foreign particles (25 μm≦, <100 μm) was 200 or less, the content of intact immunoglobulin G was 93% or more, the IL-6R binding affinity was 80% to 120%, and the charge variant (main peak%) was 40% to 60%, and it was found to be a pharma- ceutical acceptable stable example. Therefore, it was found that the example in which a mixture of threonine and methionine was added as a stabilizer and histidine was added as a buffer was a pharma-ceutical acceptable stable formulation.

[0130] Experimental Example 4-3. Comparison of buffer concentrations The stability of Examples 23 to 27 prepared according to Experimental Example 1 was measured under the initial condition, thermal acceleration 1 condition, and thermal acceleration 2 condition, and the results are shown in Table 6 and Figures 13 to 15 below. The initial condition was a sample stored at a temperature of 5±3°C for 0 days, the thermal acceleration 1 condition was a sample stored at a temperature of 40±2°C and a relative humidity of 75±5% for 3 weeks, and the thermal acceleration 2 condition was a sample stored at a temperature of 40±2°C and a relative humidity of 75±5% for 6 weeks.

[0131] [Table 6]

[0132] Under the initial conditions, all of Examples 23 to 27 had a turbidity of 0.03 or less, a main component content of 98% or more, a high molecular weight component content of 1.5% or less, a low molecular weight component content of 1% or less, the number of insoluble foreign particles (10 μm≦, <100 μm) measured by MFI was 1000 or less, the number of insoluble foreign particles (25 μm≦, <100 μm) was 150 or less, the content of intact immunoglobulin G was 96% or more, and the charge-transformed form (main peak%) was 60% to 70%, which was found to be a pharma- ceutical acceptable stable example. Under the conditions of thermal acceleration 1 and 2, all of Examples 23 to 27 had a turbidity of 0.06 or less, a main component content of 97% or more, a high molecular weight component content of 2% or less, The content of low molecular weight components was less than 1.5%, the number of insoluble foreign particles (10 μm≦, <100 μm) measured by MFI was less than 2000, the number of insoluble foreign particles (25 μm≦, <100 μm) was less than 200, the content of intact immunoglobulin G was more than 93%, the IL-6R binding affinity was 80%-120%, and the charge transformed form (main peak%) was 40%-60%, indicating that this is a pharma- ceutical acceptable and stable embodiment.

[0133] Experimental Example 4-4. Comparison of antibody concentrations The stability of Examples 25, 28 to 30 prepared according to Experimental Example 1 was measured under the initial condition, thermal acceleration 1 condition, and thermal acceleration 2 condition, and the results are shown in Table 7 and Figures 16 to 18 below. The initial condition was a sample stored at a temperature of 5±3°C for 0 days, the thermal acceleration 1 condition was a sample stored at a temperature of 40±2°C and a relative humidity of 75±5% for 3 weeks, and the thermal acceleration 2 condition was a sample stored at a temperature of 40±2°C and a relative humidity of 75±5% for 6 weeks.

[0134] [Table 7]

[0135] Under the initial conditions, in all of Examples 25, 28 to 30, the turbidity was 0.03 or less, the content of the main component was 98% or more, the content of the high molecular weight component was 1.5% or less, the content of the low molecular weight component was 1% or less, and the MFI was used. The number of insoluble foreign particles (10 μm ≦, <100 μm) determined was 1000 or less, the number of insoluble foreign particles (25 μm ≦, <100 μm) was 150 or less, the content of intact immunoglobulin G was 96% or more, and the charge transformed form (main peak%) was 60% to 70%, indicating that this is a pharma- ceutical acceptable, stable embodiment. Under conditions of thermal acceleration 1 and 2, Examples 25, 28 to 30 had a turbidity of 0.06 or less, a main component content of 97% or more, a high molecular weight component content of 2% or less, a low molecular weight component content of 1.5% or less, the number of insoluble foreign particles (10 μm≦, <100 μm) measured by MFI of 2,000 or less, the number of insoluble foreign particles (25 μm≦, <100 μm) of 200 or less, a content of intact immunoglobulin G of 93% or more, an IL-6R binding affinity of 80% to 120%, and a charge-transformed form (main peak%) of 40% to 60%, and were found to be pharma- ceutical acceptable and stable Examples.

[0136] Experimental Example 4-5. Comparison of pH The stability of Examples 31 and 32 and Comparative Example 1 prepared according to Experimental Example 1 was measured under the initial condition, thermal acceleration 1 condition, and thermal acceleration 2 condition, and the results are shown in Table 8 and Figure 19 below. The initial condition was a sample stored at a temperature of 5±3°C for 0 days, the thermal acceleration 1 condition was a sample stored at a temperature of 40±2°C and a relative humidity of 75±5% for 3 weeks, and the thermal acceleration 2 condition was a sample stored at a temperature of 40±2°C and a relative humidity of 75±5% for 6 weeks.

[0137] [Table 8]

[0138] Under the initial conditions, both Examples 31 and 32 had a turbidity of 0.03 or less, a main component content of 98% or more, a high molecular weight component content of 1.5% or less, a low molecular weight component content of 1% or less, the number of insoluble foreign particles (10 μm ≦, <100 μm) measured by MFI was 1000 or less, the number of insoluble foreign particles (25 μm ≦, <100 μm) was 150 or less, the content of intact immunoglobulin G was 96% or more, and the charge-transformed form (main peak%) was 60% to 70%, and it was found to be a pharma- ceutical acceptable stable example. Under the conditions of thermal acceleration 1 and 2, Examples 31 and 32 had a turbidity of 0.06 or less, a main component content of 97% or more, a high molecular weight component content of 2% The following are found to be stable and pharma- ceutically acceptable examples, with a low molecular weight component content of 1.5% or less, insoluble foreign particle (10 μm≦, <100 μm) count of 2000 or less, insoluble foreign particle (25 μm≦, <100 μm) count of 200 or less, intact immunoglobulin G content of 93% or more, IL-6R binding affinity of 80% to 120%, and charge variant (main peak%) of 40% to 60%. However, it was confirmed that Comparative Example 1 had a charge variant (main peak%) of less than 40% under the condition of thermal acceleration 2, which resulted in a decrease in the stability of the examples at pH 7 or higher.

[0139] Experimental Example 4-6. Comparison of surfactants The stability of Examples 33 to 35 and Comparative Example 2 prepared according to Experimental Example 1 was measured under the initial condition, thermal acceleration 1 condition, and thermal acceleration 2 condition, and the results are shown in Table 9, Figures 20 and 21 below. The initial condition was a sample stored at a temperature of 5±3°C for 0 days, the thermal acceleration 1 condition was a sample stored at a temperature of 40±2°C and a relative humidity of 75±5% for 3 weeks, and the thermal acceleration 2 condition was a sample stored at a temperature of 40±2°C and a relative humidity of 75±5% for 6 weeks.

[0140] [Table 9]

[0141] Under the initial conditions, all of Examples 33 to 35 had a turbidity of 0.03 or less, a main component content of 98% or more, a high molecular weight component content of 1.5% or less, a low molecular weight component content of 1% or less, the number of insoluble foreign particles (10 μm≦, <100 μm) measured by MFI was 1000 or less, the number of insoluble foreign particles (25 μm≦, <100 μm) was 150 or less, the content of intact immunoglobulin G was 96% or more, and the charge transformed form (main peak%) was 60% to 70%, so it was found that these were pharma- ceutical acceptable stable examples. Under the conditions of thermal acceleration 1 and 2, Examples 33 to 35 were found to be pharma- ceutical acceptable stable examples. 35 has a turbidity of 0.06 or less, a main component content of 97% or more, a high molecular weight component content of 2% or less, a low molecular weight component content of 1.5% or less, the number of insoluble foreign particles (10 μm≦, <100 μm) measured by MFI is 2000 or less, the number of insoluble foreign particles (25 μm≦, <100 μm) is 200 or less, the content of intact immunoglobulin G is 93% or more, the IL-6R binding affinity is 80% to 120%, and the charge transformation form (main peak%) is 40% to 60%, so it was found to be a stable example that is pharma- ceutical acceptable. In contrast, Comparative Example 2 had an IL-6R binding affinity of less than 80% under the condition of thermal acceleration 2. This revealed that the stability of the example that does not contain a surfactant was reduced.

Claims

1. (A) an antibody or an antigen-binding fragment thereof that binds to the interleukin-6 receptor; (B) a surfactant; (C) ii) a stabilizer which is a sugar or sugar alcohol; and (D) a buffering agent; The antibody or antigen-binding fragment thereof comprises a light chain variable region comprising 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 comprising 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. A stable pharmaceutical formulation.

2. The antibody or antigen-binding fragment thereof a) a light chain variable region comprising the amino acid sequence of SEQ ID NO:7, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:8; or b) a light chain comprising the amino acid sequence of SEQ ID NO:9, and a heavy chain comprising the amino acid sequence of SEQ ID NO:

10.

2. The stable pharmaceutical formulation of claim 1, comprising:

3. 2. The stable pharmaceutical formulation of claim 1, wherein the antibody or antigen-binding fragment thereof is Tocilizumab.

4. The stable pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation is in liquid form.

5. The stable pharmaceutical formulation according to claim 1, wherein the pharmaceutical formulation exhibits a therapeutic effect on an interleukin-6 receptor-associated disease.

6. 2. The stable pharmaceutical formulation of claim 1, wherein the concentration of the antibody or antigen-binding fragment thereof is 1-300 mg / ml.

7. 2. The stable pharmaceutical formulation of claim 1, wherein the sugar or sugar alcohol is any one or more selected from the group consisting of sucrose, trehalose, and sorbitol.

8. The stable pharmaceutical formulation according to claim 1, wherein the concentration of ii) sugar or sugar alcohol is 0.1 to 30% (w / v).

9. 2. The stable pharmaceutical formulation of claim 1, wherein the buffer is histidine or a salt thereof, acetic acid or a salt thereof, phosphoric acid or a salt thereof, citric acid or a salt thereof, succinic acid or a salt thereof, or a mixture thereof.

10. (A) an antibody or an antigen-binding fragment thereof that binds to an interleukin-6 receptor, at 1 to 300 mg / ml; (B) surfactant 0.001-1% (w / v); (C) as a stabilizer, ii) 0.1-30% (w / v) of a sugar or sugar alcohol; and (D) buffer 0.1 to 50 mM Including, The antibody or antigen-binding fragment thereof has a CDR1 domain comprising the amino acid sequence of SEQ ID NO:

1. a light chain variable region comprising 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; 2. The stable pharmaceutical formulation of claim 1, wherein the pH of the pharmaceutical formulation is greater than or equal to 5 and less than 7.

11. (A) an antibody or an antigen-binding fragment thereof that binds to an interleukin-6 receptor, at 1 to 300 mg / ml; (B) 0.001 to 1% (w / v) of polysorbate 80 as a surfactant; (C) 0.1-30% (w / v) trehalose as a stabilizer; and (D) 0.1 to 50 mM histidine as a buffer Including, The antibody or antigen-binding fragment thereof comprises a light chain variable region comprising 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 comprising 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, 2. The stable pharmaceutical formulation of claim 1, wherein the pH of the pharmaceutical formulation is greater than or equal to 5 and less than 7.

12. 10. The stable pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is for intravenous or subcutaneous administration.

13. The stable pharmaceutical formulation according to claim 12, which is used as a preparation for intravenous administration after a dilution step of the preparation for subcutaneous administration.

14. A container filled with a stable pharmaceutical formulation according to any one of claims 1 to 13.

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