Anti-il-23p19 antibody formulations

Abstract

The present invention provides an anti-IL-23p19 antibody liquid pharmaceutical formulation comprising 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 high concentration formulations disclosed herein advantageously have storage stability and are suitable for subcutaneous administration.

Description

[0001] This application is a divisional application of Chinese invention patent application filed on September 9, 2020, with Chinese application number 202080062754.3 and invention title "Anti-IL-23p19 Antibody Preparation".

[0002] Cross-reference to related applications

[0003] This application claims priority to U.S. Provisional Application No. 62 / 897,930, filed September 9, 2019, the entire contents of which are incorporated herein by reference. Technical Field

[0004] This invention generally relates to formulations of anti-IL-23p19 antibodies, such as risankizumab, that contain 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 a stable liquid pharmaceutical formulation containing 150 mg / ml of the antibody risankizumab. Background Technology

[0005] Human IL-23 is composed of a common subunit (p40) with IL-12 and a unique p19 subunit. Despite sharing the p40 subunit, IL-23 and IL-12 have completely different functions. IL-12 is crucial for the Th1 response by promoting Th1 cell differentiation, proliferation, and activation. In contrast, IL-23 supports CD4+ cells called Th17 cells. + The development and maintenance of the T helper cell group are crucial 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.

[0006] 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 skin-infiltrating 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.

[0007] A highly effective and specific inhibitor of IL-23 is the antibody repaglinide. Relaxazumab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody targeting the p19 subunit of IL-23. Relaxazumab'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. Relaxazumab is particularly effective in treating autoimmune and inflammatory diseases, specifically psoriasis. Clinical studies have revealed excellent safety and efficacy of repaglinide in the treatment of plaque psoriasis. The approved recommended dose for the treatment of psoriasis is 150 mg, administered subcutaneously twice at weeks 0 and 4, and every 12 weeks thereafter.

[0008] The need for larger injection volumes presents challenges, especially in patients with chronic conditions whose medication adherence and persistence are significantly lower than those 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 formulation being administered. Most drugs administered subcutaneously, such as ressazumab, are typically used 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 adherence.

[0009] Therefore, to allow for the administration of high doses of antibodies such as ressazumab in a single injection, pharmaceutical formulations with increased antibody concentrations are required. However, increasing the antibody concentration in antibody formulations can cause stability issues, such as aggregation of high molecular weight species (HMWS) and increased viscosity. Therefore, providing stable, high-concentration liquid antibody formulations suitable for non-enteral administration, such as subcutaneous injection, is a significant challenge. Summary of the Invention

[0010] This invention provides a liquid antibody formulation comprising 150 mg / ml of an antibody as defined herein. The antibody is rexazumab or an antibody comprising the same heavy and light chain sequences as rexazumab. Such antibody formulations having such high antibody concentrations are not described or are not available in the art, and this invention makes a significant contribution to the art by providing such high-concentration antibody formulations. Despite 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 comprising 150 mg / ml of the antibody rexazumab provide advantageous stability characteristics and are well-suited for subcutaneous administration. They offer long-term stability. Advantageously, a 150 mg dose of antibody can be administered in a single 1 ml injection.

[0011] According to a first aspect of the invention, a liquid pharmaceutical preparation comprising 150 mg / ml anti-IL-23p19 antibody is 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.

[0012] According to the first aspect of this first aspect, the liquid pharmaceutical preparation contains

[0013] 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;

[0014] b) Polyols; and

[0015] c) Surfactants.

[0016] 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 aspect is stable.

[0017] According to the second aspect of this first aspect, a stable liquid pharmaceutical preparation comprising the following is provided:

[0018] 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;

[0019] b) Tension regulators; and

[0020] c) Surfactants,

[0021] The formulation has a pH of 5.5-5.9 and is isotonic.

[0022] This formulation may additionally contain d) a buffer.

[0023] The first and second aspects of the antibody preparation based on the first aspect of 150 mg / ml can also be provided in lyophilized form.

[0024] In related aspects, a sealed container containing the formulation of the present invention is provided.

[0025] In related aspects, the present 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.

[0026] 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 specific embodiments indicate preferred embodiments of this application, they are given by way of illustration only. Attached Figure Description

[0027] Figure 1 The light chain amino acid sequence of the antibody is shown (SEQ ID NO: 1).

[0028] Figure 2 The heavy chain amino acid sequence of the antibody is shown (SEQ ID NO: 2). Detailed Implementation

[0029] 150 mg / ml antibody preparations and related aspects

[0030] According to the first aspect, a liquid pharmaceutical preparation comprising 150 mg / ml anti-IL-23p19 antibody is 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.

[0031] According to the first aspect of this first aspect, a liquid pharmaceutical preparation comprising the following is provided:

[0032] 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;

[0033] b) Polyols; and

[0034] c) Surfactants.

[0035] The formulation according to this first aspect 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 aspect is stable.

[0036] According to the second aspect of this first aspect, a stable liquid pharmaceutical preparation comprising the following is provided:

[0037] 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;

[0038] b) Tension regulators; and

[0039] c) Surfactants,

[0040] The formulation has a pH of 5.5-5.9 and is isotonic.

[0041] The stabilizing agent according to this second aspect may additionally contain d) a buffer.

[0042] The formulation of the present invention contains a high antibody concentration of 150 mg / ml. Despite the high antibody concentration, the liquid pharmaceutical formulation of the present invention is stable and advantageously provides long-term stability. Furthermore, the formulation of the present invention addresses the core administration challenges of high-concentration antibody formulations suitable for injection by providing, in particular, suitable viscosity and good injectability, thus making the formulation of the present invention particularly suitable for injections such as subcutaneous injections. These advantageous properties of the formulation are demonstrated in the examples. The formulation according to the first aspect 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.

[0043] As disclosed herein, the formulation according to the first aspect may be provided in the form of a buffer-free formulation or a buffer-containing formulation. According to one core embodiment, the liquid pharmaceutical formulation according to the first aspect includes d) a buffer. In another embodiment, the liquid pharmaceutical formulation does not contain a buffer as an additive.

[0044] Subsequently, the components of the 150 mg / ml antibody formulation according to the first aspect are described in further detail. In particular, suitable embodiments and features of components a), b), c), and optionally d) contained in the formulation according to the first and second aspects are disclosed.

[0045] a) Antibodies

[0046] 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... Figure 1 and Figure 2The 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, an antibody has the same light and heavy chains as the antibody risankizumab (see INN risankizumab, WHODrug Information, Vol. 29, No. 2, 2015), and such an 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. Recombinant risankizumab can be produced in various host cells, and the suitability for cells that produce recombinant antibodies is known in the art.

[0047] In one embodiment, the antibody is recombinantly produced in mammalian cells. Suitable mammalian cells are 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.

[0048] Component b)

[0049] The formulation of the first aspect of the 150 mg / ml formulation according to the first aspect comprises a polyol as component b). Suitable polyols that can be used as excipients in pharmaceutical formulations are known in the art and described herein.

[0050] The formulation of the second aspect of the 150 mg / ml formulation according to the first aspect comprises a tonic modifier as component b). A tonic modifier is a reagent suitable for adjusting the tension of a formulation. Tonic modifiers that can be used to adjust the tension of a pharmaceutical formulation are compounds known in the art and include compounds such as salts and, in addition, polyols such as sugars and sugar alcohols. Therefore, the tonic modifier used as component b) in the 150 mg / ml stable formulation according to the second aspect can be a polyol, as is generally the case for component b) in the 150 mg / ml formulation according to the first aspect. According to one embodiment, therefore, the tonic modifier included in the stable liquid formulation according to the second aspect is a polyol, optionally a sugar and / or sugar alcohol.

[0051] 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. Polyols may contain at least three, four, or 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 and capable of reducing metal ions or covalently reacting 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. The use of trehalose is particularly useful as disclosed herein. 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 tonics in formulations.

[0052] 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 prepared formulation.

[0053] 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 the 150 mg / ml formulation 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).

[0054] In a particular embodiment, 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 a particular embodiment, 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.

[0055] 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 comprises mannitol as a polyol. In another embodiment, the formulation comprises sorbitol. As disclosed herein, mannitol and sorbitol may be used as a single polyol or may be used in combination with each other or in combination with different polyols such as sugars or other sugar alcohols.

[0056] Sorbitol can be used to provide the stable formulation of the present invention. In some embodiments, a sorbitol-free formulation is provided. A sorbitol-free formulation is 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.

[0057] As demonstrated in the examples, mannitol and / or trehalose can be used as polyols in the formulations of the present invention to adjust the desired permeation molality. 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 preparation steps. Therefore, in embodiments, 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.

[0058] Polyols can be used to adjust the osmotic molality. In embodiments, the osmotic molality 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 embodiments, the osmotic molality 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 a substantially the same osmotic pressure as human blood. The osmotic molality can be measured, for example, using a vapor pressure or a cryo-osmometer.

[0059] The concentration of polyol in the formulation may be at least 80 mM or at least 95 mM. In embodiments, the concentration of polyol 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 embodiments, the concentration of polyol in the formulation is ≤ 500 mM, ≤ 450 mM, or ≤ 400 mM. As disclosed herein, two or more polyols may also be used as excipient b). As disclosed herein, in one 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 aspect. As disclosed herein, the tension modifier may be a polyol.

[0060] According to the first aspect, specifically the first and second aspects, the concentration of the polyol in the formulation may 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 the polyol in the formulation include, but are not limited to, 125 mM to 250 mM and 125 mM to 225 mM. In one embodiment, the concentration of the polyol in the formulation is in the range of 125 mM to 225 mM. In one embodiment, the concentration of the polyol 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.

[0061] 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, a liquid pharmaceutical preparation comprising 150 mg / ml antibody and 185 mM of trehalose as a polyol is also disclosed herein. Trehalose may be added, for example, in the form of trehalose dihydrate.

[0062] c) Surfactants

[0063] The liquid formulation according to the first aspect further comprises 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 aspects of the 150 mg / ml formulation according to the first aspect contain a surfactant as component c).

[0064] 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 one 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.

[0065] 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 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 embodiments, the surfactant concentration in the formulation is ≤ 1 mg / ml, optionally ≤ 0.75 mg / ml or ≤ 0.5 mg / ml. In 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 a core embodiment, the surfactant is a polysorbate, optionally selected from polysorbate 20 and / or polysorbate 80. In an embodiment, the surfactant is polysorbate 20. Polysorbate 20 can be advantageously used at concentrations as shown in the examples and as disclosed herein.

[0066] The surfactant concentration 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 embodiments, 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 a core embodiment, the surfactant is a polysorbate, optionally selected from polysorbate 20 and / or polysorbate 80. In embodiments, the surfactant is polysorbate 20, which can be advantageously used in the concentration ranges shown in the examples.

[0067] In a particular 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.

[0068] pH

[0069] In the core implementation, the pH of the liquid pharmaceutical formulation, which is an aqueous preparation, can be in the range of pH 5.0 to 7.5, such as pH 5.0 to 7.0.

[0070] 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 an embodiment, the pH of the liquid pharmaceutical preparation is ≤ 6.1, such as ≤ 6.0 or ≤ 5.9. In an embodiment, 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 illustrative pH ranges for liquid pharmaceutical preparations 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 illustrative pH ranges for liquid pharmaceutical preparations 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 illustrative pH ranges for liquid pharmaceutical preparations 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. Exemplary 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 another embodiment, the pH of the formulation is in the range of 5.6 to 6.0 or 5.6 to 5.9.

[0071] 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.

[0072] According to one embodiment, the pH of the liquid pharmaceutical preparation is in the range of 5.5 to 6.5. In another embodiment, the pH of the liquid pharmaceutical preparation is in the range of 5.5 to 6.2.

[0073] According to one embodiment, the pH is 5.5 to 5.9. In another embodiment, the pH is 5.6 to 5.8. A 150 mg / ml formulation of rexazumab with this pH was tested in the examples and showed advantageous characteristics.

[0074] In another embodiment, the pH of the liquid pharmaceutical preparation is 5.7.

[0075] In another embodiment, the pH of the liquid pharmaceutical preparation is 6.2.

[0076] As disclosed herein, the pH of the stable liquid pharmaceutical formulation according to the second aspect is 5.5 to 5.9. It may be in the range of 5.5 to 5.8. In the embodiments, the pH of the 150 mg / ml stable formulation according to the second aspect is 5.7.

[0077] d) Buffer

[0078] The 150 mg / ml antibody formulation according to the first aspect 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 the formulations of the first and second aspects of the 150 mg / ml Torracilumab formulation according to the first aspect.

[0079] Buffers can be used to maintain the solution pH of liquid pharmaceutical formulations. Buffers suitable 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.

[0080] The formulation may contain a carboxylic acid buffer as buffer d).

[0081] According to one embodiment, the buffer is selected from acetate buffers and succinate buffers. As shown in the examples, formulations containing said buffers provide advantageous stability characteristics for the high-concentration antibody formulations provided herein. In another embodiment, the buffer is a histidine buffer.

[0082] 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.

[0083] Other buffers that can be used include, but are not limited to, citrate, glutamate, glycine, lactate, maleate, phosphate, or tartrate buffers.

[0084] The presence of a buffer salt supports the stability of the contained antibody, which, according to the present invention, is rexazumab.

[0085] 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.

[0086] The buffer is included in an amount sufficient to maintain the selected pH of the formulation under storage conditions for the product's shelf life.

[0087] 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. Exemplary concentration ranges of the included buffers include, but are 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. Further 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 concentrations described.

[0088] In one embodiment, the buffer concentration is 20 mM or less, or 15 mM or less. 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.

[0089] In some embodiments, the formulation comprises a single buffer. In a particular embodiment, the single buffer is an acetate buffer.

[0090] Specific embodiments of a buffer-containing formulation containing 150 mg / ml antibody

[0091] According to one implementation scheme, the liquid pharmaceutical preparation contains

[0092] a) 150 mg / ml of this antibody;

[0093] b) Sugar;

[0094] c) Nonionic surfactants; and

[0095] d) Buffer;

[0096] The pH of any of the formulations 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.

[0097] Suitable concentrations and embodiments of excipients b) to d) 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.

[0098] According to one implementation scheme, the liquid pharmaceutical preparation contains

[0099] a) 150 mg / ml of this antibody;

[0100] b) Trehalose;

[0101] c) Polysorbate; and

[0102] d) Buffer;

[0103] The pH of any of the formulations 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.

[0104] Suitable concentrations and implementation methods of excipients b) to d) 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.

[0105] The buffers contained in these liquid pharmaceutical formulations may be acetate or succinate, optionally with a concentration in the range of 5 mM to 25 mM. The polysorbate may be polysorbate 20.

[0106] According to one implementation scheme, the liquid pharmaceutical preparation contains

[0107] a) 150 mg / ml of this antibody;

[0108] b) 170 mM to 200 mM trehalose;

[0109] c) 0.1 mg / ml to 0.3 mg / ml polysorbate, optionally polysorbate 20; and

[0110] d) Buffer, optionally an acetate buffer.

[0111] 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.

[0112] According to one implementation scheme, the liquid pharmaceutical preparation contains

[0113] a) 150 mg / ml of this antibody;

[0114] b) 185 mM trehalose;

[0115] c) 0.2 mg / ml polysorbate 20; and

[0116] d) 10 mM acetate buffer;

[0117] The pH value is 5.7.

[0118] This liquid formulation may be an aqueous formulation and, in one embodiment, does not contain any other additives.

[0119] Specific implementation plan of a buffer-free formulation containing 150 mg / ml antibody

[0120] As disclosed herein, buffer-free liquid pharmaceutical formulations, specifically aqueous formulations, are also provided. According to one embodiment, the liquid pharmaceutical formulation comprises...

[0121] a) 150 mg / ml of this antibody;

[0122] b) A polyol, wherein the polyol is optionally a sugar or a sugar alcohol; and

[0123] c) Nonionic surfactant, optionally polysorbate;

[0124] d) Does not contain buffer.

[0125] As noted above, the present invention also provides buffer-free formulations without the addition of buffers as excipients. Antibodies having the light and heavy chain sequences shown in SEQ ID NO: 1 and SEQ ID NO: 2 at a concentration of 150 mg / ml have high buffering capacity. As also shown in the examples, buffer-free formulations with storage stability can be provided based on the disclosure provided herein.

[0126] In this embodiment, the buffer-free formulation has a pH range of 5.2 to 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.

[0127] In one embodiment, the buffer-free formulation comprises 80 mM to 250 mM of a polyol. Suitable polyols, such as sugars and sugar alcohols, are disclosed in detail above and with reference to the present invention. In one embodiment, the sugar is trehalose.

[0128] 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 a polysorbate. It may be selected from polysorbate 20 and polysorbate 80, and in one embodiment, polysorbate 20.

[0129] Other optional components

[0130] 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.

[0131] In one embodiment, the formulation comprises an amino acid having a charged side chain, optionally having a positively charged side chain. An example of such amino acid is L-arginine.

[0132] According to one embodiment, the formulation comprises an amino acid, wherein the amino acid is present in the formulation as a salt, optionally as a hydrochloric acid (HCl) salt.

[0133] According to one embodiment, the formulation comprises methionine. According to one embodiment, the formulation comprises the amino acid L-proline.

[0134] 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 of antibody but not arginine.

[0135] 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.

[0136] Other excipients known in the art may be used in formulations, as long as they do not adversely affect stability.

[0137] However, in some embodiments, the formulations of the present invention do not contain additional excipients. Particularly advantageously, the storage-stable formulation of the antibody rexazumab may comprise essentially the following: a) the antibody (150 mg / ml); b) a component; c) a surfactant; and optionally d) a buffer. As disclosed herein, advantageously, the formulation may comprise only a single polyol, a single surfactant, and (if present) a single buffer. Thus, a non-compound, yet still storage-stable, formulation for the 150 mg / ml antibody rexazumab is provided.

[0138] Stability characteristics

[0139] As disclosed herein, it is advantageous to provide a stable liquid pharmaceutical formulation containing 150 mg / ml of antibody. Providing this stable, high-concentration antibody formulation of rexazumab is particularly advantageous for therapeutic use.

[0140] In the embodiments, 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 the art and disclosed herein. Stability can be measured at a selected temperature over a selected time period.

[0141] The stability characteristics of different liquid pharmaceutical formulations of the present invention containing 150 mg / ml antibody were tested in the examples and showed favorable stability characteristics.

[0142] 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.

[0143] 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 the pharmaceutical formulation. Protein conformational changes can be assessed by fluorescence spectroscopy to determine the tertiary structure of the protein and by FTIR spectroscopy to determine the secondary structure of the protein.

[0144] If the antibody's biological activity at a given time is within a predetermined range of the biological activity exhibited when the drug formulation is prepared, then the antibody specifically retains its biological activity in the drug formulation. The biological activity of an antibody can be determined, for example, by an antigen-binding assay.

[0145] 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. Aggregation 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 said formulations is demonstrated by the reduced amount of HMWS and / or the reduced rate of HMWS formation over varying 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 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.

[0146] 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.

[0147] In some embodiments, the antibodies in the formulations disclosed herein remain substantially in monomeric form during storage. In certain embodiments, the formulations may satisfy one or more of the following stability characteristics:

[0148] In some embodiments, after storage at 5°C for 36 months, as measured by UP-SEC, at least 94% of the antibody remains in monomeric form, 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, as measured by UP-SEC, at least 95% or at least 96% of the antibody remains in monomeric form, 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, as measured by UP-SEC, at least 94% of the antibody remains in monomeric form, 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, as measured by UP-SEC, at least 95% or at least 96% of the antibody remains in monomeric form, 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, as measured by UP-SEC, at least 96% or at least 96.5% of the antibody remains in monomeric form, 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, as measured by UP-SEC, at least 96% or at least 97% of the antibody remains in monomeric form, 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, as measured by UP-SEC, at least 90% or at least 92% of the antibody remains in monomeric form, 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, as measured by UP-SEC, at least 95% of the antibody remains in monomeric form, 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 for 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.

[0149] In some embodiments, the antibodies in the formulations disclosed herein do not form significant amounts of high molecular weight vapor sinks (HMWS) during storage. In particular, the formulations meet one or more of the following stability characteristics:

[0150] 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, less than 4%, 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%, more than 0.8%, or more than 0.6%. In some embodiments, after storage at 25°C for 12 months, less than 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 3%, more than 2.5%, or more than 2%. In some embodiments, after storage at 25°C for 3 months, less than 4%, less than 3.5%, or less than 3.2% 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% or more than 1.5%. In some embodiments, after storage at 25°C for 1 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 3 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 1 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 for the indicated storage time and temperature and is determined specifically by comparing the relative HMWS content at the beginning and end of the indicated storage.In certain implementations, measurements are performed as described in the examples.

[0151] In another embodiment, the antibody in the formulation disclosed herein does not form a large amount of LMWS during storage. In a particular embodiment, the formulation may satisfy one or more of the following stability characteristics:

[0152] 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, less than 2%, less than 1.5%, or less than 1% 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 0.5%, or more than 0.25%. In some embodiments, after storage at 25°C for 12 months, less than 6%, less than 5%, or less than 4.5% 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 5%, more than 4%, or more than 3%. In some embodiments, after storage at 25°C for 3 months, less than 3%, less than 2%, or less than 1.8% 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 2%, more than 1.5%, or more than 1%. In some embodiments, after storage at 25°C for 1 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 3 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 1 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 for 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 certain implementations, measurements are performed as described in the examples.

[0153] In some implementations, particularly 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 comprising a size exclusion chromatography (SEC) column is used in the Acquity UPLC system from Waters (Milford, MA, USA). Protein elution 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 elution peak. Peaks can be assigned to different species based on the elution time corresponding to different species 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, as is done in their presence in the formulation. In particular, the relative content or amount is indicated as a percentage value, and the sum of the monomeric, HMWS, and LMWS antibodies is 100%.

[0154] In some embodiments, the turbidity or milky whiteness of the formulations disclosed herein does not increase significantly during storage. In certain embodiments, the formulations may satisfy one or more of the following stability characteristics:

[0155] In some embodiments, after storage at 5°C for at least 36 months, the formulation exhibits a milky luster of 12 FNU (Formazin Nephelometry Unit) 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 storage at 5°C for at least 3, 6, 9, 12, 18, or 24 months, the formulation exhibits a milky luster of 12 FNU (Formazin Nephelometry Unit) 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 storage at 25°C for at least 1, 3, 6, 9, or 12 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 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 for 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.

[0156] In some embodiments, the milky light or turbidity is measured according to a pharmacopoeia or industry standard ISO 7027. In some embodiments, particularly as described in the examples, the milky light or turbidity of the formulation is determined using a turbidimeter such as the HACH Lange milky light meter from Hach-Lange GmbH (Germany). 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 FNA values ​​indicate higher milky light and turbidity.

[0157] In some embodiments, the antibodies in the formulations disclosed herein do not form additional large amounts of acidic or basic variants during storage. In certain embodiments, the formulations may satisfy one or more of the following stability characteristics:

[0158] 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, 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%. In some embodiments, 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%. In some embodiments, after storage at 5°C for 24 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%.In some embodiments, after storage at 5°C for 6 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%. In some embodiments, after storage at 5°C for 3 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 3%, more than 2%, or more than 1%. In some embodiments, after storage 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%. In some embodiments, after storage at 25°C for 3 months, less than 40%, less than 35%, or less than 30% 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 10%, more than 8%, or more than 6%. In some embodiments, after storage at 25°C for 1 month, less than 35%, 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% or more than 3%. In some embodiments, after storage 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 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, 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 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, less than 15% or less than 10% of the antibody is present as a basic peak group variant, as determined by ion exchange chromatography (IEC), and / or the relative basic 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, less than 15% or less than 10% of the antibody is present as a basic peak group variant, as determined by ion exchange chromatography (IEC), and / or the relative basic peak group variant content of the antibody does not increase by more than 3% or more than 2%.In some embodiments, after 12 months of storage at 25°C, less than 30%, less than 25%, or less than 22% of the antibody is present as a basic peak group variant, as determined by ion exchange chromatography (IEC), and / or the relative basic peak group variant content of the antibody does not increase by more than 25%, more than 20%, or more than 15%. In some embodiments, after 3 months of storage at 25°C, less than 20%, less than 15%, or less than 12% of the antibody is present as a basic peak group variant, as determined by ion exchange chromatography (IEC), 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 1 month of storage at 25°C, less than 15%, less than 10%, or less than 9% of the antibody is present as a basic peak group variant, as determined by ion exchange chromatography (IEC), 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 the relative content of the main peak variant and the increase in the relative content of the acidic and basic peak group variants are calculated for the indicated storage time and temperature, and are specifically determined by comparing the relative content of each individual peak variant at the beginning and end of the indicated storage. In a particular embodiment, the measurement is performed as described in the examples.

[0159] In some implementations, particularly as described in the examples, the relative amounts of antibodies for the main 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 is used with an Alliance HPLC system such as those from Waters (Milford, MA, USA). Protein elution by 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 elution peak or group of elution peaks. Peaks can be assigned to different species based on the antibody species elution conditions corresponding to the surface charge of the antibody species. The main peak is the largest peak in the IEC chromatogram of the undegraded antibody. For stability analysis, measurements can be performed after formulation preparation (TO) and subsequently after the indicated storage time under indicated storage conditions. The acidic peak group (APG) includes all peaks preceding the main peak. These peaks include variants of the native antibody peak that are more acidic than the main peak 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 peak that are more acidic than the main peak 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 variants, and / or basic peak group variants of the antibody in the formulation, the main peak is specifically separated from the acidic and basic peak groups, as is the case when they are present in the formulation. In particular, the relative content or amount is indicated as a percentage value and the sum of the main peak variant, acidic peak group variants, and basic peak group variants is 100%.

[0160] In some embodiments, the antibodies in the formulations disclosed herein substantially maintain their specific binding activity to human IL-23 during storage. In certain embodiments, the formulations satisfy one or more of the following stability characteristics:

[0161] 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 measurements are performed as described in the examples.

[0162] In some implementations, particularly as described in the examples, the specific binding activity of the antibody in the formulation to human IL-23 is measured using surface plasmon resonance, for example using a Biacore instrument such as the GE Healthcare Life Science (United Kingdom) Biacore T200.

[0163] According to the other characteristics of the liquid pharmaceutical preparation in the first aspect

[0164] In an advantageous embodiment, the liquid pharmaceutical formulation of the present invention is an aqueous formulation. In one embodiment, all liquid formulations disclosed herein are aqueous formulations. Unless otherwise indicated by specific circumstances, the following description applies to the 150 mg / ml formulation according to the first aspect, and therefore also to the formulations according to the first and second aspects as disclosed herein.

[0165] According to one embodiment, the measured dynamic viscosity of the liquid pharmaceutical formulation according to the first aspect 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 that makes the formulation suitable for subcutaneous administration. The dynamic viscosity can be determined as described in the examples.

[0166] 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 another embodiment, the conductivity range is 1 to 2 mS / cm or 1.2 to 1.8 mS / cm. In yet another 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.

[0167] The liquid formulation of the present invention is a pharmaceutical formulation. A pharmaceutical formulation specifically refers to a composition in which the permitted active ingredient (here, an antibody comprising a light chain as shown in SEQ ID NO: 1 and a heavy chain as shown in SEQ ID NO: 2) is effective and does not contain any additional components that are toxic to the individual to which the formulation is administered.

[0168] The formulations disclosed herein according to the first aspect 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 via various conventional methods, such as intraperitoneal, non-enteral, intra-arterial, or intravenous injection. In one embodiment, the disclosed formulation is an injectable formulation. In an embodiment, the formulations disclosed herein are suitable for subcutaneous, intravenous, or intramuscular administration. Advantageously, the disclosed formulations are suitable for subcutaneous injection. The 150 mg / ml formulation disclosed herein is particularly advantageous because it achieves the overall characteristics that make 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. Additionally, as disclosed in the examples, they have advantageous viscosity and osmotic molality characteristics and achieve good slip forces (maximum and average values), as well as during storage. In an embodiment, the liquid pharmaceutical formulations of the present invention are isotonic to the desired site of application. For example, if the formulation is intended for non-enteral administration, it can be isotropic to blood (approximately 300 mOsm / kg osmolar concentration). Suitable osmolar concentration ranges are described elsewhere.

[0169] Liquid antibody formulations can be manufactured by taking a drug substance in liquid form (e.g., in an aqueous pharmaceutical preparation) as the final step in a purification process, replacing its buffer, and preparing a desired buffer. The drug substance in the final buffer can be concentrated to the desired concentration or diluted to achieve a more concentrated form of antibody to reach a concentration of 150 mg / ml. Formulation concentration can be performed by any suitable method. In one aspect, the concentration process may include ultrafiltration.

[0170] In one core embodiment, the liquid pharmaceutical formulation according to the first aspect 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 generally sterile. In some embodiments, this may be achieved by filtration through a sterile filter membrane. Thus, the finally prepared 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 so that no lyophilization or reconstitution step is required. The liquid pharmaceutical formulation disclosed herein and also manufactured and analyzed in the examples.

[0171] Lyophilized and reconstituted pharmaceutical preparations

[0172] According to one embodiment, the liquid pharmaceutical formulation of the first aspect 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 liquid formulations of the 150 mg / ml antibody formulation of the first and second aspects.

[0173] The term "lyophilization" or "lyophilized" specifically refers to a process in which the material to be dried is first frozen and then sublimated in a vacuum environment to remove ice or freezing solvent. This technique is well known in the art and 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, such as sucrose and trehalose. The disclosed liquid pharmaceutical formulation according to the first aspect comprises excipients qualified as cryoprotectants and / or lyophilization protectants. Therefore, a lyophilized formulation can be prepared from said formulation. In one embodiment, the antibody rexazumab is formulated as a lyophilized powder for intravenous administration for reconstitution and utilization.

[0174] "Reconstituted" formulations are preparations made by dissolving lyophilized drug antibody formulations in a diluent to disperse the antibodies in the reconstituted formulation. Reconstituted formulations are suitable for oral administration and may optionally be used for subcutaneous administration.

[0175] The lyophilized drug formulation is expected to be prepared at the required concentration, in this case 150 mg / ml, of antibody before reconstitution.

[0176] According to one embodiment, a lyophilized formulation of an anti-IL-23p19 antibody is 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. According to one embodiment, the lyophilized formulation of the antibody rexazumab is defined in relation to a solution used for manufacturing the lyophilized formulation, for example, a solution prior to lyophilization. This lyophilized formulation is manufactured by lyophilizing a 150 mg / ml liquid antibody formulation according to the first aspect, such as a liquid pharmaceutical formulation according to the first aspect as defined in any one of embodiments 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.

[0177] In other embodiments, a lyophilized formulation of the antibody resorcinol is defined as a 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 for reconstitution of a 150 mg / ml liquid antibody formulation according to the first aspect, detailed in its first and second aspects. According to an embodiment, the lyophilized formulation is provided for reconstitution of a liquid pharmaceutical formulation as defined in any one of embodiments 1 to 86 or 104 to 119 below. This resorcinol preparation may be an aqueous formulation.

[0178] Lyophilized formulations containing the following are also available:

[0179] 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;

[0180] b) Polyols;

[0181] c) Surfactants; and

[0182] d) Optional buffer.

[0183] In one embodiment, the lyophilized pharmaceutical preparation contains 150 mg of antibody. The antibody is ressazumab.

[0184] Lyophilized formulations containing the following are also available:

[0185] 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;

[0186] b) Tension regulator;

[0187] c) Surfactants; and

[0188] d) Optional buffer.

[0189] In one embodiment, the lyophilized pharmaceutical preparation contains 150 mg of antibody. The antibody is ressazumab.

[0190] The components, such as suitable polyols, used in pharmaceutical formulations have been disclosed above in combination with liquid pharmaceutical formulations, and the above disclosures mentioned herein also apply. Suitable polyols include sugars and sugar alcohols, which may also be used in combination. The polyol may have one or more of the characteristics defined in any of the following embodiments 6 to 13 of the liquid pharmaceutical formulation according to the first aspect. In one embodiment, the polyol is a sugar, optionally selected from trehalose and sucrose. In one embodiment, the sugar is trehalose.

[0191] Suitable surfactants have been disclosed in conjunction with liquid pharmaceutical formulations above and are referred to herein as the disclosure also applies. The surfactant may have one or more of the characteristics defined in any of the following embodiments 22 to 25 of the liquid pharmaceutical formulation according to the first aspect. In one embodiment, the surfactant is a polysorbate, optionally selected from polysorbate 20 and polysorbate 80. In one embodiment, the polysorbate is polysorbate 20.

[0192] In one embodiment, the lyophilized formulation comprises a buffer. Suitable buffers for preparing lyophilized formulations are known in the art, and suitable buffers are also disclosed above in conjunction with liquid pharmaceutical formulations according to the first aspect and are referred to as the above disclosure.

[0193] 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 aspect. 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 the following embodiments 31 to 36 of 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 aspect. Upon reconstitution, the pH may be 5.5 to 5.9, for example, 5.6 to 5.8.

[0194] The lyophilized rexazumab formulation of the present invention is reconstituted before administration. In some cases, it may be necessary to lyophilize the rexazumab formulation in a container where antibody reconstitution is performed to avoid a transfer step.

[0195] Containers and uses

[0196] According to another aspect of the invention, a sealed container is provided containing a liquid pharmaceutical preparation or a lyophilized pharmaceutical preparation according to the 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, optionally 1.5 ml or less, or 1 ml or less of the liquid pharmaceutical preparation. The container may contain a liquid pharmaceutical preparation of the first or second aspect, which is advantageously stable according to the first aspect of the 150 mg / ml antibody preparation.

[0197] In the core implementation, a container, such as a syringe, contains a single 150 mg dose of the antibody. As disclosed herein, the antibody is rexazumab.

[0198] 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.

[0199] According to one embodiment, the average sliding force of the pre-filled syringe equipped with a needle is 20 N or less. In another embodiment, the average sliding force is in the range of 5 to 20 N or 5 to 15 N. In yet another embodiment, the break loose force of the pre-filled syringe is 3 to 12 N, preferably 3 to 9 N.

[0200] In some embodiments, the syringe equipped with a needle and containing a liquid pharmaceutical formulation according to the first aspect substantially maintains the maximum and / or average slip force required to eject the formulation from the syringe during storage. In some embodiments, after storage at 5°C for 36 months, the maximum slip force of the syringe pre-filled with the liquid formulation 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 the syringe pre-filled with the liquid formulation 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.

[0201] 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 aspect 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 aspect 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.

[0202] 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 certain embodiments, the measurement is performed as described in the examples.

[0203] 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, particularly 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 a speed of approximately 300 to 500 mm / min, such as approximately 380 mm / min, specifically 379.2 mm / min, for example, for 5 seconds.

[0204] Another aspect of the invention relates to a liquid pharmaceutical preparation or a lyophilized pharmaceutical preparation 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 an anti-IL-23p19 antibody and is known in the art. Diseases can be selected from the group consisting of inflammatory diseases, autoimmune diseases, respiratory diseases, metabolic disorders, and cancer. In an embodiment, 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 the liquid pharmaceutical preparation of the invention at 150 mg / ml to the patient for treatment.

[0205] Alternative formulation of the 150 mg / ml preparation

[0206] Further specific embodiments of the 150 mg / ml antibody formulation according to the first aspect are disclosed below:

[0207] 1. A liquid pharmaceutical preparation comprising...

[0208] 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;

[0209] b) Polyols; and

[0210] c) Surfactants.

[0211] 2. The formulation as described in embodiment 1, comprising...

[0212] d) Buffer.

[0213] 3. The formulation of embodiment 1 or 2, wherein the antibody is rexazumab.

[0214] 4. A formulation according to any one of embodiments 1 to 3, wherein the antibody has been produced in a recombinant manner in mammalian cells.

[0215] 5. The formulation of embodiment 4, wherein the antibody has been generated in CHO cells in a recombinant manner.

[0216] 6. A formulation of one or more of the embodiments 1 to 5, wherein the polyol is selected from sugars, sugar alcohols and combinations thereof.

[0217] 7. The formulation of embodiment 6, wherein the polyol is selected from trehalose, sucrose, sorbitol, mannitol and combinations thereof.

[0218] 8. The formulation of embodiment 6, wherein the polyol is a sugar, which is optionally selected from trehalose and sucrose.

[0219] 9. The formulation of embodiment 6, wherein trehalose is a polyol.

[0220] 10. The formulation of embodiment 6, wherein the polyol is selected from sorbitol and mannitol.

[0221] 11. The formulation of embodiment 6, wherein mannitol is a polyol.

[0222] 12. A formulation as described in any of embodiments 1 to 11, wherein the liquid pharmaceutical formulation does not contain sorbitol.

[0223] 13. A formulation of one or more of the embodiments 1 to 9, wherein the formulation does not contain sugar alcohols.

[0224] 14. A formulation according to one or more of embodiments 1 to 13, having one or more of the following characteristics:

[0225] (i) The concentration of the polyol in the formulation is at least 95 mM;

[0226] (ii) The concentration of the polyol in the formulation is at least 125 mM;

[0227] (iii) The concentration of the polyol in the formulation is at least 150 mM;

[0228] (iv) The concentration of the polyol in the formulation is ≤ 500 mM, ≤ 450 mM or ≤ 400 mM;

[0229] (v) The concentration of the polyol in the formulation is ≤ 350 mM, ≤ 300 mM, or ≤ 275 mM; and / or

[0230] (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;

[0231] The polyol may be selected as a sugar and / or a sugar alcohol.

[0232] 15. A formulation of one or more of embodiments 1 to 13, wherein the concentration of the polyol in the formulation is in the range of 95 mM to 250 mM, wherein the polyol is optionally a sugar.

[0233] 16. A formulation of one or more of embodiments 1 to 13, wherein the concentration of the polyol in the formulation is in the range of 125 mM to 225 mM, wherein the polyol is optionally a sugar such as trehalose.

[0234] 17. A formulation as described in one or more of embodiments 1 to 13, wherein the concentration of the polyol is in the range of 145 mM to 225 mM, wherein the polyol is optionally a sugar such as trehalose.

[0235] 18. A formulation of one or more of embodiments 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, optionally wherein the sugar is trehalose.

[0236] 19. A formulation of one or more of embodiments 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, optionally wherein the sugar is trehalose.

[0237] 20. A formulation of one or more of embodiments 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, optionally wherein the sugar is trehalose.

[0238] 21. A formulation of one or more of the embodiments 1 to 13, comprising 185 mM of trehalose as a polyol.

[0239] 22. A formulation as described in one or more of embodiments 1 to 21, wherein the surfactant is a nonionic surfactant.

[0240] 23. The formulation of embodiment 22, wherein the surfactant is polysorbate.

[0241] 24. The formulation of embodiment 22 or 23, wherein the nonionic surfactant is selected from polysorbate 20 and / or polysorbate 80.

[0242] 25. A formulation of one or more of embodiments 1 to 24, wherein the surfactant is polysorbate 20.

[0243] 26. A formulation of one or more of embodiments 1 to 25, specifically any one of embodiments 23 to 25, wherein the concentration of the surfactant in the formulation is at least 0.05 mg / ml, optionally at least 0.075 mg / ml.

[0244] 27. A formulation of one or more of embodiments 1 or 26, specifically any one of embodiments 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.

[0245] 28. A formulation of any one of embodiments 1 or 27, specifically embodiments 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.

[0246] 29. The formulation of embodiment 25, wherein the formulation comprises 0.2 mg / ml of polysorbate 20 as a surfactant.

[0247] 30. The formulation of embodiment 29, wherein the polyol is a sugar and wherein the concentration of the sugar is in the range of 145 mM to 225 mM, optionally wherein the sugar is trehalose.

[0248] 31. A formulation of one or more of embodiments 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.

[0249] 32. A formulation of one or more of the embodiments 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.

[0250] 33. A formulation of one or more of the embodiments 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.

[0251] 34. A formulation of one or more of the embodiments 1 to 30, wherein the pH of the liquid pharmaceutical formulation is in the range of 5.5 to 5.9.

[0252] 35. A formulation of one or more of the embodiments 1 to 30, wherein the pH of the liquid pharmaceutical formulation is in the range of 5.6 to 5.8.

[0253] 36. A formulation of one or more of embodiments 1 to 30, wherein the pH of the liquid pharmaceutical formulation is 5.7 or 6.2.

[0254] 37. A formulation of one or more of embodiments 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, optionally wherein 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.

[0255] 38. A formulation of one or more of embodiments 2 to 37, wherein the buffer is an organic buffer, optionally selected from acetate buffers and succinate buffers.

[0256] 39. The formulation of embodiment 38, wherein the buffer is an acetate buffer, optionally wherein the acetate buffer comprises sodium acetate and acetic acid.

[0257] 40. A formulation of one or more of embodiments 2 to 37, wherein the buffer is a histidine buffer, or wherein the formulation satisfies at least one of the following characteristics:

[0258] (i) It contains a carboxylic acid buffer; (ii) It does not contain a succinate buffer.

[0259] 41. A formulation of one or more of embodiments 2 to 40, comprising at least 1 mM, at least 2 mM or at least 3 mM buffer, optionally comprising at least 4 mM, at least 4.5 mM or at least 5 mM buffer.

[0260] 42. A formulation as described in one or more of embodiments 2 to 41, wherein the concentration of the buffer is 100 mM or less, 75 mM or less, or 50 mM or less.

[0261] 43. A formulation of one or more of the embodiments 2 to 41, wherein the concentration of the buffer is 20 mM or less or 15 mM or less.

[0262] 44. A formulation as described in one or more of embodiments 2 to 41, wherein the concentration of the buffer is in the range of 4 mM to 50 mM.

[0263] 45. A formulation of one or more of the embodiments 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.

[0264] 46. ​​A formulation of one or more of the embodiments 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.

[0265] 47. A formulation of one or more of the embodiments 2 to 41, wherein the concentration of the buffer is 10 mM.

[0266] 48. A formulation of one or more of embodiments 2 to 47, wherein the formulation comprises a single buffer, optionally an acetate buffer.

[0267] 49. A formulation of any one of technical solutions 1 or 3 to 36, wherein the formulation does not contain a buffer.

[0268] 50. A formulation of one or more of the embodiments 1 to 49, wherein the formulation is an aqueous formulation.

[0269] 51. A formulation comprising any one of embodiments 2 to 48 or 50, wherein...

[0270] a) 150 mg / ml of this antibody;

[0271] b) Sugar, wherein the concentration of the sugar is optionally in the range of 95 mM to 250 mM or 145 mM to 225 mM;

[0272] c) A nonionic surfactant, optionally 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; and

[0273] d) Buffer.

[0274] 52. A formulation comprising any one of embodiments 2 to 48 or 50 to 51, wherein...

[0275] a) 150 mg / ml of this antibody;

[0276] b) Trehalose, wherein the concentration of trehalose is optionally in the range of 95 mM to 250 mM or 145 mM to 225 mM;

[0277] c) Polysorbate, optionally in a concentration ranging from 0.05 mg / ml to 0.5 mg / ml or from 0.075 mg / ml to 0.3 mg / ml; and

[0278] d) Buffer.

[0279] 53. The formulation of embodiment 51 or 52, wherein the buffer is an acetate buffer or a succinate buffer, optionally wherein the concentration of the buffer is in the range of 5 mM to 25 mM.

[0280] 54. The formulation of embodiment 52 or 53, wherein the polysorbate is polysorbate 20.

[0281] 55. A formulation of any one of embodiments 51 to 54, wherein the pH of the formulation is in the range of pH 5.2 to pH 6.5, optionally in the range of 5.2 to 6.2 or 5.5 to 6.2 or 5.7.

[0282] 56. A formulation comprising any one of embodiments 2 to 48 or 50 to 55, wherein...

[0283] a) 150 mg / ml of this antibody;

[0284] b) 170 mM to approximately 200 mM trehalose;

[0285] c) 0.1 mg / ml to 0.3 mg / ml polysorbate, optionally polysorbate 20; and

[0286] d) Buffer, optionally an acetate buffer.

[0287] 57. Liquid pharmaceutical preparations as described in one or more of embodiments 1, 3 to 36 or 49 to 50, comprising...

[0288] a) 150 mg / ml of this antibody;

[0289] b) A polyol, wherein the polyol is optionally a sugar or a sugar alcohol; and

[0290] c) Nonionic surfactant, optionally polysorbate;

[0291] d) Does not contain buffer.

[0292] 58. The formulation of embodiment 57, wherein the pH of the formulation is in the range of pH 5.2 to pH 6.5, optionally in the range of pH 5.2 to 6.2 or 5.5 to 6.2.

[0293] 59. The formulation of embodiment 58, wherein the pH is 5.7.

[0294] 60. A formulation according to any one of embodiments 57 to 59, comprising 80 mM to 250 mM of a polyol, wherein the polyol is optionally trehalose.

[0295] 61. The formulation of any one of embodiments 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.

[0296] 62. The formulation of embodiment 61, wherein the nonionic surfactant is polysorbate, optionally polysorbate 20.

[0297] 63. A formulation of one or more of embodiments 1 to 62, further comprising an amino acid as an additive.

[0298] 64. The formulation of embodiment 63, wherein the amino acid has a charged side chain, optionally a positively charged side chain, such as L-arginine.

[0299] 65. The formulation of embodiment 63 or 64, wherein the amino acid is present in the formulation as a salt, optionally as a hydrochloric acid (HCl) salt.

[0300] 66. The formulation of embodiment 63, wherein the amino acid is methionine.

[0301] 67. The formulation of embodiment 63, wherein the amino acid is L-proline.

[0302] 68. A formulation of one or more of embodiments 1 to 67, wherein the formulation has one or more of the following characteristics:

[0303] (i) It does not contain arginine;

[0304] (ii) It does not contain amino acids with positively charged side chains;

[0305] (iii) It does not contain amino acids with charged side chains;

[0306] (iv) It does not contain methionine; and / or

[0307] (v) It does not contain amino acids as additives.

[0308] 69. A liquid pharmaceutical preparation as described in any of embodiments 2 to 68, comprising...

[0309] a) 150 mg / ml of this antibody;

[0310] b) 185 mM trehalose;

[0311] c) 0.2 mg / ml polysorbate 20; and

[0312] d) 10 mM acetate buffer;

[0313] The pH value is in the range of 5.2 to 6.2, and is optionally 5.7.

[0314] 70. A formulation as described in any one of embodiments 1 to 69, wherein the formulation is stable.

[0315] 71. The formulation of embodiment 70 satisfies one or more of the following stability characteristics:

[0316] (i) After being stored at 5°C for 36 months, at least 94%, 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 3%, more than 2.5%, more than 2%, or more than 1.5%;

[0317] (ii) After being stored at 5°C for 24 months, at least 94%, 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 3%, more than 2.5%, more than 2%, more than 1.5%, or more than 1%;

[0318] (iii) After being stored at 5°C for 9 months, at least 96% or at least 96.5% 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 1.5% or more than 1%;

[0319] (iv) After storage at 5°C for 3 months, at least 96% or at least 97% 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 1% or more than 0.7% or more than 0.5%;

[0320] (v) After being stored at 25°C for 12 months, at least 90% or at least 92% 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 7%, more than 6%, or more than 5%;

[0321] (vi) After storage 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%;

[0322] (vii) 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%;

[0323] (viii) 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%, more than 9%, or more than 8%; and / or

[0324] (ix) After storage at 40°C for 1 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%.

[0325] 72. The formulation of embodiment 70 or 71 satisfies one or more of the following stability characteristics:

[0326] (i) After being stored at 5°C for at least 36 months, the formulation has a milky white light of 12 FNU (formazan turbidity unit) or less or 10 FNU or less, and / or the milky white light does not increase by more than 5 FNU or more than 3 FNU.

[0327] (ii) After being stored at 5°C for at least 3, 6, 9, 12, 18 or 24 months, the formulation has a milky white light of 12 FNU (formazan turbidity unit) or less or 10 FNU or less, and / or the milky white light does not increase by more than 5 FNU or more than 3 FNU.

[0328] (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.

[0329] (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

[0330] (v) 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.

[0331] 73. A formulation according to any one of embodiments 70 to 72, which satisfies one or more of the following stability characteristics:

[0332] (i) 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%; and / or

[0333] (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%.

[0334] 74. A formulation according to any one of embodiments 70 to 73, which satisfies one or more of the following stability characteristics:

[0335] (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%;

[0336] (ii) After storage at 5°C for 24 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 HMW content of the antibody does not increase by more than 2% or more than 1.5% or more than 1%;

[0337] (iii) After being stored at 5°C for 9 months, less than 4%, less than 3%, or less than 2.5% 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%, more than 0.8%, or more than 0.6%;

[0338] (iv) After storage at 5°C for 3 months, less than 4%, less than 3%, or less than 2.5% 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%, more than 0.8%, or more than 0.6%;

[0339] (v) After storage at 40°C for 3 months, as 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

[0340] (vi) After storage at 40°C for 1 month, less than 5% or less than 4.5% 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 2.5% or more than 2%.

[0341] 75. A formulation according to any one of embodiments 70 to 74, which satisfies one or more of the following stability characteristics:

[0342] (i) After being stored 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%;

[0343] (ii) After storage at 25°C for 3 months, 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, 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%; and / or

[0344] (iii) After storage at 25°C for 1 month, less than 4% or 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%.

[0345] 76. A formulation according to any one of embodiments 70 to 75, which satisfies one or more of the following stability characteristics:

[0346] (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%;

[0347] (ii) After storage at 5°C for 24 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 LMW content of the antibody does not increase by more than 1.5% or more than 0.5%;

[0348] (iii) After storage at 5°C for 9 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 LMW content of the antibody does not increase by more than 1.5% or more than 0.5%;

[0349] (iv) After storage at 5°C for 3 months, less than 2%, less than 1.5%, or less than 1% of the antibody is present in the form of a low molecular weight (LMW) species, as measured by UP-SEC, 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%;

[0350] (v) After storage at 40°C for 3 months, less than 8%, less than 7%, or less than 6% of the antibody is present in the form of a low molecular weight (LMW) species, as measured by UP-SEC, 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

[0351] (vi) After storage at 40°C for 1 month, less than 4% or less than 3.5% or less than 3% of the antibody is present in the form of a low molecular weight (LMW) species as measured by UP-SEC, and / or the relative LMW content of the antibody does not increase by more than 3% or more than 2.5% or more than 2.2%.

[0352] 77. A formulation according to any one of embodiments 70 to 76, which satisfies one or more of the following stability characteristics:

[0353] (i) After being stored at 25°C for 12 months, less than 6%, less than 5%, or less than 4.5% of the antibody is present in the form of a low molecular weight (LMW) species, as measured by UP-SEC, and / or the relative LMW content of the antibody does not increase by more than 5%, more than 4%, or more than 3%;

[0354] (ii) After storage at 25°C for 3 months, 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, as measured by UP-SEC, 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

[0355] (iii) After storage at 25°C for 1 month, 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 as measured by UP-SEC, 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%.

[0356] 78. A formulation according to any one of embodiments 70 to 77, which satisfies one or more of the following stability characteristics:

[0357] (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%;

[0358] (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%;

[0359] (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%;

[0360] (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%;

[0361] (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%;

[0362] (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

[0363] (vii) After storage 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%.

[0364] 79. A formulation according to any one of embodiments 70 to 78, which satisfies one or more of the following stability characteristics:

[0365] (i) After being stored 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%;

[0366] (ii) After storage at 5°C for 24 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%;

[0367] (iii) After being stored at 5°C for 6 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%;

[0368] (iv) After storage at 5°C for 3 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 3%, more than 2%, or more than 1%;

[0369] (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%;

[0370] (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

[0371] (vii) After storage at 25°C for 1 month, less than 35% or 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% or more than 3%.

[0372] 80. A formulation according to any one of embodiments 70 to 79, which satisfies one or more of the following stability characteristics:

[0373] (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%;

[0374] (ii) 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 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 10%, more than 8%, or more than 6%;

[0375] (iii) After being stored at 5°C for 6 months, less than 15% or less than 10% 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 4%, more than 3%, or more than 2%;

[0376] (iv) After storage at 5°C for 3 months, less than 15% or less than 10% 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 3% or more than 2%;

[0377] (v) After storage at 25°C for 12 months, as 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%;

[0378] (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

[0379] (vii) After storage at 25°C for 1 month, less than 15%, less than 10%, or less than 9% 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 3% or more than 2%.

[0380] 81. A formulation according to any one of embodiments 70 to 80, which satisfies one or more of the following stability characteristics:

[0381] (i) After storage at 5°C for 36 months, the specific binding activity with IL-23 is measured to be at least 95% or at least 97% compared to a reference antibody, wherein the reference antibody has not been stored;

[0382] (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 been stored is measured.

[0383] (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 that has not yet been stored; and / or

[0384] (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.

[0385] 82. A formulation of one or more of the embodiments 1 to 81, wherein the dynamic viscosity measured at 20°C is ≤ 30 mPas (mPa·s), ≤ 25 mPas, or ≤ 20 mPas.

[0386] 83. A formulation of one or more of the embodiments 1 to 82, wherein the conductivity of the formulation is in the range of 0.8 to 5 mS / cm, optionally in the range of 1 to 2 mS / cm or 1.2 to 1.8 mS / cm.

[0387] 84. A formulation of one or more of embodiments 1 to 83, wherein the osmotic weight molality 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.

[0388] 85. A formulation of one or more of the embodiments 1 to 84, wherein the formulation is an injectable formulation.

[0389] 86. The formulation of embodiment 85, wherein the formulation is suitable for subcutaneous injection.

[0390] 87. A formulation of one or more of the embodiments 1 to 86, wherein the formulation has not undergone and has not yet undergone a reconstitution step prior to application.

[0391] 88. The formulation according to any one of embodiments 1 to 86 is prepared by reconstitution of a lyophilized formulation.

[0392] 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 manufactured by lyophilizing a liquid formulation as described in any one of embodiments 1 to 69, optionally wherein the liquid formulation is an aqueous solution.

[0393] 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 embodiments 1 to 69 or 82 to 86 upon reconstitution.

[0394] 91. A lyophilized formulation comprising...

[0395] 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;

[0396] b) Polyols;

[0397] c) Surfactants; and

[0398] d) Optional buffer.

[0399] 92. The lyophilized formulation of embodiment 91, wherein the antibody is rexazumab.

[0400] 93. The freeze-dried formulation of embodiment 91 or 92, wherein the polyol has one or more of the characteristics of any one of embodiments 6 to 13, wherein the polyol is optionally a sugar, the sugar optionally selected from trehalose and sucrose.

[0401] 94. A lyophilized formulation as described in any one of embodiments 91 to 93, wherein the surfactant has one or more of the features described in any one of embodiments 22 to 25, optionally wherein the surfactant is a polysorbate.

[0402] 95. A lyophilized formulation of any one of embodiments 91 to 94, comprising d) a buffer having one or more of the features of any one of embodiments 37 to 40.

[0403] 96. A lyophilized formulation as described in any one of embodiments 91 to 95, wherein the formulation has a pH as described in any one of embodiments 31 to 36 upon reconstitution.

[0404] 97. A sealed container, optionally a vial or a pre-filled syringe, containing a liquid pharmaceutical preparation as described in any one of embodiments 1 to 87.

[0405] 98. A container, optionally a sealed vial, containing a lyophilized formulation as described in any one of embodiments 88 to 96.

[0406] 99. The product of embodiment 97, wherein the container contains 2 ml or less of the liquid formulation, optionally containing 1.5 ml or less or 1 ml or less of the liquid formulation.

[0407] 100. The product of any one of embodiments 97 to 99, comprising a single dose of 150 mg of antibody.

[0408] 101. A formulation of any one of embodiments 1 to 96 or a product of any one of embodiments 97 to 100, used for the therapeutic treatment of a human individual.

[0409] 102. A formulation of any one of embodiments 1 to 96 or a product of any one of embodiments 97 to 100, for the treatment of a disease selected from psoriasis and inflammatory bowel disease.

[0410] 103. A formulation of any one of embodiments 1 to 96 or a product of any one of embodiments 97 to 100, for the treatment of diseases selected from psoriatic arthritis and Crohn's disease.

[0411] 104. A stable liquid pharmaceutical preparation comprising...

[0412] 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;

[0413] b) Tension regulators; and

[0414] c) Surfactants,

[0415] The formulation has a pH of 5.5-5.9 and is isotonic.

[0416] 105. A stable formulation as described in embodiment 104, wherein the antibody is rexazumab.

[0417] 106. A stable formulation as described in embodiment 104 or 105, wherein the tension modifier is a polyol.

[0418] 107. A stable formulation as described in any of embodiments 104 to 106, wherein the tension modifier is a polyol as described in any of embodiments 6 to 11 above.

[0419] 108. A stable formulation as described in any of embodiments 104 to 107, wherein the concentration of the tension modifier has one or more of the characteristics defined for the polyols in any of embodiments 14 to 21 above, optionally wherein the tension modifier is a polyol as defined therein, optionally a sugar and / or sugar alcohol, the sugar optionally selected from trehalose and sucrose.

[0420] 109. A stable formulation as described in any one of embodiments 104 to 108, wherein the surfactant has one or more of the features described in any one of embodiments 22 to 25 above, optionally wherein the surfactant is a polysorbate, optionally selected from polysorbate 20 and polysorbate 80.

[0421] 110. A stable formulation as described in any of embodiments 104 to 109, wherein the concentration of the surfactant in the formulation is as defined in any of embodiments 26 to 30 above.

[0422] 111. A stable formulation as described in any one of embodiments 104 to 110, wherein the pH of the formulation is in the range of 5.6 to 5.8, optionally wherein the pH of the formulation is 5.7.

[0423] 112. A stable formulation as described in any of embodiments 104 to 111, comprising d) a buffer, optionally wherein the buffer has one or more of the features described in any of embodiments 37 to 40 and 48.

[0424] 113. A stabilizing formulation as described in embodiment 112, wherein the buffer has a concentration as described in any one of embodiments 41 to 47.

[0425] 114. A stable formulation as described in any of embodiments 104 to 113, wherein the formulation is an aqueous formulation.

[0426] 115. A stable formulation of any one of embodiments 104 to 114, which satisfies one or more of the stability characteristics of any one of embodiments 71 to 81.

[0427] 116. A stable formulation as described in any one of embodiments 104 to 111 or 114 to 115, wherein the formulation does not contain a buffer.

[0428] 117. A stable formulation as described in any of embodiments 104 to 116, wherein the osmotic weight molality of the formulation is 290-320 mOsm / kg.

[0429] 118. A stable formulation according to any one of embodiments 104 to 117, having at least one or at least two of the following characteristics:

[0430] (i) The surfactant is a nonionic surfactant;

[0431] (ii) The surfactant is a polysorbate, which is optionally selected from polysorbate 20 and polysorbate 80;

[0432] (iii) wherein the concentration of the surfactant in the formulation is in the range of 0.05 mg / ml to 0.5 mg / ml, optionally 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

[0433] (iv) It has any one of the features of implementation schemes 12, 13 or 63 to 68.

[0434] 119. A stable formulation as described in any of embodiments 104 to 118, which is prepared by reconstitution of a lyophilized formulation.

[0435] 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 embodiments 104 to 118, wherein optionally the stable liquid formulation is an aqueous solution.

[0436] 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 for reconstitution of a stable liquid formulation as described in any one of embodiments 104 to 118.

[0437] Numerical ranges include the values ​​that define the range. The headings provided herein are not intended to limit the various aspects or embodiments of the invention, which can be read in their entirety in this specification.

[0438] 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 conceivable that the composition may also consist substantially of any combination of the described components or materials in an embodiment. The techniques illustratively disclosed herein may suitably be practiced in the absence of any element not specifically disclosed herein.

[0439] Example

[0440] The following examples are for illustrative purposes only and are not intended to limit the invention in any way.

[0441] I. Materials and Methods

[0442] 1. Preparation of starting materials

[0443] If necessary, prior to the UF / DF process, the purified rexazumab 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 the formulation according to subsequent examples.

[0444] 2. Syringe

[0445] The preparation is essentially stored in the syringe using a Neopak syringe with a rubber stopper from Becton Dickinson (USA). The syringe is used to measure the loosening force and the maximum and average slip force. In this embodiment, a 1 ml Neopak syringe from Becton Dickinson (USA) with a 27 gauge ½-inch needle and a rubber stopper is used.

[0446] II. Example 1: Characterization of starting material

[0447] 1. The effect of pH on antibodies

[0448] RALS (Right-angle light scattering) measurements were performed on rexazumab 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 Table 1.

[0449] Table 1: RALS measurement results for different pH values.

[0450]

[0451] 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).

[0452] 2. Determine the buffer capacity of the starting material.

[0453] In particular, the buffer capacity of the antibody starting material is determined to facilitate pH adjustment of the formulation solution for subsequent stability studies and to avoid protein damage. Titrations for determining antibody buffer capacity are performed at the following concentrations: 150 mg / mL; 100 mg / mL; 50 mg / mL (twice); and 20 mg / mL.

[0454] Dilute in a beaker according to Table 2.

[0455] Table 2: Dilution procedure for determining the buffer capacity of starting materials.

[0456]

[0457] 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. Calculate the slope and its reciprocal as shown in Table 3 using Excel.

[0458] Table 3: Calculation results of slope and corresponding reciprocal value.

[0459]

[0460] Concentration-dependent buffer capacity levels were obtained by plotting the inverse of the concentration versus the slope. 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 rexazumab itself possesses a substantial buffer capacity, allowing for the preparation of a buffer-free formulation of the present invention at 150 mg / ml without any additional / extra buffering substances.

[0461] III. Example 2: Analysis of different pH values ​​and buffer substances

[0462] 1. Compare acetate and succinate buffer systems with different pH values ​​to evaluate the stability of the 150 mg / mL formulation.

[0463] 1.1. Preparation of Formulation

[0464] Prepare and analyze the formulations shown in Table 4:

[0465] Table 4: Composition of the analyzed formulations.

[0466]

[0467] 0.02% PS20 corresponds to 0.2 mg / mL PS20.

[0468] 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 formulation was stored in syringes (Becton Dickinson (USA) Neopak syringes).

[0469] 1.2. Analysis

[0470] To analyze samples, high-performance size exclusion chromatography (HP-SEC) and ultra-high performance size exclusion chromatography (UP-SEC) were performed, and turbidity (also known as milky white light) at 860 nm was measured. 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). Formulation viscosity was measured at 20°C using a HAAKE RheoStress 600 with a C35 / 1 rotor. Dual measurements were performed.

[0471] Further details of the analytical methods used are described below.

[0472] 1.3. Results

[0473] 1.3.1. Measurement of monomer content

[0474] The monomer content was determined by analyzing the samples using HP-SEC and UP-SEC.

[0475] HP-SEC Analysis

[0476] The results obtained by HP-SEC analysis at storage temperatures of 25°C and 5°C are shown in Table 5:

[0477] Table 5: HP-SEC monomer analysis results in percentage (%) during 18 months of storage at different temperatures in syringes.

[0478]

[0479] The monomer content remained between 91% and 94% during a storage period of 18 months at 25°C. In this embodiment, the strongest reduction of -5% was measured for F1 tested; the lowest reduction of -3% was measured for formulations 4 and 5 tested. The monomer content remained between 93% and 96% during a storage period of 18 months at 5°C. The strongest reduction of -2.4% was measured for F1; the lowest reductions of -0.9% and -1.1% were measured for formulations 4 and 5, respectively.

[0480] UP-SEC Analysis

[0481] The UP-SEC analysis results are similar to the HP-SEC analysis results, and therefore confirm these results.

[0482] Table 5a: UP-SEC monomer analysis results in percentage (%) during 18 months of storage at different temperatures in syringes.

[0483]

[0484] At 25°C, the monomer content (UP-SEC) remained between 88% and 91% over an 18-month storage period. For F1, the strongest reduction was measured at -6.4%; for formulations 4 and 5, the lowest reductions were -5.1% and -5.4%, respectively. At 5°C, the monomer content (UP-SEC) remained between 93% and 95% over an 18-month storage period. For F1, the strongest reduction was measured at -2.2%; for formulations 4 and 5, the lowest reduction was measured at -1%.

[0485] Results and Discussion

[0486] Given the monomer content, all tested formulations were generally stable, demonstrating their stability at 5°C and 25°C over a long storage period of up to 18 months.

[0487] 1.3.2. Measurement of HMW content

[0488] The HMW content was determined by analyzing the samples using HP-SEC and UP-SEC.

[0489] HP-SEC Analysis

[0490] The results obtained by HP-SEC analysis at storage temperatures of 25°C and 5°C are shown in Table 6:

[0491] Table 6: HP-SEC HMW content (in %) at different storage temperatures in syringes over 18 months.

[0492]

[0493] At 25°C, the 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 formulations 4 and 5, respectively. At 5°C, the 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 formulations 4 and 5, respectively.

[0494] UP-SEC Analysis

[0495] The UP-SEC analysis results are similar to the HP-SEC analysis results, and therefore confirm these results.

[0496] Table 6a: UP-SEC HMW content (in %) at different storage temperatures in syringes over 18 months.

[0497]

[0498] 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 formulations 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 formulations 4 and 5, respectively.

[0499] Results and Discussion

[0500] 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.

[0501] 1.3.3. Turbidity Measurement

[0502] Table 7: Turbidity results at 860 nm in FNU at different storage temperatures over 18 months in syringes.

[0503]

[0504] 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. Formulation 1 showed the strongest increase of 3 FNU, while formulation 2 showed the smallest increase of 1 FNU. Formulation 4, containing L-arginine, exhibited the highest turbidity from the start.

[0505] Turbidity was measured at a wavelength of 860 nm, showing an increase of 0-1 FNU during a storage period of 18 months at 5 °C.

[0506] Results and Discussion

[0507] 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 the formulation without arginine more advantageous.

[0508] 1.3.4. Conductivity Measurement

[0509] Measure the conductivity of the formulation.

[0510] Table 8: Conductivity measurements in mS / cm over a storage temperature of 25°C for up to 18 months.

[0511]

[0512] Results and Discussion

[0513] 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, which contains L-arginine, had a relatively high conductivity of less than 4 mS / cm.

[0514] 1.4. Additional Analysis and Results

[0515] In addition, further analyses were performed on the five formulations tested (storage time and temperature as described above), and the results are as follows.

[0516] ● 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.

[0517] ● The permeate molality 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.

[0518] ● The dynamic viscosity remained substantially constant at 20°C over a storage period of 18 months and at the different storage temperatures tested. The dynamic viscosity was in the range of 10-14 mPas.

[0519] ● Protein concentration remained substantially constant over the 18-month storage period and at the different storage temperatures tested. Small deviations in protein concentration were attributed to analytical variations, resulting in a range of 148–159 mg / mL.

[0520] ● The HP-SEC fragment content remained substantially constant over an 18-month storage period and at the different storage temperatures tested. 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 at the different storage temperatures tested. Specifically, a low increase of 3% was measured at 25°C and a low increase of 0.1% to 0.3% at 5°C over 18 months. LMW content ranged from 1.0% to 4.5%.

[0521] ● The levels of the weak cation exchange (WCX) main peak, acidic peak group (APG), and basic peak group (BPG) remained constant during a 18-month storage period at 5°C. No differences in the main peak, APG, and BPG were observed between formulations.

[0522] ● The hydrophobic interaction chromatography (HIC) peak content remained substantially constant over 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 were observed between formulations regarding the main peak, subsequent peaks, and foremost peak.

[0523] ● 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%.

[0524] ●No visible particles were observed.

[0525] 1.5. Results Overview

[0526] All five formulations were stable during an 18-month storage period at 25°C and 5°C. However, formulation 4 contained an additional adjuvant. Formulation 3 was stable and did not contain any additional adjuvant, in contrast to formulation F4, which contained arginine. Less aggregate formation was observed at a pH of approximately 5.7.

[0527] 2. Compare acetate and succinate buffer systems with different pH values ​​in freezing / thawing experiments.

[0528] To investigate whether freezing and thawing of the 150 mg / mL formulation affected the product quality of rexazumab, three formulations were filled into small bags with initial volumes of 10 mL or 14 mL 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.

[0529] Perform freezing using a controlled freezing method. Afterward, transfer the bag to a -40°C freezer and maintain freezing for the indicated storage time.

[0530] 2.1. Preparation of Formulation

[0531] 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 Table 9.

[0532] Table 9: Composition of the formulation.

[0533]

[0534] Store the starting material in a refrigerator at 2°C–8°C until use. Freeze 10 mL sample bags (“small Flexboy bags”) using a freeze dryer at a controlled freezing rate of 0.5°C / min until the temperature reaches -40°C.

[0535] 2.2. Analysis

[0536] 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.

[0537] 2.3. Results

[0538] 2.3.1. Measurement of monomer and HMW content

[0539] HP-SEC and UP-SEC analyses were performed to determine formulation stability, showing monomer and HMW content. The following results were obtained:

[0540] Table 10: HP-SEC monomer content and initial values ​​in percentage after 3 weeks of storage (frozen at -40°C and 2°C-8°C).

[0541]

[0542] UP-SEC measurement confirms HP-SEC measurement results.

[0543] Table 10a: UP-SEC monomer content and initial values ​​in percentage after 3 weeks of storage (frozen at -40°C and 2°C-8°C).

[0544]

[0545] The remaining antibodies with a 100% loss in content exist in the form of HMW species.

[0546] Results and Discussion

[0547] Overall, HP-SEC analysis results demonstrated the stability of all formulations, indicating that they are permissible for freeze / thaw cycles. For formulations with higher monomer content and fewer HMW species, some showed even better results.

[0548] 2.3.2. Measurement of binding activity

[0549] Binding activity against rhIL-23 was measured using surface plasmon resonance (Biacore) measurements. The binding activity was generally consistent across all formulations, confirming their applicability. Specifically, binding activity was measured in the range of 95% to 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.

[0550] 2.3.3. Measuring viscosity

[0551] Another important parameter for protein formulations is viscosity, which is preferably not too high to allow for injection (e.g., passing through a needle without excessive force). Therefore, dynamic viscosity was measured.

[0552] The dynamic viscosities of F1, F2, and F3 are very similar, ranging from 8.7 to 10 mPas.

[0553] 2.4. Additional Analysis and Results

[0554] In addition, further analysis was performed on the three formulations tested, and the results are as follows.

[0555] ● The content of non-visually visible 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 was substantially the same for all three formulations.

[0556] ● The permeate 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.

[0557] ● 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.

[0558] ● 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.

[0559] ● 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.

[0560] ● Protein concentration remained substantially constant over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. Small deviations in protein concentration were attributed to analytical variations, resulting in a range of 149–157 mg / mL for an initial protein concentration of 150 mg / mL.

[0561] ● The hydrophobic interaction chromatography (HIC) main peak content remained substantially constant over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. The HIC main peak value ranged from 97.1% to 97.7%. Both the preceding and following peaks remained substantially constant over 3 weeks at 5°C or -40°C, including freeze / thaw cycles.

[0562] ● The weak cation exchange (WCX) chromatographic peak concentration remained substantially constant over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. The WCX peak concentration 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 in the main peak, APG, and BPG were observed between formulations.

[0563] ●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%.

[0564] 2.5. Results Overview

[0565] The results of this example demonstrate the stability of rexazumab 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 rexazumab. Therefore, the 150 mg / mL formulation is a suitable concentrate. pH 5.7 appears to perform slightly better compared to other pH values.

[0566] 3. Compare acetate and succinate buffer systems with different pH values.

[0567] Particularly suitable pH values ​​are between 5.2 and 6.2, such as 5.5 to 6.2 or around 5.7. Higher pH values, as measured by SEC, 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 embodiment, 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.

[0568] The composition of formulations 1-7 is described in Table 11 below.

[0569] Table 11: Composition of the analyzed formulations.

[0570]

[0571] 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 (excipients, buffers, etc.). The filled syringes were stored horizontally in light-proof Rondo trays using cardboard boxes at 2°C–8°C. The following filling materials were used:

[0572] Neopak syringe (1 ml syringe with a 27 gauge ½-inch needle)

[0573] rubber stopper

[0574] Rondo tray

[0575] 3.1. Analysis

[0576] To analyze the sample, HP-SEC and UP-SEC were performed, and turbidity (also known as opalescence) was measured. The following equipment was used for the analysis:

[0577] -UPLC, UPSEC: UPLC 29 / 31 Waters ACQUITY, Waters, MA

[0578] -HPLC, WCX / SEC: HPLC 82 / 83 / 107 Waters ALLIACE, Waters, MA

[0579] -Based on particle count / size in MFI: Microflow Imagine, 5200 BOT A / B (Roboter), Protein Simple, GER

[0580] - Osmometer: Osmomat 3000 Gonotec GmbH, GER

[0581] - pH meter: SevenGo, Mettler Toledo, GER

[0582] - Turbidity meter: 2100AN turbidity meter, Hach-Lange GmbH, GER

[0583] -Based on the protein concentration of Solo VPE: Solo VPE, C. Technologies, Inc., NJ

[0584] - Biacore: Biacore T200, GE Healthcare Life Science, UK

[0585] - Tensile and compression testing equipment: Zwick 2.5TS / N 21159574 Zwick, Germany

[0586] Further details of the analytical methods used are described below.

[0587] 3.2. Results

[0588] 3.2.1. Measurement of monomer content

[0589] UP-SEC and HP-SEC were used to determine monomer content loss. Monomer content is a key quality attribute of protein stability and quality during stress-induced storage. The table below shows the UP-SEC measurement results.

[0590] Table 12: Monomer content [%] of seven formulations stored at 5°C, 25°C and 40°C as measured by UP-SEC.

[0591]

[0592] HP-SEC confirms the UP-SEC results. HP-SEC does not generate additional information compared to UP-SEC.

[0593] Results and Discussion

[0594] All analyzed formulations were stable under the tested conditions.

[0595] 3.2.2. Measurement of HMW content

[0596] UP-SEC and HP-SEC were used to determine HMW formation levels. The table below shows the UP-SEC measurement results. HMW content is correlated with monomer content. Monomer loss leads to an increase in HMW.

[0597] Table 13: HMW [%] of seven formulations stored at 5°C, 25°C and 40°C as measured by UP-SEC.

[0598]

[0599] HP-SEC confirmed the UP-SEC results. HP-SEC did not generate any additional information compared to UP-SEC.

[0600] Results and Discussion

[0601] Overall, all formulations with low HMW species content remained stable even after storage at 40°C.

[0602] 3.2.3. Measurement of LMW content

[0603] UP-SEC was used to determine the level of LMW formation. The table below shows the UP-SEC measurement results.

[0604] Table 14: LMW content [%] of seven formulations stored at 5°C, 25°C and 40°C as measured by UP-SEC.

[0605]

[0606] Results and Discussion

[0607] Overall, all formulations with low levels of LMW species remained stable even after storage at 40°C.

[0608] 3.2.4. Measurement of LMW content

[0609] To assess formulation stability, the LMW content was also measured using HP-SEC analysis. The results are shown below.

[0610] Table 15: LMW content [%] of seven formulations stored at 5°C, 25°C and 40°C as measured by HP-SEC.

[0611]

[0612] Results and Discussion

[0613] LMW content increased only slightly over time, but all tested formulations generally caused low-level fragmentation.

[0614] 3.2.5. Turbidity Measurement

[0615] 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 tested formulations.

[0616] Table 16: Milky white light of seven formulations stored at 5°C, 25°C and 40°C [FNU].

[0617]

[0618] Results and Discussion

[0619] Preparations containing L-arginine HCl showed an increase in milky white light.

[0620] 3.3. Further Analysis and Results

[0621] In addition, further analyses were performed on the seven formulations tested (storage time and temperature as described above), and the results are as follows.

[0622] ● The protein concentration remained substantially constant over the 18-month storage period and at the different storage temperatures tested.

[0623] ● The pH value remained substantially constant during the 18-month storage period and at the different storage temperatures tested.

[0624] ● The permeate molality 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.

[0625] ●No visible particles were observed.

[0626] ● 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 for all formulations within similar ranges. At 25°C and 40°C, the BPG content of formulations with pH 6.0 was slightly lower (at most 2%) than that of formulations with pH 5.7.

[0627] ● The particle count, as 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 in any formulation during storage at 5 °C and 25 °C / 60% rh for all formulations. For particles ≥ 2 µm, the particle count increased at 25 °C. The increase was within a similar range for all formulations.

[0628] ● 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%.

[0629] ● The loosening force and slip force remained substantially constant during the 18-month storage period and at 5°C. During storage at 25°C, the maximum slip force, average slip force, and loosening force increased for all formulations. No differences were observed between formulations. 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.

[0630] ● The dynamic viscosity at 20°C remained substantially constant over an 18-month storage period and at the various storage temperatures tested. The dynamic viscosity ranged from 8.3 to 10.7 mPas.

[0631] 3.4. Results Overview

[0632] This example describes the storage stability of seven different 150 mg / mL rexazumab formulations. Trehalose and mannitol were used instead of sorbitol to adjust the tonicity. F2 was analyzed after 18 months.

[0633] UP-SEC results showed that, in the tested formulations, pH 6.0 caused slightly higher degradation of rexazumab compared to pH 5.7, resulting in lower monomer content and higher HMW (high molecular weight molecular weight). 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 molality, viscosity, loosening and slipping forces, and both invisible and visible particles. Based on this data, no differences were observed between formulations.

[0634] 4. Compare acetate and succinate buffer systems with different pH values ​​during long-term storage.

[0635] This embodiment analyzes the storage stability of seven different 150 mg / mL rexazumab formulations in Neopak syringes to analyze the storage stability of the formulations and identify advantageous formulations. The tonicity was slightly modified compared to the seven formulations in the previous embodiment. Three conditions (as identified above) were tested again. The analyzed formulations are summarized in Table 17.

[0636] Table 17: Composition of the analyzed formulations.

[0637]

[0638] Formulations are prepared by mixing starting materials with a concentrated feed solution (containing excipients, i.e., excipients and buffers).

[0639] 4.1. Analysis

[0640] To analyze the samples, UP-SEC was performed, and the opalescence was measured. Further details of the analytical methods used are described below.

[0641] 4.2. Results

[0642] 4.2.1. Measurement of HMW content

[0643] Table 18: HMW content measured in % for UP-SEC analysis after long-term storage at 5℃, 25℃ and 40℃.

[0644]

[0645] Results and Discussion

[0646] The overall HMW content in all tested formulations remained low, indicating that the high concentrations used stabilized rexazumab. UP-SEC results further showed that pH 6.0 caused higher rexazumab degradation compared to pH 5.7, resulting in a lower monomer content and a higher HMW content. 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.

[0647] 4.2.2. Measurement of LMW content

[0648] Table 19: Measured LMW content (in %) of UP-SEC analysis after long-term storage at 5°C, 25°C and 40°C.

[0649]

[0650] Results and Discussion

[0651] The tested formulation was stable throughout the measurement time at all tested temperatures. Therefore, the tested formulation effectively stabilized a high protein concentration of 150 mg / mL Torracilumab. At higher storage temperatures, a slight increase in the LMW content was observed in the formulation containing L-arginine HCl. 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 Torracilumab formulation differs from other protein formulations. Therefore, the arginine-free formulation of the present invention is preferred.

[0652] 4.2.3. Measuring milky white light

[0653] Table 20: Measured milky light in FNU after long-term storage at 5℃, 25℃ and 40℃.

[0654]

[0655] Results and Discussion

[0656] 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).

[0657] 4.3. Results Overview

[0658] The measured parameters showed that all formulations were suitable for the stable preparation of 150 mg / mL high-concentration rexazumab. Long-term stability revealed some differences between the formulations:

[0659] - UP-SEC showed that pH 6.0 caused higher degradation of rexazumab in the form of lower monomers and higher HMW compared to pH 5.7.

[0660] Formulations containing L-arginine HCl showed lower degradation, but increased milky whiteness and a slight increase in LMW, as measured by UP-SEC.

[0661] An additional analysis of F2 was conducted 18 months later.

[0662] 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 of ressazumab.

[0663] In summary, formulation F2 was found to be particularly stable in terms of measured LMW and HMW levels and milky whiteness, indicators of excellent stability. This result was highly unexpected, as ressazumab is generally known to be used at higher pH values. Therefore, the particularly high concentration of ressazumab shifted the optimal pH to approximately 5.7, which was unexpected. Furthermore, unexpectedly, L-arginine HCl did not induce further stability, but rather actually reduced the formulation stability supported by the higher milky whiteness and measured LMW levels. Therefore, the specific characteristics of ressazumab at, for example, a high concentration of 150 mg / mL necessitate optimal conditions different from previously known ressazumab formulations.

[0664] 5. Compare acetate and succinate buffer systems with different pH values ​​during shaking.

[0665] The objective of this embodiment is to evaluate the effect of shaking stress on the product quality of different 150 mg / mL rexazumab formulations. The ability of different formulations to stabilize rexazumab against shaking stress is tested. Therefore, formulations at 150 mg / mL antibody concentrations are exposed to different shaking stresses.

[0666] In all eleven formulations with different pH values, the buffer and tonic were filled into 6R vials and 1 mL Neopak syringes with 27.5-gauge needles and shaken at room temperature for 21 days. The corresponding buffer solutions, which were shaken, stored, and analyzed, were also analyzed to remove proteins. Shaking conditions:

[0667] - Shake at room temperature (approximately 25°C)

[0668] - Shaking time: 21 days

[0669] - Shaking type: horizontal shaker (bottle), agitator (syringe); shake in the dark.

[0670] To eliminate the impact of temperature as an additional stress on product quality, store the additional vials and syringes at room temperature without shaking.

[0671] 5.1. Preparation of Formulation

[0672] Eleven test formulations of rexazumab were prepared (see Table 21) and subjected to the following conditions:

[0673] a) Shake the vials at 300 U / min in a horizontal shaker for 1, 5, 7, 14, and 21 days (away from light);

[0674] 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

[0675] c) At room temperature (25℃) for 1, 5, 7, 14, or 21 days (away from light).

[0676] Table 21: Formulations selected for shaking studies.

[0677]

[0678] The formulation is added as encapsulation material to vials (Schott) or Neopak syringes. The sterile-filtered protein solution is filled into the sterile primary encapsulation material under laminar flow. The vial filling volume is defined as 3.6 mL. Each syringe is filled with 1.04 mL. All vials and syringes are inspected for visible particles, and the results are recorded.

[0679] 5.2. Analysis

[0680] Analyses are performed directly at each time point after sampling, except for SEC chromatographic analyses, where samples are stored at -70°C until measurement is performed. The following equipment is used for analysis:

[0681] - UV-Vis spectrophotometer Solo VPE: Concentration at 280 nm, baseline correction at 320 nm, extinction coefficient: 1.52; C Technologies, Inc., NJ, USA

[0682] - Optical magnifier: HACH Lange opalescent meter; Filter: 400-600 nm; Hach Lange GmbH, Düsseldorf, Germany

[0683] -Ultra-efficient size exclusion chromatography (UP-SEC): UPLC26, H-class UV detection at 280 nm. Waters, Milford, MA

[0684] -Based on the charge inhomogeneity of weak cation exchange chromatography (WCX): HPLC 75; fluorescence detection: extinction: 278 nm, emission: 350 nm; Waters, Milford, MA

[0685] -IL-23 binding activity: Biacore T200 chip: CM5 GE Healthcare, Chalfont St Giles, UK

[0686] -PH meter: SevenGo - Mettler Toledo, Columbus, OH

[0687] - Particle size analyzer: Micro Flow Imaging™ flow cytometer; utilizing microfluidic imaging (MFI); Brightwell Technologies Inc, Ottawa, ON, Canada

[0688] - Osmometer: Osmomat 030 with freezing point depression, Gonotec GmbH, Berlin, Germany

[0689] Further details of the analytical methods used are described below.

[0690] 5.3. Results

[0691] 5.3.1. Measurement of monomer content

[0692] 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 the formulation.

[0693] UP-SEC Analysis

[0694] Table 22: UP-SEC monomers in syringes and vials, in percentage: initial values ​​and values ​​after shaking for 1 / 5 / 7 / 14 / 21 days, and values ​​after 21 days of no movement at 25°C. *Corresponds to no movement, while shaking other samples for the indicated time.

[0695]

[0696] HP-SEC Analysis

[0697] 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%.

[0698] Results and Discussion

[0699] Overall, measurements in syringes and vials showed a similar trend, demonstrating that all formulations were stable, with only a slight decrease in monomer content.

[0700] 5.3.2. Measurement of HMW content

[0701] HP-SEC and UP-SEC were used to measure the monomer content of the formulation. HP-SEC was used to determine the level of aggregate (HMW) formation during syringe and vial shaking.

[0702] UP-SEC Analysis

[0703] The UP-SEC analysis results are as follows. The data show similar results to the HP-SEC analysis, namely, 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 prepared solution 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.

[0704] Formulations containing L-arginine, such as F3 and F7, showed the lowest aggregation levels after 21 days of shaking. Differences in monomer content among the eleven formulations tested in this study, observed in UP-SEC and HP-SEC, were non-significant. 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.

[0705] The data obtained using UP-SEC is summarized in Table 23.

[0706] Table 23: UP-SEC HMW content (%) of syringes and vials: initial values ​​and values ​​after shaking for 1 / 5 / 7 / 14 / 21 days, and values ​​after 21 days of no movement at 25°C. * Corresponds to no movement, while shaking other samples for the indicated time.

[0707]

[0708] HP-SEC Analysis

[0709] The HP-SEC analysis data trend is similar to the UP-SEC analysis data trend, thus confirming these results.

[0710] Results and Discussion

[0711] Overall, all tested formulations were found to be stable. Similar results were obtained for vials and syringes.

[0712] 5.3.3. Measurement of milky white light and other parameters

[0713] After 21 days of shaking the syringe on a horizontal shaker and the vial on a vortex shaker, the opalescence, osmotic molality, pH, and protein concentration of all tested formulations remained substantially unchanged (see subsequent data). The lowest level of opalescence was observed in buffer-free formulation F11, which did not contain any additional buffers such as acetate or succinate. No opinion can be given regarding visual inspection. No significant differences were observed by comparing the data generated from vials and syringes.

[0714] The increased milky light levels at F6 after 1 day and F10 after 5 days may not 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.

[0715] Table 24: Shaking of formulations in syringes and vials: initial values ​​for milky white light, penetrant molality, 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 other samples were shaken for the indicated time.

[0716]

[0717]

[0718]

[0719] Binding activity

[0720] SPR (Biacore) measurements showed that shaking did not affect the molecular binding activity of the syringe on a oscillating shaker or the vial on a horizontal shaker. Overall, binding activity remained high, in the range of 91%–111%, and specific binding activity remained in the range of 98%–107%.

[0721] Results and Discussion

[0722] The opalescent light depends on the formulation composition and ranges from 5 FNU to 14 FNU in formulations without excipients or buffers, but does not increase significantly over time.

[0723] Throughout the study period, the pH, permeation molality, opalescence and protein concentration, and binding activity against IL-23 remained constant for all formulations.

[0724] 5.4. Additional Analysis and Results

[0725] In addition, further analyses were performed on the eleven formulations tested, and the results are as follows. Shaking type and time, storage, and syringes and vials used are as described above.

[0726] ● 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%.

[0727] ● Weak cation exchange chromatography (WCX) showed that the percentage distributions of the main peak, APG, and BPG remained constant across all formulations tested during 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 formulations.

[0728] ● The particle content, as measured by microfluidic imaging (MFI), remained substantially constant over the 21-day shaking period.

[0729] 5.5. Overview

[0730] In summary, only minor differences were detected in parameters indicative of 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 level of milky whiteness. In summary, the formulations tested in this study are viable.

[0731] 6. Compare acetate and succinate buffer systems with different pH values ​​in multiple freeze / thaw cycles.

[0732] The freezing and thawing behavior of different 150 mg / mL rexazumab formulations and their impact on product quality were evaluated. Therefore, the formulations were exposed to freezing and thawing stress in miniature 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.

[0733] In all eleven formulations with different pH values, the buffering agent and tonic agent, along with the intermediate storage block, were filled into miniature bags at 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.

[0734] Table 25: Overview of Experiment Scheduling

[0735]

[0736] Light gray shade: frozen; darker gray shade: thawed

[0737] 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 at 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.

[0738] A complete freeze / thaw cycle (1 × F / T) is defined as follows:

[0739] 1. Freeze from room temperature to -40°C (0.5°C / min)

[0740] 2. The holding time at -40℃ is 16 hours.

[0741] 3. Thaw from -40℃ to room temperature (0.5℃ / min)

[0742] 4. The time to keep at room temperature is 4 hours.

[0743] This procedure is performed for 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.

[0744] 6.1. Preparation of Formulation

[0745] The formulation was prepared as described in the previous embodiment (see Table 21). Another formulation, F12, containing 0.02% PS20 and pH 5.7, without excipients, was prepared. 12 mL of aseptically filtered protein solution was filled under laminar flow into sterile primary packaging material, which was a small 15 mL Flexboy bag. All bags were inspected for visible particles, and the results were recorded.

[0746] 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 per formulation. The bags are distributed throughout the defined process to eliminate the influence of bag placement within the freeze-dryer.

[0747] 6.2. Analysis

[0748] After completing all cycles according to the experimental plan described above, continuously thaw the bags in an additional thawing step. This procedure has the advantage of allowing simultaneous analysis of samples. Transfer the bags to a pre-cooled freeze-dryer at -40°C, followed by the thawing step. Perform HP-SEC, UP-SEC, permeate molality, pH, protein concentration, opacity, binding activity, and non-visual particle measurements. Use the following equipment for analysis:

[0749] -UV-Vis spectrophotometer Solo VPE: Concentration at 280 nm, baseline correction at 320 nm, extinction coefficient: 1.52; C Technologies, Inc., NJ, USA

[0750] - Milky white light: HACH Lange milky white light meter; filter: 400-600 nm; Hach Lange GmbH, Düsseldorf, Germany

[0751] -Ultra-efficient size exclusion chromatography (UP-SEC): UPLC26, H-class UV detection at 280 nm. Waters, Milford, MA

[0752] -Based on the charge inhomogeneity of weak cation exchange chromatography (WCX): HPLC 75; fluorescence detection: extinction: 278 nm, emission: 350 nm; Waters, Milford, MA

[0753] - IL-23 binding activity: Biacore T200 chip: CM5 GE Healthcare, Chalfont StGiles, UK

[0754] -PH meter: SevenGo - Mettler Toledo, Columbus, OH

[0755] - Particle size analyzer: Micro Flow Imaging™ flow cytometer; utilizing microfluidic imaging (MFI); Brightwell Technologies Inc, Ottawa, ON, Canada

[0756] - Osmometer: Osmomat 030 with freezing point depression, Gonotec GmbH, Berlin, Germany

[0757] Further details of the analytical methods used are described below.

[0758] 6.3. Results

[0759] 6.3.1. Measurement of monomer and HMW content

[0760] 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.

[0761] Table 26: HP-SEC / UP-SEC: Initial values ​​in % and values ​​after 1 / 3 / 6 F / T cycles and after three weeks at 5°C.

[0762]

[0763]

[0764] Results and Discussion

[0765] Data shows that aggregate formation is primarily pH-driven. Comparing results after six F / T cycles, it is evident that formulations at pH 6.0 or 6.2 showed a slight increase in HMW content of 0.2%–0.6% compared to solutions prepared at pH 5.7. Formulations containing L-arginine, such as F3 and F7, showed the lowest aggregation levels after six F / T cycles. In general, it can be summarized that freeze / thaw stress does not significantly increase HMW content compared to results after 21 days at 5°C.

[0766] 6.3.2. Measurement of milky white light and other parameters

[0767] After 6 F / T cycles and 3 weeks of storage at 5°C, the milky whiteness, permeate molality, pH, and protein concentration of all tested formulations remained unchanged. The lowest milky whiteness levels were observed in the buffer-free formulations (F11 and F12).

[0768] Table 27: Initial values ​​of milky light in FNU, osmotic molality in mOsm / kg, pH value, and protein concentration in g / L, and values ​​after 1 / 3 / 6 F / T cycles.

[0769]

[0770]

[0771] Binding activity

[0772] 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%.

[0773] Results and Discussion

[0774] The measured opalescence depends 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 and were therefore stable throughout the study period.

[0775] 6.3.3. Measuring Particles

[0776] The following table summarizes the particle number for each STP. No clear trend was observed for all 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.

[0777] Table 28: Invisible Particles - MFI: Initial values ​​and values ​​after one, three and six F / T cycles and values ​​after three weeks at 5°C.

[0778]

[0779] Results and Discussion

[0780] While a similar trend was observed for particles ≥ 2 μm, a slight increase in particles ≥ 10 μm was observed for 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 F / T.

[0781] 6.4. Additional Analysis and Results

[0782] In addition, further analysis was performed on the twelve formulations tested (freezing / thawing cycles as described above), and the results are as follows.

[0783] ● Weak cation exchange chromatography (WCX) showed that the percentage distributions of the main peak, APG, and BPG remained constant across all formulations tested during 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 formulations.

[0784] 6.5. Results Overview

[0785] The results can be summarized as follows:

[0786] - Visual inspection: After six F / T cycles, no observation of the entire formulation should be made during the visual inspection period.

[0787] - SVP: Regarding the content of non-visible particles, no major issues were observed. Compared with other formulations, F3, F7, and F9 were slightly increased, but significantly lower than the pharmacopoeia specifications.

[0788] - HP-SEC and UP-SEC: For protein integrity-focused testing methods such as HP-SEC and UP-SEC, F3 was demonstrated to be the most stable formulation and F4 the least stable. F12, without any buffers or excipients, exhibited acceptable stability during freeze / thaw cycles.

[0789] - IEC: No difference in formulation was observed for the IEC results. The F / T cycle did not negatively affect the contributions of APG and BPG.

[0790] - Milky white light: Milky white light varies depending on the formulation and ranges from 4 FNU to 13 FNU for formulations without excipients or buffers.

[0791] Regardless of stress conditions (F / T and holding time at 5°C), the pH, permeation molality, opalescence, protein concentration, and binding of all formulations remained constant throughout the study.

[0792] In summary: For the 150 mg / mL formulation, most of the formulations tested in this example were viable. Only minor effects of freezing / thawing stress on protein stability were observed. Due to medical concerns regarding formulations containing sorbitol, these formulations may be found to be less advantageous for patients with fructose intolerance. Nevertheless, for other patients, solutions containing sorbitol may be found to be useful. 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 increased amount of non-visible particles was detected.

[0793] 7. Effect of pH on formulation stability

[0794] The effect of pH on the stability of the 150 mg / mL rexazumab formulation was tested using the formulations shown in Table 29.

[0795] Table 29: Composition of the formulation.

[0796]

[0797] 7.1. Preparation of Formulation

[0798] The formulation is prepared as described above.

[0799] 7.2. Analysis

[0800] 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.

[0801] 7.3. Results

[0802] 7.3.1. Measurement of monomer content

[0803] As in the previous embodiments, UP-SEC analysis was used to measure monomer content, and the results are shown in Table 30.

[0804] Table 30: UP-SEC monomer measurements in percentage for formulations with different pH values.

[0805]

[0806] Results and Discussion

[0807] Monomer content measurements showed that the tested formulation was stable within a pH range of pH 5.0 to 6.2. Therefore, a wide pH range is applicable to obtain a highly stable 150 mg / mL rexazumab formulation. 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, a high concentration of rexazumab (150 mg / mL in this case) at a pH of approximately 5.7 proves particularly advantageous, especially in the formulation provided in this example.

[0808] 7.3.2. Measurement of HMW content

[0809] The HMW content of the formulation was also determined using UP-SEC, and the following results were obtained:

[0810] Table 31: UP-SEC-HMW measurement results in % for formulations with different pH values.

[0811]

[0812] Results and Discussion

[0813] HMW content correlated with monomer measurements. Overall, the tested formulations were stable within a certain pH range. Particularly low increases in HMW content were observed at pH around 5.7. However, higher pH values ​​(e.g., pH 6.2) appeared to induce slightly higher HMW values.

[0814] 7.3.3. Measurement of LMW content

[0815] The LMW content was measured by UP-SEC analysis, which revealed the following results:

[0816] Table 32: UP-SEC-LMW measurement results in % for formulations with different pH values.

[0817]

[0818] Results and Discussion

[0819] LMW content correlated with monomer measurements. Particularly low increases in LMW content were observed at pH values ​​of approximately 5.7. However, lower pH values ​​appeared to result in slightly higher LMW values. Overall, the tested formulations were stable within a certain pH range.

[0820] 7.3.4. Species determination by ion exchange chromatography (IEC)

[0821] 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).

[0822] Table 33: IEC main peak measurement results in percentage for formulations with different pH values.

[0823]

[0824] Table 34: IEC APG measurement results in % for formulations with different pH values.

[0825]

[0826] Table 35: IEC BPG measurement results in % for formulations with different pH values.

[0827]

[0828] Results and Discussion

[0829] Overall, IEC measurements showed that the tested formulation was 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, which respectively indicated an increase in APG or BPG species. Therefore, a pH of approximately 5.7 is deemed advantageous.

[0830] 7.3.5. Species determination by hydrophobic interaction chromatography (HIC)

[0831] Variants / subspecies of rexazumab were measured using hydrophobic interaction chromatography (HIC). The results were then classified into main peak, leading peak, and trailing peak.

[0832] Table 36: HIC main peak measurement results in percentage (%) for formulations with different pH values.

[0833]

[0834] Table 37: HIC front peak measurement results in percentage for formulations with different pH values.

[0835]

[0836] Table 38: HIC post-peak measurement results in percentage for formulations with different pH values.

[0837]

[0838] Results and Discussion

[0839] Overall, HIC measurements showed that the tested formulation was 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, which respectively showed increases in the initial and subsequent peaks.

[0840] 7.3.6. Binding activity

[0841] The binding activity of ressazolam against IL-23 was measured using a Biacore T200. The following results were obtained:

[0842] Table 39: Binding activity of formulations with different pH values, in percentage.

[0843]

[0844] Table 40: Specific binding activity, in percentage, for formulations with different pH values.

[0845]

[0846] Results and Discussion

[0847] Combined activity measurements showed generally high values ​​for the tested formulation. Therefore, the tested formulation stabilized ressazolizumab to achieve high binding activity in the pH range of 5.0 to 6.2.

[0848] 7.3.7. Measuring Milky White Light

[0849] In addition, the milky white light of the formulation was measured. The milky white light 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. It is noteworthy that lower pH values ​​generally exhibit a milky white light lower than higher pH values ​​(7 to 11 FNU for pH 6.2, and 3 to 6 FNU for pH 5.0). An intermediate pH of 5.7 exhibits a milky white light within the range of 5 to 7 FNU, indicating that providing a formulation with a pH of approximately 5.7 is advantageous, especially in the formulation according to this embodiment.

[0850] 7.3.8. Measure viscosity, syringe slippage force, and release force.

[0851] Viscosity and syringe force, which include average and maximum slip force and loosening force, were measured as additional parameters. The following results were obtained:

[0852] Table 41: Viscosity measurements of the tested formulations at different pH values ​​over time, in mPas.

[0853]

[0854] Table 42: Maximum slip force measurements in N for the tested formulations at different pH values ​​over time.

[0855]

[0856] Table 43: Average slip force measurements in N for the tested formulations at different pH values ​​over time.

[0857]

[0858] Table 44: Results of loosening power measurements (in N) for the tested formulations with different pH values ​​over time.

[0859]

[0860] Results and Discussion

[0861] At higher pH values, viscosity measurements reveal slightly higher viscosity. Therefore, lower pH values, such as pH 5.7, are advantageous for obtaining formulations with lower viscosity. It should be noted that mechanical measurements of slip and loosening forces reveal generally very similar performance.

[0862] 7.4. Additional Analysis and Results

[0863] In addition, further analysis was performed on the six formulations tested, and the results are as follows. Storage time and temperature were as described above.

[0864] ● Protein concentrations remained substantially constant at the different storage temperatures tested (5°C, 25°C, and 40°C) over 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.

[0865] ● The pH value remained substantially constant at the different storage temperatures tested at 5°C, 25°C, and 40°C, respectively, during storage periods of 36, 24, 12, and 3 months. Therefore, the measured pH values ​​were in the range of 4.9–6.3.

[0866] ●The permeate molality remained substantially constant at different storage temperatures tested at 5°C, 25°C, and 40°C over storage periods of 36, 24, 12, and 3 months. The tested values ​​ranged from 301 to 323 mOsm / kg.

[0867] ● During the storage period, the levels of protein-associated particles and foreign particles remained substantially constant at the different storage temperatures tested.

[0868] 7.5. Results Overview

[0869] The formulations were stable at all tested pH values ​​over extended storage periods of 24 and 36 months. Although temperature appears to have an effect on stability (i.e., higher temperatures induce more instability-related effects), all formulations exhibited sufficient stability even at high temperatures.

[0870] 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.

[0871] 8. Effect of acetate concentration on formulation stability

[0872] Preparations containing different concentrations of acetate were stored at three different temperatures (5°C, 25°C, and 40°C) at different time points (see Table 45).

[0873] Table 45: Composition of the formulation.

[0874]

[0875] 8.1. Preparation of Formulation

[0876] The formulation is prepared as described above.

[0877] 8.2. Analysis

[0878] 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, permeate molality, opalescence, and pH were measured. Further details of the analytical methods used are described below.

[0879] 8.3. Results

[0880] 8.3.1. Measurement of monomer content

[0881] UP-SEC analysis was performed to measure monomer content. The following results were obtained.

[0882] Table 46: UP-SEC monomer measurements in % for formulations containing varying amounts of acetate.

[0883]

[0884] Results and Discussion

[0885] Monomer measurements showed that the formulation was stable within a certain range of acetate content, indicating the stability of formulations containing 150 mg / mL rexazumab with and without buffer, as well as the formulation according to this embodiment.

[0886] 8.3.2. Measurement of HMW content

[0887] The HMW content of the formulation was also determined by UP-SEC analysis, and the results are as follows:

[0888] Table 47: UP-SEC-HMW measurements in % for formulations containing varying amounts of acetate.

[0889]

[0890] Results and Discussion

[0891] HMW content measurement showed that the formulation was stable within a certain range of acetate content, indicating the stability of formulations containing 150 mg / mL rexazumab with and without buffer, as well as the formulation according to this embodiment.

[0892] 8.3.3. Measurement of LMW content

[0893] For LMW content measurement, UP-SEC analysis was performed. The following results were obtained.

[0894] Table 48: UP-SEC-LMW measurements of formulations containing varying amounts of acetate, expressed in % (%).

[0895]

[0896] Results and Discussion

[0897] LMW measurements show that the formulation is stable within a certain range of acetate content, indicating the stability of formulations containing and without buffers.

[0898] 8.3.4. Measurement of binding activity

[0899] To analyze whether acetate content affects the binding activity of restazolidone to IL-23, a Biacore analysis was performed. Binding activity measurements 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 suitable for application.

[0900] 8.3.5. Measurement of osmotic molality

[0901] Because the acetate content also affects the osmotic weight molality of the formulation, this parameter was measured. The results are shown in Table 49.

[0902] Table 49: Permeation molality of formulations containing varying amounts of acetate at different temperatures and storage times, expressed in mOsm / kg.

[0903]

[0904] Results and Discussion

[0905] Measurements showed that the osmotic molality varied between approximately 290 and 338 mOsm / kg, depending on the amount of acetate added. The more acetate added, the higher the measured osmotic molality. Typically, an osmotic molality of approximately 310 mOsm / kg is required, and a 10 mM acetate concentration produces the desired osmotic molality 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 molality to approximately 310 mOsm / kg.

[0906] 8.3.6. Measuring Milky White Light

[0907] The milky white light of the formulations in this embodiment was also measured to assess stability. The measured milky white light was generally similar across the different formulations, ranging from 4 to 9 FNU. Higher concentrations of acetate resulted in slightly higher milky white light (7 to 9 FNU for 0 mM acetate) compared to lower concentrations (4-6 FNU for 0 mM acetate). Based on the measured milky white light, all formulations according to this embodiment are stable.

[0908] 8.3.7. Measure pH

[0909] To determine the pH stability of the buffer containing varying amounts, specifically the acetate formulation in this example, pH values ​​were measured at different temperatures during storage. The results are shown in the following table.

[0910] Table 50: Measured pH values ​​of formulations containing varying amounts of acetate at 5°C, 25°C, or 40°C during varying storage periods.

[0911]

[0912] Results and Discussion

[0913] pH measurements show that the pH of the formulations tested according to this embodiment remained generally constant. Therefore, the formulations are pH stable for all acetate contents, including those without acetate.

[0914] 8.3.8. Measurement of slip force and loosening force

[0915] The maximum and average slip force and release force of syringes containing different formulations according to this embodiment were measured. These measurement results are shown below.

[0916] Table 51: Maximum 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.

[0917]

[0918] Table 52: Average 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.

[0919]

[0920] Table 53: Relaxing power 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.

[0921]

[0922] Results and Discussion

[0923] Measurements of slip force and release force showed that all formulations were stable, and neither slip force nor release force increased significantly over time. Notably, formulations that did not contain acetate (F1) or contained 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.

[0924] 8.4. Additional Analysis and Results

[0925] In addition, further analysis was performed on the five formulations tested, and the results are as follows. Storage time and temperature were as described above.

[0926] ● The levels of the IEC main peak, APG, and BPG remained constant at 5°C for 24 and 36 months. No differences in main peak, APG, and BPG were observed between formulations.

[0927] ● 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 formulations.

[0928] ● 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, ranging from 147–155 mg / mL (24 months) and 147–157 mg / mL (36 months).

[0929] ● The dynamic viscosity remained substantially constant at the tested storage temperatures for storage periods of up to 24 and 36 months. The dynamic viscosity ranged from 8.9 to 10.0 mPas.

[0930] ● During the storage period, the levels of protein-associated particles and foreign particles remained substantially constant at the different storage temperatures tested.

[0931] 8.5. Results Overview

[0932] The tested formulations exhibited generally high stability. Therefore, both acetate-containing and buffer-free formulations 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 buffer-free formulations. Furthermore, to achieve an osmotic weight molality of 310 mOsm / kg, a 10 mM acetate content has proven appropriate, considering the other compounds present in the formulation according to this embodiment.

[0933] IV. Example 3: Analysis of other excipients

[0934] 1. Effect of PS20 content on shaking experiment

[0935] Formulations were prepared (see Table 54) in which 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 periods of 0, 1, 5, 7, 14 and 21 days.

[0936] Table 54: Composition of the formulation.

[0937]

[0938] 1.1. Preparation of Formulation

[0939] 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).

[0940] 1.2. Analysis

[0941] 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 PFS was kinematically adjusted to individual viscosities to ensure bubble movement (tilting shaker (Vari Mix platform shaker)). All samples were protected from light. The opalescent color of the formulation was measured at the indicated measurement points. Further details of the analytical methods used are described below.

[0942] 1.3. Results

[0943] Measuring milky white light

[0944] To measure the stability of a formulation containing varying amounts of PS20 and subjected to shaking stress, opalescence was measured at different time points. The results obtained from the opalescence measurement are shown below:

[0945] Table 55: Milky white light in FNU units for formulations with varying amounts of PS20 in syringes.

[0946]

[0947] Table 56: Milky white light in FNU units for formulations with varying amounts of PS20 in vials.

[0948]

[0949] 1.4. Results Overview

[0950] Shaking studies clearly revealed a significant increase in milky whiteness in formulations without PS20 during the 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 in formulations containing 150 mg / mL of rexazumab.

[0951] 2. The impact of PS20 content during storage

[0952] The prepared formulation was analyzed at different time points at three different storage temperatures (5°C, 25°C, and 40°C) (see Table 54).

[0953] 2.1. Analysis

[0954] Sample measurements were performed during storage at 1, 3, 6, 9, 12, 18, 24, and 36 months, 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 force, and loosening force were measured. Further details of the analytical methods used are described below.

[0955] 2.2. Results

[0956] 2.2.1. Measurement of monomer content

[0957] The stability of the formulation was assessed by measuring the monomer content using UP-SEC analysis. The results are shown below.

[0958] Table 57: UP-SEC monomer measurements in percentage for formulations containing variations in PS20.

[0959]

[0960] Results and Discussion

[0961] Monomer measurements showed that the formulation was stable within a certain range of PS20 contents. Particularly high monomer values ​​were obtained for PS20 contents of approximately 0.2 mg / mL.

[0962] 2.2.2. Measurement of HMW content

[0963] The stability of the formulation was further evaluated by measuring the HMW content again using UP-SEC. The results are shown below.

[0964] Table 58: UP-SEC HMW measurements of formulations containing variations in PS20, expressed as a percentage.

[0965]

[0966] Results and Discussion

[0967] HMW content correlated with monomer measurements. Overall, the tested formulations were stable within a certain range of PS20 contents. A particularly low increase in HMW content was obtained for a PS20 content of 0.2 mg / mL. However, the highest and lowest tested PS20 contents appeared to have resulted in slightly higher HMW values.

[0968] 2.2.3. Measurement of LMW content

[0969] The LMW content was also measured using UP-SEC and the following results were obtained:

[0970] Table 59: UP-SEC-LMW measurements of PS20 formulations including variations, expressed as a percentage.

[0971]

[0972] Results and Discussion

[0973] LMW content correlated with monomer measurements. Overall, the tested formulations were stable within a certain range of PS20 contents. A particularly low increase in LMW was obtained 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.

[0974] 2.2.4. Measuring milky white light

[0975] In addition, the opalescent light of the formulation containing varying amounts of PS20 was measured. The results are depicted below.

[0976] Table 60: Milky white light measurement results in FNU for formulations containing variations in PS20.

[0977]

[0978] Results and Discussion

[0979] Measurements showed that none of the formulations caused an increase in milky whiteness at higher temperatures of 25°C and 40°C. However, at a temperature of 5°C and at subsequent storage time points (e.g., 18, 24, and 36 months), formulation F1 (without PS20) showed an increase in milky whiteness. Therefore, the presence of a surfactant such as the nonionic surfactant PS20 is advantageous.

[0980] 2.2.5. Measurement of the content of non-visually visible particles

[0981] 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.

[0982] Table 61: Measurement results of non-visual particle content of particles with sizes ≥ 2 µm, ≥ 10 µm and ≥ 25 µm in formulations containing varying amounts of PS20 stored at 5°C for up to 24 and 36 months.

[0983]

[0984] Results and Discussion

[0985] Measurements of non-visual particle content showed that all formulations were stable at 5°C for up to 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.

[0986] 2.2.6. Measure the slip force and loosening force.

[0987] The maximum and average slip force and loosening force of the PS20 formulation, including variations, were measured. The measurement results are shown below.

[0988] Table 62: Maximum slip force in N. The formulation contains varying amounts of PS20.

[0989]

[0990] Table 63: Average slip force in N. The formulation contains varying amounts of PS20.

[0991]

[0992] Table 64: Relaxing power in N. The formulation contains varying amounts of PS20.

[0993]

[0994] Results and Discussion

[0995] Slip force measurements 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, virtually no difference was observed between formulations in terms of relaxation power.

[0996] 2.3. Additional Analysis and Results

[0997] In addition, further analysis was performed on the seven formulations tested, and the results are as follows. Storage time and temperature were as described above.

[0998] ● The levels of the IEC main peak, APG, and BPG remained constant at 5°C for 24 and 36 months. No differences in main peak, APG, and BPG were observed between formulations.

[0999] ● 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 formulations.

[1000] ●Specific binding activity remained substantially constant at the tested storage temperatures for storage periods of up to 24 and 36 months. Specific binding activity ranged from 97% to 101%.

[1001] ● 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, ranging from 147–155 mg / mL (24 months) and 147–159 mg / mL (36 months).

[1002] ● 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.

[1003] ● The permeate molality 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.

[1004] ● The dynamic viscosity remained substantially constant at the tested storage temperatures for storage periods of up to 24 and 36 months. The dynamic viscosity ranged from 9.2 to 11.0 mPas.

[1005] ● During the storage period, the levels of protein-associated particles and foreign particles remained substantially constant at the different storage temperatures tested.

[1006] 2.4. Results Overview

[1007] In summary, the formulations tested were stable under long-term storage conditions ranging from 5°C to 40°C for 24 and 36 months. In particular, 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. A particularly suitable concentration of surfactants such as the nonionic surfactant PS20 appears to be 0.2 g / L under the tested conditions.

[1008] 3. Change the trehalose content

[1009] In this embodiment, the trehalose concentration was varied between 145, 165, 185, 205 and 225 mM and analyzed at different time points at three different storage temperatures (5°C, 25°C and 40°C). The prepared formulation is shown in Table 65.

[1010] Table 65: Composition of the formulation.

[1011]

[1012] 3.1. Analysis

[1013] 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.

[1014] 3.2. Results

[1015] 3.2.1. Measurement of monomer content

[1016] The stability of formulations containing varying amounts of trehalose was assessed using UP-SEC analysis to measure monomer content, and the results are shown below.

[1017] Table 66: UP-SEC monomer measurements in percentage (%) for formulations containing different amounts of trehalose.

[1018]

[1019] Results and Discussion

[1020] Monomer measurements showed that the formulation was stable within a certain range of trehalose content, indicating its stability within that range.

[1021] 3.2.2. Measurement of HMW content

[1022] The HMW content of the formulation was measured using UP-SEC. The analytical results are shown below.

[1023] Table 67: UP-SEC HMW measurements in % for formulations containing different amounts of trehalose.

[1024]

[1025] Results and Discussion

[1026] HMW content measurement showed that the formulation was stable within a certain range of trehalose content.

[1027] 3.2.3. Measurement of LMW content

[1028] The LMW content of the formulation containing varying amounts of trehalose was also measured by UP-SEC. The results are shown below.

[1029] Table 68: UP-SEC-LMW measurements in % for formulations containing different amounts of trehalose.

[1030]

[1031] Results and Discussion

[1032] LMW measurements showed that the formulation was stable within a certain range of trehalose content.

[1033] 3.2.4. Measurement of binding activity

[1034] The binding activity of resveratrol contained in the formulations of this invention was measured. Antigen binding measurements 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.

[1035] 3.2.5. Measurement of osmotic molality

[1036] The osmotic molality was measured to ensure that the tested formulation had an osmotic molality suitable for injection. The results are shown below:

[1037] Table 69: Measured osmotic molality in mOsm / kg for formulations containing varying amounts of trehalose.

[1038]

[1039] Results and Discussion

[1040] For trehalose concentrations of 145 to 225 mM, the osmotic molality ranges from approximately 245 to 380 mOsm / kg. Since the optimal osmotic molality is approximately 310 mOsm / kg, it may be advantageous to provide a formulation having this osmotic molality. This can be achieved, for example, using a trehalose concentration of 185 mM and the formulation according to this embodiment.

[1041] 3.3. Further Analysis and Results

[1042] In addition, further analyses were performed on the five formulations tested (storage time and temperature as described above).

[1043] ● The levels of the IEC main peak, APG, and BPG remained constant at 5°C for 24 and 36 months. No differences in main peak, APG, and BPG were observed between formulations.

[1044] ● 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 between formulations.

[1045] ● 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, ranging from 145–153 mg / mL (24 months) and 148–158 mg / mL (36 months).

[1046] ● 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.

[1047] ● The opalescent light remained substantially constant at the different storage temperatures tested for up to 24 and 36 months. The opalescent light ranged from 5 to 9 FNU.

[1048] ● The dynamic viscosity remained substantially constant at the tested storage temperatures for storage periods of up to 24 and 36 months. The dynamic viscosity ranged from 8.9 to 10.3 mPas.

[1049] ● 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.

[1050] ● During the storage period, the levels of protein-associated particles and foreign particles remained substantially constant at the different storage temperatures tested.

[1051] 3.4. Results Overview

[1052] In summary, all tested formulations were stable, demonstrating high stability despite variations in trehalose concentration. Therefore, the indicated trehalose concentration can be flexibly applied to produce a stable protein formulation of 150 mg / mL restazazumab.

[1053] V. Example 4: Analysis of additional parameters of a specific formulation

[1054] In view of the results of the previous embodiments, particularly suitable formulations comprise the following compounds:

[1055] -150 mg / mL Rexazumab,

[1056] -10 mM acetate buffer,

[1057] -185 mM trehalose, and

[1058] -0.2 mg / mL PS20;

[1059] The pH of the formulation is 5.7.

[1060] This formulation has a clear to slightly milky white appearance and is substantially free of foreign particles. Its penetrating molality 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 electrical conductivity at 20°C is approximately 1.53 mS / cm, and its density at 20°C is approximately 1.067 g / cm³. 3Furthermore, its density at 4°C is approximately 1.071 g / cm³. 3 .

[1061] The 150 mg / mL Rexazumab formulation is available as follows:

[1062]

[1063] Abbreviation list

[1064]

[1065]

[1066] This disclosure relates to the following implementation plan.

[1067] 1. A liquid pharmaceutical preparation comprising...

[1068] 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;

[1069] b) Polyols; and

[1070] c) Surfactants.

[1071] 2. The formulation as described in embodiment 1, comprising...

[1072] d) Buffer.

[1073] 3. The formulation as described in implementation scheme 1 or 2, wherein the antibody is risankizumab.

[1074] 4. A formulation according to any one of embodiments 1 to 3, wherein the polyol is selected from sugars, sugar alcohols and combinations thereof.

[1075] 5. The formulation of embodiment 4, wherein the polyol is selected from trehalose, sucrose, sorbitol, mannitol and combinations thereof, optionally wherein the polyol is trehalose.

[1076] 6. A formulation of one or more of embodiments 1 to 5, wherein the concentration of the polyol in the formulation is at least 95 mM, optionally in the range of 125 mM to 250 mM or 145 mM to 225 mM.

[1077] 7. The formulation of any one of embodiments 1 to 6, wherein the surfactant is a nonionic surfactant, optionally a polysorbate.

[1078] 8. A formulation of one or more of embodiments 1 to 7, wherein the concentration of the surfactant in the formulation is in the range of 0.05 mg / ml to 0.5 mg / ml, optionally in the range of 0.075 mg / ml to 0.4 mg / ml or 0.1 mg / ml to 0.3 mg / ml.

[1079] 9. A formulation of one or more of embodiments 1 to 8, wherein the pH of the liquid pharmaceutical formulation is in the range of pH 5.0 to 7.5, pH 5.0 to 7.0, or pH 5.2 to 6.5.

[1080] 10. A formulation of one or more of embodiments 1 to 9, wherein the pH of the liquid pharmaceutical formulation is in the range of 5.2 to 6.2, 5.5 to 6.2, 5.5 to 5.9 or 5.6 to 5.8, optionally wherein the pH is 5.7.

[1081] 11. A formulation as described in one or more of embodiments 1 to 10, wherein the buffer has a pKa at 25°C within 1.5 or one pH unit of the final pH of the liquid pharmaceutical formulation, optionally wherein the buffer has a pKa at 25°C in the pH range of 4.2 to 7.2, 4.5 to 7, or 4.6 to 5.8.

[1082] 12. A formulation of one or more of embodiments 1 to 11, wherein the buffer is selected from acetate buffers, succinate buffers or histidine buffers, optionally wherein the buffer is an acetate buffer.

[1083] 13. A formulation as described in one or more of embodiments 1 to 12, wherein the concentration of the buffer is in the range of 3 mM to 50 mM or 5 mM to 25 mM, or is 10 mM.

[1084] 14. A formulation as described in one or more of embodiments 1 to 13, wherein the formulation is an aqueous formulation.

[1085] 15. A formulation according to any one of embodiments 1 to 14, having one or more, optionally two or more or all of the following characteristics:

[1086] (i) It contains trehalose as a polyol;

[1087] (ii) It contains 185 mM trehalose as a polyol;

[1088] (iii) It contains 0.2 mg / ml polysorbate 20 as a surfactant;

[1089] (iv) It contains an acetate buffer;

[1090] (v) It contains 5 mM to 25 mM of buffer, optionally wherein the concentration of the buffer is 10 mM;

[1091] (vi) It contains a single buffer, optionally an acetate buffer;

[1092] (vii) The pH of the liquid pharmaceutical preparation is in the range of 5.2 to 6.2, 5.5 to 5.9, or 5.6 to 5.8; and / or

[1093] (viii) The pH of the liquid preparation is 5.7 or 6.2.

[1094] 16. A formulation as described in any one of embodiments 1 to 15, comprising...

[1095] a) 150 mg / ml of this antibody;

[1096] b) Sugar, optionally wherein the concentration of the sugar is in the range of 145 mM to 225 mM;

[1097] c) A nonionic surfactant, optionally 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; and

[1098] d) Buffer;

[1099] Optionally, the pH of the formulation is in the range of pH 5.2 to pH 6.5, 5.2 to 6.2, or 5.5 to 6.2.

[1100] 17. A formulation according to any one of embodiments 1 to 16, comprising

[1101] a) 150 mg / ml of this antibody;

[1102] b) Trehalose, optionally wherein the concentration of trehalose is in the range of 145 mM to 225 mM;

[1103] c) Polysorbate, optionally 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; and

[1104] d) Buffer;

[1105] Optionally, the pH of the formulation is in the range of pH 5.2 to pH 6.5, 5.2 to 6.2, or 5.5 to 6.2.

[1106] 18. A formulation as described in any of embodiments 1 to 17, comprising...

[1107] a) 150 mg / ml of this antibody;

[1108] b) 170 mM to approximately 200 mM trehalose;

[1109] c) 0.1 mg / ml to 0.3 mg / ml or 0.2 mg / ml polysorbate, optionally polysorbate 20; and

[1110] d) A buffer, optionally wherein the buffer is an acetate buffer;

[1111] Optionally, the pH of the formulation is in the range of pH 5.2 to pH 6.5, 5.2 to 6.2, or 5.5 to 6.2.

[1112] 19. A formulation comprising one or more of embodiments 1 to 18, wherein...

[1113] a) 150 mg / ml of this antibody;

[1114] b) A polyol, optionally wherein the polyol is a sugar or a sugar alcohol; and

[1115] c) A nonionic surfactant, optionally a polysorbate; and

[1116] d) No buffer;

[1117] The pH of the formulation is in the range of pH 5.2 to pH 6.5, optionally in the range of pH 5.2 to 6.2 or 5.5 to 6.2.

[1118] 20. A formulation as described in any of embodiments 2 to 19, comprising...

[1119] a) 150 mg / ml of this antibody;

[1120] b) 185 mM trehalose;

[1121] c) 0.2 mg / ml polysorbate 20; and

[1122] d) 10 mM acetate buffer;

[1123] The pH value is 5.7.

[1124] 21. A formulation as described in any one of embodiments 1 to 20, wherein the formulation is stable.

[1125] 22. A stable liquid pharmaceutical preparation comprising...

[1126] 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;

[1127] b) Tension regulators; and

[1128] c) Surfactants,

[1129] The formulation has a pH of 5.5-5.9 and is isotonic.

[1130] 23. A stable formulation as described in embodiment 22, wherein the pH of the formulation is 5.7.

[1131] 24. A stable formulation as described in embodiment 22 or 23, wherein the osmotic weight molality of the formulation is 290-320 mOsm / Kg.

[1132] 25. A stable formulation as described in any of embodiments 22 to 24, comprising...

[1133] d) A buffer, optionally wherein the buffer is as defined in embodiment 11 or 12 and / or wherein the concentration of the buffer is as defined in embodiment 13.

[1134] 26. A stable formulation as described in any of embodiments 22 to 24, wherein the formulation does not contain a buffer.

[1135] 27. A stabilizing formulation as described in any of embodiments 22 to 26, wherein the tension modifier is a polyol.

[1136] 28. A stable formulation as described in embodiment 27, wherein the polyol is as defined in embodiment 4 or 5, optionally wherein the formulation comprises a polyol at a concentration as defined in embodiment 6.

[1137] 29. A stable formulation of any one of embodiments 22 to 28, having one or more of the following characteristics:

[1138] (i) The surfactant is a nonionic surfactant;

[1139] (ii) The surfactant is a polysorbate, optionally selected from polysorbate 20 and polysorbate 80; and / or

[1140] (iii) wherein the concentration of the surfactant in the formulation is in the range of 0.05 mg / ml to 0.5 mg / ml, optionally in the range of 0.075 mg / ml to 0.4 mg / ml or 0.1 mg / ml to 0.3 mg / ml.

[1141] 30. A stable formulation of one or more of the embodiments 22 to 29, wherein the antibody is rexazumab.

[1142] 31. A formulation according to any one of embodiments 21 to 30, which satisfies one or more of the following stability characteristics:

[1143] (i) After being stored at 5°C for 24 months, at least 94%, at least 95%, or at least 96% of the antibody remains in monomer form as measured by UP-SEC, and / or the relative monomer content of the antibody does not decrease by more than 3%, more than 2%, more than 1.5%, or more than 1%;

[1144] (ii) After being stored at 5°C for 9 months, at least 96% or at least 96.5% of the antibody remains as monomers 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%;

[1145] (iii) After storage at 5°C for 3 months, at least 96% or at least 97% of the antibody remains as monomers 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%;

[1146] (iv) After 12 months of storage at 25°C, at least 90% or at least 92% of the antibody remains as monomers as measured by UP-SEC, and / or the relative monomer content of the antibody does not decrease by more than 7%, more than 6%, or more than 5%;

[1147] (v) After storage at 25°C for 3 months, at least 95% of the antibody remains as a monomer 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%;

[1148] (vi) After storage at 25°C for 1 month, at least 96% of the antibody remains as a monomer 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%;

[1149] (vii) After storage at 40°C for 3 months, at least 87% or at least 88% of the antibody remains as monomer as measured by UP-SEC, 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

[1150] (viii) After storage at 40°C for 1 month, at least 93% or at least 94% of the antibody is present as monomers 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%.

[1151] 32. A formulation according to any one of embodiments 21 to 31, which satisfies one or more of the following stability characteristics:

[1152] (i) After being stored at 5°C for at least 3, 6, 9, 12, 18 or 24 months, the formulation has a milky white light of 12 FNU (Formazin Nephelometry Unit) or less or 10 FNU or less, and / or the milky white light does not increase by more than 5 FNU or more than 3 FNU.

[1153] (ii) 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.

[1154] (iii) 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

[1155] (iv) 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.

[1156] 33. A formulation according to any one of embodiments 21 to 32, which satisfies one or two of the following stability characteristics:

[1157] (i) After shaking at 25°C for 21 days, at least 95% or at least 96% of the antibody remains as monomer 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

[1158] (ii) After shaking at 25°C for 21 days, less than 3% or less than 2% of the antibody is present as 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%.

[1159] 34. A formulation according to any one of embodiments 21 to 33, which satisfies one or more of the following stability characteristics:

[1160] (i) After storage at 5°C for 24 months, less than 4% or less than 3% of the antibody is present as 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%;

[1161] (ii) After being stored at 5°C for 9 months, less than 4%, less than 3%, or less than 2.5% of the antibody is present as 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%, more than 0.8%, or more than 0.6%;

[1162] (iii) After storage at 5°C for 3 months, less than 4%, less than 3%, or less than 2.5% of the antibody is present as 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%, more than 0.8%, or more than 0.6%;

[1163] (iv) After 12 months of storage at 25°C, less than 5% or less than 4% of the antibody is present as 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%;

[1164] (v) After storage at 25°C for 3 months, less than 4%, less than 3.5%, or less than 3.2% of the antibody is present as 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%;

[1165] (vi) After storage at 25°C for 1 month, if measured by UP-SEC, less than 4%, less than 3.5%, or less than 3% of the antibody is present as a high molecular weight (HMW) species, and / or the relative HMW content of the antibody does not increase by more than 1.5% or more than 1%;

[1166] (vii) After storage at 40°C for 3 months, if, as measured by UP-SEC, less than 6.5% or less than 6% or less than 5.5% of the antibody exists as 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

[1167] (viii) After storage at 40°C for 1 month, less than 5% or less than 4.5% or less than 4% of the antibody is present as 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 2.5% or more than 2%.

[1168] 35. A formulation according to any one of embodiments 1 to 34, wherein the formulation is suitable for injection, optionally suitable for subcutaneous injection.

[1169] 36. A formulation according to any one of embodiments 1 to 35, having one or more of the following characteristics:

[1170] (i) wherein the preparation has not undergone and has not yet undergone a reconstitution step before use;

[1171] (ii) wherein the liquid pharmaceutical preparation does not contain sorbitol;

[1172] (iii) It does not contain arginine;

[1173] (iv) It does not contain amino acids with positively charged side chains;

[1174] (v) It does not contain amino acids with charged side chains;

[1175] (vi) It does not contain methionine; and / or

[1176] (vii) It does not contain amino acids as additives.

[1177] 37. A sealed container, optionally a vial or a pre-filled syringe, containing a pharmaceutical preparation as described in any one of embodiments 1 to 36.

[1178] 38. A liquid pharmaceutical preparation of any one of embodiments 1 to 36 or a product of embodiment 37, for the therapeutic treatment of a human individual, optionally for the treatment of a disease selected from psoriasis, inflammatory bowel disease, psoriatic arthritis and Crohn's disease.

Claims

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

2. A stable liquid aqueous pharmaceutical preparation comprising... a) Rexazumab at concentrations ranging from 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; The stable liquid aqueous pharmaceutical formulation has a pH in the range of 5.5 to 5.9, and the viscosity of the formulation, measured at 20°C, is less than 20.0 mPas.

3. The stable liquid aqueous pharmaceutical formulation according to claim 1, wherein the pH of the formulation is 5.

5.

4. The stable liquid aqueous pharmaceutical formulation according to claim 1, wherein the pH of the formulation is 5.

7.

5. The stable liquid aqueous pharmaceutical formulation according to claim 1, wherein the pH of the formulation is 5.

9.

6. The stable liquid aqueous pharmaceutical formulation according to claim 2, wherein the pH of the formulation is 5.

5.

7. The stable liquid aqueous pharmaceutical formulation according to claim 2, wherein the pH of the formulation is 5.

7.

8. The stable liquid aqueous pharmaceutical formulation according to claim 2, wherein the pH of the formulation is 5.9.

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