Stable pharmaceutical formulation

Abstract

A stable pharmaceutical formulation according to the present invention comprises: (A) Ixekizumab; and (B) a histidine buffer. A stable pharmaceutical formulation according to the present invention comprises an antibody, has excellent long-term storage stability on the basis of having excellent stability especially under accelerated conditions and severe conditions, and can be administered intravenously or subcutaneously.

Description

Stable pharmaceutical preparations

[0001] The present invention relates to a pharmaceutical preparation capable of stably preserving ixekizumab and a finished pharmaceutical product containing the same.

[0002] Interleukin-17A (IL-17A) is secreted by immune cells including Th17 and CD8, and promotes the secretion of pro-inflammatory cytokines such as G-SCF, IL-6, and IL-8, which induce immunopathology and neutrophil recruitment. IL-17A can be the cause of immune diseases such as psoriasis, psoriatic arthritis, ankylosing spondylitis, and non-radiometric axial spondyloarthritis, and drugs containing antibodies that selectively bind to IL-17A can neutralize IL-17A and suppress the worsening of symptoms. In this regard, various IL-17 binding antibodies have been studied (International Patent Publication No. WO2007-070750 A1).

[0003] Ixekizumab, which may be a component of the above drug, is a humanized monoclonal antibody that selectively binds to and neutralizes interleukin-17A (IL-17A), and was approved for use by the FDA and EMA in March 2016 and April 2016, respectively.

[0004] However, ixekizumab is an unstable protein and may undergo physical or chemical changes due to heat stress, light stress, etc. Therefore, long-term storage of the product may impair its stability and / or activity.

[0005] Meanwhile, antibodies are immunoglobulin molecules composed of four polypeptide chains, two heavy chains and two light chains linked by disulfide bonds. Each heavy chain is composed of a heavy chain variable region and a heavy chain constant region. The heavy chain constant region is composed of three domains (CH1, CH2, and CH3). Each light chain is composed of a light chain variable region and a light chain constant region. The light chain constant region is composed of one domain (CL). The heavy chain variable region and light chain variable region can be further subdivided into hypervariable regions, called complementarity determining regions (CDRs), which are arranged alongside more conserved regions, called framework regions (FRs). Each heavy chain variable region and light chain variable region consists of three CDRs and four FRs, which are arranged in the following order from amino terminus to carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0006] The problem to be solved by the present invention is to provide a stable pharmaceutical preparation comprising ixekizumab.

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

[0008] Another problem to be solved by the present invention is to provide an auto-injector having the pre-filled syringe included therein.

[0009]

[0010] The problem to be solved by the present invention is to provide a stable pharmaceutical preparation comprising (A) 1 to 150 mg / ml of ixekizumab; and (B) 0.1 to 50 mM of a histidine buffer.

[0011] The stable pharmaceutical preparation according to the present invention, when containing ixekizumab, has excellent long-term storage stability based on stability under accelerated and harsh conditions, and can be administered intravenously or subcutaneously.

[0012]

[0013] This is explained in detail as follows. Meanwhile, each description and embodiment disclosed in this application can also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in this application fall within the scope of this application. Furthermore, the scope of this application is not limited by the specific descriptions described below. Furthermore, numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated into this specification in their entirety by reference to more clearly explain the level of the technical field to which this application belongs and the contents of this application.

[0014]

[0015] The inventors of the present invention have conducted repeated research to overcome the above-described problems and have developed a stable formulation containing ixekizumab.

[0016] The present inventors developed a formulation comprising a histidine buffer for long-term storage of a formulation comprising ixekizumab.

[0017] One embodiment of the present invention provides a stable pharmaceutical formulation comprising (A) 1 to 150 mg / ml of ixekizumab; and (B) 0.1 to 50 mM of a histidine buffer.

[0018]

[0019] In one embodiment of the present invention, (A) Ixekizumab may be a stable pharmaceutical formulation comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3; and a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 6.

[0020] In one embodiment of the present invention, (A) ixekizumab may be a stable pharmaceutical formulation comprising a light chain variable region comprising an amino acid sequence of SEQ ID NO: 7; and a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 8.

[0021] In one embodiment of the present invention, (A) Ixekizumab may be a stable pharmaceutical formulation comprising a light chain comprising an amino acid sequence of SEQ ID NO: 9; and a heavy chain comprising an amino acid sequence of SEQ ID NO: 10.

[0022] In one embodiment of the present invention, (A) the concentration of ixekizumab may be 1 to 150 mg / mL, specifically 1 to 100 mg / mL, and may be a stable pharmaceutical formulation.

[0023] In one embodiment of the present invention, (B) the concentration of the histidine buffer may be 0.1 to 50 mM, specifically 1 to 30 mM, in a stable pharmaceutical formulation.

[0024] In one embodiment of the present invention, it may be a stable pharmaceutical preparation having a pH of 4 to 7, specifically 5 to 7.

[0025] One embodiment of the present invention provides a stable pharmaceutical formulation comprising (A) 1 to 150 mg / ml of ixekizumab; (B) 0.1 to 50 mM of a histidine buffer; (C) 1 to 30% (w / v) of a stabilizer; and (D) 0.001% (w / v) to 1% (w / v) of a surfactant.

[0026] In one embodiment of the present invention, (A) Ixekizumab may be a stable pharmaceutical formulation comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3; and a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 6.

[0027] In one embodiment of the present invention, (A) ixekizumab may be a stable pharmaceutical formulation comprising a light chain variable region comprising an amino acid sequence of SEQ ID NO: 7; and a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 8.

[0028] In one embodiment of the present invention, (A) Ixekizumab may be a stable pharmaceutical formulation comprising a light chain comprising an amino acid sequence of SEQ ID NO: 9; and a heavy chain comprising an amino acid sequence of SEQ ID NO: 10.

[0029] In one embodiment of the present invention, (A) the concentration of ixekizumab may be 1 to 150 mg / mL, specifically 1 to 100 mg / mL, and may be a stable pharmaceutical formulation.

[0030] In one embodiment of the present invention, (B) the histidine buffer concentration may be 0.1 to 50 mM, specifically 1 to 30 mM, and may be a stable pharmaceutical preparation.

[0031] In one embodiment of the present invention, (C) the stabilizer may be a stable pharmaceutical preparation comprising at least one selected from the group consisting of sugars and sugar alcohols.

[0032] In one embodiment of the present invention, the sugar or sugar alcohol may be a stable pharmaceutical preparation comprising at least one selected from the group consisting of trehalose, sucrose, sorbitol, and mannitol.

[0033] In one embodiment of the present invention, the concentration of the stabilizer (C) may be 1 to 30% (w / v), specifically 1 to 10% (w / v), which may be a stable pharmaceutical preparation.

[0034] In one embodiment of the present invention, (D) the surfactant may be a stable pharmaceutical formulation that is a nonionic surfactant.

[0035] In one embodiment of the present invention, (D) the surfactant may be a stable pharmaceutical formulation comprising polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 or a mixture of two or more thereof.

[0036] In one embodiment of the present invention, (D) the surfactant may be a stable pharmaceutical formulation comprising polysorbate 20 or polysorbate 80.

[0037] In one embodiment of the present invention, the concentration of the (D) surfactant may be 0.001% (w / v) to 1% (w / v), specifically 0.01 to 0.1% (w / v), which may be a stable pharmaceutical preparation.

[0038] One embodiment of the present invention specifically provides a stable pharmaceutical formulation comprising: (A) 80 mg / ml of ixekizumab; (B) 1 to 10 mM of a histidine buffer; (C) 1 to 10% (w / v) of trehalose or sucrose; and (D) 0.01% (w / v) to 0.1% (w / v) of polysorbate 20 or polysorbate 80.

[0039] In one embodiment of the present invention, the formulation may be a liquid formulation.

[0040]

[0041] (A) Ixekizumab

[0042] In the present invention, the term "Ixekizumab" refers to the product name Taltz ® Ixekizumab, also known as Ixekizumab, described in International Publication No. WO2007-070750, may be the original drug substance as is well known in the art, or a biosimilar thereof.

[0043] In the present invention, ixekizumab may include a light chain variable region comprising a CDR1 domain comprising an amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising an amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising an amino acid sequence of SEQ ID NO: 3; and a heavy chain variable region comprising a CDR1 domain comprising an amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising an amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising an amino acid sequence of SEQ ID NO: 6.

[0044] In the present invention, ixekizumab may include a light chain variable region comprising an amino acid sequence of SEQ ID NO: 7; and a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 8.

[0045] In one embodiment of the present invention, (A) Ixekizumab may be a stable liquid pharmaceutical formulation comprising a light chain comprising an amino acid sequence of SEQ ID NO: 9; and a heavy chain comprising an amino acid sequence of SEQ ID NO: 10.

[0046] In one embodiment of the present invention, the concentration of ixekizumab may be 1 to 150 mg / mL, specifically 1 to 100 mg / mL, 10 to 130 mg / mL, 10 to 120 mg / mL, 10 to 100 mg / mL, 20 to 120 mg / mL, 20 to 100 mg / mL, 20 to 90 mg / mL, 30 to 100 mg / mL, 30 to 90 mg / mL, 50 to 150 mg / mL, 50 to 100 mg / mL, 50 to 90 mg / mL, 60 to 100 mg / mL, 60 to 90 mg / mL, 70 to 90 mg / mL, and most specifically, but not limited to, 80 mg / mL. When the concentration of ixekizumab is within the above-described range, the degree of freedom in administration dose and administration cycle can be increased, and long-term stability is excellent.

[0047]

[0048] (B) Buffer

[0049] In the present invention, the term “buffer” means a neutralizing substance that minimizes changes in pH caused by acids or alkalis.

[0050] For example, the buffer may be histidine or a salt thereof, acetic acid or a salt thereof, phosphoric acid or a salt thereof, citric acid or a salt thereof, succinic acid or a salt thereof, glutamic acid or a salt thereof, 2-(N-morpholino)ethanesulfonic acid (MES) buffer, trometamine (Tris) or a salt thereof, etc.

[0051] In a more specific example, the buffer may be histidine or a salt thereof. In one experimental example of the present invention, it was confirmed that when histidine is included as a buffer in the formulation of the present invention comprising ixekizumab, a formulation with significantly improved formulation stability can be prepared.

[0052] For example, histidine salts can be histidine chloride, histidine acetate, histidine phosphate, histidine sulfate, etc.

[0053] In the present invention, the concentration of the buffer can be freely adjusted within a range that does not substantially adversely affect the stability and viscosity of the pharmaceutical preparation according to the present invention.

[0054] In one embodiment of the present invention, the content of the buffer may be 0.1 to 50 mM, specifically 1 to 30 mM, 1 to 25 mM, 1 to 20 mM, 1 to 15 mM, 1 to 10 mM, 2 to 30 mM, 2 to 20 mM, 2 to 15 mM, 2 to 10 mM, 3 to 30 mM, 3 to 20 mM, 3 to 10 mM, 5 to 30 mM, 5 to 20 mM, or 5 to 10 mM, more specifically 1 to 9 mM or 2 to 8 mM, and most specifically 7 mM, but is not limited thereto.

[0055]

[0056] (C) stabilizer

[0057] In the present invention, the term "stabilizer" refers to a substance that is physiologically acceptable and imparts stability to the formulation.

[0058] For example, the stabilizer may be a sugar or sugar alcohol, an amino acid or amino acid derivative, or a mixture thereof.

[0059] For example, the sugar or sugar alcohol can be sucrose, trehalose, sorbitol, glucose, fructose, galactose, xylose, maltose, lactose, xylitol, mannitol, D-maltitol, inositol, lactitol, or isomalt.

[0060] For example, the amino acid or amino acid derivative can be threonine, arginine, proline, leucine, glycine, taurine, phenylalanine, tryptophan, glutamine, aspartate, glutamate, alanine, asparagine, serine, glycine, or tyrosine.

[0061] In a more specific example, the stabilizer may be a sugar or a sugar alcohol, and the sugar or sugar alcohol may be at least one selected from the group consisting of trehalose, sucrose, sorbitol, and mannitol. In a more specific example, the sugar or sugar alcohol may be trehalose or sucrose. In one experimental example of the present invention, it was confirmed that when the above substances were included as stabilizers in the formulation of the present invention including ixekizumab, the tendency of the formulation to maintain quality increased.

[0062]

[0063] In the present invention, the concentration of the stabilizer can be freely adjusted within a range that does not substantially adversely affect the stability and viscosity of the pharmaceutical preparation according to the present invention.

[0064] In one embodiment of the present invention, the concentration of the sugar or sugar alcohol is 1 to 30% (w / v), specifically 1 to 25% (w / v), 1 to 20% (w / v), 1 to 18% (w / v), 1 to 15% (w / v), 1 to 12% (w / v), 1 to 10% (w / v), 3 to 25% (w / v), 3 to 20% (w / v), 3 to 18% (w / v), 3 to 15% (w / v), 3 to 12% (w / v), 3 to 10% (w / v), 5 to 25% (w / v), 5 to 20% (w / v), 5 to 17% (w / v), 5 to 15% (w / v), 5 to 12% (w / v), 5 to It can be 10% (w / v), 7 to 25% (w / v), 7 to 20% (w / v), 7 to 15% (w / v), 7 to 12% (w / v), 8 to 20% (w / v), 8 to 15% (w / v), or 8 to 12% (w / v), more specifically 8 to 10% (w / v), and most specifically 8 or 10% (w / v), but is not limited thereto. When the concentration of the stabilizer is within the above-described range, it exhibits excellent long-term stability.

[0065]

[0066] (D) Surfactant

[0067] In the present invention, the term "surfactant" means a substance that can be used to significantly increase the water solubility of a hydrophobic or oily substance or to increase the miscibility of two substances having different hydrophobicities.

[0068] For example, surfactants include polyoxyethylene sorbitan fatty acid esters (e.g., polysorbates), polyoxyethylene alkyl ethers (e.g., Brij ® etc.), alkylphenylpolyoxyethylene ethers (e.g., Triton-X etc.), polyoxyethylene-polyoxypropylene copolymers (e.g., poloxamers, Pluronic ®etc.), sodium dodecyl sulfate (SDS), etc.

[0069] For example, the polysorbate can be polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

[0070] In a more specific example, the surfactant may include polysorbate 80 or polysorbate 20. In one experimental example of the present invention, it was confirmed that when polysorbate 80 or polysorbate 20 is included as a surfactant in the formulation of the present invention including ixekizumab, a tendency for the formulation to maintain stable quality can be exhibited.

[0071]

[0072] In one embodiment of the present invention, the concentration of the surfactant can be freely adjusted within a range that does not adversely affect the stability and viscosity of the stable pharmaceutical preparation according to the present invention.

[0073] In one embodiment of the present invention, the concentration of the (C) surfactant is 0.001 to 1% (w / v), specifically 0.001 to 0.7% (w / v), 0.001 to 0.5% (w / v), 0.001 to 0.3% (w / v), 0.001 to 0.1% (w / v), 0.005 to 1% (w / v), 0.005 to 0.7% (w / v), 0.005 to 0.5% (w / v), 0.005 to 0.3% (w / v), 0.005 to 0.1% (w / v), 0.01 to 1% (w / v), 0.01 to 0.7% (w / v), 0.01 to 0.5% (w / v), 0.01 to It can be 0.3% (w / v), 0.01 to 0.1% (w / v), 0.01 to 0.07% (w / v), or 0.01 to 0.05% (w / v), and most specifically, 0.03% (w / v), but is not limited thereto. When the concentration of the surfactant is within the above-described range, it exhibits excellent long-term stability.

[0074]

[0075] (E) Other ingredients

[0076] In the present invention, the stable pharmaceutical preparation according to the present invention may not contain a preservative. The preservative may be, for example, octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl alcohol, benzyl alcohol, alkyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, m-cresol, etc. If a preservative is included, it may have a negative effect on improving stability.

[0077] As used herein, the term "does not comprise" or "does not comprise" means not comprising any component at all. In addition, the term means substantially not comprising any component, i.e., comprising any component to an extent that does not affect the activity of the antibody, the stability or viscosity of the pharmaceutical preparation. For example, it means comprising any component in an amount of 1% (w / v) or less, 1 mM or less, 1 mg / ml or less, 1 ppm (w / v) or less, or 1 ppb (w / v) or less, based on the total weight of the pharmaceutical preparation.

[0078] In the present invention, the stable pharmaceutical preparation of the present invention may further include an additive known in the art within a range that does not substantially adversely affect the stability and viscosity of the preparation. The additive may be, for example, an aqueous carrier, an antioxidant, or a mixture thereof. In the present invention, the aqueous carrier may be a carrier useful for the manufacture of a pharmaceutical preparation that is safe and non-toxic when administered to humans. Examples of the aqueous carrier include, but are not limited to, sterile water for injection (SWFI), bacteristetic water for injection (BWFI), sterile saline solution, Ringer's solution, dextrose, and the like.

[0079]

[0080] (F) pH

[0081] In one embodiment of the present invention, the formulation of the present invention may have a pH of 4 to 7. Specifically, the formulation of the present invention has a pH of 5 to 7, pH 5 to 6.8, pH 5 to 6.6, pH 5 to 6.5, pH 5 to 6.3, pH 5 to 6.2, pH 5 to 6, pH 5 to 5.8, pH 5 to 5.7, pH 5.2 to 7, pH 5.2 to 6.8, pH 5.2 to 6.6, pH 5.2 to 6.4, pH 5.2 to 6.3, pH 5.2 to 6.2, pH 5.2 to 6, pH 5.2 to 5.8, pH 5.4 to 7, pH 5.4 to 6.8, pH 5.4 to 6.6, pH 5.4 to 6.4, pH 5.4 to 6.3, pH 5.4 to 6.2, pH 5.4 to 6, pH 5.4 to 6.8, pH 5.5 to 7, pH 5.5 to 6.8, pH 5.5 to 6.5, pH 5.5 to 6.3, pH 5.5 to 6.2, pH 5.5 to 6, pH 5.5 to 5.8, pH 5.6 to 6.2, pH 5.6 to 6.0, or pH 5.7 to 6.2, most specifically but not limited to pH 5.7.

[0082]

[0083] (G) “Stable” pharmaceutical preparations

[0084] In the present invention, the term "stable" or "stabilization" means that a component according to the present invention, or a composition or formulation containing the same, exhibits physical stability, chemical stability, and / or biological activity during the manufacturing process and / or during storage or preservation. Various analytical techniques for measuring stability in the present invention are readily available in the art.

[0085] In the present invention, the physical stability can be assessed by methods known in the art, such as by measuring the apparent attenuation of light (absorbance or optical density) in a sample. This attenuation measurement is related to the turbidity and transparency of the formulation. Furthermore, the amount of intact protein, monomers, charge variants, etc. can be measured for physical stability.

[0086] In one embodiment of the present invention, the term “stable” pharmaceutical formulation means a pharmaceutical formulation that satisfies one or more of the following (G)-1 to (G)-6.

[0087]

[0088] (G)-1 Apparent Transparency (Clarity)

[0089] - A pharmaceutical preparation that is transparent or slightly milky in appearance after being stored at a temperature of 5±3℃ for 0 days, 3 days, 5 days, 6 days, 7 days, 10 days, or 2 weeks;

[0090] - A pharmaceutical preparation that is transparent or slightly milky in appearance after being stored for 0 days, 3 days, 5 days, 6 days, 7 days, 10 days, or 2 weeks under a temperature of 40±2℃, a relative humidity of 75±5%, and a sealed condition;

[0091] - A pharmaceutical preparation that is transparent or slightly milky in appearance after storage for 0, 5, or 9 days at a temperature of 45±2℃ and in a sealed condition;

[0092] - A pharmaceutical preparation that is transparent or slightly milky in appearance after being stored for 72 hours under conditions of 12,000 Lux, temperature 25±2℃, and relative humidity 60±5%;

[0093]

[0094] (G)-2 Content of surfactant (Polysorbate %)

[0095] - A pharmaceutical preparation having a surfactant content (Polysorbate %) of 0.03% to 0.04% as measured by CAD after storage at a temperature of 5±3℃ for 0, 5, and 10 days;

[0096] - A pharmaceutical preparation having a surfactant content (Polysorbate %) of 0.02% to 0.04% as measured by CAD after storage for 0, 5, and 10 days under a temperature of 40±2℃, a relative humidity of 75±5%, and a sealed condition;

[0097] - A pharmaceutical preparation having a surfactant content (Polysorbate %) of 0.02% to 0.04% as measured by CAD after storage for 0, 5, and 10 days at 50°C and in a sealed condition;

[0098] - A pharmaceutical preparation having a surfactant content (Polysorbate %) of 0.02% to 0.04% as measured by CAD after storage for 72 hours under conditions of 12,000 Lux, temperature 25±2℃, and relative humidity 60±5%;

[0099]

[0100] (G)-3 Intact immunoglobulin G content (Intact IgG%)

[0101] - A pharmaceutical preparation having an intact immunoglobulin G content (Intact IgG%) of 95% to 100% as measured by non-reducing CE-SDS after storage at a temperature of 5±3℃ for 0 days, 3 days, 5 days, 6 days, 7 days, 10 days, or 2 weeks;

[0102] - A pharmaceutical preparation having an intact immunoglobulin G content (Intact IgG%) of 94% to 100% as measured by non-reducing CE-SDS after storage for 0 days, 3 days, 5 days, 6 days, 7 days, 10 days, or 2 weeks at a temperature of 40±2℃, a relative humidity of 75±5%, and in a sealed condition;

[0103] - A pharmaceutical preparation having an intact immunoglobulin G content (Intact IgG%) of 93% to 100% as measured by non-reducing CE-SDS after storage for 0, 5, or 9 days at a temperature of 45±2℃ and in a sealed condition;

[0104] - A pharmaceutical preparation having an intact immunoglobulin G content (Intact IgG%) of 91% to 100% as measured by non-reducing CE-SDS after storage for 0, 3, 5, 6, or 10 days at 50°C and in a sealed condition;

[0105] - A pharmaceutical preparation having an intact immunoglobulin G content (Intact IgG%) of 92% to 100% as measured by non-reducing CE-SDS after storage for 72 hours under conditions of 12,000 Lux, temperature 25±2℃, and relative humidity 60±5%;

[0106]

[0107] (G)-4 Intact heavy and light chain content (Intact LC+HC%)

[0108] - A pharmaceutical preparation having an intact immunoglobulin G content (Intact LC+HC%) of 98% to 100% as measured by non-reducing CE-SDS after storage at a temperature of 5±3℃ for 0 days, 3 days, 5 days, 6 days, 7 days, 10 days, or 2 weeks;

[0109] - A pharmaceutical preparation having an intact immunoglobulin G content (Intact LC+HC%) of 97% to 100% as measured by non-reducing CE-SDS after storage for 0 days, 3 days, 5 days, 6 days, 7 days, 10 days, or 2 weeks at a temperature of 40±2℃, a relative humidity of 75±5%, and in a sealed condition;

[0110] - A pharmaceutical preparation having an intact immunoglobulin G content (Intact LC+HC%) of 96% to 100% as measured by non-reducing CE-SDS after storage for 0, 5, or 9 days at a temperature of 45±2℃ and in a sealed condition;

[0111] - A pharmaceutical preparation having an intact immunoglobulin G content (Intact LC+HC%) of 96% to 100% as measured by non-reducing CE-SDS after storage for 0, 3, 5, 6, or 10 days at 50°C and in a sealed condition;

[0112] - A pharmaceutical preparation having an intact immunoglobulin G content (Intact LC+HC%) of 98% to 100% as measured by non-reducing CE-SDS after storage for 72 hours under conditions of 12,000 Lux, temperature 25±2℃, and relative humidity 60±5%;

[0113]

[0114] (G)-5 SEC-HPLC monomer

[0115] - A pharmaceutical preparation having a main component (monomer %) of 97% to 100% as measured by SEC-HPLC after storage at a temperature of 5±3℃ for 0 days, 3 days, 5 days, 6 days, 7 days, 10 days, or 2 weeks;

[0116] - A pharmaceutical preparation having a main component (monomer %) of 96% to 100% as measured by SEC-HPLC for 0 days, 3 days, 5 days, 6 days, 7 days, 10 days, or 2 weeks at a temperature of 40±2℃, a relative humidity of 75±5%, and in a sealed condition;

[0117] - A pharmaceutical preparation having a main component (monomer %) of 93% to 100% as measured by SEC-HPLC for 0, 5, or 9 days at a temperature of 45±2℃ and under sealed conditions;

[0118] - A pharmaceutical preparation having a main component (monomer %) of 90% to 100% as measured by SEC-HPLC for 0, 3, 5, 6, or 10 days at a temperature of 50°C and under sealed conditions;

[0119] - A pharmaceutical preparation having a main component (monomer %) of 93% to 100% as measured by SEC-HPLC under conditions of 12,000 Lux, temperature 25±2℃, and relative humidity 60±5% for 72 hours;

[0120]

[0121] (G)-6 IEC-HPLC acid peak %

[0122] - Pharmaceutical preparations having an acid peak of 0% to 20% as measured by IEC-HPLC after storage at a temperature of 5±3℃ for 0 days, 3 days, 5 days, 6 days, 7 days, 10 days, or 2 weeks;

[0123] - A pharmaceutical preparation having an acid peak of 0% to 25% as measured by IEC-HPLC for 0 days, 3 days, 5 days, 6 days, 7 days, 10 days, or 2 weeks under a temperature of 40±2℃, a relative humidity of 75±5%, and a sealed condition;

[0124] - A pharmaceutical preparation having an acid peak of 0% to 30% as measured by IEC-HPLC for 0, 5, or 9 days at a temperature of 45±2℃ and under sealed conditions;

[0125] - A pharmaceutical preparation having an acid peak of 0% to 50% as measured by IEC-HPLC for 0, 3, 5, 6, or 10 days at a temperature of 50°C and under sealed conditions;

[0126] - A pharmaceutical preparation having an acid peak of 0% to 30% as measured by IEC-HPLC under conditions of 12,000 Lux, temperature 25±2℃, and relative humidity 60±5% for 72 hours;

[0127]

[0128] [Implementation Example]

[0129] One embodiment of the present invention provides a stable pharmaceutical formulation comprising (A) 50 to 100 mg / ml of ixekizumab; (B) 0.1 to 20 mM of a histidine buffer; (C) 1 to 20% (w / v) of a stabilizer; and (D) 0.001% (w / v) to 0.1% (w / v) of a surfactant, and having a pH of 5 to 6.2.

[0130] One embodiment of the present invention provides a stable pharmaceutical formulation comprising (A) 50 to 100 mg / ml of ixekizumab; (B) 0.1 to 20 mM of a histidine buffer; (C) 1 to 20% (w / v) of a sugar or sugar alcohol; and (D) 0.001 to 0.1% (w / v) of a polysorbate, wherein the formulation has a pH of 5 to 6.2.

[0131] One embodiment of the present invention provides a stable pharmaceutical formulation comprising (A) 50 to 100 mg / ml of ixekizumab; (B) 0.1 to 10 mM of a histidine buffer; (C) 1 to 20% (w / v) of trehalose or sucrose; and (D) 0.001% (w / v) to 0.1% (w / v) of polysorbate, and having a pH of 5.5 to 6.2.

[0132] One embodiment of the present invention provides a stable pharmaceutical formulation comprising (A) 50 to 100 mg / ml of ixekizumab; (B) 0.1 to 10 mM of histidine buffer; (C) 1 to 10% (w / v) of trehalose or sucrose; and (D) 0.001% (w / v) to 0.1% (w / v) of polysorbate, and having a pH of 5.7 to 6.2.

[0133] One embodiment of the present invention provides a stable pharmaceutical formulation comprising (A) 60 to 100 mg / ml of ixekizumab; (B) 0.1 to 10 mM of a histidine buffer; (C) 1 to 10% (w / v) of trehalose or sucrose; and (D) 0.01 to 0.1% (w / v) of polysorbate 80 or polysorbate 20, and having a pH of 5.5 to 6.

[0134] One embodiment of the present invention provides a stable pharmaceutical formulation comprising (A) 60 to 100 mg / ml of ixekizumab; (B) 1 to 9 mM of a histidine buffer; (C) 1 to 10% (w / v) of trehalose or sucrose; and (D) 0.01 to 0.05% (w / v) of polysorbate 80 or polysorbate 20, and having a pH of 5.7 to 6.2.

[0135] One embodiment of the present invention provides a stable pharmaceutical formulation comprising (A) 80 mg / ml of ixekizumab; (B) 7 mM histidine buffer; (C) 8 to 10% (w / v) of trehalose; and (D) 0.03% (w / v) of polysorbate 80, and having a pH of 5.7.

[0136]

[0137] [product]

[0138] In one embodiment of the present invention, the present invention provides a product comprising a stable pharmaceutical preparation according to the present invention; and a container containing the stable pharmaceutical preparation in a sealed state.

[0139] The above stable pharmaceutical preparation is as described herein.

[0140] In the present invention, the container may be formed from a material such as glass, polymer (e.g., plastic), metal, etc., but is not limited thereto.

[0141] For example, a container according to the present invention may be, but is not limited to, a bottle, a vial, a cartridge, a syringe (e.g., a pre-filled syringe, an auto-injector, etc.) or a tube, most specifically a glass or polymer vial, or a glass or polymer pre-filled syringe.

[0142] In one embodiment of the present invention, the present invention provides a vial filled with a pharmaceutical preparation according to the present invention, a cartridge filled with the pharmaceutical preparation, a pre-filled syringe filled with the pharmaceutical preparation, or an auto-injector containing the pre-filled syringe therein.

[0143] The specific product forms of the vials, cartridges, pre-filled syringes, automatic syringes, etc. and the method of filling the stable pharmaceutical preparation into the vials, cartridges, pre-filled syringes, automatic syringes, etc. can be easily obtained or practiced by a person having ordinary skill in the art to which the present invention pertains. For example, U.S. Patent Nos. 4,861,335 and 6,331,174 disclose specific product forms and filling methods for pre-filled syringes. For example, U.S. Patent Nos. 5,085,642 and 5,681,291 disclose specific product forms and assembly methods for automatic syringes. In addition, the commercialized products such as the vials, cartridges, pre-filled syringes, automatic syringes, etc. can be used as is, or a separately custom-made product can be used in consideration of the physical properties, administration site, administration amount, etc. of the stable pharmaceutical preparation.

[0144] In the present invention, the container may be a single-use container.

[0145] In the present invention, the product according to the present invention may further include instructions for use, storage, or both of the stable pharmaceutical preparation. These instructions may include treatment methods, administration routes, dosages, or timing of administration for diseases in which interleukin-17A activity is detrimental.

[0146] In the present invention, the product may include other tools necessary from a commercial and user standpoint, such as needles, syringes, etc.

[0147]

[0148] [Method for manufacturing a stable pharmaceutical preparation]

[0149] The stable pharmaceutical formulation of the present invention can be manufactured using known methods and is not limited to a specific manufacturing method. For example, a pharmaceutical formulation can be manufactured by adjusting the pH of a solution containing a surfactant and a stabilizer by adding a buffer, and then adding an antibody to the mixed solution. Alternatively, a pharmaceutical formulation can be manufactured by preparing a solution containing an antibody, a buffer, and a stabilizer in the final stage of the purification process, and then adding a surfactant to the solution.

[0150]

[0151] [How to use stable pharmaceutical preparations]

[0152] In the present invention, the stable pharmaceutical preparation according to the present invention can exhibit a therapeutic effect on a disease related to interleukin-17A (IL-17A).

[0153] In the present invention, the stable pharmaceutical preparation according to the present invention can be used for intravenous (IV) administration or subcutaneous (SC) administration.

[0154] In one embodiment of the present invention, the stable pharmaceutical preparation may not undergo a reconstitution step prior to use.

[0155] The concentrations of other components, including antibodies, in the pharmaceutical preparation are as described above, and the total volume of the pharmaceutical preparation according to the present invention may be 0.5 to 2.0 mL.

[0156] The dosage or timing of administration of the above pharmaceutical preparation may vary depending on the type of disease, severity and progress of the disease, the patient's health and response to treatment, or the judgment of the treating physician, and is not limited to a specific dosage or timing of administration.

[0157]

[0158] [Treatment and stabilization methods]

[0159] In one embodiment of the present invention, the present invention provides a method for treating a disease, comprising administering to a patient having a disease in which inhibition of interleukin-17A (IL-17A) activity is effective in alleviating symptoms, a stable pharmaceutical formulation comprising (A) ixekizumab and (B) a histidine buffer.

[0160] In another embodiment of the present invention, the present invention provides a method of stabilizing an antibody in a pharmaceutical formulation, comprising preparing a stable pharmaceutical formulation comprising (A) ixekizumab and (B) a histidine buffer.

[0161] The above stable pharmaceutical preparation is as described herein.

[0162] The treatment method or stabilization method according to the present invention applies the description described above in this specification.

[0163] Each of the above features described herein may be used in combination, and the fact that each of the above features is described in different dependent claims of the patent claims does not indicate that they cannot be used in combination.

[0164]

[0165] Hereinafter, the present invention will be described in detail through examples. The following examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The references cited herein are incorporated by reference into the specification of the present invention.

[0166]

[0167] Regarding the antibody used in the following experimental examples, ixekizumab, cultured and purified at the Celltrion Research Institute, was used. The following methods were used to measure the physical stability, chemical stability, and biological activity of the pharmaceutical preparations described below.

[0168] Clarity

[0169] Apparent clarity was measured using the naked eye.

[0170]

[0171] Content of surfactant (Polysorbate)

[0172] The content of surfactant (polysorbate) was measured using a charged aerosol detector (CAD).

[0173]

[0174] Intact IgG content (%)

[0175] The content (%) of intact immunoglobulin G was measured using non-reduced capillary electrophoresis-sodium dodecyl sulfate (NR CE-SDS).

[0176]

[0177] Intact heavy and light chain content (Intact HC+LC%)

[0178] The content (%) of intact heavy and light chains was measured using reduced capillary electrophoresis-sodium dodecyl sulfate (R CE-SDS).

[0179]

[0180] SEC-HPLC main component

[0181] Monomer (%) was measured using Size Exclusion High Performance Liquid Chromatography (SEC-HPLC).

[0182]

[0183] charge transformant

[0184] The acid peak (%) was measured by ion exchange chromatography-high performance liquid chromatography (IEC-HPLC).

[0185]

[0186] Experimental Example 1: Preparation of a pharmaceutical formulation containing ixekizumab

[0187] Examples 1 to 7 and Comparative Examples 1 to 3 in Table 1 below were prepared by preparing each buffer at a pH appropriate for each pH, ​​adding a stabilizer, then adding an antibody, and then adding a surfactant. The specific contents of each component are as described in Table 1 below.

[0188] Antibody Surface active agent Stabilizer Buffer pH Container Example 180 mg / mL Polysorbate 80 0.03% (w / v) Sucrose 8% (w / v) Histidine 7 mM 5.5 Vial Example 280 mg / mL Polysorbate 80 0.03% (w / v) Sucrose 8% (w / v) Histidine 7 mM 5.7 Vial Example 380 mg / mL Polysorbate 80 0.03% (w / v) Sucrose 8% (w / v) Histidine 7 mM 6.2 Vial Example 480 mg / mL Polysorbate 80 0.03% (w / v) Trehalose 10% (w / v) Histidine 7 mM 5.7 Vial Example 580 mg / mL Polysorbate 80 0.03% (w / v) Mannitol 8% (w / v) Histidine 7 mM 5.7 Vial Example 680 mg / mL Polysorbate 80 0.03% (w / v) Sorbitol 5% (w / v) Histidine 7 mM 5.7 Vial Example 780 mg / mL Polysorbate 20 0.03% (w / v) Trehalose 10% (w / v) Histidine 7 mM 5.7 Vial Comparative Example 180 mg / mL Polysorbate 80 0.03% (w / v) Sucrose 8% (w / v) -5.7 Vial Comparative Example 280 mg / mL Polysorbate 80 0.03% (w / v) Sucrose 8% (w / v) Succinic acid 10 mM 5.2 Vial Comparative Example 380 mg / mLPolysorbate 80 0.03% (w / v)Sucrose 8% (w / v)Succinic acid 10 mM5.7 Vial

[0189]

[0190] Experimental Example 2: Buffer Comparison

[0191] Examples 1 to 3 and Comparative Examples 1 to 3 manufactured according to Experimental Example 1 were stored for 72 hours under i) a temperature of 5±3°C, ii) a temperature of 40±2°C and a relative humidity of 75±5%, iii) a temperature of 45°C, and iv) irradiation with 12,000 Lux of light, a temperature of 25±2°C, and a relative humidity of 60±5%, and the stability results are shown in Table 2 below.

[0192]

[0193] Evaluation Examples and ResultsExample 1Example 2Example 3Comparative Example 1Comparative Example 2Comparative Example 3Antibody (mg / ml)80808080808080BufferHistidine 7 mMHistidine 7 mMHistidine 7 mM-Succinic acid 10 mMSuccinic acid 10 mMStabilizerSucrose 8% (w / v)Sucrose 8% (w / v)Sucrose 8% (w / v)Sucrose 8% (w / v)Sucrose 8% (w / v)Sucrose 8% (w / v)pH5.55.76.25.75.25.7Polysorbate 80 (%, w / v)0.030.030.030.030.030.03Initial TransparencyVery slightly milkyVery slightly milkyVery slightly milkyVery slightly milkySlightly milky Milky white Milky white Intact IgG content 95.5 295.5 395.6 395.5 795.6 195.5 8 Intact heavy and light chain content LC+HC 99.7 499.7 499.7 499.7 399.7 499.3 599.3 2 SEC-HPLC Monomer (%) 97.7 297.8 497.7 497.7 298.0 297.7 8 IEC-HPLC (Acid peak %) 18.5 18.2 218.5 6 17.9 4 18.4 18.5 5 Temperature 5±3℃ 1st week Transparency Very slightly milky Very slightly milky Very slightly milky Slightly milky Milky white Intact IgG content 95.5 295.5 395.6 395.5 795.6 195.5 8 Intact heavy and light chain content LC+HC 99.7 499.7 499.7 499.7 399.7 3599.3 2 SEC-HPLC Monomer (%) 97.7 297.8 497.7 497.7 298.0 297.7 8 IEC-HPLC (Acid peak %) 18.5 18.2 218.5 6 17.9 4 18.4 18.5 5 Temperature 5±3℃ 1st week Transparency Very slightly milky Very slightly milky Very slightly milky Slightly milky Milky white Intact immunoglobulin G content IgG%)95.8895.9095.9795.3195.7195.52 Content of intact heavy and light chains (Intact LC+HC%)99.7299.7099.6999.6999.3399.34SEC-HPLC monomer (%)97.6597.7897.6597.6397.8497.58IEC-HPLC (acid peak %)19.1818.6118.6419.0419.1318.90Temperature 40±2℃, relative humidity 75±5%, 2 weeksTransparencyVery slightly milkyVery slightly milkyVery slightly milkyVery slightly milkySlightly milkyMilky milkyContent of intact immunoglobulin G (Intact IgG%)95.4094.9495.5495.4494.8395.35Intact heavy and light chain content (Intact LC+HC%)98.3298.2898.4998.4097.2398.27SEC-HPLC monomer (%)96.3696.4096.3796.1896.2795.74IEC-HPLC (acid peak %)24.6621.7722.3622.2620.4324.14Temperature 45℃Day 9TransparencyVery slightly milkyVery slightly milkyVery slightly milkyVery slightly milkySlightly milkyMilkyIntact IgG content (Intact IgG%)94.1394.3594.9994.5893.1094.86Intact heavy and light chain content (Intact LC+HC%)96.2596.5697.8997.7194.4497.26SEC-HPLC Monomer (%)93.7094.0694.3994.3492.9594.21IEC-HPLC (acid peak %)26.6924.9526.2227.0125.0129.9312,000 Lux light irradiation, temperature 25±2℃, relative humidity 60±5%, 72 hours Transparency Very slightly milky Very slightly milky Very slightly milky Very slightly milky Slightly milky Milky Intact immunoglobulin G content (Intact IgG%)94.3894.5694.4794.6594.7293.69 Intact heavy and light chain content (Intact LC+HC%)99.7399.7399.7099.7099.1999.18 SEC-HPLC monomer (%)94.7694.7093.6492.1894.8892.46 IEC-HPLC (acid peak %)28.5626.2526.6727.5125.6825.73.

[0194] Under the temperature condition of 5±3℃, the formulations of Examples 1 to 3 were found to be pharmaceutically acceptable stable examples, with apparent transparency, a content of intact immunoglobulin G (Intact IgG%) of 95% or more, a content of intact heavy and light chains (Intact LC+HC%) of 98% or more, a SEC-HPLC monomer component of 97% or more, and an IEC-HPLC (acid peak%) of 20% or less.

[0195] Under conditions of a temperature of 40±2℃ and a relative humidity of 75±5%, the formulations of Examples 1 to 3 were found to be pharmaceutically acceptable stable examples, with apparent transparency, a content of intact immunoglobulin G (Intact IgG%) of 94% or more, a content of intact heavy and light chains (Intact LC+ HC%) of 97% or more, a SEC-HPLC monomer component of 96% or more, and an IEC-HPLC (acid peak%) of 25% or less.

[0196] Under conditions of a temperature of 45°C, the formulations of Examples 1 to 3 were found to be pharmaceutically acceptable stable examples, with apparent transparency, a content of intact immunoglobulin G (Intact IgG%) of 93% or more, a content of intact heavy and light chains (Intact LC+HC%) of 96% or more, a SEC-HPLC monomer component of 93% or more, and an IEC-HPLC (acid peak%) of 30% or less.

[0197] Under conditions of irradiation with 12,000 Lux light, temperature 25±2℃, relative humidity 60±5%, and storage for 72 hours, it was found that the examples 1 to 3 were stable examples that were pharmaceutically acceptable, with an apparent transparency, an intact immunoglobulin G content (Intact IgG%) of 92% or more, an intact heavy and light chain content (Intact LC+HC%) of 98% or more, an SEC-HPLC monomer component of 93% or more, and an IEC-HPLC (acid peak%) of 30% or less.

[0198] Based on the above experimental results, it was found that Examples 1 to 3 containing a histidine buffer were stable under all experimental conditions.

[0199]

[0200] On the other hand, Comparative Examples 2 to 3 containing a succinic acid buffer showed a slightly milky or milky transparency under all conditions, which did not meet the formulation stability standard, and Comparative Example 1 not containing a buffer did not meet the formulation stability standard with an SEC-HPLC monomer of 92.18% under conditions of 12,000 Lux light irradiation, temperature 25±2℃, relative humidity 60±5%, and storage for 72 hours.

[0201] Based on the above results, in the following Experimental Example 3, stability was further confirmed by changing the types of sugars and amino acids as stabilizers based on the histidine buffer that had shown excellent effects in Experimental Example 2.

[0202]

[0203] Experimental Example 3: Comparison of stabilizers in an example including a histidine buffer.

[0204] The stability results of Examples 4 to 6 manufactured according to Experimental Example 1 under i) a temperature of 5±3°C, ii) a temperature of 40±2°C, a relative humidity of 75±5%, iii) a temperature of 50°C, and iv) 12,000 Lux light irradiation, a temperature of 25±2°C, a relative humidity of 60±5%, for 72 hours are shown in Table 3 below.

[0205] Evaluation Examples and ResultsExample 4Example 5Example 6Antibody (mg / ml)808080BufferHistidine7 mMHistidine7 mMHistidine7 mMStabilizerTrehalose 10% (w / v)Mannitol8% (w / v)Sorbitol5% (w / v)pH5.75.75.7Polysorbate 80 (%, w / v)0.030.030.03Initial Polysorbate 80 (%) Concentration0.0330.0340.034Content of Intact Immunoglobulin G (Intact IgG%)97.0596.9396.98Content of Intact Heavy and Light Chains (Intact LC+HC%)99.0899.1399.28SEC-HPLC Monomer (%)98.4298.4898.49IEC-HPLC (acid peak %)18.9318.9218.92Temperature 5±3℃Day 5Polysorbate 80 (%)Concentration0.0330.0330.037Intact immunoglobulin G content (Intact IgG%)96.6596.4896.53Content of intact heavy and light chains (Intact LC+HC%)99.4699.4799.54SEC-HPLC Monomer (%)98.2698.4698.45IEC-HPLC (acid peak %)19.0219.0818.89IEC-HPLC (main peak %)61.0161.7660.62Temperature 5±3℃Day 10Polysorbate 80 (%) Concentration 0.033 0.034 0.034 Intact immunoglobulin G content (Intact IgG%) 96.25 95.8 95.86 Intact heavy and light chain content (Intact LC+HC%) 99.29 99.27 99.38 SEC-HPLC monomer (%) 98.43 98.46 98.48 IEC-HPLC (acid peak %) 18.79 18.68 18.8 Temperature 40±2℃, relative humidity 75±5%, 5th day Polysorbate 80 (%) Concentration 0.031 0.032 0.033 Intact immunoglobulin G content (Intact IgG%) 96.02 95.84 95.87 Intact heavy and light chain content (Intact LC+HC%)99.3499.3499.34SEC-HPLC Monomer (%)97.8397.4897.89IEC-HPLC(Acid peak %)20.6720.5620.62Temperature 40±2℃, relative humidity 75±5%, 10th day Polysorbate 80 (%) concentration 0.0310.0320.032Intact immunoglobulin G content (Intact IgG%) 95.0894.8994.92Content of intact heavy and light chains (Intact LC+HC%) 98.7698.698.58SEC-HPLC monomer (%) 97.5397.5897.59IEC-HPLC (acid peak %) 23.1322.6722.89Temperature 50℃5th day Polysorbate 80 (%) concentration 0.0330.0330.033Content of intact immunoglobulin G (Intact IgG%) 94.4793.6494.03Content of intact heavy and light chains Content (Intact LC+HC%) 98.5898.6598.64SEC-HPLC Monomer (%) 94.7694.1894IEC-HPLC (Acidic Peak %) 30.3529.9230.0712,000 Lux light irradiation, temperature 25±2℃, relative humidity 60±5%, 72 hours Polysorbate 80 (%) Concentration 0.0340.0330.034 Intact immunoglobulin G content (Intact IgG%) 92.8893.293.3 Intact heavy and light chain content (Intact LC+HC%) 99.1899.1999.22SEC-HPLC Monomer (%) 95.4195.2695.53IEC-HPLC (Acidic Peak %) 27.0127.3527.10.

[0206] Under the temperature condition of 5±3℃, it was found that all examples were pharmaceutically acceptable stable examples, with a surfactant content (Polysorbate %) of 0.03% or more, an intact immunoglobulin G content (Intact IgG%) of 95% or more, an intact heavy and light chain content (Intact LC+HC%) of 98% or more, an SEC-HPLC monomer component of 97% or more, and an IEC-HPLC (acid peak %) of 20% or less.

[0207] Under conditions of a temperature of 40±2℃ and a relative humidity of 75±5%, all examples were found to be pharmaceutically acceptable and stable examples, with a surfactant content (Polysorbate %) of 0.03% or more, an intact immunoglobulin G content (Intact IgG%) of 94% or more, an intact heavy and light chain content (Intact LC+HC%) of 96% or more, an SEC-HPLC monomer component of 96% or more, and an IEC-HPLC (acid peak %) of 25% or less.

[0208] Under the temperature condition of 50℃, it was found that all examples were pharmaceutically acceptable stable examples, with a surfactant content (Polysorbate %) of 0.03% or more, an intact immunoglobulin G content (Intact IgG%) of 91% or more, an intact heavy and light chain content (Intact LC+HC%) of 96% or more, an SEC-HPLC monomer component of 92% or more, and an IEC-HPLC (acid peak %) of 50% or less.

[0209] Under conditions of 12,000 Lux light irradiation, temperature 25±2℃, relative humidity 60±5%, and storage for 72 hours, all examples were found to be pharmaceutically acceptable stable examples, with a surfactant content (Polysorbate %) of 0.03% or more, an intact immunoglobulin G content (Intact IgG%) of 92% or more, an intact heavy and light chain content (Intact LC+HC%) of 98% or more, an SEC-HPLC monomer component of 94% or more, and an IEC-HPLC (acid peak %) of 30% or less.

[0210] Based on the above experimental results, it was found that all of Examples 4 to 6 were pharmaceutically acceptable and stable examples, and in particular, Example 4 showed the most stable quality maintenance tendency with a surfactant concentration decrease rate of -11.24%, an intact immunoglobulin G content (Intact IgG%) of 94.47%, and an SEC-HPLC monomer component of 94.76% after 5 days at 50°C, indicating that it had the highest stability under trehalose stabilizer conditions.

[0211] Therefore, in Experimental Example 4 below, stability was additionally confirmed by comparing surfactant types based on trehalose stabilizer in histidine buffer.

[0212]

[0213] Experimental Example 4: Comparison of Surfactant Types

[0214] The stability results of Examples 4 and 7 manufactured according to Experimental Example 1 and Comparative Example 1 under i) a temperature of 5±3°C, ii) a temperature of 40±2°C, a relative humidity of 75±5%, and iii) 12,000 Lux light irradiation, a temperature of 25±2°C, a relative humidity of 60±5%, and 72 hours are shown in Table 4 below.

[0215] Evaluation Examples and ResultsExample 4Example 7Comparative Example 1Antibody (mg / ml)808080BufferHistidine 7 mMHistidine 7 mM-StabilizerTrehalose 10% (w / v)Trehalose 10% (w / v)Sucrose 8% (w / v)pH5.75.75.7SurfactantPolysorbate 800.03 (%, w / v)Polysorbate 200.03 (%, w / v)Polysorbate 800.03 (%, w / v)InitialIntactIgG Content (Intact IgG%)96.6396.6196.72SEC-HPLCMonomer (%)98.598.5498.41SEC-HPLCHigh Molecular Weight Component (%)1.441.411.53SEC-HPLCLow Molecular Weight Ingredients (%) 0.06 0.05 0.06 IEC-HPLC (acid peak %) 18.2 18.18 18.55 Temperature 5±3℃ 3 Content of primary intact immunoglobulin G (Intact IgG%) 96.77 96.7 196.59 SEC-HPLC Monomer (%) 98.5 98.5 198.39 SEC-HPLC High molecular weight components (%) 1.44 1.43 1.55 SEC-HPLC Low molecular weight components (%) 0.06 0.06 0.06 IEC-HPLC (acid peak %) 18.5 118.24 18.55 Temperature 40±2℃, relative humidity 75±5%, 3 Content of primary intact immunoglobulin G (Intact IgG%) 96.26 96.4 196.12 SEC-HPLC Monomer (%)98.1998.297.82IEC-HPLC (acid peak %)18.4818.2919.37Temperature 40±2℃, relative humidity 75±5%,6 Primary Intact Immunoglobulin G Content (Intact IgG%)96.4596.4396.22SEC-HPLCMonomer (%)97.9397.9797.50IEC-HPLC (acid peak %)19.8519.6120.8112,000 Lux light irradiation, temperature 25±2℃, relative humidity 60±5%, 72 hours Intact Immunoglobulin G Content (Intact IgG%)94.7995.3591.40Content of Intact Heavy and Light Chains (Intact LC+HC%)98.5098.2998.57SEC-HPLC Monomer (%)95.5996.2190.51IEC-HPLC(Acid peak %)26.4525.4528.59

[0216] Under the temperature condition of 5±3℃, it was found that all examples were pharmaceutically acceptable stable examples, with the content of intact immunoglobulin G (Intact IgG%) being 95% or more, the SEC-HPLC monomer component being 97% or more, and the IEC-HPLC (acid peak%) being 20% ​​or less.

[0217] Under conditions of a temperature of 40±2℃ and a relative humidity of 75±5%, it was found that all examples were pharmaceutically acceptable and stable examples, with a content of intact immunoglobulin G (Intact IgG%) of 94% or more, a SEC-HPLC monomer component of 96% or more, and an IEC-HPLC (acid peak%) of 25% or less.

[0218] Under conditions of 12,000 Lux light irradiation, temperature 25±2℃, relative humidity 60±5%, and storage for 72 hours, Examples 4 and 7 were found to be pharmaceutically acceptable stable examples, with the content of intact immunoglobulin G (Intact IgG%) being 92% or more, SEC-HPLC monomer component being 94% or more, and IEC-HPLC (acid peak %) being 30% or less.

[0219] Based on the above experimental results, it was found that Examples 4 and 7 were pharmaceutically acceptable and stable examples. In particular, Examples 4 and 7 had intact immunoglobulin G contents (Intact IgG%) of 94.79% and 95.35%, respectively, under conditions of 12,000 Lux light irradiation, 25±2℃ temperature, 60±5% relative humidity, and 72 hours of storage, and SEC-HPLC monomer components were 95.59% and 96.21%, respectively, showing the most stable quality maintenance tendency compared to Comparative Example 1, and it was confirmed that there was no significant difference depending on the type of polysorbate.

[0220]

[0221] From the above description, those skilled in the art will understand that the present application can be implemented in other specific forms without altering its technical concept or essential characteristics. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of this application should be interpreted to include all changes or modifications derived from the meaning and scope of the following claims and their equivalents, rather than the detailed description above.

Claims

1. (A) Ixekizumab at 1 to 150 mg / ml; and (B) 0.1 to 50 mM histidine buffer A stable pharmaceutical preparation comprising:

2. In the first paragraph, the (A) ixekizumab comprises a light chain variable region comprising a CDR1 domain comprising an amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising an amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising an amino acid sequence of SEQ ID NO: 3; and a heavy chain variable region comprising a CDR1 domain comprising an amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising an amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising an amino acid sequence of SEQ ID NO: 6, which is a stable pharmaceutical formulation.

3. In the first paragraph, the (A) ixekizumab is a stable pharmaceutical formulation comprising a light chain variable region comprising an amino acid sequence of SEQ ID NO: 7; and a heavy chain variable region comprising an amino acid sequence of SEQ ID NO:

8.

4. A stable pharmaceutical formulation according to claim 1, wherein (A) ixekizumab comprises a light chain comprising an amino acid sequence of SEQ ID NO: 9; and a heavy chain comprising an amino acid sequence of SEQ ID NO:

10.

5. In the first paragraph, the concentration of (A) ixekizumab is 1 to 100 mg / ml, a stable pharmaceutical preparation.

6. A stable pharmaceutical formulation according to claim 1, wherein the concentration of the (B) histidine buffer is 1 to 30 mM.

7. A stable pharmaceutical preparation having a pH of 4 to 7 according to claim 1. 8.(A) Ixekizumab at 1 to 150 mg / ml; (B) 0.1 to 50 mM histidine buffer; (C) 1 to 30% (w / v) of a stabilizer; and (D) 0.001% (w / v) to 1% (w / v) of surfactant A stable pharmaceutical preparation comprising:

9. In claim 8, the (A) ixekizumab comprises a light chain variable region comprising a CDR1 domain comprising an amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising an amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising an amino acid sequence of SEQ ID NO: 3; and a heavy chain variable region comprising a CDR1 domain comprising an amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising an amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising an amino acid sequence of SEQ ID NO: 6, which is a stable pharmaceutical formulation.

10. In the 8th paragraph, the (A) ixekizumab is a stable pharmaceutical formulation comprising a light chain variable region comprising an amino acid sequence of SEQ ID NO: 7; and a heavy chain variable region comprising an amino acid sequence of SEQ ID NO:

8.

11. A stable pharmaceutical formulation according to claim 8, wherein (A) ixekizumab comprises a light chain comprising an amino acid sequence of SEQ ID NO: 9; and a heavy chain comprising an amino acid sequence of SEQ ID NO:

10.

12. In the 8th paragraph, the concentration of (A) ixekizumab is 1 to 100 mg / ml, a stable pharmaceutical preparation 13. A stable pharmaceutical formulation according to claim 8, wherein the concentration of the (B) histidine buffer is about 1 to 30 mM.

14. In the 8th paragraph, the (C) stabilizer is a stable pharmaceutical preparation comprising at least one selected from the group consisting of sugars and sugar alcohols.

15. A stable pharmaceutical preparation according to claim 14, wherein the sugar or sugar alcohol comprises at least one selected from the group consisting of trehalose, sucrose, sorbitol, and mannitol.

16. A stable pharmaceutical preparation according to claim 8, wherein the concentration of the stabilizer is 1 to 10% (w / v).

17. A stable pharmaceutical formulation according to claim 8, wherein the (D) surfactant is a nonionic surfactant.

18. A stable pharmaceutical formulation according to claim 8, wherein the (D) surfactant comprises polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a mixture of two or more thereof.

19. A stable pharmaceutical formulation according to claim 8, wherein the (D) surfactant comprises polysorbate 20 or polysorbate 80.

20. A stable pharmaceutical formulation according to claim 8, wherein the concentration of the (D) surfactant is 0.01 to 0.1% (w / v). 21.(A) Ixekizumab at 80 mg / ml; (B) 1 to 10 mM histidine buffer; (C) 1 to 10% (w / v) of trehalose or sucrose; and (D) 0.01 to 0.1% (w / v) polysorbate 20 or polysorbate 80 A stable pharmaceutical preparation comprising: