Anti-il-23p19 antibody formulations

Abstract

The present invention particularly provides a liquid pharmaceutical formulation comprising a) a 150 mg / ml anti-IL-23p19 antibody, wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2; b) a polyol; and c) a surfactant. The disclosed high-concentration formulation advantageously exhibits storage stability and is suitable for subcutaneous administration.

Description

Technical Field

[0001] This invention generally relates to formulations containing anti-IL-23p19 antibodies such as risankizumab, which bind to the p19 subunit of human IL-23. More specifically, it discloses pharmaceutical formulations containing high concentrations of the anti-IL-23p19 antibody risankizumab, and related products and uses for treating various diseases and conditions. This document discloses stable liquid pharmaceutical formulations containing 150 mg / ml of the antibody risankizumab. Prior Technology

[0002] Human IL-23 is composed of a common subunit (p40) with IL-12 and a unique p19 subunit. Regardless of this shared p40 subunit, the functions of IL-23 and IL-12 are completely different. IL-12 is crucial for the Th1 response by promoting Th1 cell differentiation, proliferation, and activation. In contrast, IL-23 supports the development and maintenance of a group of CD4+ T helper cells called Th17 cells, because these cells have the ability to produce IL-17 and related cytokines. IL-23 is involved in chronic autoimmune inflammation, and the regulation of IL-23 activity provides effective therapies for autoimmune diseases.

[0003] One of the autoimmune diseases in which IL-23 plays a major role is psoriasis, a chronic immune-mediated inflammatory disease characterized by the overproliferation of keratinocytes and infiltrative T lymphocytes that overexpress pro-inflammatory mediators. This disease is a chronic, painful, immune-mediated inflammatory skin disease with a lifelong remission and relapse process characterized by variable factors that trigger exacerbations in susceptible individuals, making treatment challenging. Uncontrolled inflammation in psoriasis can lead to common comorbidities, including cardiovascular (CV) diseases (including hypertension and an increased risk of myocardial infarction, stroke, and CV death), obesity, type 2 diabetes, arthritis, and chronic kidney disease. Psoriasis is also associated with serious psychiatric comorbidities, including depression, anxiety, and suicidal tendencies, as well as substance abuse.

[0004] A highly effective and specific inhibitor of IL-23 is the antibody risenosumab. Risenosumab is a monoclonal antibody targeting the p19 subunit of IL-23, humanized immunoglobulin G1 (IgG1). Risenosumab's binding to IL-23 p19 inhibits IL-23-induced and maintains the activity of T helper (Th) 17 cells, innate lymphocytes, γδT cells, and natural killer (NK) cells, which cause tissue inflammation, destruction, and abnormal tissue repair. Risenosumab is particularly effective in treating autoimmune and inflammatory diseases, specifically psoriasis. Clinical studies have revealed excellent safety and efficacy of risenosumab in the treatment of plaque psoriasis. The approved recommended dose for the treatment of psoriasis is 150 mg, administered subcutaneously twice daily at weeks 0, 4, and every 12 weeks thereafter.

[0005] Larger drug volumes present challenges, especially in patients with chronic conditions whose drug compliance and duration of action are significantly lower than those in patients with acute conditions. Subcutaneous administration is preferred for therapeutic indications requiring home (self-)medication, such as chronic diseases like psoriasis. However, subcutaneous administration is limited by injection volume, which can be attributed to tissue back pressure and injection pain. This also depends on the compound being administered. Most drugs, such as risenolimumab, are administered subcutaneously in unit doses not exceeding 1 ml. Therefore, for larger volumes, such as greater than 2 ml, multiple injections are usually used, but this method may increase the rate of attrition or reduce patient compliance.

[0006] Therefore, to allow for the administration of high doses of antibodies such as risenosumab in a single injection, pharmaceutical formulations with increased antibody concentrations are required. However, increasing the antibody concentration in antibody formulations can cause stability problems, such as aggregation leading to high molecular weight species (HMWS) formation and increased viscosity. Therefore, providing stable, high-concentration liquid antibody formulations suitable for non-enteral administration, such as subcutaneous injection, presents a significant challenge. Summary of the Invention

[0007] This invention provides a liquid antibody formulation containing 150 mg / ml of an antibody as defined herein. The antibody is risenosumab or an antibody containing the same heavy and light chain sequences as risenosumab. Such antibody formulations with high antibody concentrations are not described or are not available in this art, and this invention makes a significant contribution to this art by providing such high-concentration antibody formulations. Regardless of the high antibody concentration, the formulations of this invention are stable and suitable for therapeutic use. As demonstrated in the examples, the formulations of this invention containing 150 mg / ml of risenosumab antibody provide advantageous stability characteristics and are well-suited for subcutaneous administration. It provides long-term stability. Advantageously, a 150 mg dose of antibody can be administered in a single 1 ml injection.

[0008] According to a first embodiment of the present invention, a liquid pharmaceutical formulation comprising 150 mg / ml anti-IL-23p19 antibody is provided, wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2.

[0009] Based on this first-state sample, the liquid pharmaceutical preparation contains... a) 150 mg / ml anti-IL-23p19 antibody, wherein the antibody comprises the light chain amino acid sequence according to SEQ ID NO: 1 and the heavy chain amino acid sequence according to SEQ ID NO: 2; b) Polyols; and c) Surfactants. This formulation may additionally contain d) a buffer. Furthermore, the present invention provides a buffer-free formulation containing 150 mg / ml of antibody. As disclosed herein, the liquid pharmaceutical formulation according to the first state is stable.

[0010] Based on the second state of this first state sample, a stable liquid pharmaceutical formulation comprising the following is provided: a) 150 mg / ml anti-IL-23p19 antibody, wherein the antibody comprises the light chain amino acid sequence according to SEQ ID NO: 1 and the heavy chain amino acid sequence according to SEQ ID NO: 2; b) Tension regulators; and c) Surfactants, The formulation has a pH of 5.5-5.9 and is isotonic. This formulation may additionally contain d) a buffer.

[0011] The first and second state formulations of the antibody formulation based on the first state sample of 150 mg / ml can also be provided in lyophilized form.

[0012] In the relevant sample, a sealed container containing the formulation of the present invention is provided. []

[0013] In related embodiments, this invention relates to formulations of the invention or containers containing formulations of the invention for therapeutic treatment of human individuals. Diseases to be treated may include psoriasis and inflammatory bowel disease. In another embodiment, diseases to be treated may include psoriatic arthritis and Crohn's disease.

[0014] Other objects, features, advantages, and aspects of this application will become apparent to those skilled in the art from the following description and the appended claims. However, it should be understood that while the following description, the appended claims, and the specific examples indicate preferred embodiments of this application, they are given for illustrative purposes only. Simple Explanation of the Diagram

[0015] Figure 1 shows the light chain amino acid sequence of the antibody (SEQ ID NO: 1). Figure 2 shows the heavy chain amino acid sequence of the antibody (SEQ ID NO: 2). Implementation

[0016] [Cross-reference to related applications] []

[0017] This application claims priority to U.S. Provisional Application No. 62 / 897,930, filed on September 9, 2019, the entire contents of which are incorporated herein by reference.

[0018]

[0150] [] [mg] [ / ] [ml] [Antibody formulations and related morphologies] [] According to the first state sample, a liquid pharmaceutical formulation containing 150 mg / ml anti-IL-23p19 antibody is provided, wherein the antibody contains the light chain amino acid sequence according to SEQ ID NO: 1 and the heavy chain amino acid sequence according to SEQ ID NO: 2.

[0019] Based on this first-state sample, a liquid pharmaceutical preparation comprising the following is provided: a) 150 mg / ml anti-IL-23p19 antibody, wherein the antibody comprises the light chain amino acid sequence according to SEQ ID NO: 1 and the heavy chain amino acid sequence according to SEQ ID NO: 2; b) Polyols; and c) Surfactants. The formulation based on this first-state sample may additionally contain d) a buffer. Furthermore, the present invention provides a buffer-free formulation containing 150 mg / ml of antibody. As disclosed herein, the liquid pharmaceutical formulation based on the first-state sample is stable.

[0020] Based on the second state of this first state sample, a stable liquid pharmaceutical formulation comprising the following is provided: a) 150 mg / ml anti-IL-23p19 antibody, wherein the antibody comprises the light chain amino acid sequence according to SEQ ID NO: 1 and the heavy chain amino acid sequence according to SEQ ID NO: 2; b) Tension regulators; and c) Surfactants, The formulation has a pH of 5.5-5.9 and is isotonic. The stable formulation of this second state may additionally include d) a buffer.

[0021] The formulation of this invention contains a high antibody concentration of 150 mg / ml. Regardless of this high antibody concentration, the liquid pharmaceutical formulation of this invention is stable and advantageously provides long-term stability. Furthermore, the formulation of this invention addresses the core dispensing challenges of high-concentration antibody formulations suitable for injection by providing, in particular, suitable viscosity and good injectability, thus making the formulation of this invention particularly suitable for injections such as subcutaneous injections. These advantageous properties of the formulation are demonstrated in examples. The formulation according to the first state addresses the challenges of formulation injection by providing a stable and robust formulation containing 150 mg / ml of antibody, thereby enabling the subcutaneous administration of a 150 mg dose of antibody using only a target volume of 1 ml.

[0022] As disclosed herein, the formulation according to the first state sample can be provided in the form of a buffer-free formulation or a buffer-containing formulation. According to a core embodiment, the liquid pharmaceutical formulation according to the first state sample includes d) a buffer. In another embodiment, the liquid pharmaceutical formulation does not contain a buffer as an additive.

[0023] Subsequently, the components of the 150 mg / ml antibody formulation according to the first state sample are described in further detail. Specifically, suitable embodiments and features of components a), b), c), and d), as appropriate, contained in the formulations according to the first and second state samples are disclosed.

[0024] [a)] [Antibody] [] The antibody contained in the formulation comprises the light chain amino acid sequence according to SEQ ID NO: 1 and the heavy chain amino acid sequence according to SEQ ID NO: 2. SEQ ID NO: 1 and SEQ ID NO: 2 are shown in Figures 1 and 2. The light and heavy chains of the antibody risankizumab correspond to the light and heavy chain sequences shown in SEQ ID NO: 1 and SEQ ID NO: 2. According to one embodiment, the antibody has the same light and heavy chains as the antibody risankizumab (see INN risankizumab, WHO Drug Information, Vol. 29, No. 2, 2015), and the antibody is referred to herein as risankizumab. Advantageously, the present invention provides a stable, high-concentration liquid pharmaceutical formulation of the antibody risankizumab approved for the treatment of psoriasis. The entire disclosure provided herein is specifically incorporated into and applied to the antibody risankizumab contained in the disclosed formulation. Rissenkiumab can be produced recombinantly in various host cells, and the cells suitable for recombinant antibody production are known in this technology.

[0025] In one embodiment, the antibody is recombinantly produced in mammalian cells. Suitable mammalian cells are those known in the art and include rodent and human cell lines. In one embodiment, the antibody has been recombinantly produced in hamster cells. In one embodiment, the antibody has been recombinantly produced in CHO cells.

[0026] [] [Components] [b] [)] [] The first-state formulation of the 150 mg / ml formulation contains a polyol as component b). Suitable polyols that can be used as excipients in pharmaceutical formulations are known in the art and are described herein.

[0027] The formulation of the second state of the 150 mg / ml formulation according to the first state sample contains a tension modifier as component b). The tension modifier is a reagent suitable for adjusting the tension of the formulation. Tension modifiers that can be used to adjust the tension of pharmaceutical formulations are compounds known in the art and include compounds such as salts and, in addition, polyols such as sugars and sugar alcohols. Therefore, the tension modifier used as component b) in the 150 mg / ml stable formulation according to the second state sample can be a polyol, as is the case with component b) in the 150 mg / ml formulation according to the first state sample. According to one embodiment, the tension modifier contained in the stable liquid formulation according to the second state sample is therefore a polyol, which may be a sugar and / or sugar alcohol.

[0028] As used herein, the term "polyol" refers to a substance having multiple hydroxyl groups and includes sugars (reducing and non-reducing sugars) and sugar alcohols. A polyol may contain at least three, at least four, or at least five hydroxyl groups. In some embodiments, the molecular weight of the polyol is ≤ 600 Da (e.g., in the range of 120 Da to 400 Da). "Reducing sugar" is a sugar containing a free aldehyde or ketone group that can reduce metal ions or covalently react with lysine and other amino groups in proteins. "Non-reducing sugar" is a sugar lacking a free aldehyde or ketone group and not oxidized by a mild oxidizing agent such as Fehling's solution or Benedict's solution. Examples of reducing and non-reducing sugars suitable for use in pharmaceutical formulations are known to those skilled in the art. Non-reducing sugars include, for example, sucrose and trehalose. As disclosed herein, the use of trehalose is particularly useful. Examples of sugar alcohols suitable for use in pharmaceutical formulations are known to those skilled in the art and include, for example, mannitol and sorbitol. Polyols can be used as tensioning agents in formulations.

[0029] Polyols can function and can be used as tension modifiers to regulate tension. For example, some polyols in sugars can also act as stabilizers, thereby supporting the stability of the formulation provided.

[0030] As disclosed herein, the polyol may be selected from sugars and sugar alcohols. Furthermore, as shown in the examples, combinations of two or more different polyols may be used as component b). As shown in the examples, sugars and sugar alcohols, and combinations thereof, may be advantageously used in 150 mg / ml formulations of the present invention. According to one embodiment, the polyol is selected from trehalose, sucrose, sorbitol, mannitol, and combinations thereof. According to one embodiment, the formulation contains only a polyol selected from sugars and / or sugar alcohols as component b). According to one embodiment, the formulation contains only a single polyol as component b).

[0031] In certain embodiments, the polyol is a sugar. The polyol may be selected from trehalose and sucrose. As shown in the examples, the formulation may contain trehalose as a polyol, and the use of trehalose is advantageous. Trehalose may be used alone or in combination with another polyol, such as another sugar or sugar alcohol. According to certain embodiments, the formulation contains only a single sugar, such as trehalose, as a single polyol. Using a single polyol as an excipient, for example, to adjust tension, may be advantageous.

[0032] According to one embodiment, the polyol is a sugar alcohol. The sugar alcohol may be selected from sorbitol and mannitol. In one embodiment, the formulation contains mannitol as a polyol. In another embodiment, the formulation contains sorbitol. As disclosed herein, mannitol and sorbitol can be used as single polyols or in combination with each other or with different polyols such as sugars or other sugar alcohols.

[0033] Sorbitol can be used to provide the stable formulations of the present invention. In some embodiments, sorbitol-free formulations are provided. Sorbitol-free formulations are advantageous for patients with hereditary fructose intolerance. In a particular embodiment, therefore, the liquid pharmaceutical formulation does not contain sorbitol. In some embodiments, the formulation does not contain sugar alcohols.

[0034] As demonstrated in the examples, mannitol and / or trehalose can be used as polyols in the formulations of this invention to adjust the desired osmotic weight molar concentration. However, the amount of mannitol in a 150 mg / ml formulation is limited by the solubility of mannitol and the amount of stock solution that can be added during the formulation steps. Therefore, in the examples, mannitol is used in combination with sugars such as highly soluble trehalose. Trehalose has been found to be advantageous for the antibody formulations disclosed herein because its solubility is sufficient to achieve isotonic formulations with one excipient. Therefore, in some embodiments, trehalose is used as a polyol and may be the sole polyol in the formulation used to adjust isotonicity.

[0035] Polyols can be used to adjust the osmolar concentration. In examples, the osmolar concentration of the formulation is in the range of 200 mOsm / kg to 400 mOsm / kg, such as in the range of 225 mOsm / kg to 375 mOsm / kg. In examples, the osmolar concentration is in the range of 250 mOsm / kg to 350 mOsm / kg, such as in the range of 275 mOsm / kg to 330 mOsm / kg or 290 mOsm / kg to 320 mOsm / kg. The formulation may be isotonic, where "isotonic" means that the formulation of interest has an osmotic pressure substantially the same as that of human blood. The osmolar concentration can be measured, for example, using a vapor pressure or cryo-osmometer.

[0036] The concentration of polyols in the formulation may be at least 80 mM or at least 95 mM. In examples, the concentration of polyols in the formulation is at least 115 mM, at least 125 mM, at least 135 mM, at least 140 mM, at least 150 mM, or at least 160 mM. In examples, the concentration of polyols in the formulation is ≤ 500 mM, ≤ 450 mM, or ≤ 400 mM. As disclosed herein, two or more polyols may also be used as excipients (b). As disclosed herein, in a core embodiment, the polyol is a sugar used at this concentration. In one embodiment, the sugar is trehalose. The same applies to the tension modifier used as component (b) in the formulation according to the second state sample. As disclosed herein, the tension modifier may be a polyol.

[0037] According to the first state sample, specifically the first and second state samples, the polyol concentration in the formulation can be in the range of 95 mM to 400 mM, such as 95 mM to 300 mM or 95 mM to 250 mM. Exemplary concentration ranges of polyols in the formulation include, but are not limited to, 125 mM to 250 mM and 125 mM to 225 mM. In one embodiment, the polyol concentration in the formulation is in the range of 125 mM to 225 mM. In another embodiment, the polyol concentration is in the range of 145 mM to 225 mM. As disclosed herein, in a core embodiment, the polyol is a sugar used at such concentrations as described herein. In one embodiment, the sugar is trehalose.

[0038] According to one embodiment, the polyol is a sugar, and the sugar concentration is in the range of 125 mM to 250 mM, 150 mM to 250 mM, 150 mM to 200 mM, or in the range of 160 mM to 200 mM. In another embodiment, the sugar concentration is in the range of 170 mM to 200 mM. The concentration may be 185 mM. In one embodiment, the sugar is trehalose. Therefore, this document also discloses liquid pharmaceutical formulations comprising 150 mg / ml antibody and 185 mM of trehalose as a polyol. Trehalose may be added, for example, in the form of trehalose dihydrate.

[0039] [c)] [Surfactants] [] The liquid formulation according to the first state sample further includes a surfactant. As shown in the examples, it is advantageous to incorporate a surfactant into the 150 mg / ml formulation. The formulations of the first and second states of the 150 mg / ml formulation according to the first state sample include a surfactant as component c).

[0040] According to one embodiment, the surfactant is a nonionic surfactant. Nonionic surfactants suitable for pharmaceutical formulations are known in the art and are also described herein. At least one surfactant may be a polysorbate (e.g., polysorbate 20) or poloxamer (e.g., poloxamer 188). Combinations of surfactants may also be used. In a core embodiment, the surfactant is a polysorbate. The nonionic surfactant may be selected from polysorbate 20 and / or polysorbate 80. Combinations may also be used. In one embodiment, the surfactant is polysorbate 20. In one embodiment, the formulation of the present invention comprises a single surfactant, such as a single nonionic surfactant, for example, a single polysorbate.

[0041] In one embodiment, the surfactant concentration in the formulation is at least 0.05 mg / ml. The concentration may be at least 0.075 mg / ml. As demonstrated in the examples, even low amounts of surfactant provide benefits. In the embodiments, the surfactant concentration in the formulation is at least 0.1 mg / ml, at least 0.125 mg / ml, at least 0.15 mg / ml, at least 0.175 mg / ml, or at least 0.185 mg / ml. In the embodiments, the surfactant concentration in the formulation is ≤ 1 mg / ml, and may be ≤ 0.75 mg / ml or ≤ 0.5 mg / ml. In the embodiments, the surfactant concentration in the formulation is ≤ 0.4 mg / ml, ≤ 0.3 mg / ml, or ≤ 0.25 mg / ml. As disclosed herein, the surfactant may be a nonionic surfactant. As disclosed herein, in core embodiments, the surfactant is a polysorbate, which may be selected from polysorbate 20 and / or polysorbate 80. In the embodiments, the surfactant is polysorbate 20. Polysorbate 20 may advantageously be used at concentrations as shown in the examples and disclosed herein.

[0042] The concentration of the surfactant in the formulation may range from 0.05 mg / ml to 0.75 mg / ml. Exemplary concentration ranges of the surfactant in the formulation include, but are not limited to, 0.05 mg / ml to 0.5 mg / ml, 0.075 mg / ml to 0.4 mg / ml, or 0.075 mg / ml to 0.3 mg / ml. In examples, the surfactant concentration in the formulation ranges from 0.05 mg / ml to 0.5 mg / ml, 0.075 mg / ml to 0.3 mg / ml, or 0.1 mg / ml to 0.3 mg / ml. The surfactant concentration in the formulation may be 0.2 mg / ml. As disclosed herein, the surfactant may be a nonionic surfactant. In core embodiments, the surfactant is a polysorbate, which may be selected from polysorbate 20 and / or polysorbate 80, depending on the specific circumstances. In the embodiments, the surfactant is polysorbate 20, which can be advantageously used in the concentration ranges shown in the examples.

[0043] In a specific embodiment, the formulation of the present invention comprises 0.2 mg / ml of polysorbate 20 as a surfactant. This formulation may contain a sugar as component b), wherein the sugar concentration is in the range of 95 mM to 250 mM, 125 mM to 250 mM, or 145 mM to 225 mM. The sugar contained may be trehalose.

[0044] [, , ] [pH] In the core embodiment, the pH of the liquid pharmaceutical formulation, which is an aqueous formulation, can be in the range of pH 5.0 to 7.5, such as pH 5.0 to 7.0.

[0045] The pH of the liquid pharmaceutical preparation may be ≤ 6.8, such as ≤ 6.7, ≤ 6.6, ≤ 6.5, ≤ 6.4, ≤ 6.3, or ≤ 6.2. In embodiments, the pH of the liquid pharmaceutical preparation is ≤ 6.1, such as ≤ 6.0 or ≤ 5.9. In embodiments, the pH of the liquid pharmaceutical preparation is ≥ 5.2, such as ≥ 5.3, ≥ 5.4, or ≥ 5.5. Exemplary pH ranges for liquid pharmaceutical preparations with pH ≥ 5.2 include, but are not limited to, 5.2 to 6.8, such as 5.2 to 6.7, 5.2 to 6.6, 5.2 to 6.5, 5.2 to 6.4, 5.2 to 6.3, and 5.2 to 6.2. Examples of pH ranges for liquid pharmaceutical formulations with pH ≥ 5.3 include, but are not limited to, 5.3 to 6.8, such as 5.3 to 6.7, 5.3 to 6.6, 5.3 to 6.5, 5.3 to 6.4, 5.3 to 6.3, and 5.3 to 6.2. Examples of pH ranges for liquid pharmaceutical formulations with pH ≥ 5.4 include, but are not limited to, 5.4 to 6.8, such as 5.4 to 6.7, 5.4 to 6.6, 5.4 to 6.5, 5.4 to 6.4, 5.4 to 6.3, and 5.4 to 6.2. Examples of pH ranges for liquid pharmaceutical formulations with pH ≥ 5.5 include, but are not limited to, 5.5 to 6.8, such as 5.5 to 6.7, 5.5 to 6.6, 5.5 to 6.5, 5.5 to 6.4, 5.5 to 6.3, and 5.5 to 6.2. Examples of pH ranges for liquid pharmaceutical formulations with pH ≥ 5.6 include, but are not limited to, 5.6 to 6.8, such as 5.6 to 6.7, 5.6 to 6.6, 5.6 to 6.5, 5.6 to 6.4, 5.6 to 6.3, and 5.6 to 6.2. In other embodiments, the pH of the formulation is in the range of 5.6 to 6.0 or 5.6 to 5.9.

[0046] According to one embodiment, the pH of the liquid pharmaceutical formulation is in the range of 5.2 to 6.5. As can be seen from the examples, lower pH values ​​showed less aggregation during stability and physical stress studies.

[0047] According to one embodiment, the pH of the liquid pharmaceutical preparation is in the range of 5.5 to 6.5. In one embodiment, the pH of the liquid pharmaceutical preparation is in the range of 5.5 to 6.2.

[0048] According to one embodiment, the pH is 5.5 to 5.9. In one embodiment, the pH is 5.6 to 5.8. Rissenkiumab formulations at 150 mg / ml with this pH have been tested in examples and have shown advantageous characteristics.

[0049] In another embodiment, the pH of the liquid pharmaceutical preparation is 5.7.

[0050] In another embodiment, the pH of the liquid pharmaceutical preparation is 6.2.

[0051] As disclosed herein, the pH of the stable liquid pharmaceutical formulation according to the second state sample is 5.5 to 5.9. It can be in the range of 5.5 to 5.8. In the examples, the pH of the 150 mg / ml stable formulation according to the second state sample is 5.7.

[0052] [, , ] [d] [)] [Buffer] [] The 150 mg / ml antibody formulation according to the first state sample can be provided in a buffer-free formulation or in a buffer-containing formulation. According to a core embodiment disclosed herein, the pharmaceutical formulation includes d) a buffer. Compared to a buffer-free formulation, the buffer-containing formulation showed less increase in slip force (maximum and average) in experiments. Therefore, the buffer can be used as component d) in both the first and second state formulations of the 150 mg / ml rissonitumol antibody formulation according to the first state sample.

[0053] Buffers can be used to maintain the solution pH of liquid pharmaceutical formulations. Suitable buffers for pharmaceutical formulations are known in the art and described herein. Buffers may be organic buffers. According to one embodiment, the buffer has a pKa at 25°C within 1.5 or 1 pH unit of the final pH of the liquid pharmaceutical formulation. In some embodiments, the buffer has a pKa at 25°C in the pH range of 4.2 to 7.2 or 4.5 to 7. Buffers may comprise a combination of buffers. In one embodiment, a single buffer is used as component d) in the formulation.

[0054] The formulation may contain a carboxylic acid buffer as buffer d).

[0055] According to one embodiment, the buffer is selected from acetate buffers and succinate buffers. As shown in the examples, formulations containing such buffers provide advantageous stability characteristics for the high-concentration antibody formulations provided herein. In another embodiment, the buffer is a histidine buffer.

[0056] In one embodiment, the buffer is an acetate buffer. The acetate buffer may contain sodium acetate and acetic acid. Other acetates may also be used in the acetate buffer.

[0057] Other buffers that can be used include, but are not limited to, citrate, glutamate, glycine, lactate, maleate, phosphate, or tartrate buffers.

[0058] The presence of buffer salts can support the stability of the antibody contained in the rissenkiramab according to the present invention.

[0059] According to one embodiment, the buffer d) included in the formulation is not a succinate buffer. In some embodiments, the formulation does not contain a succinate buffer. In some embodiments, a single buffer, such as an acetate buffer provided by acetate (e.g., sodium acetate) and acetic acid, is used.

[0060] The amount of buffer used is included to maintain the selected pH of the formulation under storage conditions for the product's shelf life.

[0061] The liquid pharmaceutical formulations disclosed herein may contain at least 1 mM buffer, at least 2 mM buffer, or at least 3 mM buffer. The buffer concentration may be at least 4 mM, at least 4.5 mM, or at least 5 mM. In embodiments, the buffer concentration is 100 mM or less, such as 75 mM or less or 50 mM or less. In embodiments, the buffer concentration in the formulation is 80 mM or less, such as 75 mM or less, 70 mM or less, 60 mM or less, or 50 mM or less. In another embodiment, the buffer concentration is 45 mM or less, such as 40 mM or less, 35 mM or less, 30 mM or less, or 25 mM or less. In another embodiment, the buffer concentration is 20 mM or less or 15 mM or less. The exemplary concentration range of the included buffers includes, but is not limited to, 3 mM to 100 mM, such as 4 mM to 75 mM, 4 mM to 60 mM, and 4 mM to 50 mM. Other exemplary buffer concentration ranges include, but are not limited to, 4 mM to 45 mM, such as 5 mM to 40 mM, 5 mM to 35 mM, and 5 mM to 30 mM. Still other exemplary buffer concentration ranges include, but are not limited to, 5 mM to 25 mM, such as 5 mM to 20 mM and 5 mM to 15 mM. In one particular embodiment, the buffer concentration is in the range of 7 mM to 12 mM. Suitable buffers are disclosed herein. In one embodiment, the formulation comprises an acetate buffer at the concentration described.

[0062] In one embodiment, the buffer concentration is 20 mM or lower, or 15 mM or lower. In another embodiment, the buffer concentration is in the range of 4 mM to 50 mM. The buffer concentration of the formulation may be in the range of 5 mM to 25 mM or 5 mM to 20 mM. The buffer concentration may also be in the range of 5 mM to 15 mM or 7 mM to 12 mM. In one embodiment, the buffer concentration is 10 mM.

[0063] In some embodiments, the formulation contains a single buffer. In a particular embodiment, the single buffer is an acetate buffer.

[0064] [Include]

[0150] [] [mg] [ / ] [ml] [Specific Examples of Antibody Buffer-Containing Formulations] According to one embodiment, the liquid pharmaceutical preparation comprises a) 150 mg / ml of this antibody; b) Sugar; c) Nonionic surfactants; and d) Buffer; Depending on the situation, the pH of the formulation may be in the range of pH 5.2 to pH 6.5, for example, in the range of 5.2 to 6.2 or 5.5 to 6.2. Suitable concentrations of excipients b) through d) and examples are described above. In one embodiment, the sugar concentration is in the range of 145 mM to 225 mM and / or the nonionic surfactant concentration is in the range of 0.05 mg / ml to 0.5 mg / ml or 0.075 mg / ml to 0.3 mg / ml. The sugar may be trehalose and the nonionic surfactant may be a polysorbate such as polysorbate 20. The pH may be 5.7. In another embodiment, the pH is 6.2.

[0065] According to one embodiment, the liquid pharmaceutical preparation comprises a) 150 mg / ml of this antibody; b) Trehalose; c) Polysorbate; and d) Buffer; Depending on the situation, the pH of the formulation may be in the range of pH 5.2 to pH 6.5, for example, in the range of 5.2 to 6.2 or 5.5 to 6.2. Suitable concentrations of excipients b) through d) and examples are described above. In one embodiment, the trehalose concentration is in the range of 145 mM to 225 mM and / or the polysorbate concentration is in the range of 0.05 mg / ml to 0.5 mg / ml or 0.075 mg / ml to 0.3 mg / ml. The pH may be 5.7. In another embodiment, the pH is 6.2.

[0066] The buffers contained in these liquid pharmaceutical formulations may be acetates or succinates, with the buffer concentration ranging from 5 mM to 25 mM, depending on the application. The polysorbate may be polysorbate 20.

[0067] According to one embodiment, the liquid pharmaceutical preparation comprises a) 150 mg / ml of this antibody; b) 170 mM to 200 mM trehalose; c) 0.1 mg / ml to 0.3 mg / ml polysorbate, as appropriate, polysorbate 20; and d) Buffer, as appropriate, wherein the buffer is an acetate buffer. The pH of this formulation can be in the range of pH 5.2 to pH 6.5, for example, in the range of 5.2 to 6.2 or 5.5 to 6.2.

[0068] According to one embodiment, the liquid pharmaceutical preparation comprises a) 150 mg / ml of this antibody; b) 185 mM trehalose; c) 0.2 mg / ml polysorbate 20; and d) 10 mM acetate buffer; The pH value is 5.7. This liquid formulation may be an aqueous formulation and, in one embodiment, does not contain any other additives.

[0069] [Include]

[0150] [] [mg] [ / ] [ml] [Specific Examples of Buffer-Free Antibody Formulations] As disclosed herein, buffer-free liquid pharmaceutical formulations are also provided, specifically aqueous formulations. According to one embodiment, the liquid pharmaceutical formulation comprises… a) 150 mg / ml of this antibody; b) A polyol, wherein the polyol is a sugar or a sugar alcohol; and c) Nonionic surfactants, such as polysorbate, depending on the situation; d) Does not contain buffer.

[0070] As noted above, the present invention also provides buffer-free formulations without the addition of buffers as excipients. Antibodies at 150 mg / ml having the light and heavy chain sequences shown in SEQ ID NO: 1 and SEQ ID NO: 2 have high buffering capacity. As also shown in the examples, storage-stable buffer-free formulations can be provided based on the disclosures provided herein.

[0071] In this embodiment, the pH of the buffer-free formulation is in the range of pH 5.2 to pH 6.5. The pH may be in the range of 5.2 to 6.2 or 5.5 to 6.2. In one embodiment, the pH is 5.7. In another embodiment, the pH is 6.2.

[0072] In the embodiments, the buffer-free formulation comprises 80 mM to 250 mM of polyol. Suitable polyols, such as sugars and sugar alcohols, are disclosed in detail above and are referred to as the present invention. In one embodiment, the sugar is trehalose.

[0073] According to one embodiment, the concentration of the nonionic surfactant in the buffer-free formulation is in the range of 0.05 mg / ml to 0.5 mg / ml, 0.075 mg / ml to 0.4 mg / ml, or 0.1 mg / ml to 0.3 mg / ml. According to one embodiment, the nonionic surfactant is polysorbate. It may be selected from polysorbate 20 and polysorbate 80, and is polysorbate 20 as one embodiment.

[0074] [Additional components may be selected depending on the circumstances] [] In one embodiment, the liquid pharmaceutical formulation of the present invention comprises an amino acid as another additive. Suitable amino acids that can be added to the pharmaceutical formulation as excipients are known in the art and are also disclosed in the examples.

[0075] In one embodiment, the formulation comprises an amino acid having charged side chains, and optionally positively charged side chains. An example of such amino acid is L-arginine.

[0076] According to one embodiment, the formulation contains an amino acid, wherein the amino acid is present in the formulation as a salt, or, where appropriate, as a hydrochloric acid (HCl) salt.

[0077] According to one embodiment, the formulation contains methionine. According to one embodiment, the formulation contains the amino acid L-proline.

[0078] According to one embodiment, the 150 mg / ml formulation of the present invention does not contain arginine. Formulations containing arginine were found to show a slightly increased particle count and higher turbidity values ​​during freeze / thaw stress studies, even though the turbidity did not increase over time. Higher viscosity was also observed. The amount of aggregates was slightly lower compared to other formulations containing 150 mg / ml antibody but not arginine.

[0079] According to one embodiment, the formulation of the present invention does not contain amino acids with positively charged side chains as excipients. According to one embodiment, the formulation of the present invention does not contain amino acids with charged side chains as excipients. According to one embodiment, the formulation of the present invention does not contain methionine as an excipient. According to one embodiment, the formulation of the present invention does not contain amino acids as additives.

[0080] Other excipients known in this technology can be used in formulations, as long as they do not adversely affect stability.

[0081] However, in some embodiments, the formulations of the present invention do not contain additional excipients. A particular advantage is that the formulations for the storage stability of the antibody rissenzilmab can comprise essentially or consist of: a) the antibody (150 mg / ml); b) a component; c) a surfactant; and d) a buffer, if appropriate. As disclosed herein, advantageously, the formulation may comprise only a single polyol, a single surfactant, and (if present) a single buffer. This provides a non-compound, yet still storage-stable formulation for the 150 mg / ml antibody rissenzilmab formulation.

[0082] [] [Stability Characteristics] [] As disclosed herein, it is advantageous to provide a stable liquid pharmaceutical formulation containing 150 mg / ml of antibody. Providing this stable, high-concentration risenomyzab formulation is particularly advantageous for therapeutic use.

[0083] In this embodiment, a stable antibody formulation is a formulation in which the antibody substantially retains its physical stability and / or biological activity during storage. Various analytical techniques for measuring protein stability are available in this art and disclosed herein. Stability can be measured at a selected temperature over a selected time period.

[0084] Unlike the present invention, the stability characteristics of the liquid pharmaceutical formulation containing 150 mg / ml antibody were tested in examples and showed favorable stability characteristics.

[0085] In embodiments, the stable liquid pharmaceutical formulations of the present invention do not show significant changes at freezing temperatures (2-8°C) for at least 3 months, such as 6 months, 1 year, or even up to 2 years or longer. Stable liquid formulations include those exhibiting the desired characteristics at temperatures including 25°C and 40°C for periods including 1 month, 3 months, 6 months, 12 months, and / or 24 months.

[0086] If an antibody does not show significant aggregation, precipitation, and / or increased denaturation when visually inspected for color and / or clarity, or when measured by UV light scattering, size exclusion chromatography (SEC), and / or dynamic light scattering, then the antibody particularly maintains its physical stability in pharmaceutical formulations. Protein conformational changes can be assessed by fluorescence spectroscopy to determine the tertiary structure of proteins and by FTIR spectroscopy to determine the secondary structure of proteins.

[0087] If the antibody's biological activity at a given time is within a predetermined range of the biological activity exhibited when preparing the pharmaceutical formulation, then the antibody specifically retains its biological activity in the pharmaceutical formulation. The biological activity of an antibody can be determined, for example, by antigen-binding assay.

[0088] Aggregates can differ in origin, size, and type. Aggregates that may affect the efficacy or safety of biological products are of particular concern, such as those that can enhance immune responses and may cause adverse clinical effects. High molecular weight aggregates, also known as high molecular weight species (HMWS), may be of particular concern. Aggregates may also potentially affect the subcutaneous bioavailability and pharmacokinetics of therapeutic proteins. Advantageously, the present invention provides formulations in which the amount of high molecular weight species is low, even over extended storage periods. The present invention particularly provides stabilized (or stable) aqueous pharmaceutical formulations, as demonstrated by the reduced amount of aggregates and / or the reduced rate of aggregate formation after storage. As described herein, the stability of such formulations is indicated by the reduced amount of HMWS and / or the reduced rate of HMWS formation over varying time periods and at varying temperatures after storage. Generally, higher stability formulations are associated with lower amounts of HMWS, lower rates of HMWS formation, and / or higher antibody peaks at higher storage temperatures relative to lower storage temperatures. As used herein, the terms "high molecular weight species" or "HMWS" refer to both high-order aggregates of the formulation antibody and low-order aggregates of the formulation antibody. Low-order aggregates include, for example, dimer species. The amount of aggregates and the rate of formation can be measured or monitored using various techniques, including those disclosed in the examples.

[0089] As used herein, the terms "low molecular weight species" or "LMWS" specifically refer to antibody fragments smaller than monomers, including but not limited to free light chains, free heavy chains, molecules containing one light chain and one heavy chain, antibody molecules lacking one or two light chains, and antibody fragments obtained by cleaving one or more polypeptide chains (such as proteolytic fragments) or other antibody molecules degraded enzymatically or chemically.

[0090] In some embodiments, the antibodies in the formulations disclosed herein remain substantially in monomeric form during storage. In specific embodiments, the formulations may achieve one or more of the following stability characteristics: In some embodiments, after storage at 5°C for 36 months, at least 94% of the antibody remains in monomeric form as measured by UP-SEC, and / or the relative monomer content of the antibody does not decrease by more than 3% or more than 2.5%. In some embodiments, after storage at 5°C for 36 months, at least 95% or at least 96% of the antibody remains in monomeric form as measured by UP-SEC, and / or the relative monomer content of the antibody does not decrease by more than 2% or more than 1.5%. In some embodiments, after storage at 5°C for 24 months, at least 94% of the antibody remains in monomeric form as measured by UP-SEC, and / or the relative monomer content of the antibody does not decrease by more than 3% or more than 2.5%. In some embodiments, after storage at 5°C for 24 months, at least 95% or at least 96% of the antibody remains in monomeric form as measured by UP-SEC, and / or the relative monomer content of the antibody does not decrease by more than 2% or more than 1.5% or more than 1%. In some embodiments, after storage at 5°C for 9 months, at least 96% or at least 96.5% of the antibody is present in monomeric form, as measured by UP-SEC, and / or the relative monomer content of the antibody does not decrease by more than 1.5% or more than 1%. In some embodiments, after storage at 5°C for 3 months, at least 96% or at least 97% of the antibody is present in monomeric form, as measured by UP-SEC, and / or the relative monomer content of the antibody does not decrease by more than 1% or more than 0.7% or more than 0.5%. In some embodiments, after storage at 25°C for 12 months, at least 90% or at least 92% of the antibody is present in monomeric form, as measured by UP-SEC, and / or the relative monomer content of the antibody does not decrease by more than 7% or more than 6% or more than 5%. In some embodiments, after storage at 25°C for 3 months, at least 95% of the antibody is present in monomeric form, as measured by UP-SEC, and / or the relative monomer content of the antibody does not decrease by more than 3% or more than 2%. In some embodiments, after storage at 25°C for 1 month, at least 96% of the antibody remains in monomeric form as measured by UP-SEC, and / or the relative monomer content of the antibody does not decrease by more than 2% or more than 1%. In some embodiments, after storage at 40°C for 3 months, at least 87% or at least 88% of the antibody remains in monomeric form as measured by UP-SEC, and / or the relative monomer content of the antibody does not decrease by more than 10% or more than 9% or more than 8%. In some embodiments, after storage at 40°C for 1 month, at least 93% or at least 94% of the antibody remains in monomeric form as measured by UP-SEC, and / or the relative monomer content of the antibody does not decrease by more than 5% or more than 4%. In some embodiments, after shaking at 25°C for 21 days, at least 95% or at least 96% of the antibody remains in monomeric form as measured by UP-SEC, and / or the relative monomer content of the antibody does not decrease by more than 2% or more than 1%.The reduction in relative monomer content is calculated over the indicated storage time and temperature, and is specifically determined by comparing the relative monomer content at the start and end of the indicated storage. In certain embodiments, the measurement is performed as described in the examples.

[0091] In some embodiments, the antibodies in the formulations disclosed herein do not form significant amounts of high molecular weight vapor (HMWS) during storage. Specifically, the formulations achieve one or more of the following stability characteristics: In some embodiments, after storage at 5°C for 36 months, less than 4% or less than 3% of the antibody is present in HMWS form as measured by UP-SEC, and / or the relative HMWS content of the antibody does not increase by more than 2% or more than 1.5%. In some embodiments, after storage at 5°C for 24 months, less than 4% or less than 3% of the antibody is present in HMWS form as measured by UP-SEC, and / or the relative HMWS content of the antibody does not increase by more than 2% or more than 1.5% or more than 1%. In some embodiments, after storage at 5°C for 9 months, less than 4% or less than 3% or less than 2.5% of the antibody is present in HMWS form as measured by UP-SEC, and / or the relative HMWS content of the antibody does not increase by more than 1% or more than 0.8% or more than 0.6%. In some embodiments, after storage at 5°C for 3 months, as measured by UP-SEC, less than 4%, less than 3%, or less than 2.5% of the antibody is present in HMWS form, and / or the relative HMWS content of the antibody does not increase by more than 1%, more than 0.8%, or more than 0.6%. In some embodiments, after storage at 25°C for 12 months, as measured by UP-SEC, less than 5% or less than 4% of the antibody is present in HMWS form, and / or the relative HMWS content of the antibody does not increase by more than 3%, more than 2.5%, or more than 2%. In some embodiments, after storage at 25°C for 3 months, as measured by UP-SEC, less than 4%, less than 3.5%, or less than 3.2% of the antibody is present in HMWS form, and / or the relative HMWS content of the antibody does not increase by more than 2% or more than 1.5%. In some embodiments, after storage at 25°C for one month, less than 4%, less than 3.5%, or less than 3% of the antibody is present in HMWS form, as measured by UP-SEC, and / or the relative HMWS content of the antibody does not increase by more than 1.5% or more than 1%. In some embodiments, after storage at 40°C for three months, less than 6.5%, less than 6%, or less than 5.5% of the antibody is present in HMWS form, as measured by UP-SEC, and / or the relative HMWS content of the antibody does not increase by more than 5% or more than 4%. In some embodiments, after storage at 40°C for one month, less than 5%, less than 4.5%, or less than 4% of the antibody is present in HMWS form, as measured by UP-SEC, and / or the relative HMWS content of the antibody does not increase by more than 2.5% or more than 2%. In some embodiments, after shaking at 25°C for 21 days, less than 3% or less than 2% of the antibody is present in HMWS form, as measured by UP-SEC, and / or the relative HMWS content of the antibody does not increase by more than 2%, more than 1.5%, or more than 1%. The increase in relative HMWS content is calculated with respect to the indicated storage time and temperature and is specifically determined by comparing the relative HMWS content at the beginning and end of the indicated storage.In certain embodiments, measurements are performed as described in the examples.

[0092] In another embodiment, the antibody in the formulation disclosed herein does not form a large amount of LMWS during storage. In certain embodiments, the formulation may achieve one or more of the following stability characteristics: In some embodiments, after storage at 5°C for 36 months, less than 2% or less than 1.5% of the antibody is present in LMWS form as measured by UP-SEC, and / or the relative LMWS content of the antibody does not increase by more than 1.5% or more than 0.5%. In some embodiments, after storage at 5°C for 24 months, less than 2% or less than 1.5% of the antibody is present in LMWS form as measured by UP-SEC, and / or the relative LMWS content of the antibody does not increase by more than 1.5% or more than 0.5%. In some embodiments, after storage at 5°C for 9 months, less than 2% or less than 1.5% of the antibody is present in LMWS form as measured by UP-SEC, and / or the relative LMWS content of the antibody does not increase by more than 1.5% or more than 0.5%. In some embodiments, after storage at 5°C for 3 months, as measured by UP-SEC, less than 2%, less than 1.5%, or less than 1% of the antibody is present in LMWS form, and / or the relative LMWS content of the antibody does not increase by more than 1%, more than 0.5%, or more than 0.25%. In some embodiments, after storage at 25°C for 12 months, as measured by UP-SEC, less than 6%, less than 5%, or less than 4.5% of the antibody is present in LMWS form, and / or the relative LMWS content of the antibody does not increase by more than 5%, more than 4%, or more than 3%. In some embodiments, after storage at 25°C for 3 months, as measured by UP-SEC, less than 3%, less than 2%, or less than 1.8% of the antibody is present in LMWS form, and / or the relative LMWS content of the antibody does not increase by more than 2%, more than 1.5%, or more than 1%. In some embodiments, after storage at 25°C for one month, less than 2%, less than 1.5%, or less than 1.2% of the antibody is present in LMWS form, as measured by UP-SEC, and / or the relative LMWS content of the antibody does not increase by more than 1%, more than 0.6%, or more than 0.4%. In some embodiments, after storage at 40°C for three months, less than 8%, less than 7%, or less than 6% of the antibody is present in LMWS form, as measured by UP-SEC, and / or the relative LMWS content of the antibody does not increase by more than 8%, more than 7%, or more than 6%. In some embodiments, after storage at 40°C for one month, less than 4%, less than 3.5%, or less than 3% of the antibody is present in LMWS form, as measured by UP-SEC, and / or the relative LMWS content of the antibody does not increase by more than 3%, more than 2.5%, or more than 2.2%. The increase in relative LMWS content is calculated relative to the indicated storage time and temperature and is specifically determined by comparing the relative LMWS content at the beginning and end of the indicated storage. In a particular embodiment, measurements are performed as described in the examples.

[0093] In some embodiments, specifically, as described in the examples, the relative amounts of antibodies in monomeric, HMWS, and / or LMWS forms are determined using UP-SEC. For example, an ultra-high performance liquid chromatography (UPLC) system incorporating a size exclusion chromatography (SEC) column is used in the Acquity UPLC system from Waters (Milford, MA, USA). Protein dissociation by the SEC column can be detected by UV absorption at 280 nm, and the relative amount determination can be performed by calculating the area under the curve (AUC) of each dissociation peak. Peaks can be assigned to different species based on the dissociation time corresponding to different molecular sizes. To measure the relative monomeric, relative HMWS, and / or relative LMWS content of antibodies in the formulation, the monomeric, HMWS, and LMWS antibodies are specifically separated from each other, even in their presence in the formulation. Specifically, the relative content or amount is indicated as a percentage value, and the sum of the monomeric, HMWS, and LMWS antibodies is 100%.

[0094] In some embodiments, the turbidity or milky whiteness of the formulations disclosed herein does not increase significantly during storage. In particular embodiments, the formulations may achieve one or more of the following stability characteristics: In some embodiments, after storage at 5°C for at least 36 months, the formulation exhibits a milky white luster of 12 FNU (Formazin Nephelometry Unit) or less, or 10 FNU or less, and / or the milky white luster does not increase by more than 5 FNU or more than 3 FNU. In some embodiments, after storage at 5°C for at least 3, 6, 9, 12, 18, or 24 months, the formulation exhibits a milky white luster of 12 FNU (Formazin Nephelometry Unit) or less, or 10 FNU or less, and / or the milky white luster does not increase by more than 5 FNU or more than 3 FNU. In some embodiments, after storage at 25°C for at least 1, 3, 6, 9, or 12 months, the formulation exhibits a milky white luster of 12 FNU or less, or 10 FNU or less, and / or the milky white luster does not increase by more than 7 FNU or more than 5 FNU. In some embodiments, after storage at 40°C for at least 1 or 3 months, the formulation has a milky luster of 12 FNU or less, or 10 FNU or less, and / or the milky luster does not increase by more than 5 FNU or more than 3 FNU. In some embodiments, after shaking at 25°C for 21 days, the formulation has a milky luster of 12 FNU or less, or 10 FNU or less, and / or the milky luster of the formulation does not increase by more than 3 FNU or more than 2 FNU. The increase in milky luster is calculated relative to the indicated storage time and temperature and is specifically determined by comparing the milky luster at the beginning and end of the indicated storage. In certain embodiments, measurements are performed as described in the examples.

[0095] In some embodiments, the milky light or turbidity is measured according to a pharmacopoeia or industry standard ISO 7027. In some embodiments, specifically, as described in the examples, the milky light or turbidity of the formulation is measured using a turbidimeter such as the HACH Lange milky light meter from Hach-Lange GmbH (Germany). The milky light can be measured at different wavelengths, including 400-600 nm. In the embodiments, the FNA values ​​indicated above are measured at 400-600 nm. Higher FNU values ​​indicate higher milky light and turbidity.

[0096] In some embodiments, the antibodies in the formulations disclosed herein do not form additional large amounts of acidic or basic variants during storage. In specific embodiments, the formulations may achieve one or more of the following stability characteristics: In some embodiments, after storage at 5°C for 36 months, at least 55%, at least 60%, or at least 65% of the antibody is present as a main peak variant, as determined by ion exchange chromatography (IEC), and / or the relative main peak variant content of the antibody does not decrease by more than 8%, more than 7%, or more than 5%. In some embodiments, after storage at 5°C for 24 months, at least 55%, at least 60%, or at least 65% of the antibody is present as a main peak variant, as determined by ion exchange chromatography (IEC), and / or the relative main peak variant content of the antibody does not decrease by more than 8%, more than 7%, or more than 5%. In some embodiments, after storage at 5°C for 6 months, at least 60% or at least 65% of the antibody is present as a main peak variant, as determined by ion exchange chromatography (IEC), and / or the relative main peak variant content of the antibody does not decrease by more than 5% or more than 4%. In some embodiments, after storage at 5°C for 3 months, at least 60% or at least 65% of the antibody is present as a main peak variant, as determined by ion exchange chromatography (IEC), and / or the relative main peak variant content of the antibody does not decrease by more than 4%, more than 3%, or more than 2%. In some embodiments, after storage at 25°C for 12 months, at least 35% or at least 40% or at least 45% of the antibody is present as a main peak variant, as determined by ion exchange chromatography (IEC), and / or the relative main peak variant content of the antibody does not decrease by more than 35%, more than 30%, or more than 25%. In some embodiments, after storage at 25°C for 3 months, at least 55% or at least 60% of the antibody is present as a main peak variant, as determined by ion exchange chromatography (IEC), and / or the relative main peak variant content of the antibody does not decrease by more than 15% or more than 10%. In some embodiments, after storage at 25°C for 1 month, as determined by ion exchange chromatography (IEC), at least 60% or at least 65% of the antibody is present as a main peak variant, and / or the relative main peak variant content of the antibody does not decrease by more than 10% or more than 5%. In some embodiments, after storage at 5°C for 36 months, as determined by ion exchange chromatography (IEC), less than 30% or less than 28% of the antibody is present as an acidic peak group variant, and / or the relative acidic peak group variant content of the antibody does not increase by more than 4%, more than 3%, or more than 2%. In some embodiments, after storage at 5°C for 24 months, as determined by ion exchange chromatography (IEC), less than 30% or less than 28% of the antibody is present as an acidic peak group variant, and / or the relative acidic peak group variant content of the antibody does not increase by more than 4%, more than 3%, or more than 2%. In some embodiments, after storage at 5°C for 6 months, as determined by ion exchange chromatography (IEC), less than 30% or less than 28% of the antibody is present as an acidic peak group variant, and / or the relative acidic peak group variant content of the antibody does not increase by more than 4%, more than 3%, or more than 2%.In some embodiments, after storage at 5°C for 3 months, as determined by ion exchange chromatography (IEC), less than 30% or less than 28% of the antibody is present as an acidic peak group variant, and / or the relative acidic peak group variant content of the antibody does not increase by more than 3%, more than 2%, or more than 1%. In some embodiments, after storage at 25°C for 12 months, as determined by ion exchange chromatography (IEC), less than 50%, less than 45%, or less than 40% of the antibody is present as an acidic peak group variant, and / or the relative acidic peak group variant content of the antibody does not increase by more than 30%, more than 25%, or more than 20%. In some embodiments, after storage at 25°C for 3 months, as determined by ion exchange chromatography (IEC), less than 40%, less than 35%, or less than 30% of the antibody is present as an acidic peak group variant, and / or the relative acidic peak group variant content of the antibody does not increase by more than 10%, more than 8%, or more than 6%. In some embodiments, after storage at 25°C for 1 month, as determined by ion exchange chromatography (IEC), less than 35%, less than 30%, or less than 28% of the antibody is present as an acidic peak group variant, and / or the relative acidic peak group variant content of the antibody does not increase by more than 4% or more than 3%. In some embodiments, after storage at 5°C for 36 months, as determined by ion exchange chromatography (IEC), less than 20%, less than 17%, less than 15%, or less than 13% of the antibody is present as a basic peak group variant, and / or the relative basic peak group variant content of the antibody does not increase by more than 10%, more than 8%, or more than 6%. In some embodiments, after storage at 5°C for 24 months, as determined by ion exchange chromatography (IEC), less than 20%, less than 17%, less than 15%, or less than 13% of the antibody is present as a basic peak group variant, and / or the relative basic peak group variant content of the antibody does not increase by more than 10%, more than 8%, or more than 6%. In some embodiments, after storage at 5°C for 6 months, as determined by ion exchange chromatography (IEC), less than 15% or less than 10% of the antibody is present as a basic peak group variant, and / or the relative content of the antibody as a basic peak group variant does not increase by more than 4%, more than 3%, or more than 2%. In some embodiments, after storage at 5°C for 3 months, as determined by ion exchange chromatography (IEC), less than 15% or less than 10% of the antibody is present as a basic peak group variant, and / or the relative content of the antibody as a basic peak group variant does not increase by more than 3% or more than 2%. In some embodiments, after storage at 25°C for 12 months, as determined by ion exchange chromatography (IEC), less than 30% or less than 25% or less than 22% of the antibody is present as a basic peak group variant, and / or the relative content of the antibody as a basic peak group variant does not increase by more than 25%, more than 20%, or more than 15%.In some embodiments, after storage at 25°C for 3 months, as determined by ion exchange chromatography (IEC), less than 20%, less than 15%, or less than 12% of the antibody is present as a basic peak group variant, and / or the relative basic peak group variant content of the antibody does not increase by more than 9%, more than 7%, or more than 5%. In some embodiments, after storage at 25°C for 1 month, as determined by ion exchange chromatography (IEC), less than 15%, less than 10%, or less than 9% of the antibody is present as a basic peak group variant, and / or the relative basic peak group variant content of the antibody does not increase by more than 3% or more than 2%. The decrease in relative main peak variant content and the increase in relative acidic and basic peak group variant content are calculated with respect to the indicated storage time and temperature and are specifically determined by comparing the relative individual peak variant contents at the beginning and end of the indicated storage. In certain embodiments, measurements are performed as described in the examples.

[0097] In some embodiments, specifically, as described in the examples, the relative amounts of antibodies for the dominant peak variant, acidic peak variant, and / or basic peak variant are determined using ion exchange chromatography (IEC). Specifically, weak cation exchange chromatography (WCX) is used. For example, a high-performance liquid chromatography (HPLC) system incorporating a WCX column, such as the Alliance HPLC system from Waters (Milford, MA, USA), is used. Protein dissociation via the WCX column can be detected by UV absorption at 280 nm, and relative amount determination can be performed by calculating the area under the curve (AUC) of each dissociation peak or group of dissociation peaks. Peaks can be assigned to different species based on the antibody species dissociation conditions corresponding to the surface charge of the antibody species. The dominant peak is the largest peak in the IEC chromatogram of the undegraded antibody. For stability analysis, measurements can be performed after preparation of the formulation (TO) and subsequently after the indicated storage time under the indicated storage conditions. The acidic peak group (APG) includes all peaks preceding the main peak. These peaks include variants of the native antibody main peak that are more acidic and / or antibody variants that have a greater negative charge on their surface under chromatographic conditions. The basic peak group includes all peaks following the main peak. These peaks include variants of the native antibody main peak that are more acidic and / or antibody variants that have a greater positive charge on their surface under chromatographic conditions. For measuring the relative amounts of the main peak variant, acidic peak group variant, and / or basic peak group variant of the antibody in the formulation, the main peak is specifically separated from the acidic and basic peak groups, provided they are present in the formulation. Specifically, the relative content or amount is indicated as a percentage value, and the sum of the main peak variant, acidic peak group variant, and basic peak group variant is 100%.

[0098] In some embodiments, the antibodies in the formulations disclosed herein substantially maintain their specific binding activity to human IL-23 during storage. In particular embodiments, the formulations achieve one or more of the following stability characteristics: In some embodiments, after storage at 5°C for 36 months, at least 95% or at least 97% specific binding activity with IL-23 is measured relative to a reference antibody, wherein the reference antibody has not been stored. In some embodiments, after storage at 5°C for 4, 6, 9, 12, 18, or 24 months, at least 95% or at least 97% specific binding activity with IL-23 is measured relative to a reference antibody, wherein the reference antibody has not been stored. In some embodiments, after storage at 25°C for 2, 3, 4, 6, 9, 12, or 18 months, at least 93% or at least 96% specific binding activity with IL-23 is measured relative to a reference antibody, wherein the reference antibody has not been stored. In some embodiments, after storage at 40°C for 3, 4, or 6 months, at least 90% or at least 95% specific binding activity with IL-23 is measured relative to a reference antibody, wherein the reference antibody has not been stored. In certain embodiments, the measurement is performed as described in the examples.

[0099] In some embodiments, specifically, as described in the examples, the antibody-specific binding activity to human IL-23 in the formulation is measured using surface plasma resonance, for example, using a Biacore instrument such as the GE Healthcare Life Science (United Kingdom) Biacore T200.

[0100] [] [Based on other characteristics of the first-state liquid pharmaceutical preparation] [] In an advantageous embodiment, the liquid pharmaceutical formulations of the present invention are aqueous formulations. In one embodiment, all liquid formulations disclosed herein are aqueous formulations. Unless otherwise specified, the following description applies to formulations based on a 150 mg / ml first state sample, and therefore also to formulations based on the first and second state samples as disclosed herein.

[0101] According to one embodiment, the measured dynamic viscosity of the liquid pharmaceutical formulation according to the first state sample at 20°C is ≤ 30 mPas (mPa·s), such as ≤ 25 mPas or ≤ 20 mPas. In another embodiment, the measured dynamic viscosity of the formulation at 20°C is ≤ 18 mPas, such as ≤ 16 mPas, ≤ 15 mPas, ≤ 14 mPas, ≤ 13 mPas or ≤ 12 mPas. In a particular embodiment, as also shown in the examples, the dynamic viscosity is the dynamic viscosity to which the formulation is suitable for subcutaneous administration. The dynamic viscosity can be measured as described in the examples.

[0102] According to one embodiment, the conductivity of the formulation of the present invention is in the range of 0.8 to 5 mS / cm. In the embodiment, the conductivity range is 1 to 2 mS / cm or 1.2 to 1.8 mS / cm. In the embodiment, the formulation is characterized in that the conductivity change at 25°C during a storage period of at least 12 months is ≤ 1 mS / cm, such as ≤ 0.75 mS / cm, ≤ 0.5 mS / cm, or ≤ 0.3 mS / cm.

[0103] The liquid formulation of the present invention is a pharmaceutical formulation. A pharmaceutical formulation specifically refers to a composition which is in a form that enables the permitted active ingredient (here, an antibody comprising the light chain as shown in SEQ ID NO: 1 and the heavy chain as shown in SEQ ID NO: 2) to be effective and does not contain any additional components that are toxic to the individual to which the formulation is administered.

[0104] The formulations disclosed herein, according to the first-state sample, are advantageously suited for non-enteral delivery. Non-enteral administration includes, for example, subcutaneous, intramuscular, intradermal, intramedullary injection, as well as intrathecal, direct intracerebral or intraventricular, intravenous, intraperitoneal, and intravitreal administration. The drug can be administered in various conventional methods, such as intraperitoneal, non-enteral, intra-arterial, or intravenous injection. In one embodiment, the disclosed formulation is an injectable formulation. In embodiments, the formulations disclosed herein are suitable for subcutaneous, intravenous, or intramuscular administration. Advantageously, the disclosed formulation is suitable for subcutaneous injection. The 150 mg / ml formulation disclosed herein is particularly advantageous because it achieves the overall characteristic of making the formulation particularly suitable for subcutaneous administration. The high concentration allows for the administration of small volumes of formulation while still achieving a high antibody dose (here, for example, 1 ml for a 150 mg dose). Furthermore, the formulations of the present invention exhibit good injectability. Furthermore, as illustrated in the examples, it exhibits favorable viscosity and osmotic molar concentration characteristics and achieves good slippage (maximum and average values), as well as during storage. In the embodiments, the liquid pharmaceutical formulation of the present invention is isotropic to the desired site of administration. For example, if the formulation is intended for non-enteral administration, it may be isotropic to blood (at approximately 300 mOsm / kg osmotic molar concentration). Suitable osmotic molar concentration ranges are described elsewhere.

[0105] Liquid antibody formulations can be manufactured by taking a drug substance in liquid form (e.g., in an aqueous pharmaceutical formulation) as the final step in a purification process, replacing its buffer, and preparing the desired buffer. The drug substance in the final buffer can be concentrated to the desired concentration or diluted to a more concentrated form of antibody to achieve a concentration of 150 mg / ml. Formulation concentration can be performed by any suitable method. In one state, the concentration process may include ultrafiltration.

[0106] In one core embodiment, the liquid pharmaceutical formulation according to the first state is not a formulation prepared by reconstitution of a lyophilized formulation. In this core embodiment, there is no lyophilization step during the preparation of the liquid pharmaceutical formulation. Excipients such as component b) and surfactant c) may be added to the pharmaceutical substance, which may be diluted with an appropriate buffer to a final protein concentration of 150 mg / ml. The pharmaceutical formulation intended for in vivo administration is typically sterile. In some embodiments, this may be achieved by filtration through a sterile filter membrane. Thus, the final formulated pharmaceutical substance may be filtered (e.g., using a 0.22 µm filter) and filled into a final container (e.g., a glass vial or syringe). In this embodiment, the prepared liquid formulation is administered directly to the patient without lyophilization or reconstitution steps. These liquid pharmaceutical formulations are disclosed herein and have also been manufactured and analyzed in examples.

[0107] [Freeze-dried and reconstituted pharmaceutical formulations] [] According to one embodiment, the liquid pharmaceutical formulation based on the first state sample is prepared by reconstitution of a lyophilized pharmaceutical formulation. Therefore, in this embodiment, the liquid pharmaceutical composition described herein is a reconstituted formulation. This applies to the first and second state liquid formulations of the 150 mg / ml antibody formulation based on the first state sample.

[0108] The term "lyophilization" or "lyophilized" specifically refers to a process in which the material to be dried is first frozen and then the ice or freezing solvent is removed by sublimation in a vacuum environment. These techniques are well known in this field and are therefore not described in detail herein. Excipients may be included in the pre-lyophilized formulation to enhance the stability of the lyophilized product during storage. The lyophilized formulation may contain cryoprotectants, which generally include agents that provide stability to proteins against freeze-induced stress. They may also provide protection during primary and secondary drying and during long-term product storage. Examples include sugars such as sucrose and trehalose, and surfactants such as polysorbates. The lyophilized formulation may also include lyophilization protectants, which include agents that provide stability to proteins during the drying or dehydration process (primary and secondary drying cycles). This helps maintain protein conformation, minimizes protein degradation during lyophilization cycles, and improves long-term product stability. Examples include polyols, such as sugars like sucrose and trehalose. The disclosed liquid pharmaceutical formulation according to the first state includes excipients qualified as cryoprotectants and / or lyophilization protectants. Therefore, lyophilized formulations can be prepared from such formulations. In one embodiment, the antibody risenkiumab is formulated as a lyophilized powder for intravenous administration for decongestion and utilization.

[0109] "Reconstituted" formulations are prepared by dissolving lyophilized pharmaceutical antibody formulations in a diluent to disperse the antibodies in the reconstituted formulation. Reconstituted formulations are suitable for administration and may be used subcutaneously as appropriate.

[0110] The lyophilized pharmaceutical formulation was prepared at the required concentration, in this case 150 mg / ml, before reconstitution.

[0111] According to one embodiment, a lyophilized formulation of an anti-IL-23p19 antibody is provided, wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2. According to one embodiment, the lyophilized formulation of the antibody rissenzil is defined in relation to, for example, a solution used to manufacture the lyophilized formulation from a pre-lyophilized solution. This lyophilized formulation is manufactured by lyophilizing a 150 mg / ml liquid antibody formulation according to a first state sample, such as a liquid pharmaceutical formulation according to a first state sample as defined in any one of Examples 1 to 86 below. As disclosed herein, in one embodiment, the liquid formulation is an aqueous formulation. This aqueous formulation can be used to prepare the lyophilized pharmaceutical formulation.

[0112] In other embodiments, the lyophilized formulation of the rissonitumol antibody is defined in relation to the reconstituted solution generated from the lyophilized formulation. According to one embodiment, a lyophilized formulation of an anti-IL-23p19 antibody is thus provided, wherein the antibody comprises the light chain amino acid sequence according to SEQ ID NO: 1 and the heavy chain amino acid sequence according to SEQ ID NO: 2, the lyophilized formulation being provided in reconstitution of a 150 mg / ml liquid antibody formulation according to a first state, specifically its first and second states. According to an embodiment, the lyophilized formulation is provided in reconstitution of a liquid pharmaceutical formulation as defined in any one of Examples 1 to 86 or 104 to 119 below. This rissonitumol antibody formulation may be an aqueous formulation.

[0113] Also available are freeze-dried formulations containing the following: a) Anti-IL-23p19 antibody, wherein the antibody comprises the light chain amino acid sequence according to SEQ ID NO: 1 and the heavy chain amino acid sequence according to SEQ ID NO: 2, and the amount of antibody provides an antibody concentration of 150 mg / ml upon recovery; b) Polyols; c) Surfactants; and d) Buffers to be selected as appropriate. In one embodiment, the lyophilized pharmaceutical formulation contains 150 mg of antibody. The antibody is rissenkiumab.

[0114] Also available are freeze-dried formulations containing the following: a) Anti-IL-23p19 antibody, wherein the antibody comprises the light chain amino acid sequence according to SEQ ID NO: 1 and the heavy chain amino acid sequence according to SEQ ID NO: 2, and the amount of antibody provides an antibody concentration of 150 mg / ml upon recovery; b) Tension regulator; c) Surfactants; and d) Buffers to be selected as appropriate. In one embodiment, the lyophilized pharmaceutical formulation contains 150 mg of antibody. The antibody is rissenkiumab.

[0115] The components, such as suitable polyols, included in pharmaceutical formulations have been disclosed in combination with liquid pharmaceutical formulations above and are referred to herein as such. Suitable polyols include sugars and sugar alcohols, which may also be used in combination. A polyol may have one or more of the characteristics defined in any of the following Examples 6 to 13 of the liquid pharmaceutical formulation according to the first state. In one embodiment, the polyol is a sugar, which may be selected from trehalose and sucrose. In one embodiment, the sugar is trehalose.

[0116] Suitable surfactants have been disclosed in connection with the liquid pharmaceutical formulation above and are referred to herein as such. The surfactant may have one or more of the characteristics defined in any of Examples 22 to 25 below for the liquid pharmaceutical formulation according to the first state. In one embodiment, the surfactant is a polysorbate, which may be selected from polysorbate 20 and polysorbate 80. In one embodiment, the polysorbate is polysorbate 20.

[0117] In one embodiment, the lyophilized formulation contains a buffer. Suitable buffers for preparing the lyophilized formulation are known in the art, and suitable buffers are also disclosed above in conjunction with the liquid pharmaceutical formulation according to the first state sample, and are referred to as the above disclosure.

[0118] According to one embodiment, the lyophilized formulation is characterized in that, upon reconstitution, it has a pH as disclosed herein with respect to the liquid pharmaceutical formulation according to the first state sample. Suitable pH values ​​are disclosed above and are referred to herein as the respective disclosures. Upon reconstitution, the pH may be as defined in any of Examples 31 to 36 below for the 150 mg / ml liquid pharmaceutical formulation. Furthermore, upon reconstitution, the pH may be as defined with respect to the formulation according to the second state sample. Upon reconstitution, the pH may be 5.5 to 5.9, for example, 5.6 to 5.8.

[0119] The lyophilized rissenitumoab formulation of this invention is reconstituted before administration. In some cases, it may be necessary to lyophilize the rissenitumoab formulation in a container where antibody reconstitution is performed to avoid a transfer step.

[0120] [] [Container and Use] [] According to another aspect of the invention, a sealed container is provided containing a liquid pharmaceutical formulation or a lyophilized pharmaceutical formulation according to a first aspect of the invention. The container may be a vial or a pre-filled syringe. In embodiments, the container contains 2 ml or less, depending on the case, 1.5 ml or less, or 1 ml or less of the liquid pharmaceutical formulation. The container may contain a favorable stable liquid pharmaceutical formulation of a first or second aspect of a 150 mg / ml antibody formulation according to the first aspect.

[0121] In a core embodiment, a container such as a syringe contains a single 150 mg dose of the antibody. As disclosed herein, the antibody is risenoside.

[0122] In one embodiment, the syringe equipped with a needle contains a liquid pharmaceutical preparation according to the first aspect of the invention. In a particular embodiment, the needle is suitable for subcutaneous administration. The needle may be a 27 gauge spinal cord thin-walled needle or other needles suitable for subcutaneous use.

[0123] According to one embodiment, the average sliding force of the pre-filled syringe equipped with a needle is 20 N or less. In this embodiment, the average sliding force is in the range of 5 to 20 N or 5 to 15 N. In this embodiment, the break loose force of the pre-filled syringe is 3 to 12 N, preferably 3 to 9 N.

[0124] In some embodiments, a syringe equipped with a needle and containing a liquid pharmaceutical preparation according to a first-state sample substantially maintains the maximum and / or average slip force required to eject the preparation from the syringe during storage. In some embodiments, after storage at 5°C for 36 months, the maximum slip force of a syringe pre-filled with the liquid preparation is 14 N or less, 12 N or less, or 10 N or less, and / or the maximum slip force does not increase by more than 5 N, more than 4 N, or more than 3 N. In some embodiments, after storage at 5°C for 24 months, the maximum slip force of a syringe pre-filled with the liquid preparation is 14 N or less, 12 N or less, 10 N or less, or 8 N or less, and / or the maximum slip force does not increase by more than 3 N, more than 2 N, or more than 1.5 N. In some embodiments, after storage at 5°C for 9 months, the maximum slip force is 9 N or less, or 8 N or less, and / or the maximum slip force does not increase by more than 2 N, more than 1.5 N, or more than 1 N. In some embodiments, after storage at 5°C for 3 months, the maximum slip force is 8 N or less or 7.5 N or less, and / or the maximum slip force does not increase by more than 1.5 N or more than 1 N. In some embodiments, after storage at 25°C for 3 months, the maximum slip force is 10 N or less or 8 N or less, and / or the maximum slip force does not increase by more than 3 N or more than 2 N or more than 1.5 N. In some embodiments, after storage at 25°C for 1 month, the maximum slip force of the pre-filled syringe equipped with a needle is 8 N or less or 7.5 N or less, and / or the maximum slip force does not increase by more than 1.5 N or more than 1 N. In some embodiments, after storage at 40°C for 1 month, the maximum slip force is 16 N or less or 13 N or less, and / or the maximum slip force does not increase by more than 10 N or more than 8 N or more than 6 N.

[0125] In some embodiments, after storage at 5°C for 36 months, the average slip force of a syringe pre-filled with the liquid formulation according to the first state sample and equipped with a needle is 14 N or less, 12 N or less, 10 N or less, or 9 N or less, and / or the average slip force does not increase by more than 5 N, more than 4 N, or more than 3 N. In some embodiments, after storage at 5°C for 24 months, the average slip force of a syringe pre-filled with the liquid formulation according to the first state sample and equipped with a needle is 14 N or less, 12 N or less, 10 N or less, or 8 N or less, and / or the average slip force does not increase by more than 3 N, more than 2 N, or more than 1.5 N. In some embodiments, after storage at 5°C for 9 months, the average slip force of a pre-filled syringe equipped with a needle is 9 N or less, or 7.5 N or less, and / or the average slip force does not increase by more than 2 N, more than 1.5 N, or more than 1 N. In some embodiments, after storage at 5°C for 3 months, the average slip force is 8 N or less, or 7 N or less, and / or the average slip force does not increase by more than 1.5 N, more than 1 N, or less than 0.5 N. In some embodiments, after storage at 25°C for 12 months, the average slip force is 15 N or less, or 13 N or less, and / or the average slip force does not increase by more than 9 N, more than 8 N, or more than 7 N. In some embodiments, after storage at 25°C for 3 months, the average slip force is 9 N or less, or 8 N or less, and / or the average slip force does not increase by more than 3 N, more than 2 N, or more than 1.5 N. In some embodiments, after storage at 25°C for 1 month, the average slip force is 8 N or less, or 7 N or less, and / or the average slip force does not increase by more than 1.5 N, more than 1 N, or less than 0.5 N. In some embodiments, after storage at 40°C for 3 months, the average slip force is 18 N or less, or 15 N or less, and / or the average slip force does not increase by more than 12 N, or more than 10 N, or more than 9 N. In some embodiments, after storage at 40°C for 1 month, the average slip force is 13 N or less, or 10 N or less, and / or the average slip force does not increase by more than 7 N, or more than 5 N, or more than 3 N.

[0126] The increase in maximum or average slip force is calculated for the indicated storage time and temperature, and is specifically determined by comparing the maximum or average slip force at the start and end of the indicated storage. In a particular embodiment, the measurement is performed as described in the examples.

[0127] The maximum slip force of the formulation refers to the maximum mechanical force required to eject the formulation from the syringe. The average slip force of the formulation refers to the average mechanical force required to eject the formulation from the syringe. In some embodiments, the slip force is determined according to industry standards such as ISO 7886, ISO 11040, and ISO 11499. In some embodiments, specifically, as described in the examples, the maximum and average slip forces of the formulation are determined using a tensile and compressive testing machine such as the Zwick 2.5TS / N from Zwick (Germany). Measurements can be performed using a Neopak 1 ml syringe from Becton Dickinson (USA), specifically a 1 ml syringe with a 27 gauge x ½ inch needle, as used in the examples. Measurements can be performed at speeds of approximately 300 to 500 mm / min, such as approximately 380 mm / min, specifically 379.2 mm / min, for example, for 5 seconds.

[0128] Another aspect of the invention relates to a liquid pharmaceutical formulation or a lyophilized pharmaceutical formulation according to the first aspect, or a container according to another aspect disclosed herein, for the therapeutic treatment of human individuals. The disease to be treated is a disease treatable with anti-IL-23p19 antibodies and such diseases are known in this art. Diseases can be selected from the group consisting of inflammatory diseases, autoimmune diseases, respiratory diseases, metabolic disorders, and cancer. In an example, the disease is a chronic disease. The disease to be treated can be psoriasis and inflammatory bowel disease. In another embodiment, the disease to be treated can be psoriatic arthritis and Crohn's disease. For the reasons discussed herein, it is advantageous to administer a high concentration of 150 mg / ml of the liquid pharmaceutical formulation of the present invention to the patient for treatment.

[0129] []

[0150] [] [mg] [ / ] [ml] [Another embodiment of the formulation] [] The following discloses further specific considered examples of antibody formulations based on the first state sample at a concentration of 150 mg / ml: 1. A liquid pharmaceutical preparation comprising a) 150 mg / ml anti-IL-23p19 antibody, wherein the antibody comprises the light chain amino acid sequence according to SEQ ID NO: 1 and the heavy chain amino acid sequence according to SEQ ID NO: 2; b) Polyols; and c) Surfactants. 2. [ ] As in Example 1, the formulation contains d) Buffer. 3. A formulation as described in Example 1 or 2, wherein the antibody is rissenzil antibody. 4. A formulation as described in any of Examples 1 to 3, wherein the antibody has been produced in a recombinant manner in mammalian cells. 5. The formulation as in Example 4, wherein the antibody has been produced in CHO cells in a recombinant manner. 6. A formulation of one or more of Examples 1 to 5, wherein the polyol is selected from sugars, sugar alcohols and combinations thereof. 7. The formulation as in Example 6, wherein the polyol is selected from trehalose, sucrose, sorbitol, mannitol, and combinations thereof. 8. The formulation as in Example 6, wherein the polyol is a sugar, which may be selected from trehalose and sucrose. 9. The formulation as in Example 6, which contains trehalose as a polyol. 10. The formulation as in Example 6, wherein the polyol is selected from sorbitol and mannitol. 11. The formulation as in Example 6, which contains mannitol as a polyol. 12. A formulation as described in any of Examples 1 to 11, wherein the liquid pharmaceutical formulation does not contain sorbitol. 13. A formulation of one or more of Examples 1 to 9, wherein the formulation does not contain sugar alcohols. 14. A formulation of one or more of Examples 1 to 13, having one or more of the following characteristics: (i) The concentration of the polyol in the formulation is at least 95 mM; (ii) The concentration of the polyol in the formulation is at least 125 mM; (iii) The concentration of the polyol in the formulation is at least 150 mM; (iv) The concentration of the polyol in the formulation is ≤ 500 mM, ≤ 450 mM, or ≤ 400 mM; (v) The concentration of the polyol in the formulation is ≤ 350 mM, ≤ 300 mM, or ≤ 275 mM; and / or (vi) The concentration of the polyol in the formulation is in the range of 95 mM to 450 mM or 125 mM to 400 mM; Depending on the circumstances, the polyol may be a sugar and / or a sugar alcohol. 15. A formulation of one or more of Examples 1 to 13, wherein the concentration of the polyol in the formulation is in the range of 95 mM to 250 mM, and wherein the polyol is a sugar, as appropriate. 16. A formulation of one or more of Examples 1 to 13, wherein the concentration of the polyol in the formulation is in the range of 125 mM to 225 mM, and wherein the polyol is, where appropriate, a sugar such as trehalose. 17. A formulation of one or more of Examples 1 to 13, wherein the concentration of the polyol is in the range of 145 mM to 225 mM, and wherein the polyol is, where appropriate, a sugar such as trehalose. 18. A formulation of one or more of Examples 1 to 13, wherein the polyol is a sugar and wherein the concentration of the sugar is in the range of 150 mM to 200 mM, and wherein the sugar is trehalose, if applicable. 19. A formulation of one or more of Examples 1 to 13, wherein the polyol is a sugar and wherein the concentration of the sugar is in the range of 160 mM to 200 mM, and wherein the sugar is trehalose, if applicable. 20. A formulation of one or more of Examples 1 to 13, wherein the polyol is a sugar and wherein the concentration of the sugar is in the range of 170 mM to 200 mM, and wherein the sugar is trehalose, if applicable. 21. A formulation of one or more of Examples 1 to 13, comprising 185 mM of trehalose as a polyol. 22. A formulation of one or more of Examples 1 to 21, wherein the surfactant is a nonionic surfactant. 23. The formulation as in Example 22, wherein the surfactant is polysorbate. 24. A formulation as described in Example 22 or 23, wherein the nonionic surfactant is selected from polysorbate 20 and / or polysorbate 80. 25. A formulation of one or more of Examples 1 to 24, wherein the surfactant is polysorbate 20. 26. A formulation of one or more of Examples 1 to 25, specifically any of Examples 23 to 25, wherein the concentration of the surfactant in the formulation is at least 0.05 mg / ml, and, where applicable, at least 0.075 mg / ml. 27. A formulation of one or more of Examples 1 or 26, or any of Examples 23 to 25, wherein the concentration of the surfactant in the formulation is in the range of 0.05 mg / ml to 0.75 mg / ml. 28. A formulation of one or more of Examples 1 or 27, or any of Examples 23 to 25, wherein the concentration of the surfactant in the formulation is in the range of 0.05 mg / ml to 0.5 mg / ml or 0.075 mg / ml to 0.3 mg / ml. 29. The formulation of Example 25, wherein the formulation contains 0.2 mg / ml of polysorbate 20 as a surfactant. 30. A formulation as in Example 29, wherein the polyol is a sugar and wherein the concentration of the sugar is in the range of 145 mM to 225 mM, and wherein the sugar is trehalose, if applicable. 31. A formulation of one or more of Examples 1 to 30, wherein the pH of the liquid pharmaceutical formulation is in the range of pH 5.0 to 7.5 or pH 5.0 to 7.0. 32. A formulation of one or more of Examples 1 to 30, wherein the pH of the liquid pharmaceutical formulation is in the range of 5.2 to 6.5 or 5.2 to 6.2. 33. A formulation of one or more of Examples 1 to 30, wherein the pH of the liquid pharmaceutical formulation is in the range of 5.5 to 6.5 or 5.5 to 6.2. 34. A formulation of one or more of Examples 1 to 30, wherein the pH of the liquid pharmaceutical formulation is in the range of 5.5 to 5.9. 35. A formulation of one or more of Examples 1 to 30, wherein the pH of the liquid pharmaceutical formulation is in the range of 5.6 to 5.8. 36. A formulation of one or more of Examples 1 to 30, wherein the pH of the liquid pharmaceutical formulation is 5.7 or 6.2. 37. A formulation as described in one or more of Examples 2 to 36, wherein the pKa of the buffer at 25°C is within 1.5 or one pH unit of the final pH of the liquid pharmaceutical formulation, wherein, where applicable, the pKa of the buffer at 25°C is in the range of 4.2 to 7.2 pH or 4.5 to 7 pH. 38. A formulation of one or more of Examples 2 to 37, wherein the buffer is an organic buffer selected, as appropriate, from acetate buffers and succinate buffers. 39. The formulation of Example 38, wherein the buffer is an acetate buffer, and where applicable, the acetate buffer comprises sodium acetate and acetic acid. 40. A formulation as described in Examples 2 to 37, wherein the buffer is a histidine buffer, or wherein the formulation achieves at least one of the following characteristics: (i) It contains a carboxylic acid buffer; (ii) It does not contain a succinate buffer. 41. A formulation of one or more of Examples 2 to 40, comprising at least 1 mM, at least 2 mM or at least 3 mM of buffer, and, where applicable, at least 4 mM, at least 4.5 mM or at least 5 mM of buffer. 42. A formulation of one or more of Examples 2 to 41, wherein the concentration of the buffer is 100 mM or less, 75 mM or less, or 50 mM or less. 43. A formulation of one or more of Examples 2 to 41, wherein the concentration of the buffer is 20 mM or less or 15 mM or less. 44. A formulation of one or more of Examples 2 to 41, wherein the concentration of the buffer is in the range of 4 mM to 50 mM. 45. A formulation of one or more of Examples 2 to 41, wherein the concentration of the buffer is in the range of 5 mM to 25 mM or 5 mM to 20 mM. 46. ​​A formulation of one or more of Examples 2 to 41, wherein the concentration of the buffer is in the range of 5 mM to 15 mM or 7 mM to 12 mM. 47. A formulation of one or more of Examples 2 to 41, wherein the concentration of the buffer is 10 mM. 48. A formulation of one or more of Examples 2 to 47, wherein the formulation comprises a single buffer, which may be an acetate buffer. 49. A formulation of any one of technical solutions 1 or 3 to 36, wherein the formulation does not contain a buffer. 50. A formulation of one or more of Examples 1 to 49, wherein the formulation is an aqueous formulation. 51. A formulation as described in any one of Examples 2 to 48 or 50, comprising... a) 150 mg / ml of this antibody; b) Sugars, where the concentration of the sugar is in the range of 95 mM to 250 mM or 145 mM to 225 mM, depending on the situation; c) A nonionic surfactant, wherein the concentration of the nonionic surfactant is in the range of 0.05 mg / ml to 0.5 mg / ml or 0.075 mg / ml to 0.3 mg / ml, as appropriate; and d) Buffer. 52. A formulation as described in any one of Examples 2 to 48 or 50 to 51, comprising... a) 150 mg / ml of this antibody; b) Trehalose, wherein the concentration of trehalose is in the range of 95 mM to 250 mM or 145 mM to 225 mM, depending on the situation; c) Polysorbate, wherein the concentration of the polysorbate is in the range of 0.05 mg / ml to 0.5 mg / ml or 0.075 mg / ml to 0.3 mg / ml, as appropriate; and d) Buffer. 53. A formulation as described in Examples 51 or 52, wherein the buffer is an acetate buffer or a succinate buffer, wherein the concentration of the buffer is in the range of 5 mM to 25 mM, as appropriate. 54. A formulation as in Example 52 or 53, wherein the polysorbate is polysorbate 20. 55. A formulation of any one of Examples 51 to 54, wherein the pH of the formulation is in the range of pH 5.2 to pH 6.5, and, as appropriate, the pH is in the range of 5.2 to 6.2 or 5.5 to 6.2 or is 5.7. 56. A formulation as described in any one of Examples 2 to 48 or 50 to 55, comprising... a) 150 mg / ml of this antibody; b) Trehalose from 170 mM to approximately 200 mM; c) 0.1 mg / ml to 0.3 mg / ml polysorbate, as appropriate, polysorbate 20; and d) Buffer, as appropriate, wherein the buffer is an acetate buffer. 57. A liquid pharmaceutical preparation as described in Examples 1, 3 to 36, or 49 to 50, comprising... a) 150 mg / ml of this antibody; b) a polyol, wherein the polyol is a sugar or a sugar alcohol, as appropriate; and c) Nonionic surfactants, such as polysorbate, depending on the situation; d) Does not contain buffer. 58. A formulation as described in Example 57, wherein the pH of the formulation is in the range of pH 5.2 to pH 6.5, or, where appropriate, the pH is in the range of 5.2 to 6.2 or 5.5 to 6.2. 59. The formulation as in Example 58, wherein the pH is 5.7. 60. A formulation of any one of Examples 57 to 59, comprising 80 mM to 250 mM of a polyol, wherein the polyol is, where appropriate, trehalose. 61. A formulation as described in any of Examples 57 to 60, wherein the concentration of the nonionic surfactant is in the range of 0.05 mg / ml to 0.5 mg / ml, 0.075 mg / ml to 0.4 mg / ml, or 0.1 mg / ml to 0.3 mg / ml. 62. A formulation as in Example 61, wherein the nonionic surfactant is polysorbate, or polysorbate 20, as appropriate. 63. A formulation of one or more of Examples 1 to 62, further comprising an amino acid as an additive. 64. A formulation as described in Example 63, wherein the amino acid has charged side chains, or positively charged side chains as appropriate, such as L-arginine. 65. A formulation as in Examples 63 or 64, wherein the amino acid is present in the formulation as a salt, or, where appropriate, as a hydrochloric acid (HCl) salt. 66. The formulation as in Example 63, wherein the amino acid is methionine. 67. The formulation as in Example 63, wherein the amino acid is L-proline. 68. A formulation as described in Examples 1 to 67, wherein the formulation has one or more of the following characteristics: (i) It does not contain arginine; (ii) It does not contain amino acids with positively charged side chains; (iii) It does not contain amino acids with charged side chains; (iv) It does not contain methionine; and / or (v) It does not contain amino acids as additives. 69. The liquid pharmaceutical preparation of any one of Examples 2 to 68, comprising: a) 150 mg / ml of this antibody; b) 185 mM trehalose; c) 0.2 mg / ml polysorbate 20; and d) 10 mM acetate buffer; The pH value is in the range of 5.2 to 6.2, and may be 5.7 depending on the situation. 70. A formulation as described in any one of Examples 1 to 69, wherein the formulation is stable. 71. The formulation of Example 70 achieves one or more of the following stability characteristics: (i) After storage at 5°C for 36 months, at least 94%, at least 95%, or at least 96% of the antibody, as measured by UP-SEC, is present in monomeric form, and / or the relative monomer content of the antibody does not decrease by more than 3%, more than 2.5%, more than 2%, or more than 1.5%; (ii) After storage at 5°C for 24 months, as measured by UP-SEC, at least 94%, at least 95%, or at least 96% of the antibody is present in monomeric form, and / or the relative monomer content of the antibody does not decrease by more than 3%, more than 2.5%, more than 2%, more than 1.5%, or more than 1%; (iii) After being stored at 5°C for 9 months, at least 96% or at least 96.5% of the antibody is present in monomeric form as measured by UP-SEC, and / or the relative monomer content of the antibody does not decrease by more than 1.5% or more than 1%; (iv) After storage at 5°C for 3 months, at least 96% or at least 97% of the antibody is present in monomeric form as measured by UP-SEC, and / or the relative monomer content of the antibody does not decrease by more than 1% or more than 0.7% or more than 0.5%; (v) After being stored at 25°C for 12 months, at least 90% or at least 92% of the antibody is present in monomeric form as measured by UP-SEC, and / or the relative monomer content of the antibody does not decrease by more than 7%, 6%, or 5%; (vi) After being stored at 25°C for 3 months, at least 95% of the antibody remains in monomeric form as measured by UP-SEC, and / or the relative monomer content of the antibody does not decrease by more than 3% or more than 2%; (vii) After storage at 25°C for one month, at least 96% of the antibody remains in monomeric form as measured by UP-SEC, and / or the relative monomer content of the antibody does not decrease by more than 2% or more than 1%; (viii) After storage at 40°C for 3 months, as measured by UP-SEC, at least 87% or at least 88% of the antibody is present in monomeric form, and / or the relative monomer content of the antibody does not decrease by more than 10%, more than 9%, or more than 8%; and / or (ix) After being stored at 40°C for one month, at least 93% or at least 94% of the antibody is present in monomeric form as measured by UP-SEC, and / or the relative monomer content of the antibody does not decrease by more than 5% or more than 4%. 72. The formulations of Examples 70 or 71 achieve one or more of the following stability characteristics: (i) After being stored at 5°C for at least 36 months, the formulation has a milky white luster of 12 FNU (formazan turbidity unit) or less or 10 FNU or less, and / or the milky white luster does not increase by more than 5 FNU or more than 3 FNU; (ii) After being stored at 5°C for at least 3, 6, 9, 12, 18, or 24 months, the formulation has a milky white luster of 12 FNU (formazan turbidity unit) or less or 10 FNU or less, and / or the milky white luster does not increase by more than 5 FNU or more than 3 FNU; (iii) After being stored at 25°C for at least 1, 3, 6, 9 or 12 months, the formulation has a milky white light of 12 FNU or less or 10 FNU or less, and / or the milky white light does not increase by more than 7 FNU or more than 5 FNU; (iv) After being stored at 40°C for at least 1 or 3 months, the formulation exhibits a milky luster of 12 FNU or less or 10 FNU or less, and / or the milky luster does not increase by more than 5 FNU or more than 3 FNU; and / or (v) After shaking at 25°C for 21 days, the formulation has a milky white light of 12 FNU or less or 10 FNU or less, and / or the milky white light of the formulation does not increase by more than 3 FNU or more than 2 FNU. 73. The formulation of any one of Examples 70 to 72 achieves one or more of the following stability characteristics: (i) After shaking at 25°C for 21 days, at least 95% or at least 96% of the antibody is present in monomeric form, as measured by UP-SEC, and / or the relative monomer content of the antibody does not decrease by more than 2% or more than 1%; and / or (ii) After shaking at 25°C for 21 days, less than 3% or less than 2% of the antibody is present in the form of a high molecular weight (HMW) species as measured by UP-SEC, and / or the relative HMW content of the antibody does not increase by more than 2% or more than 1.5% or more than 1%. 74. The formulation of any one of Examples 70 to 73 achieves one or more of the following stability characteristics: (i) After storage at 5°C for 36 months, less than 4% or less than 3% of the antibody is present in the form of a high molecular weight (HMW) species, as measured by UP-SEC, and / or the relative HMWS content of the antibody does not increase by more than 2% or more than 1.5%; (ii) After storage at 5°C for 24 months, if measured by UP-SEC, less than 4% or less than 3% of the antibody exists in the form of a high molecular weight (HMW) species, and / or the relative HMW content of the antibody does not increase by more than 2%, 1.5%, or 1%; (iii) After storage at 5°C for 9 months, if measured by UP-SEC, less than 4%, less than 3%, or less than 2.5% of the antibody exists in the form of a high molecular weight (HMW) species, and / or the relative HMW content of the antibody does not increase by more than 1%, more than 0.8%, or more than 0.6%; (iv) After storage at 5°C for 3 months, if measured by UP-SEC, less than 4%, less than 3%, or less than 2.5% of the antibody exists in the form of a high molecular weight (HMW) species, and / or the relative HMW content of the antibody does not increase by more than 1%, more than 0.8%, or more than 0.6%; (v) After storage at 40°C for 3 months, if measured by UP-SEC, less than 6.5% or less than 6% or less than 5.5% of the antibody exists in the form of a high molecular weight (HMW) species, and / or the relative HMW content of the antibody does not increase by more than 5% or more than 4%; and / or (vi) After storage at 40°C for 1 month, if measured by UP-SEC, less than 5% or less than 4.5% or less than 4% of the antibody exists in the form of a high molecular weight (HMW) species, and / or the relative HMW content of the antibody does not increase by more than 2.5% or more than 2%. 75. A formulation of any one of Examples 70 to 74, which achieves one or more of the following stability characteristics: (i) After storage at 25°C for 12 months, less than 5% or less than 4% of the antibody is present in the form of a high molecular weight (HMW) species as measured by UP-SEC, and / or the relative HMW content of the antibody does not increase by more than 3% or more than 2.5% or more than 2%; (ii) After storage at 25°C for 3 months, if measured by UP-SEC, less than 4%, less than 3.5%, or less than 3.2% of the antibody exists in the form of a high molecular weight (HMW) species, and / or the relative HMW content of the antibody does not increase by more than 2% or more than 1.5%; and / or (iii) After being stored at 25°C for 1 month, less than 4%, less than 3.5%, or less than 3% of the antibody is present in the form of a high molecular weight (HMW) species as measured by UP-SEC, and / or the relative HMW content of the antibody does not increase by more than 1.5% or more than 1%. 76. The formulation of any one of Examples 70 to 75 achieves one or more of the following stability characteristics: (i) After storage at 5°C for 36 months, less than 2% or less than 1.5% of the antibody is present in the form of a low molecular weight (LMW) species, as measured by UP-SEC, and / or the relative LMWS content of the antibody does not increase by more than 1.5% or more than 0.5%; (ii) After storage at 5°C for 24 months, if measured by UP-SEC, less than 2% or less than 1.5% of the antibody exists in the form of a low molecular weight (LMW) species, and / or the relative LMW content of the antibody does not increase by more than 1.5% or more than 0.5%; (iii) After storage at 5°C for 9 months, if measured by UP-SEC, less than 2% or less than 1.5% of the antibody exists in the form of a low molecular weight (LMW) species, and / or the relative LMW content of the antibody does not increase by more than 1.5% or more than 0.5%; (iv) After storage at 5°C for 3 months, if measured by UP-SEC, less than 2%, less than 1.5%, or less than 1% of the antibody exists in the form of a low molecular weight (LMW) species, and / or the relative LMW content of the antibody does not increase by more than 1%, more than 0.5%, or more than 0.25%; (v) After storage at 40°C for 3 months, as measured by UP-SEC, less than 8%, less than 7%, or less than 6% of the antibody exists in the form of a low molecular weight (LMW) species, and / or the relative LMW content of the antibody does not increase by more than 8%, more than 7%, or more than 6%; and / or (vi) After storage at 40°C for 1 month, if measured by UP-SEC, less than 4%, less than 3.5%, or less than 3% of the antibody exists in the form of a low molecular weight (LMW) species, and / or the relative LMW content of the antibody does not increase by more than 3%, more than 2.5%, or more than 2.2%. 77. A formulation of any one of Examples 70 to 76, which achieves one or more of the following stability characteristics: (i) After being stored at 25°C for 12 months, if measured by UP-SEC, less than 6%, less than 5%, or less than 4.5% of the antibody exists in the form of a low molecular weight (LMW) species, and / or the relative LMW content of the antibody does not increase by more than 5%, more than 4%, or more than 3%; (ii) After storage at 25°C for 3 months, if measured by UP-SEC, less than 3%, less than 2%, or less than 1.8% of the antibody exists in the form of a low molecular weight (LMW) species, and / or the relative LMW content of the antibody does not increase by more than 2%, more than 1.5%, or more than 1%; and / or (iii) After being stored at 25°C for 1 month, if measured by UP-SEC, less than 2% or less than 1.5% or less than 1.2% of the antibody is present in the form of a low molecular weight (LMW) species, and / or the relative LMW content of the antibody does not increase by more than 1% or more than 0.6% or more than 0.4%. 78. The formulation of any one of Examples 70 to 77 achieves one or more of the following stability characteristics: (i) After being stored at 5°C for 36 months, at least 55%, at least 60%, or at least 65% of the antibody is present as a main peak variant, as determined by ion exchange chromatography (IEC), and / or the relative content of the main peak variant of the antibody does not decrease by more than 8%, more than 7%, or more than 5%; (ii) After being stored at 5°C for 24 months, at least 55%, at least 60%, or at least 65% of the antibody is present as a main peak variant, as determined by ion exchange chromatography (IEC), and / or the relative content of the main peak variant of the antibody does not decrease by more than 8%, more than 7%, or more than 5%; (iii) After being stored at 5°C for 6 months, at least 60% or at least 65% of the antibody is present as a main peak variant, as determined by ion exchange chromatography (IEC), and / or the relative content of the main peak variant of the antibody does not decrease by more than 5% or more than 4%; (iv) After storage at 5°C for 3 months, at least 60% or at least 65% of the antibody is present as a main peak variant, as determined by ion exchange chromatography (IEC), and / or the relative content of the main peak variant of the antibody does not decrease by more than 4%, more than 3%, or more than 2%; (v) After being stored at 25°C for 12 months, at least 35% or at least 40% or at least 45% of the antibody is present as a main peak variant, as determined by ion exchange chromatography (IEC), and / or the relative content of the main peak variant of the antibody does not decrease by more than 35% or more than 30% or more than 25%; (vi) After storage at 25°C for 3 months, at least 55% or at least 60% of the antibody is present as a main peak variant, as determined by ion exchange chromatography (IEC), and / or the relative content of the main peak variant of the antibody does not decrease by more than 15% or more than 10%; and / or (vii) After being stored at 25°C for 1 month, at least 60% or at least 65% of the antibody is present as a main peak variant as determined by ion exchange chromatography (IEC), and / or the relative main peak variant content of the antibody does not decrease by more than 10% or more than 5%. 79. A formulation of any one of Examples 70 to 78, which achieves one or more of the following stability characteristics: (i) After storage at 5°C for 36 months, less than 30% or less than 28% of the antibody is present as an acidic peak group variant as determined by ion exchange chromatography (IEC), and / or the relative acidic peak group variant content of the antibody does not increase by more than 4%, more than 3%, or more than 2%; (ii) After storage at 5°C for 24 months, if determined by ion exchange chromatography (IEC), less than 30% or less than 28% of the antibody exists in the form of an acidic peak group variant, and / or the relative acidic peak group variant content of the antibody does not increase by more than 4%, more than 3%, or more than 2%; (iii) After being stored at 5°C for 6 months, if determined by ion exchange chromatography (IEC), less than 30% or less than 28% of the antibody exists in the form of an acidic peak group variant, and / or the relative content of the acidic peak group variant of the antibody does not increase by more than 4%, more than 3%, or more than 2%; (iv) After storage at 5°C for 3 months, if determined by ion exchange chromatography (IEC), less than 30% or less than 28% of the antibody exists in the form of an acidic peak group variant, and / or the relative content of the acidic peak group variant of the antibody does not increase by more than 3%, more than 2%, or more than 1%; (v) After being stored at 25°C for 12 months, less than 50%, less than 45%, or less than 40% of the antibody is present as an acidic peak group variant, as determined by ion exchange chromatography (IEC), and / or the relative acidic peak group variant content of the antibody does not increase by more than 30%, more than 25%, or more than 20%; (vi) After storage at 25°C for 3 months, if determined by ion exchange chromatography (IEC), less than 40%, less than 35%, or less than 30% of the antibody exists as an acidic peak group variant, and / or the relative acidic peak group variant content of the antibody does not increase by more than 10%, more than 8%, or more than 6%; and / or (vii) After being stored at 25°C for 1 month, if determined by ion exchange chromatography (IEC), less than 35%, less than 30%, or less than 28% of the antibody is present in the form of an acidic peak group variant, and / or the relative acidic peak group variant content of the antibody does not increase by more than 4% or more than 3%. 80. A formulation of any one of Examples 70 to 79, which achieves one or more of the following stability characteristics: (i) After being stored at 5°C for 36 months, less than 20%, less than 17%, less than 15%, or less than 13% of the antibody is present as a basic peak group variant, as determined by ion exchange chromatography (IEC), and / or the relative content of the antibody as a basic peak group variant does not increase by more than 10%, more than 8%, or more than 6%; (ii) After storage at 5°C for 24 months, if determined by ion exchange chromatography (IEC), less than 20%, less than 17%, less than 15%, or less than 13% of the antibody exists in the form of a basic peak group variant, and / or the relative content of the antibody in the basic peak group variant does not increase by more than 10%, more than 8%, or more than 6%; (iii) After being stored at 5°C for 6 months, if determined by ion exchange chromatography (IEC), less than 15% or less than 10% of the antibody exists in the form of a basic peak group variant, and / or the relative content of the antibody in the basic peak group variant does not increase by more than 4%, 3%, or 2%; (iv) After storage at 5°C for 3 months, if determined by ion exchange chromatography (IEC), less than 15% or less than 10% of the antibody exists in the form of a basic peak group variant, and / or the relative content of the antibody in the basic peak group variant does not increase by more than 3% or more than 2%; (v) After storage at 25°C for 12 months, if determined by ion exchange chromatography (IEC), less than 30%, less than 25%, or less than 22% of the antibody exists as a basic peak group variant, and / or the relative content of the antibody as a basic peak group variant does not increase by more than 25%, more than 20%, or more than 15%; (vi) After storage at 25°C for 3 months, if determined by ion exchange chromatography (IEC), less than 20%, less than 15%, or less than 12% of the antibody exists as a basic peak group variant, and / or the relative content of the antibody as a basic peak group variant does not increase by more than 9%, more than 7%, or more than 5%; and / or (vii) After being stored at 25°C for 1 month, if determined by ion exchange chromatography (IEC), less than 15%, less than 10%, or less than 9% of the antibody is present as a basic peak group variant, and / or the relative content of the antibody as a basic peak group variant does not increase by more than 3% or more than 2%. 81. The formulation of any one of Examples 70 to 80 achieves one or more of the following stability characteristics: (i) After storage at 5°C for 36 months, a specific binding activity to IL-23 of at least 95% or at least 97% compared to a reference antibody that has not been stored is measured; (ii) After storage at 5°C for 4, 6, 9, 12, 18, or 24 months, a specific binding activity to IL-23 of at least 95% or at least 97% compared to a reference antibody that has not yet been stored is measured; (iii) After storage at 25°C for 2, 3, 4, 6, 9, 12, or 18 months, a specific binding activity to IL-23 of at least 93% or at least 96% compared to a reference antibody, wherein the reference antibody has not been stored; and / or (iv) After storage at 40°C for 3, 4 or 6 months, a specific binding activity to IL-23 of at least 90% or at least 95% compared to a reference antibody that has not yet been stored is measured. 82. A formulation of one or more of Examples 1 to 81, wherein the dynamic viscosity measured at 20°C is ≤ 30 mPas (mPa·s), ≤ 25 mPas, or ≤ 20 mPas. 83. A formulation of one or more of Examples 1 to 82, wherein the conductivity of the formulation is in the range of 0.8 to 5 mS / cm, or, as appropriate, in the range of 1 to 2 mS / cm or 1.2 to 1.8 mS / cm. 84. A formulation of one or more of Examples 1 to 83, wherein the osmotic weight molar concentration of the formulation is in the range of 225 mOsm / kg to 375 mOsm / kg, such as 250 mOsm / kg to 350 mOsm / kg, 275 mOsm / kg to 330 mOsm / kg or 290 mOsm / kg to 320 mOsm / kg. 85. A formulation of one or more of Examples 1 to 84, wherein the formulation is an injectable formulation. 86. A formulation as described in Example 85, wherein the formulation is suitable for subcutaneous injection. 87. A formulation of one or more of Examples 1 to 86, wherein the formulation has not undergone and has not yet undergone a reconstitution step before being administered. 88. The formulation of any one of Examples 1 to 86 is prepared by reconstitution of the lyophilized formulation. 89. A lyophilized formulation of an anti-IL-23p19 antibody, wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2, the lyophilized formulation being prepared by lyophilizing a liquid formulation as described in any one of Examples 1 to 69, wherein the liquid formulation is, where appropriate, an aqueous solution. 90. A lyophilized formulation of an anti-IL-23p19 antibody, wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2, the lyophilized formulation providing a liquid formulation as described in any one of Examples 1 to 69 or 82 to 86 upon reconstitution. 91. A freeze-dried formulation comprising... a) Anti-IL-23p19 antibody, wherein the antibody comprises the light chain amino acid sequence according to SEQ ID NO: 1 and the heavy chain amino acid sequence according to SEQ ID NO: 2, and the amount of antibody provides an antibody concentration of 150 mg / ml upon recovery; b) Polyols; c) Surfactants; and d) Buffers to be selected as appropriate. 92. The lyophilized formulation as in Example 91, wherein the antibody is rissenkiramab. 93. The freeze-dried formulation of Example 91 or 92, wherein the polyol has one or more of the characteristics of any one of Examples 6 to 13, wherein the polyol is a sugar, which is selected from trehalose and sucrose. 94. A lyophilized formulation of any one of Examples 91 to 93, wherein the surfactant has one or more of the characteristics of any one of Examples 22 to 25, wherein, where appropriate, the surfactant is polysorbate. 95. A lyophilized formulation of any one of Examples 91 to 94, comprising d) a buffer having one or more of the features of any one of Examples 37 to 40. 96. A lyophilized formulation of any one of Examples 91 to 95, wherein the formulation has a pH of any one of Examples 31 to 36 upon reconstitution. 97. A sealed container, which may be a vial or a pre-filled syringe, contains a liquid pharmaceutical preparation as described in any one of Examples 1 to 87. 98. A container, which may be a sealed vial, contains a freeze-dried formulation as described in any one of Examples 88 to 96. 99. The product of Example 97, wherein the container contains 2 ml or less of the liquid formulation, or, depending on the circumstances, 1.5 ml or less or 1 ml or less of the liquid formulation. 100. The product of any one of Examples 97 to 99, comprising a single dose of 150 mg of antibody. 101. A formulation of any one of Examples 1 to 96 or a product of any one of Examples 97 to 100, used for the therapeutic treatment of a human individual. 102. A formulation of any one of Examples 1 to 96 or a product of any one of Examples 97 to 100, used to treat diseases selected from psoriasis and inflammatory bowel disease. 103. A formulation of any one of Examples 1 to 96 or a product of any one of Examples 97 to 100, for the treatment of diseases selected from psoriatic arthritis and Crohn's disease. 104. A stable liquid pharmaceutical formulation comprising... a) 150 mg / ml anti-IL-23p19 antibody, wherein the antibody comprises the light chain amino acid sequence according to SEQ ID NO: 1 and the heavy chain amino acid sequence according to SEQ ID NO: 2; b) Tension regulators; and c) Surfactants, The formulation has a pH of 5.5-5.9 and is isotonic. 105. The stable formulation as in Example 104, wherein the antibody is rissenzil. 106. The stable formulation as in Examples 104 or 105, wherein the tension modifier is a polyol. 107. A stable formulation as described in any of Examples 104 to 106, wherein the tension modifier is a polyol as described in any of Examples 6 to 11 above. 108. A stable formulation as described in any of Examples 104 to 107, wherein the concentration of the tension modifier has one or more of the characteristics defined for the polyols in any of Examples 14 to 21 above, wherein the tension modifier is a polyol as defined therein, and wherein the sugar is selected from trehalose and sucrose. 109. A stable formulation of any one of Examples 104 to 108, wherein the surfactant has one or more of the characteristics of any one of Examples 22 to 25 above, wherein the surfactant is, where appropriate, a polysorbate selected from polysorbate 20 and polysorbate 80. 110. A stable formulation as described in any of Examples 104 to 109, wherein the concentration of the surfactant in the formulation is as defined in any of Examples 26 to 30 above. 111. A stable formulation as described in any of Examples 104 to 110, wherein the pH of the formulation is in the range of 5.6 to 5.8, and where appropriate, wherein the pH of the formulation is 5.7. 112. A stable formulation as described in any of Examples 104 to 111, comprising d) a buffer, wherein the buffer has one or more of the features described in any of Examples 37 to 40 and 48. 113. A stable formulation as in Example 112, wherein the buffer has a concentration as in any one of Examples 41 to 47. 114. A stable formulation as described in any of Examples 104 to 113, wherein the formulation is an aqueous formulation. 115. A stable formulation of any one of Examples 104 to 114, which achieves one or more of the stability characteristics of any one of Examples 71 to 81. 116. A stable formulation as described in any of Examples 104 to 111 or 114 to 115, wherein the formulation is free of buffers. 117. A stable formulation as described in any of Examples 104 to 116, wherein the osmotic weight molar concentration of the formulation is 290-320 mOsm / kg. 118. A stable formulation of any one of Examples 104 to 117, having at least one or at least two of the following characteristics: (i) The surfactant is a nonionic surfactant; (ii) The surfactant is a polysorbate, which may be selected from polysorbate 20 and polysorbate 80, depending on the circumstances; (iii) wherein the concentration of the surfactant in the formulation is in the range of 0.05 mg / ml to 0.5 mg / ml, or, as appropriate, in the range of 0.075 mg / ml to 0.4 mg / ml or 0.1 mg / ml to 0.3 mg / ml; and / or (iv) It has any one of the features of Examples 12, 13 or 63 to 68. 119. The stable formulation of any one of Examples 104 to 118 is prepared by reconstitution of a lyophilized formulation. 120. A lyophilized formulation of an anti-IL-23p19 antibody, wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2, the lyophilized formulation being manufactured by lyophilizing a liquid formulation as described in any one of Examples 104 to 118, wherein the stable liquid formulation is, where appropriate, an aqueous solution. 121. A lyophilized formulation of an anti-IL-23p19 antibody, wherein the antibody comprises a light chain amino acid sequence according to SEQ ID NO: 1 and a heavy chain amino acid sequence according to SEQ ID NO: 2, the lyophilized formulation being provided in the reconstitution of a stable liquid formulation as described in any one of Examples 104 to 118.

[0130] Numerical ranges include the values ​​that define the range. The headings provided herein are not intended to limit the various forms or embodiments of the invention, which can be read in the entirety of this specification.

[0131] Unless the context clearly indicates otherwise, the singular forms "a / an" and "the" as used herein include plural references. The terms "comprising," "having," "including," and variations thereof are used synonymously and are not restrictive. Throughout this specification, unless otherwise described, where a composition is described as comprising components or materials, it is contemplated that the composition may also consist substantially of any combination of the described components or materials in the embodiments. The techniques illustratively disclosed herein may suitably be practiced in the absence of any element not specifically disclosed herein.

[0132] [] [Example] The following examples are for illustrative purposes only and are not intended to limit the invention in any way.

[0133] [] [I] [.] [Substances and Methods] [] [1] [.] [Preparation of starting materials] [] If necessary, prior to the UF / DF process, the purified rissenzil starting material produced in CHO cells is adjusted to pH 5.9. Finally, the solution is concentrated and the concentrated starting material is used to prepare formulations according to subsequent examples.

[0134] [2.] [syringe] [] Essentially, the storage of the preparation in the syringe is performed using a Neopak syringe with a rubber stopper from Becton Dickinson (USA). These syringes are used to measure loosening force and maximum and average slip force. In this embodiment, a 1 ml Neopak syringe from Becton Dickinson (USA) with a 27.5-gauge needle and a rubber stopper is used.

[0135] [II.] [Example] [1] [:] [Characterizing the starting material] [] [1. pH] [right] [The impact of antibodies] [] RALS (Right-Angle Light Scattering) measurements were performed on rissonitumol at different pH values ​​in a buffer mixture of 10 mM acetate, 10 mM citrate, 10 mM phosphate, and 115 mM NaCl. The results are shown in... [surface] [1] in. [surface] [1] [:]RALS measurement results for different pH values. [pH] [value] 4.5 5.0 5.5 6.0 6.5 7.0 [RALS] [T] [, 起始 , ] [ / ] [℃] 70 / 71 72 / 72 75 / 75 76 / 76 76 / 75 76 / 76

[0136] The results showed that the development starting point increased with increasing pH until it reached the plateau region. The highest onset temperature indicating high stability was measured at pH values ​​above 5.0 to 7. Therefore, the pH should not be too acidic (˂ 5).

[0137] [2.] [Determination of the buffer capacity of the starting material] [] In particular, the buffer capacity of the antibody starting material was determined to facilitate pH adjustment of the formulation solution for subsequent stability studies and to avoid protein damage. Titrations for determining antibody buffer capacity were performed at the following concentrations: 150 mg / mL; 100 mg / mL; 50 mg / mL (twice); and 20 mg / mL.

[0138] according to [surface] [2] Dilute in a beaker. [] [surface] [2] [:] A dilution procedure used to determine the buffer capacity of the starting material. [Target Concentration] [[mg / mL]] [Initial solution volume] [[mL] []] [MilliQ] [volume] [[] [mL] []] [Final volume [mL]] 150 4.67 1.33 5.00 100 3.11 2.89 5.00 50 1.56 4.44 5.00 50 2.6 7.40 10.00

[0139] After dilution, transfer 5 mL of each solution to a 10R glass vial using a dropper and titrate. Use 0.2 M NaOH solution for titration (stirring at 250 rpm). Perform titration for each antibody concentration and calculate the amount of NaOH added. Use Excel to calculate as follows: [surface] The slope and its reciprocal are shown in [3]. [surface] [3] [:] The calculation results of the slope and its corresponding reciprocal. [] [Protein Concentration] [(mg) [ / mL] [)] [Slope] [Reciprocal of slope] 20.47 1.090000 0.92 50.74 0.434821 2.30 50.77 0.432378 2.31 102.33 0.201703 4.96 152.30 0.133120 7.51

[0140] Concentration-dependent buffer capacity levels were obtained by plotting a concentration versus slope inverse equation. A straight line with a slope of 0.0505 and a y-intercept of -0.2007 was thus obtained. The results and examples below demonstrate that rissenkiumab itself possesses a considerable buffer capacity, allowing for the preparation of a 150 mg / ml buffer-free formulation of the present invention that does not contain any additional / extra buffering substances.

[0141] [] [III.] [Example] [2] [:] [Analysis of differences] [PH] [value] [and buffering materials] [] [1.] [The comparisons are different] [pH] [Value] [Evaluation of Acetate and Succinate Buffer Systems]

[0150] [] [mg] [ / ] [mL] [Stability of the compound] [] [1.1.] [Preparation of formulations] [] Preparation and analysis [surface] [4] shows the following ingredients: [surface] [4] [:] The composition of the compound being analyzed. [] [Ingredients] [pH] [Protein concentration (mg)] [ / mL] [Buffer] [Excipient 1] [Excipient 2] [Excipient 3] F1 6.2 150 4.4 mM succinate 200 mM sorbitol --- 0.02% PS20 F2 5.9 150 4.4 mM succinate 200 mM sorbitol --- 0.02% PS20 F3 5.7 150 10 mM acetate 190 mM sorbitol --- 0.02% PS20 F4 5.7 150 10 mM acetate 115 mM sorbitol 50 mM L-arginine HCl 0.02% PS20 F5 5.7 150 10 mM acetate 150 mM sorbitol 50 mM L-proline 0.02% PS20 0.02% PS20 corresponds to 0.2 mg / mL PS20.

[0142] Samples were collected over an 18-month period (0, 3, 6, 8, 12, and 18 months). Storage conditions were 5°C and 25°C / 60% relative humidity. Each formulation was filled into a Neopak syringe. The laminar flow filling volume was set to 1.1 mL. The syringe was sealed with a stopper and the particles were visually analyzed prior to storage. The syringes were then stored in a suspended syringe tray at their respective temperatures. Buffer solutions were stored concurrently as controls. After formulation preparation, each solution was aseptically filtered and the prepared formulations were stored in syringes (Becton Dickinson (USA) Neopak syringes).

[0143] [1.2.] [analyze] [] To analyze samples, high-pressure size exclusion chromatography (HP-SEC) and ultra-high efficiency size exclusion chromatography (UP-SEC) were performed, with turbidity (also known as milky light) measured at 860 nm. The injectability of the formulation stored in the syringe (Neopak) was analyzed by measuring the mechanical force required to release / inject the formulation. Pressure testing was performed at a speed of 379.2 mm / min (5 seconds). The viscosity of the formulation was measured at 20°C using a HAAKE RheoStress 600 with a C35 / 1 rotor. Dual gravimetric assays were performed.

[0144] Further details of the analytical methods used are described below.

[0145] [1.3.] [result] [] [1.3.1.] [Measuring monomer content] [] The monomer content was determined by analyzing the samples using HP-SEC and UP-SEC.

[0146] [,HP , ] [, - , ] [, SEC , ] [, analyze , ] [, , ] Results obtained by HP-SEC analysis at storage temperatures of 25°C and 5°C are shown below. [surface] [5] in: [surface] [5] [:] HP-SEC monomer analysis results, expressed as a percentage, during 18 months of storage at different temperatures in syringes. [time] [temperature] [F1] [,by] [%] [Unit] [F2] [,by] [%] [Unit] [F3] [,by] [%] [Unit] [F4] [,by] [%] [Unit] [F5] [,by] [%] [Unit] [initial] 25℃ 95.8 96.4 96.6 96.7 96.5 [3] [months] 94.5 95.1 95.4 96.1 95.6 [6] [months] 94.4 94.9 95.1 95.8 95.4 [8] [months] 93.7 94.3 94.6 95.3 94.9

[12] [months] 92.9 93.5 93.9 94.8 94.3

[18] [months] 91.1 92.4 92.8 94.0 93.4 [initial] 5℃ 95.8 96.4 96.6 96.7 96.5 [6] [months] 95.6 96.2 96.4 96.6 96.4 [8] [months] 95.2 95.9 96.1 96.4 96.2

[18] [months] 93.4 94.7 95.1 95.8 95.4

[0147] At 25°C, the monomer content remained between 91% and 94% over an 18-month storage period. In this example, the strongest reduction was measured at -5% for F1 and the lowest reduction at -3% for formulations 4 and 5. At 5°C, the monomer content remained between 93% and 96% over an 18-month storage period. The strongest reduction was measured at -2.4% for F1 and the lowest reductions at -0.9% and -1.1% for formulations 4 and 5, respectively.

[0148] [, UP , ] [, - , ] [, SEC , ] [, analyze , ] [, , ] The UP-SEC analysis results are similar to the HP-SEC analysis results, and therefore these results are confirmed. [surface] [5a] [:] UP-SEC monomer analysis results in percentage (%) during 18 months of storage at different temperatures in syringes. [time] [temperature] [F1] [,by] [%] [Unit] [F2] [,by] [%] [Unit] [F3] [,by] [%] [Unit] [F4] [,by] [%] [Unit] [F5] [,by] [%] [Unit] [initial] 25℃ 94.9 95.4 95.5 95.7 95.4 [3] [months] 93.5 94.2 94.4 95.0 94.6 [8] [months] 93.6 92.7 93.0 93.6 93.3

[12] [months] 90.6 91.2 91.4 92.1 91.7

[18] [months] 88.4 89.4 89.8 90.6 90.3 [initial] 5℃ 94.9 95.4 95.5 95.7 95.4 [8] [months] 94.6 95.3 95.5 95.7 95.7

[18] [months] 92.7 93.8 94.2 94.7 94.4

[0149] At 25°C, the monomer content (UP-SEC) remained between 88% and 91% over an 18-month storage period. The strongest decrease was measured at -6.4% for F1; the lowest decreases were measured at -5.1% and -5.4% for formulations 4 and 5, respectively. At 5°C, the monomer content (UP-SEC) remained between 93% and 95% over an 18-month storage period. The strongest decrease was measured at -2.2% for F1; the lowest decrease was measured at -1% for formulations 4 and 5.

[0150] [, Results and Discussion , ] [, , ] Given the monomer content, all tested formulations were generally stable, indicating that these formulations were stable at 5°C and 25°C over a storage period of up to 18 months.

[0151] [1.3.2.] [Measurement] [HMW] [content] [] The HMW content was determined by analyzing the samples using HP-SEC and UP-SEC.

[0152] [, HP , ] [, - , ] [, SEC , ] [, analyze , ] [, , ] Results obtained by HP-SEC analysis at storage temperatures of 25°C and 5°C are shown below. [surface] [6] in: [surface] [6] [:] Results of HP-SEC HMW content (in %) in syringes at different storage temperatures over 18 months. [time] [temperature] [F1] [,by] [%] [Unit] [F2] [,by] [%] [Unit] [F3] [,by] [%] [Unit] [F4] [,by] [%] [Unit] [F5] [,by] [%] [Unit] [initial] 25℃ 4.0 3.4 3.2 3.1 3.3 [3] [months] 5.1 4.5 4.3 3.6 4.0 [6] [months] 5.1 4.6 4.4 3.6 4.1 [8] [months] 5.7 5.1 4.8 4.0 4.5

[12] [months] 6.2 5.5 5.2 4.2 4.8

[18] [months] 7.6 6.4 5.9 4.7 5.3 [initial] 5℃ 4.0 3.4 3.2 3.1 3.3 [6] [months] 4.2 3.6 3.4 3.2 3.4 [8] [months] 4.6 3.9 3.7 3.4 3.7

[18] [months] 6.2 5.0 4.5 3.9 4.3

[0153] At 25°C, HMW species increased by 2%-4% over an 18-month storage period. The strongest increase was measured at +3.6% for F1; the lowest increases were measured at +1.6% and +2.0% for blends 4 and 5, respectively. At 5°C, HMW species increased by 1%-2% over an 18-month storage period. The strongest increase was measured at +2.2% for F1; the lowest increases were measured at +0.8% and +1.0% for blends 4 and 5, respectively.

[0154] [, UP-SEC , ] [, analyze , ] [, , ] The UP-SEC analysis results are similar to the HP-SEC analysis results, and therefore these results are confirmed. [surface] [6a] [:] Results of UP-SEC HMW content in syringes at different storage temperatures over 18 months, expressed as a percentage. [time] [temperature] [F1] [,by] [%] [Unit] [F2] [,by] [%] [Unit] [F3] [,by] [%] [Unit] [F4] [,by] [%] [Unit] [F5] [,by] [%] [Unit] [initial] 25℃ 3.9 3.4 3.2 3.1 3.3 [3] [months] 5.1 4.5 4.2 3.6 3.9 [8] [months] 4.0 5.0 4.8 4.0 4.4

[12] [months] 6.0 5.4 5.0 4.2 4.7

[18] [months] 7.4 6.4 6.0 4.9 5.5 [initial] 5℃ 3.9 3.4 3.2 3.1 3.3 [8] [months] 4.4 3.7 3.5 3.3 3.5

[18] [months] 5.8 4.7 4.3 3.8 4.1

[0155] At 25°C, HMW increased by 2%-3.5% over an 18-month storage period. The strongest increase was measured at +3.5% for F1; the lowest increases were measured at +1.8% and +2.2% for blends 4 and 5, respectively. At 5°C, HMW increased by 0.7%-1.9% over an 18-month storage period. The strongest increase was measured at +1.9% for F1; the lowest increases were measured at +0.7% and +0.8% for blends 4 and 5, respectively.

[0156] [, Results and Discussion , ] [, , ] Given the HMW content, all tested formulations were generally stable, demonstrating that the various formulations of the present invention are stable at 5°C and 25°C over a long storage period of up to 18 months.

[0157] [1.3.3.] [Turbidity Measurement] [] [surface] [7] [:] Turbidity results at 860 nm, expressed in FNU, at different storage temperatures over 18 months in a syringe. [time] [temperature] [F1] [,by] [FNU] [Unit] [F2] [,by] [FNU] [Unit] [F3] [,withFNU] [Unit] [F4] [,by] [FNU] [Unit] [F5] [,by] [FNU] [Unit] [initial] 25℃ 6 6 5 8 5 [3] [months] 6 6 6 8 5 [6] [months] 6 5 4 7 5 [8] [months] 7 7 6 9 7

[12] [months] 8 7 --- 9 6

[18] [months] 9 7 7 10 7 [initial] 5℃ 6 6 5 8 5 [6] [months] 6 5 4 8 4 [8] [months] 6 5 4 7 4

[18] [months] 7 6 5 9 5

[0158] Turbidity was measured at a wavelength of 860 nm, showing an increase of 1 to 3 formalin turbidity units (FNU) during an 18-month storage period at 25°C. Blend 1 showed the strongest increase of 3 FNU, while blend 2 showed the smallest increase of 1 FNU. Blend 4, containing L-arginine, exhibited the highest turbidity from the beginning.

[0159] Turbidity was measured at a wavelength of 860 nm, showing an increase of 0-1 FNU during an 18-month storage period at 5°C.

[0160] [, Results and Discussion , ] [, , ] Turbidity measurements showed no change in relative turbidity after 18 months of storage in the refrigerator. Formulation 4, containing L-arginine, exhibited the highest turbidity, making formulations without arginine more advantageous.

[0161] [1.3.4.] [Conduction Measurement] [] Measuring the conductivity of the formulation. [surface] [8]: Conductivity measurement results in mS / cm after being stored at 25°C for up to 18 months. [time] [temperature] [F1] [F2] [F3] [F4] [F5] [initial] 25℃ 1.25 1.37 1.53 3.96 1.54 [3] [months] 1.08 1.27 1.40 3.71 1.41 [6] [months] 1.29 1.34 1.52 3.85 1.52 [8] [months] 1.14 1.22 1.35 3.66 1.42

[12] [months] 1.18 1.23 1.43 3.61 1.43

[18] [months] 1.15 1.26 1.39 4.05 1.38 [initial] 5℃ 1.25 1.37 1.53 3.96 1.54 [6] [months] 1.25 1.35 1.48 3.92 1.54 [8] [months] 1.12 1.18 1.36 3.67 1.38

[18] [months] 1.07 1.14 1.29 3.99 1.36

[0162] [, Results and Discussion , ] [, , ] The conductivity of all five formulations remained constant during an 18-month storage period and at temperatures of 5°C and 25°C. The conductivity values ​​of F1, F2, F3, and F5 were between 1 and 2 mS / cm, while the formulation F4, containing L-arginine, had a relatively high conductivity of only less than 4 mS / cm.

[0163] [1.4.] [Further Analysis and Results] [] In addition, further analysis was performed on the five formulations tested (storage time and temperature as described above), and the results are as follows. ● The pH value remained substantially constant during the 18-month storage period and at the different storage temperatures tested. Therefore, the measured pH values ​​were in the range of 5.7–6.3. ● The permeate concentration remained substantially constant over an 18-month storage period and at the different storage temperatures tested. The tested values ​​ranged from 296 to 333 mOsm / kg. ● The dynamic viscosity remained substantially constant at 20°C for 18 months of storage and at the different storage temperatures tested. The dynamic viscosity was in the range of 10-14 mPas. ● Protein concentration remained substantially constant over the 18-month storage period and at the different storage temperatures tested. Small deviations in protein concentration are attributed to analytical variations, resulting in a range of 148–159 mg / mL. ● The HP-SEC fragment content remained substantially constant over an 18-month storage period and under the different storage temperatures tested. The fragment content ranged from 0.2% to 1.4%. The UP-SEC LMW content also remained substantially constant over an 18-month storage period and under the different storage temperatures tested. Specifically, within 18 months, a low increase of 3% was measured at 25°C, and a low increase of 0.1% to 0.3% was measured at 5°C. The LMW content ranged from 1.0% to 4.5%. ● The content of the weak cation exchange (WCX) main peak, acidic peak group (APG), and basic peak group (BPG) remained constant during a storage period of 18 months at 5°C. No differences in the main peak, APG, and BPG were observed between formulations. ● The hydrophobic interaction chromatography (HIC) peak content remained essentially constant during a 12-month storage period at 25°C or an 8-month storage period at 5°C. Subsequent peaks increased by approximately 2%-3% over storage time and temperature. The foremost peak increased slightly by 5%-7% over 12 months at 25°C and did not increase over 8 months at 5°C. No differences in the main, subsequent, and foremost peaks were observed between formulations. ● The specific binding activity remained substantially constant over an 18-month storage period and at the different storage temperatures tested, with minimal decreases of only 3% and 1%-2% at 25°C and 5°C for 18 months, respectively. The specific binding activity was in the range of 96%-101%. ● No visible particles were observed.

[0164] [] [1.5.] [Results Overview] [] All five formulations were stable during an 18-month storage period at 25°C and 5°C. However, formulation 4 contained additional additives. Formulation 3 was stable and, in contrast to formulation F4 which contained arginine, did not contain additional additives. Less aggregate formation was observed at a pH of approximately 5.7.

[0165] [2.] [In frozen] [ / ] [Comparison of different characteristics in thawing experiments] [pH] [Value] [Acetate and Succinate Buffer System] [] To analyze whether freezing and thawing of the 150 mg / mL formulation affected the product quality of rissenkiumab, three formulations were filled into small bags with a volume of 10 mL or 14 mL relative to the initial value and then frozen at -40°C. Additionally, one bag was stored at 2°C–8°C. The storage time under both conditions (-40°C and 2°C–8°C) was 3 weeks.

[0166] Freezing was performed using a controlled freezing method. The bag was then transferred to a -40°C freezer and kept frozen for the indicated storage time.

[0167] [2.1.] [Preparation of formulations] [] Each freeze / thaw cycle consisted of freezing in a lyophilizer at -40°C, followed by transfer to a -40°C freezer and thawing in the lyophilizer at a maximum thawing rate of 20°C / min until reaching room temperature after 3 weeks. The tested formulations are shown in... [surface] [9] in. [, , ] [] [surface] [9] [:] The composition of the blend. [] [Ingredients] [pH] [Protein concentration mg / mL] [Buffer] [Excipient 1] [Excipient 2] F1 6.2 150 10 mM succinate 185 mM sorbitol 0.02 w% PS20 F2 5.7 150 10 mM acetate 6.5 mM succinate 185 mM sorbitol 0.02 w% PS20 F3 5.7 150 10 mM acetate 6.5 mM succinate 160 mM Trehalose 0.02 w% PS20

[0168] Store the starting material in a refrigerator at 2°C–8°C until use. Freeze 10 mL bags (“small Flexboy bags”) using a freeze dryer at a controlled freezing rate of 0.5°C / min until the temperature reaches -40°C.

[0169] [2.2.] [analyze] [] Samples were thawed directly in a controlled manner using a lyophilizer prior to analysis. HP-SEC analysis was performed to measure protein stability and binding activity. Turbidity was measured at 860 nm and in the 400–600 nm range. Further details of the analytical methods used are described below.

[0170] [2.3.] [result] [] [2.3.1.] [Measuring monomers and] [HMW] [content] [] HP-SEC and UP-SEC analyses were performed to determine the stability of the formulation, showing the monomer and HMW content. The following results were obtained: [surface]

[10] [:] Results of HP-SEC monomer content and initial values ​​in percentage form after 3 weeks of storage (frozen at -40°C and 2°C-8°C). [] [] [F1-] [bag 1] [%] [F1-] [bag 2] [%] [F2-] [bag 1] [%] [F2-] [bag 2] [%] [F3-] [bag 1] [%] [F3-] [bag 2] [%] [initial] 98.7 98.6 98.9 98.9 98.9 98.9 [3] [Week] [5] [℃] 98.3 98.3 98.7 98.7 98.7 98.7 [3] [Week] [-40] [℃] 98.6 98.6 98.9 98.9 98.9 98.9

[0171] UP-SEC measurements confirm HP-SEC measurement results. Table 10a: [3] [Weekly Storage] [(] [exist] [-]

[40] [℃] [Below and in] [2] [℃] [-] [8] [℃] [Freezing] [)] [Afterwards] [%] [as a unit] [UP] [-] [SEC] [Monomer content and initial values.] [] [F1-] [bag 1] [%] [F1-] [bag 2] [%] [F2-] [bag 1] [%] [F2-] [bag 2] [%] [F3-] [bag 1] [%] [F3-] [bag 2] [%] [initial] 97.0 97.0 97.4 97.5 97.4 97.4 [3] [week] [5] [℃] 97.0 97.0 97.4 97.4 97.3 97.3 [3] [week] [-40] [℃] 97.0 97.0 97.4 97.5 97.4 97.4

[0172] The remaining antibodies with a 100% loss in content exist in the form of HMW species.

[0173] [, , ] [, Results and Discussion , ] [, , ] Overall, HP-SEC analysis results demonstrated the stability of all formulations, indicating that they are suitable for freeze / thaw cycles. Some formulations showed better results with higher monomer content and fewer HMW species.

[0174] [2.3.2.] [Measurement of binding activity] [] Binding activity against rhIL-23 was measured using surface plasma resonance (Biacore) measurements. Overall, the binding activity was consistent across all formulations, confirming their applicability. Specifically, binding activity was measured to be between 95% and 110%, with specific binding activity of approximately 100%. Freezing or storage at 2°C–8°C for 3 weeks did not alter the binding activity.

[0175] [] [2.3.3.] [Viscosity Measurement] [] Another important parameter for protein formulations is viscosity, which is preferably not too high to allow for injection of the formulation (e.g., through a needle without excessive force). Therefore, dynamic viscosity is measured.

[0176] The dynamic viscosities of F1, F2, and F3 are very similar, ranging from 8.7 to 10 mPas.

[0177] [] [2.4.] [Further Analysis and Results] [] In addition, further analysis was performed on the three formulations tested, and the results are as follows. ● The content of non-visual particles (≥ 25 µm, ≥ 10 µm, ≥ 5 µm) remained substantially constant over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. The total number of counted particles in all three formulations was substantially the same. ● The osmotic weight molar concentration remained substantially constant over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. The tested values ​​for the 150 mg / mL formulation ranged from 299 to 321 mOsm / kg. ● Turbidity remained substantially constant at 860 nm and 400–600 nm over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. The measured values ​​ranged from 2–7 FNU at 860 nm and 4–13 FNU at 400–600 nm. ● The pH value remained substantially constant over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. Therefore, the measured pH values ​​were in the range of 5.7–6.2. ● The conductivity remained substantially constant over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. Therefore, the measured conductivity was in the range of 1.3–2.5 mS. ● Protein concentration remained substantially constant over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. Small deviations in protein concentration are attributed to analytical variations, resulting in an initial protein concentration of 150 mg / mL ranging from 149 to 157 mg / mL. ● The content of the main peak in hydrophobic interaction chromatography (HIC) remained essentially constant over a 3-week period at 5°C or -40°C, including freeze / thaw cycles. The HIC main peak value ranged from 97.1% to 97.7%. The content of both the preceding and following peaks remained essentially constant over a 3-week period at 5°C or -40°C, including freeze / thaw cycles. ● The concentration of the weak cation exchange (WCX) main peak remained substantially constant over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. The WCX main peak value ranged from 72.5% to 73.8%. The acidic peak group (APG) and basic peak group (BPG) remained substantially constant over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. No differences were observed in the main peak, APG, and BPG concentrations between formulations. ● Capillary gel electrophoresis (CGE) analysis showed substantially constant values ​​over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. The undiminished main peak content ranged from 96.7% to 97.6%.

[0178] [] [2.5.] [Results Overview] [] The results of this invention demonstrate the stability of risenosumab provided in different 150 mg / mL formulations during freeze / thaw cycles. A single freeze / thaw cycle at -40°C for 3 weeks or at 2°C–8°C for 3 weeks did not affect the product quality of risenosumab. Therefore, the 150 mg / mL formulation is a suitable concentrate. pH 5.7 appears to perform slightly better compared to other pH values.

[0179] [] [3.] [The comparisons are different] [pH] [Value] [Acetate and Succinate Buffer System] [] Particularly suitable pH values ​​are between 5.2 and 6.2, such as 5.5 to 6.2 or about 5.7. As measured by SEC, higher pH values ​​may lead to increased protein aggregation. Lower pH values ​​may lead to chemical degradation. In previous studies, sorbitol was used to regulate stress. In this invention, trehalose and mannitol were used instead of sorbitol to regulate stress. Seven sorbitol-free formulations were selected and tested under the following three conditions: (i) 5°C for 18 months without monitoring rh; (ii) 25°C / 60% rh for 18 months; and (iii) 40°C / 75% rh for 6 months.

[0180] The composition of ingredients 1-7 is described below. [surface]

[11] in. Table 11: [The composition of the analyzed formulation.] [Ingredients] [composition] F1 150 mg / mL risenoside, 10 mM acetate + 100 mM trehalose + 100 mM mannitol + 0.2 mg / mL PS20, pH 5.7 F2 150 mg / mL risenoside, 10 mM acetate + 200 mM trehalose + 0.2 mg / mL PS20, pH 5.7 F3 150 mg / mL risenoside, 10 mM acetate + 100 mM trehalose + 50 mM L-arginine HCl + 0.2 mg / mL PS20, pH 5.7 F4 150 mg / mL risenoic acid, 4.4 mM succinate + 200 mM trehalose + 0.2 mg / mL PS20, pH 6.0 F5 150 mg / mL risenoic acid, 4.4 mM succinate + 100 mM trehalose + 50 mM L-arginine HCl + 0.2 mg / mL PS20, pH 6.0 F6 150 mg / mL risenoic acid, 4.4 mM succinate + 100 mM trehalose + 100 mM mannitol + 0.2 mg / mL PS20, pH 6.0 F7 150 mg / mL risenosumab, 200 mM trehalose + 0.2 mg / mL PS20, pH 5.7 (without buffer)

[0181] The formulation and formulation buffer were aseptically filtered (0.22 μm filter type) and filled into syringes (Neopak) at a filling volume of 1.04 mL under laminar flow. The formulation was prepared by mixing the starting material with a concentrated solution containing excipients, buffers, etc. The filled syringes were stored horizontally in a light-proof Rondo tray using a cardboard box at 2°C–8°C. The following filling materials were used: - Neopak syringe (1 ml syringe with a 27.5-gauge needle) - Rubber stopper - Rondo tray

[0182] [3.1.] [analyze] [] To analyze the sample, HP-SEC and UP-SEC were performed, and turbidity (also known as milky light) was measured. The following instruments were used for analysis: - UPLC, UPSEC:UPLC 29 / 31 Waters ACQUITY,Waters,MA - HPLC, WCX / SEC:HPLC 82 / 83 / 107 Waters ALLIACE,Waters,MA - Based on particle count / size in MFI: Microflow Imaging (Micro Flow Imagine), 5200 BOT A / B (Roboter), Protein Simple, GER - Osmomat 3000 Gonotec GmbH, GER - pH meter: SevenGo, Mettler Toledo, GER - Turbidiphotometer: 2100AN turbidity meter, Hach-Lange GmbH, GER - Based on the protein concentration of Solo VPE: Solo VPE, C. Technologies, Inc., NJ - Biacore:Biacore T200,GE Healthcare Life Science,UK - Tensile and compression testing equipment: Zwick 2.5TS / N 21159574 Zwick, Germany

[0183] Further details of the analytical methods used are described below.

[0184] [3.2.] [result] [] [3.2.1.] [Measuring monomer content] [] UP-SEC and HP-SEC were used to determine monomer content loss. Monomer content is a key quality attribute for protein stability and quality during stress-induced storage. The table below shows the UP-SEC measurement results. [, , ] [] [surface]

[12] [:] The monomer content [%] of seven formulations stored at 5°C, 25°C and 40°C, as measured by UP-SEC. [store] [condition] [store] [time,] [moon] [F1] [F2] [F3] [F4] [F5] [F6] [F7] [5] [℃] [0] 98.2 98.2 98.2 97.9 98.1 97.9 98.1 [4] 97.8 97.8 98.0 97.5 97.8 97.5 97.8 [6] 97.6 97.6 97.8 97.3 97.7 97.3 97.6 [9] 97.5 97.5 97.7 97.0 97.5 97.0 97.4

[12] 97.5 97.5 97.8 97.1 97.5 97.1 97.5

[18] - 97.3 - - - - - [] []

[25] [℃] [0] 98.2 98.2 98.2 97.9 98.1 97.9 98.1 [2] 97.1 97.1 97.4 96.8 97.3 96.8 97.1 [4] 96.5 96.5 96.9 96.3 96.8 96.2 96.5 [6] 95.8 95.8 96.2 95.6 96.2 95.5 95.8 [9] 95.1 95.1 95.5 94.9 95.5 94.9 95.2

[12] 94.7 94.7 95.0 94.5 95.1 94.5 94.7

[18] - 93.3 - - - - - [] []

[40] [℃] [0] 98.2 98.2 98.2 97.9 98.1 97.9 98.1 [2] 92.6 92.7 92.4 92.6 92.4 92.4 92.8 [4] 88.4 88.5 87.7 88.6 88.2 88.5 88.8 [6] 84.3 84.4 83.6 84.9 84.3 84.7 84.7

[0185] HP-SEC confirms the UP-SEC results. HP-SEC does not generate additional information compared to UP-SEC.

[0186] [, Results and Discussion , ] [, , ] All analyzed formulations were stable under the tested conditions.

[0187] [3.2.2.] [Measurement] [HMW] [content] [] UP-SEC and HP-SEC were used to determine the HMW formation level. The table below shows the UP-SEC measurement results. HMW content is related to monomer content. Monomer loss leads to an increase in HMW. [surface]

[13] [:] HMW [%] of seven formulations stored at 5°C, 25°C and 40°C, as measured by UP-SEC. [store] [condition] [store] [time,] [moon] [F1] [F2] [F3] [F4] [F5] [F6] [F7] [5] [℃] [0] 1.3 1.3 1.2 1.6 1.4 1.6 1.4 [4] 1.5 1.6 1.4 1.9 1.5 1.9 1.6 [6] 1.6 1.7 1.5 2.0 1.6 2.0 1.7 [9] 1.8 1.8 1.6 2.3 1.8 2.3 1.9

[12] 1.9 1.9 1.6 2.3 1.8 2.3 1.9

[18] - 2.0 - - - - - [] []

[25] [℃] [0] 0 1.3 1.3 1.2 1.6 1.4 1.6 [2] 2.0 2.0 1.7 2.4 1.8 2.4 2.0 [4] 2.2 2.2 1.8 2.5 1.9 2.5 2.2 [6] 2.4 2.4 2.0 2.7 2.1 2.8 2.4 [9] 2.7 2.7 2.2 3.0 2.3 3.0 2.7

[12] 2.8 2.8 2.3 3.2 2.4 3.2 2.9

[18] - 3.2 - - - - - [] []

[40] [℃] [0] 0 1.3 1.3 1.2 1.6 1.4 1.6 [2] 3.7 3.6 3.4 3.9 3.4 4.0 3.5 [4] 5.2 5.1 5.1 5.3 4.8 5.4 4.9 [6] 6.7 6.7 6.5 6.8 6.2 6.8 6.4

[0188] HP-SEC confirms the UP-SEC results. HP-SEC does not generate additional information compared to UP-SEC.

[0189] [, Results and Discussion , ] [, , ] Overall, all blends of species with low levels of HMW remained stable even after storage at 40°C.

[0190] [3.2.3.] [Measurement] [LMW] [content] [] UP-SEC was used to determine the LMW formation level. The table below shows the UP-SEC measurement results. [surface]

[14] [:] The LMW content [%] of seven blends stored at 5°C, 25°C and 40°C, as measured by UP-SEC. [store] [condition] [store] [time,] [moon] [F1] [F2] [F3] [F4] [F5] [F6] [F7] [5] [℃] [0] 0.5 0.5 0.5 0.5 0.5 0.6 0.6 [4] 0.6 0.6 0.7 0.6 0.7 0.7 0.7 [6] 0.7 0.7 0.7 0.7 0.7 0.7 0.7 [9] 0.7 0.7 0.7 0.7 0.7 0.7 0.7

[12] 0.6 0.6 0.6 0.6 0.6 0.6 0.6

[18] - 0.7 - - - - - [] []

[25] [℃] [0] 0.5 0.5 0.5 0.5 0.5 0.6 0.6 [2] 0.9 0.9 1.0 0.9 0.9 0.9 0.9 [4] 1.3 1.3 1.4 1.3 1.3 1.3 1.3 [6] 1.8 1.7 1.8 1.7 1.7 1.7 1.7 [9] 2 2 2.2 2.4 2.1 2.2 2.1 2.2

[12] 2.4 2.4 2.6 2.3 2.5 2.4 2.4

[18] - 3.6 - - - - - [] []

[40] [℃] [0] 0.5 0.5 0.5 0.5 0.5 0.6 0.6 [2] 3.7 3.7 4.3 3.5 4.1 3.5 3.7 [4] 6.4 6.4 7.2 6.1 7.0 6.1 6.4 [6] 8.9 8.9 9.9 8.4 9.5 8.5 8.9

[0191] [, Results and Discussion , ] [, , ] Overall, all blends containing low levels of LMW species remained stable even after storage at 40°C.

[0192] [3.2.4.] [Measurement] [LMW] [content] [] To assess the stability of the formulation, the LMW content was also measured by HP-SEC analysis. The results are shown below. [surface]

[15] [:] The LMW content [%] of seven formulations stored at 5°C, 25°C and 40°C was measured by HP-SEC. [store] [condition] [store] [time,] [moon] [F1] [F2] [F3] [F4] [F5] [F6] [F7] [5] [℃] [0] 0.2 0.2 0.2 0.2 0.2 0.2 0.2 [4] 0.3 0.3 0.3 0.3 0.3 0.3 0.3 [6] 0.3 0.3 0.3 0.3 0.3 0.3 0.3 [9] 0.3 0.3 0.3 0.3 0.3 0.3 0.3

[12] 0.4 0.3 0.3 0.3 0.3 0.3 0.3

[18] - 0.3 - - - - - [] []

[25] [℃] [0] 0.2 0.2 0.2 0.2 0.2 0.2 0.2 [2] 0.4 0.4 0.4 0.4 0.4 0.4 0.4 [4] 0.5 0.5 0.6 0.5 0.5 0.5 0.6 [6] 0.6 0.6 0.6 0.6 0.6 0.6 0.6 [9] 0.8 0.8 0.8 0.8 0.8 0.8 0.8

[12] 1.0 1.0 1.0 1.0 1.0 1.0 1.0

[18] - 1.2 - - - - - [] []

[40] [℃] [0] 0.2 0.2 0.2 0.2 0.2 0.2 0.2 [2] 1.3 1.3 1.4 1.3 1.4 1.2 1.3 [4] 2.2 2.2 2.4 2.1 2.3 2.1 2.2 [6] 3.0 3.0 3.3 2.8 3.1 2.8 3.0

[0193] [, Results and Discussion , ] [, , ] The LMW content increased only slightly over time, but all tested formulations generally caused low-level fragmentation.

[0194] [3.2.5.] [Turbidity Measurement] [] The results for milky white emission are summarized below. No change in milky white emission was observed under different conditions during storage time. Formulations containing L-arginine HCl (F3 and F5) showed the highest milky white emission. However, no gradual increase in milky white emission was observed during the studies of F3 and F5. No visible particles were observed in any of the formulations tested. [surface]

[16] [:] Milky white light from seven formulations stored at 5°C, 25°C and 40°C [FNU]. [store] [condition] [store] [time,] [moon] [F1] [F2] [F3] [F4] [F5] [F] [6] [F7] [5] [℃] [0] 1 5 11 7 15 6 4 [4] 5 5 11 7 13 7 4 [6] 6 6 12 7 14 8 4 [9] 5 5 11 7 15 8 6

[12] 6 6 12 7 12 8 3

[18] - 6 - - - - - [] []

[25] [℃] [0] 5 5 11 7 15 6 4 [2] 6 5 12 7 13 7 4 [4] 5 5 13 7 13 7 3 [6] 7 6 12 8 14 8 4 [9] 8 7 13 9 14 8 4

[12] 6 6 12 8 14 8 4

[18] - 7 - - - - -

[0195] [, , ] [, Results and Discussion , ] [, , ] Formulas containing L-arginine HCl showed an increase in milky white light.

[0196] [3.3.] [Further Analysis and Results] [] In addition, further analysis was performed on the seven formulations tested (storage time and temperature as described above), and the results are as follows. ● The protein concentration remained substantially constant over the 18-month storage period and at the different storage temperatures tested. ● The pH value remained essentially constant during the 18-month storage period and at the different storage temperatures tested. ● The permeate concentration remained substantially constant over an 18-month storage period and at the different storage temperatures tested. The tested values ​​ranged from 298 to 326 mOsm / kg. ● No visible particles were observed. ● IEC / WCX measurements of formulations stored at 5°C for the tested duration showed the following constant contents: main peak (69.7-72.2%), APG (18-20%), and BPG (8-13%). At 25°C and 40°C, the main peak decreased and the APG content increased in all formulations within similar ranges. At 25°C and 40°C, the BPG content of formulations at pH 6.0 was slightly lower (at most 2%) than that of formulations at pH 5.7. ● Particle counts measured by MFI remained substantially constant over the 18-month storage period and at the different storage temperatures tested. Specifically, for particles ≥ 10 µm and ≥ 25 µm, no corresponding increase in particle count was observed for all formulations at 5°C and 25°C / 60% rh during the storage period. For particles ≥ 2 µm, the particle count increased at 25°C. The increase was within a similar range for all formulations. ● The specific binding activity remained substantially constant over an 18-month storage period and at the different storage temperatures tested. The specific binding activity was in the range of 95%–100%. ● During the 18-month storage period and at 5°C, the loosening force and slip force remained essentially constant. During the storage period at 25°C, the maximum slip force, average slip force, and loosening force increased for all blends. No differences were observed between blends. The maximum slip force ranged from 7.1 to 23.6 N, the average slip force ranged from 6.7 to 20.5 N, and the loosening force ranged from 3.4 to 7.1 N. ● The dynamic viscosity at 20°C remained substantially constant over an 18-month storage period and at the different storage temperatures tested. The dynamic viscosity ranged from 8.3 to 10.7 mPas.

[0197] [3.4.] [Results Overview] [] This invention describes the storage stability of seven different 150 mg / mL rissonitumopram formulations. Trehalose and mannitol were used instead of sorbitol to adjust tonicity. F2 was analyzed after 18 months.

[0198] UP-SEC results showed that, compared to pH 5.7, pH 6.0 caused a slightly higher degradation of rissenzumab in the form of lower monomers and higher HMW (high molecular weight molecular weight) in the tested formulations. Formulations containing L-arginine HCl showed slightly lower degradation as measured by UP-SEC, but increased milky whiteness and a slight increase in LMW content. IEC results showed no significant differences between formulations and were therefore not a decisive factor. The same was true for pH, protein concentration, osmotic weight molar concentration, viscosity, loosening and slipping forces, and both invisible and visible particles. Based on this data, no differences were observed between formulations.

[0199] [] [4.] [The differences are noticeable during long-term storage] [pH] [Value] [Acetate and Succinate Buffer System] [] This invention analyzes the storage stability of seven different 150 mg / mL risenosumab formulations in Neopak syringes to determine their storage stability and identify favorable formulations. The tonicity was slightly improved compared to the seven formulations in the previous example. Three conditions (as identified above) were tested again. The analyzed formulations are summarized in... [surface]

[17] [, , ] [] [surface]

[17] [:] The composition of the compound being analyzed. [] [Ingredients] [composition] F1 150 mg / mL risenoside, 10 mM acetate + 95 mM trehalose + 95 mM mannitol + 0.2 mg / mL PS20, pH 5.7 F2 150 mg / mL risenosumab, 10 mM acetate + 185 mM trehalose + 0.2 mg / mL PS20, pH 5.7 F3 150 mg / mL risenoside, 10 mM acetate + 110 mM trehalose + 50 mM L-arginine HCl + 0.2 mg / mL PS20, pH 5.7 F4 150 mg / mL risenoic acid, 4.4 mM succinate + 180 mM trehalose + 0.2 mg / mL PS20, pH 6.0 F5 150 mg / mL risenoic acid, 4.4 mM succinate + 110 mM trehalose + 50 mM L-arginine HCl + 0.2 mg / mL PS20, pH 6.0 F6 150 mg / mL risenoic acid, 4.4 mM succinate + 95 mM trehalose + 95 mM mannitol + 0.2 mg / mL PS20, pH 6.0 F7 150 mg / mL risenosumab, 200 mM trehalose + 0.2 mg / mL PS20, pH 5.7 (without buffer)

[0200] Formulations are prepared by mixing starting materials with a concentrated feed solution (containing excipients, i.e., excipients and buffers).

[0201] [4.1.] [analyze] [] To analyze the samples, UP-SEC was performed, and the milky white light was measured. Further details of the analytical methods used are described below.

[0202] [4.2.] [result] [] [4.2.1.] [Measurement] [HMW] [content] [] [, , ] [] [surface]

[18] [:] HMW content measured in % by UP-SEC analysis after long-term storage at 5℃, 25℃ and 40℃. [Storage conditions] [Storage time, month] [F1] [,by%] [Unit] [F2] [,by%] [Unit] [F3] [,by%] [Unit] [F4] [,by%] [Unit] [F5] [,by%] [Unit] [F6] [,by%] [Unit] [F7] [,by%] [Unit] [5] [℃] 0 1.3 1.3 1.2 1.6 1.4 1.6 1.4 4 1.5 1.6 1.4 1.9 1.5 1.9 1.6 6 1.6 1.7 1.5 2.0 1.6 2.0 1.7 9 1.8 1.8 1.6 2.3 1.8 2.3 1.9 12 1.9 1.9 1.6 2.3 1.8 2.3 1.9 18 - 2.0 - - - - -

[25] [℃] 0 0 1.3 1.3 1.2 1.6 1.4 1.6 2 2.0 2.0 1.7 2.4 1.8 2.4 2.0 4 2.2 2.2 1.8 2.5 1.9 2.5 2.2 6 2.4 2.4 2.0 2.7 2.1 2.8 2.4 9 2.7 2.7 2.2 3.0 2.3 3.0 2.7 12 2.8 2.8 2.3 3.2 2.4 3.2 2.9 18 - 3.2 - - - - -

[40] [℃] 0 0 1.3 1.3 1.2 1.6 1.4 1.6 2 3.7 3.6 3.4 3.9 3.4 4.0 3.5 4 5.2 5.1 5.1 5.3 4.8 5.4 4.9 6 6.7 6.7 6.5 6.8 6.2 6.8 6.4

[0203] [, , ] [, Results and Discussion , ] [, , ] The overall HMW content in all tested formulations remained low, indicating that the high concentrations of formulations used stabilized rissenitumab. UP-SEC results further showed that pH 6.0 caused higher degradation of rissenitumab in the form of lower monomers and higher HMWs compared to pH 5.7. Therefore, pH 5.7 is particularly advantageous for the formulations of this invention. Nevertheless, given the UP-SEC analysis results, formulations such as F4, F5, and F6, with higher pH values ​​of 6.0, also showed generally good efficacy.

[0204] [4.2.2.] [Measurement] [LMW] [content] [] [surface]

[19] [:] The LMW content measured in % by UP-SEC analysis after long-term storage at 5℃, 25℃ and 40℃. [Storage conditions] [Storage time, month] [F1] [,by%] [Unit] [F2] [,by%] [Unit] [F3] [,by%] [Unit] [F4] [,by%] [Unit] [F5] [,by%] [Unit] [F6] [,by%] [Unit] [F7] [,by%] [Unit] [5] [℃] 0 0.5 0.5 0.5 0.5 0.5 0.6 0.6 4 0.6 0.6 0.7 0.6 0.7 0.7 0.7 6 0.7 0.7 0.7 0.7 0.7 0.7 0.7 9 0.7 0.7 0.7 0.7 0.7 0.7 0.7 12 0.6 0.6 0.6 0.6 0.6 0.6 0.6 18 - 0.7 - - - - -

[25] [℃] 0 0.5 0.5 0.5 0.5 0.5 0.6 0.6 2 0.9 0.9 1.0 0.9 0.9 0.9 0.9 4 1.3 1.3 1.4 1.3 1.3 1.3 1.3 6 1.8 1.7 1.8 1.7 1.7 1.7 1.7 9 2.2 2.2 2.4 2.1 2.2 2.1 2.2 12 2.4 2.4 2.6 2.3 2.5 2.4 2.4 18 - 3.6 - - - - -

[40] [℃] 0 0.5 0.5 0.5 0.5 0.5 0.6 0.6 2 3.7 3.7 4.3 3.5 4.1 3.5 3.7 4 6.4 6.4 7.2 6.1 7.0 6.1 6.4 6 8.9 8.9 9.9 8.4 9.5 8.5 8.9

[0205] [] [, Results and Discussion , ] [, , ] The formulations tested exhibited stability throughout the measurement time at all tested temperatures. Therefore, the tested formulations effectively stabilized 150 mg / mL rissenitumumab at high protein concentrations. At higher storage temperatures, a slight increase in the LMW content of the formulation containing L-arginine HCl was observed. This was an unexpected finding, as it is generally known that formulations containing L-arginine further stabilize the formulation. Therefore, in this respect, the 150 mg / mL rissenitumumab formulation differs from other protein formulations. Therefore, the arginine-free formulation of the present invention is preferred.

[0206] [] [4.2.3.] [Measurement of milky white light] [] [surface]

[20] : Milky white light measured in FNU after long-term storage at 5℃, 25℃ and 40℃. [Storage conditions] [Storage time, month] [F1] [,withFNU] [Unit] [F2] [,withFNU] [Unit] [F3] [,withFNU] [Unit] [F4] [,withFNU] [Unit] [F5] [,withFNU] [Unit] [F6] [,withFNU] [Unit] [F7] [,withFNU] [Unit] [5] [℃] 0 1 5 11 7 15 6 4 4 5 5 11 7 13 7 4 6 6 6 12 7 14 8 4 9 5 5 11 7 15 8 6 12 6 6 12 7 12 8 3 18 - 6 - - - - -

[25] [℃] 0 5 5 11 7 15 6 4 2 6 5 12 7 13 7 4 4 5 5 13 7 13 7 3 6 7 6 12 8 14 8 4 9 8 7 13 9 14 8 4 12 6 6 12 8 14 8 4 18 - 7 - - - - -

[0207] [] [, Results and Discussion , ] [, , ] Overall, the observed lack of increase or only a slight increase in milky white light over time indicates the stability of all tested formulations. Higher milky white light was observed in formulations containing L-arginine HCl (F3 and F5).

[0208] [4.3.] [Results Overview] [] The measured parameters showed that all formulations were suitable for the stable preparation of 150 mg / mL high concentrations of rissentiumab. Long-term stability revealed some differences between the formulations: - UP-SEC showed that pH 6.0 caused higher degradation of rissenkiramab in the form of lower monomers and higher HMW compared to pH 5.7. - Formulations containing L-arginine HCl showed lower degradation, but increased milky whiteness and a slight increase in LMW, as measured by UP-SEC.

[0209] Analyze F2 again after 18 months.

[0210] It is worth noting that formulations F1 and F7 are also stable. Buffer-free formulations and formulations containing more than one type of tonic agent are also stable and therefore suitable for providing formulations containing 150 mg / mL rissenkiramab.

[0211] In summary, formulation F2 was found to be particularly stable in terms of measured LMW and HMW levels and milky light, indicators of excellent stability. This result was quite unexpected, as risenosumab is generally known to be used at higher pH values. Therefore, the particularly high concentration of risenosumab shifted the optimal pH to approximately 5.7, which was unexpected. Furthermore, unexpectedly, L-arginine HCl did not cause further stabilization, but actually reduced the formulation stability supported by higher milky light and measured LMW levels. Therefore, the specific characteristics of high concentrations of risenosumab, such as 150 mg / mL, necessitate optimal conditions different from previously known risenosumab formulations.

[0212] [] [5.] [Different when shaken] [pH] [Value] [Acetate and Succinate Buffer System] [] The objective of this invention is to evaluate the effect of shaking stress on the product quality of different 150 mg / mL risenosumab formulations. The ability of different formulations to stabilize risenosumab against shaking stress is tested. Therefore, formulations at 150 mg / mL antibody concentrations are exposed to different shaking stresses.

[0213] Of the eleven formulations with different pH values, the buffers and tonics were filled into 6R vials and 1 mL Neopak syringes equipped with 27.5-gauge needles and shaken at room temperature for 21 days. The corresponding buffer solutions without proteins were also shaken, stored, and analyzed. Shaking conditions: - Shaking temperature: room temperature (approximately 25°C) - Shaking time: 21 days - Shaking type: horizontal shaker (vial), agitator (syringe); shake in the dark.

[0214] To eliminate the impact of temperature as an additional stress on product quality, store the additional vials and syringes at room temperature without shaking.

[0215] [5.1.] [Preparation of formulations] [] Preparation of 11 risenjilmab assay formulations (see [surface]

[21] ) and subject it to: a) Shake the vials at 300 U / min in a horizontal shaker for 1, 5, 7, 14, and 21 days (protected from light); b) Shake the syringe in a shaker for 1, 5, 7, 14, and 21 days, adjusting the motion to the respective viscosity to ensure bubble movement (avoid light); and c) At room temperature (25℃) for 1, 5, 7, 14, or 21 days (away from light). [surface]

[21] : The formulation selected for the shaking study. [] F1 10 mM acetate + 6.5 mM succinate + 185 mM sorbitol + 0.02% PS2O, pH 5.7 F2 10 mM acetate + 200 mM sorbitol + 0.02% PS2O, pH 5.7 F3 10 mM acetate + 50 mM L-arginine HCl + 110 mM sorbitol + 0.02% PS2O, pH 5.7 F4 10 mM succinate + 185 mM sorbitol + 0.02% PS2O, pH 6.2 F5 10 mM acetate + 95 mM mannitol + 95 mM trehalose + 0.02% PS2O, pH 5.7 F6 10 mM acetate + 185 mM trehalose + 0.02% PS2O, pH 5.7 F7 10 mM acetate + 50 mM L-arginine HCl + 110 mM trehalose + 0.02% PS2O, pH 5.7 F8 4.4 mM succinate + 185 mM trehalose + 0.02% PS20, pH 6.0 F9 4.4 mM succinate + 50 mM L-arginine HCl + 110 mM trehalose + 0.02% PS2O, pH 6.0 F10 4.4 mM succinate + 95 mM mannitol + 95 mM trehalose + 0.02% PS2O, pH 6.0 F11 Buffer-free, 200 mM trehalose, 0.02% PS20, pH 5.7

[0216] Add the formulation as encapsulation material to vials (Schott) or Neopak syringes. Fill the sterile, primary encapsulation material with the aseptically filtered protein solution under laminar flow. The vial filling volume is defined as 3.6 mL. Each syringe is filled with 1.04 mL. Inspect all vials and syringes for visible particles and record the results.

[0217] [5.2.] [analyze] [] After sampling, analyses are performed directly at each analytical time point, except for chromatographic analyses such as SEC. Samples are stored at -70°C until measurement is performed. The following devices are used for analysis: - UV-Vis spectrophotometer Solo VPE: Concentration at 280 nm, baseline correction at 320 nm, extinction coefficient: 1.52; C Technologies, Inc., NJ, USA - Optical fluorometer: HACH Lange opalescent meter; Filter: 400-600 nm; Hach Lange GmbH, Düsseldorf, Germany - Ultra-high efficiency size exclusion chromatography (UP-SEC): UPLC26, H-class UV detection at 280 nm, Waters, Milford, MA - Based on the charge inhomogeneity of weak cation exchange chromatography (WCX): HPLC 75; fluorescence detection: extinction: 278 nm, emission: 350 nm; Waters, Milford, MA - IL-23 binding activity: Biacore T200 chip: CM5 GE Healthcare, Chalfont St Giles, UK - pH meter:SevenGo - Mettler Toledo, Columbus, OH - Particle size analyzer: Micro Flow Imaging™ flow cytometer; utilizing microflow imaging (MFI); Brightwell Technologies Inc, Ottawa, ON, Canada - Osmomat 030, Gonotec GmbH, Berlin, Germany: Utilizing freezing point depression.

[0218] Further details of the analytical methods used are described below.

[0219] [5.3.] [result] [] [5.3.1.] [Measuring monomer content] [] Monomer content is a key quality attribute for protein stability and quality during stress-induced storage. HP-SEC and UP-SEC were used to measure the monomer content of formulations.

[0220] [, UP-SEC , ] [, analyze , ] [, , ] [surface]

[22] : UP-SEC monomers in syringes and vials, expressed as a percentage: initial value and values ​​after shaking for 1 / 5 / 7 / 14 / 21 days and after 21 days of no movement at 25°C. * corresponds to no movement, while shaking other samples for the indicated time. [time] [loading] [F1] [F2] [F3] [F4] [F5] [F6] [F7] [F8] [F9] [F10] [F11] [(%) [(%) [(%) [(%) [(%) [(%) [(%) [(%) [(%) [(%) [(%) [initial] syringe 97.9 97.9 97.9 97.5 97.8 97.8 97.9 97.4 97.5 97.5 97.7 [1] [sky] 97.6 97.6 97.7 97.0 97.6 97.6 97.7 97.3 97.5 97.3 97.6 [5] [sky] 97.5 97.5 97.6 96.9 97.5 97.5 97.6 97.2 97.4 97.2 97.5 [7] [sky] 97.4 97.4 97.5 96.7 97.4 97.3 97.5 97.0 97.3 96.9 97.3

[14] [sky] 97.3 97.2 97.4 96.6 97.2 97.2 97.4 96.9 97.2 96.8 97.2 [twenty one] [sky] 97.3 97.3 97.4 96.7 97.2 97.3 97.4 96.9 97.2 96.9 97.3 [twenty one] [sky] [*] 97.3 97.3 97.5 96.8 97.3 97.3 97.5 97.1 97.4 97.0 97.4 [initial] small bottle 97.9 97.8 97.9 97.5 97.8 97.7 97.9 97.6 97.8 97.7 97.9 [1] [sky] 97.7 97.7 97.8 97.3 97.7 97.7 97.8 97.5 97.7 97.5 97.7 [5] [sky] 97.5 97.5 97.6 97.0 97.5 97.5 97.6 97.3 97.5 97.3 97.6 [7] [sky] 97.5 97.5 97.6 97.0 97.5 97.5 97.6 97.2 97.5 97.3 97.4

[14] [sky] 97.3 97.3 97.4 96.7 97.2 97.2 97.4 97.0 97.3 97.0 97.3 [twenty one] [sky] 97.2 97.2 97.4 96.7 97.2 97.2 97.4 96.9 97.2 97.0 97.3 [twenty one] [sky] [*] 97.3 97.3 97.4 96.7 97.2 97.2 97.4 97.0 97.3 97.0 97.3

[0221] [, HP-SEC , ] [, analyze , ] [, , ] The HP-SEC analysis trend is similar to that of the UP-SEC analysis trend, thus confirming these results. Individual values ​​were obtained in the range of 97.4%–98.8%.

[0222] [] [, Results and Discussion , ] [, , ] Overall, measurements in syringes and vials showed a similar trend and demonstrated that all formulations were stable, with only a slight decrease in monomer content.

[0223] [5.3.2.] [Measurement] [HMW] [content] [] HP-SEC and UP-SEC were used to measure the monomer content of the formulation. HP-SEC was used to determine the level of aggregation (HMW) formation during syringe and vial shaking.

[0224] [, , ] [, UP-SEC , ] [, analyze , ] [, , ] The UP-SEC analysis results are as follows. The data show similar results to the HP-SEC analysis, indicating that aggregate formation is primarily pH-driven. When comparing initial values, it is evident that formulations at pH 6.0 or 6.2 show a slight increase in HMW content of 0.2% to 0.5% compared to the formulation at pH 5.7. This trend was also observed after 21 days of shaking, with HMW content of approximately 1.6% in formulations at pH ≥ 6.0 and 1.3% in formulations at pH 5.7.

[0225] Formulations containing L-arginine, such as F3 and F7, showed the lowest aggregation levels after 21 days of shaking. The differences in monomer content among the eleven formulations tested in this study, observed in UP-SEC and HP-SEC, were not significant. The monomer content loss was within acceptable limits for all formulations tested. In general, it can be summarized as follows: shaking did not significantly increase HMW content compared to results after 21 days without shaking.

[0226] The data obtained using UP-SEC is summarized in [surface]

[23] in. [surface]

[23] : UP-SEC HMW content in syringes and vials, expressed as a percentage: initial value and values ​​after shaking for 1 / 5 / 7 / 14 / 21 days and after 21 days of no movement at 25°C. * Corresponds to no movement, while shaking other samples for the indicated time. [time] [loading] [F1] [F2] [F3] [F4] [F5] [F6] [F7] [F8] [F9] [F10] [F11] [(%) [(%) [(%) [(%) [(%) [(%) [(%) [(%) [(%) [(%) [(%) [initial] syringe 0.9 0.9 0.8 1.3 0.9 0.9 0.8 1.1 1.0 1.0 0.9 [1] [sky] 1.0 1.0 1.0 1.6 1.0 1.0 0.9 1.3 1.1 1.3 1.0 [5] [sky] 1.1 1.1 1.1 1.8 1.2 1.2 1.0 1.4 1.2 1.4 1.1 [7] [sky] 1.2 1.3 1.1 2.0 1.3 1.3 1.2 1.7 1.4 1.7 1.3

[14] [sky] 1.3 1.4 1.2 2.0 1.4 1.4 1.2 1.7 1.4 1.8 1.4 [twenty one] [sky] 1.4 1.4 1.3 2.0 1.5 1.5 1.2 1.7 1.5 1.8 1.4 [twenty one] [sky] [*] 1.4 1.3 1.2 1.9 1.4 1.4 1.2 1.6 1.3 1.6 1.3 [initial] small bottle 0.9 0.9 0.8 1.3 0.9 0.9 0.8 1.1 0.9 1.1 0.9 [1] [sky] 1.0 1.0 0.9 1.4 1.0 1.0 0.9 1.2 1.0 1.2 1.0 [5] [sky] 1.1 1.1 1.0 1.6 1.1 1.1 1.0 1.4 1.2 1.3 1.1 [7] [sky] 1.2 1.2 1.1 1.7 1.2 1.2 1.0 1.4 1.1 1.4 1.2

[14] [sky] 1.4 1.4 1.2 1.9 1.4 1.4 1.2 1.7 1.3 1.7 1.3 [twenty one] [sky] 1.4 1.4 1.3 1.9 1.4 1.4 1.2 1.7 1.4 1.7 1.4 [twenty one] [sky] [*] 1.4 1.4 1.3 2.0 1.5 1.5 1.2 1.7 1.4 1.7 1.4

[0227] [, HP-SEC , ] [, analyze , ] [, , ] The HP-SEC analysis data trend is similar to the UP-SEC analysis data trend, thus confirming these results.

[0228] [, Results and Discussion , ] [, , ] Overall, the results demonstrate that all tested formulations are stable. Similar results were obtained for vials and syringes.

[0229] [5.3.3.] [Measuring milky white light and other parameters] [] After 21 days of shaking the syringe on a horizontal shaker and the vial on a vortex shaker, the opalescence, osmotic weight molar concentration, pH, and protein concentration of all tested formulations remained substantially unchanged (see subsequent information). The lowest opalescence level was observed in buffer-free formulation F11, which did not contain any additional buffers such as acetate or succinate. No visual inspection was possible. No significant differences were observed by comparing the data generated from the vial and the syringe.

[0230] The increased milky white light level at F6 after 1 day and F10 after 5 days cannot be confirmed by the results at the following sampling time points. Therefore, measurement errors may occur and these results may not be relevant to the interpretation of the results. [surface] [twenty four] [:] Shaking of the preparation in syringes and vials: initial values ​​for milky white light, osmotic weight molar concentration, pH, and protein concentration; values ​​after 1 / 5 / 7 / 14 / 21 days of shaking; and values ​​after 21 days of no movement (shaking at room temperature). *Corresponds to no movement, while shaking other samples for the indicated time. [] [Ingredients] [time] [Milk-white light] [(FNU)] [Osmotic weight molar concentration] [(mOsm / kg)] [pH] [protein] [(mg / mL)] [syringe] [Small bottle] [syringe] [Small bottle] [syringe] [Small bottle] [syringe] [Small bottle] [F1] [initial] 9.0 8.1 307 306 5.6 5.7 150 152 [1] [sky] 8.1 8.3 304 305 5.7 5.7 151 151 [5] [sky] 7.6 9.2 307 305 5.7 5.8 151 151 [7] [sky] 8.5 9.0 307 306 5.7 5.7 148 150

[14] [sky] 8.6 8.3 305 307 5.7 5.7 152 151 [twenty one] [sky] 8.8 8.6 304 306 5.8 5.7 150 149 [twenty one] [sky] [*] 9.6 8.0 308 304 5.7 5.7 151 149 [F2] [initial] 5.6 5.4 306 307 5.6 5.6 151 152 [1] [sky] 5.9 5.7 304 305 5.7 5.7 149 152 [5] [sky] 5.2 5.6 305 305 5.7 5.7 149 149 [7] [sky] 5.7 5.8 304 305 5.7 5.7 149 149

[14] [sky] 5.4 5.4 306 307 5.7 5.7 151 151 [twenty one] [sky] 6.5 7.0 304 304 5.7 5.7 151 150 [twenty one] [sky] [*] 5.7 4.8 309 305 5.7 5.7 150 151 [F3] [initial] 12.8 11.3 298 289 5.6 5.7 154 152 [1] [sky] 13.0 12.2 289 282 5.7 5.8 151 149 [5] [sky] 12.7 12.7 291 286 5.6 5.7 153 151 [7] [sky] 12.2 13.3 292 291 5.7 5.7 153 149

[14] [sky] 12.2 11.9 293 291 5.7 5.7 152 151 [twenty one] [sky] 12.7 12.2 291 290 5.7 5.7 153 151 [twenty one] [sky] [*] 13.0 11.3 293 292 5.7 5.7 152 154 [F4] [initial] 13.4 11.1 301 294 6.1 6.2 151 150 [1] [sky] 11.4 11.4 296 297 6.0 6.3 151 152 [5] [sky] 11.9 12.4 297 296 6.0 6.2 150 148 [7] [sky] 11.7 12.8 299 295 6.2 6.2 153 149

[14] [sky] 11.9 11.2 298 296 6.2 6.2 152 153 [twenty one] [sky] 12.2 12.3 301 298 6.2 6.2 151 151 [twenty one] [sky] [*] 12.9 11.5 297 299 6.2 6.2 153 152 [F5] [initial] 5.9 4.9 310 306 5.6 5.7 156 154 [1] [sky] 5.6 5.3 306 303 5.7 5.7 154 153 [5] [sky] 5.7 5.8 305 305 5.6 5.7 154 154 [7] [sky] 5.5 6.0 309 304 5.7 5.7 153 151

[14] [sky] 4.9 5.0 306 305 5.7 5.7 156 157 [twenty one] [sky] 5.4 7.5 306 308 5.7 5.7 155 154 [twenty one] [sky] [*] 6.3 4.7 307 305 5.6 5.7 154 153 [F6] [initial] 5.7 4.9 313 311 5.7 5.7 153 151 [1] [sky] 11.0 6.1 304 307 5.6 5.8 152 151 [5] [sky] 6.0 6.1 308 305 5.6 5.7 150 149 [7] [sky] 5.6 5.9 307 308 5.7 5.7 151 151

[14] [sky] 5.2 4.9 307 309 5.7 5.7 150 151 [twenty one] [sky] 5.7 6.5 311 310 5.7 5.7 152 152 [twenty one] [sky] [*] 5.5 4.8 311 310 5.7 5.7 153 150 [F7] [initial] 12.3 10.8 307 304 5.6 5.7 153 153 [1] [sky] 12.3 11.3 302 302 5.6 5.7 153 154 [5] [sky] 12.1 12.5 301 302 5.6 5.7 151 153 [7] [sky] 11.4 12.6 302 302 5.7 5.7 153 154

[14] [sky] 12.2 10.9 304 303 5.7 5.7 153 152 [twenty one] [sky] 11.5 12.1 306 304 5.7 5.7 153 152 [twenty one] [sky] [*] 12.6 10.6 305 303 5.6 5.7 153 153 [F8] [initial] 7.0 6.1 295 290 5.9 6.0 151 151 [1] [sky] 6.7 7.3 290 287 5.9 6.0 151 150 [5] [sky] 6.9 7.6 289 286 5.9 6.0 150 150 [7] [sky] 6.5 7.1 293 297 6.0 6.0 150 151

[14] [sky] 6.5 6.6 294 289 6.0 6.0 151 149 [twenty one] [sky] 7.0 6.5 293 292 6.0 6.0 150 150 [twenty one] [sky] [*] 7.5 6.3 291 288 6.0 6.0 151 147 [F9] [initial] 13.9 12.4 298 291 5.9 6.0 149 149 [1] [sky] 12.5 12.7 292 293 5.9 6.0 151 148 [5] [sky] 13.6 13.5 291 292 5.9 6.0 150 148 [7] [sky] 12.8 13.7 295 296 6.0 6.0 150 153

[14] [sky] 12.7 12.3 295 294 6.0 6.0 149 150 [twenty one] [sky] 13.1 12.9 295 296 6.0 6.0 150 150 [twenty one] [sky] [*] 13.8 12.4 294 297 6.0 6.0 152 149 [F10] [initial] 7.1 6.3 301 295 6.0 6.0 148 149 [1] [sky] 6.7 6.5 295 293 5.9 6.0 149 148 [5] [sky] 11.1 8.3 292 291 5.9 6.0 146 147 [7] [sky] 6.5 7.5 296 296 6.0 6.0 149 148

[14] [sky] 6.1 6.1 297 298 6.0 6.0 151 148 [twenty one] [sky] 6.6 6.5 295 295 6.0 6.0 149 149 [twenty one] [sky] [*] 7.4 5.9 295 295 6.0 6.0 150 148 [F11] [initial] 4.9 3.3 306 298 5.6 5.6 148 146 [1] [sky] 3.8 4.0 299 300 5.6 5.7 147 144 [5] [sky] 4.9 4.2 300 297 5.6 5.7 145 147 [7] [sky] 3.7 4.2 300 300 5.7 5.7 147 146

[14] [sky] 3.7 3.2 301 301 5.7 5.7 147 148 [twenty one] [sky] 3.7 3.3 303 301 5.6 5.7 148 146 [twenty one] [sky] [*] 5.2 3.2 302 298 5.6 5.7 146 147

[0231] [, Binding activity , ] SPR (Biacore) measurements showed that shaking did not affect the molecular binding activity of the syringe on the oscillating shaker or the vial on the horizontal shaker. Overall, the binding activity remained high, in the range of 91%–111%, and the specific binding activity remained in the range of 98%–107%.

[0232] [, Results and Discussion , ] The milky white light ranges from 5 FNU to 14 FNU in formulations without excipients or buffers, but does not increase significantly over time.

[0233] Throughout the study period, the pH, osmotic weight molar concentration, opalescent and protein concentrations, and binding activity against IL-23 remained constant for all formulations.

[0234] [5.4.] [Further Analysis and Results] [] In addition, further analysis was performed on the eleven formulations tested, and the results are as follows. The type and duration of shaking, storage, and syringes and vials used are as described above. ● The HP-SEC fragment content remained substantially constant during shaking in vials and syringes. The fragment content ranged from 0.3% to 0.5%. The UP-SEC LMW content remained substantially constant during shaking in vials and syringes. The fragment content ranged from 1.3% to 1.4%. ● Weak cation exchange chromatography (WCX) showed that the percentage distributions of the main peak, APG, and BPG in all formulations tested remained constant throughout the study period. The concentrations of the main peak, APG, and BPG did not change significantly during the shaking time. No differences were observed between the formulations. ● The particle content measured by microfluidic imaging (MFI) remained essentially constant over the 21-day shaking period.

[0235] [5.5.] [Overview] In summary, only minor differences were detected in parameters indicating stability among the formulations exposed to shaking stress. For example, formulations F3 and F7 showed the highest monomer content (HP-SEC and UP-SEC), but also the highest opalescent light level. In summary, the formulations tested in this study are viable formulations.

[0236] [] [6.] [Comparison across multiple freezers] [ / ] [Different in the thawing cycle] [pH] [Value] [Acetate and Succinate Buffer System] [] The freezing and thawing behavior of different 150 mg / mL rissenkiramab formulations and their impact on product quality were evaluated. Therefore, the formulations were exposed to freezing and thawing stress in small bags at a desired target concentration of 150 mg / mL and a fill volume of 12 mL to simulate small-scale or large-scale bag freezing conditions.

[0237] In all eleven formulations with different pH values, the buffering agent and tension agent, along with the intermediate storage block, were filled into small bags with a filling volume of 12 mL, followed by a controlled freezing step to -40°C. The bags were then stored at 5°C. It should be noted that the eleven formulations correspond to the formulations tested in the previous example. [surface]

[25] : Overview of Experiment Scheduling [] Target Week 1 Week 2 Week 3 Week 4 M T W T F S S M T W T F S S M T W T F S S M T W T F S S 6 freeze / thaw cycles 1 1 2 2 3 3 4 4 5 5 6 6 3 freeze / thaw cycles 1 1 2 2 3 3 analyze 1 freeze / thaw cycle 1 1 Reference material stored at 2℃-8℃ Light gray shade: frozen; darker gray shade: thawed

[0238] The freezing step was performed using a freeze-thaw apparatus provided by a classic freeze-dryer. Here, a small bag with a sample volume of 12 mL was frozen to -40°C using a freezing ramp of 0.5°C / min. The temperature was then maintained constant for sixteen hours to ensure complete freezing of the sample volume. The thawing step was performed according to the freezing procedure, with a heating rate of 0.5°C / min. The holding time at room temperature was set to four hours.

[0239] A complete freeze / thaw cycle (1 × F / T) is defined as follows: 1. Freeze from room temperature to -40°C (0.5°C / min) 2. The holding time at -40℃ is 16 hours. 3. Thaw from -40℃ to room temperature (0.5℃ / min) 4. The time to keep at room temperature is 4 hours.

[0240] This procedure is performed at 1 × F / T, 3 × F / T, and 6 × F / T. After completing the final process cycle, the bag is transferred to a freezer at -40°C and stored until the sample is thawed and analyzed.

[0241] [6.1.] [Preparation of formulations] [] Prepare the formulation as described in the previous example (see [reference]). [surface]

[21] ) Prepare another formulation F12 containing 0.02% PS20 and pH 5.7 without excipients. Fill 12 mL of sterile filtered protein solution into sterile primary packaging material, which is a small 15 mL Flexboy bag, under laminar flow. Inspect all bags for visible particles and record the results.

[0242] In each freeze-thaw operation, twelve bags are placed on trays within the freeze-dryer. A total of 36 bags are used for freezing / thawing, with each operation involving three bags / formulations. The bags are distributed throughout the defined process to eliminate the influence of bag placement within the freeze-dryer.

[0243] [6.2.] [analyze] [] After completing all cycles according to the experimental plan described above, the bags are continuously thawed in an additional thawing step. This procedure has the advantage of allowing simultaneous analysis of samples. The bags are then transferred to a pre-cooled freeze-dryer at -40°C, followed by the thawing step. HP-SEC, UP-SEC, permeate molar concentration, pH, protein concentration, opacity, binding activity, and non-visual particle measurement are performed. The following instruments are used for analysis: - UV-Vis spectrophotometer Solo VPE: Concentration at 280 nm, baseline correction at 320 nm, extinction coefficient: 1.52; C Technologies, Inc., NJ, USA - Milky white light: HACH Lange milky white light meter; filter: 400-600 nm; Hach Lange GmbH, Düsseldorf, Germany - Ultra-high efficiency size exclusion chromatography (UP-SEC): UPLC26, H-class UV detection at 280 nm, Waters, Milford, MA - Based on the charge inhomogeneity of weak cation exchange chromatography (WCX): HPLC 75; fluorescence detection: extinction: 278 nm, emission: 350 nm; Waters, Milford, MA - IL-23 binding activity: Biacore T200 chip: CM5 GE Healthcare, Chalfont St Giles, UK - pH meter:SevenGo - Mettler Toledo, Columbus, OH - Particle size analyzer: Micro Flow Imaging™ flow cytometer; utilizing microfluidic imaging (MFI); Brightwell Technologies Inc, Ottawa, ON, Canada - Osmomat 030, Gonotec GmbH, Berlin, Germany: Utilizing freezing point depression.

[0244] Further details of the analytical methods used are described below.

[0245] [6.3.] [result] [] [6.3.1.] [Measuring monomers and] [HMW] [content] [] Monomer content is a key quality attribute for protein stability and quality during stress-induced storage. HP-SEC and UP-SEC were used to determine aggregate formation levels during freezing / thawing of mini-bags. The following tables summarize the HP-SEC and UP-SEC analysis results. [surface]

[26] :HP-SEC / UP-SEC: Initial value in % and value after 1 / 3 / 6 F / T cycles and value after three weeks at 5°C. [] [Ingredients] [Sampling Time Point] [Aggregate] [HP-SEC] [%] [monomer] [HP-SEC] [%] [Excerpt] [HP-SEC] [%] [Aggregate] [UP-SEC] [%] [monomer] [UP-SEC] [%] [Excerpt] [UP-SEC] [%] F1 initial 1.4 98.3 0.4 1.3 97.2 1.5 1 × F / T 1.5 98.1 0.4 1.4 97 3 1.3 3 × F / T 1.5 98.2 0.4 1.4 97.4 1.2 6 × F / T 1.5 98.1 0.4 1.4 97 4 1.3 5℃ 1.6 98.1 0.4 1.4 97.3 1.3 F2 initial 1.4 98.3 0.3 1.3 97.2 1.5 1 × F / T 1.5 98.1 0.4 1.5 97.2 1.3 3 × F / T 1.4 98.2 0.4 1.4 97 3 1.2 6 × F / T 1.5 98.2 0.4 1.4 97 3 1.3 5℃ 1.5 98.1 0.4 1.4 97.3 1.3 F3 initial 1.2 98.4 0.3 1.2 97.3 1.5 1 × F / T 1.3 98.3 0.4 1.3 97 4 1.3 3 × F / T 1.3 98.4 0.4 1.3 97 5 1.3 6 × F / T 1.4 98.3 0.4 1.3 97.5 1.3 5℃ 1.4 98.3 0.4 <00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​97.7 0.4 1.9 96 8 1.3 6 × F / T 2.1 97.5 0.4 1.9 96 8 1.3 5℃ 2.0 97.6 0.4 1.9 96.9 1.3 F5 initial 1.6 98.0 0.3 1.3 97.2 1.5 1 × F / T 1.5 98.1 0.4 1.4 97 3 1.3 3 × F / T 1.4 98.2 0.4 1.4 97 3 1.3 6 × F / T 1.5 98.2 0.4 1.4 97.3 1.3 5℃ 1.5 98.2 0.4 1.4 97.3 1.3 F6 initial 1.3 98.3 0.3 1.3 97.2 1.5 1 × F / T 1.5 98.1 0.4 1.4 97.3 1.3 3 × F / T 1.4 98.2 0.4 1.4 97.3 1.3 6 × F / T 1.5 98.2 0.4 1.4 97 3 1.3 5℃ 1.5 98.1 0.4 1.4 97.3 1.3 F7 initial 1.3 98.4 0.3 1.2 97 3 1.5 1 × F / T 1.4 98.3 0.4 1.3 97.4 1.3 3 × F / T 1.3 98.3 0.4 1.3 97.5 1.3 6 × F / T 1.4 98.3 0.4 1.2 97.5 1.3 5℃ 1.4 98.3 0.4 1.3 97 5 1.3 F8 initial 1.5 98.2 0.3 1.5 97 0 1.4 1 × F / T 1.8 97.8 0.4 1.7 97.0 1.3 3 × F / T 1.7 97.9 0.4 1.6 97.1 1.3 6 × F / T 1.7 97.9 0.4 1.6 97.1 1.3 5℃ 1.7 97.9 0.4 1.6 97.1 1.3 <00,06209> F9 Initial 1.5 98.2 0.3 1.3 <00,06223> 97.2 1.5 1 × F / T 1.5 98.1 0.4 1.4 97 3 <000623'' 1.3 3 × F / T 1.4 98.2 0.4 1.4 97.3 1.3 6 × F / T 1.5 98.1 0.4 1.4 97.3 1.3 5℃ 1.5 98.1 0.4 1.4 97.3 1.3 F10 initial 1.6 98.1 0.3 1.5 97.0 1.5 1 × F / T 1.7 97.9 0.4 1.6 97.1 1.3 3 × F / T 1.7 98.0 0.4 1.6 97.1 1.3 6 × F / T 1.7 98.0 0.4 1.6 97.1 1.3 5℃ 1.7 97.9 0.4 1.5 97.3 1.3 F11 initial 1.4 98.3 0.3 1.3 97 3 1.5 1 × F / T 1.4 98.2 0.4 1.4 97.3 1.3 3 × F / T 1.4 98.2 0.4 1.4 97.3 1.3 6 × F / T 1.4 98.2 0.4 1.4 97 3 1.3 5℃ 1.4 98.2 0.4 1.4 97 3 1.3 F12 initial 1.5 98.2 0.3 1.3 97 2 1.5 1 × F / T 1.7 98.0 0.4 1.6 97.1 1.3 3 × F / T 1.8 97.8 0.4 1.7 97.0 1.3 6 × F / T 2.0 97.6 0.4 1.9 96.8 1.3 5℃ 1.5 98.1 0.4 1.3 97.4 1.3

[0246] [, Results and Discussion , ] [, , ] Data shows that aggregate formation is primarily pH-driven. Comparing results after six freeze / thaw cycles, it is evident that formulations at pH 6.0 or 6.2 exhibit a slight increase in HMW content of 0.2%–0.6% compared to solutions formulated at pH 5.7. Formulations containing L-arginine, such as F3 and F7, showed the lowest aggregation levels after six freeze / thaw cycles. In general, it can be summarized that freezing / thawing stress does not significantly increase HMW content compared to results after 21 days at 5°C.

[0247] [] [6.3.2.] [Measuring milky white light and other parameters] [] After 6 F / T cycles and 3 weeks of storage at 5°C, the opalescence, osmotic weight molar concentration, pH, and protein concentration of all tested formulations remained unchanged. The lowest opalescence level was observed in the buffer-free formulations (F11 and F12). [surface]

[27] : Initial values ​​of milky light in FNU, osmotic weight molar concentration in mOsm / kg, pH value, and protein concentration in g / L, and values ​​after 1 / 3 / 6 F / T cycles. [Ingredients] [Components] [Sampling Time Point] [Milk-white light] [FNU] [Osmotic weight molar concentration] [mOsmol] [·] [kg, -1 , ] [pH] [protein] [concentration] [gL, 1 , ] F1 10 mM acetate + 6.5 mM succinate + 185 mM sorbitol + 0.02% PS2O, pH 5.7 initial 77 306 5.6 153 1 × F / T 8.0 307 5.6 150 3 × F / T 8.1 308 5.7 151 6 × F / T 8.1 307 5.7 153 5℃ 8.8 306 5.7 151 F2 10 mM acetate + 200 mM sorbitol + 0.02% PS20, pH 5.7 initial 4.8 304 5.7 153 1 × F / T 5.2 305 5.6 152 3 × F / T 4.8 306 5.6 153 6 × F / T 5.4 306 5.7 152 5℃ 5.6 306 5.7 150 F3 10 mM acetate + 50 mM L-arginine HCl + 110 mM sorbitol + 0.02% PS2O, pH 5.7 initial 11.1 292 5.7 153 1 × F / T 11.8 292 5.6 152 3 × F / T 12.1 292 5.6 152 6 × F / T 12.2 291 5.6 153 5℃ 11.5 292 5.6 150 F4 10 mM succinate + 185 mM sorbitol + 0.02% PS20, pH 6.2 initial 10.6 306 6.1 154 1 × F / T 11.1 296 6.1 150 3 × F / T 12.1 300 6.1 151 6 × F / T 11.3 301 6.1 151 5℃ 11.3 300 6.1 151 F5 10 mM acetate + 95 mM mannitol + 95 mM trehalose + 0.02% PS2O, pH 5.7 initial 4.7 307 5.6 154 1 × F / T 4.9 302 5.6 151 3 × F / T 5.4 305 5.6 153 6 × F / T 5.1 305 5.6 153 5℃ 4.9 306 5.6 150 F6 10 mM acetate + 185 mM trehalose + 0.02% PS2O, pH 5.7 initial 4.5 309 5.6 152 1 × F / T 4.7 306 5.6 152 3 × F / T 5.0 309 5.6 152 6 × F / T 4.3 309 5.6 151 5℃ 4.7 309 5.6 150 F7 10 mM acetate + 50 mM L-arginine HCl + 110 mM trehalose + 0.02% PS2O, pH 5.7 initial 10.6 307 5.7 152 1 × F / T 11.2 303 5.6 151 3 × F / T 11.8 301 5.6 151 6 × F / T 11.0 305 5.6 153 5℃ 12.0 304 5.6 152 F8 4.4 mM succinate + 135 mM trehalose + 0.02% PS20, pH 6.0 initial 6.2 300 5.9 148 1 × F / T 6.4 291 5.9 150 3 × F / T 6.7 296 5.9 151 6 × F / T 6.3 295 5.9 152 5℃ 6.2 296 5.9 151 F9 4.4 mM succinate + 50 mM arginine HCl + 110 mM trehalose + 0.02% PS2O, pH 6.0 initial 11.9 303 5.9 153 1 × F / T 12.4 294 5.9 151 3 × F / T 12.9 296 5.8 153 6 × F / T 12.3 295 5.8 153 5℃ 11.8 295 5.9 150 F10 4.4 mM succinate + 95 mM mannitol + 95 mM trehalose + 0.02% PS2O, pH 6.0 initial 6.0 314 5.9 153 1 × F / T 5.8 298 5.9 151 3 × F / T 6.6 298 5.8 150 6 × F / T 6.1 298 5.8 153 5℃ 5.9 301 5.9 150 F11 Buffer-free, 200 mM trehalose, 0.02% PS20, pH 5.7 initial 3.4 322 5.6 154 1 × F / T 3.3 305 5.6 150 3 × F / T 3.7 306 5.6 151 6 × F / T 3.6 305 5.7 153 5℃ 3.6 306 5.6 152 F12 Excipient-free, 0.02% PS20, pH 5.7 initial 3.5 29 5.6 151 1 × F / T 3.8 25 5.6 152 3 × F / T 4.0 25 5.6 151 6 × F / T 3.8 25 5.6 151 5℃ 3.6 27 5.6 151

[0248] [, , ] [, Binding activity , ] SPR (Biacore) measurements of IL23 binding activity showed that freeze / thaw cycles did not affect molecular binding activity. The binding activity ranged from 96% to 117%.

[0249] [, Results and Discussion , ] The measured opalescence is dependent on the formulation. It is independent of stress conditions (F / T and holding time at 5°C), and the pH, osmotic weight molar concentration, opalescence and protein concentration, and IL-23 binding of all formulations remained essentially constant throughout the study period, thus demonstrating stability.

[0250] [6.3.3.] [Measuring Particles] [] The following table summarizes the particle number for each STP. No clear trend was observed for any of the formulations tested. Formulations F3, F7, and F9 showed a slight increase in SVP compared to the other formulations tested. This observation primarily pertains to SVPs ≥ 2 μm and ≥ 10 μm. [, , ] [] [surface]

[28] : Invisible particles - MFI: Initial value and values ​​after one, three and six F / T cycles and values ​​after three weeks at 5°C. [deal with] [Particle size] [Number of particles measured] [F1] [F2] [F3] [F4] [F5] [F6] [F7] [F8] [F9] [F10] [F11] [F12] [initial] [≥] [2 µm] 505 1104 1604 723 508 1046 878 1259 622 1255 1314 673 [≥] [10 µm] 44 32 50 34 31 38 18 71 19 38 41 36 [≥] [25 µm] 2 2 2 2 2 3 2 7 2 1 2 2 [1 × F / T] [≥] [2 µm] 1443 660 2426 831 710 883 2784 1260 2557 1070 925 1759 [≥] [10 µm] 49 19 639 18 38 21 683 28 995 45 35 63 [≥] [25 µm] 1 0 6 2 5 2 1 2 8 4 1 2 [3 × F / T] [≥] [2 µm] 1485 836 2764 1440 717 656 3501 698 2708 901 520 1513 [≥] [10 µm] 79 42 898 56 49 44 604 34 950 60 30 59 [≥] [25 µm] 6 6 10 3 2 3 10 5 3 5 5 3 [6 × F / T] [≥] [2 µm] 1392 1008 4551 1214 714 1121 3265 1051 2752 810 925 1868 [≥] [10 µm] 81 41 1089 31 48 69 518 38 1209 60 43 54 [≥] [25 µm] 7 10 41 4 9 6 17 1 5 7 3 3 [5] [℃] [≥] [2 µm] 1780 1259 2222 1341 555 784 2148 879 2825 1343 983 2131 [≥] [10 µm] 121 37 439 54 32 35 599 17 815 50 38 80 [≥] [25 µm] 4 1 6 6 3 4 2 1 2 6 3 7

[0251] [] [, Results and Discussion , ] [, , ] While a similar trend for particles ≥ 2 μm was observed, a slight increase in particles ≥ 10 μm was observed in F3, F7, and F9 compared to other formulations. For particles ≥ 25 μm, a slight increase in F3 was observed after 6 × F / T. Overall, particle formation was not a major issue for all tested formulations during the F / T period.

[0252] [6.4.] [Further Analysis and Results] [] In addition, further analysis was performed on the twelve formulations tested (freezing / thawing cycles as described above), and the results are as follows. ● Weak cation exchange chromatography (WCX) showed that the percentage distributions of the main peak, APG, and BPG in all formulations tested remained constant throughout the study period. The contents of the main peak, APG, and BPG did not change significantly over six freeze / thaw cycles. The main peak ranged from 65% to 67%, APG from 21% to 23%, and BPG from approximately 11% to 14%. No differences were observed between the formulations.

[0253] [6.5.] [Results Overview] [] The results can be summarized as follows: - Visual inspection: After six F / T cycles, no observation of the entire mixture should be made during the visual inspection period. - SVP: Regarding the content of non-visible particles, there are no major issues that can be observed. Compared with other formulations, F3, F7, and F9 are slightly increased, but significantly lower than the pharmacopoeia specifications. - HP-SEC and UP-SEC: For protein integrity-focused assays such as HP-SEC and UP-SEC, F3 was demonstrated to be the most stable formulation and F4 the least stable formulation. F12, without any buffers or excipients, exhibited acceptable stability during freeze / thaw cycles. - IEC: No difference in formulations was observed for the IEC results. The F / T cycle does not negatively affect the contributions of APG and BPG. - Milky white light: Milky white light depends on the formulation and ranges from 4 FNU to 13 FNU for formulations without excipients or buffers. - Regardless of stress conditions (F / T and holding time at 5°C), the pH, osmotic weight molar concentration, opalescence, protein concentration, and binding of all formulations remained unchanged throughout the study period.

[0254] In summary: For the 150 mg / mL formulation, most of the formulations tested in this example were feasible. Only a minor effect of freezing / thawing stress on protein stability was observed. Due to medical concerns regarding formulations containing sorbitol, these formulations were found to be less beneficial for patients with fructose intolerance. Nevertheless, solutions containing sorbitol were found to be useful for other patients. In conclusion, only minor differences in indicators of stability parameters were detected between formulations exposed to freezing / thawing stress. For example, formulation F3 was the most stable in terms of monomer content (HP-SEC), but conversely, an increase in the amount of non-visible particles was detected.

[0255] [] [7. pH] [right] [The effect on the stability of the formulation] [] by [surface]

[29] shows the effect of pH on the stability of the 150 mg / mL rissenkiramab formulation. [surface]

[29] [:] The composition of the blend. [Ingredients] [pH] [Acetate] Trehalose [Polysorbide 20] F1 [5.0] 10 mM 185 mM 0.2 mg / mL F2 [5.2] F3 [5.5] F4 [5.7] F5 [5.9] F6 [6.2]

[0256] [7.1.] [Preparation of formulations] [] Prepare the formulation as described above.

[0257] [7.2.] [analyze] [] Sample measurements were performed during storage at 1, 3, 6, 9, 12, 18, 24, and 36 months, as well as initially prior to storage. A variety of analytical methods were used, including HIC, UP-SEC, IEC, and measurements of viscosity, loosening force, and slip force, as well as combined specific measurements. Further details of the analytical methods used are described below.

[0258] [7.3.] [result] [] [7.3.1.] [Measuring monomer content] [] As in previous examples, UP-SEC analysis was used to measure monomer content, and the results are shown in... [surface]

[30] in. [surface]

[30] : UP-SEC monomer measurement results in % of formulations with different pH values. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] [F6] initial 0 98.3 98.3 98.2 98.0 97.8 97.3 5℃ 3 98.1 98.1 97.9 97.7 97.4 96.8 5℃ 6 98.0 98.0 97.8 97.6 97.4 96.9 5℃ 9 97.5 97.5 97.3 97.2 97.0 96.5 5℃ 12 97.5 97.5 97.4 97.2 97.0 96.5 5℃ 18 97.6 97.6 97.5 97.4 97.2 96.8 5℃ twenty four 97.3 97.4 97.3 97.2 97.0 96.6 5℃ 36 97.1 97.0 97.0 96.9 96.8 96.0 25℃ 1 97.6 97.6 97.4 97.2 97.0 96.4 25℃ 3 96.4 96.6 96.5 96.4 96.1 95.7 25℃ 6 95.1 95.4 95.7 95.7 95.5 95.1 25℃ 9 93.4 94.0 94.4 94.5 94.4 94.0 25℃ 12 92.3 93.1 93.8 93.9 93.9 93.5 40℃ 1 94.2 94.6 94.9 94.8 94.7 94.3 40℃ 3 87.6 89.0 90.3 90.6 90.8 90.7

[0259] [] [, Results and Discussion , ] Monomer content measurements showed that the tested formulations were stable within a pH range of pH 5.0 to 6.2. Therefore, a wide pH range is applicable to obtain highly stable 150 mg / mL rissenitumumab formulations. High monomer values ​​were obtained at a pH of approximately 5.7, while relatively low monomer contents were measured at more acidic conditions such as approximately pH 5.0 (see, for example, the last pH 5.0 measurement point at 25°C or 40°C). Therefore, high-concentration rissenitumumab formulations (here, 150 mg / mL) at a pH of approximately 5.7 are particularly advantageous, especially in the formulations provided in the examples of the present invention.

[0260] [] [7.3.2.] [Measurement] [HMW] [content] [] The HMW content of the formulation was also determined using UP-SEC, and the following results were obtained: [surface]

[31] [:] UP-SEC-HMW measurement results in % for formulations with different pH values. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] [F6] initial 0 0.8 0.9 1.1 1.2 1.4 1.9 5℃ 3 1.0 1.1 1.3 1.4 1.8 2.4 5℃ 6 1.1 1.2 1.4 1.6 1.8 2.3 5℃ 9 1.3 1.4 1.6 1.7 1.9 2.4 5℃ 12 1.4 1.4 1.6 1.7 2.0 2.4 5℃ 18 1.4 1.5 1.6 1.7 1.9 2.3 5℃ 24 1.8 1.8 1.9 2.1 2.3 2.7 5℃ 36 1.8 1.9 2.0 2.1 2.3 2.8 25℃ 1 1.3 1.4 1.6 1.8 2.1 2.7 25℃ 3 1.7 1.8 2.1 2.3 2.6 3.0 25℃ 6 2.1 2.2 2.3 2.4 2.6 3.1 25℃ 9 2.6 2.6 2.9 2.8 3.0 3.4 25℃ 12 2.9 2.9 2.8 3.0 3.1 3.5 40℃ 1 2.5 2.5 2.7 2.9 3.1 3.6 40℃ 3 4.9 4.5 4.3 4.5 4.6 4.8

[0261] [] [, Results and Discussion , ] HMW content correlated with monomer measurements. Overall, the tested formulations were stable within a certain pH range. A particularly low increase in HMW content was observed at a pH of approximately 5.7. However, higher pH values ​​(e.g., pH 6.2) appeared to result in slightly higher HMW values.

[0262] [] [7.3.3.] [Measurement] [LMW] [content] [] The LMW content was measured by UP-SEC analysis, which revealed the following results: [surface]

[32] [:] UP-SEC-LMW measurement results in % for formulations with different pH values. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] [F6] initial 0 0.8 0.8 0.8 0.8 0.8 0.8 5℃ 3 0.9 0.8 0.8 0.8 0.8 0.8 5℃ 6 0.9 0.8 0.9 0.9 0.8 0.8 5℃ 9 1.2 1.2 1.1 1.1 1.1 1.1 5℃ 12 1.1 1.1 1.1 1.0 1.0 1.0 5℃ 18 1.0 0.9 0.9 0.9 0.9 0.9 5℃ twenty four 0.9 0.8 0.8 0.7 0.7 0.7 5℃ 36 1.1 1.1 1.0 1.0 0.9 1.2 25℃ 1 1.2 1.1 1.0 1.0 1.0 1.0 25℃ 3 1.8 1.6 1.4 1.4 1.4 1.3 25℃ 6 2.8 2.4 2.0 1.9 1.9 1.8 25℃ 9 4.1 3.5 2.7 2.8 2.7 2.6 25℃ 12 4.8 4.1 3.4 3.1 3.0 3.0 40℃ 1 3.3 2.9 2.5 2.3 2.2 2.1 40℃ 3 7.5 6.5 5.4 5.0 4.7 4.5

[0263] [, Results and Discussion , ] LMW content correlated with monomer measurements. A particularly low increase in LMW content was observed at a pH of approximately 5.7. However, lower pH values ​​appeared to result in slightly higher LMW values. Overall, the formulations tested exhibited stability within a certain pH range.

[0264] [] [7.3.4.] [By using ion exchange chromatography] [(] [IEC] [)] [Species Measurement] [] Ion species were measured using ion exchange chromatography. The results were then classified into the main peak, acidic peak group (APG), and basic peak group (BPG). [surface]

[33] [:] IEC main peak measurement results in percentage (%) for formulations with different pH values. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] [F6] initial 0 72 71 71 72 72 71 5℃ 3 71 71 71 71 70 70 5℃ 6 70 70 70 70 70 70 5℃ 12 68 70 71 71 71 71 5℃ 18 67 69 70 70 71 70 5℃ twenty four 65 67 68 69 69 68 5℃ 36 65 66 68 69 69 69 25℃ 1 68 68 69 69 69 69 25℃ 3 61 62 63 64 64 65 25℃ 6 52 54 57 58 59 60 25℃ 12 39 43 48 50 51 53 40℃ 1 46 48 50 52 54 55 40℃ 3 25 26 28 31 33 35 [surface]

[34] [:] IEC APG measurement results in percent for formulations with different pH values. [Storage Conditions] [Storage time, months] [F1] [F2] [F3] [F4] [F5] [F6] initial 0 twenty two twenty two twenty two twenty two twenty two twenty two 5℃ 3 twenty two twenty two twenty three twenty three twenty three twenty three 5℃ 6 twenty three twenty three twenty three twenty three twenty three twenty three 5℃ 12 20 20 20 20 twenty one twenty one 5℃ 18 twenty two twenty two twenty three twenty three twenty three twenty three 5℃ twenty four 20 twenty one twenty one twenty one twenty two twenty two 5℃ 36 twenty one twenty two twenty two twenty two twenty three twenty three 25℃ 1 twenty three twenty four twenty four twenty four twenty four twenty four 25℃ 3 27 28 28 27 28 27 25℃ 6 32 33 33 33 32 32 25℃ 12 34 37 39 39 38 38 40℃ 1 37 38 39 38 37 37 40℃ 3 55 59 61 60 59 58 [] [surface]

[35] [:] IEC BPG measurement results in % for formulations with different pH values. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] [F6] initial 0 6 6 7 6 7 7 5℃ 3 7 7 7 7 7 7 5℃ 6 7 7 7 7 7 7 5℃ 12 12 10 9 9 8 8 5℃ 18 11 9 8 7 7 6 5℃ 24 15 13 11 10 9 9 5℃ 36 15 12 10 9 8 8 25℃ 1 9 8 8 7 8 8 25℃ 3 12 11 9 9 8 8 25℃ 6 16 13 10 9 9 8 25℃ 12 27 20 14 11 10 9 40℃ 1 17 14 11 10 9 9 40℃ 3 20 15 10 9 8 7

[0265] [] [, Results and Discussion , ] Overall, IEC measurements showed that the tested formulations were stable. High concentration peaks were observed at all pH values. Notably, the intermediate pH of 5.7 and the pH of approximately 5.7 showed a good trade-off compared to the highest and lowest tested pH values, respectively, which indicated increases in APG or BPG species. Therefore, a pH of approximately 5.7 is deemed favorable.

[0266] [7.3.5.] [Using hydrophobic interaction chromatography] [(] [HIC] [)] [Species Measurement] [] The variants / subspecies of rissenkiramab were measured using hydrophobic interaction chromatography (HIC). The results were then classified into the main peak, leading peak, and trailing peak. [, , ] [] [surface]

[36] [:] Measurement results of HIC main peak in percentage (%) for formulations with different pH values. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] [F6] initial 0 96.8 96.7 96.7 96.7 96.4 96.0 5℃ 3 96.7 96.7 96.7 96.6 96.3 95.8 5℃ 6 96.7 96.7 96.7 96.5 96.5 95.9 5℃ 12 97.2 97.2 97.1 97.1 96.9 96.6 5℃ 18 96.0 96.1 96.2 96.1 95.9 95.6 5℃ 24 96.7 96.7 96.9 96.8 96.7 96.5 5℃ 36 95.3 95.4 95.7 95.7 95.7 95.4 25℃ 1 96.2 96.1 96.1 95.9 95.7 95.3 25℃ 3 95.4 95.3 95.4 95.4 95.1 94.7 25℃ 6 94.7 95.0 95.1 95.1 95.1 94.8 25℃ 12 93.8 94.1 94.6 94.7 94.7 94.4 40℃ 1 93.6 94.2 94.3 94.2 94.2 93.6 40℃ 3 88.5 89.8 90.4 90.8 90.7 90.7 [surface]

[37] [:] Results of HIC peak measurement in percentage (%) for formulations with different pH values. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] [F6] initial 0 1.8 1.7 1.7 1.6 1.6 1.6 5℃ 3 1.9 1.9 1.8 1.8 1.8 1.8 5℃ 6 1.9 1.9 1.7 1.8 1.6 1.7 5℃ 12 1.6 1.5 1.4 1.3 1.3 1.3 5℃ 18 2.1 2.0 1.8 1.8 1.7 1.6 5℃ twenty four 1.8 1.7 1.5 1.4 1.4 1.4 5℃ 36 2.2 2.0 1.7 1.5 1.5 1.4 25℃ 1 2.1 2.1 2.0 1.9 2.0 1.9 25℃ 3 2.8 2.7 2.4 2.3 2.3 2.5 25℃ 6 3.3 3.0 2.7 2.5 2.4 2.3 25℃ 12 4.1 3.6 3.1 2.8 2.7 2.6 40℃ 1 3.7 3.3 3.1 3.0 2.8 3.0 40℃ 3 7.5 6.4 6.1 5.6 5.5 5.4 [] [, , ] [] [surface]

[38] [:] Results of HIC peak measurements, expressed as a percentage, for formulations with different pH values. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] [F6] initial 0 1.5 1.6 1.6 1.7 2.0 2.4 5℃ 3 1.4 1.4 1.6 1.7 1.9 2.5 5℃ 6 1.4 1.4 1.6 1.7 1.9 2.3 5℃ 12 1.2 1.2 1.4 1.6 1.7 2.1 5℃ 18 1.9 1.9 2.0 2.1 2.4 2.8 5℃ 24 1.5 1.6 1.6 1.7 1.9 2.1 5℃ 36 2.5 2.6 2.6 2.8 2.8 3.2 25℃ 1 1.8 1.8 2.0 2.2 2.3 2.9 25℃ 3 1.8 1.9 2.2 2.2 2.6 2.9 25℃ 6 2.1 2.1 2.3 2.4 2.5 2.9 25℃ 12 2.0 2.1 2.2 2.4 2.5 2.9 40℃ 1 2.7 2.6 2.6 2.8 2.9 3.5 40℃ 3 4.1 3.8 3.5 3.6 3.8 3.9

[0267] [, , ] [, Results and Discussion , ] Overall, HIC measurements showed that the tested formulations were stable. All pH values ​​resulted in high concentration peaks. Notably, the intermediate pH of 5.7 and the pH of approximately 5.7 showed a good trade-off compared to the highest and lowest tested pH values, which respectively showed increases in the initial and subsequent peaks.

[0268] [] [7.3.6.] [Binding Activity] [] The binding activity of risenoside against IL-23 was measured using a Biacore T200 analyzer. The following results were obtained: [, , ] [] [surface]

[39] [:] Binding activity of formulations with different pH values, expressed as a percentage. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] [F6] initial 0 103 103 103 106 105 107 5℃ 6 101 104 102 103 104 103 5℃ 12 94 97 96 93 97 99 5℃ 18 104 102 102 106 105 105 5℃ twenty four 102 96 101 100 97 102 5℃ 36 95 97 96 95 96 98 25℃ 3 109 107 106 106 103 103 25℃ 6 105 99 99 100 103 103 25℃ 12 93 101 93 94 92 97 40℃ 3 98 100 100 98 97 101 [surface]

[40] : Specific binding activity of formulations with different pH values, expressed in % (%). [Storage Conditions] [Storage time, months] [F1] [F2] [F3] [F4] [F5] [F6] initial 0 100 100 100 100 100 100 5℃ 6 100 99 99 99 99 99 5℃ 12 99 100 100 100 100 100 5℃ 18 99 99 99 100 100 100 5℃ 24 99 99 99 99 99 99 5℃ 36 100 100 100 100 100 100 25℃ 3 99 99 99 99 99 99 25℃ 6 98 98 99 98 99 98 25℃ 12 98 98 98 98 98 98 40℃ 3 96 96 97 97 98 98

[0269] [] [, Results and Discussion , ] Combined activity assays showed generally high values ​​for the tested formulations. Therefore, the tested formulations stabilized rissenzilmab to achieve high binding activity in the pH range of 5.0 to 6.2.

[0270] [7.3.7.] [Measurement of milky white light] [] In addition, the milky sheen of the formulation was measured. The milky sheen changed slightly over the analytical time but remained generally highly constant within the range of 3 to 11. The results indicate that the formulation is generally stable. Notably, lower pH values ​​generally show a lower milky sheen than higher pH values ​​(7 to 11 FNU for pH 6.2) (3 to 6 FNU for pH 5.0). An intermediate pH of 5.7 exhibits milky sheen within the range of 5 to 7 FNU, indicating that providing a formulation with a pH of approximately 5.7 is advantageous, especially in formulations according to examples of the invention.

[0271] [] [7.3.8.] [Measuring viscosity, syringe slippage force, and release force] [] Viscosity and syringe force, which are measured as additional parameters, include average and maximum slip force and loosening force. The following results were obtained: [surface]

[41] : Viscosity measurements of tested formulations with different pH values ​​over time, expressed in mPas. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] [F6] initial 0 8.5 8.8 9.2 9.6 9.9 10.3 5℃ 6 8.5 8.6 9.0 9.2 9.5 10.0 5℃ 12 8.7 8.7 8.9 9.3 9.7 10.1 5℃ twenty four 8.8 9.0 9.3 9.5 9.4 10.4 5℃ 36 8.6 8.7 8.9 9.4 9.8 10.3 25℃ 6 8.7 8.8 8.9 9.2 9.5 10.0 25℃ 12 8.7 8.5 9.0 9.3 9.7 10.3 [] [, , ] [] [surface]

[42] : Maximum slip force measured in N for tested formulations with different pH values ​​over time. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] [F6] initial 0 6.3 5.9 6.0 6.6 6.0 7.1 5℃ 3 6.4 6.9 6.3 6.5 6.5 7.0 5℃ 6 8.4 7.1 6.3 6.3 6.2 6.7 5℃ 9 7.7 8.5 6.4 6.3 7.1 6.9 5℃ 12 9.4 7.6 6.6 6.9 7.3 6.8 5℃ 18 9.2 10.4 8.4 6.5 6.9 7.0 5℃ 24 9.0 8.2 7.7 7.7 6.9 6.6 5℃ 36 9.2 8.3 7.7 7.7 6.9 7.1 25℃ 1 7.0 8.6 7.3 6.4 6.0 5.6 25℃ 3 11.8 10.0 8.5 7.3 8.3 6.8 25℃ 6 12.4 11.9 11.0 11.2 8.4 7.2 25℃ 9 12.9 13.3 13.2 10.7 11.1 8.4 25℃ 12 13.6 16.7 13.7 11.9 12.5 10.2 40℃ 1 10.8 10.3 11.8 8.7 7.9 7.2 40℃ 3 18.1 20.9 20.6 18.0 17.1 13.4 [surface]

[43] [:] The average slip force measured in N for the tested formulations with different pH values ​​over time. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] [F6] initial 0 5.9 5.6 5.6 6.1 5.7 6.5 5℃ 3 5.9 6.3 5.8 6.0 6.1 6.5 5℃ 6 7.4 6.5 5.9 5.9 5.9 6.4 5℃ 9 6.9 7.7 6.0 5.9 6.6 6.5 5℃ 12 8.1 6.8 6.2 6.5 6.8 6.4 5℃ 18 8.1 9.2 7.6 6.1 6.5 6.6 5℃ 24 7.9 7.2 7.0 7.1 6.4 6.2 5℃ 36 8.0 7.6 7.1 7.1 6.5 6.7 25℃ 1 6.5 7.5 6.6 6.0 5.7 5.4 25℃ 3 9.8 8.8 7.7 6.9 7.6 6.4 25℃ 6 10.1 9.7 9.0 9.6 7.6 6.8 25℃ 9 10.6 11.1 10.8 8.6 9.3 7.6 25℃ 12 10.8 13.5 10.8 9.7 9.9 8.6 40℃ 1 9.2 8.5 9.6 7.5 7.1 6.6 40℃ 3 14.1 15.8 14.5 12.9 12.5 10.5 [surface]

[44] [:] The loosening force measured in N for formulations with different pH values ​​over time. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] [F6] initial 0 3.9 3.9 4.1 4.1 4.1 4.1 5℃ 3 4.9 4.9 5.2 5.1 5.1 5.0 5℃ 6 4.4 4.4 4.5 4.6 4.6 4.6 5℃ 9 4.0 4.0 4.0 4.2 4.1 4.1 5℃ 12 4.7 4.6 4.6 4.6 4.7 4.7 5℃ 18 4.7 4.6 4.7 4.8 4.8 4.9 5℃ 24 4.6 4.4 4.6 4.6 4.6 4.9 5℃ 36 4.5 4.5 4.7 4.7 4.7 4.6 25℃ 1 4.4 4.6 4.7 5.0 4.6 4.4 25℃ 3 5.5 5.5 5.7 5.7 5.7 5.5 25℃ 6 5.4 5.3 5.2 5.4 5.2 5.4 25℃ 9 5.4 5.2 5.3 5.0 5.0 5.0 25℃ 12 5.4 5.3 5.3 5.3 5.3 5.4 40℃ 1 5.4 5.3 5.4 5.5 5.4 5.3 40℃ 3 7.0 6.7 6.7 6.2 6.5 6.1

[0272] [, , ] [, Results and Discussion , ] At higher pH values, viscosity measurements reveal slightly higher viscosity. Therefore, lower pH values, such as pH 5.7, can be found to be advantageous for obtaining formulations with lower viscosity. It should be noted that mechanical measurements of slip force and loosening force reveal generally very similar performance.

[0273] [] [7.4.] [Further Analysis and Results] [] In addition, further analysis was performed on the six formulations tested, and the results are as follows. Storage time and temperature are as described above. ● Protein concentrations remained substantially constant at different storage temperatures tested at 5°C, 25°C, and 40°C during storage periods of 36, 24, 12, and 3 months, respectively. Small deviations in protein concentrations (145–155 mg / mL (24 months) and 145–158 mg / mL (36 months)) are attributed to analytical variations. ● The pH value remained substantially constant at different storage temperatures tested at 5°C, 25°C, and 40°C during storage periods of 36, 24, 12, and 3 months, respectively. Therefore, the measured pH values ​​were in the range of 4.9–6.3. ● The permeate weight molar concentration remained substantially constant during storage periods of 36, 24, 12, and 3 months at different storage temperatures of 5°C, 25°C, and 40°C, respectively. The tested values ​​ranged from 301 to 323 mOsm / kg. ● During the storage period, the levels of protein-associated particles and foreign particles remained substantially low at the different storage temperatures tested.

[0274] [] [7.5.] [Results Overview] [] Formulations remained stable at all tested pH values ​​over extended storage periods of 24 and 36 months. While temperature appeared to have an effect on stability (i.e., higher temperatures induced more instability-related effects), all formulations exhibited sufficient stability even at high temperatures.

[0275] In summary, a pH of 5.7 and around 5.7 (e.g., 5.5, 5.9) appear to present a favorable trade-off regarding storage parameters under the test conditions used. For example, UP-SEC measurements show intermediate to low HMW and LMW values ​​at pH 5.7, while the highest and lowest pH values ​​each show the highest HMW and LMW contents. Similar results were obtained in IEC and HIC measurements.

[0276] [] [8.] [Acetate concentration] [right] [The effect on the stability of the formulation] [] Formulas containing different concentrations of acetate were stored at three different temperatures (5°C, 25°C, and 40°C) at different time points (see [reference]). [surface]

[45] ). [surface]

[45] [:] The composition of the blend. [Ingredients] [Acetate / mM] [PS20] Trehalose [pH] F1 [0] 0.2 []mg / mL 185 mM 5.7 F2 [5] F3

[10] F4

[15] F5

[20]

[0277] [8.1.] [Preparation of formulations] [] Prepare the formulation as described above.

[0278] [8.2.] [analyze] [] Sample measurements were performed during storage at 1, 3, 6, 9, 12, 18, 24, and 36 months, as well as initially before storage. Storage temperatures were adjusted to 5°C, 25°C, or 40°C. Analysis was performed using UP-SEC to measure monomer, HMW, and LMW content, and Biacore to measure binding activity. Additionally, the required slip and loosening forces, osmotic weight molar concentration, opalescence, and pH were measured. Further details of the analytical methods used are described below.

[0279] [8.3.] [result] [] [8.3.1.] [Measuring monomer content] [] UP-SEC analysis was performed to measure monomer content. The following results were obtained. [, , ] [] [surface]

[46] : UP-SEC monomer measurement results in % of the formulation containing varying amounts of acetate. [] [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] 5℃ 0 97.9 97.9 97.9 98.0 98.0 5℃ 3 97.6 97.6 97.7 97.7 97.7 5℃ 6 97.5 97.5 97.6 97.6 97.5 5℃ 9 97.2 --- 97.3 --- 97.3 5℃ 12 97.2 97.2 97.3 97.3 97.3 5℃ 18 97.4 97.4 97.4 97.4 97.5 5℃ 24 97.2 97.2 97.3 97.2 97.3 5℃ 36 97.0 97.0 97.1 97.1 97.0 25℃ 0 97.9 97.9 97.9 98.0 98.0 25℃ 1 97.3 --- 97.3 --- 97.4 25℃ 3 96.4 96.4 96.4 96.4 96.4 25℃ 6 95.7 95.7 95.7 95.7 95.6 25℃ 9 94.7 --- 94.6 --- 94.6 25℃ 12 94.1 94.1 94.1 94.1 94.1 40℃ 0 97.9 97.9 97.9 98.0 98.0 40℃ 1 95.2 --- 95.2 --- 95.2 40℃ 3 90.9 90.8 90.8 90.7 90.8

[0280] [, , ] [, Results and Discussion , ] Monomer assays showed that the formulations were stable within a certain range of acetate content, indicating the stability of formulations containing 150 mg / mL rissenkiramab with and without buffer, as well as formulations according to examples of the present invention.

[0281] [] [8.3.2.] [Measurement] [HMW] [content] [] The HMW content of the formulation was also determined by UP-SEC analysis, and the results are as follows: [, , ] [] [surface]

[47] [:] UP-SEC-HMW measurement results of the formulation containing varying amounts of acetate, expressed as a percentage. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] 5℃ 0 1.3 1.3 1.3 1.3 1.2 5℃ 3 1.5 1.5 1.5 1.5 1.5 5℃ 6 1.7 1.6 1.6 1.6 1.6 5℃ 9 1.7 --- 1.6 --- 1.6 5℃ 12 1.9 1.8 1.8 1.7 1.7 5℃ 18 1.7 1.7 1.7 1.7 1.6 5℃ 24 2.0 2.0 2.0 2.0 2.0 5℃ 36 2.2 2.1 2.1 2.1 2.1 25℃ 0 1.3 1.3 1.3 1.3 1.2 25℃ 1 1.7 --- 1.7 --- 1.7 25℃ 3 2.3 2.2 2.2 2.2 2.2 25℃ 6 2.5 2.5 2.4 2.5 2.5 25℃ 9 2.7 --- 2.7 --- 2.7 25℃ 12 2.9 2.9 2.9 2.9 2.9 40℃ 0 1.3 1.3 1.3 1.3 1.2 40℃ 1 2.7 --- 2.6 --- 2.7 40℃ 3 4.3 4.4 4.4 4.4 4.4

[0282] [] [, Results and Discussion , ] HMW content measurement showed that the formulations were stable within a certain range of acetate content, indicating the stability of formulations containing 150 mg / mL rissenkiramab with and without buffer, as well as formulations according to examples of the present invention.

[0283] [] [8.3.3.] [Measurement] [LMW] [content] [] For the determination of LMW content, UP-SEC analysis was performed. The following results were obtained. [] [surface]

[48] [:] UP-SEC-LMW measurement results of the mixture containing varying amounts of acetate, expressed as a percentage. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] 5℃ 0 0.8 0.9 0.9 0.8 0.8 5℃ 3 0.9 0.9 0.9 0.8 0.8 5℃ 6 0.8 0.9 0.9 0.9 0.9 5℃ 9 1.1 --- 1.1 --- 1.1 5℃ 12 1.0 1.0 1.0 1.0 1.0 5℃ 18 0.9 0.9 0.9 0.9 0.9 5℃ 24 0.8 0.8 0.8 0.8 0.8 5℃ 36 0.9 0.9 0.8 0.9 0.9 25℃ 0 0.8 0.9 0.9 0.8 0.8 25℃ 1 1.0 --- 1.0 --- 0.9 25℃ 3 1.4 1.4 1.4 1.4 1.4 25℃ 6 1.8 1.8 1.9 1.8 1.9 25℃ 9 2.7 --- 2.7 --- 2.7 25℃ 12 3.0 3.0 3.0 3.0 3.0 40℃ 0 0.8 0.9 0.9 0.8 0.8 40℃ 1 2.2 --- 2.2 --- 2.2 40℃ 3 4.8 4.8 4.8 4.8 4.9

[0284] [] [, Results and Discussion , ] LMW measurements show that formulations are stable within a certain range of acetate content, indicating the stability of formulations containing and without buffers.

[0285] [8.3.4.] [Measurement of binding activity] [] To analyze whether acetate content affects the binding activity of rissenitumumab to IL-23, Biacore analysis was performed. Binding activity assays showed high binding activity against human IL-23 for all tested formulations, ranging from 92% to 105% binding activity and 97% to 100% specific binding activity, as well as storage time. These results support the favorable stability of the tested formulations and indicate, according to the present invention, that formulations containing acetate and those without buffers are applicable.

[0286] [8.3.5.] [Measurement of osmotic weight molar concentration] [] Because acetate content also affects the osmotic weight molar concentration of the formulation, this parameter was measured. The results are shown in... [surface]

[49] in. [surface]

[49] : The permeation weight molar concentration of the formulation containing varying amounts of acetate at different temperatures and storage times, expressed in mOsm / kg. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] 5℃ 0 288 293 309 322 335 5℃ 3 290 294 310 324 335 5℃ 6 291 296 311 322 334 5℃ 9 304 --- 309 --- 333 5℃ 12 292 293 305 320 333 5℃ 18 284 287 305 322 330 5℃ 24 290 290 306 322 333 5℃ 36 288 291 306 322 334 25℃ 0 288 293 309 322 335 25℃ 1 290 --- 309 --- 335 25℃ 3 288 293 311 322 334 25℃ 6 290 295 313 324 334 25℃ 9 295 --- 311 --- 333 25℃ 12 294 294 309 312 333 40℃ 0 288 293 309 322 335 40℃ 1 287 --- 308 --- 334 40℃ 3 291 297 314 324 338

[0287] [, Results and Discussion , ] Measurements showed that the osmotic molar concentration varied between approximately 290 and 338 mOsm / kg, depending on the amount of acetate added. The more acetate added, the higher the measured osmotic molar concentration. Typically, an osmotic molar concentration of approximately 310 mOsm / kg is required, and a 10 mM acetate concentration produces the desired osmotic molar concentration of approximately 310 mOsm / kg (measurement range 305 to 314 mOsm / kg) in the tested formulation. In cases where a higher acetate concentration is required, it may be advantageous to modify the content of other compounds in the formulation (e.g., another excipient, such as trehalose) to adjust the osmotic molar concentration to approximately 310 mOsm / kg.

[0288] [] [8.3.6.] [Measurement of milky white light] [] The milky white light of the formulations according to the examples of the present invention was also measured to assess stability. The measured milky white light of the different formulations was generally the same, ranging from 4 to 9 FNU. Compared with the milky white light of lower concentrations of acetate (4-6 FNU for 0 mM acetate), higher concentrations of acetate caused a slightly higher milky white light of 7-9 FNU for 20 mM acetate. Based on the measured milky white light, all formulations according to the examples of the present invention are stable. []

[0289] [] [8.3.7.] [Measurement] [pH] To determine the pH stability of the buffer containing varying amounts, specifically the acetate formulation in this example, the pH values ​​were measured at different temperatures during storage. The results are shown in the following table. [, , ] [] [surface]

[50] : pH value measured in formulations containing varying amounts of acetate at 5°C, 25°C or 40°C during varying storage periods. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] 5℃ 0 5.8 5.8 5.8 5.8 5.8 5℃ 3 5.8 5.8 5.7 5.8 5.8 5℃ 6 5.8 5.8 5.8 5.8 5.8 5℃ 9 5.8 --- 5.8 --- 5.8 5℃ 12 5.7 5.8 5.8 5.7 5.8 5℃ 18 5.7 5.8 5.8 5.8 5.7 5℃ 24 5.8 5.8 5.8 5.8 5.8 5℃ 36 5.8 5.8 5.8 5.8 5.8 25℃ 0 5.8 5.8 5.8 5.8 5.8 25℃ 1 5.8 --- 5.7 --- 5.7 25℃ 3 5.8 5.7 5.8 5.8 5.7 25℃ 6 5.8 5.8 5.8 5.8 5.8 25℃ 9 5.8 --- 5.8 --- 5.8 25℃ 12 5.7 5.8 5.7 5.7 5.8 40℃ 0 5.8 5.8 5.8 5.8 5.8 40℃ 1 5.8 --- 5.8 --- 5.7 40℃ 3 5.7 5.7 5.7 5.8 5.7

[0290] [, Results and Discussion , ] pH measurements show that the pH of the formulations tested according to the present invention remains generally constant. Therefore, the formulations are stable in terms of pH for all acetate contents, including formulations that do not contain acetate.

[0291] [8.3.8.] [Measuring slip force and slack force] [] The measurements included the maximum and average slip force and loosening force of syringes with different formulations according to the present invention. The results of these measurements are shown below. [] [surface]

[51] : Maximum slip force in N for formulations containing varying amounts of acetate, both initially and after the indicated storage time at 5°C, 25°C, or 40°C. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] 5℃ 0 6.9 6.3 6.6 7.1 6.7 5℃ 3 7.3 7.0 6.3 7.4 7.6 5℃ 6 7.5 6.9 6.6 7.0 6.4 5℃ 9 8.1 --- 7.1 --- 6.6 5℃ 12 7.5 7.0 7.1 6.7 7.1 5℃ 18 7.9 8.8 6.1 5.9 7.0 5℃ 24 8.8 7.7 7.1 7.4 5.9 5℃ 36 7.8 9.3 7.0 7.4 7.1 25℃ 0 6.9 6.3 6.6 7.1 6.7 25℃ 1 8.1 --- 5.9 --- 5.9 25℃ 3 9.9 8.2 6.9 7.8 7.3 25℃ 6 12.5 12.5 8.5 8.2 7.1 25℃ 9 13.9 --- 11.8 --- 10.5 25℃ 12 18.4 14.7 14.5 13.1 10.8 40℃ 0 6.9 6.3 6.6 7.1 6.7 40℃ 1 11.8 --- 11.5 --- 7.6 40℃ 3 25.1 24.0 16.4 15.6 14.2 [surface]

[52] : Average slip force in N for formulations containing varying amounts of acetate initially and after the indicated storage time at 5°C, 25°C or 40°C. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] 5℃ 0 6.3 6.0 6.2 6.6 6.2 5℃ 3 6.5 6.4 6.0 6.8 6.9 5℃ 6 7.0 6.5 6.2 6.6 6.1 5℃ 9 7.2 --- 6.6 --- 6.2 5℃ 12 6.9 6.5 6.6 6.3 6.7 5℃ 18 7.2 7.9 5.8 5.7 6.6 5℃ 24 8.2 7.2 6.6 7.0 5.6 5℃ 36 7.0 8.1 6.6 6.8 6.7 25℃ 0 6.3 6.0 6.2 6.6 6.2 25℃ 1 7.3 --- 5.5 --- 5.7 25℃ 3 8.2 7.5 6.5 6.9 6.7 25℃ 6 10.5 10.5 7.6 7.6 6.7 25℃ 9 11.1 --- 9.5 --- 9.1 25℃ 12 14.0 11.9 11.5 10.2 8.9 40℃ 0 6.3 6.0 6.2 6.6 6.2 40℃ 1 9.5 --- 8.8 --- 6.8 40℃ 3 17.2 16.2 11.9 12.0 10.4 [surface]

[53] [:] The easing force in N for the formulation containing varying amounts of acetate, both initially and after the indicated storage time at 5°C, 25°C, or 40°C. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] 5℃ 0 4.1 4.0 3.9 3.8 4.1 5℃ 3 4.5 4.6 4.3 4.4 4.4 5℃ 6 4.5 4.3 4.3 4.1 4.4 5℃ 9 4.2 --- 4.5 --- 4.3 5℃ 12 4.5 4.4 4.3 4.3 4.3 5℃ 18 4.6 4.5 4.7 4.5 4.5 5℃ twenty four 4.7 4.6 4.6 4.6 4.7 5℃ 36 4.5 4.6 4.7 4.5 4.6 25℃ 0 4.1 4.0 3.9 3.8 4.1 25℃ 1 4.3 --- 4.3 --- 4.7 25℃ 3 5.0 5.4 5.0 4.8 5.2 25℃ 6 5.1 5.4 5.1 5.0 5.2 25℃ 9 5.2 --- 5.2 --- 4.7 25℃ 12 5.5 5.7 5.5 5.1 5.4 40℃ 0 4.1 4.0 3.9 3.8 4.1 40℃ 1 5.2 --- 5.0 --- 5.3 40℃ 3 6.3 6.0 6.0 5.9 6.0

[0292] [, , ] [, Results and Discussion , ] Slip and loosening force tests showed that all formulations were stable, and the slip and loosening forces did not increase significantly over time. Notably, formulations without acetate (F1) or containing very low concentrations of acetate (F2) exhibited higher forces, indicating that the addition of buffers such as acetate is useful, especially when the aim is to minimize the force required for application to the syringe.

[0293] [] [8.4.] [Further Analysis and Results] [] In addition, further analysis was performed on the five formulations tested, and the results are as follows. Storage time and temperature are as described above. ● The contents of the IEC main peak, APG, and BPG remained constant at 5°C over 24 and 36 months. No differences in the main peak, APG, and BPG were observed between formulations. ● Within 24 months at 5°C, the HIC main peak content remained constant within the range of 96.8%-97.2%, the HIC pre-peak content remained constant within the range of 1.4%-1.7%, and the HIC post-peak content remained constant within the range of 1.5%-1.9%. Within 36 months at 5°C, the HIC main peak content was obtained within the range of 96.3%-97.2%, the HIC pre-peak content within the range of 1.4%-1.7%, and the HIC post-peak content within the range of 1.5%-2.2%. After storage at 25°C for up to 12 months, the main peak content was obtained between 94.3%-97.1%, the pre-peak content between 1.4%-3.0%, and the post-peak content between 1.5%-2.7%. After storage at 40°C for up to 3 months, the main peak content was obtained between 92.0% and 97.1%, the preceding peak content between 1.4% and 4.6%, and the subsequent peak content between 1.5% and 3.4%. No differences in the main peak, preceding peak, and subsequent peak were observed between the formulations. ● Protein concentrations remained substantially constant at the different storage temperatures tested for up to 24 and 36 months of storage. Small deviations in protein concentration were attributed to analytical variations, resulting in ranges of 147–155 mg / mL (24 months) and 147–157 mg / mL (36 months). ● The dynamic viscosity remained substantially constant for storage periods of up to 24 and 36 months at the different storage temperatures tested. The dynamic viscosity ranged from 8.9 to 10.0 mPas. ● During the storage period, the levels of protein-associated particles and foreign particles remained substantially low at the different storage temperatures tested.

[0294] [] [8.5.] [Results Overview] [] The tested formulations showed generally high stability. Therefore, both formulations containing acetate and those without buffers are suitable for the formulations of this invention. Given the force required to be applied to the syringe, solutions containing buffers such as acetate buffers have proven superior to formulations without buffers. Furthermore, to achieve an osmotic weight molar concentration of 310 mOsm / kg, a 10 mM acetate content has proven suitable, taking into account the other compounds present in the formulations according to examples of this invention.

[0295] [] [IV.] [Example] [3] [:] [Analysis of other excipients] [] [1.] [During the shaking experiment] [PS20] [Influence of content] Preparation of formulations (see) [surface]

[54] ), wherein the content of PS20 (polysorbate 20) varied between 0, 0.05, 0.075, 0.1, 0.2, 0.3 and 0.5 mg / mL and was analyzed during shaking time of 0, 1, 5, 7, 14 and 21 days. [surface]

[54] [:] The composition of the blend. [Ingredients] [PS20 / mg / mL] [Acetate] Trehalose [pH] F1 [0.0] 10 mM 185 mM 5.7 F2 [0.05] F3 [0.075] F4 [0.1] F5 [0.2] F6 [0.3] F7 [0.5]

[0296] [1.1.] [Preparation of formulations] [] Prepare formulations as described above. For each formulation, as well as for the control and unshaken formulations, package the formulations in 2R vials (1.0 mL) or pre-filled syringes (PFS, Neopak, 1.0 mL).

[0297] [1.2.] [analyze] [] Sample measurements were performed on days 0, 1, 5, 7, 14, and 21. Therefore, the total shaking duration for both vials and PFS was 21 days. Vials were shaken at 200 U / min (rotary shaker) at room temperature (25°C), and the PFS was kinematically adjusted to achieve the desired viscosity to ensure bubble movement (tilting shaker (Vari Mix platform shaker)). All samples were protected from light. The milky white light of the formulations was measured at the indicated measurement points. Further details of the analytical methods used are described below.

[0298] [1.3.] [result] [] [, Measurement of milky white light , ] [, , ] To measure the stability of formulations containing varying amounts of PS20 subjected to shaking stress, opalescence was measured at different time points. The results obtained from the opalescence measurement are shown below: [surface]

[55] : The milky light of PS20 formulation with varying amounts in the syringe, expressed in FNU units. Shaking time, days; storage / shaking conditions [Ingredients] [PS20] [,] [g / l] [0] [1] [3] [7]

[14] [twenty one] [initial] [Swinging rocker] [Swinging rocker] [Swinging rocker] [Swinging rocker] [Swinging rocker] [No exercise] [F1_S] [0.00] 8.18 8.26 8.48 11.00 15.20 19.95 7.13 [F2_S] [0.05] 5.72 5.82 5.70 5.78 5.86 5.83 4.97 [F3_S] [0.08] 5.90 5.95 5.68 6.53 6.13 5.67 5.49 [F4_S] [0.10] 5.61 5.19 5.94 6.12 6.10 6.01 5.47 [F5_S] [0.20] 6.32 5.93 5.60 6.12 6.33 6.30 5.12 [F6_S] [0.30] 6.22 6.23 5.75 5.55 5.75 5.87 5.05 [F7_S] [0.50] 6.10 5.77 5.61 6.01 7.33 5.78 5.32 [surface]

[56] [:] A milky white light in FNU units, consisting of a mixture of PS20 in varying amounts contained in a small vial. Shake time, days; save / shake conditions [Ingredients] [PS20] [,] [g / l] [0] [1] [3] [7]

[14] [twenty one] [] [initial] [level] [Rock] [level] [Rock] [level] [Rock] [level] [Rock] [level] [Rock] [No exercise] [F1_V] [0.00] 6.83 8.29 8.37 10.72 14.52 22.50 7.96 [F2_V] [0.05] 6.70 5.70 6.10 5.45 5.91 5.72 5.46 [F3_V] [0.08] 5.84 5.47 6.57 5.85 6.26 6.86 6.21 [F4_V] [0.10] 5.67 5.10 6.24 5.39 5.75 6.28 5.81 [F5_V] [0.20] 7.23 6.21 5.94 6.07 5.58 6.87 6.89 [F6_V] [0.30] 6.60 5.20 5.89 5.36 5.78 5.61 5.66 [F7_V] [0.50] 5.70 5.62 5.61 5.81 5.54 5.48 5.89

[0299] [] [1.4.] [Results Overview] [] Shaking studies clearly revealed a significant increase in milky whiteness in formulations without PS20 over a 21-day shaking period. In contrast, all formulations containing PS20, even at the minimum amount of 0.05 g / L, showed no increase in milky whiteness over time. These results confirm the importance of surfactants such as the nonionic surfactant PS20 in the formulations of this invention, specifically the formulation containing 150 mg / mL rissenkiramab.

[0300] [] [2.] [Storage period] [PS20] [Influence of content] The prepared formulations were analyzed at different time points at three different storage temperatures (5°C, 25°C, and 40°C) (see [reference]). [surface]

[54] ).

[0301] [2.1.] [analyze] [] Sample measurements were performed at 1, 3, 6, 9, 12, 18, 24, and 36 months of storage, as well as initially before storage. UP-SEC analysis was performed to determine monomer, HMW, and LMW content. Additionally, the content of non-visual particles, slip forces, and loosening forces were measured. Further details of the analytical methods used are described below.

[0302] [2.2.] [result] [] [2.2.1.] [Measuring monomer content] [] The stability of the formulation was assessed by measuring the monomer content using UP-SEC analysis. The results are shown below. [surface]

[57] : UP-SEC monomer measurement results of PS20 formulations including variations, expressed as a percentage. [] [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] [F6] [F7] initial 0 97.9 97.9 97.9 97.9 97.8 97.8 97.8 5℃ 3 97.5 97.5 97.6 97.5 97.5 97.5 97.5 5℃ 6 97.3 97.3 97.3 97.3 97.3 97.3 97.2 5℃ 9 97.1 97.1 97.1 97.1 97.1 97.1 97.1 5℃ 12 97.2 97.2 97.2 97.2 97.2 97.2 97.2 5℃ 18 97.4 97.3 97.3 97.5 97.4 97.4 97.4 5℃ 24 97.1 97.2 97.2 97.1 97.2 97.1 97.2 5℃ 36 96.8 96.9 96.9 96.9 97.0 97.0 97.0 25℃ 1 97.2 97.2 97.2 97.2 97.2 97.2 97.2 25℃ 3 96.2 96.2 96.3 96.2 96.2 96.3 96.2 25℃ 6 95.2 95.3 95.4 95.4 95.4 95.4 95.4 25℃ 9 94.2 94.4 94.5 94.5 94.5 94.5 94.5 25℃ 12 93.5 93.8 93.9 93.9 94.0 94.0 93.9 40℃ 1 94.9 94.9 94.9 94.9 94.9 94.8 94.8 40℃ 3 89.6 90.1 90.4 90.3 90.4 90.4 89.7

[0303] [, , ] [, Results and Discussion , ] Monomer assays showed that the formulations were stable within a certain range of PS20 concentrations. Particularly high monomer values ​​were obtained for approximately 0.2 mg / mL of PS20.

[0304] [] [2.2.2.] [Measurement] [HMW] [content] [] The stability of the formulation was further evaluated by measuring the HMW content again using UP-SEC. The results are shown below. [surface]

[58] [:] UP-SEC HMW measurement results of PS20 formulations with varying amounts, expressed as a percentage. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] [F6] [F7] initial 0 1.3 1.4 1.4 1.4 1.4 1.4 1.4 5℃ 3 1.7 1.7 1.7 1.7 1.7 1.7 1.7 5℃ 6 1.9 1.9 1.9 1.9 1.9 1.9 1.9 5℃ 9 1.8 1.8 1.8 1.8 1.8 1.8 1.8 5℃ 12 1.0 1.0 1.0 1.0 1.0 1.0 1.0 5℃ 18 1.7 1.8 1.8 1.7 1.7 1.7 1.7 5℃ 24 2.1 2.1 2.0 2.1 2.1 2.1 2.1 5℃ 36 2.3 2.2 2.2 2.2 2.2 2.2 2.2 25℃ 1 1.9 1.9 1.9 1.9 1.9 1.9 1.9 25℃ 3 2.4 2.4 2.4 2.4 2.4 2.4 2.5 25℃ 6 2.9 2.8 2.8 2.8 2.8 2.8 2.8 25℃ 9 3.0 2.9 2.8 2.8 2.8 2.8 2.8 25℃ 12 3.2 3.1 3.1 3.1 3.0 3.0 3.1 40℃ 1 2.9 2.9 2.9 2.9 2.9 2.9 3.0 40℃ 3 5.1 4.9 4.7 4.7 4.7 4.7 5.3

[0305] [] [, Results and Discussion , ] HMW levels correlated with monomer assays. Overall, the tested formulations exhibited stability within a certain range of PS20 concentrations. A particularly low increase in HMW was observed at a PS20 concentration of 0.2 mg / mL. However, the highest and lowest tested PS20 concentrations appeared to result in slightly higher HMW values.

[0306] [] [2.2.3.] [Measurement] [LMW] [content] [] The LMW content was also measured using UP-SEC and the following results were obtained: [surface]

[59] [:] UP-SEC-LMW measurement results of PS20 formulations with varying amounts, expressed as a percentage. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] [F6] [F7] initial 0 0.8 0.8 0.8 0.8 0.8 0.8 0.8 5℃ 3 0.8 0.8 0.8 0.8 0.8 0.8 0.8 5℃ 6 0.8 0.8 0.8 0.8 0.8 0.8 0.8 5℃ 9 1.1 1.1 1.1 1.1 1.1 1.1 1.1 5℃ 12 1.9 1.8 1.8 1.8 1.8 1.8 1.8 5℃ 18 0.8 1.0 1.0 0.8 0.9 0.9 0.9 5℃ 24 0.8 0.8 0.8 0.8 0.8 0.8 0.8 5℃ 36 0.9 0.9 0.9 0.9 0.9 0.9 0.9 25℃ 1 1.0 1.0 1.0 1.0 1.0 1.0 0.9 25℃ 3 1.4 1.3 1.3 1.4 1.4 1.3 1.3 25℃ 6 1.9 1.9 1.8 1.8 1.8 1.8 1.8 25℃ 9 2.8 2.7 2.7 2.7 2.7 2.7 2.7 25℃ 12 3.3 3.1 3.1 3.1 3.0 3.0 3.0 40℃ 1 2.2 2.3 2.2 2.2 2.2 2.3 2.3 40℃ 3 5.3 5.1 5.0 5.0 4.9 4.9 5.0

[0307] [] [, Results and Discussion , ] The LMW content correlated with the monomer assay results. Overall, the tested formulations exhibited stability within a certain range of PS20 content. A particularly low increase in LMW was observed for a PS20 content of 0.2 mg / mL. The lowest tested PS20 content (see F1) appeared to have resulted in a slightly higher LMW value.

[0308] [2.2.4.] [Measurement of milky white light] [] In addition, the milky white light of the formulation containing varying amounts of PS20 was measured. The results are described below. [] [surface]

[60] [:] The results of the measurement of the milky white light of the PS20 formulation, including the variation amount, in FNU units. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] [F6] [F7] initial 0 8 6 6 6 6 6 6 5℃ 3 7 6 6 6 7 6 6 5℃ 6 6 6 6 6 7 6 6 5℃ 9 12 5 7 6 6 7 8 5℃ 12 11 10 8 7 7 6 7 5℃ 18 19 9 12 8 7 7 6 5℃ 24 13 6 7 7 7 7 7 5℃ 36 12 6 7 7 7 7 7 25℃ 1 6 6 5 6 5 6 6 25℃ 3 6 6 6 6 6 6 6 25℃ 6 6 6 6 6 7 7 7 25℃ 9 6 6 6 7 6 7 8 25℃ 12 7 7 7 7 8 7 9 40℃ 1 7 6 6 6 6 7 6 40℃ 3 7 6 6 7 7 7 8

[0309] [] [, Results and Discussion , ] Measurements showed that none of the formulations caused an increase in milky whiteness at higher temperatures of 25°C and 40°C. However, formulation F1 (without PS20) showed an increase in milky whiteness at a temperature of 5°C and at subsequent storage time points (e.g., 18, 24, and 36 months). Therefore, surfactants such as the nonionic surfactant PS20 are advantageous.

[0310] [] [2.2.5.] [Measuring the content of particles not visible to the naked eye] [] The formulations were analyzed for the content of non-visible particles (≥ 2 µm, ≥ 10 µm and ≥ 25 µm) in formulations stored at 5°C for 24 and 36 months. [] [surface]

[61] : Measurement results of the non-visual particle content of PS20 formulations containing variations in size ≥ 2 µm, ≥ 10 µm and ≥ 25 µm particles stored at 5°C for 24 and 36 months. [deal with] [Particle size] [Number of particles measured] [F1] [F2] [F3] [F4] [F5] [F6] [F7] [initial] [≥] [2 µm] 58318 1876 4832 3607 7780 5121 6578 [≥] [10 µm] 6061 70 99 88 312 111 278 [≥] [25 µm] 183 9 5 2 31 9 26 [5] [℃] [,] [3] [months] [≥] [2 µm] 41237 1442 4559 9475 14173 10810 4201 [≥] [10 µm] 3650 48 170 225 177 224 94 [≥] [25 µm] 196 2 6 15 1 3 1 [5] [℃] [,] [6] [months] [≥] [2 µm] 51615 4949 3580 5282 11069 16838 18125 [≥] [10 µm] 3501 38 48 45 71 105 131 [≥] [25 µm] 29 0 2 0 1 6 1 [5] [℃] [,] [9] [months] [≥] [2 µm] 70311 11911 6453 6982 35316 6358 10660 [≥] [10 µm] 5195 42 17 60 60 33 79 [≥] [25 µm] 122 1 0 2 0 2 9 [5] [℃] [,]

[12] [months] [≥] [2 µm] 58322 16911 9064 28517 7761 15372 41782 [≥] [10 µm] 4529 121 183 360 141 132 295 [≥] [25 µm] 184 2 7 7 1 0 6 [[ID=5​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ [25 µm] 181 2 6 1 3 2 6 [5] [℃] [,] [twenty four] [months] [≥] [2 µm] 61469 5862 9427 7969 17688 37040 3688 [≥] [10 µm] 5407 84 163 197 355 290 148 [≥] [25 µm] 66 1 9 9 6 3 5 [5] [℃] [,]

[36] [months] [≥] [2 µm] 17157 4306 7984 12335 16377 21911 14799 [≥] [10 µm] 2255 49 54 146 172 136 65 [≥] [25 µm] 257 1 2 8 5 2 3

[0311] [] [, Results and Discussion , ] Measurements of non-visual particle content showed that all formulations remained stable at 5°C for 24 and 36 months. Only the formulation lacking PS20 (F1) appeared to result in some particle formation, confirming the advantage of adding surfactants such as the nonionic surfactant PS20 to the formulations of this invention.

[0312] [2.2.6.] [Measurement of slip force and loosening force] [] The measurements included the maximum and average slip force and loosening force of the PS20 formulation with varying degrees of slip. The measurement results are shown below. [surface]

[62] : Maximum slip force in N. The formulation includes variations in PS20. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] [F6] [F7] initial 0 7.2 7.1 6.2 6.5 6.4 6.3 6.9 5℃ 3 7.8 7.4 8.1 6.8 6.8 6.5 6.4 5℃ 6 7.7 7.0 6.7 6.6 6.1 6.5 6.7 5℃ 9 8.7 6.4 7.4 7.6 6.7 6.6 8.2 5℃ 12 7.1 7.5 6.7 7.2 5.9 6.7 7.3 5℃ 18 8.9 7.4 6.1 6.9 6.1 7.4 7.1 5℃ 24 8.1 6.2 7.6 8.0 7.2 6.7 7.1 5℃ 36 9.2 8.5 9.1 7.0 7.5 6.7 7.2 25℃ 1 7.4 6.5 6.4 6.8 6.6 6.1 6.2 25℃ 3 8.1 7.0 7.4 7.7 7.0 7.7 7.7 25℃ 6 8.1 7.3 9.4 8.9 9.9 9.6 10.8 25℃ 9 7.2 11.9 10.2 9.8 11.2 11.3 12.6 25℃ 12 8.4 11.1 12.0 13.6 12.8 15.1 16.1 40℃ 1 7.7 8.1 9.2 11.2 8.7 9.5 8.6 [surface]

[63] : Average slip force in N. The formulation includes variations in PS20. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] [F6] [F7] initial 0 6.5 6.5 5.8 6.1 5.9 5.9 6.4 5℃ 3 7.1 6.7 7.3 6.3 6.2 6.0 6.0 5℃ 6 6.8 6.5 6.3 6.2 5.7 6.1 6.2 5℃ 9 7.5 6.1 6.7 6.9 6.3 6.1 7.2 5℃ 12 6.4 6.8 6.4 6.8 5.7 6.2 6.7 5℃ 18 7.9 7.0 5.8 6.4 5.8 6.8 6.6 5℃ 24 7.2 5.9 7.0 7.3 6.7 6.4 6.6 5℃ 36 7.8 7.7 8.2 6.6 6.8 6.4 6.6 25℃ 1 6.7 6.0 6.0 6.4 6.2 5.8 5.8 25℃ 3 7.4 6.5 6.9 7.2 6.3 7.0 7.2 25℃ 6 7.3 6.9 8.4 7.8 8.0 8.3 9.2 25℃ 9 6.4 10.0 8.5 8.6 9.1 9.5 9.9 25℃ 12 7.7 9.6 10.0 11.2 10.5 12.1 12.4 40℃ 1 6.9 7.0 7.9 9.2 7.0 8.0 7.5 [surface]

[64] [:] Loosening force in N. The formulation includes variations in PS20. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] [F6] [F7] initial 0 4.1 4.3 4.2 4.1 4.2 4.3 4.1 5℃ 3 4.7 4.6 4.8 4.8 4.6 4.7 4.7 5℃ 6 4.6 4.3 4.5 4.5 4.5 4.5 4.7 5℃ 9 3.8 4.1 4.0 4.1 3.9 4.2 4.2 5℃ 12 4.5 4.5 4.5 4.7 4.7 4.3 4.5 5℃ 18 4.6 4.9 4.8 4.6 4.7 4.6 4.7 5℃ 24 5.0 5.1 4.8 4.7 4.8 4.6 4.8 5℃ 36 4.2 4.3 4.3 4.0 4.0 4.5 4.6 25℃ 1 4.8 4.8 4.6 4.7 4.7 4.4 4.7 25℃ 3 5.1 5.4 5.3 5.5 5.4 5.2 5.4 25℃ 6 5.1 5.1 5.1 5.3 4.9 5.1 5.3 25℃ 9 4.4 4.9 4.4 5.0 5.0 4.9 5.0 25℃ 12 5.4 5.4 5.4 5.7 5.3 5.6 5.3 40℃ 1 5.0 5.0 5.0 5.2 5.1 4.9 5.0 40℃ 3 5.9 5.8 6.1 6.3 6.0 6.0 6.4

[0313] [ , Results and Discussion , ] Slip force assays revealed a relatively high slip force at a high concentration of PS20 (0.5 g / L) compared to lower concentrations. While a minimum slip force was observed at 0 g / L, an intermediate concentration of 0.2 g / L showed a good trade-off between high and low slip forces. Notably, no significant difference was observed in the loosening power among the formulations.

[0314] [] [2.3.] [Further Analysis and Results] [] In addition, further analysis was performed on the seven formulations tested, and the results are as follows. Storage time and temperature are as described above. ● The contents of the IEC main peak, APG, and BPG remained constant at 5°C over 24 and 36 months. No differences in the main peak, APG, and BPG were observed between formulations. ● Within 24 months at 5°C, the HIC main peak content remained constant within the range of 96.5%-97.3%, the HIC pre-peak content remained constant within the range of 1.4%-1.7%, and the HIC post-peak content remained constant within the range of 1.4%-1.9%. Within 36 months at 5°C, the HIC main peak content was obtained within the range of 95.9%-97.3%, the HIC pre-peak content within the range of 1.4%-1.7%, and the HIC post-peak content within the range of 1.4%-2.4%. After storage at 25°C for up to 12 months, the main peak content was obtained between 93.9%-96.8%, the pre-peak content between 1.4%-3.0%, and the post-peak content between 1.7%-2.7%. After storage at 40°C for up to 3 months, the main peak content was obtained between 90.3% and 95.2%, the preceding peak content between 2.5% and 6.0%, and the subsequent peak content between 2.3% and 3.7%. No differences in the main peak, preceding peak, and subsequent peak were observed between the formulations. ● The specific binding activity remained substantially constant at the tested storage temperatures for storage periods of up to 24 and 36 months. The specific binding activity was in the range of 97%-101%. ● Protein concentrations remained substantially constant at the different storage temperatures tested for up to 24 and 36 months of storage. Small deviations in protein concentration were attributed to analytical variations, resulting in ranges of 147–155 mg / mL (24 months) and 147–159 mg / mL (36 months). ● The pH value remained substantially constant for storage periods of up to 24 and 36 months at different storage temperatures tested. The pH ranged from 5.7 to 5.9. ● The permeate molar concentration remained substantially constant for storage periods of up to 24 and 36 months at different storage temperatures tested. The tested values ​​ranged from 305 to 322 mOsm / kg. ● The dynamic viscosity remained substantially constant for storage periods of up to 24 and 36 months at the different storage temperatures tested. The dynamic viscosity ranged from 9.2 to 11.0 mPas. ● During the storage period, the levels of protein-associated particles and foreign particles remained substantially low at the different storage temperatures tested.

[0315] [2.4.] [Results Overview] [] In summary, the formulations tested under long-term storage conditions of 24 and 36 months within a temperature range of 5°C to 40°C exhibited stability. Specifically, formulations containing surfactants such as PS20 were found to be stable, while formulations lacking PS20 showed some non-visible particle formation and increased milky whiteness. The LMW content of formulations lacking PS20 was also slightly increased. Under the tested conditions, a particularly suitable concentration of surfactants such as the nonionic surfactant PS20 appears to be 0.2 g / L.

[0316] [] [3.] [Change trehalose content] In this example, trehalose concentrations varied between 145, 165, 185, 205, and 225 mM and were analyzed at different time points at three different storage temperatures (5°C, 25°C, and 40°C). The prepared formulation is shown in... [surface]

[65] in. [surface]

[65] [:] The composition of the blend. [Ingredients] [Trehalose / mM] [PS20 / mg / mL] [Acetate / mM] [pH] F1

[0145] 0.2 10 5.7 F2

[0165] F3

[0185] F4

[0205] F5

[0225]

[0317] [3.1.] [analyze] [] Sample measurements were performed during storage at 1, 3, 6, 9, 12, 18, 24, and 36 months, as well as initially prior to storage. Further details of the analytical methods used are described below.

[0318] [3.2.] [result] [] [3.2.1.] [Measuring monomer content] [] The stability of formulations containing varying amounts of trehalose was assessed by using UP-SEC analysis to measure monomer content, and the results are shown below. [surface]

[66] [:] UP-SEC monomer content of formulations containing varying amounts of trehalose, expressed as a percentage. [] [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] 5℃ 0 98.1 98.0 98.0 98.1 98.0 5℃ 3 97.7 97.7 97.7 97.7 97.6 5℃ 6 97.6 97.5 97.5 97.5 97.5 5℃ 9 97.2 --- 97.2 --- 97.1 5℃ 12 97.2 97.3 97.2 97.3 97.2 5℃ 18 97.5 97.5 97.4 97.4 97.3 5℃ twenty four 97.2 97.1 97.2 97.2 97.1 5℃ 36 97.0 97.0 97.0 97.0 96.9 25℃ 0 98.1 98.0 98.0 98.1 98.0 25℃ 1 97.2 --- 97.3 --- 97.2 25℃ 3 96.5 96.5 96.4 96.4 96.3 25℃ 6 95.7 95.6 95.6 95.6 95.6 25℃ 9 94.6 --- 94.6 --- 94.6 25℃ 12 94.1 94.1 94.1 94.1 94.1 40℃ 0 98.1 98.0 98.0 98.1 98.0 40℃ 1 95.0 --- 95.0 --- 95.0 40℃ 3 90.7 90.8 90.8 90.7 90.8

[0319] [, , ] [, Results and Discussion , ] Monomer analysis showed that the formulation was stable within a certain range of trehalose content, indicating its stability within that range.

[0320] [] [3.2.2.] [Measurement] [HMW] [content] [] The HMW content of the formulation was determined using UP-SEC. The analytical results are shown below. [surface]

[67] [:] UP-SEC HMW measurement results in percentage (%) of formulations containing varying amounts of trehalose. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] 5℃ 0 1.1 1.1 1.1 1.1 1.2 5℃ 3 1.4 1.4 1.5 1.4 1.5 5℃ 6 1.5 1.6 1.6 1.6 1.6 5℃ 9 1.7 --- 1.7 --- 1.8 5℃ 12 1.8 1.8 1.8 1.8 1.9 5℃ 18 1.7 1.7 1.7 1.7 1.8 5℃ 24 2.0 2.0 2.0 2.0 2.1 5℃ 36 2.1 2.1 2.2 2.2 2.2 25℃ 0 1.1 1.1 1.1 1.1 1.2 25℃ 1 1.7 --- 1.7 --- 1.7 25℃ 3 2.2 2.2 2.2 2.2 2.3 25℃ 6 2.4 2.4 2.5 2.4 2.5 25℃ 9 2.7 --- 2.7 --- 2.8 25℃ 12 2.9 3.0 3.0 3.0 3.0 40℃ 0 1.1 1.1 1.1 1.1 1.2 40℃ 1 2.8 --- 2.7 --- 2.8 40℃ 3 4.4 4.3 4.3 4.3 4.4

[0321] [] [, Results and Discussion , ] HMW content measurement showed that the formulation was stable within a certain range of trehalose content.

[0322] [] [3.2.3.] [Measurement] [LMW] [content] [] The LMW content of the formulation, which includes varying amounts of trehalose, was also measured using UP-SEC. The results are shown below. [surface]

[68] [:] UP-SEC-LMW measurement results in percentage (%) of formulations containing varying amounts of trehalose. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] 5℃ 0 0.9 0.9 0.9 0.9 0.9 5℃ 3 0.9 0.9 0.9 0.9 0.9 5℃ 6 0.9 0.9 0.9 0.9 0.9 5℃ 9 1.1 --- 1.1 --- 1.1 5℃ 12 1.0 1.0 1.0 1.0 1.0 5℃ 18 0.9 0.9 0.9 0.9 0.9 5℃ 24 0.8 0.8 0.8 0.8 0.8 5℃ 36 0.9 0.8 0.9 0.9 0.9 25℃ 0 0.9 0.9 0.9 0.9 0.9 25℃ 1 1.1 --- 1.0 --- 1.0 25℃ 3 1.4 1.4 1.4 1.4 1.4 25℃ 6 1.9 1.9 1.9 1.9 1.9 25℃ 9 2.6 --- 2.6 --- 2.6 25℃ 12 2.9 2.9 2.9 3.0 2.9 40℃ 0 0.9 0.9 0.9 0.9 0.9 40℃ 1 2.3 --- 2.3 --- 2.3 40℃ 3 4.9 4.9 4.9 4.9 4.9

[0323] [] [, Results and Discussion , ] LMW measurements showed that the formulations exhibited stability within a certain range of trehalose content.

[0324] [3.2.4.] [Measurement of binding activity] [] The binding activity of risenoic acid monoclonal antibody contained in the formulations of this invention was measured. Antigen binding assays showed high binding activity of all tested formulations with IL-23, ranging from 92% to 122% binding activity and 96% to 100% specific binding activity. These results support the favorable stability of the tested formulations and indicate, according to this invention, the applicability of formulations containing trehalose at various concentrations.

[0325] [3.2.5.] [Measurement of osmotic weight molar concentration] [] The osmotic weight molar concentration was measured to ensure that the tested formulation had an osmotic weight molar concentration suitable for injection. The results are shown below: [surface]

[69] : The osmotic weight molar concentration of the formulation containing varying amounts of trehalose, measured in mOsm / kg. [Storage conditions] [Storage time, month] [F1] [F2] [F3] [F4] [F5] 5℃ 0 246 274 309 337 376 5℃ 3 247 277 307 340 378 5℃ 6 247 275 309 338 375 5℃ 9 251 --- 310 --- 380 5℃ 12 245 274 305 335 375 5℃ 18 248 271 303 340 370 5℃ 24 248 277 308 339 376 5℃ 36 248 275 307 338 374 25℃ 0 246 274 309 337 376 25℃ 1 248 --- 307 --- 373 25℃ 3 252 287 311 338 378 25℃ 6 246 276 310 335 371 25℃ 9 253 --- 310 --- 380 25℃ 12 241 278 302 336 377 40℃ 0 246 274 309 337 376 40℃ 1 245 310 373 40℃ 3 249 278 312 340 379

[0326] [, , ] [, Results and Discussion , ] For trehalose concentrations of 145 to 225 mM, the osmotic weight molar concentration ranges from approximately 245 to 380 mOsm / kg. Since the optimal osmotic weight molar concentration is approximately 310 mOsm / kg, it is advantageous to provide formulations with this osmotic weight molar concentration. This can be achieved, for example, using a trehalose concentration of 185 mM and formulations according to embodiments of the invention.

[0327] [] [3.3.] [Further Analysis and Results] [] In addition, further analysis was performed on the five formulations tested (storage time and temperature as described above). ● The contents of the IEC main peak, APG, and BPG remained constant at 5°C over 24 and 36 months. No differences in the main peak, APG, and BPG were observed between formulations. ● Within 24 months at 5°C, the HIC main peak content remained constant within the range of 96.4%-97.4%, the HIC pre-peak content remained constant within the range of 1.4%-1.8%, and the HIC post-peak content remained constant within the range of 1.2%-2.0%. Within 36 months at 5°C, the HIC main peak content was obtained within the range of 96.0%-97.4%, the HIC pre-peak content within the range of 1.4%-1.8%, and the HIC post-peak content within the range of 1.2%-2.3%. After storage at 25°C for up to 12 months, the main peak content was obtained between 94.2%-97.4%, the pre-peak content between 1.4%-3.0%, and the post-peak content between 1.2%-2.8%. After storage at 40°C for up to 3 months, the main peak content was obtained between 90.3% and 97.4%, the preceding peak content between 1.4% and 5.9%, and the subsequent peak content between 1.2% and 3.7%. No differences in the main peak, preceding peak, and subsequent peak were observed among the formulations. ● Protein concentrations remained substantially constant at the different storage temperatures tested for up to 24 and 36 months of storage. Small deviations in protein concentration were attributed to analytical variations, resulting in ranges of 145–153 mg / mL (24 months) and 148–158 mg / mL (36 months). ● The pH value remained substantially constant for storage periods of up to 24 and 36 months at different storage temperatures tested. The pH ranged from 5.7 to 5.9. ● The opalescence remained substantially constant for storage periods of up to 24 and 36 months at different storage temperatures tested. The opalescence ranged from 5 to 9 FNU. ● The dynamic viscosity remained substantially constant for storage periods of up to 24 and 36 months at different storage temperatures tested. The dynamic viscosity ranged from 8.9 to 10.3 mPas. ● Within 24 months at 5°C, the sliding force remains constant within the range of 6.5-7.7 N (maximum) and 5.8-7.4 N (average), while the loosening force remains constant within the range of 3.9-5.0 N. Within 36 months at 5°C, the sliding force remains constant within the range of 6.1-8.5 N (maximum) and 5.8-7.7 N (average), while the loosening force remains constant within the range of 3.9-5.0 N. At 25°C for up to 12 months of storage, the sliding force ranges between 6.7-15.7 N (maximum) and 6.2-12.4 N (average), and the loosening force ranges between 3.9-5.6 N. At 40°C for up to 3 months of storage, the sliding force ranges between 8.7-23.1 N (maximum) and 7.3-16.4 N (average), and the loosening force ranges between 5.1-6.6 N. ● During the storage period, the levels of protein-associated particles and foreign particles remained substantially low at the different storage temperatures tested.

[0328] [3.4.] [Results Overview] In summary, all tested formulations demonstrated stability, confirming that high stability is maintained despite variations in trehalose concentration. Therefore, the indicated trehalose concentration can be flexibly applied to produce stable protein formulations of 150 mg / mL rissenkiramab. []

[0329] [] [V.] [Example] [4] [:] [Analyze additional parameters of a specific formulation] [] Based on the results of previous examples, particularly suitable formulations include the following compounds: - 150 mg / mL Rissenkiumab, - 10 mM acetate buffer, - 185 mM trehalose, and - 0.2 mg / mL PS20; The pH of the formulation is 5.7.

[0330] This formulation has a clear to slightly milky white appearance and is substantially free of foreign particles. Its penetrating weight molar concentration is approximately 310 mOsm / kg. The formulation is particularly suitable for injection, especially subcutaneous injection. Furthermore, its viscosity of approximately 9.6 mPas makes it suitable for injection using a syringe. Its conductivity at 20°C is approximately 1.53 mS / cm, its density at 20°C is approximately 1.067 g / cm³, and its density at 4°C is approximately 1.071 g / cm³.

[0331] This 150 mg / mL risenosumab formulation can be provided as follows: Element Concentration [mmol / L] Concentration [g / l] Function In one embodiment where this preparation is provided in a syringe (V = 1 ml), the nominal amount [mg / syringe] is as follows: Lissenki monoclonal antibody 1.00 150 Drug substances 150 Sodium acetate trihydrate 9.10 1.24 buffer 1.24 Acetic acid 0.900 0.0540 buffer 0.0540 Trehalose dihydrate 185 70.0 Adjusting tension 70.0 Polysorbate 20 0.163 0.200 surfactants 0.200 [List of Abbreviations] [abbreviation] [Full Form] APG acid peak group AUC Area under the curve BPG alkaline peak group CGE Capillary gel electrophoresis FNU Formalhydrazine turbidity measurement unit F / T Freezing / thawing HIC Hydrophobic interaction chromatography HMW High molecular weight HP-SEC High-pressure size exclusion chromatography IEC Ion exchange chromatography IL-23 Interleukin-23 LMW low molecular weight MFI Microfluidic imaging mOsm / kg milliliters per kilogram mPas millipascal second mS / cm millimeter / cm PS20 Polysorbate 20 RALS Right-angle light scattering rh relative humidity rhIL-23 Recombinant human interleukin-23 SEC Size exclusion chromatography SPR Surface plasma resonance STP Sampling time point SVP Invisible particles UF / DF Ultrafiltration / Permeation U / min revolutions per minute UP-SEC High-efficiency size exclusion chromatography WCX Weak cation exchange chromatography

[0332] <![CDATA[ <110> Boehringer Ingelheim International GmbH <![CDATA[ <120> Anti-IL-23P19 antibody formulation <![CDATA[ <150> US62 / 897930]]> <![CDATA[ <151> 2019-09-09 <![CDATA[ <160> 2]]> <![CDATA[ <170> BiSSAP 1.3.6 <![CDATA[ <210> 1]]> <![CDATA[ <211> 214]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> Antibody light chain <![CDATA[ <400> 1]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Arg Asp Val Ala Ile Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile 35 40 45 Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Val Ala Asp Tyr Phe Cys His Gln Tyr Ser Ser Tyr Pro Phe 85 90 95 Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <![CDATA[ <210> 2]]> <![CDATA[ <211> 449]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> Antibody heavy chain <![CDATA[ <400> 2]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Gln 20 25 30 Thr Ile His Trp Met Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Pro Arg Asp Asp Ser Pro Lys Tyr Asn Glu Asn Phe 50 55 60 Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ile Pro Asp Arg Ser Gly Tyr Ala Trp Phe Ile Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly

Claims

1. A stable liquid aqueous pharmaceutical formulation comprising: a) risankizumab at a concentration of 150 mg / ml to 192.3 mg / ml; b) 185 mM trehalose; c) 0.2 mg / ml polysorbate 20; and d) 10 mM acetate buffer; wherein the pH of the stable liquid aqueous pharmaceutical formulation is in the range of 5.5 to 5.9, and wherein the viscosity of the formulation, measured at 20°C, is less than 20.0 mPas.

2. The stable liquid aqueous pharmaceutical formulation of claim 1, comprising: a) 150 mg / ml rissenkiramab; b) 185 mM trehalose; c) 0.2 mg / ml polysorbate 20; and d) 10 mM acetate buffer; wherein the pH of the stable liquid aqueous pharmaceutical formulation is in the range of 5.5 to 5.9, and wherein the viscosity of the formulation is less than 20.0 mPas when measured at 20°C after 12 months of storage at 5°C.

3. A stable liquid aqueous pharmaceutical formulation, as requested in item 1 or 2, wherein the pH of the formulation is 5.

5.

4. A stable liquid aqueous pharmaceutical formulation, as requested in item 1 or 2, wherein the pH of the formulation is 5.

7.

5. A stable liquid aqueous pharmaceutical formulation as requested in item 1 or 2, wherein the pH of the formulation is 5.9.

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