Pharmaceutical products and stable liquid compositions containing IL-17 antibodies

Abstract

To provide pharmaceutical products and stable liquid compositions of IL-17 antibodies and antigen-binding fragments thereof, e.g., AIN457 (secukinumab), and processes of making these pharmaceutical products and compositions.SOLUTION: A pharmaceutical product comprises: a. a container having a headspace, where the oxygen content in the headspace is less than about 12%, and b. a liquid pharmaceutical composition disposed within the container and having a pH of about 5.2 to about 6.2, the liquid pharmaceutical composition comprising i. about 20 mg / ml to about 175 mg / ml secukinumab; and ii. about. 2.5 to about 20 mM L-methionine, where the liquid pharmaceutical composition is not reconstituted from a lyophilisate.SELECTED DRAWING: None

Description

Technical Field

[0001] Related Applications This application claims priority to U.S. Patent Application No. 62 / 009,467, filed on December 22, 2014, which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to pharmaceutical products comprising stable liquid pharmaceutical compositions of IL-17 antibodies and antigen-binding fragments thereof, such as AIN457 (secukinumab), as well as methods of making such pharmaceutical products and liquid pharmaceutical compositions.

Background Art

[0003] IL-17A is a central cytokine of a newly defined subset of inflammatory T cells, Th17 cells, which are important in several autoimmune and inflammatory processes. Neutralization of IL-17 A is expected to treat the pathophysiology underlying immune-mediated diseases and, as a result, result in symptom reduction. Secukinumab (AIN457) is a high-affinity fully human monoclonal anti-human antibody that inhibits IL-17A activity and has emerged as a potential treatment for patients with various autoimmune diseases, such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, diabetes, asthma, chronic plaque psoriasis, and multiple sclerosis. Several Phase II and III trials have shown that secukinumab is superior to placebo in achieving PASI 75 in the treatment of chronic plaque psoriasis (e.g., in the CAIN457A2220 study, both 3×150 mg and 3×75 mg of secukinumab were superior to placebo in achieving PASI 75 at week 12 (81.5% and 57.1% respectively vs. 9% ). ). ). ). ). ). ). ​0.1%). Secukinumab is a global Phase I drug for the treatment of chronic plaque-type psoriasis. It is currently being used in the II trial and is once again superior to placebo, and new etanercept It has also been shown to be superior to [another method].

[0004] International patent application PCT / EP2011 / 069476 is a sucrose-based secchi A lyophilized composition of Numabu is provided, which is restored with 1 mL of water immediately before use. However, PCT / EP2011 / 069476 is a readily available secukinumab with long-term stability. Neither the disclosure of pharmaceutical products nor the disclosure of liquid pharmaceutical compositions is provided. In fact, the protein in the liquid composition The limited stability of the solution often hinders long-term storage at room temperature or under refrigerated conditions. Inside, various physical and chemical reactions occur (aggregation [covalent and non-covalent], deamide, oxidation, Clipping, isomerization, and denaturation can occur, leading to an increase in the level of degradation products and / or This can lead to a loss of biological activity. Dosage and product safety when the molecule is administered to the patient. To ensure that the claims regarding this are met, commercially available ready-to-use liquid antibody compositions are shipped and The antibodies should be provided with sufficient physical and chemical stability during handling. Specifically The acceptable liquid antibody composition has enhanced stability to avoid serious immunogenic reactions. Furthermore, protein degradation, especially protein aggregation, must be minimized. It must have an osmolality and pH value acceptable for subcutaneous application, and Furthermore, it must also have low viscosity as a requirement for manufacturing (mixing, filtering, filling) and passage through the injection needle. No. It's difficult to balance these countless requirements, making it commercially unrealistic. The production of aqueous biopharmaceutical compositions presents technical challenges.

[0005] Despite the technical challenges outlined above, the inventors of the I disclosed herein Novel, beneficial, ready-to-use pharmaceutical products and liquid pharmaceuticals containing L-17 antibodies and antigen-binding fragments. We have now successfully developed a composition, such as secukinumab. [Overview of the Initiative] [Means for solving the problem]

[0006] This disclosure refers to oxygen content of less than approximately 12% (e.g., less than approximately 10% oxygen, less than approximately 8% oxygen, approximately A container having headspace with less than 6% oxygen (e.g., pen, syringe, We provide pharmaceutical products containing liquid compositions disposed in vials, automatic dispensing devices, and containers. The liquid composition is not restored from a freeze-dried product, but is a ready-to-use liquid composition. Yes, generally, at least one of the disclosed IL-17 antibody or its antigen-binding fragment (e.g.) For example, secukinumab), buffers, surfactants, methionine and stabilizers, and below Includes positional combinations. Combinations of specific stabilizers with low oxygen levels in the container's headspace. The use of the IL-17 antibody contained in the composition significantly contributes to the long-term stability of the liquid pharmaceutical product. For example, the inventors determined that these liquid compositions inhibit the oxidation of secukinumab. It has excellent properties, for example: 2.5 mM methionine, measured by SEC after 13 months of storage at 25°C. 3.5% or less, 3.0% or less at 5 mM; and 2.2% in a 20 mM methionine-containing composition. The following aggregates are formed; and RP-HPLC (total of mutants before the main peak) after storage at 25°C for 13 months. According to the results, the percentages were 39.4% or less at 2.5 mM, 37.8% or less at 5.0 mM, and 20 mM methyl Decomposition products of 34.5% or less in onine-containing compositions.

[0007] Therefore, in this specification, headspaces in which the oxygen content is less than approximately 12% A container having a sac, and a container placed inside the said container having a pH of approximately 5.2 to approximately 6.2 A liquid pharmaceutical composition comprising approximately 20 mg / ml to approximately 175 mg / ml of secukinumab, It contains approximately 2.5 to 20 mM L-methionine and is a liquid that has not been restored from freeze-dried material. A pharmaceutical product containing a compound pharmaceutical composition is disclosed.

[0008] In this specification, a container having a headspace in which the oxygen content is less than approximately 6% , and a liquid pharmaceutical composition disposed in the container, comprising approximately 25 mg to approximately 1 50 mg / mL of the IL-17 antibody disclosed herein (e.g., secukinumab), approximately 1 0 mM to approximately 30 mM histidine pH 5.8, approximately 200 mM to approximately 225 mM trehalose, Contains approximately 0.02% polysorbate 80 and approximately 2.5 mM to 20 mM methionine, frozen Pharmaceutical products containing liquid pharmaceutical compositions that have not been restored from the dried product are also disclosed.

[0009] In this specification, a pH of approximately 5.2 to approximately 6.2 and a concentration of approximately 25 mg / ml to approximately 150 ml are used. g / ml of the IL-17 antibody disclosed herein (e.g., secukinumab), and about 2 Prepare a liquid composition containing 0.5 mM to approximately 20 mM methionine; with headspace Placing the liquid composition in a container; and the oxygen content in the headspace Methods for reducing the oxidation of secukinumab, including adjusting it to approximately 12% or less, are also disclosed.

[0010] In this specification, the I disclosed herein is used in concentrations ranging from approximately 25 mg / mL to approximately 150 mg / mL. L-17 antibody (e.g., secukinumab), approximately 10 mM to approximately 30 mM buffer (e.g., hi Stidine) pH 5.8, stabilizer (e.g., trehalose) at approximately 200 mM to 225 mM , approximately 0.02% surfactant (e.g., polysorbate 80) and approximately 2.5 mM to approximately 2 A stable liquid pharmaceutical composition containing 0 mM methionine is also disclosed.

[0011] This disclosure relates to various IL-17-mediated disorders (e.g., autoimmune disorders, e.g., psoriasis, ankylosing leukemia). These pharmaceutical products are for the treatment of spondylitis, psoriatic arthritis, and rheumatoid arthritis. The use of stable liquid compositions, and the inclusion of these pharmaceutical products and stable liquid compositions. Kits that include this are also included.

[0012] The following description and attached claims may include additional compositions, products, methods, regimens, and uses. Uses and kits are provided. Further features, advantages and aspects of this disclosure are described below. This will be apparent to those skilled in the art from the attached claims. [Brief explanation of the drawing]

[0013] [Figure 1] (Figure 1A-D) Figures show the effects of different antioxidant stabilizers on the stability of 150 mg / ml secukinumab syringe solution: Parameter estimates (particle count / ml) of 1 μm subvisible particles by light-darkening after 8 weeks at 5°C (A) Pre-main peak species (%) by RP-HPLC after 8 weeks at 25°C (B) DP-SEC (%) after 8 weeks at 40°C (C) AP-SEC (%) after 8 weeks at 40°C (D) [Figure 2]This figure shows the effect of L-methionine concentration on the stability of 25 mg / ml secukinumab when stored at 25°C: Pre-main peak species (%) by RP-HPLC. Gray dashed line: Linear fit to 10 mM L-methionine / 5% headspace oxygen content data; Black dashed line: Linear fit to 0 mM L-methionine / 5% headspace oxygen content data. [Figure 3] This figure shows the effects of L-methionine, trehalose, and polysorbate 80 on the stability of a 150 mg / ml secukinumab syringe solution stored at 25°C for 6 months: species (%) of the pre-main peak by RP-HPLC. [Figure 4] (Figures 4A and B) These figures show the effect of L-methionine concentration on the stability of 150 mg / ml secukinumab syringe solution stored at 5°C. AP-SEC (%) (A) and pre-main peak species (%) (B) by RP-HPLC in the presence of 5 mM and 0 mM L-methionine. [Figure 5] This figure shows the effect of L-methionine concentration on the stability of 150 mg / ml secukinumab syringe solution after 30 months at 5°C and 13 months at 25°C. AP-SEC (%) (A) and pre-main peak species (%) (B) by RP-HPLC. [Figure 6] (Figures 6A and B) These figures show the effect of L-methionine concentration on the stability of a 25 mg / ml secukinumab vial solution (10% headspace oxygen content) after 3 months of storage at 40°C. AP-SEC (%) (A) and total impurities (%) by CE-SDS (non-reducing) (B). [Figure 7] This figure shows the effect of headspace oxygen content on a 150 mg / ml secukinumab syringe solution stored at 25°C: AP-SEC(%). [Figure 8] (Figures 8A-D) These figures show the effect of headspace oxygen content and packing volume on AP-SEC (%) in 150 mg / ml secukinumab syringe solution after storage at 25°C (A, B) and 5°C (C, D). The packing volume for A and C is 0.5 mL. The packing volume for B and D is 1.0 mL. [Figure 9] This figure shows the effect of headspace oxygen content and packing volume on the stability of 150 mg / ml secukinumab syringe solution after 6 months at 5°C and 25°C: purity by RP-HPLC. [Figure 10] Figure (A): AP-SEC(%) shows the effect of L-methionine concentration and headspace oxygen content on the stability of a 150 mg / ml secukinumab syringe solution stored at 25°C for 6 months. [Figure 11] This figure shows the effects of nitrogen purging and L-methionine concentration on the stability of a 150 mg / ml secukinumab syringe solution: species (%) of the pre-main peak as determined by RP-HPLC. [Figure 12] (Figures 12A and B) These figures show the effect of pH on the stability of 150 mg / ml secukinumab syringe solution after 4 weeks of storage at 40°C. Scaled estimates for stability are given for each 0.3 unit increase in pH (effect). Pre-main peak species (% change) by RP-HPLC (A) and AP-SEC (% change) (B). [Figure 13] (Figure 13A~D) This figure shows the effect of pH on the stability of 150 mg / ml secukinumab syringe solution after storage at 5°C: Turbidity (NTU) (A), Purity by SEC (%) (B), Acidity variant by CEX (%) (C), AP-SEC (%) (D). [Figure 14] This figure shows the effect of stabilizers on the stability of 150 mg / ml secukinumab syringe solution after 8 weeks of storage at 25°C: AP-SEC parameter estimates. [Figure 15] This figure shows the effect of surfactants on the stability of 150 mg / ml secukinumab syringe solution after shaking: parameter estimates (number of particles / ml) for sub-visible particles ≥ 1 μm due to light darkening. [Figure 16](Figure 16A~D) This figure shows the effect of the type of buffer on the stability of 150 mg / ml secukinumab syringe solution: estimated AP-SEC parameters (%) after freeze-thaw stress (A), AP-SEC (%) after shaking stress (B), species of pre-main peak by RP-HPLC after storage at 25°C for 8 weeks (C), and DP-SEC (%) after shaking stress (D). [Modes for carrying out the invention]

[0014] The term "contains" includes both "contains" and "consists of," for example, a composition "contains" X. , can be exclusive to X, or can include additional elements, for example X +Y.

[0015] Unless otherwise indicated by the context, the term "approximately" in relation to the number × means + / - 10%.

[0016] "Every month" means approximately every 4 weeks (for example, every 4 weeks), which is approximately every 28 days (for example) (Every 28 days)

[0017] The term "antibody" as used herein refers to a complete antibody and any antigen-binding fragment thereof. These include single chains. Naturally occurring "antibodies" are interconnected by disulfide bonds. It is a glycoprotein containing at least two heavy (H) chains and two light (L) chains. This is the heavy chain variable region (V in this specification). H It consists of the heavy chain steady region (abbreviated as ) and the heavy chain steady region. The region consists of three domains, CH1, CH2, and CH3. Each light chain is light chain-responsive. It consists of a variable region (abbreviated as VL in this specification) and a light chain steady region. The light chain steady region is 1 It consists of domains, CLs. H and V L The domain is the framework domain (FR). A more conserved region called a hypervariable region or complementary determination region is scattered between them. It can be further subdivided into a region of hypervariability called CDR. H and V L It consists of three CDRs and four CDRs arranged in the following order from the amino terminus to the carboxyl terminus. It consists of FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 The variable regions of the heavy and light chains contain binding domains that interact with the antigen. The normal domain includes various cells of the immune system (e.g., effector cells) and the first part of the classical complement system. It mediates the binding of immunoglobulins to host tissues or factors, including the component (C1q). It is possible to disclose some of the methods, regimens, kits, processes, uses, and compositions. In the embodiment, an antibody against IL-17 or the IL-17 receptor, preferably against IL-17. Antibodies, such as secukinumab, are used.

[0018] As used herein, “isolated antibody” refers to other antibodies having different antigen specificities. This refers to an antibody that is virtually nonexistent (for example, an isolated antibody that specifically binds to IL-17). (The body essentially lacks antibodies that specifically bind to antigens other than IL-17.) The terms "monoclonal antibody" or "monoclonal antibody composition" used in this book are single This refers to a preparation of a single-molecule antibody molecule. The term "human antibody" as used herein refers to a single-molecule antibody preparation. The antibody contains both the workpiece and CDR regions, which have variable regions derived from human sequences. It is assumed that "human antibodies" do not need to be produced by humans, human tissues, or human cells. The human antibodies of this disclosure may contain amino acid residues not encoded by human sequences. introduced (e.g., by random or site-directed mutagenesis in vitro, by N-nucleotide addition at the junctions during in vivo recombination of antibody genes, or by somatic mutations in vivo). In some embodiments of the disclosed methods, regimens, kits, processes, uses, and compositions, the IL-17 antibody is a human antibody, an isolated antibody, and / or a monoclonal antibody. As used herein, the term "antigen-binding fragment" of an antibody refers to a fragment of an antibody that retains the ability to specifically bind to an antigen (e.g., IL-17). It has been found that the antigen-binding function of an antibody can be

[0019] performed by fragments of a full-length antibody. Examples of binding fragments included within the term "antigen-binding fragment" of an antibody include Fab fragments, which are monovalent fragments consisting of the V, V, CL, and CH1 domains; F(ab)2 fragments, which are bivalent fragments comprising two Fab fragments linked by disulfide bridges in the hinge region; Fd fragments consisting of the V and CH1 domains; Fv fragments consisting of the V L and V H domains of a single arm of an antibody; dAb fragments consisting of the V domain (Ward et al., 1989 Nature 341:544-546); and isolated CDRs. Exemplary antigen-binding sites include the CDRs of secukinumab shown in SEQ ID NOs: 1-6 and 11-13 H (Table1), preferably the heavy chain CDR3. Further, the two domains of the Fv fragment, V and V L and V H are encoded by separate genes, but they can be H recombined using recombinant methods to form a single chain variable fragment (scFv) in which the V domains are covalently linked. Exemplary antigen-binding sites include the CDRs of secukinumab shown in SEQ ID NOs: 1-6 and 11-13 (Table1), preferably the heavy chain CDR3. Additionally, although the two domains of the Fv fragment, V L and V H are encoded by separate genes, they can be linked together using recombinant methods to form a single chain variable fragment (scFv) in which the VL and V H The regions pair up to form a monovalent molecule. A single protein chain (known as a single-chain Fv (scFv); e.g., Bird et al., 1988) Science 242:423-426; and Huston et al., 1988 Proc. Natl. Acad. Sci. 85:5879-58 (See 83) They are linked by a synthetic linker, which makes it possible for them to be fabricated as such. This is possible. Such single-chain antibodies are also included in the term "antibody". The bodies and antigen-binding fragments are obtained using the prior art known to those skilled in the art. In some embodiments of the methods, regimens, kits, processes, uses, and compositions, IL-17 (For example, secukinumab) or single-chain antibodies or antigenic antibodies against the IL-17 receptor Composite fragments are used.

[0020] The term "pharmaceutical product" refers to a container having a pharmaceutical composition placed inside it (for example, a pen, This refers to syringes, bags, pumps, etc. "Container" refers to a container for holding liquid pharmaceutical compositions. Any means of injection, such as a pen, syringe, vial, automatic injection device, patch, etc. Each container is a "headspace," that is, a container that does not contain the liquid pharmaceutical composition. It has a region. This headspace is found in gases, such as oxygen and air. It contains a mixture of other gases. The level of oxygen in the headspace is, for example, oxygen Instead, an inert gas (e.g., nitrogen, argon, etc.) is introduced into the headspace. Therefore, it can be adjusted. This can be done, for example, by actively purging, or for example By placing a container in the system and removing oxygen (for example, by vacuum), passive This can be achieved. For example, by purging using an inert gas, preferably nitrogen. This refers to the occurrence before, during, or before the installation of the stopper before or in between filling the container with the composition. It can be filtered. As used herein, the term "oxygen content in headspace" means, This refers to the percentage of oxygen found in the headspace of a given container.

[0021] A "stable" composition is defined by the stability of the proteins within it (e.g., physical, chemical, etc.). It effectively preserves protein stability (and / or biological activity) even after storage. Various analytical techniques for measurement are available in this field, including Peptide and Protein Drug Del ivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, NY, Pubs. (199 1) and Jones, A. Adv. Drug Delivery Rev. 10:29-90 (1993) are discussed. Stable The properties can be measured at a selected temperature for a selected time. "Stable" liquid The antibody composition should be stored at a refrigerated temperature (2-8°C) for at least 6 months, 12 months, preferably 2 years. and more preferably for three years; or at least three months at room temperature (23-27°C), preferably Or for 6 months and more preferably 1 year; or under stress conditions (approximately 40°C) Significant changes are observed for at least one month, preferably three months, and more preferably six months. It is a liquid antibody composition that does not meet various stability standards, for example, 10% or less of antibody monomer. Preferably, 5% or less is decomposed (e.g., SEC purity, RP-HPLC purity, CEX purity) You can use the purity measured by CE-SDS (non-reducing), etc. Alternatively, by using visual analysis or turbidimetric analysis, the solution may change from clear to slightly milky. If it remains white, it can indicate stability. Alternatively, the concentration of the composition, pH and The osmolality is maintained for a given period, for example, at least 3 months, preferably 6 months and more preferably Furthermore, if the fluctuation is less than + / -10% over a year, it can be considered stable. Alternatively, efficacy (e.g., inhibition or biological activity in a CEX assay) can be determined by the efficacy of the substance. The measurement was taken over a given period, for example, at least 3 months, preferably 6 months, more preferably Or over a year, within the range of 70-130% of the control (for example, at least 70%). At least 75%, at least 76%, at least 80%, at least 90%, and If the stability is 91%, at least 95%, preferably in the range of 80-120%, then This can be shown. Alternatively, a given period, for example, at least 3 months, preferably 6 months Over a period of months, more preferably one year, 10% or less of the antibody clipping, preferably 5% or less. If stuttering is observed (for example, when measured by DP-SEC), stability is considered. It can be shown. Alternatively, for a given period, for example, at least 3 months, preferably 6 months. More preferably, less than 10%, and more preferably less than 5%, of aggregates are formed over a period of one year. When measured (for example by AP-SEC), stability can be demonstrated. Alternatively, aggregate formation, as measured by SEC, after storage at 25°C for 13 months, Stability can be demonstrated if the values ​​are ≤ approximately 3.5%, ≤ approximately 3.0%, or ≤ approximately 2.2%. Alternatively, after 13 months of storage at 25°C, the formation of degradation products (RP-HPLC) When measured by the pre-main peak species, the percentages were ≤ approximately 39.4%, ≤ approximately 37.8%, Alternatively, if the value is ≤ approximately 34.5%, it can be considered stable.

[0022] Visual inspection of color and / or transparency (turbidity), or UV light scattering, size exclusion When measured by dechromatography (SEC) and dynamic light scattering (DLS), If it does not show a significant increase in aggregation, precipitation, and / or denaturation, the antibody is in the pharmaceutical composition. This maintains its physical stability. Furthermore, for example, fluorescence spectroscopy (to determine the tertiary structure of proteins) When evaluated by (or by FTIR spectroscopy (to determine the protein secondary structure)) The protein conformation should not be significantly altered.

[0023] If it does not exhibit significant chemical modification, the antibody maintains its chemical stability in the pharmaceutical composition. To maintain. By detecting and quantifying the chemically modified form of proteins, Stability can be evaluated. Degradation processes that often alter the chemical structure of proteins include Hydrolysis or clipping (size exclusion chromatography [SEC] and SDS- (Assessed by methods such as PAGE), oxidation (e.g., mass spectrometry or MALDI / T) (Evaluated by methods such as peptide mapping used in combination with OF / MS), deamide ( Cation exchange chromatography (CEX), capillary isoelectric focusing, peptide ion chromatography (Assessed by methods such as saturation and isoaspartic acid measurement) and isomerization (iso It contains (evaluated by measurements such as aspartic acid content and peptide mapping). ru.

[0024] The biological activity of a protein / antibody at a given time is shown at the time of preparation of the pharmaceutical composition. When within a predetermined range of biological activity, an antibody retains its biological activity in a pharmaceutical composition. The biological activity of antibodies can be measured, for example, by antigen-binding ELISA assays, efficacy assays (for example) For example, an IL-17 antibody binds to IL-17 and inhibits the release of IL-6 from chondrocytes (for example) If the ability of secukinumab is evaluated, it can be determined by cysteamine-CEX derivatization. It can be determined.

[0025] As used herein, "purity by RP-HPLC" refers to the purity obtained by RP-HPLC. This refers to the percentage of peak performance and can be used to assess the stability of secukinumab. RP-HPLC is used to separate secukinumab and its variants due to their hydrophobicity. Used for this purpose. Pre-main peak species by RP-HPLC elute before the main peak. This is the sum of the percentages of peaks, and includes fragmented, isomerized, and oxidized species of antibodies. It is possible.

[0026] As used herein, "purity by CEX" refers to the percentage of the main peak in CEX. This refers to and can be used to evaluate the stability of secukinumab antibodies. Acidic and The charge heterogeneity of secukinumab is evaluated by measuring the percentage of basic mutants. CEX is used for this purpose.

[0027] As used herein, “purity by SEC” refers to the percentage of monomers in SEC. It can be used to evaluate the stability of secukinumab under non-denaturing conditions. To separate monomer secukinumab from aggregates and fragments based on their size, SE C is used. The sum of peaks that elute before the main peak is the aggregate product (AP-SE). As a percentage of C), the sum of the peaks that elute after the main peak is the degradation product (DP-S It is reported as a percentage of the EC.

[0028] As used herein, "purity by CE-SDS" refers to the purity obtained by CE-SDS. This refers to the percentage of the antibody and can be used to evaluate the stability of secukinumab. Under non-reducing conditions, by-products and degradation products are separated by their molecular size into intact se CE-SDS is used to isolate cukinumab. It is isolated from the main peak. The sum of the peaks is reported as a percentage of impurities.

[0029] As used herein, the phrase “liquid pharmaceutical composition” means that it is not restored from a freeze-dried product and at least 1 One IL-17 antibody or its antigen-binding fragment (e.g., secukinumab) and at least This refers to an aqueous composition containing one additional excipient (e.g., a buffer). Liquid pharmaceutical compositions This may include additional excipients (stabilizers, surfactants) and additional active ingredients. This type of formulation is also called a "ready-to-use" formulation.

[0030] As used herein, the term “freeze-dried product” means a product that is dry with little to no water (for example) This refers to a pharmaceutical composition (that has been freeze-dried). The freeze-drying technology for antibodies is well known in this art. Yes, for example, Rey & May (2004) Freeze-Drying / Lyophilization of Pharmaceuticals & See Biological Products ISBN 0824748689. Restored freeze-dried material has limited storage capacity. Because freeze-dried products tend to have a limited shelf life, they are usually used immediately (e.g., within 1-10 days). ) is restored to give an aqueous composition.

[0031] The term "high concentration" refers to a set containing more than 50 mg / ml of antibody or antigen-binding fragment. This refers to the finished product. In preferred embodiments, the high-concentration liquid composition has a concentration of ≥ approximately 50 mg / ml and ≥ approximately 7 5mg / ml, ≧about 100mg / ml, ≧about 125mg / ml, ≧about 150mg / ml, It contains ≥ approximately 175 mg / ml, ≥ approximately 200 mg / ml, or ≥ approximately 225 mg / ml.

[0032] The term "IL-17" refers to IL-17A, formerly known as CTLA8, and Wild-type IL-17A, IL-17A from various species (e.g., humans, mice, and monkeys) This disclosure includes polymorphic variants and functional equivalents of IL-17A. The functional equivalent is preferably wild-type IL-17A (e.g., human IL-17A) and at least Approximately 65%, 75%, 85%, 95%, 96%, 97%, 98%, or even 99% of the total It possesses somatic sequence identity and has virtually the ability to induce IL-6 production by human dermal fibroblasts. To hold.

[0033] The term “K D " refers to the dissociation rate of a specific antibody-antigen interaction. In this specification, Use the term "K D " is K d vs K a The ratio (i.e., K d / K a ) obtained from, This refers to the dissociation constant expressed as the antibody concentration (M). D The value is established in this field. The determination can be made using the method described. Antibody K D The method for determining this is the surface Using razmon resonance, or bio such as the Biacore® system. By using a sensor system. In some embodiments, IL-17 antibody or The antigen-binding fragment is approximately 100-250 pM (measured by Biacore®). K (when) D It then binds to human IL-17.

[0034] The term "affinity" refers to the strength of the interaction between an antibody and an antigen at a single antigen site. Within the original site, the variable region of the antibody "arm" is linked to multiple sites via weak non-covalent bonding forces. It interacts with the progenitor, and the more interaction there is, the stronger the affinity. Various species of IL-17 Standard assays for evaluating the binding affinity of antibodies to a substance include, for example, ELISA and Western blot. This is known in the art, including TT and RIA. Antibody binding kinetics (e.g., binding affinity) The sex can be determined by standard assays known in the art, for example, Biacore®. It can also be tested through analysis.

[0035] As used herein, the terms “subject” and “patient” refer to any human or non-human. This includes animals. The term "non-human animals" includes all vertebrates, such as mammals and non-human animals. Mammals, such as primates other than humans, sheep, dogs, cats, horses, cows, chickens, and amphibians. This includes animals, reptiles, and so on.

[0036] These ILs, which are known in the art and determined by the methods described herein -17 Functional properties (e.g., biochemical, immunochemical, cellular, physiological, or other biological activity) Antibodies that "inhibit" one or more of the following (such as sex): Statistically significant differences in specific activity compared to those observed when opposite-sex control antibodies are present. It is understood to be related to a decrease. Antibodies that inhibit IL-17 activity are measured, for example. At least approximately 10%, at least 50%, 80%, or 90% of the parameters are statistically significant. Any particular implementation of the disclosed methods, uses, processes, kits, and compositions may be affected by an unintended reduction. In terms of form, the IL-17 antibody used has 95%, 98%, or the functional activity of IL-17. It can inhibit over 99%.

[0037] As used herein, "inhibiting IL-6" means reducing IL-6 production from chondrocytes. This refers to the ability of an IL-17 antibody (e.g., secukinumab) to induce IL-17. The biological activity of antigen-binding fragments, such as secukinumab, is observed in immortalized human chondrocyte cell lines. For example, inhibiting the release of IL-6 from C-20 / A4s induced by IL-17. It can be measured based on its ability. In short, on day 1 of the assay, C-20 / A Four cells were seeded into a 96-well plate, allowed to adhere, and then immobilized in a submaximal concentration of IL-1. 7 (for example, about 20-200 ng / mL in the culture medium, e.g., about 80 ng / mL) and Various concentrations of antibody (for example, approximately 0.01 μg / mL to approximately 4 μg / mL in the assay plate) Incubate overnight in the presence of (for example, approximately 0.5 μg / mL to approximately 2 μg / mL). To increase the dynamic range of the assay, IL-17-induced IL -6 contains TNFα that promotes production (for example, about 0.01 ng / mL in the culture medium ~ 1 ng / mL, for example, about 0.5 ng / mL). On the second day, the concentration of IL-6 in the cell supernatant is The amount of IL-6 in the cell supernatant is quantified by ELISA. -17 antibody activity is inversely proportional. The biological activity of the antibody test sample is inversely proportional to IL-6 and IL-17. Its ability to inhibit dependent release was quantified by comparing it to that of the antibody reference standard. Samples and standards are normalized based on protein content. Relative potency is determined by the European Pharmacopoeia. Depending on the method, calculations are performed using parallel line assays. The final results are compared to the reference standard. It is expressed as the relative efficacy (percentage) of the substance.

[0038] Unless otherwise specified, the term "derivative" refers to, for example, a specified sequence (e.g., variable domain). The present disclosure relates to an IL-17 antibody or its antigen-binding fragment, for example, secukinumab. Mino acid sequence variants and covalent modifications (e.g., pegylation, deamidation, hydroxylation) It is used to define (phosphorylation, methylation, etc.). "Functional derivatives" are disclosed. It contains molecules that have qualitative biological activity common to IL-17 antibodies or their antigen-binding fragments. The functional derivative is a fragment of the IL-17 antibody or its antigen-binding fragment disclosed herein. Includes fragments and peptide analogs. The fragments are, for example, of a specified sequence, the peptide analogs according to this disclosure. Includes a region within the sequence of the plutide. IL-17 antibody or its antigen binding disclosed herein. Functional derivatives of the fragment (e.g., functional derivatives of secukinumab) are disclosed herein. V of IL-17 binding molecule H and / or V L Array (for example, V in Table 1) H and / or V L (array) and at least approximately 65%, 75%, 85%, 95%, 96%, 97%, 98%, Or, having 99% overall sequence identity and virtually no ability to bind to human IL-17 To retain, or, for example, IL-17-induced IL- in human dermal fibroblasts 6 inhibits production, V H and / or VL Preferably include the domain.

[0039] The phrase "substantially identical" refers to the related amino acid or nucleotide sequence (e.g., For example, V H or V L The domain is either identical or non-substantial compared to a specific reference sequence. This means having a substantial difference (for example, through conserved amino acid substitutions). The difference is the difference within the specified region (for example, V H or V L Among the five amino acid sequences of the domain This includes minor amino acid changes such as one or two substitutions. In the case of antibodies, the second antibody is the same It has the same specificity and has at least 50% of its affinity. The sequences disclosed herein and Sequences that are substantially identical (for example, at least about 85% sequence identity) are also included in this application. Yes. In some embodiments, derivative IL-17 antibodies (e.g., derivatives of secukinumab, e.g.) are used. For example, the sequence identity of the secukinumab biological analog antibody is approximately 90% compared to the disclosed sequence. % or more, for example 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 9 It can be 8%, 99%, or even higher.

[0040] The "identity" of natural polypeptides and their functional derivatives is, in this specification, most Align the sequences to achieve a high percentage of identity and introduce gaps where necessary. When no subsequent conservative substitutions are considered part of sequence identity, the corresponding natural polyp It is defined as the percentage of amino acid residues in a candidate sequence that are identical to a ptyde residue. N-terminus or Neither C-terminus extension nor insertion shall be interpreted as reducing identity. Methods and computer programs for this are well known. The identity percentage is the standard Lineage algorithms, e.g., Altshul et al. ((1990) J. Mol. Biol., 215: 40 Basic Local Alignment Seerk (as described in 3 410) h Tool(BLAST); Needleman et al. ((1970) J. Mol. Biol., 48: 444 4 53) The algorithm of Meyers et al. ((1988) Comput. Appl. Biosci., 4: 11 17 The determination can be made using the algorithm. The parameter set consists of 12 gaps. Penalties: 4 gap extension penalty and 5 frame shift gap penalty It may also be a Blosum62 scoring matrix. Two amino acids or The percentage of identity between nucleotide sequences is determined by the ALIGN program (version 2.0) ) incorporated by E. Meyers and W. Miller ((1989) CABIOS, 4: 11- Using the algorithm in 17), the PAM120 weight residue table and 12 gap length penalties are used. The decision can also be made using the gap penalty for rule 4.

[0041] "Amino acids" refers to, for example, all naturally occurring L-α-amino acids, D Contains amino acids. The term "amino acid sequence variant" is used when compared to the sequence described herein. This refers to molecules that have some differences in their amino acid sequences. The polypeptides according to this disclosure For example, an amino acid sequence variant of a specified sequence binds to human IL-17, or, for example, For example, the ability to inhibit IL-6 production in human dermal fibroblasts induced by IL-17. Furthermore, amino acid sequence variants are substitutional variants (in which at least one amino acid residue is removed). It is removed, and instead a different amino acid is inserted at the same position in the polypeptide according to this disclosure. (Those that are inserted), insertion mutants (those that are immediately adjacent to an amino acid at a specific position in the polypeptide according to this disclosure) (In which one or more amino acids are inserted), and deletion variants (Po by the present disclosure) Includes lipeptides from which one or more amino acids have been removed.

[0042] The term "pharmaceutically acceptable" means that the effectiveness of the biological activity of the active ingredient(s) does not interfere with the effectiveness of the active ingredient(s). It means non-toxic material.

[0043] The term "administering" in relation to a compound, such as an IL-17 binding molecule or another drug, It is used to refer to delivering the compound to the patient via any route.

[0044] As used herein, “therapeutic dose” refers to a single or multiple dose administered to a patient (e.g., a human). Several doses are administered to treat, prevent, or alleviate at least one symptom of a disorder or recurrent disorder. For the prevention, cure, or delay of the disease, or for reducing or improving its severity, or in the absence of such treatment. IL-17 antibodies or that are effective in extending patient survival beyond what is expected. This refers to the amount of antigen-binding fragments, such as secukinumab. It also refers to the individual active ingredients administered alone (for example...) However, when applied to IL-17 antibodies (e.g., secukinumab), this term refers only to its component. This refers to the combination of drugs administered together, sequentially, or simultaneously. Regardless of whether it is a therapeutic agent or not, it refers to the combined amount of active ingredients that produce a therapeutic effect.

[0045] The term "treatment" or "to treat" refers to preventive or deterrent treatments as well as therapeutic or disease-related treatments. This refers to both disease correction treatments and treatments for patients who are at risk of developing a disease or are suspected of having developed a disease. Persons, and patients who are ill or have been diagnosed with a disease or medical condition. This includes treatment, and also includes suppression of clinical relapse. Treatment is for one or more of the disorder or relapsed disorder. For the prevention, treatment, delay of onset, reduction or improvement of the severity of multiple symptoms, or In order to extend the patient's survival beyond what would be expected in the absence of such treatment, It can be administered to patients who have an academic disability or who are at risk of eventually developing one.

[0046] The phrase "means for administration" refers to any means of administering a drug systemically to a patient. Suitable instruments, such as, but not limited to, pre-filled syringes, vials and syringes, and injection pens. Used to indicate automatic infusion devices, IV infusions, bags, pumps, patch pumps, etc. Such items allow patients to self-administer medication (i.e., by themselves). (To administer drugs) or a doctor can administer drugs. Generally The dosage given in "mg / kg" is administered via the IV route, and the dosage given in "mg" is administered via the IV route. The dose is administered via IM or SC injection. Disclosed method, kit In some embodiments of the regimen and use, an IL-17 antibody or its antigen-binding fragment is used. For example, secukinumab is delivered to the patient via the IV route. Disclosed method, kit In some embodiments of the regimen and use, an IL-17 antibody or its antigen-binding fragment is used. For example, secukinumab is delivered to the patient via the SC pathway.

[0047] IL-17 antibody and its antigen-binding fragment Disclosed pharmaceutical products, compositions, liquid compositions, regimens, processes, uses, methods and keys The product contains or utilizes an IL-17 antibody or its antigen-binding fragment.

[0048] In one embodiment, an IL-17 antibody or its antigen-binding fragment, such as secukinumab, is super At least one immunoglobulin heavy chain containing variable regions CDR1, CDR2, and CDR3 Variable domain (V H ) comprises, and the CDR1 has the amino acid sequence of SEQ ID NO: 1, and the C DR2 has the amino acid sequence of SEQ ID NO: 2, and CDR3 has the amino acid sequence of SEQ ID NO: 3 It possesses. In one embodiment, an IL-17 antibody or its antigen-binding fragment, for example, secukinumab This includes at least one immunoglobulin containing hypervariable regions CDR1', CDR2', and CDR3'. Robulin light chain variable domain (V L ) includes, and the CDR1' is the amino acid sequence of SEQ ID NO: 4 The CDR2' has the amino acid sequence of SEQ ID NO. 5, and the CDR3' has the amino acid sequence of SEQ ID NO. 5. It has an amino acid sequence of 6. In one embodiment, an IL-17 antibody or its antigen-binding fragment, For example, secukinumab contains hypervariable regions CDR1-x, CDR2-x, and CDR3-x. at least one immunoglobulin heavy chain variable domain (V H ) including the above CDR1-x CDR2-x has the amino acid sequence of SEQ ID NO: 11, and CDR2-x has the amino acid sequence of SEQ ID NO: 12. The CDR3-x has the amino acid sequence of SEQ ID NO: 13.

[0049] In one embodiment, an IL-17 antibody or its antigen-binding fragment, such as secukinumab, is used in small amounts. Even without one immunoglobulin V H domain and at least one immunoglobulin V L Including the domain, a) immunoglobulin V H The domains are (for example, in order): i) CDR 1 has the amino acid sequence of SEQ ID NO: 1, CDR2 has the amino acid sequence of SEQ ID NO: 2, C DR3 has the amino acid sequence of SEQ ID NO: 3, and is part of the hypervariable regions CDR1, CDR2, and CD. R3, or ii) CDR1-x has the amino acid sequence of SEQ ID NO: 11, and CDR2-x is CDR3-x has the amino acid sequence of SEQ ID NO: 12, and CDR3-x has the amino acid sequence of SEQ ID NO: 13. b) Immunoglobulin Phosphorus V L The domains are (for example, in order) the hypervariable regions CDR1', CDR2', and CD It contains R3', the CDR1' has the amino acid sequence of SEQ ID NO: 4, and the CDR2' is The CDR3' has the amino acid sequence of sequence number 5, and the CDR3' has the amino acid sequence of sequence number 6.

[0050] In one embodiment, an IL-17 antibody or its antigen-binding fragment, for example, secukinumab, is a )Immunoglobulin heavy chain variable domain (V) containing the amino acid sequence shown in Sequence ID No. 8 H );b) The immunoglobulin light chain variable domain (V) contains the amino acid sequence shown in SEQ ID NO: 10. L );c) Immunoglobulin V containing the amino acid sequence shown in SEQ ID NO: 8 H Domain and sequence number 10 Immunoglobulin V containing the amino acid sequence shown L Domain; d) Sequence ID 1, Sequence ID 2 and Immunoglobulin V containing the hypervariable region shown in Sequence ID No. 3 H Domain; e) Sequence ID 4, distribution Immunoglobulin V containing the hypervariable region shown in column 5 and sequence number 6. L Domain; f) distribution Immunoglobulin V containing the hypervariable region shown in column 11, sequence number 12, and sequence number 13. HDomain; g) Immunity including the hypervariable region shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 Globulin V H The domain and the hypervariable shown in SEQ ID NOs: 4, 5, and 6. Immunoglobulin V including the region L Domain; or h) Sequence ID 11, Sequence ID 12 and Immunoglobulin V containing the hypervariable region shown in Sequence ID No. 13 H Domain and Sequence ID No. 4, Immunoglobulin V containing the hypervariable region shown in SEQ ID NOs. 5 and 6. L Including domains .

[0051] For ease of reference, based on Kabat's definition and determined by X-ray analysis, Using the approach of Chothia and her collaborators, seckinuma bmonocoruna The amino acid sequences of the hypervariable region of the antibody are provided in Table 1 below.

[0052] [Table 1]

[0053] In preferred embodiments, for example, "Sequences of Proteins of Immunological Interest", Kabat EA et al, US Department of Health and Human Services, Public Health Ser As stated by the National Institute of Health, the constant region domain is suitable for The constant region domain is also preferably included. The DNA encoding the VL of secukinumab is sequence This is shown in number 9. The DNA encoding VH of secukinumab is shown in sequence number 7.

[0054] In some embodiments, an IL-17 antibody or its antigen-binding fragment, such as secukinumab, is used. , containing three CDRs of SEQ ID NO: 10. In other embodiments, the IL-17 antibody is SEQ ID NO: It contains three CDRs of 8. In other embodiments, the IL-17 antibody contains three of SEQ ID NO: 10 Includes CDR and three CDRs with sequence number 8. Definitions of Chothia and Kabat. The CDRs for Sequence IDs 8 and 10 can be found in Table 1.

[0055] In some embodiments, an IL-17 antibody or its antigen-binding fragment, such as secukinumab, is used. , including the light chain of SEQ ID NO: 14. In other embodiments, IL-17 antibody or its antigen binding cleavage. One example is secukinumab, which contains the heavy chain of SEQ ID NO: 15. In other embodiments, IL-17 The antibody or its antigen-binding fragment, for example, secukinumab, has a light chain and sequence number of SEQ ID NO: 14. Includes heavy chain of no. 15. In some embodiments, IL-17 antibody or its antigen-binding fragment, e.g. For example, secukinumab contains three CDRs of SEQ ID NO: 14. In other embodiments, IL-1 7. Antibodies or their antigen-binding fragments, such as secukinumab, have three CDRs of SEQ ID NO: 15 In other embodiments, an IL-17 antibody or its antigen-binding fragment, such as secukinumab, may be included. This includes three CDRs with sequence number 14 and three CDRs with sequence number 15. The CDRs for sequence numbers 15 and 17, as defined by ia and Kabat, are shown in Table 1. It can be found.

[0056] The hypervariable region may be combined with any type of framework region, but preferably with human-generated regions. It is the source. Suitable framework areas are described in Kabat EA et al, ibid. A preferred heavy chain framework is a human heavy chain framework, such as that of a secukinumab antibody. That is, for example, FR1 (amino acids 1-30 of sequence number 8), FR2 ( Amino acids 36-49 of SEQ ID NO: 8, FR3 (amino acids 67-98 of SEQ ID NO: 8) and It consists of the FR4 region (amino acids 117-127 of SEQ ID NO: 8). This was determined by X-ray analysis. Considering the hypervariable region of secukinumab, another preferred heavy chain framework is, in order FR1-x (amino acids 1-25 of SEQ ID NO: 8), FR2-x (amino acids 3 of SEQ ID NO: 8) 6-49), FR3-x (amino acids 61-95 of SEQ ID NO: 8) and FR4 (SEQ ID NO: 8) It consists of the amino acid region (119-127). Similarly, the light chain framework is FR in order. 1' (amino acids 1-23 of SEQ ID NO: 10), FR2' (amino acids 36-5 of SEQ ID NO: 10) 0), FR3' (amino acids 58-89 of SEQ ID NO: 10) and FR4' (amino acids 58-89 of SEQ ID NO: 10) It consists of the amino acid region (99-109).

[0057] In one embodiment, an IL-17 antibody or its antigen-binding fragment, such as secukinumab, is used in small amounts. At the very least: a) It may include the hypervariable regions CDR1, CDR2, and CDR3 of the human heavy chain in order. It includes a variable domain and a steady portion or a fragment thereof, and the CDR1 is the ami of SEQ ID NO: 1 The CDR2 has an amino acid sequence, and the CDR3 has the amino acid sequence of SEQ ID NO 2. an immunoglobulin heavy chain or fragment having amino acid sequence number 3, and b) human A variable domain containing, in order, the hypervariable regions CDR1', CDR2', and CDR3' of the light chain. Furthermore, it includes a constant portion or a fragment thereof, and the CDR1' has the amino acid sequence of SEQ ID NO: 4 The CDR2' has the amino acid sequence of SEQ ID NO: 5, and the CDR3' has the amino acid sequence of SEQ ID NO: 6 A human anti-IL-17 comprising an immunoglobulin light chain or fragment having the amino acid sequence of the following: Selected from antibodies.

[0058] In one embodiment, an IL-17 antibody or its antigen-binding fragment, for example, secukinumab, is: a ) Includes super-variable regions CDR1, CDR2 and CDR3 in order, where CDR1 is sequence number The CDR2 has the amino acid sequence of sequence number 2, and the CDR 3 is the first domain having the amino acid sequence of SEQ ID NO: 3; and b) the hypervariable region CDR It contains 1', CDR2', and CDR3' in order, where CDR1' is the amino acid of SEQ ID NO: 4. It has an acid sequence, and the CDR2' has the amino acid sequence of SEQ ID NO: 5, and the CDR3' has The second domain having the amino acid sequence of column number 6; and c) the N-terminus of the first domain The tip and the C-terminal tip of the second domain, or the C-terminal tip of the first domain and the second A peptide linker bound to one of the N-terminal tips of the domain, including an antigen-binding region. Selected from single-chain molecules containing the 11th position.

[0059] Alternatively, an IL-17 antibody or its antigen-binding fragment for use in the disclosed method, For example, secukinumab is a derivative of the molecule shown herein by sequence (e.g., secukinumab It may include a pegged version of the .b. Or, for use in the disclosed manner. IL-17 antibody or its antigen-binding fragment, for example, secukinumab V H or V L Domaine The V shown in this specification is H or V L Domains (for example, as shown in sequence numbers 8 and 10) V is substantially identical to (of) H or V LIt may have a domain. The human IL-17 antibody shown is substantially identical to the one shown in SEQ ID NO: 15, in terms of heavy chain and It may contain a light chain that is substantially identical to the one shown in Sequence ID No. 14. The human IL-17 antibody disclosed in this document contains the heavy chain including SEQ ID NO: 15 and SEQ ID NO: 14. It may contain a light chain. The human IL-17 antibodies disclosed herein are: a) sequence number Variable domain and human heavy chain having an amino acid sequence substantially identical to that shown in item 8. A heavy chain containing the steady portion of; and b) substantially identical to that shown in Sequence ID No. 10 A variable domain having a specific amino acid sequence and a single light chain containing a constant portion of a human light chain, comprising It is possible to use an IL-17 antibody or the method disclosed. Antigen-binding fragments, such as secukinumab, are amino acid sequence variants of the reference molecule shown herein. It may be present. In all such cases of derivatives and variants, IL-17 antibody The antigen-binding fragment, for example, secukinumab, contains approximately 1 nM (=30 ng / ml) of human I The activity of L-17 is reduced to approximately 50 nM or less, approximately 20 nM or less, approximately 10 nM or less, and approximately 5 50% inhibition is possible at concentrations of nM or less, approximately 2nM or less, and more preferably approximately 1nM or less. The inhibitory activity is induced by hu-IL-17 in human dermal fibroblasts. It is measured by IL-6 production.

[0060] The inhibition of IL-17 binding to that receptor is described in WO2006 / 013107. It can be conveniently tested with various assays, including those such as the one described above. "The reference and derivative molecules are essentially identical in one of the assays mentioned herein." This means statistically demonstrating IL-17 inhibitory activity (implementation of WO2006 / 013107). (See Example 1). For example, the IL-17 antibody or its antigen-binding fragment disclosed herein is When assayed as described in Example 1 of WO2006 / 013107, human skin Regarding IL-6 production induced by human IL-17 in fibroblasts, human IL-17 Inhibition of the corresponding reference molecule IC 50 Less than approximately 10 nM, more preferably about 9, 8 IC5 of 7, 6, 5, 4, 3, 2 or about 1 nM, preferably substantially the same as thereto. It generally has 0. Alternatively, the assay used is for soluble IL-17 receptor (e.g., Human IL-17R / Fc construct of Example 1 of WO2006 / 013107 and the present disclosure In an assay for competitive inhibition of IL-17 binding by an IL-17 antibody or its antigen-binding fragment: It's okay to have it.

[0061] This disclosure relates to, for example, mutation, for example, site-directed mutagenesis of the corresponding DNA sequence. Furthermore, V shown in sequence numbers 8 and 10 H or V L V compared to domain H or V L One or more amino acid residues in a domain, generally only a small number (e.g., 1-10). This includes IL-17 antibodies or their antigen-binding fragments, such as secukinumab, which have undergone a transformation. This disclosure includes DNA sequences encoding such altered IL-17 antibodies.

[0062] This disclosure relates to an IL-17 antibody having binding specificity to human IL-17 or its antigen binding. It is possible to inhibit the binding of fragments, such as secukinumab, and especially its binding of IL-17 to its receptor. The IL-17 antibody and the activity of 1 nM (=30 ng / ml) human IL-17 were used to determine the activity of the IL-17 antibody. Molecular molecular weights of approximately 50 nM or less, approximately 20 nM or less, approximately 10 nM or less, approximately 5 nM or less, and approximately 2 nM or less. IL-17 antibodies that can inhibit 50% at concentrations of approximately 1 nM or less, more preferably IL-17 antibodies (The inhibitory activity is induced by hu-IL-17 in human dermal fibroblasts.) (Measured by IL-6 production).

[0063] In some embodiments, the IL-17 antibody, for example, secukinumab, is Leu74, Tyr8 5, His86, Met87, Asn88, Val124, Thr125, Pro126 Epitope of mature human IL-17 including Ile127, Val128, and His129 It binds. In some embodiments, an IL-17 antibody, such as secukinumab, binds to Tyr43. Epitone of mature human IL-17, including Tyr44, Arg46, Ala79, and Asp80 It binds to the p. In some embodiments, an IL-17 antibody, such as secukinumab, binds to the two components. It binds to the epitope of an IL-17 homodimer having a mature human IL-17 chain, and the epitope The chain contains Leu74, Tyr85, His86, Met87, Asn88, V on one side. al124, Thr125, Pro126, Ile127, Val128, His129 The other chain contains Tyr43, Tyr44, Arg46, Ala79, and Asp80. The residue numbering scheme used to define these epitopes is such that residue 1 is mature Based on being the first amino acid of a protein (i.e., the N-terminal signal of the 23 amino acids) IL-17A lacks the ulupeptide and starts with glycine. The sequence of immature IL-17A is: As shown in Swiss-Prot registration Q16552. In some embodiments, IL-1 7. Antibodies, when measured by, for example, Biacore®, yield approximately 100-200 pM's K D It has. In some embodiments, the IL-17 antibody is approximately 0.67 nM human I Regarding the in vitro neutralization of the biological activity of L-17A, approximately 0.4 nM IC50 is used. 50 of It possesses. In some embodiments, the absolute biological properties of IL-17 antibodies administered subcutaneously (sc) The usability ranges from about 60% to about 80%, for example, about 76%. In some embodiments, IL-17 antibodies, such as secukinumab, have an excretion half-life of approximately 4 weeks (for example, approximately 23 weeks). ~Approximately 35 days, approximately 23 to approximately 30 days, for example, approximately 30 days). In some embodiments, IL-17 anti For example, secukinumab has a 7-8 day T max It has.

[0064] Particularly preferred IL-17 antibodies for use in the disclosed methods, uses, kits, etc. Its antigen-binding fragment, for example, secukinumab, is a human antibody, particularly WO2006 / 01310 Example 7 (US7,807,155, the entirety of which is incorporated herein by reference) As described in 1 and 2, it is secukinumab. Secukinumab is used to treat immune-mediated inflammatory conditions. High affinity recombinant IgG1 / kappa isotype is currently undergoing clinical trials for placement. Completely human monoclonal anti-human interleukin-17A (IL-17A, IL-17) It is an antibody. Secukinumab (e.g., WO2006 / 013107 and WO2007 / (See 117749) has a very high affinity for IL-17, i.e., K D about 100 It is ~200 pM (for example, when measured by Biacore®), and approximately IC258 50 Approximately It is 0.4 nM. Therefore, secukinumab inhibits the antigen in a molar ratio of approximately 1:1. The high binding affinity makes secukinumab antibodies particularly suitable for therapeutic application. Furthermore, Secukinumab was determined to have a very long half-life, approximately 4 weeks, which is why it is not suitable for long-term use. It allows for intervals between doses and is a special property when treating chronic, lifelong disorders such as psoriasis.

[0065] Pharmaceutical products containing IL-17 antibodies or antigen-binding fragments This disclosure generally describes a headspace having less than approximately 12% oxygen in the headspace. The present invention provides a pharmaceutical product comprising a container and a liquid composition disposed within the container, wherein the liquid The composition comprises the IL-17 antibody or its antigen-binding fragment, for example, secukinumab.

[0066] container The pharmaceutical products disclosed herein are primary for storing, transporting, and maintaining the disclosed liquid compositions. Packaging, i.e., a container, is used. Pharmaceutically for use as part of the disclosed pharmaceutical product. Acceptable containers include syringes (e.g., Beckton Dickinson, Nuo Available from VA Ompi, etc.), vials with stoppers, cartridges, automatic dispensing devices, Includes a patch pump and injection pen.

[0067] Headspace oxygen The present inventors have found that IL-17 antibodies or their antigen-binding fragments in the disclosed liquid compositions (e.g.) For example, the stability of secukinumab is determined by the oxygen in the headspace of the pharmaceutical product container being an inert gas. (For example, argon, helium, nitrogen), preferably N2, are replaced simultaneously and in parallel. It has been found that this can be enhanced by including certain stabilizers (e.g., methionine). It was determined. Specifically, for example, when measured by SEC and RP-HPLC, oxygen The container has been purged, i.e., has less than 12% oxygen in the headspace. The pharmaceutical product has improved stability compared to the unpurged product, according to the inventors. He made that judgment.

[0068] Modification of the oxygen content in the headspace using purging (e.g., nitrogen purging) is a filling process. This can be achieved during the purging stage or the plugging stage (or both). For example, nitrogen purging involves actively introducing an inert gas (e.g., using a needle). This can be achieved while plugging it.

[0069] In some embodiments, the oxygen content in headspace is less than about 12% (for example, about 10%). (less than %, less than approximately 8%, less than approximately 6%, etc.) In some embodiments, the headspace The oxygen content inside is less than approximately 6%. The oxygen content in the headspace is determined by laser absorption spectroscopy. It can be monitored by quenching, fluorescence quenching, or gas chromatography. The oxygen content in the headspace of a given container increases over time, for example, due to leakage. It will be understood that there is a headspace. Therefore, as used in this specification, "headspace The phrase "oxygen content inside" refers to the head of the container immediately after the product is sealed (e.g., by putting a stopper on it). This refers to the initial level of oxygen in space.

[0070] liquid composition The liquid composition of this disclosure is the above-mentioned IL-17 antibody or its antigen-binding fragment (e.g., sec At least one kinumab, and at least one additional excipient, e.g., a buffering agent. , and includes surfactants and stabilizers (or more). In some embodiments, the liquid composition is The formulation includes at least two additional excipients, such as a buffer and a stabilizer. In some embodiments, The liquid composition comprises a buffer, at least one stabilizer, and a surfactant.

[0071] Generally, pharmaceutical compositions are formulated with excipients that are compatible with the intended route of administration (for example) (The oral composition generally contains an inert diluent or a food-grade carrier.) Examples of administration routes include This includes parenteral (e.g., intravenous), intradermal, subcutaneous, oral (e.g., oral or inhalation), and transdermal ( This includes local, transmucosal, and rectal administration. The liquid antibody composition of this disclosure is administered intravenously, intramuscularly, It is suitable for parenteral administration, such as intraperitoneal or subcutaneous injection, and is particularly suitable for subcutaneous injection.

[0072] In some embodiments, the liquid compositions of the present disclosure undergo RP-HP after storage at 2-8°C for 6 months. RP-H: At least approximately 86% purity as determined by LC, stored at 25°C / 60%RH for 6 months. Purity of at least about 76% (preferably at least about 76%) by PLC, and / or Alternatively, after storage at 30°C / 75%RH for 6 months, at least approximately 60% can be determined by RP-HPLC. Maintain purity. In some embodiments, the liquid compositions of this disclosure can be stored at 2-8°C for 24 months. After storage, maintain a purity of at least approximately 84% by RP-HPLC.

[0073] In some embodiments, the liquid compositions of the present disclosure are stored at 2-8°C for 6 months and then subjected to CEX. At least approximately 77% purity, minimal CEX testing after 6 months of storage at 25°C / 60%RH. At least 62% purity, and / or CEX after 6 months of storage at 30°C / 75%RH. Maintain a purity of at least about 50% by [method]. In some embodiments, the liquid composition of the present disclosure maintains a purity of at least about 73% by CEX after storage at 2 - 8°C for 24 months.

[0074] In some embodiments, the liquid composition of the present disclosure, after storage at 2 - 8°C for 6 months, by SEC maintains a purity of at least about 98%, after storage at 25°C / 60%RH for 6 months by SEC at least about 96% purity, and / or after storage at 30°C / 75%RH for 6 months by SEC maintains a purity of at least about 94%. In some embodiments, the liquid composition of the present disclosure maintains a purity of at least about 97% by SEC after storage at 2 - 8°C for 24 months.

[0075] In some embodiments, the liquid composition of the present disclosure, after storage at 2 - 8°C for 6 months, by CE - SDS S (non - reducing conditions) maintains a purity of at least about 97%, after storage at 25°C / 60%RH for 6 months maintains a purity of at least about 95% by CE - SDS (non - reducing conditions), and / or after storage at 30 °C / 75%RH for 6 months maintains a purity of at least about 94 % (preferably at least about 92%) by CE - SDS (non - reducing conditions). In some embodiments, the liquid composition of the present disclosure maintains a purity of at least about 97% by CE - SDS (non - reducing conditions) after storage at 2 - 8°C for 24 months.

[0076] In some embodiments, the liquid composition of the present disclosure, after storage at 2 - 8°C for 6 months, by CE - SDS S (reducing conditions) has less than about 0.57% impurities, after storage at 25°C / 60%RH for 6 months has less than about 1.1% impurities by CE - SDS (reducing conditions), and / or after storage at 30°C / 7 5%RH for 6 months has less than about 1.9% impurities by CE - SDS (reducing conditions) Maintain. In some embodiments, the liquid compositions of the present disclosure can be stored at 2-8°C for 24 months. Maintains an impurity level of less than approximately 0.91% under CE-SDS (non-reducing conditions).

[0077] In some embodiments, the liquid compositions of the present disclosure are C-20 after storage at 2-8°C for 24 months. Inhibition of IL-6 release from A4 chondrocytes reduces relative biological activity by at least approximately 88%. Sex, after storage at 25°C / 60%RH for 6 months, the inhibition of IL-6 release from chondrocytes was reduced. At least approximately 94% relative biological activity, and / or 6 months at 30°C / 75%RH After preservation, inhibition of IL-6 release from chondrocytes resulted in at least approximately 85% of the relative biological Maintain activity.

[0078] antibody concentration IL-17 antibody or its antigen-binding fragment used in the disclosed liquid composition (e.g., Secukinumab is described above. A preferred composition contains secukinumab. The antibody concentration is within the range of approximately 25 mg / ml to approximately 150 mg / ml, and the composition stability is maintained. The inventors determined that it did not have any unintended effects. Therefore, in some embodiments, The antibody in the liquid composition should be at least 25 mg / ml (for example, about 25 mg / ml to about 1 It is present at a concentration of 50 mg / ml. In some embodiments, the concentration of the antibody in the liquid composition is , at least about 25 mg / mL, at least about 50 mg / mL, at least about 75 mg / At a high concentration of at least approximately 100 mg / mL or at least approximately 150 mg / mL in ml Yes. In some embodiments, the concentration of the antibody in the liquid composition is about 25 mg / mL to about 150 mg / mL. This is a high concentration of mg / mL. In one embodiment, the concentration of secukinumab in the liquid composition is It is approximately 25 mg / ml. In one embodiment, the concentration of secukinumab in the liquid composition is approximately 1 The concentration is 50 mg / ml.

[0079] Buffering agent and pH Suitable buffers for the disclosed liquid compositions include, but are not limited to, gluconate buffers. Agents, histidine buffers, citrate buffers, phosphates [e.g., sodium or potassium] [M] buffering agent, succinate [e.g., sodium] buffering agent, acetate buffering agent, Tris buffering agent, Contains glycine, arginine, and combinations thereof. Stability of the liquid composition of secukinumab. The inventors determined that there was no beneficial effect of using succinate or acetate buffers on this matter. Regarding the decomposition products by SEC and CEX acids and the aggregation products by RP-HPLC, Therefore, the citrate buffer was evaluated as beneficial in the composition. Overall, the histidine buffer was evaluated as beneficial. The agent demonstrated advantages in the aggregation and decomposition products by SEC, CEX acid, and RP-B. Therefore, the histidine buffer is for the disclosed stable liquid composition of secukinumab. It is a desirable buffering agent.

[0080] Histidine buffer (for example, approximately 5 mM to approximately 50 mM, for example, approximately 20 mM to approximately 50 mM) , about 5mM, about 10mM, about 15mM, about 20mM, about 25mM, about 30mM, about 35m Concentrations of M, approximately 40 mM, approximately 45 mM, and approximately 50 mM are particularly beneficial. In one embodiment, The stable liquid composition contains approximately 20 mM to 50 mM of histidine buffer. The pH may be in the range of 4.0 to 8.0, and approximately 5.5 to approximately 7.4, for example. For example, approximately 5.2 to 6.2, approximately 5.2 to 5.8, for instance, approximately 5.2, approximately 5.3, approximately 5. 4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6, about 6.2, about 6.4, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4 are common. By increasing the pH from 5.2 to 5.8, a positive trend in stability is observed (SEC-AP, DLS, SEC-DP, ALP-DP, CEX base, R P-HPLC), and the inventors have determined. The overall tests have shown that the ideal composition pH of the disclosed liquid composition is 5.8. Therefore, in one embodiment, the pH of the stable liquid antibody composition is about 5.8.

[0081] Surfactant Suitable surfactants for the disclosed liquid composition include, without limitation, nonionic surfactants, ionic surfactants, zwitterionic surfactants, and combinations thereof. Common surfactants for use in the present invention include, without limitation, sorbitan fatty acid esters (e.g., sorbitan monocaprylate, sorbitan monolaurate, sorbitan monopalmitate), [[ID=2۳]] sorbitan trioleate, glycerin fatty acid esters (e.g., glycerin monocaprylate, glycerin monomyristate, glycerin monostearate), polyglycerin fatty acid esters (e.g., decaglyceryl monostearate, decaglyceryl distearate, decaglyceryl monolinoleate), polyoxyethylene sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan trioleate, polyoxy ethylene sorbitan tristearate), for example, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan trioleate, polyoxyethylene sorbitan tristearate, polyoxy ethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan ​Polyethylene sorbitan tristearate, polyoxyethylene sorbitol fatty acid Tel (for example, polyoxyethylene sorbitol tetrastearate, polyoxyethylene (Isosorbitol tetraoleate), polyoxyethylene glycerol fatty acid ester (e.g.) For example, polyoxyethylene glyceryl monostearate, polyethylene glycol fat Acid esters (e.g., polyethylene glycol distearate), polyoxyethylene Polyoxyethylene lauryl ether (e.g., polyoxyethylene lauryl ether), polyoxyethylene Polyoxypropylene alkyl ether (e.g., polyoxyethylene polyoxypropylene Polyethylene glycol, polyoxyethylene polyoxypropylene propyl ether, polyoxy Polyethylene polyoxypropylene cetyl ether, polyoxyethylene alkylphenyl Polyethylene ethers (e.g., polyoxyethylene nonylphenyl ether), polyoxyethylene Hydrogenated castor oil (e.g., polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil) ), polyoxyethylene beeswax derivatives (e.g., polyoxyethylene sorbitol beeswax), Polyoxyethylene lanolin derivatives (e.g., polyoxyethylene lanolin) and poly Oxyethylene fatty acid amide (e.g., polyoxyethylene stearate amide); C1 0-C18 alkyl sulfates (e.g., sodium cetyl sulfate, sodium lauryl sulfate, etc.) (Sodium leucolate), with an average of 2-4 moles of ethylene oxide units added to the polyoxygenated polyoxygen. Ethylene C10-C18 alkyl ether sulfate (e.g., polyoxyethylene lauryl sulfate) Sodium sulfate and C1-C18 alkyl sulfosuccinate salts (e.g., lau Sodium lyl sulfosuccinate; as well as natural surfactants, such as lecithin. , glycerophospholipids, sphingophospholipids (e.g., sphingomyelin) and C12 ~Contains sucrose esters of C18 fatty acids. The composition contains one of these surfactants or It can include multiple surfactants. Preferred surfactants are poloxamers (e.g., poloxamers) -188) or polyoxyethylene sorbitan fatty acid ester, e.g., polysorbate It is 20, 40, 60, or 80. Polysorbate 80 (Tween80) (for example) Approximately 0.01% to approximately 0.1% (w / v), for example, approximately 0.01% to approximately 0.04% (w / v) For example, approximately 0.01%, approximately 0.02%, approximately 0.04%, approximately 0.06%, approximately 0.08% A concentration of approximately 0.1% is particularly beneficial. In one embodiment, the stable liquid composition is approximately 0 Contains 0.02% (w / v) of polysorbate 80. In one embodiment, a stable liquid composition It contains approximately 0.02% (w / v) of polysorbate 20.

[0082] In liquid compositions lacking surfactants, there is a significant increase in turbidity and an increase in the amount of visible particles. The inventors determined that there was a difference. However, apart from the increase in ALP-DP and RP, No advantage of poloxamer 188 was detected compared to resorbate 20 and 80. Polysorbates 20 and 80 prevent the increase of turbidity, subvisible and visible particles. They showed equivalent effectiveness in both cases. Therefore, polysorbate 20 and 80 are disclosed. It is a preferred surfactant for use in stable liquid compositions.

[0083] Stabilizer Pharmaceutical compositions, particularly those with a tendency for proteins to oxidize and / or aggregate in aqueous solutions. To prevent the oxidation and aggregation of proteins in liquid pharmaceutical compositions with shorter shelf lives, The confirmatory agent provides support. Various analytical methods are used to evaluate the stability of a given composition. For example, in the liquid compositions disclosed herein, the oxidation product (pre-main peak) RP-HPLC can be used to assay the levels, as disclosed herein. SEC can be used to assay the level of aggregation in liquid compositions.

[0084] Stabilizers suitable for use in the disclosed liquid compositions include ionic and nonionic stabilizers. Stabilizers (and combinations thereof), for example, sugar, glycine, sodium chloride, arginine, E DTA, sodium ascorbate, cysteine, sodium bisulfate, sodium citrate It contains methionine and benzyl alcohol. In some embodiments, a liquid pharmaceutical compound The products belong to the first group (e.g., sugars [e.g., trehalose, mannitol], amino acids [e.g., For example, at least one stabilizer from glycine, arginine, and sodium chloride Contains. In some embodiments, the liquid pharmaceutical composition contains the second group (EDTA, ascorbyl). Sodium phosphate, cysteine, sodium bisulfate, sodium citrate, methionine and It contains at least one stabilizer (benzyl alcohol). The stabilizers of the second group are anti- It tends to have oxidizing properties, which means that the oxidation of residues can be reduced by IL-17 antibodies. In a preferred embodiment, the liquid pharmaceutical composition comprises one from the first group and one from the second group. It contains one or two stabilizers.

[0085] For the stabilizers of the first group, nonionic stabilizers are preferred. Suitable nonionic stabilizers These include monosaccharides, disaccharides, and trisaccharides, such as trehalose, raffinose, maltose, and solubyl. It contains vitol or mannitol. The sugar may be a sugar alcohol or an amino sugar. Good. The concentration of the stabilizer in the first group is approximately 175 mM to approximately 350 mM, for example, approximately 200 mM. ~300mM, for example; ~250mM~270mM, for example; ~180~300mM M, approx. 200mM to approx. 225mM, approx. 175mM, approx. 180mM, approx. 185mM, approx. 19 0mM, approx. 195mM, approx. 200mM, approx. 225mM, approx. 250mM, approx. 270mM, 2 75 mM, or approximately 300 mM. Approximately 200 mM to approximately 300 mM (for example, approximately 25 Mannitol at concentrations of 0 mM to approximately 270 mM, and approximately 180 mM to approximately 300 mM (for example, Trehalose at concentrations of approximately 200 mM to 225 mM, and trehalose at concentrations of approximately 130 mM to 150 mM. Sodium chloride at approximately 160 mM concentration, arginine at approximately 160 mM concentration, and glycine at approximately 270 mM concentration. This is particularly beneficial.

[0086] Glycine as a stabilizer (Group 1) has a slight effect on SEC-AP and DLS. Although the inventors determined that this was advantageous, an increase in almost all decomposition products was observed. NaCl as a stabilizer (Group 1) is degraded by SEC and CEX basic mutants. This led to an increase in aggregated products. Trehalose and mannitol are equivalent in beneficial effects. It acted as a confirming agent and was confirmed in almost all analyses, but compared to trehalose, manni Tor showed slightly inferior efficacy (SEC-AP, DLS) and lower water solubility. Therefore, trehalose is the first preferred stabilizer due to its positive effect on degradation products. This is a group of. In one embodiment, the liquid composition contains about 200 mM to about 225 mM trehalose. Contains trehalose. In one embodiment, the liquid composition contains about 200 mM trehalose. In terms of form, the liquid composition contains approximately 225 mM trehalose.

[0087] The inventors found that the second group had a significant effect on the stability of the liquid composition of secukinumab. They determined that, compared to compositions containing stabilizers of the second group, the inventors' experiments showed that the second group was superior. The study showed that the absence of stabilizers in group 2 was inferior (SEC-AP, DLS, turbidity, RP-B). Tetrasodium EDTA and cysteine ​​showed aggregation and degradation products in their respective analytical methods. The addition of cysteine ​​as a stabilizer to the second group showed an increase in storage at 40°C for 4 weeks. Within a short time, freeze-thaw stress and precipitation resulted in a turbid composition. However, analysis revealed The inventors determined that methionine is advantageous in all compositions. Therefore, For the second group of stabilizers, methionine, which also has antioxidant properties, is preferred. The concentration of the stabilizer (e.g., methionine) should be at least about 2.5 mM, for example, about 2.5 to about 20mM, for example, at least about 2.5mM, at least about 5mM, at least about 10mM Or at least about 20 mM (for example, about 2.5 mM, about 5 mM, about 10 mM or about 2 It may be 0 mM). In a preferred embodiment, the liquid pharmaceutical composition is at least from the first group. It contains at least one stabilizer and methionine. In some embodiments, the disclosed liquid The composition contains approximately 5 mM methionine.

[0088] Other excipients The liquid antibody composition of this disclosure may be further excipients, such as additional buffers, salts (e.g., salts) Sodium phosphate, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride (magnesium sulfate and calcium chloride), additional stabilizers, tonicity modifiers (e.g., salts) and amino acids [for example, proline, alanine, L-arginine, asparagine, L-arginine] Spartic acid, glycine, serine, lysine and histidine), glycerol, albutin It may contain amine, alcohol, preservatives, additional surfactants, antioxidants, etc. For a complete discussion of such additional pharmaceutical ingredients, see Gennaro (2000) Remington: The Science and Pr It is available in Act of Pharmacy, 20th edition, ISBN: 0683306472.

[0089] Additional active agents The pharmaceutical products and stable liquid compositions of this disclosure are IL-17 antibodies or their antigen binding cleavage. One, for example, secukinumab, plus one or more other active agents (e.g., psoriasis agents, It may contain (drugs for psoriatic arthritis, drugs for ankylosing spondylitis, drugs for chronic rheumatoid arthritis). To produce a synergistic effect with IL-17 antibody or its antigen-binding fragment, or IL- 17. Minimize side effects caused by antibodies or their antigen-binding fragments, such as secukinumab. For this reason, such additional factors and / or agents may be included in the pharmaceutical composition.

[0090] Psoriasis drugs that may be formulated together with disclosed IL-17 antibodies such as secukinumab Examples include cyclosporine, methotrexate, mycophenolate mofetil, mycopheno Sulfasalates, sulfasalazines, 6-thioguanine, fumarates (e.g., dimethyl fumarate) (and fumarate esters), azathioprine, corticosteroids, leflunomide, ta Chlorimus, T-cell blockers (e.g., Amevive® (Alefacept)) ) and Raptiva® (ephalizumab), tumor necrosis factor alpha (TN F-alpha) blockers (e.g., Enbrel® (etanercept), H Umir(registered trademark) (adalimumab), Remicade(registered trademark) (inflix) Simab and Simponi (registered trademark) (golimumab) and interleukin-1 2 / 23 Blockers (e.g., Stellara® (ustekinumab), tasocitin) It contains nib and briakinumab.

[0091] Formulated together with disclosed IL-17 antibodies such as secukinumab for the treatment of psoriasis. Other good additional psoriasis medications include apremilast, mometazom, voclosporine, and ketoconazole. Neuroskin Forte, Recombinant Human Interleukin-10, Boxross Polin, MK-3222, Tofacitinib, VX-765, MED-I545, Flufe Nazindecanoate, acetomycinofen, bimothiamors cream, doxycycline, Vancomycin, AbGn168, Vitamin D3, RO5310074, Fludaravinca Lucipotriol and hydrocortisone (LEO80190), Focetria ( Valuable MF59 adjuvant-added vaccine, tgAAC94 gene therapy vector, capsaicin Syn, Psirelax, ABT-874 (anti-IL-12), IDEC-114, MED I-522, LE29102, BMS587101, CD2027, CRx-191, 8 -Methoxypsoralen or 5-Methoxypsoralen, Bicillin LA, LY 2525623, INCB018424, LY2439821, CEP-701, CC- 10004, certolizumab (CZP), GW786034 (pazopanib), doxycycline Crinklecuminoid C3 complex, NYC0462, RG3421, hOKT3 gamma 1 (Ala-Ala), BT061, Teprizumab, Chondroitin Sulfate, CNTO127 5. Monoclonal antibodies against IL-12p40 and IL-23p40 subunits , BMS-582949, MK0873, MEDI-507, M518101, ABT- 874, AMG827, AN2728, AMG714, AMG139, PTH(1-34 ), U0267 form, CNTO1275, QRX-101, CNTO1959, LE O22811, Imiquimod, CTLA4Ig, Alga Dunaliella baldawir (La Bardawil), pioglitazone, pimecrolimus, ranibizumab, zidovudine CDP8 70 (Certolizumab pegol), Onercept (r-hTBP-1), ACT-128 800, 4,4-dimethyl-benzoiso-2H-selenazine, CRx-191, CRx- 197, Doxel, Calciferol, LAS41004, WBI-1001, Tacrolim S, RAD001, rapamycin, rodiglitazone, pioglitazone, ABT-874, Aminopterin, AN2728, CD2027, ACT-128800, Mometazol Furoate N, CT327, Clobetasol + LCD, BTT1023, E6201, Topical Vitamin B12, IP10.C8, BFH772, LEO22811, Fluphenazine, MM-0 93, Clobex, SCH527123, CF101, SRT2104, BIRT25 84, CC10004, Tetrathiomolybdate, CP-690, 550, U0267, ASP015K, VB-201, Acitretin (also known as U0279), RWJ-4 45380, Clobetasol propionate, Botulinum toxin type A, Alefacept, El Rotinib, BCT194, roflumilast, CNTO1275, halobetazole, ILV -094, CTA018 cream, COL-121, MEDI-507, AEB071 It is included.

[0092] Additional psoriasis treatments that may be formulated together with disclosed IL-17 antibodies such as secukinumab. The drugs include IL-6 antagonists, CD20 antagonists, and CTLA4 antagonists. T, IL-17 Antagonist, IL-8 Antagonist, IL-21 Antagonist, IL-22 Antagonist, VGEF Antagonist, CXCL Antagonist, MMP Antagonists, Defensin Antagonists, IL-1 Beta Antagonists and I Includes L-23 antagonists (e.g., receptor decoys, antagonist antibodies, etc.) Preferred psoriasis medications that may be formulated together with secukinumab include DMARDs (e.g., MTX and cyclosporine), IL-12 / -23 antagonists (e.g., Usteck Numab), CTLA-4 antagonist (e.g., CTLA4-Ig), and TNF-A He is a rufa antagonist.

[0093] In a broader sense, it may be formulated together with disclosed IL-17 antibodies such as secukinumab. Drugs for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis are particularly immunosuppressive. Antidotes, disease-modifying agents (DMARDs), pain management drugs, steroids, non-steroidal anti-inflammatory drugs (NSAIDs), This may include cytokine antagonists, anabolic agents, bone antiretroglycerides, or combinations thereof. Representative drugs include cyclosporine, retinoids, corticosteroids, and propionic acid derivatives. Body, acetic acid derivatives, enolic acid derivatives, fenamic acid derivatives, Cox-2 inhibitors, Lumiracococcus Sibu, ibuprofencholine, magnesium salicylate, fenoprofen, salsalate Difunisal, tolmetin, ketoprofen, flurbiprofen, oxaprozin, i Ndomethacin, sulindac, etodolac, ketrolac, nabumetone, naproxen, val Decoxib, etoricoxib, MK0966; rofecoxib, acetominofen, cele Coxib, diclofenac, tramadol, piroxicam, meloxicam, tenoxicam , droxicam, lornoxicam, isoxicam, mefanamic acid, meclofenamic acid, f Lufenamic acid, tolfenamic acid, valdecoxib, parecoxib, etodolac, indomene Tacin, aspirin, ibuprofen, firocoxib, methotrexate (MTX), Antimalarial drugs (e.g., hydroxychloroquine and chloroquine), sulfasalazine, Leflunomide, azathioprine, cyclosporine, gold salt, minocycline, cyclophosph Amid, D-penicillamine, minocycline, auranofin, tacrolimus, myocrypha Syn, chlorambucil, TNF alpha antagonist (for example, TNF alpha antagonist) (Gonist or TNF-alpha receptor antagonist), for example, adalimumab (Hum ira (registered trademark), Etanercept (Enbrel (registered trademark)), Inflixima Remicade (registered trademark); TA-650, Certolizumab pegol (Cim zia(registered trademark); CDP870), golimumab (Simponi(registered trademark); CN TO148), Anakinra (Kineret®), Rituximab (Ritux an(registered trademark); MabThera(registered trademark)), Abatacept (Orencia( (Registered Trademark), Tocilizumab (RoActemra / Actemra(Registered Trademark)), I Integrin antagonist (TYSABRI® (natalizumab)), IL-1 Antagonist (ACZ885 (Ilaris)), Anakinra (Kineret (Registered) Trademarks))), CD4 Antagonist, IL-23 Antagonist, IL-20 Antagonist St, IL-6 antagonist, BlyS antagonist (for example, Ataccept, Be nlysta (registered trademark) / LymphoStat-B (registered trademark) (belimumab), p38 inhibitors, CD20 antagonists (ocrelizumab, ofatumumab (Arzer) ra(registered trademark), interferon-gamma antagonist (fontrizumab), Prednisolone, prednisone, dexamethasone, cortisol, cortisone, hydroco Lutisone, methylprednisolone, betamethasone, triamcinolone, beclometazom Fludrocothion, deoxycorticosterone, aldosterone, SB-681323, Rob 803, AZD5672, AD 452, SMP 114, HZT-501, C P-195, 543, Doxycycline, Vancomycin, CRx-102, AMG10 8. Pioglitazone, SBI-087, SCIO-469, Cura-100, Oncox Syn+Biucid, TwHF, PF-04171327, AZD5672, Methoxsalen, ARRY-438162, Vitamin D-ergocalciferol, Milnacipran, Pak Ritaxel, GW406381, logiglitazone, SC12267 (4SC-101); LY2439821, BTT-1023, ERB-041, ERB-041, KB003 , CF101, ADL5859, MP-435, ILV-094, GSK706769, GW856553, ASK8007, MOR103, HE3286, CP-690,55 0 (Tasocitinib), REGN88 (SAR153191), TRU-015, BMS- 582949, SBI-087, LY2127399, E-551S-551, H-55 1. GSK3152314A, RWJ-445380, Tacrolimus (Prograf( Registered trademarks)), RAD001, Rapamun, Rapamycin, Fostamatinib, Fentanyl Lu, XOMA 052, CNTO 136, JNJ 38518168, Imatinib, A TN-103, ISIS 104838, folic acid, folate, TNFα quinoid, MM-09 3. Type II collagen, VX-509, AMG 827 70, masitinib (AB101) 0), LY2127399, Cyclosporine, SB-681323, MK0663, NN C 0151-0000-0000, ATN-103, CCX 354-C, CAM30 01, LX3305, Setorelix, MDX-1342, TMI-005, MK08 73, CDP870, tranilast, CF101, mycophenolic acid (and its estates) (Lu), VX-702, GLPG0259, SB-681323, BG9924, ART6 21, LX3305, T-614, Fostamatinib disodium (R935788), CCI-779, ARRY-371797, CDP6038, AMG719, BMS-5 82949, GW856553, Logiglitazone, CH-4051, CE-224, 53 5, GSK1827771, GW274150, BG9924, PLX3397, TAK -783, INCB028050, LY2127399, LY3009104, R788 Curcumin (Longvida®), Rosuvastatin, PRO283698, A MG 714, MTRX1011A, Maraviroc, MEDI-522, MK0663, S TA 5326 Mesylate, CE-224, 535, AMG108, BG00012 (BG -12; Biogen), Lamipril, VX-702, CRx-102, LY21891 02, SBI-087, SB-681323, CDP870, Milnashiplan, PD03 60324, PH-797804, AK106-001616, PG-760564, P LA-695, MK0812, ALD518, Cobiprostone, Somatropin, tgAA C94 gene therapy vector, MK0359, GW856553, ezomeprazole, eve Lolimus, trastuzumab, anabolic and antiresorbing agents (e.g., PTH, bisphosphonates) (e.g., zoledronic acid), JAK1 and JAK2 inhibitors, pan-JAK inhibitors, for example Tetracyclic pyridone 6 (P6), 325, PF-956980, Sclerostin antagonistis (For example, WO09047356, WO2000 / 32773, WO20061020) 70. U.S. Patent Application Publication No. 20080227138, U.S. Patent Application Publication No. 201000 Patent No. 28335, U.S. Patent Application Publication No. 20030229041, WO200500315 8, WO2009039175 WO2009079471, WO03106657, W O2006119062, WO08115732, WO2005 / 014650, WO2 005 / 003158, WO2006 / 119107, WO2008 / 061013, W O2008 / 133722, WO2008 / 115732, U.S. Patent No. 7592429 This information is disclosed in U.S. Patent No. 7,879,322 and U.S. Patent No. 7,744,874, and is available for reference. By reference, the whole of the disclosed methods, pharmaceutical compositions, kits and The preferred anti-sclerostin antibody and its antigen-binding moiety for use in the application of WO 09047356 (equivalent to U.S. Patent No. 7879322), WO06119107 (United States Patent No. (Equivalent to Japanese Patent No. 7872106 and U.S. Patent No. 7592429) and WO0811 [Found in 5732 (equivalent to U.S. 7,744,874)], denosumab, IL-6 Antagonist, CD20 Antagonist, CTLA4 Antagonist, IL-8 Antagonist Nist, IL-21 Antagonist, IL-22 Antagonist, Integrin Antagon Nist (Tysarbri(registered trademark)(natalizumab)), VGEF antagonist, CXCL antagonist, MMP antagonist, Defensin antagonist, IL- 1 Antagonist (including IL-1 Beta Antagonist) and IL-23 Antagonist This includes stimulants (e.g., receptor decoys, antagonist antibodies, etc.), such as secukinumab. Preferred rheumatoid arthritis agents which may be formulated together with the disclosed IL-17 antibody These include DMARDs, such as methotrexate and TNF alpha antagonists. Preferred tonicity which may be formulated together with disclosed IL-17 antibodies such as secukinumab. Drugs for spondylitis include NSAIDs, DMARDs, such as sulfasalazine, and TNF-AL It is a phantagonist. It is formulated together with disclosed IL-17 antibodies such as secukinumab. Preferred psoriatic arthritis medications that may be modified include DMARDs, such as cyclosporine, CT LA-4 blockers (e.g., CLTA4-Ig), alefacept and TNF-A1 He is an antagonist.

[0094] Those skilled in the art will know the above drug for co-composition with a disclosed IL-17 antibody such as secukinumab. It allows you to determine the appropriate dosage of the medication.

[0095] In this specification, approximately 20 mg / ml to approximately 175 mg / ml (for example, approximately 25 mg / ml) 1.5 to approximately 150 mg / ml of the IL-17 antibody or its antigen binding cleavage disclosed herein. One component (e.g., secukinumab), and approximately 10 mM to 30 mM of buffering agent (e.g., histidine). pH 5.2 to approximately 6.0, stabilizer (e.g., trehalose) at approximately 200 mM to 225 mM. , approximately 0.02% surfactant (e.g., polysorbate 80) and approximately 2.5 mM to approximately 2 A stable liquid pharmaceutical composition containing 0 mM methionine is disclosed.

[0096] In some embodiments, the concentration of methionine in the liquid pharmaceutical composition of the disclosed pharmaceutical is approximately The concentration is 2.5 mM, approximately 5 mM, approximately 10 mM, or approximately 20 mM, preferably approximately 5 mM. In some embodiments, the pH of the liquid pharmaceutical composition is approximately 5.8. In some embodiments, disclosures are made. The concentration of secukinumab in the composition is approximately 25 mg / ml or approximately 150 mg / ml. In some embodiments, the liquid pharmaceutical composition includes a histidine buffer, a citrate buffer, and acetic acid. The buffer includes a buffer selected from the group consisting of buffers and succinate buffers. In some embodiments, The liquid pharmaceutical composition uses a histidine buffer at a concentration of approximately 20 mM. (Some embodiments) The liquid pharmaceutical composition then contains a surfactant selected from polysorbate and poloxamer. Includes. In some embodiments, the liquid pharmaceutical composition includes polysorbate 80, polysorbate Further comprising surfactants selected from 20 and poloxamer 188. Some embodiments The liquid pharmaceutical composition is preferably about 0.01% (w / v) to about 0.04% (w / v). It contains polysorbate 80 at a concentration of approximately 0.02% (w / v). In some embodiments, liquid The pharmaceutical composition contains polysorbate 20 at a concentration of approximately 0.02% (w / v). In terms of application form, the liquid pharmaceutical composition contains mannitol, sodium chloride, trehalose, and argy It contains a stabilizer selected from the group consisting of ninHCl and glycine. In some embodiments, it contains a stabilizer selected from the group consisting of ninHCl and glycine. The liquid pharmaceutical composition should be approximately 180 mM to approximately 300 mM, preferably approximately 200 mM or approximately 2 Contains trehalose at a concentration of 25 mM.

[0097] In this specification, a container having a headspace in which the oxygen content is less than approximately 12% A vessel, and a liquid pharmaceutical composition disposed within the said vessel, comprising approximately 5.2 to approximately 6.2 It has a pH of approximately 20 mg / ml to approximately 175 mg / ml (for example, approximately 25 mg / ml to approximately 150 mg / ml) of the IL-17 antibody or its antigen-binding fragment disclosed herein (e.g., For example, it contains secukinumab and approximately 2.5 to 20 mM L-methionine, and is freeze-dried. A pharmaceutical product containing a liquid pharmaceutical composition that has not been restored from a physical object is disclosed.

[0098] In some embodiments, the concentration of methionine in the liquid pharmaceutical composition of the disclosed pharmaceutical is approximately The concentration is 2.5 mM, approximately 5 mM, approximately 10 mM, or approximately 20 mM, preferably approximately 5 mM. In the embodiment, the oxygen content in the headspace of the disclosed pharmaceutical product is less than about 10%. For example, less than about 8%, preferably less than about 6%. In some embodiments, the disclosed pharmaceutical The liquid pharmaceutical composition of the product has a pH of approximately 5.8. In some embodiments, the disclosed pharmaceutical The concentration of secukinumab in the drug product is approximately 25 mg / ml or approximately 150 mg / ml. In one embodiment, the liquid pharmaceutical composition of the disclosed pharmaceutical product is a histidine buffer, citrate The buffer further comprises a buffer selected from the group consisting of acid buffers, acetic acid buffers, and succinate buffers. In some embodiments, the liquid pharmaceutical composition of the disclosed pharmaceutical product is approximately 10 mM to approximately 30 mM. A buffer with a concentration of mM is used. In some embodiments, the liquid pharmaceutical composition of the disclosed pharmaceutical product The substance uses a histidine buffer at a concentration of approximately 20 mM. In some embodiments, this is disclosed. The liquid pharmaceutical composition of the pharmaceutical product is an interface selected from polysorbate and poloxamer. It further contains a fertilizer. In some embodiments, the liquid pharmaceutical composition of the disclosed pharmaceutical product is poly Surface activity selected from Sorbate 80, Polysorbate 20, and Poloxamer 188 The agent further comprises. In some embodiments, the liquid pharmaceutical composition of the disclosed pharmaceutical product is about 0. Concentration of 0.01% (w / v) to approximately 0.04% (w / v), preferably approximately 0.02% (w / v) The invention further comprises polysorbate 80. In some embodiments, the disclosed pharmaceutical product is liquid The drug composition further contains polysorbate 20 at a concentration of approximately 0.02% (w / v). In the embodiments, the liquid pharmaceutical composition of the disclosed pharmaceutical product is mannitol, sodium chloride. A stabilizer selected from the group consisting of trehalose, arginine HCl, and glycine is used. It also includes. In some embodiments, the liquid pharmaceutical composition of the disclosed pharmaceutical product is approximately 180 mM. A trehalose solution with a concentration of approximately 300 mM, preferably approximately 200 mM or approximately 225 mM, is used. These include. In some embodiments, the container of the disclosed pharmaceutical product is a cartridge, syringe, etc. It is a pen or vial.

[0099] In this specification, a container having a headspace in which the oxygen content is less than approximately 6% , and a liquid pharmaceutical composition disposed in the container, comprising approximately 20 mg / ml to approximately Disclosed herein: 175 mg / ml (for example, approximately 25 mg / ml to approximately 150 mg / ml) The IL-17 antibody or its antigen-binding fragment (e.g., secukinumab), approximately 10 mM~ Approximately 30 mM histidine pH 5.8, approximately 200 mM to approximately 225 mM trehalose, approximately 0 It contains 0.02% polysorbate 80 and approximately 2.5 mM to 20 mM methionine. A pharmaceutical product is disclosed that includes a liquid pharmaceutical composition that has not been restored from a freeze-dried product.

[0100] In some embodiments, the pharmaceutical product contains approximately 25 mg / ml of secukinumab and approximately 225 mg / ml of secukinumab. Contains trehalose M. In some embodiments, the pharmaceutical product contains approximately 150 mg / ml of sec. It contains kinumab and approximately 200 mM trehalose. In some embodiments, the disclosed medical The containers for pharmaceutical products are cartridges, syringes, pens, or vials.

[0101] In some embodiments, the pharmaceutical product contains at least about 75 mg to about 300 mg per unit dose. Delivery of IL-17 antagonists (e.g., IL-17 antibodies, e.g., secukinumab) It has a sufficient amount of IL-17 antagonist to enable this. In some embodiments, The pharmaceutical product is sufficient to allow delivery of at least approximately 10 mg / kg per unit dose. Having a certain amount of IL-17 antagonist (e.g., IL-17 antibody, e.g., secukinumab) In some embodiments, the pharmaceutical product contains approximately 10 mg / kg of IL-17 per unit dose. This enables intravenous delivery of antagonists (e.g., IL-17 antibodies, e.g., secukinumab). It is formulated in a dosage. In some embodiments, the pharmaceutical product contains at least per unit dose. Approximately 75 mg to approximately 300 mg of IL-17 antagonist (for example, IL-17 antibody, for example) It is formulated in a dosage that allows for subcutaneous delivery of secukinumab.

[0102] Method for preparing liquid compositions and pharmaceutical products Methods for preparing the pharmaceutical products and liquid compositions of this disclosure are also described herein. This method helps reduce the oxidation of the disclosed IL-17 antibody. In short, the liquid composition The substance is a desired excipient (e.g., a stabilizer from group 1 (e.g., trehalose), from group 2) Stabilizer (methionine), surfactant (e.g., PS80), buffer (e.g., histidine) )) with IL-17 antibody or its antigen-binding fragment (e.g., secukinumab) and the desired concentration (For example, approximately 25-150 mg / ml secukinumab, approximately 20 mM histidine pH 5.8) Approximately 200 mM to approximately 225 mM trehalose, approximately 0.02% polysorbate 80 and approximately Adjust the concentration to 2.5 mM to approximately 20 mM methionine and the pH (for example, approximately pH 5.8). It is prepared by the following. Next, this liquid composition is placed in a selected container (e.g., vial). It is placed inside a syringe or cartridge (for example, for an automatic infusion device). The oxygen content during pacing should be at the desired level (e.g., less than approximately 12%, less than 10%, less than approximately 8%). The concentration is adjusted to less than approximately 6%, but this is done before filling the container with the liquid composition. This may occur while filling the container with the body composition, or while stowing / sealing the container.

[0103] In this specification, a pH of approximately 5.2 to approximately 6.2 and a concentration of approximately 20 mg / ml to approximately 175 mg / ml are used. g / ml (for example, approximately 25 mg / ml to approximately 150 mg / ml) of the I disclosed herein L-17 antibody or its antigen-binding fragment (e.g., secukinumab), and approximately 2.5 mM ~ Prepare a liquid composition containing approximately 20 mM methionine; in a container with headspace. Placing the liquid composition within; and maintaining an oxygen content of approximately 12% in the headspace. A method for reducing the oxidation of secukinumab is disclosed, including the following adjustments.

[0104] In some embodiments of the disclosed method, adjustment step c) uses an inert gas to This is done by purging the file space. In some embodiments of the disclosed method The inert gas is nitrogen or argon. In some embodiments of the disclosed method, The concentration of methionine in the liquid composition is approximately 2.5 mM, approximately 5 mM, approximately 10 mM, or approximately 20 mM. The concentration is mM, preferably about 5 mM. In some embodiments of the disclosed method, the headspace The oxygen content in the solution is adjusted to less than approximately 10%, for example, less than approximately 8%, preferably less than approximately 6%. In some embodiments of the disclosed method, the liquid composition has a pH of about 5.8. In some embodiments of the method shown, the concentration of secukinumab in the liquid composition is about 25 mg The amount is / ml or approximately 150 mg / ml. In some embodiments of the disclosed method, the container is These are cartridges, syringes, pens, or vials.

[0105] Methods for using pharmaceutical products and liquid compositions The disclosed pharmaceutical products and liquid compositions are for use in, for example, autoimmune diseases (e.g., psoriasis, chronic diseases). It is used for the treatment of patients with conditions such as rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. The appropriate dosage is, for example, the specific IL-17 antibody or its antigen-binding fragment used. For example, secukinumab, host, mode of administration, and the nature and severity of the condition being treated, It naturally varies depending on the nature of the treatments the patient has received so far. Ultimately, the doctor in charge... The healthcare provider determines the amount of IL-17 antibody to treat each individual patient. In some embodiments, the healthcare provider administers a low dose of IL-17 antibody. The patient's response can be observed. In other embodiments, IL-17 is administered to the patient. The initial dose(s) of the antibody is high, and then the dose is lowered until signs of relapse appear. . Administer a larger dose of IL-17 antibody until the patient achieves the optimal therapeutic effect. This is possible, and the dosage is generally not increased further.

[0106] The timing of administration is also known as the "baseline," and the active compound (e.g., sec It is generally measured from the first day of administration of kinumab. However, as shown in Table 2 below, different results are available. Different healthcare providers use different nomenclature.

[0107] [Table 2]

[0108] Notably, week 0 is sometimes referred to as week 1 by some healthcare providers. Yes, and day 0 is sometimes referred to as day 1 by some healthcare providers. For example, different doctors may refer to the same dosing schedule, but the dosage may vary, such as the dosage being 21 / 3 weeks. It is administered on day 1, during week 3 / day 22, during week 4 / day 21, during week 4 / day 22. It may be called [this]. For consistency, in this specification, the first week of administration is referred to as week 0. The first day of administration is called Day 1. However, this nomenclature is used simply for consistency. Those skilled in the art will understand that this should not be interpreted as limiting, that is, a physician can specify Regardless of whether you refer to the week as "week 1" or "week 2," the weekly administration of IL-17 antibody This involves providing the weekly dose of the antigen-binding fragment, for example, secukinumab. As an example of naming using the rule, five doses of secukinumab administered weekly are given during week 0 (e.g.) For example, around day 1), during the first week (for example, around day 8), during the second week (for example, around day 15) ), provided during the third week (for example, around day 22) and during the fourth week (for example, around day 29). It is possible. As long as it is provided in the appropriate week, the dose does not need to be provided at the exact time. Without it, for example, the planned dose for approximately day 29, for example, day 24 to day 34, for example, 3 It is understood that it may be provided on day 0.

[0109] In some embodiments, the disclosed methods and uses include 1, 2, 3, 4, 5, 6, 7, Initial (sometimes called "induction") lasts for 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. A regimen called "initial regimen" is used. In some embodiments, the initial regimen is 0, 1, 2 and medication is used during the third week. In other embodiments, the initial regimen is 0, 1, Medication is used during periods 2, 3, 4, 8, and 12 weeks. In some embodiments, the initial dose Dimen is a small amount of IL-7 antibody, such as secukinumab, in doses of about 150 mg to 300 mg. (For example, 1, 2, 3, 4, 5, 6, 7, preferably 4 or 5) doses, for example 150 ml Approximately 4 or 5 doses of g or 300 mg (preferably 5 doses of approximately 150 mg to approximately 300 mg) This includes administering a certain amount. In further embodiments, the initial dose may be weekly, twice a week, every other week, or It is delivered monthly [every four weeks], preferably weekly. In some embodiments, 0, 1, 2 and In the initial dose administered in the third week, an IL-17 antibody, such as secukinumab 150mg, is administered by subcutaneous injection. g or 300 mg is administered.

[0110] For maintenance regimens, the dose is administered monthly (also called "monthly" administration) (i.e., every 4 weeks). Every 28 days (i.e., every 28 days), every 2 months (i.e., every 8 weeks, i.e., every 56 days) Provided daily or every three months (i.e., every 12 weeks, i.e., every approximately 84 days). It is possible. In some embodiments, the maintenance regimen begins after week 12. In this embodiment, the maintenance regimen begins after the third week. The initial dose of the maintenance regimen is It is administered on the day usually measured from the final dose of the introductory regimen. Therefore, for example, the induction dose If the final dose of Dimen is administered during week 12, then a maintenance regimen of every four weeks is given monthly. The initial dose, as part of the treatment regimen, is delivered during week 16 and is part of the maintenance regimen every two months. The initial dose is delivered during week 20 and as part of a 3-month maintenance regimen. The first dose is delivered during the 24th week, etc. In some embodiments, the maintenance regimen The dosage of IL-17 antibody or its antigen-binding fragment, such as secukinumab, is administered weekly for two weeks. This includes administering it every, every four weeks, every other month, four times a year, twice a year, or annually. In some embodiments, the maintenance regimen is administered monthly (every four weeks). The first dose of the maintenance regimen is delivered between weeks 4 and 16. (Some embodiments) So, the maintenance regimen is an IL-17 antibody or its antigen-binding fragment, for example, secukinumab. Administer a dose of approximately 150 mg to 300 mg, for example, approximately 150 mg or approximately 300 mg. This includes.

[0111] IL-17 antibody between load regimen, induction regimen and / or maintenance regimen, for example Secukinumab is delivered via the subcutaneous route, for example, approximately 75 mg to approximately 300 mg (for example, approximately 50 mg). mg, about 75mg, about 100mg, about 125mg, about 150mg, about 175mg, about 20 (0mg, approximately 225mg, approximately 250mg, approximately 275mg, approximately 300mg, approximately 325mg) Drug delivery, intravenous route, for example, approximately 1 mg / kg to approximately 50 mg / kg (for example, approximately 1 mg / kg) g / kg, approx. 3mg / kg, approx. 10mg / kg, approx. 30mg / kg, approx. 40mg / kg, Delivery of a dosage of approximately 50 mg / kg, or any other route of administration (e.g., intramuscular, This can be done by im). In a preferred embodiment, the dose of IL-17 antibody is s. c. It will be delivered.

[0112] In a preferred embodiment, the patient receives initial doses at weeks 0, 1, 2, and 3, and then for the following 4 weeks... With monthly maintenance doses initiated at the eye, approximately 150 mg to approximately 300 mg (for example, approximately 150 mg) IL-17 antibody or its antigen-binding fragment in doses of mg or approximately 300 mg, for example, sec Kinumab is administered by subcutaneous injection. In this regimen, the dosage is 0, 1, 2, 3, 4 It is administered during the 8th, 12th, 16th, and 20th weeks, etc. The 300mg dose is 150 It may be administered as two subcutaneous injections of mg each.

[0113] In this specification, autoimmune diseases (e.g., psoriasis, rheumatoid arthritis, ankylosing spondylitis) are referred to as autoimmune diseases. A method for treating psoriatic arthritis, and for patients who need it, 0, 1, 2 and The initial dose is administered in the third week, followed by monthly maintenance doses starting in the fourth week, totaling approximately 150 mg. ~ A dose of IL-17 antibody of approximately 300 mg (for example, approximately 150 mg or approximately 300 mg) or administering the antigen-binding fragment, for example, secukinumab, by subcutaneous injection, IL -17 Antibodies or their antigen-binding fragments, such as secukinumab, are present in doses of approximately 20 mg / ml to approximately 17 Disclosed herein are 5 mg / ml (for example, approximately 25 mg / ml to approximately 150 mg / ml) IL-17 antibody or its antigen-binding fragment (e.g., secukinumab), approximately 5.2 to 6. A pharmaceutical composition comprising a buffer with a pH of 2 and approximately 2.5-20 mM methionine. Provided as a part, a method is disclosed in which the liquid pharmaceutical composition is not restored from a lyophilized product. .

[0114] In this specification, autoimmune diseases in patients (e.g., psoriasis, rheumatoid arthritis, IL-17 antibody for the manufacture of pharmaceuticals for the treatment of ankylosing spondylitis, psoriatic arthritis (for example) For example, the use of secukinumab, and the drug, is less than approximately 12% (for example, less than approximately 10%). Each headspace has an oxygen content of less than 8%, approximately less than 7%, approximately less than 6%, etc. A container, and a liquid pharmaceutical composition to be placed inside the container, are formulated to include the above. The composition is approximately 20 mg / ml to approximately 175 mg / ml (for example, approximately 25 mg / ml to approximately 1 50 mg / ml) of the IL-17 antibody or its antigen-binding fragment disclosed herein (e.g. (For example, secukinumab), a buffer with a pH of approximately 5.2 to 6.2, and approximately 2.5 to 20 The liquid pharmaceutical composition contains mM methionine and is not reconstituted from lyophilized material. It will be shown.

[0115] Kits containing pharmaceutical products and liquid compositions This disclosure also includes kits for treating various autoimmune diseases (e.g., psoriasis). In a broad sense, such a kit includes at least one of the disclosed pharmaceutical product or liquid composition. Includes instructions for use. The instructions are part of a drug administration regimen for a stable liquid composition. Appropriate techniques for providing these to patients are disclosed. These kits contain a liquid composition Autoimmune diseases for delivery along with other substances (i.e., simultaneously or sequentially [before or after]) For example, it may also contain additional medications (as listed above) to treat conditions such as psoriasis.

[0116] In this specification, kits for the treatment of patients with autoimmune diseases (e.g., psoriasis) a) The oxygen content is less than approximately 12% (for example, less than approximately 10%, less than approximately 8%, or about 7%) a) a container having a headspace of less than, less than approximately 6%, etc. A liquid pharmaceutical composition that contains approximately 20 mg / ml to approximately 175 mg / ml (for example, approximately IL-17 antibody or so disclosed herein (25 mg / ml to approximately 150 mg / ml) ii) an antigen-binding fragment (e.g., secukinumab); ii) a slow-release agent with a pH of approximately 5.2 to 6.2. Amphetamine; and iii) containing approximately 2.5-20 mM methionine, restored from freeze-dried material. liquid pharmaceutical compositions that have not been prepared; and c) instructions for administering the liquid pharmaceutical composition to a patient. A kit containing the following is disclosed. In some embodiments, the container includes a pen, a pre-filled syringe, and an auto-injector. It is an input device or vial.

[0117] General In some embodiments of this disclosure, the IL-17 antibody or its antigen-binding fragment is derived from the following: Selected from the group: a) Leu74, Tyr85, His86, Met87, Asn8 8, Val124, Thr125, Pro126, Ile127, Val128, His IL-17 antibodies that bind to IL-17 epitopes including 129; b) Tyr43, Ty It binds to IL-17 epitopes including r44, Arg46, Ala79, and Asp80. IL-17 antibody; c) IL-17 homodimeric with two mature IL-17 protein chains - is bound to an epitope, and the epitope has Leu74, Tyr85, and Hi on one chain. s86, Met87, Asn88, Val124, Thr125, Pro126, Ile 127, Val128, His129 on the other chain, Tyr43, Tyr44, Arg 46, Ala79, Asp80, and IL-17 antibodies; d) two mature IL-17 tannins The epitope of the IL-17 homodimer having a protein chain is bound to the epitope on one side. On the chain are Leu74, Tyr85, His86, Met87, Asn88, Val124 , Thr125, Pro126, Ile127, Val128, His129, the other IL-1 contains Tyr43, Tyr44, Arg46, Ala79, and Asp80 on its chain. 7 antibodies, at approximately 100-200 pM (for example, measured with Biacore®). (When) K D IL-1 has an in vivo half-life of approximately 23 to 30 days. 7. IL-17 antibody containing a binding molecule and an antibody selected from the group consisting of e) and the following: )Immunoglobulin heavy chain variable domain (V) containing the amino acid sequence shown in Sequence ID No. 8 H );ii )Immunoglobulin light chain variable domain (V) containing the amino acid sequence shown in SEQ ID NO: 10 L );i ii) Immunoglobulin V containing the amino acid sequence shown in SEQ ID NO: 8 H Domain and sequence number Immunoglobulin V containing the amino acid sequence shown in 10 L Domain; iv) Sequence ID 1, Sequence No. Immunoglobulin V containing the hypervariable regions shown in sequence numbers 2 and 3. H domain; v) Immunoglobulins containing the hypervariable regions shown in sequence 4, 5, and 6. V L Domain; vi) Hypervariable region shown in Sequence ID No. 11, Sequence ID No. 12, and Sequence ID No. 13 Immunoglobulin V containing the following in order H Domain; vii) Sequence ID 1, Sequence ID 2 and Sequence ID Immunoglobulin V containing the hypervariable regions shown in number 3 in order H Domain and Sequence ID No. 4, Immunoglobulin V containing the hypervariable regions shown in sequence numbers 5 and 6. L domain ; and viiii) the hypervariable regions shown in Sequence ID No. 11, Sequence ID No. 12 and Sequence ID No. 13 Immunoglobulin V containing the following in order H Domain, as well as Sequence ID 4, Sequence ID 5, and Sequence Number Immunoglobulin V containing the hypervariable regions shown in No. 6 in order L Domain; ix) Sequence ID 15 Immunoglobulin heavy chains containing the amino acid sequence shown (with or without C-terminal lysine); x )Immunoglobulin light chain containing the amino acid sequence shown in SEQ ID NO: 14; xi)Show Immunoglobulin heavy chains containing amino acid sequences (with or without C-terminal lysine) and An immunoglobulin light chain comprising the amino acid sequence shown in SEQ ID NO: 14. In some embodiments of this disclosure The IL-17 antibody or its antigen-binding fragment is a human antibody, preferably secukinumab. ru.

[0118] Details of one or more embodiments of this disclosure are set forth in the accompanying description above. Any methods and materials similar to or equivalent to those described herein may be used in the implementation of this disclosure. Alternatively, methods and materials that can be used in testing are described below. Other features, purposes, and advantages of the present invention will become apparent from this description and the claims. In the details and attached claims, the singular form is plural unless the context clearly indicates otherwise. Includes numerical forms. Unless otherwise specified, all technical and scientific terms used herein are This disclosure has the same meaning as would be commonly understood by a person skilled in the art. All patents and publications used are incorporated by reference. The following examples are of the disclosure. These examples are presented to more fully illustrate preferred embodiments. In some cases, the scope of the disclosed patentable subject matter is limited by the attached claims. It should not be interpreted in that way. [Examples]

[0119] The examples and embodiments described herein are for illustrative purposes only and in light of them Various modifications and changes are suggested to technicians in the art, and they reflect the spirit and purpose of this application. It is understood that this falls within the scope of the subject and the attached claims.

[0120] These examples describe the development of a stable liquid composition of secukinumab. The data are as follows: The pH of the composition and the selection of stabilizers from the second group had a significant impact on the stability of the liquid composition. This demonstrates the effect of headspace oxygen content on the stability of the liquid composition. It also shows the antibody concentration, the choice of surfactant, the choice of stabilizer in the first group, and the choice of buffer system. The impact on qualitative aspects was smaller. Therefore, the variable that has a greater impact on stability is the one that is less affected. When considering this, the disclosed pharmaceutical product is a head product in which the oxygen content is less than approximately 12%. A container having a base (e.g., PFS or vial) and disposed inside the container The liquid pharmaceutical composition comprises a pH of approximately 5.2 to approximately 6.2 and approximately 20 mg Secukinumab at concentrations of 175 mg / mL to 175 mg / mL, and L-methods of approximately 2.5 to 20 mM. Contains thionine. When considering variables that have a large and small effect on stability, disclosed Pharmaceutical products are containers that have a headspace in which the oxygen content is less than approximately 12% (e.g.) For example, a PFS (or vial) and a liquid pharmaceutical composition placed inside the container. The composition has a pH of approximately 5.2 to approximately 6.2 and contains secukinumab; a buffer; a surfactant. Contains stabilizers and approximately 2.5 to 20 mM L-methionine.

[0121] Based on the data disclosed below, preferred liquid compositions range from approximately 25 mg / mL to approximately 165 mg / mL. mg / mL secukinumab, approximately 185 mM to approximately 225 mM trehalose, approximately 0.01% to approximately 0.03% polysorbate 80, approximately 2.5 mM to approximately 20 mM L-methionine and approximately 1 A 0-30 mM histidine buffer (for example, approximately 20 mM histidine buffer) is used at approximately 5.8 p Includes H

[0122] Preferred liquid composition I contains approximately 150 mg / mL secukinumab and approximately 200 mM trehalose. S, approximately 0.02% polysorbate 80, approximately 5 mM L-methionine and approximately 20 mM histamine Contains thidine buffer at approximately 5.8 pH. Preferred pharmaceutical product I is pre-filled syringe (PFS). The liquid composition I is placed inside the container.

[0123] Another preferred liquid composition II contains approximately 25 mg / mL secukinumab and approximately 225 mM trehalose. Rose, approximately 0.02% polysorbate 80, approximately 5 mM L-methionine and approximately 20 mM Contains histidine buffer at approximately 5.8 pH. Preferred pharmaceutical product II is contained in the vial. The liquid composition II is placed within it.

[0124] [Table 3]

[0125] [Table 4]

[0126] 1.1 Variables that have a greater impact on the liquid state stability of Part I-secukinumab Detailed analysis (headspace oxygen, pH, and L-methionine) 1.1.1 Example 1: L-methionine The effects of several antioxidant stabilizers on secukinumab stability were investigated using a series of extensive analytical techniques. They used techniques to characterize it.

[0127] Initial studies have focused on tetrasodium EDTA sodium ascorbate, cysteine, and sulfite. Various antioxidant stabilizers, including sodium hydrogen and sodium citrate, were evaluated. None of these adequately stabilized the molecules, but compositions without antioxidant stabilizers and In comparison, tetrasodium EDTA and sodium citrate are used to aggregate products by SEC. A small stabilizing effect was observed (data not shown).

[0128] Further research will use a secukinumab concentration of 150 mg / mL with a DoE approach. Using cysteine, tetrasodium EDTA, and L-methionine stabilizers in a 10 mM solution. The concentration was evaluated and compared to the case without stabilizer. The composition was filled into PFS and subjected to long-term (5°C) and accelerated ( The product was subjected to a 2-month stability study under conditions of 25°C and stress (40°C), demonstrating physical stability. Properties (AP-SEC, DLS, turbidity, visible and subvisible particles due to light-darkening), chemical Stability (purity by CEX, purity by RP-HPLC, color) and biological activity (Cy The activity and free SH group indicators mediated by s-CEX were evaluated. Furthermore, freeze-thaw cycle (-2 (5 cycles from 0°C to room temperature) and shaking stress (150 rpm for 1 week), 2 mL It was added to the composition filled in the Ial.

[0129] For secukinumab, L-methionine was found to be the best second-class stabilizer. This is because the purity measured by CEX and the purity measured by RP-HPLC and the lower turbidity level Demonstrated by higher purity levels when measured by particle count and visible particle count. Compared to compositions without stabilizers, the presence of L-methionine resulted in significantly superior stability. The composition containing L-methionine was shown to have undergone 8 weeks of accelerated fertilization at 25°C and 40°C. After stability, AP-SEC levels are lower, DLS data is more consistent, and turbidity is lower. It had a lower amount of the pre-main peak species as measured by RP-HPLC. EDTA Basic variants by AP-SEC, DLS, CEX and premature mutations by RP-HPLC The increase in in-peak species was a disadvantage. As shown by various analytical methods, cis Thein leads to an increase in almost all aggregation and decomposition products.

[0130] Figure 1 shows the selected quality attributes after storage under different conditions. L-methionine Only was observed to have a consistent stabilizing effect on secukinumab. The stabilizing effect was The pre-main peak species were determined by RP-HPLC (Figure 1B) and AP-SEC (Figure 1D). This was particularly observed. Further effects were also observed in turbidity and hydrodynamic radius due to DLS. The effect of different L-methionine concentrations on secukinumab quality attributes will be evaluated in subsequent studies. It was worth it.

[0131] Figure 2 shows the results in histidine buffer at pH 5.8 in the presence and absence of L-methionine. Secukinumab concentration of 25 mg / mL and trehalose concentration of 225 mM and 0.02 Pre-treatment by RP-HPLC during storage at 25°C at a % polysorbate 80 concentration. This shows the change in the main peak species. The composition was filled into a 2 mL vial and measured under stress conditions. The samples were stored for 3 months. The black dashed line represents the values ​​obtained with a composition containing 0 mM L-methionine. This graph shows a linear fit to the formula, with the gray dashed line indicating the result obtained with a composition containing 10 mM L-methionine. This represents a linear fit to the given values. Clearly, the degradation was reduced in the presence of L-methionine. Kinetic activity was observed.

[0132] For compositions containing 150 mg / mL of secukinumab, concentration-dependent effects were also observed. Trehalose at concentrations between 200 mM and 300 mM, 0.01% to 0.04%. A composition containing polysorbate 80 and 0 mM to 10 mM L-methionine. Then, the study was conducted. The composition was filled into 1 mL of PFS and subjected to long-term, accelerated, and stressed conditions. It was stored for up to 3 months below. The physical (AP-SEC, DLS, light-darkening) of secukinumab Sub-visible and visible particles, turbidity, and chemical (purity by CEX, RP-H) Purity, color, stability, and biological activity were monitored using PLC (Programmable Calculation).

[0133] Figure 3 shows the pre-main peak species obtained by RP-HPLC after storage at 25°C for 6 months. This shows that the effects of trehalose and polysorbate 80 on decomposition were negligible. A clearly reduced degradation level was observed in the presence of L-methionine. This effect is The stability of secukinumab was more pronounced when comparing the presence and absence of L-methionine, but 2. Concentration dependence was also observed in the range of 5–10 mM L-methionine.

[0134] 150 mg / mL of histidine buffer pH 5.8, packed into 1 mL PFS. A composition containing cukinumab, 200 mM trehalose, and 0.02% polysorbate 80. The same stabilizing effect of L-methionine was observed after long-term storage (up to 30 months). Figure 4 shows AP-SEC(A) and RP-HPLC during storage at 5°C for up to 30 months. The pre-main peak species (B) is shown. The black dashed line indicates a concentration of 5 mM L-methionine. This shows a linear fit to the values ​​obtained with the composition, and the gray dashed line represents 0 mM L-methionine. This represents a linear fit to the values ​​obtained for compositions containing L-methionine. Clearly, the presence of L-methionine is evident. Reduced degradation kinetics were observed below.

[0135] Secukinumab stability (150 mg / mL, trehalose 200 mM, polysorbate 8) The effect of L-methionine concentration (0-20%) on 0.02% histidine buffer pH 5.8 In a study evaluating the effect of mM (m³), concentration dependence was further confirmed. Different compositions were compared using PFS. The samples were filled and stored for 13 months and 30 months (at 5°C only) under long-term and accelerated conditions. Stability was demonstrated in previous screenings (purity by RP-HPLC, purity by SEC, turbidity). The stability of secukinumab was observed to be assessed by a selected set of analytical techniques. However, no clear trend could be concluded from the turbidity measurements. The pre-main peak species identified by EC and RP-HPLC is clearly related to L-methionine concentration. It showed a significant dependence. This effect was small under real-time storage conditions, but a clear difference was observed at 25°C. Observed (Figure 5).

[0136] After 13 months of storage at 25°C, coagulation by SEC occurred in the composition without L-methionine. The aggregate level increased by 4.5% at t0 from the starting level of less than 1%. The addition of thionine increased this aggregate formation by 3.5% at 2.5 mM and 3% at 5 mM. At 0% and 20 mM L-methionine, the levels were reduced to 2.2%. At 5°C, L-methionine The difference between a composition without L-methionine and a composition containing 20 mM L-methionine is only 0.3%. The pre-main peak species detected by RP-HPLC contained 0 mM L-methionine. In the sample, the concentration increased from 9.1% to 42.7% during 13 months of storage at 25°C. RP -This increase in pre-main peak species by HPLC was 39.4% at 2.5 mM and 5.0 mM. The levels were reduced to 37.8% in the M-grade sample and to 34.5% in the 20 mM L-methionine-containing sample. In short, during storage at 5°C and 25°C in PFS in the presence of L-methionine, A Reduced levels of the pre-main peak species were observed using P-SEC and RP-HPLC. The difference was observed to be more pronounced after storage at 25°C, but it could still be detected after storage at 5°C. It was possible.

[0137] Already at a level of 2.5 mM L-methionine, compared to a composition without L-methionine In comparison, the decomposition rate was clearly reduced. This is due to the use of 0, 2.5, and 5.0 mM L-methionine. Further studies comparing the stability of secukinumab in the presence of nin have also confirmed this. After 24 months of storage under normal conditions, it contains 2.5 mM and 5.0 mM L-methionine. Among the compositions, there was a difference in purity by RP-HPLC, purity by SEC, and turbidity. It was not observed.

[0138] The addition of L-methionine to the liquid antibody composition in the vial is AP-SEC and CE- Impurities were also reduced by SDS (non-reducing) (Figure 6). Interestingly, the concentration was 25 mg / mL. A liquid antibody composition in a vial containing secukinumab, with reduced L-methionine concentration Existence was observed (Figure 6), and antibody integrity and stability were observed in compositions with lower antibody concentrations. This suggests that lower concentrations of L-methionine are sufficient to maintain [the desired state].

[0139] Based on the combined data from the above experiment, at least 2.5 mM (preferably about 5 mM) The methionine concentration of ) is ideal for the liquid composition of secukinumab, and other stabilizers of the second group. It is superior.

[0140] 1.1.2 Example 2: Headspace oxygen content 1.1.2.1 Primary packaging - PFS: At a concentration of 150 mg / mL secukinumab, and in a histidine buffer at pH 5.8, 20 Contains 0 mM trehalose, 5 mM L-methionine, and 0.02% polysorbate 80. The effect of headspace oxygen content on secukinumab stability was evaluated in various compositions. The composition was filled into 1 mL PFS from a PFS supplier. Headspace oxygen content The amounts are between 13% and 15% (0.5 mL filled volume), or 3-4% (0.5 mL) respectively. The measurement was found to be (L packing volume) / 7~8% (1.0 mL packing volume). The sample was subjected to long-term, rapid testing. The samples were stored for up to 6 months under advanced and stressful conditions. The selected compositions were then subjected to the most stressful conditions under long-term conditions. It was stored for 24 months. The stability of secukinumab was determined by purity measured by SEC and by RP-HPLC. Purity, purity by CEX, purity by CE-SDS (non-reducing), turbidity, color, free SH groups Biological activity was monitored using sub-visible and visible particles induced by light-darkening.

[0141] Pre-main peak species and headspace oxygen to AP-SEC by RP-HPLC The effects of content were observed under long-term, accelerated, and stressed conditions. Figure 7 shows the maximum of 9 months at 25°C. This shows AP-SEC during monthly storage. Clearly, it contains 13-15% headspace oxygen. The PFS with a certain quantity showed increased aggregation at 25°C. However, under storage conditions of 2-8°C... Compared to the headspace oxygen content, there was almost no absolute difference at the aggregate level (6% (Monthly data) (Data not shown).

[0142] Quality attributes of secukinumab (turbidity, purity by SEC, purity by RP-HPLC, CE - Purity, free SH groups, biological activity, and sub-visible particles obtained by SDS (non-reducing) and light-darkening. Different hemispheres (indicating a range of 6% to 21% (i.e., no purging) affecting children, visible particles, and color. The effect of headspace oxygen content levels was investigated at 5°C for 12 months, and under accelerated conditions (25°C). Further evaluation was performed during storage for 6 months and 3 months under stress conditions (40°C). 150 With secukinumab at mg / mL and 200 mM trehalose in histidine buffer pH 5.8 A study was conducted using a composition containing rose, 5 mM L-methionine, and 0.02% polysorbate 80. The following was performed: The sample was filled into the PFS, purged with certified oxygen mixture, and the target headspace was reached. Sustain the oxygen content.

[0143] No change in turbidity was observed over the storage period; the sub-invisible particles and color were not obscured by light darkening. No clear effect of headspace oxygen content on free SH groups was observed, and different headspace oxygen content was observed. The difference in space oxygen content between samples was within the range of method variability. Methionine concentration was measured at 5°C. Alternatively, during storage at 25°C, it does not show any relevant changes, regardless of headspace oxygen content. At 5°C, the concentration was observed to be 4.9 mM after 12 months (initial value 4.9-5.0 mM). .

[0144] This study demonstrated the relatively large effect of headspace oxygen content on aggregation products induced by SEC. In contrast to previous findings by the same researchers, this experiment showed that even unpurged reference samples were intentionally... Under the storage conditions shown (5°C), only small changes were observed during storage for a maximum of 12 months. Tested at different stability points (up to 12 months at 2-8°C and up to 6 months at 25°C). Regarding the presence of samples with different oxygen levels in headspace, SEC No relevant differences were observed in purity and aggregates (Figure 8). In contrast, the inventors found that, We noticed an increase in principal purity measured by RP-HPLC with increasing headspace oxygen content. At 5°C (after 12 months of storage) (data not shown) and 25°C (after 6 months of storage), This was observed (Figure 9). No new peaks appeared.

[0145] 1.1.2.2 Primary packaging - vial: The composition was filled into 2 mL vials and stored under refrigerated conditions for 12 months, as well as accelerated and slow-released. They were stored for up to 3 months under low-temperature conditions. Tables 5-7 show the results in the presence of 5 mM L-methionine. In the absence of histidine buffer at pH 5.8, the concentration of secukinumab at 25 mg / mL is... and at trehalose concentrations of 225 mM and polysorbate 80 concentration of 0.02% Pre-main peak species by RP-HPLC during storage at 5°C, 25°C, and 40°C And summarize the changes in SEC-AP.

[0146] [Table 5]

[0147] [Table 6]

[0148] [Table 7]

[0149] [Table 8]

[0150] The effect of headspace oxygen content on the 25 mg / ml secukinumab vial solution is 5 After 12 months at °C (4.5% vs. 20% headspace oxygen content with 5% headspace oxygen content) (7.1% content, see Table 5), after 3 months at 25°C (5% headspace oxygen content) 7.9% vs 20% oxygen (20.6%, see Table 6), and after 3 months at 40°C (5% oxygen) Headspace oxygen content 40.6% vs. 20% headspace oxygen content 46.2%, Table 6 Observable by the pre-main peak species by RP-HPLC (see reference). 3 months at 40°C. The same trend can then be derived for AP-SEC (5% headspace oxygen). (1.8% in content versus 2.5% in headspace oxygen content, see Table 6). Furthermore, When combined with a low headspace oxygen content, L-methionine concentration has a further effect. It has, for example, data on the 5% oxygen headspace content after storage at 5°C for 12 months. When comparing the pre-main peak species by RP-HPLC with compositions containing L, 5 mM L - Compared to 4.5% of compositions containing methionine (Table 5), compositions containing L-methionine In compositions without the substance, 6.1% (Table 7) was found. After 3 months at 25°C (5%~20% oxygen) : 20.9-25.5% in the absence of L-methionine (Table 8) vs. 5 mM L-methionine In the presence of 17.9-25.5% (Table 6), and after 3 months at 40°C (5%-20%) Oxygen: 44.6–50.9% in the absence of L-methionine (Table 8) vs. 5 mM L-methionine In the presence of nin, the same difference was observed in 40.6-46.2% (Table 6), as measured by RP-HPLC. This can be seen in the Remaine Peak species.

[0151] Based on the above experiment, PFS and vial (pre-main peak by RP-HPLC) In enhancing the stability of liquid compositions in both cases (when evaluated by species), head Nitrogen purging that reduces the space oxygen content to less than approximately 12% is considered beneficial.

[0152] 1.1.3 Example 3: Interaction between L-methionine concentration and headspace oxygen content Further research will evaluate the interaction between L-methionine concentration and headspace oxygen content. L-methionine in the range of 2.5-7.5 mM and headspace between 3 and 9%. A composition containing oxygen was prepared. The composition was filled into a PFS and subjected to long-term and accelerated conditions. It was stored below for 6 months. Related secukinumab quality attributes (purity by SEC, RP-HP) Purity by LC; purity by CEX, free SH groups, biological activity, and sub-visibility by light-darkening. Monitor the presence and visibility of particles, turbidity and color of the solution after 3 and 6 months of storage. Figure 10 shows the L-methionine and headspace oxygen content at 25°C. The purity measured by AP-SEC after 6 months of storage is shown. When analyzed, no interaction was observed within the tested range.

[0153] Another study examined the effects of reduced headspace oxygen content and L-methionine concentration. The evaluation was performed at a secukinumab concentration of 150 mg / mL. The composition was 270 mM mannitol. , 0.04% polysorbate 80 and different L-methionines ranging from 0.15% to 2% It contained concentration. The composition was filled into a 2 mL glass vial and purged with nitrogen or They were not stored under long-term, accelerated, and stressful conditions for up to six months.

[0154] Figure 11 shows L at concentrations of 0.15% (10 mM), 1% (67 mM), or 2% (134 mM). - In a composition containing methionine and nitrogen or air headspace for up to 36 months This shows the primary peak species as determined by RP-HPLC after storage, as previously observed. The pre-main peak species identified by RP-HPLC is the group containing a higher amount of L-methionine. The levels were lower in the product. When the headspace was purged with nitrogen, the same composition RP-HPLC showed lower levels of the pre-main peak species.

[0155] Based on combined data from various experiments using vials and PFS as primary packaging. Therefore, a head concentration of less than 12% combined with at least approximately 2.5 mM L-methionine The dospa oxygen content is ideal for the liquid composition of secukinumab.

[0156] 1.1.4 Example 4: pH The effect of pH on secukinumab stability is 90 in the pH range between 4.0 and 7.5. 10 mM citrate / sodium phosphate buffer containing mM sodium chloride The initial evaluation was performed at concentrations of mg / ml. The samples were stored at 5°C and 40°C for 3 weeks. Then, the stability of secukinumab was monitored after five freeze-thaw cycles from ≤-60°C to room temperature. did.

[0157] The optimal pH for *Secchunum* varied depending on the degradation pathway analyzed. Aggregation and ta Protein degradation is determined by purity measured by SEC and purity measured by SDS-PAGE (reduction). The average molecular weight measured by LLS was smallest at pH 5.7-6.2, but the purity measured by CEX was The optimal pH was pH 5.3. Active secukinumab has one free cysta on each light chain. It contains a residue, and thus, it is expected that 2 moles of thiol groups are present per mole of secukinumab. The reduced level of free SH groups correlates with the loss of biological activity of secukinumab. The free SH groups were quantified using a method based on Elman's reagent. At pH 4.3 alone, 1 A slightly lower value of 1.94 moles per mole was observed. Secukinumab freeze-thaw resistance Resistivity was monitored by purity measured by SEC, and the average molecular weight measured by LLS was pH 5.3 The maximum pH was found at ~5.7. pH 5.8 was selected for further formulation of secukinumab. It was done.

[0158] Further research on the effect of pH on secukinumab stability is needed using a DoE approach. The PFS was performed using 150 mg / mL. The effect of pH within the range of 5.2 to 5.8 was investigated. The composition was evaluated at the secukinumab concentration. The composition was evaluated under long-term (5°C), accelerated (25°C), and strenuous conditions. In a 2-month stability study under the conditions of (40°C), physical stability (AP-SEC, DL) was investigated. S, turbidity, visible and sub-visible particles due to light-darkening, chemical stability (purity by CEX) Degree, purity by RP-HPLC, color, and biological activity (activity by Cys-CEX). The indicator of free SH groups was evaluated. Furthermore, freeze-thaw cycles (-20°C to room temperature) were performed. A composition filled in a 2 mL vial, subjected to (L) and shaking stress (150 rpm for 1 week). In addition, the pH values ​​within the investigated range were used for secukinumab stability (AP-SEC, DP-SE). This significantly affects basic mutations (measured by C, DLS, and CEX, and purity measured by RP-HPLC). It was found that boiling was the ideal pH (AP-S). Results from previous studies have shown that pH 5.8 is ideal (AP-S Confirmation regarding the pre-main peak species by EC, DP-SEC, and RP-HPLC. (Figure 12)

[0159] Secukinumab at a concentration of 150 mg / mL, trehalose 200 mM, 2.5-7.5 m Contains L-methionine in the M range and a headspace oxygen content between 3 and 9%. The effect of pH was further evaluated in the composition. The pH of the histidine buffer ranged from 5.4 to 6.2. The values ​​fluctuated between [values]. The composition was filled into PFS and stored for 6 months under long-term and accelerated conditions. Related secukinumab quality attributes (purity by SEC, purity by RP-HPLC; CEX Purity, free SH groups, biological activity, sub-visible particles, visible particles, and soluble particles due to light-darkening. The turbidity and color of the liquid were monitored after 3 and 6 months of storage. Figure 13 shows the results at 5°C. This shows the effect of pH on the quality attributes of secukinumab after storage. Increased turbidity, AP- Acidic variants produced by SEC and CEX, as well as higher purity due to reduced SEC, are available at higher pH levels. This was observed in the values ​​and further confirmed the observations from the initial screening.

[0160] Based on combined data from various experiments, a pH range of approximately 5.2 to 6.2 is found in Seckinu. It is ideal for liquid compositions of mab.

[0161] 1.2 Part 2 - Excipients having a smaller effect on the liquid state stability of secukinumab Detailed analysis (stabilizers, surfactants, and buffers) 1.2.1 Example 5: The choice of stabilizer has little effect on stability. The solubility of secukinumab during long-term storage conditions as well as during storage under accelerated and stressed conditions. Formation of insoluble aggregates (purity by AP-SEC, SDS-PAGE, light scattering technology), chemistry Physical stability (purity by RP-HPLC, purity by CEX, color) and biological activity (C Evaluation of different stabilizers regarding activity (of ys-CEX, free SH group, and biological activity) Development of initial compositions for liquid dosage forms with a focus on specific areas.

[0162] The stabilizers were divided into three different classes: the first group was nonionic (mannitol, t Lehalose dihydrate and ionic (sodium chloride and arginine hydrochloride) stabilizers It included. All stabilizers in the first group offered advantages over those without stabilizers. However, non Ionic stabilizers (trehalose and mannitol) are lower than those used by Cys-CEX. As observed at the aggregate level and with higher activity, the molecules are more stabilized. This was observed.

[0163] Based on conclusions from initial composition development studies, further research will be conducted using the DoE approach. This was performed using PFS. Stabilizer Group 1 (glycine, mannitol, trehalose dihydrate) The effects of sodium chloride were evaluated. The composition was filled into a pre-filled syringe and subjected to long-term, accelerated treatment. In a 2-month stability study under stress conditions, physical stability (AP-SEC, DL) was observed. S, turbidity, visible and sub-visible particles due to light-darkening, chemical stability (purity by CEX) Degree, purity by RP-HPLC, color, and biological activity (activity by Cys-CEX). The indicator of free SH groups was evaluated. Furthermore, freeze-thaw cycles (-20°C to room temperature) were performed. A composition filled in a 2 mL vial, subjected to (L) and shaking stress (150 rpm for 1 week). Added: Regarding stabilizer class I, observations from previous screenings were confirmed:1 ) All stabilizers in group 1 offered advantages over those without stabilizers; and 2) non-io The antacid stabilizer was found to be a superior stabilizer for the secukinumab protein. (Figure 14). This is because the purity was determined by SEC, RP-HPLC and DLS. This was particularly pronounced in polydisperse. No related effects were observed when comparing different nonionic stabilizers. It wasn't done.

[0164] Next, the inventors of the present invention used a stabilizer class I (trehalose dihydrate, 200-300 mM) The ideal concentration was identified. The sample was packed into a PFS and subjected to long-term, accelerated, and stressed conditions. It was stored for 3 months. The physical effects of secukinumab (AP-SEC, DLS, sub-darkening) (Visible particles, visible particles, turbidity) and chemical (purity by CEX, by RP-HPLC) The purity, color, stability, and biological activity of various trehalose concentrations were monitored. No relevant differences were observed in the quality attributes of secukinumab (Figure 3).

[0165] 1.2.2 Example 6: The choice of surfactant has little effect on stability. The solubility of secukinumab during long-term storage conditions as well as during storage under accelerated and stressed conditions. Formation of insoluble aggregates (purity by AP-SEC, SDS-PAGE, light scattering technology), chemistry Physical stability (purity by RP-HPLC, purity by CEX, color) and biological activity (C Regarding activity by ys-CEX, free SH group, and biological activity, different excipients (e.g., For a 150 mg / ml liquid composition, with a focus on the evaluation of stabilizers and surfactants. Development of the initial composition. Excipients were divided into three different classes: Group III consists of surfactants. Contains Resorbate 20 and 80. During static storage, compared to no surfactant, 0.0 No difference was observed between 4% concentrations of polysorbate 20 and 80.

[0166] Based on conclusions from initial composition development studies, further research will be conducted using the DoE approach. This was performed using PFS. Surfactants (polysorbate 20, polysorbate 80, polox The effects of Summer 188 (none) were evaluated. The composition was filled into PFS and subjected to long-term, accelerated, and short-term effects. In a 2-month stability study under TRES conditions, physical stability (AP-SEC, DLS, turbidity) was measured. (Visible and sub-visible particles due to light-darkening), chemical stability (purity by CEX, RP) -Purity and color by HPLC, and biological activity (activity by Cys-CEX, free SH The indicators of the base were evaluated. Furthermore, freeze-thaw cycles (-20°C to room temperature, 5 cycles) were performed. A shaking stress (150 rpm for 1 week) was added to the composition filled in a 2 mL vial. Observation is performed based on lower turbidity levels and visible and subvisible particle counts due to light darkening. As shown, the presence of surfactants was beneficial. However, the weak influence of the type of surfactant. That was all there was (Figure 15).

[0167] The inventors have determined the ideal concentration of group III surfactants (polysorbate 80 0.01 ~0.04(w / v)%) was then identified. The sample was packed into a PFS and subjected to long-term, accelerated, and short-term testing. The samples were stored for up to 3 months under TRES conditions. The physical (AP-SEC, DLS) of secukinumab were also examined. (Sub-visible particles, visible particles, turbidity due to light-darkening) and chemical (purity by CEX, R) Purity, color, stability, and biological activity were monitored using P-HPLC. During the period of time (Figure 3) and after shaking at 150 rpm for one week, the quality attributes of secukinumab were also determined. No clear effect of polysorbate 80 concentration was observed. Furthermore, the number of sub-visible particles increased slightly due to polydispersion and light darkening by DLS. Therefore, Therefore, to maintain a safety margin for the lowest evaluation concentration, the concentration of polysorbate 80 It was set at 0.02%.

[0168] 1.2.3 Example 5: The choice of buffer has little effect on stability. Using the DOE approach, we can determine the type of buffer (citric acid, histidine, succinic acid, acetic acid). The effects of the composition were evaluated using PFS. The composition was filled into PFS and subjected to long-term, accelerated, and stressed conditions. In the 2-month stability study below, physical stability (AP-SEC, DLS, turbidity, light-darkness) was investigated. (Visible and sub-visible particles), chemical stability (purity by CEX, RP-HPLC) Indicators of purity (color) and biological activity (activity by Cys-CEX, free SH group) We evaluated the following: freeze-thaw cycles (-20°C to room temperature, 5 cycles) and shaking. Less (150 rpm for 1 week) was added to the composition filled in a 2 mL vial. Buffering agent No related effects of type were observed. Figure 16 shows the selected quality attributes.

[0169] 1.2.4 Example 6: Antibody concentrations within the tested range have little effect on stability. The effect of secukinumab concentration on the liquid composition quality attributes was investigated at 124.5–175.5 mg. The evaluation was performed within the range of / mL. The composition was 200 mM treyl in a histidine buffer at pH 5.8. It also contained halos, 5 mM L-methionine, and 0.02% polysorbate 80. The product was filled into PFS and stored for 6 months under long-term and accelerated conditions. Related species: Sekukinuma Quality attributes (purity by SEC, purity by RP-HPLC; purity by CEX, free S) (H group, biological activity, sub-invisible particles due to light-darkening, visible particles, turbidity and color of solution) This was monitored after 3 and 6 months of storage. 25 mg / ml ~ 150 mg / ml Within this range, no related effect of secukinumab concentration on the liquid composition quality attributes was observed. (Data not shown).

[0170] 1.3 Part 3 - Characteristics of Preferred Final Commercial Composition The preferred pharmaceutical product of secukinumab is 15 in 20 mM histidine buffer pH 5.8. 0 mg / ml secukinumab, 200 mM trehalose, 0.02% polysorbate 80 and a liquid composition of 5 mM L-methionine, which is provided in PFS. At the end of filling and completion, the headspace in the PFS has an oxygen content of less than 12%. These pharmaceutical products have excellent shelf life and overall stability.

[0171] Various batches of secukinumab medication during PFS (150 mg / ml secukinumab, 20 0 mM trehalose dihydrate, 20 mM L-histidine / L-histidine hydrochloride monohydrate 5 mM L-methionine, 0.02% polysorbate 80 (w / v%), pH 5.8 Stability tests were performed on the product. It was stored for up to 24 months under long-term storage conditions (2-8°C) and accelerated storage. Storage under normal conditions (25°C) for up to 6 months, and under temperature stress conditions (30°C) for up to 6 months. The results of the 1-month storage test are shown in Tables 9-11 below. Provided stability data, pre-filled silicone Real-time data for up to 24 months of secukinumab 150 mg / 1 ml solution in progression-free survival (PFS) Based on data and stability data for up to 36 months generated during development (bulk syringes). When stored under long-term conditions of 5°C ± 3°C, protected from light and freezing, the PFS (Percentage of Freezing Factor) is commercially available. A shelf life of 24 months has been proposed for the secukinumab 150 mg / 1 ml solution formulation in the product. ru.

[0172] [Table 9]

[0173] [Table 10]

[0174] Table 11 This application relates to the following invention. (1) a. A container having a headspace in which the oxygen content is less than approximately 12%, Bini, b. A liquid pharmaceutical composition having a pH of approximately 5.2 to approximately 6.2, which is placed inside the container. That is, i. Secukinumab at approximately 20 mg / ml to approximately 175 mg / ml; and ii. Approximately 2.5 to 20 mM L-methionine Liquid pharmaceutical compositions containing and not restored from freeze-dried products Pharmaceutical products containing these ingredients. (2) When the methionine concentration is approximately 2.5 mM, approximately 5 mM, approximately 10 mM, or approximately 20 mM The pharmaceutical products listed in (1) above. (3) The pharmaceutical product described in (2) above, wherein the concentration of methionine is approximately 5 mM. (4) The oxygen content in the headspace is less than approximately 10% of the above (1) to (3) Any of the pharmaceutical products listed below. (5) The oxygen content in the headspace is less than approximately 8%, as described in (1) to (4) above. Any of the listed pharmaceutical products. (6) The oxygen content in the headspace is less than approximately 6%, as described in (1) to (5) above. Any of the listed pharmaceutical products. (7) Any of (1) to (6) above, wherein the liquid pharmaceutical composition has a pH of about 5.8 The pharmaceutical products listed below. (8) The above, where the concentration of secukinumab is approximately 25 mg / ml or approximately 150 mg / ml. A pharmaceutical product listed in any of (1) to (7). (9) The liquid pharmaceutical composition contains a histidine buffer, a citrate buffer, an acetate buffer and The above (1) to (8) further includes a buffer selected from the group consisting of succinate buffers. Any of the listed pharmaceutical products. (10) The pharmaceutical product described in (9) above, wherein the buffering agent has a concentration of approximately 10 mM to approximately 30 mM. product. (11) The buffer is a histidine buffer at a concentration of approximately 20 mM, as described in (10) above. Listed pharmaceutical products. (12) The liquid pharmaceutical composition is selected from polysorbate and poloxamer. A pharmaceutical product according to any of (1) to (11) above, further comprising a surfactant. (13) The surfactant is polysorbate 80, polysorbate 20 or poloxam -188, a pharmaceutical product as described in any of (1) to (12) above. (14) The surfactant is at a concentration of approximately 0.01% (w / v) to approximately 0.04% (w / v) The pharmaceutical product described in (13) above, which is polysorbate 80. (15) The concentration of polysorbate 80 is approximately 0.02% (w / v), as in (14) above. The listed pharmaceutical products. (16) The surfactant is polysorbate 20 at a concentration of approximately 0.02% (w / v). , the pharmaceutical products listed in (13) above. (17) The liquid pharmaceutical composition contains mannitol, sodium chloride, trehalose, and The above (1) further comprises a stabilizer selected from the group consisting of ginine HCl and glycine. A pharmaceutical product listed in any one of the items (1) through (16). (18) The stabilizer is trehalose at a concentration of approximately 180 mM to approximately 300 mM. (17) The pharmaceutical products listed. (19) The trehalose concentration is approximately 200 mM or approximately 225 mM, as in (18) above. The pharmaceutical products listed below. (20) The container is a cartridge, syringe, pen or vial as described in (1) above. A pharmaceutical product listed in any of the following (19). (21) a. A container having a headspace in which the oxygen content is less than approximately 6%, Bini, b. A liquid pharmaceutical composition to be placed in the container, comprising approximately 25 mg / mL to approximately 150 mg / mL g / mL secukinumab, approximately 10 mM to 30 mM histidine pH 5.8, approximately 200 mM ~Approximately 225 mM trehalose, approximately 0.02% polysorbate 80 and approximately 2.5 mM ~ A liquid pharmaceutical composition containing 20 mM methionine that has not been reconstituted from a freeze-dried product. Pharmaceutical products containing these ingredients. (22) Containing approximately 25 mg / ml of secukinumab and approximately 225 mM of trehalose, The pharmaceutical products listed in (21) above. (23) Contains approximately 150 mg / ml of secukinumab and approximately 200 mM of trehalose , the pharmaceutical products listed in (21) above. (24) The liquid composition is a. After storage at 2-8°C for 6 months, RP-HPLC was used to determine a purity of at least approximately 86%, 25 After storage at °C / 60%RH for 6 months, purity of at least approximately 76% was determined by RP-HPLC. and / or after storage at 30°C / 75%RH for 6 months, at least by RP-HPLC Approximately 60% purity; b. After storage at 2-8°C for 6 months, purity of at least approximately 77% is determined by CEX at 25°C / 60°C. At least approximately 62% purity by CEX after storage at %RH for 6 months, and / or 3 Purity of at least approximately 50% by CEX after storage at 0°C / 75%RH for 6 months; c. After storage at 2-8°C for 6 months, SEC tests showed a purity of at least approximately 98%, 25°C / 60°C. At least approximately 96% purity by SEC after storage at %RH for 6 months, and / or 3 Purity of at least approximately 94% by SEC after storage at 0°C / 75%RH for 6 months; d. After storage at 2-8°C for 6 months, at least approximately 97% of the material was removed by CE-SDS (non-reducing conditions). The purity of the product was measured using CE-SDS (non-reducing conditions) after 6 months of storage at 25°C / 60%RH. At least 95% purity, and / or CE-14 after storage at 30°C / 75%RH for 6 months. SDS (non-reducing conditions) yields at least about 94% (preferably at least about 92%) of pure Degree; e. After storage at 2-8°C for 6 months, less than 0.57% of the material was found to be non-toxic according to CE-SDS (reducing conditions). Pure substance, stored at 25°C / 60%RH for 6 months, then measured approximately 1.1% using CE-SDS (reducing conditions). Less than % impurities, and / or CE-SDS after 6 months of storage at 30°C / 75%RH. Impurities of less than approximately 1.9% (under reduction conditions); and / or After 24 months of storage at 2-8°C, inhibition of IL-6 release from C-20 / A4 chondrocytes was observed. Based on at least approximately 88% relative biological activity, after 6 months of storage at 25°C / 60%RH. Inhibition of IL-6 release from chondrocytes reduces relative biological activity by at least approximately 94%, Inhibition of IL-6 release from chondrocytes after storage at 30°C / 75%RH for 6 months. At least approximately 85% of relative biological activity due to harm A pharmaceutical product as described in any one of the above items (1) to (23) that maintains [the condition]. (25) The liquid composition is a. Purity of at least approximately 84% by RP-HPLC after storage at 2-8°C for 24 months; b. Purity of at least approximately 73% by CEX after storage at 2-8°C for 24 months; c. At least approximately 97% purity after 24 months of storage at 2-8°C, as determined by SEC; d. After storage at 2-8°C for 24 months, at least approximately 97% of the sample size was determined by CE-SDS (non-reducing conditions). % purity; and / or e. Less than 0.91% by CE-SDS (non-reducing conditions) after 24 months of storage at 2-8°C. impurities A pharmaceutical product as described in any of (1) to (24) above, which maintains [the condition]. (26) A method for reducing the oxidation of secukinumab, a. It has a pH of approximately 5.2 to 6.2. i. Secukinumab at approximately 25 mg / ml to 150 mg / ml; and ii. L-methionine in a concentration of approximately 2.5 mM to 20 mM To prepare a liquid composition containing, b. Placing the liquid composition in a container having headspace; and c. Adjust the oxygen content in the headspace to approximately 12% or less. A method that includes this. (27) Adjustment step c) purging the headspace using an inert gas The method described in (26) above, which is carried out by... (28) The method according to (27) above, wherein the inert gas is nitrogen or argon. (29) When the methionine concentration is approximately 2.5 mM, 5 mM, 10 mM or 20 mM A method described in (26) above. (30) The method according to (29) above, wherein the concentration of methionine is approximately 5 mM. (31) The oxygen content in the headspace is adjusted to less than approximately 10%, as described in (26) above. Methods used. (32) The oxygen content in the headspace is adjusted to less than approximately 8%, as in (26) above. Method of description. (33) The oxygen content in the headspace is adjusted to less than approximately 6%, as in (26) above. Method of description. (34) The method according to (26) above, wherein the liquid composition has a pH of about 5.8. (35) The concentration of secukinumab is approximately 25 mg / ml or approximately 150 mg / ml. The method described in (26). (36) Secukinumab at approximately 25 mg / mL to approximately 150 mg / mL, approximately 10 mM to approximately 30 mM histidine pH 5.8, approximately 200 mM to 225 mM trehalose, approximately 0.02% phosphate Contains Resorbate 80 and approximately 2.5 mM to 20 mM methionine, and is derived from freeze-dried material. Unprocessed liquid pharmaceutical composition.

Claims

1. A stable liquid pharmaceutical composition comprising at least about 25 mg / mL to at least 175 mg / mL of secukinumab, a buffer, at least one stabilizer, and a surfactant, wherein the pH of the composition is about 5.2 to about 6.2, and at least one stabilizer contains methionine, with a concentration of methionine of at least about 2.5 mM to about 134 mM.

2. The stable liquid pharmaceutical composition according to claim 1, wherein the composition comprises about 25 mg / mL to about 150 mg / mL of secukinumab.

3. The stable liquid pharmaceutical composition according to claim 1 or claim 2, wherein the buffering agent is selected from the group consisting of histidine buffering agent, citrate buffering agent, acetate buffering agent and succinate buffering agent.

4. The stable liquid pharmaceutical composition according to any one of claims 1 to 3, wherein the buffering agent is a citrate buffering agent.

5. A stable liquid pharmaceutical composition according to any one of claims 1 to 4, wherein the concentration of the buffering agent is about 10 mM to about 30 mM.

6. The stable liquid pharmaceutical composition according to any one of claims 1 to 5, wherein the surfactant is poloxamer or polyoxyethylene sorbitan fatty acid ester.

7. The stable liquid pharmaceutical composition according to any one of claims 1 to 6, wherein the surfactant is polysorbate 80.

8. The stable liquid pharmaceutical composition according to any one of claims 1 to 7, wherein the surfactant is polysorbate 80 at a concentration of about 0.01% w / v to about 0.1% w / v.

9. A stable liquid pharmaceutical composition according to any one of claims 1 to 8, wherein the concentration of methionine is at least about 20 mM.

10. The stable liquid pharmaceutical composition according to any one of claims 1 to 9, wherein the composition further comprises a nonionic stabilizer selected from trehalose, raffinose, maltose, sorbitol, or mannitol.

11. The stable liquid pharmaceutical composition according to claim 10, wherein the nonionic stabilizer is sorbitol.

12. The stable liquid pharmaceutical composition according to claim 10 or claim 11, wherein the concentration of the nonionic stabilizer is approximately 175 mM to approximately 350 mM.

13. A stable liquid pharmaceutical composition according to any one of claims 1 to 12, When stored at 2-8°C for approximately 24 months, (a) Less than 10% of the secukinumab monomer is degraded when measured by size exclusion chromatography (SEC). (b) Less than 10% of the main variant of secukinumab is degraded when measured by cation exchange chromatography (CEX), or (c) A liquid pharmaceutical composition in which less than 10% of the main variant of secukinumab is degraded when measured by reverse-phase high-performance liquid chromatography (RP-HPLC).

14. A stable liquid pharmaceutical composition according to any one of claims 1 to 12, When stored at 2-8°C for approximately 24 months, (a) Less than 10% of the secukinumab monomer is degraded when measured by size exclusion chromatography (SEC). (b) Less than 10% of the main variant of secukinumab is degraded when measured by cation exchange chromatography (CEX), and (c) A liquid pharmaceutical composition in which less than 10% of the main variant of secukinumab is degraded when measured by reverse-phase high-performance liquid chromatography (RP-HPLC).

15. A stable liquid pharmaceutical composition according to any one of claims 1 to 12, When stored at 25°C for approximately 6 months, (a) Less than 10% of the secukinumab monomer is degraded when measured by size exclusion chromatography (SEC). (b) Less than 10% of the main variant of secukinumab is degraded when measured by cation exchange chromatography (CEX), or (c) A liquid pharmaceutical composition in which less than 10% of the main variant of secukinumab is degraded when measured by reverse-phase high-performance liquid chromatography (RP-HPLC).

16. A stable liquid pharmaceutical composition according to any one of claims 1 to 12, When stored at 25°C for approximately 6 months, (a) Less than 10% of the secukinumab monomer is degraded when measured by size exclusion chromatography (SEC). (b) Less than 10% of the main variant of secukinumab is degraded when measured by cation exchange chromatography (CEX), and (c) A liquid pharmaceutical composition in which less than 10% of the main variant of secukinumab is degraded when measured by reverse-phase high-performance liquid chromatography (RP-HPLC).

17. A stable liquid pharmaceutical composition according to any one of claims 1 to 12, A liquid pharmaceutical composition in which, when stored at 2-8°C for approximately 24 months, less than 10% of the main variant of secukinumab is degraded as measured by CEX.

18. A stable liquid pharmaceutical composition according to any one of claims 1 to 12, wherein the relative biological activity of secukinumab in the composition is at least 80% of a reference standard when measured by inhibition of interleukin-6 (IL-6) release from human chondrocytes after storage at 2 to 8°C for about 24 months.

19. A stable liquid pharmaceutical composition according to any one of claims 1 to 12, A liquid pharmaceutical composition in which, when stored at 2-8°C for approximately 24 months, less than 10% of the secukinumab monomer is degraded as measured by SEC.

20. A stable liquid pharmaceutical composition according to any one of claims 1 to 12, A liquid pharmaceutical composition in which, when stored at 2-8°C for approximately 24 months, less than 10% of the main variant of secukinumab is degraded as measured by RP-HPLC.

21. A stable liquid pharmaceutical composition according to any one of claims 1 to 12, A liquid pharmaceutical composition in which, when stored at 25°C for approximately 6 months, less than 10% of the secukinumab monomer is degraded as measured by size exclusion chromatography (SEC).

22. A stable liquid pharmaceutical composition according to any one of claims 1 to 21, A liquid pharmaceutical composition containing secukinumab at a concentration of approximately 75 mg / mL to approximately 150 mg / mL.

23. A stable liquid pharmaceutical composition according to any one of claims 1 to 12, A liquid pharmaceutical composition in which, when stored at 2–8°C for approximately 24 months, less than 5% of the main variant of secukinumab is degraded as measured by RP-HPLC, and less than 5% of the premain variant of secukinumab is formed as measured by RP-HPLC when stored at 2–8°C for approximately 24 months.

24. A stable liquid pharmaceutical composition according to claim 23, When stored at 2-8°C for approximately 24 months, the following criteria apply: (a) Less than 5% of the main variants of secukinumab are degraded when measured by CEX; (b) Less than 5% of secukinumab basic variants are formed when measured by CEX; and (c) Less than 5% of secukinumab acidic mutants are formed when measured by CEX; A liquid pharmaceutical composition that further satisfies at least one of the following conditions.

25. A stable liquid pharmaceutical composition according to claim 24, When stored at 2-8°C for approximately 24 months, the following criteria apply: (a) Less than 5% of the main monomer of secukinumab is degraded when measured by SEC; (b) When 5% or less of secukinumab aggregates are formed, as measured by SEC; and (c) When less than 5% of the degradation products of secukinumab are formed, as measured by SEC; A liquid pharmaceutical composition that further satisfies at least one of the following conditions.

26. A stable liquid pharmaceutical composition according to any one of claims 1 to 12, A liquid pharmaceutical composition having a methionine concentration in the range of at least about 2.5 mM to about 67 mM.

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