Anti-il-23p19 antibody formulations

Abstract

To provide a highly concentrated liquid antibody formulation that is storage stable and suitable for subcutaneous administration.SOLUTION: The present disclosure inter alia provides a liquid pharmaceutical formulation comprising a) 150 mg / ml of an anti-IL-23p19 antibody, the antibody comprising a specific light chain amino acid sequence and a specific heavy chain amino acid sequence; b) a polyol; and c) a surfactant.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority from U.S. Provisional Application No. 62 / 897,930, filed September 9, 2019, the entire contents of which are incorporated herein by reference.

[0003] Field of Disclosure

[0004] The present invention generally relates to formulations containing anti-IL-23p19 antibodies, such as risankizumab, that bind to the p19 subunit of human IL-23. More specifically, pharmaceutical formulations containing high concentrations of the anti-IL-23p19 antibody risankizumab, as well as related products and uses for the treatment of various diseases and disorders, are disclosed. Disclosed herein is a stable liquid pharmaceutical formulation containing 150 mg / ml of the antibody risankizumab.

[0005] background

[0006] Human IL-23 is composed of a subunit (p40) common to IL-12 and a unique p19 subunit. Despite this shared p40 subunit, the roles of IL-23 and IL-12 are quite different. IL-12 is important for Th1 responses through promoting the differentiation, proliferation, and activation of Th1 cells. In contrast, IL-23 activates CD4+ T cells, referred to as Th17 cells, due to their ability to produce IL-17 and related cytokines. + It supports the development and maintenance of T helper cell populations. IL-23 is involved in chronic autoimmune inflammation, and modulation of IL-23 activity provides an effective treatment for autoimmune diseases.

[0007] One of the autoimmune diseases in which IL-23 plays a central role is psoriasis, a chronic immune-mediated inflammatory disease characterized by the hyperproliferation of keratinocytes and skin-infiltrating T lymphocytes that overexpress pro-inflammatory mediators. This disease is a chronic, painful immune-mediated inflammatory skin disease that has a lifelong course of remission and relapse, with variable factors that induce exacerbations in susceptible individuals, making treatment difficult. Uncontrolled inflammation in psoriasis can contribute to commonly associated comorbidities, including cardiovascular (CV) disease (including hypertension and 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 suicidality, as well as substance abuse.

[0008] A highly effective and specific inhibitor of IL-23 is the antibody risankizumab. Risankizumab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody directed against the p19 subunit of IL-23. Risankizumab's binding to IL-23p19 inhibits IL-23's ability to induce and maintain T helper (Th)17 cells, innate lymphoid cells, gamma delta T cells, and natural killer (NK) cells, which are involved in tissue inflammation, destruction, and repair of abnormal tissue. Risankizumab is particularly effective in treating autoimmune and inflammatory diseases, particularly psoriasis. Clinical trials have demonstrated excellent safety and efficacy in treating plaque psoriasis. The approved recommended dose for the treatment of psoriasis is 150 mg, administered subcutaneously as two 75 mg injections at weeks 0 and 4 and every 12 weeks thereafter.

[0009] The need for injection of larger drug volumes poses challenges compared to patients with acute conditions, especially in patients with chronic conditions, who have significantly lower drug adherence and persistence. Subcutaneous administration is preferred for therapeutic indications where home (self) drug therapy is desirable, for example, for chronic diseases such as psoriasis. However, the subcutaneous administration route is limited by the injection volume due to tissue backpressure and injection pain. This also depends on the injection formulation. Most drugs administered by subcutaneous injection, such as risankizumab, are generally used in unit doses with a volume not exceeding 1 ml. Therefore, for higher volumes (e.g., greater than 2 ml), multiple injections are typically used, but this approach may increase the dropout rate or reduce patient adherence.

[0010] Therefore, there is a need for pharmaceutical formulations with increased antibody concentrations to enable administration of high-dose antibodies, such as risankizumab, in a single injection. However, increasing the antibody concentration in antibody formulations can cause stability problems (e.g., formation of high molecular weight species (HMWS) and aggregation leading to increased viscosity). Therefore, providing a stable, high-concentration liquid antibody formulation suitable for parenteral administration, such as subcutaneous injection, is a major challenge.

[0011] overview

[0012] The present disclosure provides a liquid antibody formulation comprising 150 mg / ml of antibody, as defined herein. The antibody is risankizumab or an antibody comprising the same heavy and light chain sequences as risankizumab. Formulations of such antibodies with such high antibody concentrations have not been described or are not available in the art, and by providing such highly concentrated antibody formulations, the present disclosure makes an important contribution to the art. Despite the high antibody concentration, formulations according to the present disclosure are stable and suitable for therapeutic use. As demonstrated in the Examples, formulations according to the present disclosure comprising 150 mg / ml of the antibody risankizumab offer advantageous stability characteristics and are well suited for subcutaneous administration. They can provide long-term stability. Advantageously, a 150 mg dose of antibody can be administered in a single 1 ml injection.

[0013] According to a first aspect of the present disclosure, there is provided a liquid pharmaceutical formulation comprising 150 mg / ml of an anti-IL-23p19 antibody, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO:1 and a heavy chain amino acid sequence set forth in SEQ ID NO:2.

[0014] According to a first sub-aspect of this first aspect, the liquid pharmaceutical formulation comprises: a) 150 mg / ml of an anti-IL-23p19 antibody, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 1 and a heavy chain amino acid sequence set forth in SEQ ID NO: 2; b) a polyol; and c) Contains surfactants.

[0015] The formulation may further comprise d) a buffer. Additionally, the present disclosure provides a buffer-free formulation comprising 150 mg / ml of antibody. As disclosed herein, the liquid pharmaceutical formulation according to the first sub-aspect is stable.

[0016] According to a second sub-aspect of this first aspect, there is provided a stable liquid pharmaceutical formulation comprising: a) 150 mg / ml of an anti-IL-23p19 antibody, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 1 and a heavy chain amino acid sequence set forth in SEQ ID NO: 2; b) a tonicity adjuster; and c) surfactants, Here, the formulation has a pH of 5.5 to 5.9, and the formulation is isotonic.

[0017] The formulation may additionally comprise d) a buffer.

[0018] The 150 mg / ml antibody formulation according to the first aspect and the formulation according to the second sub-aspect may also be provided in lyophilized form.

[0019] In a related aspect, a sealed container containing a formulation according to the present disclosure is provided.

[0020] In a related aspect, the present disclosure relates to a formulation according to the present disclosure or a container containing a formulation according to the present disclosure for therapeutic treatment of a human subject. The disease to be treated may be selected from psoriasis and inflammatory bowel disease. In a further embodiment, the disease to be treated may be selected from psoriatic arthritis and Crohn's disease.

[0021] Other objects, features, advantages, and aspects of the present application will become apparent to those skilled in the art from the following description and appended claims. It should be understood, however, that the following description, appended claims, and specific examples, while indicating preferred embodiments of the application, are given by way of illustration only. [Brief explanation of the drawings]

[0022] [Figure 1] FIG. 1 shows the amino acid sequence of the antibody light chain (SEQ ID NO: 1). [Figure 2] FIG. 2 shows the amino acid sequence of the heavy chain of the antibody (SEQ ID NO: 2).

[0023] Detailed Description

[0024] 150mg / ml Antibody Formulations and Related Aspects

[0025] According to a first aspect, there is provided a liquid pharmaceutical formulation comprising 150 mg / ml of an anti-IL-23p19 antibody, wherein said antibody comprises a light chain amino acid sequence set forth in SEQ ID NO:1 and a heavy chain amino acid sequence set forth in SEQ ID NO:2.

[0026] According to a first sub-aspect of this first aspect, there is provided a liquid pharmaceutical formulation comprising: a) 150 mg / ml of an anti-IL-23p19 antibody, the antibody comprising a light chain amino acid sequence set forth in SEQ ID NO: 1 and a heavy chain amino acid sequence set forth in SEQ ID NO: 2; b) a polyol; and c) surfactants.

[0027] Formulations according to this first sub-aspect may additionally comprise d) a buffer. Further, the present disclosure provides a buffer-free formulation comprising 150 mg / ml of antibody. As disclosed herein, the liquid pharmaceutical formulations according to the first sub-aspect are stable.

[0028] According to a second sub-aspect of this first aspect, there is provided a stable liquid pharmaceutical formulation comprising: a) 150 mg / ml of an anti-IL-23p19 antibody, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 1 and a heavy chain amino acid sequence set forth in SEQ ID NO: 2; b) a tonicity adjuster; and c) surfactants, Here, the formulation has a pH of 5.5 to 5.9, and the formulation is isotonic.

[0029] The stable formulation according to this second sub-embodiment may additionally comprise d) a buffer.

[0030] The formulation according to the present disclosure contains a high antibody concentration of 150 mg / ml. Despite this high antibody concentration, the liquid pharmaceutical formulation of the present disclosure is stable and can advantageously provide long-term stability. Furthermore, the formulation according to the present disclosure addresses the central administration challenge for highly concentrated antibody formulations suitable for injection, particularly by providing suitable viscosity and good injectability, making the formulation according to the present disclosure particularly suitable for injection, such as subcutaneous injection. The advantageous features of these formulations are demonstrated in the Examples. The formulation according to the first aspect solves the challenges faced by injectable formulations by providing a stable and robust formulation containing 150 mg / ml of antibody, thereby enabling subcutaneous administration of a 150 mg dose of antibody using a target volume of only 1 ml.

[0031] As disclosed herein, the formulation according to the first aspect can be provided as a buffer-free or buffer-containing formulation. According to one central embodiment, the liquid pharmaceutical formulation according to the first aspect comprises d) a buffer. In another embodiment, the liquid pharmaceutical formulation does not comprise a buffer as an additive.

[0032] Subsequently, the components of the 150 mg / ml antibody formulation according to the first aspect are described in more detail, and in particular suitable embodiments and features of components a), b), c) and, optionally, d) contained in the formulation according to the first and second sub-aspects are disclosed.

[0033] a) Antibodies

[0034] The antibody contained in the formulation comprises a light chain amino acid sequence set forth in SEQ ID NO: 1 and a heavy chain amino acid sequence set forth in SEQ ID NO: 2. SEQ ID NOs: 1 and 2 are shown in Figures 1 and 2. The light and heavy chains of the antibody risankizumab correspond to the light and heavy chain sequences shown in SEQ ID NOs: 1 and 2. According to one embodiment, the antibody has the same light and heavy chains as the antibody risankizumab (see INN risankizumab, WHO Drug Information, Vol. 29, No. 2, 2015), and such antibodies are referred to herein as risankizumab. Advantageously, the present disclosure provides a stable, highly concentrated liquid pharmaceutical formulation of the antibody risankizumab, which is approved for the treatment of psoriasis. All disclosures provided herein are specifically directed to and apply to the antibody risankizumab contained in the disclosed formulation. Risankizumab can be recombinantly produced in a variety of host cells, although suitable cells for recombinant antibody production are known in the art.

[0035] 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 is recombinantly produced in hamster cells. In one embodiment, the antibody is recombinantly produced in CHO cells.

[0036] component b) A formulation according to a first sub-embodiment of the 150 mg / ml formulation according to the first embodiment 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.

[0037] A formulation according to a second sub-aspect of the 150 mg / ml formulation according to the first aspect comprises a tonicity adjuster as component b). A tonicity adjuster is an agent suitable for adjusting the tonicity of the formulation. Tonicity adjusters useful for adjusting the tonicity of pharmaceutical formulations are known in the art and include compounds such as salts, as well as polyols, such as sugars and sugar alcohols. Thus, the tonicity adjuster used as component b) in the stable 150 mg / ml formulation according to the second sub-aspect can be a polyol, as it is used as component b) in the 150 mg / ml formulation according to the first sub-aspect. Thus, according to one embodiment, the tonicity adjuster included in the stable liquid formulation according to the second sub-aspect is a polyol, optionally a sugar and / or a sugar alcohol.

[0038] As used herein, the term "polyol" refers to a substance with multiple hydroxyl groups, including sugars (reducing and non-reducing sugars) and sugar alcohols. Polyols can contain at least three, at least four, or at least five hydroxyl groups. In certain embodiments, polyols have a molecular weight of ≦600 Da (e.g., in the range of 120-400 Da). A "reducing sugar" is a reducing sugar that contains a free aldehyde or ketone group and can reduce metal ions or covalently react with lysine and other amino groups in proteins. A "non-reducing sugar" is a non-reducing sugar that lacks a free aldehyde or ketone group and is not oxidized by mild oxidizing agents, 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 may also be used as tonicity agents in the formulation.

[0039] Polyols can act as, and can be used as, tonicity modifiers. Certain polyols (e.g., sugars) can also act as stabilizers, thereby supporting the stability of the provided formulations.

[0040] As disclosed herein, the polyol may be selected from sugars and sugar alcohols. Furthermore, a combination of two or more different polyols may be used as component b), as also demonstrated in the examples. As shown in the examples, sugars and sugar alcohols, as well as combinations thereof, can be advantageously used in the 150 mg / ml formulation according to the present disclosure. According to one embodiment, the polyol is selected from trehalose, sucrose, sorbitol, mannitol, and combinations thereof. According to one embodiment, the formulation contains only polyols selected from sugars and / or sugar alcohols as component b). According to one embodiment, the formulation contains only a single polyol as component b).

[0041] In certain embodiments, the polyol is a sugar. The polyol may be selected from trehalose and sucrose. As shown in the examples, the formulation may contain trehalose as the polyol, but the use of trehalose is advantageous. Trehalose can be used alone or in combination with an additional polyol (e.g., an additional sugar or sugar alcohol). According to certain embodiments, the formulation contains only a single sugar, such as trehalose, as the sole polyol. It may be advantageous to use a single polyol as an excipient, for example, to adjust tonicity.

[0042] According to one embodiment, the polyol is a sugar alcohol. The sugar alcohol may be selected from sorbitol and mannitol. In an embodiment, the formulation includes mannitol as the polyol. In a further embodiment, the formulation includes sorbitol. As disclosed herein, mannitol and sorbitol can be used as a single polyol or in combination with each other or with different polyols, such as sugars or other sugar alcohols.

[0043] Sorbitol can be used to provide a stable formulation according to the present disclosure. In certain embodiments, a sorbitol-free formulation is provided. A sorbitol-free formulation is advantageous for patients with hereditary fructose intolerance. Thus, in certain embodiments, the liquid pharmaceutical formulation does not contain sorbitol. In certain embodiments, the formulation does not contain sugar alcohols.

[0044] As demonstrated in the Examples, mannitol and / or trehalose can be used as polyols in the formulations of the present disclosure to adjust the desired osmolality. However, the amount of mannitol in a 150 mg / ml formulation is limited by the solubility of mannitol and the amount of stock solution (which can be added during the formulation process). Therefore, in embodiments, mannitol is used in combination with a sugar, such as highly soluble trehalose. For the antibody formulations disclosed herein, trehalose has been found to be advantageous because it is sufficiently soluble to achieve an isotonic formulation with one excipient. Thus, in certain embodiments, trehalose is used as a polyol and may be the only polyol in the formulation used to adjust isotonicity.

[0045] Polyols can be used to adjust the osmolarity. In embodiments, the formulation has an osmolarity in the range of 200 mOsm / kg to 400 mOsm / kg, such as 225 mOsm / kg to 375 mOsm / kg. In embodiments, the osmolarity is in the range of 250 mOsm / kg to 350 mOsm / kg, such as 275 mOsm / kg to 330 mOsm / kg or 290 mOsm / kg to 320 mOsm / kg. The formulation can be isotonic, where "isotonic" means that the formulation has essentially the same osmolarity as human blood. Osmolarity can be measured, for example, using a vapor pressure or ice-freezing osmometer.

[0046] The concentration of the polyol in the formulation may be at least 80 mM or at least 95 mM. In embodiments, the concentration of the 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 the 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 central embodiment, the polyol is a sugar used in such a concentration. In one embodiment, the sugar is trehalose. The same applies with respect to the tonicity modifier used as component b) in the formulation according to the second sub-aspect. As disclosed herein, the tonicity modifier may be a polyol.

[0047] The concentration of the polyol in the formulation according to the first aspect, particularly its first and second sub-aspects, can be in the range of 95 mM to 400 mM, such as 95 mM to 300 mM or 95 mM to 250 mM. Exemplary concentration ranges for 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 one central embodiment, the polyol is a sugar used in the concentrations described herein. In one embodiment, the sugar is trehalose.

[0048] 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 160 mM to 200 mM. In a further 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. Thus, also disclosed herein is a liquid pharmaceutical formulation comprising 150 mg / ml antibody and 185 mM trehalose as the polyol. Trehalose may be added, for example, in the form of trehalose dihydrate.

[0049] c) surfactants

[0050] The liquid formulation according to the first aspect further comprises a surfactant. As demonstrated by the examples, it is advantageous to incorporate a surfactant into the 150 mg / ml formulation. The surfactant is included as component c) in the formulation according to the first and second sub-aspects of the 150 mg / ml formulation according to the first aspect.

[0051] According to one embodiment, the surfactant is a non-ionic surfactant. Non-ionic surfactants suitable for pharmaceutical formulations are known in the art and are described herein. At least one surfactant can be a polysorbate (e.g., polysorbate 20) or a poloxamer (e.g., poloxamer 188). Combinations of surfactants may also be used. In one central embodiment, the surfactant is a polysorbate. The non-ionic 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, a formulation according to the present disclosure comprises a single surfactant, for example, a single non-ionic surfactant (e.g., a single polysorbate).

[0052] In one embodiment, the surfactant concentration in the formulation is at least 0.05 mg / ml. The concentration can 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 can be a non-ionic surfactant. As disclosed herein, in a central embodiment, the surfactant is optionally a polysorbate selected from polysorbate 20 and / or polysorbate 80. In embodiments, the surfactant is polysorbate 20. Polysorbate 20 can be used advantageously at concentrations as disclosed herein, as demonstrated by the examples.

[0053] The concentration of the surfactant in the formulation may range from 0.05 mg / ml to 0.75 mg / ml. Exemplary concentration ranges for 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 concentration of the surfactant in the formulation may range 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 concentration of the surfactant in the formulation may be 0.2 mg / ml. As disclosed herein, the surfactant may be a nonionic surfactant. In a central embodiment, the surfactant is optionally a polysorbate selected from polysorbate 20 and / or polysorbate 80. In embodiments, the surfactant is polysorbate 20, which may be advantageously used in a concentration range as demonstrated by the examples.

[0054] In certain embodiments, the formulation of the present disclosure includes 0.2 mg / ml polysorbate 20 as a surfactant. The formulation may include a sugar as component b), where the sugar concentration ranges from 95 mM to 250 mM, 125 mM to 250 mM, or 145 mM to 225 mM. The sugar may be trehalose.

[0055] pH

[0056] The pH of the liquid pharmaceutical formulation (which in the central embodiment is an aqueous formulation) may be in the range of pH 5.0 to 7.5, such as pH 5.0 to 7.0.

[0057] The pH of the liquid pharmaceutical formulation may be ≦6.8, such as ≦6.7, ≦6.6, ≦6.5, ≦6.4, ≦6.3, or ≦6.2. In embodiments, the pH of the liquid pharmaceutical formulation is ≦6.1, such as ≦6.0 or ≦5.9. In embodiments, the pH of the liquid pharmaceutical formulation is ≧5.2, such as ≧5.3, ≧5.4, or ≧5.5. Exemplary ranges for the pH of a liquid pharmaceutical formulation having a 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. Exemplary pH ranges for liquid pharmaceutical formulations having a pH of 5.3 or greater 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. Exemplary pH ranges for liquid pharmaceutical formulations having a pH of 5.4 or greater 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. Exemplary pH ranges for liquid pharmaceutical formulations having a pH of 5.5 or greater 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 having a 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 further embodiments, the pH of the formulation is in the range of 5.6 to 6.0 or 5.6 to 5.9.

[0058] According to one embodiment, the pH of the liquid pharmaceutical formulation is in the range of 5.2 to 6.5. According to one embodiment, the pH of the liquid pharmaceutical formulation is in the range of 5.2 to 6.2. Lower pH values ​​showed less aggregation during stability tests and physical stress tests, as can be seen from the examples.

[0059] According to one embodiment, the pH of the liquid pharmaceutical formulation is in the range of 5.5 to 6.5. In one embodiment, the pH of the liquid pharmaceutical formulation is in the range of 5.5 to 6.2.

[0060] According to one embodiment, the pH is 5.5 to 5.9. In one embodiment, the pH is 5.6 to 5.8. A 150 mg / ml risankizumab formulation having such a pH was tested in the Examples and showed favorable characteristics.

[0061] In a further embodiment, the pH of the liquid pharmaceutical formulation is 5.7.

[0062] In a further embodiment, the pH of the liquid pharmaceutical formulation is 6.2.

[0063] As disclosed herein, the pH of the stable liquid pharmaceutical formulation according to the second sub-aspect is ∼5.9. It may be in the range of 5.5 to 5.8. In an embodiment, the pH of the stable 150 mg / ml formulation according to the second sub-aspect is 5.7.

[0064] d) buffer solution

[0065] The 150 mg / ml antibody formulation according to the first aspect can be provided as a buffer-free formulation or as a buffer-containing formulation. According to one central embodiment disclosed herein, the pharmaceutical formulation comprises d) a buffer. Formulations containing a buffer have shown in experiments a smaller increase in sliding equilibrium stress (maximum and average) compared to formulations without a buffer. Therefore, a buffer may be used as component d) in formulations according to the first and second sub-aspects of the 150 mg / ml risankizumab formulation according to the first aspect.

[0066] A buffer can be used to maintain the solution pH of the liquid pharmaceutical formulation. Suitable buffers for pharmaceutical formulations are known in the art and are described herein. The buffer can be an organic buffer. According to one embodiment, the buffer has a pKa within 1.5 or 1 pH unit of the final pH of the liquid pharmaceutical formulation at 25°C. In certain embodiments, the buffer has a pKa in the range of pH 4.2 to 7.2 or 4.5 to 7 at 25°C. The buffer can include a combination of buffers. In one embodiment, a single buffer is used in the formulation as component d).

[0067] The formulation may comprise a carboxylic acid buffer as buffer d).

[0068] According to one embodiment, the buffer is selected from acetate buffer and succinate buffer. As demonstrated by the Examples, formulations containing such buffers provide advantageous stability characteristics for high concentration formulations of the antibodies provided herein. In a further embodiment, the buffer is a histidine buffer.

[0069] In one embodiment, the buffer is an acetate buffer. The acetate buffer may include sodium acetate and acetic acid. Other acetate salts may also be used in acetate buffers.

[0070] Additional buffers that may be used include, but are not limited to, citrate, glutamate, glycine, lactic acid, maleate, phosphate, or tartaric acid buffers.

[0071] The presence of buffer salts may support the stability of the included antibody according to the risankizumab of the present disclosure.

[0072] According to one embodiment, the buffer d) included in the formulation is not a succinate buffer. In certain embodiments, the formulation does not include a succinate buffer. In certain embodiments, a single buffer is used, which is an acetate buffer, for example, provided by an acetate salt (e.g., sodium acetate) and acetic acid.

[0073] If used, the buffer is included in an amount sufficient to maintain the selected pH of the formulation at storage conditions for the shelf life of the product.

[0074] The liquid pharmaceutical formulations disclosed herein may comprise at least 1 mM, at least 2 mM, 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 further embodiments, 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 further embodiments, the buffer concentration is 20 mM or less or 15 mM or less. Exemplary concentration ranges for the included buffer 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. Further 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 a concentration as described.

[0075] In embodiments, the buffer concentration is 20 mM or less, or 15 mM or less. In further embodiments, 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 embodiments, the buffer concentration is 10 mM.

[0076] In certain embodiments, the formulation comprises a single buffer, hi certain embodiments, the single buffer is an acetate buffer.

[0077] Specific embodiments of buffer-containing formulations comprising 150 mg / ml antibody

[0078] According to one embodiment, the liquid pharmaceutical formulation comprises: a) 150 mg / ml of antibody; b) sugar; c) nonionic surfactants; and d) containing a buffer solution; Optionally, the pH of the formulation is in the range of pH 5.2 to pH 6.5, such as 5.2 to 6.2 or 5.5 to 6.2.

[0079] Suitable concentrations and embodiments for 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 non-ionic 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 can be trehalose, and the non-ionic surfactant can be a polysorbate, such as polysorbate 20. The pH can be 5.7. In a further embodiment, the pH is 6.2.

[0080] According to one embodiment, the liquid pharmaceutical formulation comprises: a) 150 mg / ml of antibody; b) trehalose; c) polysorbates; and d) containing a buffer solution; Optionally, the pH of the formulation is in the range of pH 5.2 to pH 6.5, such as 5.2 to 6.2 or 5.5 to 6.2.

[0081] Suitable concentrations and embodiments for 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 can be 5.7. In a further embodiment, the pH is 6.2.

[0082] The buffer contained in these liquid pharmaceutical formulations can be acetic acid or succinic acid, and optionally the buffer concentration is in the range of 5 mM to 25 mM. The polysorbate can be polysorbate 20.

[0083] According to one embodiment, the liquid pharmaceutical formulation comprises: a) 150 mg / ml of antibody; b) 170mM-200mM trehalose; c) 0.1 mg / ml to 0.3 mg / ml polysorbate, optionally polysorbate 20; and d) a buffer, optionally wherein the buffer is an acetate buffer.

[0084] The pH of this formulation is 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.

[0085] According to one embodiment, the liquid pharmaceutical formulation comprises: a) 150 mg / ml of antibody; b) 185 mM trehalose; c) 0.2 mg / ml polysorbate 20; and d) containing 10 mM acetate buffer; The pH is 5.7.

[0086] The liquid formulation may be an aqueous formulation and, in one embodiment, does not contain any further additives.

[0087] Specific embodiments of buffer-free formulations comprising 150 mg / ml antibody

[0088] As disclosed herein, there is also provided a buffer-free liquid pharmaceutical formulation, particularly an aqueous formulation. According to one embodiment, the liquid pharmaceutical formulation comprises: a) 150 mg / ml of antibody; b) a polyol, optionally the polyol is a sugar or sugar alcohol; and c) a non-ionic surfactant, optionally including a polysorbate; d) Buffer-free.

[0089] As described above, the present disclosure also provides buffer-free formulations, in which no buffer is added as an excipient. At 150 mg / ml, antibodies having light and heavy chain sequences as shown in SEQ ID NOs: 1 and 2 have high buffering capacity. Storage-stable buffer-free formulations can be provided based on the disclosure provided herein, as also shown in the Examples.

[0090] In embodiments, the pH of the buffer-free formulation is in the range of pH 5.2 to pH 6.5. The pH can 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 a further embodiment, the pH is 6.2.

[0091] In embodiments, 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, the disclosure of which is incorporated herein by reference. In one embodiment, the sugar is trehalose.

[0092] According to one embodiment, the concentration of the non-ionic 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 non-ionic surfactant is a polysorbate, which may be selected from polysorbate 20 and polysorbate 80, and in one embodiment is polysorbate 20.

[0093] Further optional ingredients

[0094] In one embodiment, the liquid pharmaceutical formulation according to the present disclosure comprises an amino acid as a further additive. Suitable embodiments of amino acids that can be added as excipients to the pharmaceutical formulation are known in the art and are also disclosed in the Examples.

[0095] In one embodiment, the formulation includes an amino acid with a charged side chain, optionally a positively charged side chain. An example of such an amino acid is L-arginine.

[0096] According to one embodiment, the formulation comprises an amino acid, which is present in the formulation as a salt, optionally a hydrochloride (HCl) salt.

[0097] According to one embodiment, the formulation comprises methionine. According to one embodiment, the formulation comprises the amino acid L-proline.

[0098] According to one embodiment, the 150 mg / ml formulation according to the present disclosure does not contain arginine. The arginine-containing formulation was found to exhibit a slightly elevated particle count during freeze / thaw stress testing, as well as higher turbidity values, although there was no increase in turbidity over time. The viscosity was found to be higher. The amount of aggregates was slightly lower compared to other formulations containing 150 mg / ml antibody but not containing arginine.

[0099] According to one embodiment, a formulation according to the present disclosure does not include an amino acid with a positively charged side chain as an excipient. According to one embodiment, a formulation according to the present disclosure does not include an amino acid with a charged side chain as an excipient. According to one embodiment, a formulation according to the present disclosure does not include methionine as an excipient. According to one embodiment, a formulation according to the present disclosure does not include an amino acid as an additive.

[0100] Other excipients known in the art can be used in the formulation as long as they do not negatively affect stability.

[0101] However, in certain embodiments, additional excipients are not included in the formulations of the present disclosure. It is particularly advantageous to be able to provide a storage-stable formulation of the antibody risankizumab with a formulation consisting essentially of, or consisting of, a) antibody (150 mg / ml); component b); c) surfactant, and, optionally, d) buffer. As disclosed herein, it is advantageous for the formulation to include only a single polyol, a single surfactant, and a single buffer (if present). This provides an uncomplicated, storage-stable formulation for a 150 mg / ml formulation of the antibody risankizumab.

[0102] stability characteristics

[0103] As disclosed herein, a liquid pharmaceutical formulation comprising 150 mg / ml of antibody is provided that is advantageously stable. Providing such a stable, high-concentration formulation of the antibody risankizumab is particularly advantageous for therapeutic uses.

[0104] In embodiments, a stable antibody formulation is one in which the antibody essentially retains its physical stability and / or biological activity upon storage. Various analytical techniques for measuring protein stability are available in the art and are disclosed herein. Stability can be measured at a selected temperature and for a selected period of time.

[0105] The stability characteristics of various liquid pharmaceutical formulations containing 150 mg / ml of antibody according to the present disclosure were tested in the Examples and demonstrated advantageous stability characteristics.

[0106] In embodiments, stable liquid pharmaceutical formulations of the present disclosure do not exhibit significant change at refrigerated temperatures (2-8° C.) for at least 3 months, e.g., 6 months, or 1 year, or even up to 2 years or more. Stable liquid formulations include those that exhibit desired characteristics for periods including 1 month, 3 months, 6 months, 12 months, and / or 24 months at temperatures including 25° C. and 40° C.

[0107] An antibody retains its physical stability in a pharmaceutical formulation if it does not exhibit a significant increase in aggregation, precipitation, and / or denaturation, particularly upon visual inspection of color and / or clarity or as measured by UV light scattering, size exclusion chromatography (SEC), and / or dynamic light scattering. Protein conformational changes can be assessed by fluorescence spectroscopy, which determines protein tertiary structure, and by FTIR spectroscopy, which determines protein secondary structure.

[0108] An antibody retains its biological activity in a pharmaceutical formulation, particularly if the biological activity of the antibody at a given time point is within a predetermined range of the biological activity exhibited at the time the pharmaceutical formulation was prepared. The biological activity of an antibody can be determined, for example, by antigen binding assays.

[0109] Aggregates can vary in origin, size, and type. Aggregates that can affect the efficacy or safety of a biological product are of particular concern, for example, aggregates that can enhance immune responses and cause adverse clinical effects. High-molecular-weight aggregates, also referred to as high-molecular-weight species (HMWS), can be of particular concern. Aggregation can also potentially affect the subcutaneous bioavailability and pharmacokinetics of therapeutic proteins. Advantageously, the present disclosure provides formulations with low levels of high-molecular-weight species even over extended storage times. The present disclosure provides stabilized (or stable) aqueous pharmaceutical formulations, particularly as demonstrated by a reduced amount of aggregates and / or a reduced rate of aggregate formation after storage. As described herein, the stability of such formulations is indicated by a reduced amount of HMWS and / or a reduced rate of HMWS formation after storage over varying periods and at varying temperatures. Generally, a more stable formulation is associated with a lower amount of HMWS, a lower rate of HMWS formation, and / or a higher antibody main peak at higher storage temperatures compared to lower temperatures. As used herein, the term "high molecular weight species" or "HMWS" refers to higher order aggregates of the antibody in the formulation, as well as lower order aggregates of the antibody in the formulation. Lower order aggregates include, for example, dimeric species. The amount and rate of aggregate formation may be measured or monitored by various techniques, including those disclosed in the Examples.

[0110] As used herein, the term "low molecular weight species" or "LMWS" refers specifically to fragments of antibodies that are smaller than a monomer, and includes, but is not limited to, free light chains, free heavy chains, molecules containing one light chain and one heavy chain, antibody molecules lacking one or both light chains, and antibody fragments obtained by cleavage of the polypeptide chain, such as proteolytic fragments or other enzymatically or chemically degraded antibody molecules.

[0111] In certain embodiments, the antibodies in the formulations disclosed herein are maintained in essentially monomeric form during storage. In certain embodiments, the formulations may meet one or more of the following stability characteristics:

[0112] In certain embodiments, after 36 months of storage at 5° C., at least 94% of the antibody is present as a monomer and / or the relative monomer content of the antibody does not decrease by more than 3% or more than 2.5% as measured by UP-SEC. In certain embodiments, after 36 months of storage at 5° C., at least 95% or at least 96% of the antibody is present as a monomer and / or the relative monomer content of the antibody does not decrease by more than 2% or more than 1.5% as measured by UP-SEC. In certain embodiments, after 24 months of storage at 5° C., at least 94% of the antibody is present as a monomer and / or the relative monomer content of the antibody does not decrease by more than 3% or more than 2.5% as measured by UP-SEC. In certain embodiments, after 24 months of storage at 5° C., at least 95% or at least 96% of the antibody is present as a monomer 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%, as measured by UP-SEC. In certain embodiments, after 9 months of storage at 5° C., at least 96% or at least 96.5% of the antibody is present as a monomer and / or the relative monomer content of the antibody does not decrease by more than 1.5%, or more than 1%, as measured by UP-SEC. In certain embodiments, after 3 months of storage at 5° C., at least 96% or at least 97% of the antibody is present as a monomer 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%, as measured by UP-SEC. In certain embodiments, after 12 months of storage at 25°C, at least 90% or at least 92% of the antibody is present as a monomer, and / or the relative monomer content of the antibody does not decrease by more than 7%, or more than 6%, or more than 5%, as measured by UP-SEC.In certain embodiments, after storage for 3 months at 25° C., at least 95% of the antibody is present as a monomer and / or the relative monomer content of the antibody does not decrease by more than 3% or more than 2% as measured by UP-SEC. In certain embodiments, after storage for 1 month at 25° C., at least 96% of the antibody is present as a monomer and / or the relative monomer content of the antibody does not decrease by more than 2% or more than 1% as measured by UP-SEC. In certain embodiments, after storage for 3 months at 40° C., at least 87% or at least 88% of the antibody is present as a monomer and / or the relative monomer content of the antibody does not decrease by more than 10%, more than 9%, or more than 8% as measured by UP-SEC. In certain embodiments, after storage at 40° C. for 1 month, at least 93% or at least 94% of the antibody is present as a monomer, and / or the relative monomer content of the antibody does not decrease by more than 5% or more than 4%, as measured by UP-SEC. In certain embodiments, after shaking at 25° C. for 21 days, at least 95% or at least 96% of the antibody is present as a monomer, and / or the relative monomer content of the antibody does not decrease by more than 2% or more than 1%, as measured by UP-SEC. The decrease in relative monomer content is calculated for the indicated storage time and temperature, and is determined, in particular, by comparing the relative monomer content at the beginning and end of the indicated storage. In certain embodiments, the measurement is performed as described in the Examples.

[0113] In certain embodiments, the antibodies in the formulations disclosed herein do not form significant amounts of HMWS during storage. In particular, the formulations meet one or more of the following stability characteristics:

[0114] In certain embodiments, after 36 months of storage at 5° C., less than 4% or less than 3% of the antibody is present as HMWS, and / or the relative HMWS content of the antibody does not increase by more than 2%, or more than 1.5%, as measured by UP-SEC. In certain embodiments, after 24 months of storage at 5° C., less than 4% or less than 3% of the antibody is present as HMWS, 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%, as measured by UP-SEC. In certain embodiments, after 9 months of storage at 5° C., less than 4%, or less than 3%, or less than 2.5% of the antibody is present as HMWS, and / or the relative HMWS content does not increase by more than 1%, or more than 0.8%, or more than 0.6%, as measured by UP-SEC. In certain embodiments, after 3 months of storage at 5° C., less than 4%, or less than 3%, or less than 2.5% of the antibody is present as HMWS, and / or the relative HMWS content does not increase by more than 1%, or more than 0.8%, or more than 0.6%, as measured by UP-SEC. In certain embodiments, after 12 months of storage at 25° C., less than 5% or less than 4% of the antibody is present as HMWS, and / or the relative HMWS content of the antibody does not increase by more than 3%, or more than 2.5%, or more than 2%, as measured by UP-SEC. In certain embodiments, after 3 months of storage at 25° C., less than 4%, or less than 3.5%, or less than 3.2% of the antibody is present as HMWS, and / or the relative HMWS content of the antibody does not increase by more than 2%, or more than 1.5%, as measured by UP-SEC. In certain embodiments, 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 as HMWS, and / or the relative HMWS content of the antibody does not increase by more than 1.5%, or more than 1%, as measured by UP-SEC.In certain embodiments, after 3 months of storage at 40° C., less than 6.5%, or less than 6%, or less than 5.5% of the antibody is present as HMWS, and / or the relative HMWS content of the antibody does not increase by more than 5%, or more than 4%, as measured by UP-SEC. In certain embodiments, after 1 month of storage at 40° C., less than 5%, or less than 4.5%, or less than 4% of the antibody is present as HMWS, and / or the relative HMWS content does not increase by more than 2.5%, or more than 2%, as measured by UP-SEC. In certain embodiments, after 21 days of shaking at 25° C., less than 3% or less than 2% of the antibody is present as HMWS, and / or the relative HMWS content of the antibody does not increase by more than 2%, more than 1.5%, or more than 1%, as measured by UP-SEC. The increase in relative HMWS content is calculated for the indicated storage time and temperature, and is determined, in particular, by comparing the relative HMWS content at the beginning and end of the indicated storage. In certain embodiments, the measurement is performed as described in the Examples.

[0115] In further embodiments, the antibodies in the formulations disclosed herein do not form significant amounts of LMWS during storage. In certain embodiments, the formulations may meet one or more of the following stability characteristics:

[0116] In certain embodiments, after 36 months of storage at 5° C., less than 2% or less than 1.5% of the antibody is present as LMWS and / or the relative LMWS content of the antibody does not increase by more than 1.5%, or more than 1.5%, or more than 0.5%, as measured by UP-SEC. In certain embodiments, after 24 months of storage at 5° C., less than 2% or less than 1.5% of the antibody is present as LMWS and / or the relative LMWS content of the antibody does not increase by more than 1.5%, or more than 1.5%, or more than 0.5%, as measured by UP-SEC. In certain embodiments, after 9 months of storage at 5° C., less than 2% or less than 1.5% of the antibody is present as LMWS and / or the relative LMWS content of the antibody does not increase by more than 1.5%, or more than 1.5%, or more than 0.5%, as measured by UP-SEC. In certain embodiments, after 3 months of storage at 5° C., less than 2%, or less than 1.5%, or less than 1% of the antibody is present as LMWS, and / or the relative LMWS content of the antibody does not increase by more than 1%, or more than 0.5%, or more than 0.25%, as measured by UP-SEC. In certain embodiments, after 12 months of storage at 25° C., less than 6%, or less than 5%, or less than 4.5% of the antibody is present as LMWS, and / or the relative LMWS content of the antibody does not increase by more than 5%, or more than 4%, or more than 3%, as measured by UP-SEC. In certain embodiments, after 3 months of storage at 25° C., less than 3%, or less than 2%, or less than 1.8% of the antibody is present as LMWS, and / or the relative LMWS content of the antibody does not increase by more than 2%, or more than 1.5%, or more than 1%, as measured by UP-SEC. In certain embodiments, 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 as LMWS, and / or the relative LMWS content of the antibody does not increase by more than 1%, or more than 0.6%, or more than 0.4%, as measured by UP-SEC.In certain embodiments, after 3 months of storage at 40°C, less than 8%, less than 7%, or less than 6% of the antibody is present as LMWS, 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 certain embodiments, after 1 month of storage at 40°C, less than 4%, less than 3.5%, or less than 3% of the antibody is present as LMWS, 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 determined, in particular, by comparing the relative LMWS content at the beginning and end of the indicated storage. In certain embodiments, measurements are performed as described in the Examples.

[0117] In certain embodiments, the relative amounts of antibody, HMWS, and / or LMWS in monomeric form are determined using UP-SEC, particularly as described in the Examples. For example, an ultra-performance liquid chromatography (UPLC) system, such as an Acquity UPLC system from Waters (Milford, Massachusetts, USA), containing a size-exclusion chromatography (SEC) column is used. Proteins eluted from the SEC column may be detected by UV absorbance at 280 nm, and the relative amounts may be determined by calculating the area under the curve (AUC) for each elution peak. Peaks are assigned to different species by their elution times, which correspond to the molecular size of the species. To measure the relative monomer content, relative HMWS content, and / or relative LMWS content of antibodies, particularly monomeric antibodies, in a formulation, HMWS and LMWS, if present in the formulation, are separated from each other. In particular, the relative contents or amounts are expressed as percentage values, with the sum of the monomeric antibody, HMWS, and LMWS being 100%.

[0118] In certain embodiments, the turbidity or opalescence of the formulations disclosed herein does not increase significantly during storage. In certain embodiments, the formulations may meet one or more of the following stability characteristics:

[0119] In certain embodiments, after storage for at least 36 months at 5° C., the formulation has an opalescence of 12 FNU (formazin turbidity units) or less, or 10 FNU or less, and / or the opalescence does not increase by more than 5 FNU or by more than 3 FNU. In certain embodiments, after storage for at least 3, 6, 9, 12, 18, or 24 months at 5° C., the formulation has an opalescence of 12 FNU (formazin turbidity units) or less, or 10 FNU or less, and / or the opalescence does not increase by more than 5 FNU or by more than 3 FNU. In certain embodiments, after storage for at least 1, 3, 6, 9, or 12 months at 25° C., the formulation has an opalescence of 12 FNU or less, or 10 FNU or less, and / or the opalescence does not increase by more than 7 FNU or by more than 5 FNU. In certain embodiments, after storage at 40° C. for at least 1 or 3 months, the formulation has an opalescence of 12 FNU or less, or 10 FNU or less, and / or the opalescence does not increase by more than 5 FNU or more than 3 FNU. In certain embodiments, after shaking at 25° C. for 21 days, the formulation has an opalescence of 12 FNU or less, or 10 FNU or less, and / or the opalescence of the formulation does not increase by more than 3 FNU or more than 2 FNU. The increase in opalescence is calculated for the storage time and temperature indicated, and is determined, in particular, by comparing the opalescence at the beginning and end of the storage indicated. In certain embodiments, measurements are performed as described in the Examples.

[0120] In certain embodiments, opalescence or turbidity is measured according to Pharmacopoeias or industry standard IOS 7027. In certain embodiments, the opalescence or turbidity of a formulation is determined using a nephelometer, such as a HACH Lange opalescence meter from Hach-Lange GmbH (Germany), particularly as described in the Examples. Opalescence may be measured at different wavelengths, including 400-600 nm. In embodiments, the FNA values ​​shown above are measured at 400-600 nm. Higher FNU values ​​indicate higher opalescence and turbidity.

[0121] In certain embodiments, the antibodies in the formulations disclosed herein do not form significant additional amounts of acidic or basic variants during storage. In certain embodiments, the formulations may meet one or more of the following stability characteristics:

[0122] In certain embodiments, after storage for 36 months at 5° C., at least 55%, at least 60%, or at least 65% of the antibody is present as the main peak variant, and / or the relative content of the antibody's main peak variant does not decrease by more than 8%, more than 7%, or more than 5%, as determined by ion exchange chromatography (IEC). In certain embodiments, after storage for 24 months at 5° C., at least 55%, at least 60%, or at least 65% of the antibody is present as the main peak variant, and / or the relative content of the antibody's main peak variant does not decrease by more than 8%, more than 7%, or more than 5%, as determined by ion exchange chromatography (IEC). In certain embodiments, after storage for 6 months at 5° C., at least 60% or at least 65% of the antibody is present as the main peak variant, and / or the relative content of the antibody's main peak variant does not decrease by more than 5% or more than 4%, as determined by ion exchange chromatography (IEC). In certain embodiments, after storage for 3 months at 5° C., at least 60% or at least 65% of the antibody is present as the main peak variant, and / or the relative content of the antibody's main peak variant does not decrease by more than 4%, or more than 3%, or more than 2%, as determined by ion exchange chromatography (IEC). In certain embodiments, after storage for 12 months at 25° C., at least 35%, or at least 40%, or at least 45% of the antibody is present as the main peak variant, and / or the relative content of the antibody's main peak variant does not decrease by more than 35%, or more than 30%, or more than 25%, as determined by ion exchange chromatography (IEC). In certain embodiments, after storage for 3 months at 25° C., at least 55% or at least 60% of the antibody is present as the main peak variant, and / or the relative content of the antibody's main peak variant does not decrease by more than 15%, or more than 10%, as determined by ion exchange chromatography (IEC).In certain embodiments, after storage for 1 month at 25° C., at least 60% or at least 65% of the antibody is present as the main peak variant, and / or the relative content of the antibody's main peak variant does not decrease by more than 10% or more than 5%, as determined by ion exchange chromatography (IEC). In certain embodiments, after storage for 36 months at 5° C., less than 30% or less than 28% of the antibody is present as the acidic peak group variant, and / or the relative content of the antibody's acidic peak group variant does not increase by more than 4%, more than 3%, or more than 2%, as determined by ion exchange chromatography (IEC). In certain embodiments, after storage for 24 months at 5° C., less than 30% or less than 28% of the antibody is present as the acidic peak group variant, and / or the relative content of the antibody's acidic peak group variant does not increase by more than 4%, more than 3%, or more than 2%, as determined by ion exchange chromatography (IEC). In certain embodiments, after 6 months of storage at 5° C., less than 30% or less than 28% of the antibody is present as an acidic peak group variant and / or the relative content of the antibody's acidic peak group variant does not increase by more than 4%, or more than 3%, or more than 2%, as determined by ion exchange chromatography (IEC). In certain embodiments, after 3 months of storage at 5° C., less than 30% or less than 28% of the antibody is present as an acidic peak group variant and / or the relative content of the antibody's acidic peak group variant does not increase by more than 3%, or more than 2%, or more than 1%, as determined by ion exchange chromatography (IEC). In certain embodiments, after 12 months of storage at 25°C, less than 50%, less than 45%, or less than 40% of the antibody is present as the acidic peak group variant, and / or the relative content of the acidic peak group variant of the antibody does not increase by more than 30%, or more than 25%, or more than 20%, as determined by ion exchange chromatography (IEC).In certain embodiments, after storage for 3 months at 25° C., less than 40%, or less than 35%, or less than 30% of the antibody is present as an acidic peak group variant, and / or the relative content of the antibody's acidic peak group variant does not increase by more than 10%, or more than 8%, or more than 6%, as determined by ion exchange chromatography (IEC). In certain embodiments, after storage for 1 month at 25° C., less than 35%, or less than 30%, or less than 28% of the antibody is present as an acidic peak group variant, and / or the relative content of the antibody's acidic peak group variant does not increase by more than 4%, or more than 3%, as determined by ion exchange chromatography (IEC). In certain embodiments, after 36 months of storage at 5° C., less than 20%, less than 17%, less than 15%, or less than 13% of the antibody is present as a basic peak group variant, and / or the relative content of the antibody's basic peak group variants does not increase by more than 10%, or more than 8%, or more than 6%, as determined by ion exchange chromatography (IEC). In certain embodiments, after 24 months of storage at 5° C., less than 20%, less than 17%, less than 15%, or less than 13% of the antibody is present as a basic peak group variant, and / or the relative content of the antibody's basic peak group variants does not increase by more than 10%, or more than 8%, or more than 6%, as determined by ion exchange chromatography (IEC). In certain embodiments, after 6 months of storage at 5° C., less than 15% or less than 10% of the antibody is present as a basic peak group variant, and / or the relative content of the antibody's basic peak group variants does not increase by more than 4%, or more than 3%, or more than 2%, as determined by ion exchange chromatography (IEC). In certain embodiments, after 3 months of storage at 5° C., less than 15% or less than 10% of the antibody is present as a basic peak group variant, and / or the relative content of the antibody's basic peak group variants does not increase by more than 3%, or more than 2%, as determined by ion exchange chromatography (IEC).In certain embodiments, after 12 months of storage at 25° C., less than 30%, or less than 25%, or less than 22% of the antibody is present as a basic peak group variant, and / or the relative content of the antibody's basic peak group variants does not increase by more than 25%, or more than 20%, or more than 15%, as determined by ion exchange chromatography (IEC). In certain embodiments, after 3 months of storage at 25° C., less than 20%, or less than 15%, or less than 12% of the antibody is present as a basic peak group variant, and / or the relative content of the antibody's basic peak group variants does not increase by more than 9%, or more than 7%, or more than 5%, as determined by ion exchange chromatography (IEC). In certain embodiments, after storage at 25° C. for 1 month, less than 15%, or less than 10%, or less than 9% of the antibody is present as basic peak group variants, and / or the relative content of basic peak group variants of the antibody does not increase by more than 3%, or more than 2%, as determined by ion exchange chromatography (IEC). 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 determined, in particular, by comparing the relative content of each peak variant at the beginning and end of the indicated storage. In certain embodiments, the measurements are performed as described in the Examples.

[0123] In certain embodiments, the relative amounts of antibodies that are main peak variants, acidic peak variants, and / or basic peak variants are determined using ion exchange chromatography (IEC), particularly as described in the Examples. In particular, weak cation exchange chromatography (WCX) is used. For example, a high-performance liquid chromatography (HPLC) system, such as an Alliance HPLC system from Waters (Milford, Massachusetts, USA), containing a WCX column is used. Proteins eluted from the WCX column may be detected by UV absorbance at 280 nm, and the relative amounts may be determined by calculating the area under the curve (AUC) for each elution peak or each group of elution peaks. Peaks may be assigned to different species depending on the elution conditions corresponding to the surface charge of the antibody species. The main peak is the largest peak in the IEC chromatogram of undegraded antibody. For stability analysis, measurements can be performed after preparation of the formulation (TO) and then after the indicated storage time under the indicated storage conditions. The acidic peak group (APG) includes all peaks preceding the main peak. These peaks contain antibody variants that are more acidic than the main peak native antibody variant and / or have more negative charges on their surface under chromatographic conditions. The basic peak group includes all peaks after the main peak. These peaks contain antibody variants that are more acidic than the main peak native antibody variant and / or have more positive charges on their surface under chromatographic conditions. To measure the relative amounts of the main peak variant, acidic peak group variants, and / or basic peak group variants of an antibody in a formulation, the main peak is specifically separated from the acidic peak group and basic peak group (if present in the formulation). In particular, the relative content or amount is expressed as a percentage value, where the sum of the main peak variant, acidic peak group variant, and basic peak group variant is 100%.

[0124] In certain embodiments, the antibody in the formulations disclosed herein essentially maintains its specific binding activity to human IL-23 during storage. In certain embodiments, the formulations meet one or more of the following stability characteristics:

[0125] In certain embodiments, after 36 months of storage at 5° C., at least 95% or at least 97% of the specific binding activity to IL-23 is measured relative to a reference antibody, where the reference antibody has not been stored. In certain embodiments, after 4, 6, 9, 12, 18, or 24 months of storage at 5° C., at least 95% or at least 97% of the specific binding activity to IL-23 is measured relative to a reference antibody, where the reference antibody has not been stored. In certain embodiments, after 2, 3, 4, 6, 9, 12, or 18 months of storage at 25° C., at least 93% or at least 96% of the specific binding activity to IL-23 is measured relative to a reference antibody, where the reference antibody has not been stored. In certain embodiments, after 3, 4, or 6 months of storage at 40° C., at least 90% or at least 95% of the specific binding activity to IL-23 is measured relative to a reference antibody, where the reference antibody has not been stored. In certain embodiments, the measurement is performed as described in the Examples.

[0126] In certain embodiments, the specific binding activity of the antibody in the formulation to human IL-23 is determined using surface plasmon resonance measurements, for example using a Biacore instrument, such as a Biacore T200 from GE Healthcare Life Science (UK), particularly as described in the Examples.

[0127] Further features of the liquid pharmaceutical formulation according to the first aspect

[0128] In an advantageous embodiment, the liquid pharmaceutical formulation of the present disclosure is an aqueous formulation. All liquid formulations disclosed herein are, in one embodiment, aqueous formulations. 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 sub-aspects disclosed herein, unless the specific context indicates otherwise.

[0129] According to one embodiment, the dynamic viscosity of the liquid pharmaceutical formulation according to the first aspect, measured at 20°C, is ≦30 mPas (mPa·s), such as ≦25 mPas or ≦20 mPas. In an embodiment, the dynamic viscosity of the formulation, measured at 20°C, is ≦18 mPas, such as ≦16 mPas, ≦15 mPas, ≦14 mPas, ≦13 mPas, or ≦12 mPas. In certain embodiments, the dynamic viscosity makes the formulation suitable for subcutaneous administration, as also shown in the Examples. The dynamic viscosity may be determined as described in the Examples.

[0130] According to one embodiment, a formulation of the present disclosure has a conductivity in the range of 0.8-5 mS / cm. In embodiments, the conductivity range is 1-2 mS / cm or 1.2-1.8 mS / cm. In embodiments, the formulation is characterized by a change in conductivity over a storage time of at least 12 months at 25°C of ≦1 mS / cm, e.g., ≦0.75 mS / cm, ≦0.5 mS / cm, or ≦0.3 mS / cm.

[0131] The liquid formulation according to the present disclosure is a pharmaceutical formulation, which refers specifically to a composition that is in a form that renders the active ingredient (here, an antibody comprising a light chain set forth in SEQ ID NO: 1 and a heavy chain set forth in SEQ ID NO: 2) effective and does not contain additional ingredients that are toxic to a subject to whom the formulation may be administered.

[0132] The formulations according to the first aspect disclosed herein are advantageously suitable for parenteral delivery. Parenteral administration includes, for example, subcutaneous, intramuscular, intradermal, and intramedullary injections, as well as intrathecal, direct intracerebroventricular, intravenous, intraperitoneal, and intravitreal injections. Drugs can be administered in a variety of conventional ways, such as intraperitoneal, parenteral, intraarterial, or intravenous injections. In one embodiment, the disclosed formulations are injectable formulations. The formulations disclosed herein are in embodiments 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 overall characteristics that make the formulation particularly suitable for subcutaneous administration. The high concentration allows for the administration of a small volume of the formulation while still achieving a high antibody dose (e.g., 1 ml for a 150 mg dose). Furthermore, the formulations according to the present disclosure exhibit good injectability. They further have advantageous viscosity and osmolality characteristics, achieving good sliding equilibrium stress (maximum and average) even during storage, as disclosed in the Examples. In embodiments, liquid pharmaceutical formulations according to the present disclosure are isotonic with the intended site of administration. For example, if the formulation is intended for parenteral administration, it may be isotonic with blood (which has an osmolality of about 300 mOsm / kg). Suitable osmolality ranges are described elsewhere.

[0133] Liquid antibody formulations can be made by taking a drug substance that is in liquid form (e.g., in an aqueous pharmaceutical formulation), buffer-exchanging it, and preparing it in the desired buffer as the final step in the purification process. The drug substance in the final buffer can be concentrated to the desired concentration, or a more concentrated form of the antibody can be diluted to achieve a concentration of 150 mg / ml. Concentration of the formulation can be done by any suitable method. In one embodiment, the concentration process can include ultrafiltration.

[0134] In one central embodiment, the liquid pharmaceutical formulation according to the first aspect is not a formulation prepared by reconstituting a lyophilized formulation. In this central 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 drug substance, which may be diluted to a final protein concentration of 150 mg / ml using an appropriate buffer. Pharmaceutical formulations used for in vivo administration are typically sterile. In certain embodiments, this may be achieved by filtration through a sterile filtration membrane. The final, formulated drug substance may be filtered in this manner (e.g., using a 0.22 μm filter) and filled into the final container (e.g., a glass vial or syringe). In this embodiment, the prepared liquid formulation is for direct administration to a patient, and therefore does not undergo a lyophilization or reconstitution step. Such liquid pharmaceutical formulations are disclosed herein and have also been prepared and analyzed in the Examples.

[0135] Lyophilized and reconstituted pharmaceutical formulations

[0136] According to one embodiment, the liquid pharmaceutical formulation according to the first aspect is prepared from a lyophilized formulation by reconstitution. Thus, in an embodiment, the liquid pharmaceutical composition described herein is a reconstituted formulation. This applies to the liquid formulations according to the first and second sub-aspects of the 150 mg / ml antibody formulation according to the first aspect.

[0137] The terms "lyophilization" or "lyophilized" refer to a process in which the material to be dried is first frozen, and then the ice or freezing solvent is removed by sublimation in a vacuum environment. Such techniques are well known in the art and therefore will not be described in detail herein. Excipients may be included in the pre-freeze dried formulation to enhance the stability of the lyophilized product during storage. Lyophilized formulations may contain cryoprotectants, which generally include agents that provide protein stability against freezing-induced stresses. They may also provide protection during primary and secondary drying, as well as long-term product storage. Examples include sugars, such as sucrose and trehalose, and surfactants, such as polysorbates. Lyophilized formulations may also contain cryoprotectants, which include agents that provide protein stability during the drying or dehydration process (primary and secondary drying cycles). This helps maintain protein conformation, minimize protein degradation during the lyophilization cycle, and improve long-term product stability. Examples include polyols, such as sugars (e.g., sucrose and trehalose). The liquid pharmaceutical formulations disclosed according to the first aspect include cryoprotectants and / or cryoprotectant-qualified excipients. Thus, lyophilized formulations can be prepared from such formulations. In one embodiment, the antibody risankizumab is formulated as a lyophilized powder for reconstitution and use for intravenous administration.

[0138] A "reconstituted" formulation is one prepared by dissolving a lyophilized pharmaceutical antibody formulation in a diluent such that the antibody is dispersed in the reconstituted formulation. The reconstituted formulation is suitable for administration, and in some cases may be suitable for subcutaneous administration.

[0139] The lyophilized formulation is prepared in anticipation of reconstitution with the antibody at the desired concentration, here 150 mg / ml.

[0140] According to one embodiment, a lyophilized formulation of an anti-IL-23p19 antibody is provided, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 1 and a heavy chain amino acid sequence set forth in SEQ ID NO: 2. According to one embodiment, a lyophilized formulation of the antibody risankizumab is defined with respect to the solution (e.g., pre-lyophilization solution) used to make the lyophilized formulation. The lyophilized formulation is made by lyophilizing a liquid 150 mg / ml antibody formulation according to a first aspect, such as a liquid pharmaceutical formulation according to the first aspect defined in any one of embodiments 1 to 86 below. As disclosed herein, the liquid formulation is, in one embodiment, an aqueous formulation. Such an aqueous formulation may be used to prepare the lyophilized formulation.

[0141] In yet other embodiments, a lyophilized formulation of the antibody risankizumab is defined with respect to a reconstituted solution produced from the lyophilized formulation. Thus, according to one embodiment, there is provided a lyophilized formulation of an anti-IL-23p19 antibody, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 1 and a heavy chain amino acid sequence set forth in SEQ ID NO: 2, and the lyophilized formulation, upon reconstitution, is a liquid 150 mg / ml antibody formulation according to the first aspect, particularly its first and second subaspects. According to an embodiment, the lyophilized formulation, upon reconstitution, provides a liquid pharmaceutical formulation as defined in any one of embodiments 1 to 86 or 104 to 119 below. This risankizumab formulation may be an aqueous formulation.

[0142] Also provided is a lyophilized formulation comprising: a) an anti-IL-23p19 antibody in an amount that upon reconstitution provides an antibody concentration of 150 mg / ml, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO:1 and a heavy chain amino acid sequence set forth in SEQ ID NO:2; b) polyols; c) surfactants; and d) optionally a buffer solution.

[0143] In one embodiment, the lyophilized pharmaceutical formulation comprises 150 mg of an antibody, wherein the antibody is risankizumab.

[0144] Also provided is a lyophilized formulation comprising: a) an anti-IL-23p19 antibody in an amount that upon reconstitution provides an antibody concentration of 150 mg / ml, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO:1 and a heavy chain amino acid sequence set forth in SEQ ID NO:2; b) tonicity adjusters; c) surfactants; and d) optionally a buffer solution.

[0145] In one embodiment, the lyophilized formulation contains 150 mg of the antibody, wherein the antibody is risankizumab.

[0146] The components to be included, such as suitable polyols for pharmaceutical formulations, have already been disclosed above in connection with the liquid pharmaceutical formulation, and reference is made to the above disclosure, which also applies here. Suitable polyols include sugars and sugar alcohols, which may be used in combination. The polyol may have one or more of the characteristics defined in any one 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.

[0147] Suitable surfactants have already been disclosed above in connection with the liquid pharmaceutical formulation, and reference is made to the above disclosure, which also applies here. The surfactant may have one or more of the characteristics defined in any one of the following embodiments 22 to 25 of the liquid pharmaceutical formulation according to the first aspect. In one embodiment, the surfactant is optionally a polysorbate selected from polysorbate 20 and 80. In one embodiment, the polysorbate is polysorbate 20.

[0148] In one embodiment, the lyophilized formulation comprises a buffer. Buffers suitable for preparing lyophilized formulations are known in the art, and suitable buffers are also disclosed above in conjunction with the liquid pharmaceutical formulation according to the first aspect, and reference is made to the above disclosure.

[0149] According to one embodiment, the lyophilized formulation is characterized in that the formulation, upon reconstitution, has a pH as disclosed herein for the liquid pharmaceutical formulation according to the first aspect. Suitable pH values ​​are disclosed above, and reference is made to the respective disclosures which also apply herein. Upon reconstitution, the pH may be as defined in any one of the following embodiments 31 to 36 for the liquid 150 mg / ml pharmaceutical formulation. Furthermore, upon reconstitution, the pH may be as defined for the formulation according to the second subaspect. The pH upon reconstitution may be 5.5 to 5.9, for example 5.6 to 5.8.

[0150] The lyophilized risankizumab formulations of the present disclosure are reconstituted prior to administration. In some instances, it may be desirable to lyophilize the risankizumab formulation in the container in which the antibody will be reconstituted to avoid a transfer step.

[0151] Container and Use

[0152] According to a further aspect of the present disclosure, there is provided a sealed container containing a liquid pharmaceutical formulation or a lyophilized pharmaceutical formulation according to the first aspect of the present disclosure. The container may be a vial or a pre-filled syringe. In an embodiment, the container contains 2 ml or less of the liquid pharmaceutical formulation, optionally 1.5 ml or less, or 1 ml or less. Such a container may contain an advantageous and stable liquid pharmaceutical formulation according to the first or second sub-aspect of a 150 mg / ml antibody formulation according to the first aspect.

[0153] In a core embodiment, the container, e.g., syringe, etc., contains a single dose of 150 mg of antibody. As disclosed herein, the antibody is risankizumab.

[0154] In one embodiment, the liquid pharmaceutical formulation according to the first aspect of the present disclosure is contained in a syringe equipped with a needle. In a specific embodiment, the needle is suitable for subcutaneous administration. The needle may be a 27-gauge spinal tap needle or other needle suitable for subcutaneous use.

[0155] According to one embodiment, the pre-filled syringe with a needle has an average sliding equilibrium stress of 20 N or less. In an embodiment, the average sliding equilibrium stress is in the range of 5 to 20 N or 5 to 15 N. In an embodiment, the pre-filled syringe has a sliding yield stress of 3 to 12 N, preferably 3 to 9 N.

[0156] In certain embodiments, a syringe equipped with a needle and containing a liquid pharmaceutical formulation according to the first aspect essentially maintains the maximum and / or average sliding equilibrium stress required to expel it from the syringe during storage. In certain embodiments, after 36 months of storage at 5° C., the maximum sliding equilibrium stress of a 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 sliding equilibrium stress does not increase by more than 5 N, or more than 4 N, or more than 3 N. In certain embodiments, after 24 months of storage at 5° C., the maximum sliding equilibrium stress of a syringe pre-filled with the liquid formulation is 14 N or less, 12 N or less, 10 N or less, or more than 8 N, and / or the maximum sliding equilibrium stress does not increase by more than 3 N, or more than 2 N, or more than 1.5 N. In certain embodiments, after 9 months of storage at 5° C., the maximum sliding equilibrium stress is 9 N or less, or 8 N or less, and / or the maximum sliding equilibrium stress does not increase by more than 2 N, or more than 1.5 N, or more than 1 N. In certain embodiments, after 3 months of storage at 5° C., the maximum sliding equilibrium stress is 8 N or less, or 7.5 N or less, and / or the maximum sliding equilibrium stress does not increase by more than 1.5 N, or more than 1 N. In certain embodiments, after 3 months of storage at 25° C., the maximum sliding equilibrium stress is 10 N or less, or 8 N or less, and / or the maximum sliding equilibrium stress does not increase by more than 3 N, more than 2 N, or more than 1.5 N. In certain embodiments, after storage at 25°C for 1 month, the maximum sliding equilibrium stress of the pre-filled syringe with needle is 8N or less, or 7.5N or less, and / or the maximum sliding equilibrium stress does not increase by more than 1.5N or by more than 1N. In certain embodiments, after storage at 40°C for 1 month, the maximum sliding equilibrium stress is 16N or less, or 13N or less, and / or the maximum sliding equilibrium stress does not increase by more than 10N, or more than 8N, or more than 6N.

[0157] In certain embodiments, after 36 months of storage at 5° C., the average sliding equilibrium stress of a syringe pre-filled with a 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 sliding equilibrium stress does not increase by more than 5 N, or more than 4 N, or more than 3 N. In certain embodiments, after 24 months of storage at 5° C., the average sliding equilibrium stress of a syringe pre-filled with a 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 more than 8 N, and / or the average sliding equilibrium stress does not increase by more than 3 N, or more than 2 N, or more than 1.5 N. In certain embodiments, after 9 months of storage at 5°C, the average sliding equilibrium stress of the pre-filled syringe with needle is 9N or less, or 7.5N or less, and / or the average sliding equilibrium stress does not increase by more than 2N, or more than 1.5N, or more than 1N. In certain embodiments, after 3 months of storage at 5°C, the average sliding equilibrium stress is 8N or less, or 7N or less, and / or the average sliding equilibrium stress does not increase by more than 1.5N, or more than 1N, or more than 0.5N. In certain embodiments, after 12 months of storage at 25°C, the average sliding equilibrium stress is 15N or less, or 13N or less, and / or the average sliding equilibrium stress does not increase by more than 9N, or more than 8N, or more than 7N. In certain embodiments, after storage at 25° C. for 3 months, the average sliding equilibrium stress is 9 N or less, or 8 N or less, and / or the average sliding equilibrium stress does not increase by more than 3 N, or more than 2 N, or more than 1.5 N. In certain embodiments, after storage at 25° C. for 1 month, the average sliding equilibrium stress is 8 N or less, or 7 N or less, and / or the average sliding equilibrium stress does not increase by more than 1.5 N, or more than 1 N, or more than 0.5 N.In certain embodiments, after storage at 40° C. for 3 months, the average sliding equilibrium stress is 18 N or less, or 15 N or less, and / or the average sliding equilibrium stress does not increase by more than 12 N, or more than 10 N, or more than 9 N. In certain embodiments, after storage at 40° C. for 1 month, the average sliding equilibrium stress is 13 N or less, or 10 N or less, and / or the average sliding equilibrium stress does not increase by more than 7 N, or more than 5 N, or more than 3 N.

[0158] The increase in maximum or relative sliding equilibrium stress is calculated for the storage time and temperature indicated, and is determined, in particular, by comparing the maximum or relative sliding equilibrium stress at the beginning and end of the storage indicated. In certain embodiments, the measurements are performed as described in the Examples.

[0159] The maximum sliding equilibrium stress of a formulation refers to the maximum mechanical force required to expel the formulation from the syringe. The average sliding equilibrium stress of a formulation refers to the average mechanical force required to expel the formulation from the syringe. In some embodiments, the sliding equilibrium stress is determined according to industry standards, such as ISO 7886, ISO 11040, and ISO 11499. In certain embodiments, the maximum and average sliding equilibrium stress of a formulation are determined using a tensile and compression tester, such as a Zwick (Germany) 2.5TS / N, as described in particular in the Examples. Measurements are performed using a 27 gauge x 1 Measurements may be carried out using a 1 ml syringe with a 1 / 2 inch needle, such as a Neopak 1 ml syringe from Becton Dickinson (USA), particularly the syringe with the needle used in the Examples. Measurements may be carried out, for example, over 5 seconds, using a rate of about 300-500 mm / min, such as about 380 mm / min, particularly 379.2 mm / min.

[0160] A further aspect according to the present disclosure relates to a liquid pharmaceutical formulation or lyophilized formulation according to the first aspect, or a container according to a further aspect disclosed herein for therapeutic treatment of a human subject. The disease to be treated is a disease treatable with an anti-IL-23p19 antibody, such diseases being known in the art. The disease may 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 may be selected from psoriasis and inflammatory bowel disease. In a further embodiment, the disease to be treated may be selected from psoriatic arthritis and Crohn's disease. Administering a high-concentration 150 mg / ml liquid pharmaceutical formulation according to the present disclosure to a patient for treatment is advantageous for reasons discussed herein.

[0161] Further embodiments of the 150 mg / ml formulation

[0162] In the following, more specifically contemplated embodiments of the 150 mg / ml antibody formulation according to the first aspect are disclosed: 1. a) 150 mg / ml of an anti-IL-23p19 antibody, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 1 and a heavy chain amino acid sequence set forth in SEQ ID NO: 2; b) a polyol; and c) surfactants 1. A liquid pharmaceutical formulation comprising: 2. d) A formulation according to embodiment 1, comprising a buffer. 3. The formulation according to embodiment 1 or 2, wherein the antibody is risankizumab. 4. The formulation according to any one of embodiments 1 to 3, wherein the antibody is recombinantly produced in mammalian cells. 5. The formulation according to embodiment 4, wherein the antibody is recombinantly produced in CHO cells. 6. A formulation according to one or more of embodiments 1-5, wherein the polyol is selected from sugars, sugar alcohols, and combinations thereof. 7. A formulation according to embodiment 6, wherein the polyol is selected from trehalose, sucrose, sorbitol, mannitol, and combinations thereof. 8. A formulation according to embodiment 6, wherein the polyol is a sugar, optionally selected from trehalose and sucrose. 9. A formulation according to embodiment 6, comprising trehalose as polyol. 10. A formulation according to embodiment 6, wherein the polyol is selected from sorbitol and mannitol. 11. A formulation according to embodiment 6, comprising mannitol as polyol. 12. A formulation according to any one of embodiments 1-11, wherein the liquid pharmaceutical formulation does not contain sorbitol. 13. A formulation according to one or more of embodiments 1-9, wherein the formulation does not contain a sugar alcohol. 14. Formulations according to one or more of embodiments 1 to 13, having one or more of the following characteristics: (i) the concentration of polyol in the formulation is at least 95 mM; (ii) the concentration of the polyol in the formulation is at least 125 mM; (iii) the concentration of the polyol in the formulation is at least 150 mM; (iv) the concentration of polyol in the formulation is ≦500 mM, ≦450 mM, or ≦400 mM; (v) the concentration of polyol in the formulation is ≦350 mM, ≦300 mM, or ≦275 mM; and / or (vi) the concentration of the polyol in the formulation is in the range of 95 mM to 450 mM or 125 mM to 400 mM; Optionally, the polyol is a sugar and / or a sugar alcohol. 15. A formulation according to one or more of embodiments 1 to 13, wherein the concentration of polyol in the formulation is in the range of 95 mM to 250 mM, and optionally the polyol is a sugar. 16. A formulation according to one or more of embodiments 1-13, wherein the concentration of the polyol in the formulation is in the range of 125 mM to 225 mM, and optionally the polyol is a sugar, such as trehalose. 17. A formulation according to one or more of embodiments 1-13, wherein the concentration of the polyol is in the range of 145 mM to 225 mM, and optionally the polyol is a sugar, such as trehalose. 18. A formulation according to one or more of embodiments 1-13, wherein the polyol is a sugar and the concentration of the sugar is in the range of 150 mM to 200 mM, optionally wherein the sugar is trehalose. 19. A formulation according to one or more of embodiments 1-13, wherein the polyol is a sugar and the concentration of the sugar is in the range of 160 mM to 200 mM, optionally wherein the sugar is trehalose. 20. A formulation according to one or more of embodiments 1-13, wherein the polyol is a sugar and the concentration of the sugar is in the range of 170 mM to 200 mM, and optionally the sugar is trehalose. 21. A formulation according to one or more of embodiments 1-13, comprising 185 mM trehalose as polyol. 22. A formulation according to one or more of embodiments 1-21, wherein the surfactant is a non-ionic surfactant. 23. A formulation according to embodiment 22, wherein the surfactant is a polysorbate. 24. A formulation according to embodiment 22 or 23, wherein the non-ionic surfactant is selected from polysorbate 20 and / or polysorbate 80. 25. A formulation according to one or more of embodiments 1-24, wherein the surfactant is Polysorbate 20. 26. A formulation according to one or more of embodiments 1 to 25, in particular any one of embodiments 23 to 25, wherein the concentration of surfactant in the formulation is at least 0.05 mg / ml, optionally at least 0.075 mg / ml. 27. A formulation according to one or more of embodiments 1 or 26, in particular 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. 28. A formulation according to one or more of embodiments 1 or 27, in particular according to 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 0.5 mg / ml or 0.075 mg / ml to 0.3 mg / ml. 29. A formulation according to embodiment 25, wherein the formulation comprises 0.2 mg / ml of polysorbate 20 as a surfactant. 30. A formulation according to embodiment 29, wherein the polyol is a sugar and the concentration of the sugar is in the range of 145 mM to 225 mM, optionally wherein the sugar is trehalose. 31. A formulation according to 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. 32. A formulation according to one or more of 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. 33. A formulation according to one or more of 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. 34. A formulation according to one or more of embodiments 1 to 30, wherein the pH of the liquid pharmaceutical formulation is in the range of 5.5 to 5.9. 35. A formulation according to one or more of embodiments 1 to 30, wherein the pH of the liquid pharmaceutical formulation is in the range of 5.6 to 5.8. 36. A formulation according to one or more of embodiments 1-30, wherein the pH of the liquid pharmaceutical formulation is 5.7 or 6.2. 37. A formulation according to one or more of embodiments 2-36, wherein the buffer has a pKa within 1.5 or 1 pH unit of the final pH of the liquid pharmaceutical formulation at 25°C, optionally wherein the buffer has a pKa in the range of pH 4.2 to 7.2 or pH 4.5 to 7 at 25°C. 38. A formulation according to one or more of embodiments 2 to 37, wherein the buffer is an organic buffer, optionally selected from acetate buffer and succinate buffer. 39. The formulation according to embodiment 38, wherein the buffer is an acetate buffer, optionally comprising sodium acetate and acetic acid. 40. A formulation according to one or more of embodiments 2 to 37, wherein the buffer is a histidine buffer or wherein the formulation meets at least one of the following characteristics: (i) with carboxylic acid buffer; (ii) without succinic acid buffer. 41. A formulation according to one or more of embodiments 2-40, comprising at least 1 mM, at least 2 mM, or at least 3 mM buffer, optionally at least 4 mM, at least 4.5 mM, or at least 5 mM buffer. 42. A formulation according to one or more of embodiments 2-41, wherein the buffer concentration is 100 mM or less, 75 mM or less, or 50 mM or less. 43. A formulation according to one or more of embodiments 2-41, wherein the buffer concentration is 20 mM or less, or 15 mM or less. 44. A formulation according to one or more of embodiments 2 to 41, wherein the buffer concentration is in the range of 4 mM to 50 mM. 45. A formulation according to one or more of embodiments 2 to 41, wherein the buffer concentration is in the range of 5 mM to 25 mM or 5 mM to 20 mM. 46. ​​A formulation according to one or more of embodiments 2 to 41, wherein the buffer concentration is in the range of 5 mM to 15 mM or 7 mM to 12 mM. 47. A formulation according to one or more of embodiments 2-41, wherein the buffer concentration is 10 mM. 48. A formulation according to one or more of embodiments 2 to 47, wherein the formulation comprises a single buffer, optionally an acetate buffer. 49. A formulation according to any one of claims 1 or 3 to 36, wherein the formulation does not contain a buffer. 50. A formulation according to one or more of embodiments 1 to 49, wherein the formulation is an aqueous formulation. 51. A formulation according to any one of embodiments 2 to 48 or 50, comprising: a) 150 mg / ml of antibody; b) sugar, optionally with a sugar concentration in the range of 95 mM to 250 mM or 145 mM to 225 mM; c) a non-ionic surfactant, optionally with a concentration of the non-ionic surfactant in the range of 0.05 mg / ml to 0.5 mg / ml or 0.075 mg / ml to 0.3 mg / ml; and d) Buffer. 52. A formulation according to any one of embodiments 2-48 or 50-51, comprising: a) 150 mg / ml of antibody; b) trehalose, optionally with a trehalose concentration in the range of 95 mM to 250 mM or 145 mM to 225 mM; c) polysorbate, optionally with a concentration of polysorbate in the range of 0.05 mg / ml to 0.5 mg / ml or 0.075 mg / ml to 0.3 mg / ml; and d) Buffer. 53. A formulation according to embodiment 51 or 52, wherein the buffer is an acetate buffer or a succinate buffer, optionally with a buffer concentration in the range of 5 mM to 25 mM. 54. A formulation according to embodiment 52 or 53, wherein the polysorbate is polysorbate 20. 55. A formulation according to 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 the pH is in the range of 5.2 to 6.2 or 5.5 to 6.2, or is 5.7. 56. A formulation according to any one of embodiments 2-48 or 50-55, comprising: a) 150 mg / ml of antibody; b) 170 mM to about 200 mM trehalose; c) 0.1 mg / ml to 0.3 mg / ml of polysorbate, optionally polysorbate 20; and d) a buffer, optionally the buffer is an acetate buffer. 57. A liquid pharmaceutical formulation according to one or more of embodiments 1, 3-36 or 49-50, comprising: a) 150 mg / ml of antibody; b) a polyol, optionally the polyol is a sugar or sugar alcohol; and c) a non-ionic surfactant, optionally a polysorbate; d) No buffer. 58. The formulation according to 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. 59. The formulation according to embodiment 58, wherein the pH is 5.7. 60. A formulation according to any one of embodiments 57-59, comprising 80 mM to 250 mM of a polyol, optionally wherein the polyol is trehalose. 61. A formulation according to any one of embodiments 57-60, wherein the concentration of the non-ionic surfactant is in the range of 0.05 mg / ml to 0.5 mg / ml, 0.075 mg / ml to 0.4 mg / ml, or 0.1 mg / ml to 0.3 mg / ml. 62. A formulation according to embodiment 61, in which the non-ionic surfactant is a polysorbate, optionally polysorbate 20. 63. A formulation according to one or more of embodiments 1 to 62, further comprising an amino acid as an additive. 64. A formulation according to embodiment 63, wherein the amino acid has a charged side chain, optionally a positively charged side chain, such as L-arginine. 65. A formulation according to embodiment 63 or 64, wherein the amino acid is present in the formulation as a salt, optionally a hydrochloride (HCl) salt. 66. A formulation according to embodiment 63, wherein the amino acid is methionine. 67. A formulation according to embodiment 63, wherein the amino acid is L-proline. 68. Formulations according to one or more of embodiments 1 to 67, having one or more of the following characteristics: (i) Contains no arginine; (ii) does not contain amino acids with positively charged side chains; (iii) does not contain amino acids with charged side chains; (iv) does not contain methionine; and / or (v) Does not contain amino acids as additives. 69. A liquid pharmaceutical formulation according to any one of embodiments 2 to 68, comprising: a) 150 mg / ml of antibody; b) 185 mM trehalose; c) 0.2 mg / ml polysorbate 20; and d) 10 mM acetate buffer; Here, the pH is in the range of 5.2 to 6.2, and in some cases is 5.7. 70. The formulation according to any one of embodiments 1-69, wherein the formulation is stable. 71. A formulation according to embodiment 70, which satisfies one or more of the following stability characteristics: (i) after 36 months of storage at 5°C, at least 94%, at least 95%, or at least 96% of the antibody is present as a monomer, 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%, as measured by UP-SEC; (ii) after 24 months of storage at 5°C, at least 94%, at least 95%, or at least 96% of the antibody is present as a monomer, 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%, as measured by UP-SEC; (iii) after 9 months of storage at 5°C, at least 96% or at least 96.5% of the antibody is present as a monomer and / or the relative monomer content of the antibody does not decrease by more than 1.5% or more than 1%, as measured by UP-SEC; (iv) after 3 months of storage at 5°C, at least 96% or at least 97% of the antibody is present as a monomer, 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%, as measured by UP-SEC; (v) after 12 months of storage at 25°C, at least 90% or at least 92% of the antibody is present as a monomer, and / or the relative monomer content of the antibody does not decrease by more than 7%, or more than 6%, or more than 5%, as measured by UP-SEC; (vi) after 3 months of storage at 25°C, at least 95% of the antibody is present as a monomer and / or the relative monomer content of the antibody does not decrease by more than 3% or by more than 2%, as measured by UP-SEC; (vii) after storage at 25°C for 1 month, at least 96% of the antibody is present as a monomer and / or the relative monomer content of the antibody does not decrease by more than 2% or by more than 1%, as measured by UP-SEC; (viii) after 3 months of storage at 40°C, at least 87% or at least 88% of the antibody is present as a monomer, and / or the relative monomer content of the antibody does not decrease by more than 10%, or more than 9%, or more than 8%, as measured by UP-SEC; and / or (ix) after storage at 40°C for 1 month, at least 93% or at least 94% of the antibody is present as a monomer, and / or the relative monomer content of the antibody does not decrease by more than 5% or more than 4%, as measured by UP-SEC. 72. A formulation according to embodiment 70 or 71, which satisfies one or more of the following stability characteristics: (i) after storage at 5°C for at least 36 months, the formulation has an opalescence of 12 FNU (Formazin Turbidity Units) or less or 10 FNU or less, and / or the opalescence does not increase by more than 5 FNU or by more than 3 FNU; (ii) after storage at 5°C for at least 3, 6, 9, 12, 18, or 24 months, the formulation has an opalescence of 12 FNU (formazin turbidity units) or less or 10 FNU or less, and / or the opalescence does not increase by more than 5 FNU or by more than 3 FNU; (iii) after storage at 25°C for at least 1, 3, 6, 9, or 12 months, the formulation has an opalescence of 12 FNU or less or 10 FNU or less, and / or the opalescence does not increase by more than 7 FNU or more than 5 FNU; (iv) after storage at 40°C for at least 1 or 3 months, the formulation has an opalescence of 12 FNU or less, or 10 FNU or less, and / or the opalescence does not increase by more than 5 FNU or more than 3 FNU; and / or (v) After shaking for 21 days at 25°C, the formulation has an opalescence of 12 FNU or less, or 10 FNU or less, and / or the opalescence of the formulation does not increase by more than 3 FNU or more than 2 FNU. 73. A formulation according to any one of embodiments 70-72, which meets one or both of the following stability characteristics: (i) after 21 days of shaking at 25°C, at least 95% or at least 96% of the antibody is present as a monomer, and / or the relative monomer content of the antibody does not decrease by more than 2% or by more than 1%, as measured by UP-SEC; and / or (ii) after 21 days of shaking at 25°C, less than 3% or less than 2% of the antibody is present as high molecular weight (HMW) species and / or the relative HMW content of the antibody does not increase by more than 2%, or more than 1.5%, or more than 1%, as measured by UP-SEC. 74. A formulation according to any one of embodiments 70 to 73, which meets one or more of the following stability characteristics: (i) after 36 months of storage at 5°C, less than 4% or less than 3% of the antibody is present as high molecular weight (HMW) species, and / or the relative HMW content of the antibody does not increase by more than 2% or more than 1.5%, as measured by UP-SEC; (ii) after 24 months of storage at 5°C, less than 4% or less than 3% of the antibody is present as high molecular weight (HMW) species, and / or the relative HMW content of the antibody does not increase by more than 2%, or more than 1.5%, or more than 1%, as measured by UP-SEC; (iii) after 9 months of storage at 5°C, less than 4%, or less than 3%, or less than 2.5% of the antibody is present as high molecular weight (HMW) species, and / or the relative HMW content of the antibody does not increase by more than 1%, more than 0.8%, or more than 0.6%, as measured by UP-SEC; (iv) after 3 months of storage at 5°C, less than 4%, or less than 3%, or less than 2.5% of the antibody is present as high molecular weight (HMW) species, and / or the relative HMW content of the antibody does not increase by more than 1%, more than 0.8%, or more than 0.6%, as measured by UP-SEC; (v) after 3 months of storage at 40°C, less than 6.5%, or less than 6%, or less than 5.5% of the antibody is present as 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 5%, or more than 4%; and / or (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 as high molecular weight (HMW) species, and / or the relative HMW content of the antibody does not increase by more than 2.5%, or more than 2%, as measured by UP-SEC. 75. A formulation according to any one of embodiments 70-74, which meets one or more of the following stability characteristics: (i) after 12 months of storage at 25°C, less than 5% or less than 4% of the antibody is present as high molecular weight (HMW) species, and / or the antibody does not increase by more than 3%, or more than 2.5%, or more than 2%, as measured by UP-SEC; (ii) after 3 months of storage at 25°C, less than 4%, or less than 3.5%, or less than 3.2% of the antibody is present as high molecular weight (HMW) species, and / or the relative HMW content of the antibody does not increase by more than 2%, or more than 1.5%, as measured by UP-SEC; and / or (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 as 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%, as measured by UP-SEC. 76. A formulation according to any one of embodiments 70 to 75, which meets one or more of the following formulation stability characteristics: (i) after 36 months of storage at 5°C, less than 2% or less than 1.5% of the antibody is present as low molecular weight (LMW) species, and / or the relative HMW content of the antibody does not increase by more than 1.5%, or more than 1.5%, or more than 0.5%, as measured by UP-SEC; (ii) after 24 months of storage at 5°C, less than 2% or less than 1.5% of the antibody is present as low molecular weight (LMW) species, and / or the relative HMW content of the antibody does not increase by more than 1.5%, or more than 1.5%, or more than 0.5%, as measured by UP-SEC; (iii) after 9 months of storage at 5°C, less than 2% or less than 1.5% of the antibody is present as low molecular weight (LMW) species and / or the relative HMW content of the antibody does not increase by more than 1.5%, or more than 1.5%, or more than 0.5%, as measured by UP-SEC; (iv) after storage at 5°C for 3 months, less than 2%, or less than 1.5%, or less than 1% of the antibody is present as low molecular weight (LMW) species, and / or the relative LMW content of the antibody does not increase by more than 1%, or more than 0.5%, or more than 0.25%, as measured by UP-SEC; (v) after 3 months of storage at 40°C, less than 8%, or less than 7%, or less than 6% of the antibody is present as low molecular weight (LMW) species, and / or the relative LMW content of the antibody does not increase by more than 8%, more than 7%, or more than 6%, as measured by UP-SEC; and / or (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 as low molecular weight (LMW) species, and / or the relative LMW content of the antibody does not increase by more than 3%, more than 2.5%, or more than 2.2%, as measured by UP-SEC. 77. A formulation according to any one of embodiments 70-76, which meets one or more of the following stability characteristics: (i) after 12 months of storage at 25°C, less than 6%, or less than 5%, or less than 4.5% of the antibody is present as low molecular weight (LMW) species, and / or the relative LMW content of the antibody does not increase by more than 5%, more than 4%, or more than 3%, as measured by UP-SEC; (ii) after 3 months of storage at 25°C, less than 3%, or less than 2%, or less than 1.8% of the antibody is present as low molecular weight (LMW) species, and / or the relative LMW content of the antibody does not increase by more than 2%, more than 1.5%, or more than 1%, as measured by UP-SEC; and / or (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 as low molecular weight (LMW) species, and / or the relative LMW content of the antibody does not increase by more than 1%, more than 0.6%, or more than 0.4%, as measured by UP-SEC. 78. A formulation according to any one of embodiments 70 to 77, which meets one or more of the following stability characteristics: (i) after storage at 5°C for 36 months, at least 55%, at least 60%, or at least 65% of the antibody is present as the main peak variant, 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%, as determined by ion exchange chromatography (IEC); (ii) after storage at 5°C for 24 months, at least 55%, at least 60%, or at least 65% of the antibody is present as the main peak variant, 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%, as determined by ion exchange chromatography (IEC); (iii) after 6 months of storage at 5°C, at least 60% or at least 65% of the antibody is present as the main peak variant, and / or the relative content of the main peak variant of the antibody does not decrease by more than 5% or more than 4%, as determined by ion exchange chromatography (IEC); (iv) after storage at 5°C for 3 months, at least 60% or at least 65% of the antibody is present as the main peak variant, and / or the relative content of the main peak variant of the antibody does not decrease by more than 4%, or more than 3%, or more than 2%, as determined by ion exchange chromatography (IEC); (v) 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 the main peak variant, and / or the relative content of the main peak variant of the antibody does not decrease by more than 35%, more than 30%, or more than 25%, as determined by ion exchange chromatography (IEC); (vi) after storage at 25°C for 3 months, at least 55% or at least 60% of the antibody is present as the main peak variant, and / or the relative content of the main peak variant of the antibody does not decrease by more than 15% or more than 10%, as determined by ion exchange chromatography (IEC); and / or (vii) after storage at 25°C for 1 month, at least 60% or at least 65% of the antibody is present as the main peak variant, and / or the relative content of the main peak variant of the antibody does not decrease by more than 10%, or by more than 5%, as determined by ion exchange chromatography (IEC). 79. A formulation according to any one of embodiments 70-78, which meets one or more of the following stability characteristics: (i) after 36 months of storage at 5°C, less than 30% or less than 28% of the antibody is present as the acidic peak group variant, and / or the relative content of the acidic peak group variant of the antibody does not increase by more than 4%, or more than 3%, or more than 2%, as determined by ion exchange chromatography (IEC); (ii) after 24 months of storage at 5°C, less than 30% or less than 28% of the antibody is present as the acidic peak group variant, and / or the relative content of the acidic peak group variant of the antibody does not increase by more than 4%, or more than 3%, or more than 2%, as determined by ion exchange chromatography (IEC); (iii) after 6 months of storage at 5°C, less than 30% or less than 28% of the antibody is present as the acidic peak group variant, and / or the relative content of the acidic peak group variant of the antibody does not increase by more than 4%, or more than 3%, or more than 2%, as determined by ion exchange chromatography (IEC); (iv) after 3 months of storage at 5°C, less than 30% or less than 28% of the antibody is present as the acidic peak group variant, and / or the relative content of the acidic peak group variant of the antibody does not increase by more than 3%, or more than 2%, or more than 1%, as determined by ion exchange chromatography (IEC); (v) after 12 months of storage at 25°C, less than 50%, less than 45%, or less than 40% of the antibody is present as the acidic peak group variant, and / or the relative content of the acidic peak group variant of the antibody does not increase by more than 30%, more than 25%, or more than 20%, as determined by ion exchange chromatography (IEC); (vi) after 3 months of storage at 25°C, less than 40%, or less than 35%, or less than 30% of the antibody is present as the acidic peak group variant, and / or the relative content of the acidic peak group variant of the antibody does not increase by more than 10%, more than 8%, or more than 6%, as determined by ion exchange chromatography (IEC); and / or (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 the acidic peak group variant, and / or the relative content of the acidic peak group variant of the antibody does not increase by more than 4%, or more than 3%, as determined by ion exchange chromatography (IEC). 80. A formulation according to any one of embodiments 70 to 79, which meets one or more of the following stability characteristics: (i) after 36 months of storage at 5°C, less than 20%, less than 17%, less than 15%, or less than 13% of the antibody is present as basic peak group variants, and / or the relative content of basic peak group variants of the antibody does not increase by more than 10%, more than 8%, or more than 6%, as determined by ion exchange chromatography (IEC); (ii) after 24 months of storage at 5°C, less than 20%, less than 17%, less than 15%, or less than 13% of the antibody is present as basic peak group variant, and / or the relative content of basic peak group variant of the antibody does not increase by more than 10%, more than 8%, or more than 6%, as determined by ion exchange chromatography (IEC); (iii) after 6 months of storage at 5°C, less than 15% or less than 10% of the antibody is present as a basic peak group variant, and / or the relative content of basic peak group variants of the antibody does not increase by more than 4%, or more than 3%, or more than 2%, as determined by ion exchange chromatography (IEC); (iv) after 3 months of storage at 5°C, less than 15% or less than 10% of the antibody is present as a basic peak group variant, and / or the relative content of basic peak group variants of the antibody does not increase by more than 3% or more than 2%, as determined by ion exchange chromatography (IEC); (v) after 12 months of storage at 25°C, less than 30%, or less than 25%, or less than 22% of the antibody is present as basic peak group variant, and / or the relative content of basic peak group variant of the antibody does not increase by more than 25%, more than 20%, or more than 15%, as determined by ion exchange chromatography (IEC); (vi) after 3 months of storage at 25°C, less than 20%, or less than 15%, or less than 12% of the antibody is present as a basic peak group variant, and / or the relative content of basic peak group variants of the antibody does not increase by more than 9%, more than 7%, or more than 5%, as determined by ion exchange chromatography (IEC); and / or (vii) after storage at 25°C for 1 month, less than 15%, or less than 10%, or less than 9% of the antibody is present as basic peak group variant, and / or the relative content of basic peak group variant of the antibody does not increase by more than 3%, or more than 2%, as determined by ion exchange chromatography (IEC). 81. A formulation according to any one of embodiments 70-80, which satisfies one or more of the following stability characteristics: (i) after storage at 5°C for 36 months, at least 95% or at least 97% of the specific binding activity to IL-23 is measured relative to a reference antibody, where the reference antibody has not been stored; (ii) after storage at 5°C for 4, 6, 9, 12, 18, or 24 months, at least 95% or at least 97% of the specific binding activity to IL-23 is measured relative to a reference antibody, where the reference antibody has not been stored; (iii) after storage at 25°C for 2, 3, 4, 6, 9, 12, or 18 months, at least 93% or at least 96% of the specific binding activity to IL-23 is measured relative to a reference antibody, where the reference antibody has not been stored; and / or (iv) after storage at 40°C for 3, 4, or 6 months, at least 90% or at least 95% of the specific binding activity to IL-23 is measured relative to a reference antibody, where the reference antibody has not been stored. 82. A formulation according to one or more of embodiments 1-81, wherein the dynamic viscosity measured at 20°C is ≦30 mPas (mPa·s), ≦25 mPas, or ≦20 mPas. 83. A formulation according to one or more of embodiments 1 to 82, wherein the formulation has a conductivity 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. 84. A formulation according to one or more of embodiments 1 to 83, wherein the formulation has an osmolality in the range of 225 mOsm / kg to 375 mOsm / kg, such as 250 mOsm / kg to 350 mOsm / kg, 275 mOsm / kg to 330 mOsm / kg, or 290 mOsm / kg to 320 mOsm / kg. 85. A formulation according to one or more of embodiments 1 to 84, wherein the formulation is an injectable formulation. 86. The formulation according to embodiment 85, wherein the formulation is suitable for subcutaneous injection. 87. A formulation according to one or more of embodiments 1 to 86, wherein the formulation does not and has not undergone a reconstitution step prior to administration. 88. A formulation according to any one of embodiments 1-86, prepared by reconstitution from a lyophilized formulation. 89. A lyophilized formulation of an anti-IL-23p19 antibody, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 1 and a heavy chain amino acid sequence set forth in SEQ ID NO: 2, and wherein the lyophilized formulation is produced by lyophilizing a liquid formulation as defined in any one of embodiments 1 to 69, and optionally, the liquid formulation is an aqueous solution. 90. A lyophilized formulation of an anti-IL-23p19 antibody, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 1 and a heavy chain amino acid sequence set forth in SEQ ID NO: 2, which upon reconstitution provides a liquid formulation as defined in any one of embodiments 1-69 or 82-86. 91. Lyophilized preparations containing: a) an anti-IL-23p19 antibody in an amount that upon reconstitution provides an antibody concentration of 150 mg / ml, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO:1 and a heavy chain amino acid sequence set forth in SEQ ID NO:2; b) polyols; c) surfactants; and d) optionally a buffer solution. 92. The lyophilized formulation according to embodiment 91, wherein the antibody is risankizumab. 93. The lyophilized formulation according to embodiment 91 or 92, wherein the polyol has one or more of the characteristics defined in any one of embodiments 6 to 13, and optionally the polyol is a sugar, optionally a sugar selected from trehalose and sucrose. 94. The lyophilized formulation according to any one of embodiments 91 to 93, in which the surfactant has one or more of the characteristics defined in any one of embodiments 22 to 25, optionally wherein the surfactant is a polysorbate. 95.d) A lyophilized formulation according to any one of embodiments 91 to 94, comprising a buffer solution, the buffer solution having one or more of the characteristics defined in any one of embodiments 37 to 40. 96. The lyophilized formulation according to any one of embodiments 91 to 95, wherein the formulation, upon reconstitution, has a pH as defined in any one of embodiments 31 to 36. 97. A sealed container, optionally a vial or a pre-filled syringe, containing a liquid pharmaceutical formulation according to any one of embodiments 1 to 87. 98. A container, optionally a sealed vial, containing a lyophilized formulation according to any one of embodiments 88 to 96. 99. The product according to embodiment 97, wherein the container contains 2 ml or less of the liquid formulation, optionally 1.5 ml or less or 1 ml or less of the liquid formulation. 100. The product according to any one of embodiments 97 to 99, comprising a single dose of 150 mg antibody. 101. A formulation according to any one of embodiments 1 to 96 or a product according to any one of embodiments 97 to 100 for the therapeutic treatment of a human subject. 102. A formulation according to any one of embodiments 1 to 96 or a product according to any one of embodiments 97 to 100 for use in the treatment of a disease selected from psoriasis and inflammatory bowel disease. 103. A formulation according to any one of embodiments 1 to 96 or a product according to any one of embodiments 97 to 100 for use in the treatment of a disease selected from psoriatic arthritis and Crohn's disease. 104. A stable liquid pharmaceutical formulation comprising: a) 150 mg / ml of an anti-IL-23p19 antibody, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 1 and a heavy chain amino acid sequence set forth in SEQ ID NO: 2; b) a tonicity adjuster; and c) surfactants, Here, the formulation has a pH of 5.5 to 5.9, and the formulation is isotonic. 105. The stable formulation according to embodiment 104, wherein the antibody is risankizumab. 106. The stable formulation according to embodiment 104 or 105, wherein the tonicity modifier is a polyol. 107. The stable formulation according to any one of embodiments 104-106, wherein the tonicity modifier is a polyol as defined in any one of embodiments 6-11 above. 108. A stable formulation according to any one of embodiments 104 to 107, wherein the concentration of the tonicity modifier has one or more of the characteristics defined for the polyol in any one of embodiments 14 to 21 above, and optionally the tonicity modifier is a polyol as defined therein, optionally a sugar and / or sugar alcohol, optionally selected from trehalose and sucrose. 109. The stable formulation according to any one of embodiments 104 to 108, wherein the surfactant has one or more of the characteristics defined in any one of embodiments 22 to 25 above, and optionally the surfactant is a polysorbate, optionally selected from polysorbate 20 and polysorbate 80. 110. The stable formulation according to any one of embodiments 104-109, wherein the concentration of surfactant in the formulation is as defined in any one of embodiments 26-30 above. 111. The stable formulation according to any one of embodiments 104-110, wherein the formulation has a pH in the range of 5.6 to 5.8, optionally wherein the pH of the formulation is 5.7. 112.d) A stable formulation according to any one of embodiments 104 to 111, comprising a buffer, optionally having one or more of the characteristics defined in any one of embodiments 37 to 40 and 48. 113. The stable formulation according to embodiment 112, wherein the buffer has a concentration as defined in any one of embodiments 41 to 47. 114. The stable formulation according to any one of embodiments 104-113, wherein the formulation is an aqueous formulation. 115. A stable formulation according to any one of embodiments 104 to 114, which satisfies one or more of the stability characteristics defined in any one of embodiments 71 to 81. 116. The stable formulation according to any one of embodiments 104-111 or 114-115, wherein the formulation does not contain a buffer. 117. The stable formulation according to any one of embodiments 104-116, wherein the formulation has an osmolality of 290-320 mOsm / kg. 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: (i) the surfactant is a nonionic surfactant; (ii) the surfactant is a polysorbate, optionally selected from polysorbate 20 and polysorbate 80; (iii) the concentration of the surfactant in the formulation is in the range of 0.05 mg / ml to 0.5 mg / ml, and 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 (iv) Having any one of the features defined in embodiments 12, 13, or 63-68. 119. The stable formulation according to any one of embodiments 104-118, prepared by reconstitution from a lyophilized formulation. 120. A lyophilized formulation of an anti-IL-23p19 antibody, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 1 and a heavy chain amino acid sequence set forth in SEQ ID NO: 2, and is produced by lyophilizing a liquid formulation as defined in any one of embodiments 104 to 118, and optionally the stable liquid formulation is an aqueous solution. 121. A lyophilized formulation of an anti-IL-23p19 antibody, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 1 and a heavy chain amino acid sequence set forth in SEQ ID NO: 2, and upon reconstitution provides a stable liquid formulation as defined in any one of embodiments 104 to 118.

[0163] Numerical ranges are inclusive of the numbers defining the range. The headings provided herein are not limitations of the various aspects or embodiments of the disclosure, which can be read by reference to the specification as a whole.

[0164] As used in the subject specification, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The terms "include," "have," "comprise," and variations thereof are used synonymously and are to be construed as open-ended. Throughout this specification, when a composition is described as comprising components or materials, it is also contemplated that the composition, in embodiments, can consist essentially of, or consist of, any combination of the listed components or materials, unless otherwise stated. The technology illustratively disclosed herein may suitably be practiced in the absence of any element not specifically disclosed herein.

[0165] Example

[0166] The following examples are for illustrative purposes only and should not be construed as limiting the invention in any way.

[0167] I. Materials and Methods

[0168] 1. Preparation of Starting Materials

[0169] The purified risankizumab starting material produced in CHO cells was adjusted to pH 5.9, if necessary, prior to the UF / DF process. Finally, the solution was concentrated, and the concentrated starting material was used to prepare formulations according to the following examples.

[0170] 2. Syringe

[0171] Storage of the formulation in the syringe was essentially carried out using Neopak syringes with rubber stoppers from Becton Dickinson (USA). The sliding yield stress, as well as the maximum and average sliding equilibrium stress, were measured using such syringes. In an embodiment, a 27 gauge syringe was used. 1 A 1 ml Neopak syringe with a 1 / 2 inch needle and a Becton Dickinson (USA) rubber stopper was used.

[0172] II. Example 1: Characterization of Starting Materials

[0173] 1. Effect of pH on antibodies

[0174] RALS (right angle light scattering) measurements were performed on risankizumab at different pH values ​​in a buffer mixture of 10 mM acetic acid, 10 mM citric acid, 10 mM phosphate, 115 mM NaCl. The results are shown in Table 1. [Table 1]

[0175] The results show that increasing the pH increases the onset of unfolding until a plateau is reached. The highest onset temperature, indicating high stability, was measured above pH 5.0-7. Therefore, the pH should not be too acidic (<5).

[0176] 2. Determining the buffer capacity of the starting material

[0177] The buffering capacity of the antibody starting material was determined to, among other things, facilitate pH adjustment of formulation solutions for subsequent stability studies and to avoid protein damage. Titrations to determine the buffering capacity of the antibody were performed at the following concentrations: 150 mg / ml; 100 mg / ml; 50 mg / ml (in duplicate), and 20 mg / ml.

[0178] Dilutions were made in beakers according to Table 2. [Table 2]

[0179] After dilution, 5 mL of each solution was transferred into a 10R glass vial using a volumetric pipette and titrated. A 0.2 M NaOH solution was selected for titration (stirring speed 250 rpm). For each antibody concentration, titration was performed and the amount of NaOH added was calculated. The slope and reciprocal of the slope, shown in Table 3, were calculated using Excel. [Table 3]

[0180] The concentration-dependent buffering capacity level was obtained by plotting the concentration against the inverse of the slope. This resulted in a straight line with a slope of 0.0505 and a y-axis intercept of -0.2007. The results and the following examples demonstrate that risankizumab itself has significant buffering capacity, making it possible to prepare a 150 mg / ml buffer-free formulation according to the present disclosure without any further / additional buffering substances.

[0181] III. Example 2: Analysis of Different pH Values ​​and Buffer Substances

[0182] Comparison of acetate and succinate buffer systems with different pH values ​​for the evaluation of the stability of 1.150 mg / ml formulations

[0183] 1.1. Preparation of formulations

[0184] The formulations shown in Table 4 were prepared and analyzed. [Table 4]

[0185] Samples were collected within 18 months (0, 3, 6, 8, 12, and 18 months). The storage conditions were 5°C and 25°C / 60% relative humidity. Each formulation was filled into a Neopak syringe. Filling in a laminar flow was set to a volume of 1.1 mL. The syringes were closed with stoppers and visually analyzed for particles before storage. Afterwards, the syringes were stored hanging in a syringe tray at each temperature. A buffer solution was stored in parallel as a control. After the formulations were prepared, each solution was sterile filtered, and the prepared formulations were stored in syringes (Neopak syringes from Becton Dickinson, USA).

[0186] 1.2.Analysis

[0187] For the analysis of the samples, inter alia, high pressure size exclusion chromatography (HP-SEC) and ultra-high performance size exclusion chromatography (UP-SEC) were performed, and the turbidity at 860 nm (also referred to as opalescence) was measured. The syringability of the formulations stored in syringes (Neopak) was analyzed by measuring the mechanical force required to expel / inject the formulation. Pressure tests were performed at a speed of 379.2 mm / min (5 s). The viscosity of the formulations was measured at 20°C using a HAAKE RheoStress 600 with a C35 / 1 rotor. Duplicate measurements were performed. Further details regarding the analytical methods utilized are provided below.

[0188] 1.3.Results

[0189] 1.3.1. Determination of Monomer Content

[0190] To determine the monomer content, the samples were analyzed by HP-SEC and UP-SEC.

[0191] HP-SEC analysis

[0192] The results obtained by HP-SEC analysis at storage temperatures of 25°C and 5°C are shown in Table 5. [Table 5]

[0193] Over 18 months of storage at 25°C, the monomer content was between 91 and 94%. The strongest decrease was measured for F1, with -5%; the lowest decrease was measured for formulations 4 and 5 tested in this example, with -3%. Over 18 months of storage at 5°C, the monomer content was between 93 and 96%. The strongest decrease was measured for F1, with -2.4%; the lowest decrease was measured for formulations 4 and 5, with -0.9% and -1.1%.

[0194] UP-SEC analysis

[0195] The results of the UP-SEC analysis are similar to those of the HP-SEC, thus confirming these results. [Table 6]

[0196] Over 18 months of storage at 25°C, the monomer content (UP-SEC) was between 88 and 91%. The strongest decrease was measured for F1 with -6.4%; the lowest decrease was measured for formulations 4 and 5 with -5.1% and -5.4%. Over 18 months of storage at 5°C, the monomer content (UP-SEC) was between 93 and 95%. The strongest decrease was measured for F1 with -2.2%; the lowest decrease was measured for formulations 4 and 5 with 1%.

[0197] Results and Discussion

[0198] All tested formulations were overall stable in terms of monomer content, indicating that these formulations are stable at 5°C and 25°C over long-term storage times of up to 18 months.

[0199] 1.3.2. Measurement of HMW content

[0200] To determine the HMW content, samples were analyzed by HP-SEC and UP-SEC.

[0201] HP-SEC analysis

[0202] The results obtained by HP-SEC analysis at storage temperatures of 25°C and 5°C are shown in Table 6. [Table 7]

[0203] Over 18 months of storage at 25°C, HMW species increased by 2-4%. The strongest increase was measured for F1 with +3.6%; the lowest increases were measured for Formulations 4 and 5 with +1.6% and +2.0%. Over 18 months of storage at 5°C, HMW species increased by 1-2%. The strongest increase was measured for F1 with +2.2%; the lowest increases were measured for Formulations 4 and 5 with +0.8% and +1.0%.

[0204] UP-SEC analysis

[0205] The results of the UP-SEC analysis are similar to those of the HP-SEC, thus confirming these results. [Table 8]

[0206] Over 18 months of storage at 25°C, HMW increased by 2-3.5%. The strongest increase was measured for F1 with +3.5%; the lowest increases were measured for formulations 4 and 5 with +1.8% and +2.2%. Over 18 months of storage at 5°C, HMW increased by 0.7-1.9%. The strongest increase was measured for F1 with +1.9%; the lowest increases were measured for formulations 4 and 5 with +0.7% and +0.8%.

[0207] Results and Discussion

[0208] All tested formulations were generally stable in terms of HMW content, indicating that various formulations according to the present disclosure are stable at 5°C and 25°C over long storage times of up to 18 months.

[0209] 1.3.3. Turbidity measurement [Table 9]

[0210] Turbidity was measured at a wavelength of 860 nm and showed an increase of 1 to 3 formazin turbidity units (FNU) over 18 months of storage at 25° C. Formulation 1 had the strongest increase of 3 FNU, and formulation 2 had the smallest increase of 1 FNU. Formulation 4, which contained L-arginine, had the highest turbidity from the start.

[0211] Turbidity was measured at a wavelength of 860 nm and showed an increase of 0-1 FNU during storage time of 18 months at 5°C.

[0212] Results and Discussion

[0213] Turbidity measurements show that storage in a refrigerator for 18 months results in no relative change in turbidity. Formulation 4, which contains L-arginine, had the highest turbidity, favoring the formulation without arginine.

[0214] Conductivity Measurement

[0215] The conductivity of the formulation was measured. [Table 10]

[0216] Results and Discussion

[0217] Conductivity remained constant for all five formulations over a storage time of 18 months at temperatures of 5° C. and 25° C. The conductivities of F1, F2, F3, and F5 had values ​​between 1 and 2 mS / cm, while the conductivity of the L-arginine-containing formulation F4 had a relatively high value of just below 4 mS / cm.

[0218] 1.4. Further Analysis and Results

[0219] Further analysis was also performed on the five formulations tested (storage times and temperatures as described above) with the following results: The pH value remained essentially constant over the 18-month storage period at the different storage temperatures tested. The measured pH values ​​thus ranged from 5.7 to 6.3. Osmolality remained essentially constant at the different storage temperatures tested over an 18-month storage period. Tested values ​​ranged from 296 to 333 mOsm / kg. Dynamic viscosity at 20°C remained essentially constant at the different storage temperatures tested over a storage period of 18 months. Dynamic viscosity ranged from 10 to 14 mPas. Protein concentration remained essentially constant at the different storage temperatures tested over the 18-month storage period. Small deviations in protein concentration are due to analytical variability, leading to a range of 148-159 mg / ml. HP-SEC fragment content remained essentially constant over 18 months of storage at the different storage temperatures tested. Fragment content ranged from 0.2 to 1.4%. UP-SEC LMW content remained essentially constant over 18 months of storage at the different storage temperatures tested. Notably, a low increase of 3% was measured over 18 months at 25°C and 0.1 to 0.3% at 5°C. LMW content ranged from 1.0 to 4.5%. The contents of the main peak, acidic peak group (APG), and basic peak group (BPG) of weak cation exchange (WCX) remained constant over 18 months of storage at 5°C. No differences were observed between formulations for the main peak, APG, and BPG. The main peak content of hydrophobic interaction chromatography (HIC) remained essentially constant over storage times of 12 months at 25°C or 8 months at 5°C. The post-peak increased by approximately 2-3% over this storage temperature and time. The pre-peak increased slightly by 5-7% over 12 months at 25°C and did not increase at 5°C over 8 months. No differences between formulations were observed for the main peak, post-peak, and pre-peak. Specific binding activity remained essentially constant over the 18-month storage period at the different storage temperatures tested, with only minimal decreases of 3% and 1-2% for 25°C and 5°C, respectively, over the 18-month period. Specific binding activity ranged from 96-101%. No visible particles were observed.

[0220] 1.5. Summary of Results

[0221] All five formulations were stable over a storage time of 18 months at 25°C and 5°C. However, formulation 4 contains additional adjuvants. Formulation 3 was stable and, in contrast to the arginine-containing formulation F4, had no additional adjuvants. At a pH of approximately 5.7, less aggregate formation was observed.

[0222] 2. Comparison of acetate and succinate buffer systems with different pH values ​​in freeze / thaw experiments

[0223] We analyzed whether freezing and thawing the 150 mg / ml formulation had any effect on the product quality of risankizumab. Therefore, three formulations were filled into minibags with an initial volume of 10 mL or 14 mL and frozen at -40°C. In addition, one bag was stored at 2-8°C. The storage time for both conditions (-40°C and 2-8°C) was 3 weeks.

[0224] Freezing was performed by a controlled freezing process, after which the bags were transferred into a -40°C freezer and left frozen for the indicated storage time.

[0225] 2.1. Preparation of formulations

[0226] Each freeze / thaw cycle involved freezing at -40°C in a freeze dryer, subsequent transfer into a -40°C freezer, and thawing to room temperature after 3 weeks in the freeze dryer at a maximum thaw rate of 20°C / min. The formulations tested are shown in Table 9. [Table 11]

[0227] The starting material was stored in a refrigerator at 2-8°C until use. Bags with a sample volume of 10 mL ("Mini Flexboy Bags") were frozen using a freeze dryer at a controlled freezing rate of 0.5°C / min until a temperature of -40°C was reached.

[0228] 2.2.Analysis

[0229] The samples were thawed in a controlled manner using a freeze dryer immediately prior to analysis. To measure protein stability, HP-SEC analysis was performed and binding activity was measured. Turbidity was measured at 860 nm and 400-600 nm. Further details regarding the analytical methods used are provided below.

[0230] 2.3.Results

[0231] 2.3.1. Determination of Monomer and HMW Content

[0232] To determine the stability of the formulation, HP-SEC and UP-SEC analyses were performed to show the monomer and HMW content. The following results were obtained: [Table 12]

[0233] The UP-SEC measurements confirm the results of the HP-SEC measurements. [Table 13]

[0234] Results and Discussion

[0235] Overall, the results of the HP-SEC analysis demonstrated stability for all formulations, indicating that the formulations were able to tolerate freeze / thaw cycles, with some formulations showing better results with higher monomer content and fewer HMW species.

[0236] 2.3.2. Measurement of binding activity

[0237] Binding activity to rhIL-23 was measured using surface plasmon resonance (Biacore) measurements. Binding activity was generally consistent across all formulations, demonstrating the applicability of the formulations. Specifically, binding activity was measured to range between 95 and 110%, with specific binding activity approximately 100%. Storage in a frozen state or at 2-8°C for 3 weeks did not alter binding activity.

[0238] 2.3.3. Viscosity Measurement

[0239] Another important parameter of a protein formulation is viscosity, which preferably is not too high to allow the formulation to be injected (e.g., to pass through a needle without excessive use of force). Therefore, dynamic viscosity was measured.

[0240] The dynamic viscosities are very similar for F1, F2, and F3, ranging from 8.7 to 10 mPas.

[0241] 2.4. Further Analysis and Results

[0242] Further analysis was also performed on the three formulations tested, with the following results: The subvisible particle content (≥25 μm, ≥10 μm, ≥5 μm) remained essentially constant over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. The total particles counted was essentially the same for all three formulations. Osmolality remained essentially constant over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. Tested values ​​ranged from 299 to 321 mOsm / kg for the 150 mg / ml formulation. Turbidity at 860 nm and 400-600 nm remained essentially constant over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. Tested values ​​ranged from 2-7 FNU at 860 nm and 4-13 FNU at 400-600 nm. The pH value remained essentially constant over 3 weeks at 5°C or at -40°C, including freeze / thaw cycles. The measured pH values ​​thus ranged from 5.7 to 6.2. Conductivity remained essentially constant over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. Measured conductivities thus ranged from 1.3 to 2.5 mS. Protein concentration remained essentially constant over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. Minor deviations in protein concentration are due to analytical variability, leading to a range of 149-157 mg / ml for an initial protein content of 150 mg / ml. The main peak content of hydrophobic interaction chromatography (HIC) remained essentially constant over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. The main peak value of HIC ranged from 97.1 to 97.7%. The post-peak and pre-peak contents remained essentially constant over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. The main peak content of weak cation exchange (WCX) chromatography remained essentially constant over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. The WCX main peak value ranged from 72.5 to 73.8%. The acidic peak group (APG) and basic peak group (BPG) remained essentially constant over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. No differences were observed between formulations for the main peak, APG, and BPG. Capillary gel electrophoresis (CGE) analysis showed essentially constant values ​​over 3 weeks at 5°C or -40°C, including freeze / thaw cycles. The non-reduced main peak content ranged from 96.7 to 97.6%.

[0243] 2.5. Summary of Results

[0244] The results of this example demonstrate the stability of risankizumab provided in different 150 mg / ml formulations over freeze / thaw cycles. A single freeze / thaw cycle with storage times of over 3 weeks at -40°C or 2-8°C had no effect on the product quality of risankizumab. Therefore, the 150 mg / ml formulation is a suitable concentration. A pH of 5.7 appeared to perform slightly better compared to other pH values.

[0245] 3. Comparison of acetate and succinate buffer systems with different pH values

[0246] A particularly suitable pH is in the range of 5.2 to 6.2, such as 5.5 to 6.2 or about 5.7. Higher pH may lead to increased protein aggregation, as measured by SEC. Lower pH may lead to chemical degradation. In previous studies, sorbitol was used to adjust tonicity. In this example, trehalose and mannitol were used to adjust tonicity instead of sorbitol. Seven sorbitol-free formulations were selected and tested under three conditions: (i) 5°C for 18 months, no rh monitoring; (ii) 25°C / 60% rh for 18 months; and (iii) 40°C / 75% rh for 6 months.

[0247] The compositions of formulations 1 to 7 are shown in Table 11 below. [Table 14]

[0248] The formulations and formulation buffers were sterile filtered (filter type 0.22 μm) and filled under laminar flow with a fill volume of 1.04 mL in syringes (Neopak). The formulations were prepared by mixing the starting material with a concentrated solution containing auxiliary agents (excipients, buffers, etc.). The filled syringes were stored at 2-8°C horizontally in a round tray protected from light using a cardboard box. The following packaging materials were used: - Neopak syringe (27 gauge) 1 / 1ml syringe with 2 inch needle) - Rubber stopper - Rondo Tray

[0249] 3.1.Analysis

[0250] For the analysis of the samples, HP-SEC and UP-SEC were performed and the turbidity (also referred to as opalescence) was measured. The following devices were used for the analysis: - UPLC, UPSEC:UPLC 29 / 31 Waters ACQUITY, Waters, MA - HPLC, WCX / SEC:HPLC 82 / 83 / 107 Waters ALLIACE, Waters, MA - Particle count / size by MFI: Micro Flow Imagine, 5200 BOT A / B (Roboter), Protein Simple, Germany - Osmometer: Osmomat 3000 Gonotec GmbH, Germany - pH meter: SevenGo, Mettler Toledo, Germany - Turbidity photometer: 2100AN turbidity meter, Hach-Lange GmbH, Germany - Protein concentration by Solo VPE: Solo VPE, C.Technologies, Inc., New Jersey - Biacore: Biacore T200, GE Healthcare Life Science, UK - Tensile and compression testing machine: Zwick 2.5TS / N 21159574 Zwick, Germany Further details regarding the analytical methods utilized are provided below.

[0251] 3.2.Results

[0252] 3.2.1. Determination of Monomer Content

[0253] UP-SEC and HP-SEC were used to determine the loss of monomer content, which is an important quality attribute for protein stability and quality during stress-induced storage. The table below shows the results of the UP-SEC measurements. [Table 15]

[0254] HP-SEC confirms the results of UP-SEC. No additional information was generated by HP-SEC compared to UP-SEC.

[0255] Results and Discussion

[0256] All formulations analyzed were stable under the conditions tested.

[0257] 3.2.2. Measurement of HMW levels

[0258] UP-SEC and HP-SEC were used to determine the level of HMW formation. The table below shows the results of the UP-SEC measurements. HMW content correlates with monomer content. A loss of monomer leads to an increase in HMW. [Table 16]

[0259] HP-SEC confirms the results of UP-SEC. No additional information was generated by HP-SEC compared to UP-SEC.

[0260] Results and Discussion

[0261] Overall, all formulations were stable with small amounts of HMW species even after storage at 40°C.

[0262] 3.2.3. Measuring LMW Level

[0263] UP-SEC was used to determine the level of LMW formation. The table below shows the results of the UP-SEC measurements. [Table 17]

[0264] Results and Discussion

[0265] Overall, all formulations were stable with small amounts of LMW species even after storage at 40°C.

[0266] 3.2.4. Measuring LMW Level

[0267] To assess the stability of the formulation, the LMW content was also determined by HP-SEC analysis, and the results of this analysis are shown below. [Table 18]

[0268] Results and Discussion

[0269] The LMW content increased slightly over time, however, all tested formulations generally resulted in low levels of fragmentation.

[0270] 3.2.5. Turbidity measurement

[0271] The opalescence results are summarized below. No change in opalescence was observed over the storage time at different conditions. The formulations containing L-arginine HCl (F3 and F5) showed the highest opalescence. However, there was no increase in opalescence over the course of the test for F3 and F5. No visible particles were observed in any of the tested formulations. [Table 19]

[0272] Results and Discussion

[0273] The L-arginine HCl containing formulation showed increased opalescence.

[0274] 3.3. Further Analysis and Results

[0275] Further analysis was also performed on the seven formulations tested, with the following results (storage times and temperatures as described above): Protein concentration remained essentially constant over 18 months of storage time and at the different storage temperatures tested. The pH value remained essentially constant over the 18-month storage time and at the different storage temperatures tested. Osmolality remained essentially constant over an 18-month storage period and at the different storage temperatures tested. Tested values ​​ranged from 298 to 326 mOsm / kg. No visible particles were observed. IEC / WCX measurements of formulations at 5°C over the tested storage times show consistent levels of the main peak (69.7-72.2%), APG (18-20%), and BPG (8-13%). At 25°C and 40°C, the main peak decreases and APG levels increase for all formulations in similar ranges. At 25°C and 40°C, BPG levels for formulations with pH 6.0 are slightly lower (up to 2%) than for formulations with pH 5.7. Particle content, as measured by MFI, remained essentially constant over the 18-month storage period at the different storage temperatures tested. In particular, for particles ≥ 10 μm and ≥ 25 μm, no relevant increasing particle counts were observed for all formulations over storage time at 5°C and 25°C / 60% rh. For particles ≥ 2 μm, there was an increase in particle count at 25°C. This increase was for all formulations in a similar range. Specific binding activity remained essentially constant over an 18-month storage period and at the different storage temperatures tested. Specific binding activity ranged from 95 to 100%. The sliding yield stress and sliding equilibrium stress remained essentially constant over 18 months of storage and at 5°C. At 25°C, the maximum sliding equilibrium stress, mean sliding equilibrium stress, and sliding yield stress increased over time of storage for all formulations. No differences between formulations were observed. The maximum sliding equilibrium stress ranged from 7.1 to 23.6 N, the mean sliding equilibrium stress ranged from 6.7 to 20.5 N, and the sliding yield stress ranged from 3.4 to 7.1 N. The dynamic viscosity measured at 20°C remained essentially constant over a storage time of 18 months and at the different storage temperatures tested. The dynamic viscosity ranged from 8.3 to 10.7 mPas.

[0276] 3.4. Summary of results

[0277] This example describes the storage stability of seven different 150 mg / ml risankizumab formulations. Trehalose and mannitol were used instead of sorbitol to adjust tonicity. F2 was also analyzed after 18 months.

[0278] UP-SEC showed that a pH of 6.0 led to slightly greater degradation of risankizumab compared to pH 5.7, resulting in lower monomer content and higher HMW forms in the tested formulations. The L-arginine HCl-containing formulation showed slightly less measured degradation than UP-SEC, but increased opalescence and slightly increased LMW content. IEC did not show any relevant differences between the formulations and was therefore not a determining factor. The same applies to pH, protein concentration, osmolality, viscosity, sliding yield stress and sliding equilibrium stress, subvisible particles, and visible particles. No differences between the formulations were observed from this data.

[0279] 4. Comparison of acetate and succinate buffer systems with different pH values ​​over long-term storage

[0280] In this example, the storage stability of seven different 150 mg / ml risankizumab formulations in Neopak syringes was analyzed to analyze the storage stability of the formulations and identify advantageous formulations. Compared to the seven formulations in the previous example, tonicity was slightly modified. Three conditions were again tested (as specified above). The analyzed formulations are summarized in Table 17. [Table 20]

[0281] The formulations were prepared by mixing the starting material with a concentrated spiking solution (including auxiliary agents, ie, excipients and buffers).

[0282] 4.1.Analysis

[0283] For the analysis of the samples, inter alia, UP-SEC was performed and opalescence was measured. Further details of the analytical methods utilized are provided below.

[0284] 4.2.Results

[0285] 4.2.1. Measurement of HMW content [Table 21]

[0286] Results and Discussion

[0287] The HMW content remained generally low in all formulations tested, indicating that the formulations used can stabilize risankizumab at high concentrations. The UP-SEC results further indicate that a pH of 6.0 leads to greater degradation of risankizumab in the form of lower monomer content and higher HMW levels compared to pH 5.7. Therefore, a pH of 5.7 is particularly advantageous for formulations according to the present disclosure. Nevertheless, formulations with a higher pH value than 6.0, such as F4, F5, and F6, also performed better overall in terms of UP-SEC analysis results.

[0288] 4.2.2. Determination of LMW content [Table 22]

[0289] Results and Discussion

[0290] The tested formulations were stable over the measured time period at all tested temperatures. Thus, the high protein concentration of 150 mg / ml risankizumab was effectively stabilized using the tested formulations. At higher storage temperatures, a slight increase in LMW content was observed for the L-arginine HCl-containing formulation. This is a surprising finding, since L-arginine-containing formulations are typically known to further stabilize formulations. Therefore, the 150 mg / ml risankizumab formulation differs from other protein formulations in this respect. Therefore, formulations according to the present disclosure without arginine are preferred.

[0291] 4.2.3. Measuring Opalescence [Table 23]

[0292] Results and Discussion

[0293] Overall, no or only a slight increase in opalescence was observed over time, indicating the stability of all tested formulations. Higher opalescence was observed for formulations containing L-arginine HCl (F3 and F5).

[0294] 4.3. Summary of Results

[0295] The measured parameters show that all formulations are suitable for preparing high risankizumab concentrations of 150 mg / ml in a stable manner. Long-term stability revealed some differences between the formulations: - UP-SEC showed that a pH of 6.0 leads to greater degradation of risankizumab with lower monomer content and higher HMW forms compared to pH 5.7. - The L-arginine HCl containing formulation showed lower degradation as measured by UP-SEC, but increased opalescence and a slight increase in LMW.

[0296] F2 was also analyzed after 18 months.

[0297] Notably, formulations F1 and F7 were also stable. The buffer-free formulations and formulations containing one or more tonicity agents were also stable and therefore suitable for providing formulations containing 150 mg / ml risankizumab.

[0298] In summary, formulation F2 was found to be particularly stable with respect to the measured LMW and HMW content, as well as opalescence, indicating excellent stability. This result was quite surprising, since risankizumab is known to be typically used at higher pH values. Therefore, the particularly high concentrations of risankizumab shifted the optimum pH to approximately 5.7, which was unexpected. Furthermore, it was surprising that L-arginine HCl did not provide further stabilization but actually decreased the stability of the formulation (as evidenced by the higher opalescence and measured LMW content). Consequently, the specific characteristics of risankizumab at high concentrations (e.g., 150 mg / ml) require different optimum conditions than previously known formulations of risankizumab.

[0299] 5. Comparison of acetate and succinate buffer systems with different pH values ​​while shaking

[0300] The purpose of this example was to evaluate the effect of shaking stress on the product quality of different formulations at 150 mg / ml risankizumab. Different formulations were tested for their ability to stabilize risankizumab against shaking stress. Therefore, the formulations were exposed to different shaking stresses at an antibody concentration of 150 mg / ml.

[0301] A total of 11 formulations, differing in pH, buffer, and isotonicity agent, were prepared in 6R vials and 27 gauge tubes. 1 The solution was filled into a 1 mL Neopak syringe with a 1 / 2 inch needle and shaken at room temperature for 21 days. The corresponding buffer solution without the protein was also shaken, stored and analyzed. Shaking conditions: - Shaking temperature: room temperature (approx. 25℃) - Shaking time: 21 days - Shaking type: horizontal shaker (vials), rocking shaker (syringes); shaking was performed protected from light.

[0302] Additional vials and syringes were stored at room temperature without shaking to eliminate the effect of temperature as an additional stress on product quality.

[0303] 5.1. Preparation of formulations

[0304] Eleven risankizumab test formulations were prepared (see Table 21) and subjected to the following: a) Shaking of vials in a horizontal shaker with 300 U / min for 1, 5, 7, 14, 21 days (protected from light); b) Shaking of the syringe in a rocking shaker for 1, 5, 7, 14, and 21 days, with the movement adjusted to the respective viscosity to ensure bubble movement (protected from light); and c) Room temperature (25°C) (protected from light) for 1, 5, 7, 14, and 21 days. [Table 24]

[0305] As packaging materials, the formulation was added to vials (Schott) or Neopak syringes. The sterile-filtered protein solution was filled into the sterilized primary packaging materials under laminar flow. The fill volume for the vials was defined as 3.6 mL. The syringes were filled with 1.04 mL each. All vials and syringes were inspected for visible particles and the results were recorded.

[0306] 5.2.Analysis

[0307] Analysis at each analytical time point was performed immediately after sampling, except for chromatographic assays such as SEC, where samples were stored at -70°C until measurement. The following devices were used for the analysis: - UV-Vis spectrophotometer Solo VPE: concentration at 280 nm, baseline correction at 320 nm, extinction coefficient: 1.52; C Technologies, Inc. (New Jersey, USA) - Opalescence meter: HACHLange Opalescence Meter; filter: 400-600 nm; Hach Lange GmbH (Düsseldorf, Germany) - Ultra-high performance size exclusion chromatography (UP-SEC): UPLC26, H class UV detection at 280 nm (Waters, Milford, MA) Charge heterogeneity by weak cation exchange chromatography (WCX): HPLC 75; fluorescence detection absorbance: 278 nm, emission: 350 nm; Waters (Milford, MA) - IL-23 binding activity: Biacore T200Chip: CM5 GE Healthcare (Chalfont St. Giles, UK) - pH meter: SevenGo-Mettler Toledo (Columbus, Ohio) Particle sizer: Micro Flow Imaging™ Flow Microscope; by Micro Flow Imaging (MFI); Brightwell Technologies Inc. (Ottawa, Ontario, Canada) - Osmometer: Osmomat 030; by freezing point depression, Gonotec GmbH, Berlin, Germany Further details regarding the analytical methods utilized are provided below.

[0308] 5.3.Results

[0309] 5.3.1. Determination of Monomer Content

[0310] Monomer content is an important 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 formulations.

[0311] UP-SEC analysis [Table 25]

[0312] HP-SEC analysis

[0313] The trends of the HP-SEC analysis are similar to those of the UP-SEC, thus confirming these results. Monomer values ​​ranging from 97.4 to 98.8% were obtained.

[0314] Results and Discussion

[0315] Overall, measurements in syringes and vials showed similar trends and all formulations proved stable with only a slight decrease in monomer content.

[0316] 5.3.2. Measurement of HMW content

[0317] HP-SEC and UP-SEC were used to measure the monomer content of the formulations. HP-SEC was used to determine the level of aggregate (HMW) formation during syringe and vial shaking.

[0318] UP-SEC analysis

[0319] The results of the UP-SEC analysis are shown below. The data showed similar results to the HP-SEC analysis, in that aggregate formation was primarily driven by pH. When comparing initial values, it is clear that formulations at pH 6.0 or 6.2 exhibit a slightly increased HMW content of 0.2-0.5% compared to solutions formulated at pH 5.7. This trend was also visible after 21 days of shaking, with HMW contents of approximately 1.6% in formulations at pH 6.0 and 1.3% in formulations at pH 5.7.

[0320] Formulations containing L-arginine, such as F3 and F7, showed the lowest levels of aggregation after 21 days of shaking. The differences in monomer content observed in UP-SEC and HP-SEC for the 11 formulations tested in this study were not significant. The loss of monomer content was within acceptable limits for all formulations tested. In general, it can be concluded that shaking does not significantly increase HMW content compared to results after 21 days without movement.

[0321] The data obtained using UP-SEC is summarized in Table 23. [Table 26]

[0322] HP-SEC analysis

[0323] The data trends in the HP-SEC analysis are similar to those in the UP-SEC, thus confirming these results.

[0324] Results and Discussion

[0325] Overall, all formulations tested proved to be stable, with similar results obtained for vials and syringes.

[0326] 5.3.3. Measurement of opalescence and further parameters

[0327] The opalescence, osmolality, pH value, and protein concentration of all tested formulations remained essentially unchanged after 21 days of shaking for the syringes on a horizontal shaker and for the vials on a rocking shaker (see data below). The lowest level of opalescence was observed in the unbuffered formulation F11, which did not contain any additional buffering agents such as acetate or succinate. Upon visual inspection, no significant differences were observed by comparing the vial and syringe production data.

[0328] The increased opalescence levels of F6 after 1 day and F10 after 5 days could not be confirmed by the results of the following sampling time points, therefore measurement errors were likely introduced and these results are not relevant for the interpretation of the results. [Table 27] TIFF2025163108000028.tif212170 TIFF2025163108000029.tif85170

[0329] Binding activity

[0330] SPR (Biacore) measurements showed that shaking did not affect the binding activity of the molecules for syringes on a rocking shaker and vials on a horizontal shaker. Overall, binding activity remained high, ranging from 91 to 111%, and specific binding activity ranged from 98 to 107%.

[0331] Results and Discussion

[0332] Opalescence depended on the formulation composition, ranging from 5 FNU in excipient-free or buffer-free formulations to 14 FNU, respectively, but did not increase significantly over time.

[0333] The pH value, osmolality, opalescence, and protein concentration, as well as the binding activity to IL-23, remained unchanged for all formulations over the entire study period.

[0334] 5.4. Further Analysis and Results

[0335] Further analysis was also performed on the 11 formulations tested, with the following results: Shaking type and time, storage, and syringes and vials used were as described above. HP-SEC fragment content remained essentially constant over time in vials and syringes. Fragment content ranged from 0.3 to 0.5%. UP-SEC LMW content remained essentially constant over time in vials and syringes. Fragment content ranged from 1.3 to 1.4%. Weak cation exchange chromatography (WCX) showed that the percentage distribution of the main peak, APG, and BPG remained at a constant level for all formulations tested during the study. The levels of the main peak, APG, and BPG did not change significantly over the shaking time. No differences between formulations were observed. Particle content measured by microflow imaging (MFI) remained essentially constant over the 21-day shaking period.

[0336] Overview

[0337] Overall, only slight differences in stability parameters were detected between the formulations after exposure to shaking stress. For example, formulations F3 and F7 exhibited the highest monomer content (HP-SEC and UP-SEC), but they also exhibited the highest levels of opalescence. It can be concluded that the formulations tested in this study may be viable formulations.

[0338] 6. Comparison of acetate and succinate buffer systems with different pH values ​​over multiple freeze / thaw cycles

[0339] The freeze and thaw behavior of different formulations of 150 mg / ml risankizumab and its effect on product quality was evaluated. Thus, formulations were exposed to freeze and thaw stress in minibags with an intended target concentration of 150 mg / ml and a fill volume of 12 mL to simulate the conditions of bag freezing in pilot or large scale.

[0340] A total of 11 formulations differing in pH, buffer strategy, and tonicity agent + intermediate storage bulk were filled into minibags with a fill volume of 12 mL and followed by a controlled freezing process to -40° C. Additionally, the bags were stored at 5° C. Note that the 11 formulations correspond to those tested in the previous examples. [Table 28]

[0341] The freezing process was carried out using the freeze-thaw device provided by a classical freeze dryer. Here, minibags with a sample volume of 12 mL were frozen in a controlled manner using a freeze ramp of 0.5°C / min to -40°C. At this point, the temperature remained constant for 16 hours, ensuring complete freezing of the sample volume. The thawing process was carried out following the freezing process with a heating rate of 0.5°C / min. The holding time at room temperature was set to 4 hours.

[0342] A complete freeze / thaw cycle (1×F / T) is defined as follows: 1. Freezing from room temperature to -40°C (0.5°C / min) 2. 16 hours of holding time at -40°C 3. Thaw from -40°C to room temperature (0.5°C / min) 4. 4 hours holding time at room temperature.

[0343] This procedure was performed for 1x F / T, 3x F / T, and 6x F / T. After the final process cycle was completed, the bags were transferred to a -40°C freezer and stored until the samples were thawed and analyzed simultaneously.

[0344] 6.1. Preparation of the formulation

[0345] The formulation was prepared as described in the previous example (see Table 21). An additional formulation, F12, was prepared, containing 0.02% PS20, pH 5.7, and no excipients. 12 mL of sterile filtered protein solution was filled into a sterilized primary packaging material under laminar flow, which was a Mini Flexboy bag with a capacity of 15 mL. All bags were inspected for visible particles, and the results were recorded.

[0346] In each freeze-thaw run, 12 bags were placed on each plate in the freeze-dryer. A total of 36 bags were frozen / thawed in each run, including 3 bags per formulation. The bags were distributed in a set scheme to eliminate the effect of bag position in the freeze-dryer.

[0347] 6.2.Analysis

[0348] After all cycles according to the above experimental design were performed, the bags were successively thawed in an additional thawing step. This procedure had the advantage that the samples could be analyzed simultaneously. The bags were transferred into a freeze-dryer pre-cooled to -40°C, after which the thawing step was continued. Measurements of HP-SEC, UP-SEC, osmolality, pH, protein concentration, opalescence, binding activity, and subvisible particles were performed. The following devices were used for the analysis: - UV-Vis spectrophotometer Solo VPE: concentration at 280 nm, baseline correction at 320 nm, extinction coefficient: 1.52; C Technologies, Inc. (New Jersey, USA) - Opalescence meter: HACHLange Opalescence Meter; filter: 400-600 nm; Hach Lange GmbH (Düsseldorf, Germany) - Ultra-high performance size exclusion chromatography (UP-SEC): UPLC26, H class UV detection at 280 nm (Waters, Milford, MA) Charge heterogeneity by weak cation exchange chromatography (WCX): HPLC 75; fluorescence detection absorbance: 278 nm, emission: 350 nm; Waters (Milford, MA) - IL-23 binding activity: Biacore T200Chip: CM5 GE Healthcare (Chalfont St. Giles, UK) - pH meter: SevenGo-Mettler Toledo (Columbus, Ohio) Particle sizer: Micro Flow Imaging™ Flow Microscope; by Micro Flow Imaging (MFI); Brightwell Technologies Inc. (Ottawa, Ontario, Canada) - Osmometer: Osmomat 030; by freezing point depression, Gonotec GmbH, Berlin, Germany Further details regarding the analytical methods utilized are provided below.

[0349] 6.3.Results

[0350] 6.3.1. Determination of Monomer and HMW Content

[0351] Monomer content is an important quality attribute for protein stability and quality during stress-induced storage. HP-SEC and UP-SEC were used to determine the level of aggregate formation during freeze / thaw of minibags. The following table summarizes the results of the HP-SEC & UP-SEC analysis. [Table 29] TIFF2025163108000032.tif199170

[0352] Results and Discussion

[0353] The data indicate that aggregate formation is primarily driven by pH. By comparing the results after six freeze-thaw cycles, it is clear that formulations at pH 6.0 or 6.2 exhibit a slightly increased HMW content of 0.2-0.6% compared to solutions formulated at pH 5.7. L-arginine-containing formulations, such as F3 and F7, exhibited the lowest levels of aggregation after six freeze-thaw cycles. In general, it can be concluded that freeze / thaw stress does not significantly increase HMW content when compared to results after 21 days at 5°C.

[0354] 6.3.2. Measurement of opalescence and other parameters

[0355] The opalescence, osmolality, pH, and protein concentration of all tested formulations remained unchanged after six F / T cycles and after 3 weeks of storage at 5° C. The lowest levels of opalescence were observed in the buffer-free formulations (F11 and F12). [Table 30] TIFF2025163108000034.tif183170

[0356] Binding activity

[0357] SPR (Biacore) measurements of IL23 binding activity show that freeze / thaw cycles do not affect the binding activity of the molecule, with binding activities ranging between 96 and 117%.

[0358] Results and Discussion

[0359] The measured opalescence was formulation dependent: pH value, osmolality, opalescence, and protein concentration as well as IL-23 binding remained essentially unchanged and thus stable for all formulations over the entire study period, regardless of stress conditions (F / T and holding time at 5°C).

[0360] 6.3.3. Particle Measurement

[0361] The following table summarizes the particle counts for each SVP. No clear trends were observed for all formulations tested. Formulations F3, F7, and F9 show slightly increased amounts of SVP compared to the other formulations tested. This observation was mainly seen for SVPs ≥ 2 μm and ≥ 10 μm. [Table 31]

[0362] Results and Discussion

[0363] For particles >= 2 μm, a similar trend was observed, but a slight increase in particles with a size >= 10 μm was observed for F3, F7, and F9 compared to the others. For particles >= 25 μm, a slight increase was observed for F3 after 6x F / T. Overall, particle formation was not a major issue during F / T for all tested formulations.

[0364] 6.4. Further Analysis and Results

[0365] Further analysis was also performed on the 12 formulations tested with the following results (freeze / thaw cycles as described above): Weak cation exchange chromatography (WCX) showed that the percentage distribution of the main peak, APG, and BPG remained at a constant level for all formulations tested during the study. The levels of the main peak, APG, and BPG did not change significantly over six freeze / thaw cycles. The main peak ranged from 65-67%, the APG content from 21-23%, and the BPG content from approximately 11-14%. No differences between formulations were observed.

[0366] 6.5. Summary of Results

[0367] The results can be summarized as follows: - Visual Inspection: After 6 F / T cycles, no observations could be made during visual inspection for all formulations. - SVP: No major problems were observed regarding subvisible particle levels. There was a slight increase for F3, F7 and F9 compared to the other formulations, but they were significantly below the pharmacopoeia specifications. - HP-SEC and UP-SEC: For testing methods that focus on protein integrity such as HP-SEC and UP-SEC, F3 was found to be the most stable formulation and F4 the least stable. F12, without any buffers or excipients, showed acceptable stability during freeze / thaw cycles. - IEC: No differentiation between any of the formulations could be observed in the IEC results. The F / T cycle does not negatively affect the contribution of APG and BPG. - Opalescence: Opalescence is formulation dependent and ranges from 4 FNU in excipient-free or buffer-free formulations to 13 FNU. - pH value, osmolality, opalescence, and protein concentration and binding remained unchanged for all formulations over the entire study period, regardless of stress conditions (F / T and holding time at 5°C).

[0368] It can be summarized that the majority of the formulations tested in this example were viable for the 150 mg / ml formulation. Only a small effect of freeze / thaw stress on protein stability was observed. Due to medical concerns regarding sorbitol-containing formulations, these formulations may also prove less advantageous for treating patients with fructose intolerance. Nevertheless, for other patients, sorbitol-containing solutions may prove useful. Overall, only small differences in stability parameters could be detected between formulations after exposure to F / T. For example, formulation F3 was the most stable in monomer content (HP-SEC), but conversely, increased levels of subvisible particles could be detected.

[0369] 7. Effect of pH on formulation stability

[0370] The effect of pH value on the stability of 150 mg / ml risankizumab formulations was tested using the formulations shown in Table 29. [Table 32]

[0371] 7.1. Preparation of the formulation

[0372] The formulations were prepared as described above.

[0373] 7.2.Analysis

[0374] Sample measurements were performed at 1, 3, 6, 9, 12, 18, 24, and 36 months of storage, as well as initially before storage. Various analytical methods were used, including HIC, UP-SEC, IEC, and measurements of viscosity, sliding yield stress and equilibrium stress, and binding specificity. Further details regarding the analytical methods utilized are provided below.

[0375] 7.3.Results

[0376] 7.3.1. Determination of Monomer Content

[0377] Monomer content was measured using UP-SEC analysis as in the previous example, and the results are shown in Table 30. [Table 33]

[0378] Results and Discussion

[0379] Monomer content measurements indicate that the tested formulations were stable over the range of tested pH values ​​from pH 5.0 to 6.2. Thus, a wide range of pH values ​​is applicable to obtain highly stable formulations of 150 mg / ml risankizumab. While high monomer values ​​were obtained for pH values ​​around 5.7, relatively low monomer contents were measured for more acidic conditions of about pH 5.0 (see, e.g., the last measurement point of pH 5.0 at 25°C or 40°C). Therefore, a highly concentrated risankizumab (here, 150 mg / ml) formulation with a pH of about 5.7 proved particularly advantageous, especially in the formulation provided in this example.

[0380] 7.3.2. Measurement of HMW content

[0381] The HMW content of the formulations was also determined using UP-SEC, which gave the following results: [Table 34]

[0382] Results and Discussion

[0383] HMW content correlates with monomer measurements. Overall, the tested formulations were stable over a range of pH values. A particularly low increase in HMW content was obtained for pH values ​​around 5.7. However, higher pH values ​​(e.g., a pH of 6.2) appear to lead to slightly higher HMW values.

[0384] 7.3.3. Determination of LMW content

[0385] The LMW content was determined by UP-SEC analysis, revealing the following results: [Table 35]

[0386] Results and Discussion

[0387] The LMW content correlates with the monomer measurements. A particularly small increase in LMW content was obtained for pH values ​​around 5.7. However, lower pH values ​​appear to lead to slightly higher LMW values. Overall, the tested formulations were stable over a range of pH values.

[0388] 7.3.4. Species determination by ion exchange chromatography (IEC)

[0389] The ionic species were measured by ion exchange chromatography, and the results were then classified into main peak, acidic peak group (APG), and basic peak group (BPG). [Table 36] [Table 37] [Table 38]

[0390] Results and Discussion

[0391] The IEC measurements show that the tested formulations were generally stable. All pH values ​​led to a high content of the main peak. Notably, the intermediate pH value of 5.7 and pH values ​​around 5.7 showed a good compromise compared with the highest and lowest tested pH values ​​(which showed an increase in APG or BPG species, respectively). Therefore, a pH of about 5.7 proved to be advantageous.

[0392] 7.3.5. Species Determination by Hydrophobic Interaction Chromatography (HIC)

[0393] The determination of risankizumab mutants / subspecies was performed by hydrophobic interaction chromatography (HIC). The results were then classified into main peak, pre-peak, and post-peak. [Table 39] [Table 40] [Table 41]

[0394] Results and Discussion

[0395] HIC measurements show that the tested formulations were generally stable. All pH values ​​led to a high content of the main peak. Notably, the intermediate pH value of 5.7 and pH values ​​around 5.7 showed a good compromise compared to the highest and lowest tested pH values ​​(which showed an increase in the pre-peak and post-peak, respectively).

[0396] 7.3.6. Binding activity

[0397] The binding activity of risankizumab to IL-23 was measured using BIACORET 200. The following results were obtained: [Table 42] [Table 43]

[0398] Results and Discussion

[0399] The binding activity measurements show high values ​​overall for the tested formulations, and therefore the tested formulations stabilize risankizumab to achieve high binding activity in the pH range of 5.0 to 6.2.

[0400] 7.3.7. Measurement of opalescence

[0401] Additionally, the degree of opalescence of the formulations was measured. Opalescence varied slightly over the time of analysis, but remained generally highly constant, ranging from 3 to 11. The results indicate that the formulations are generally stable. Notably, lower pH values ​​generally exhibited lower opalescence (3 to 6 FNU for pH 5.0) than higher pH values ​​(7 to 11 FNU for pH 6.2). An intermediate pH of 5.7 had opalescence in the range of 5 to 7 FNU, indicating that providing a formulation with a pH of approximately 5.7 is advantageous, particularly in the formulation according to this example.

[0402] 7.3.8. Measurement of viscosity and sliding equilibrium stress and sliding yield stress of syringe

[0403] Further parameters measured were viscosity and syringe force, including the average and maximum sliding equilibrium stress, and sliding yield stress. The following results were obtained: [Table 44] [Table 45] [Table 46] [Table 47]

[0404] Results and Discussion

[0405] Viscosity measurements revealed slightly higher viscosities for higher pH values. Thus, lower pH values, such as pH 5.7, may prove advantageous for obtaining formulations with lower viscosities. Note that mechanical measurements of sliding equilibrium stress and sliding yield stress revealed very similar overall performance.

[0406] 7.4. Further Analysis and Results

[0407] Further analysis was also performed on the six formulations tested, with the following results: Storage times and temperatures were as described above. Protein concentration remained essentially constant over storage times of 36, 24, 12, and 3 months at the different storage temperatures tested (5°C, 25°C, and 40°C, respectively). Small deviations in protein concentration (145-155 mg / ml at 24 months and 145-158 mg / ml at 36 months) are attributable to analytical variability. The pH values ​​remained essentially constant over storage times of 36, 24, 12, and 3 months at the different storage temperatures tested (5°C, 25°C, and 40°C, respectively). The measured pH values ​​thus ranged from 4.9 to 6.3. Osmolality remained essentially constant over storage times of 36, 24, 12, and 3 months at the different storage temperatures tested (5°C, 25°C, and 40°C, respectively). Tested values ​​ranged from 301 to 323 mOsm / kg. Protein-associated particles and foreign particles remained essentially consistently low over storage time at the different storage temperatures tested.

[0408] 7.5. Summary of Results

[0409] The formulations were stable at all tested pH values ​​over long storage times up to 24 and 36 months. Although temperature appeared to have an effect on stability (i.e., higher temperatures induce more unstable related effects), all formulations were sufficiently stable even at high temperatures.

[0410] In summary, a pH value of 5.7 and values ​​around 5.7 (e.g., 5.5, 5.9) appeared to offer a favorable compromise in terms of storage parameters under the test conditions used. For example, UP-SEC measurements showed moderate to low HMW and LMW values ​​for pH 5.7, with the highest and lowest pHs showing the highest HMW and LMW contents, respectively. Similar results were obtained in IEC and HIC measurements.

[0411] 8. Effect of acetate concentration on formulation stability

[0412] Formulations containing different concentrations of acetate (see Table 45) were stored at three different temperatures (5°C, 25°C, and 40°C) for different time points. [Table 48]

[0413] 8.1. Preparation of the formulation

[0414] The formulations were prepared as described above.

[0415] 8.2.Analysis

[0416] Sample measurements were performed at 1, 3, 6, 9, 12, 18, 24, and 36 months of storage, as well as initially before storage. Storage temperatures were adjusted to 5°C, 25°C, or 40°C. Analysis was performed using UP-SEC for monomer content, HMW content, and LMW content, and Biacore for binding activity. Additionally, the required force for sliding equilibrium stress and sliding yield stress, as well as osmolality, opalescence, and pH values ​​were measured. Further details regarding the analytical methods utilized are provided below.

[0417] 8.3.Results

[0418] 8.3.1. Determination of Monomer Content

[0419] UP-SEC analysis was performed to determine the monomer content, with the following results: [Table 49]

[0420] Results and Discussion

[0421] Monomer measurements showed that the formulations were stable over a range of acetate contents, demonstrating stability for buffered and unbuffered formulations with 150 mg / ml risankizumab and formulations according to this example.

[0422] 8.3.2. Measurement of HMW Content

[0423] The HMW content of the formulations was also determined via UP-SEC analysis, with the following results: [Table 50]

[0424] Results and Discussion

[0425] HMW content measurements showed that the formulations were stable over a range of acetate contents, demonstrating the stability of buffered and unbuffered formulations with 150 mg / ml risankizumab and formulations according to this example.

[0426] 8.3.3. Determination of LMW content

[0427] UP-SEC analysis was performed to measure the LMW content, and the following results were obtained: [Table 51]

[0428] Results and Discussion

[0429] LMW measurements showed that the formulations were stable over a range of acetate contents, demonstrating stability for buffered and unbuffered formulations.

[0430] 8.3.4. Measurement of binding activity

[0431] Biacore analysis was performed to analyze whether acetate content has an effect on the binding activity of risankizumab to IL-23. Binding activity measurements demonstrated high binding activity to human IL-23 for all formulations and storage times tested, ranging from 92-105% binding activity and 97-100% specific binding activity. These results support the favorable stability of the tested formulations and demonstrate that acetate-containing and buffer-free formulations are applicable in accordance with the present disclosure.

[0432] 8.3.5. Osmolality Measurement

[0433] Acetate content also has an effect on the osmolality of the formulation, so this parameter was measured and the results are shown in Table 49. [Table 52]

[0434] Results and Discussion

[0435] The measurements show that osmolality ranges from approximately 290 to 338 mOsm / kg, depending on the amount of acetate added. The more acetate added, the higher the measured osmolality. An osmolality of approximately 310 mOsm / kg is typically desired, and a 10 mM acetate concentration resulted in tested formulations with a desired osmolality around 310 mOsm / kg (measured range of 305 to 314 mOsm / kg). If a different concentration of acetate is required or desired, it may be advantageous to modify the content of other compounds in the formulation (e.g., other excipients, such as trehalose) to adjust the osmolality to approximately 310 mOsm / kg.

[0436] 8.3.6. Measuring Opalescence

[0437] The opalescence of the formulations of this example was also measured to assess stability. The measured opalescence was generally the same for the different formulations, ranging between 4 and 9 FNU. Higher concentrations of acetate led to slightly higher opalescence, 7 to 9 FNU for 20 mM acetate, than lower concentrations (4 to 6 FNU for 0 mM acetate). All formulations according to this example were stable in terms of the measured opalescence.

[0438] pH Measurement

[0439] To determine the pH stability of formulations containing varying amounts of buffer (i.e., acetate in this example), the pH values ​​were measured over time at different temperatures, and the results are shown in the table below. [Table 53]

[0440] Results and Discussion

[0441] Measurement of the pH value demonstrates that the pH remained constant throughout the formulations tested according to this example, and thus the formulations were stable with respect to pH value for all acetate contents (including acetate-free formulations).

[0442] 8.3.8. Measurement of sliding equilibrium stress and sliding yield stress

[0443] The maximum and average sliding equilibrium stress and sliding yield stress were measured for syringes containing different formulations according to this example, and the results of these measurements are shown below. [Table 54] [Table 55] [Table 56]

[0444] Results and Discussion

[0445] Measurements of the sliding equilibrium stress and sliding yield stress show that all formulations are stable and do not significantly increase in sliding equilibrium stress and sliding yield stress over time. Notably, formulations without acetate (F1) or with very low concentrations of acetate (F2) exhibit higher stresses, indicating that adding a buffer, such as acetate, may be useful, especially if the goal is to minimize the required force applied to the syringe.

[0446] 8.4. Further Analysis and Results

[0447] Further analysis was also performed on the five formulations tested, with the following results: Storage times and temperatures were as described above. The contents of the main peak, APG, and BGP in IEC remained constant over 24 and 36 months at 5°C. No differences were observed between the formulations with respect to the main peak, APG, and BGP. The HIC main peak content remained constant at 5°C for 24 months, ranging from 96.8 to 97.2%, with 1.4 to 1.7% for the pre-peak and 1.5 to 1.9% for the post-peak. Over 36 months at 5°C, HIC main peak contents ranged from 96.3 to 97.2%, with 1.4 to 1.7% for the pre-peak and 1.5 to 2.2% for the post-peak. At 25°C, over storage times up to 12 months, main peak contents between 94.3 and 97.1%, with 1.4 to 3.0% for the pre-peak and 1.5 to 2.7% for the post-peak. At 40°C, over storage times up to 3 months, main peak contents between 92.0 and 97.1%, with 1.4 to 4.6% for the pre-peak and 1.5 to 3.4% for the post-peak. No differences between the formulations were observed for the main peak, pre-peak, and post-peak. Protein concentration remained essentially constant up to 24 and 36 months of storage time at the different storage temperatures tested. Small deviations in protein concentration were due to analytical variability, leading to ranges of 147-155 mg / ml (24 months) and 147-157 mg / ml (36 months). Dynamic viscosity remained essentially constant up to 24 and 36 months of storage time at the different storage temperatures tested. Dynamic viscosity ranged from 8.9 to 10.0 mPas. Protein-associated particles and foreign particles remained essentially constant and low over storage time at the different storage temperatures tested.

[0448] 8.5. Summary of Results

[0449] The tested formulations show comparable high stability overall. Therefore, both acetate-containing and buffer-free formulations are suitable for formulations according to the present disclosure. In terms of the required force applied to the syringe, solutions containing a buffer, such as acetate buffer, have proven advantageous over buffer-free formulations. Furthermore, to achieve an osmolality of 310 mOsm / kg, a 10 mM acetate content has proven suitable, taking into account other compounds present in the formulation according to this example.

[0450] IV. Example 3: Analysis of Additional Excipients

[0451] 1. Effect of PS20 content on shaking experiments Formulations were prepared (see Table 54) in which the PS20 (polysorbate 20) content was varied from 0, 0.05, 0.075, 0.1, 0.2, 0.3, 0.5 mg / ml and analyzed for shaking times of 0, 1, 5, 7, 14, and 21 days. [Table 57]

[0452] 1.1. Preparation of formulations

[0453] The formulations were prepared as described above and packaged in 2R vials (1.0 mL) or pre-filled syringes (PFS, Neopak, 1.0 mL) for each formulation, as well as for the control and non-shaken formulations.

[0454] 1.2.Analysis

[0455] Sample measurements were performed on days 0, 1, 5, 7, 14, and 21. The total shaking time was therefore 21 days for both the vials and the PFS. Shaking was performed (orbital shaker) at room temperature (25°C) at 200 U / min for the vials, adjusting the movement to the respective viscosity and ensuring air bubble movement for the PFS (Vari Mix Platform Rocker). All samples were protected from light. The opalescence of the formulations was measured at the indicated measuring points. Further details regarding the analytical methods used are provided below.

[0456] 1.3.Results

[0457] Measuring opalescence

[0458] To determine the stability of formulations containing varying amounts of PS20 and subjected to shaking stress, opalescence was measured at different time points. The results obtained from the opalescence measurements are shown below: [Table 58]

[0459] 1.4. Summary of Results

[0460] Shaking tests revealed that formulations without PS20 showed a significant increase in opalescence over the 21-day shaking period. In contrast, all formulations containing PS20, even the lowest amount of 0.05 g / L, showed no increase in opalescence over time. The results demonstrate the importance of surfactants, such as the nonionic surfactant PS20, in formulations according to the present disclosure, particularly formulations containing 150 mg / ml risankizumab.

[0461] 2. Effect of PS20 content during storage

[0462] The prepared formulations (see Table 54) were analyzed over different time points and stored at three different temperatures (5°C, 25°C, and 40°C).

[0463] 2.1.Analysis

[0464] Sample measurements were performed at 1, 3, 6, 9, 12, 18, 24, and 36 months of storage, as well as initially before storage. UP-SEC analysis was performed to determine the monomer, HMW, and LMW content. Additionally, subvisible particle content, sliding equilibrium stress, and sliding yield stress were measured. Further details regarding the analytical methods utilized are provided below.

[0465] 2.2.Results

[0466] 2.2.1. Determination of Monomer Content

[0467] The stability of the formulation was assessed by measuring the monomer content using UP-SEC analysis, and the results are shown below. [Table 59]

[0468] Results and Discussion

[0469] Monomer measurements show that the formulation is stable over a range of PS20 contents, with particularly high monomer values ​​obtained for PS20 contents around 0.2 mg / ml.

[0470] 2.2.2. Measurement of HMW content

[0471] The stability of the formulation was further assessed by measuring the HMW content, again using UP-SEC, and the results are shown below. [Table 60]

[0472] Results and Discussion

[0473] HMW content correlates with monomer measurements. Overall, the tested formulations were stable over the range of PS20 contents. A particularly small increase in HMW content was obtained for a PS20 content of 0.2 mg / ml. However, the highest and lowest PS20 contents tested appear to lead to slightly higher HMW values.

[0474] 2.2.3. Determination of LMW content

[0475] The LMW content was also measured using UP-SEC with the following results: [Table 61]

[0476] Results and Discussion

[0477] LMW content correlates with monomer measurements. Overall, the tested formulations were stable over the range of PS20 contents. A particularly low increase in LMW content was obtained for a PS20 content of 0.2 mg / ml. The lowest tested PS20 content (see F1) appears to have led to slightly higher LMW values.

[0478] 2.2.4. Measuring Opalescence

[0479] Additionally, opalescence was measured for formulations containing varying amounts of PS20, and the results are shown below. [Table 62]

[0480] Results and Discussion

[0481] Measurements show that at higher temperatures of 25 and 40° C., none of the formulations led to an increase in opalescence. However, at a temperature of 5° C. and at later storage time points (e.g., 18, 24, and 36 months), formulation F1 (without PS20) showed an increase in opalescence. It is therefore advantageous to incorporate a surfactant, such as the nonionic surfactant PS20.

[0482] 2.2.5. Determination of the content of subvisible particles

[0483] Formulations were analyzed for their subvisible particle content (≧2 μm, ≧10 μm, and ≧25 μm) over 24 and 36 months and stored at 5°C. [Table 63]

[0484] Results and Discussion

[0485] Measurement of the content of subvisible particles indicates that all formulations are stable for up to 24 and 36 months at 5° C. Only the formulation without PS20 (F1) appeared to result in some particle formation, demonstrating the advantage of adding a surfactant, such as the nonionic surfactant PS20, to formulations according to the present disclosure.

[0486] 2.2.6. Measurement of sliding equilibrium stress and sliding yield stress

[0487] The maximum and average sliding equilibrium stress and sliding yield stress were measured for formulations containing varying amounts of PS20. The results of the measurements are shown below. [Table 64] [Table 65] [Table 66]

[0488] Results and Discussion

[0489] Measurements of the sliding equilibrium stress revealed a relatively high sliding equilibrium stress for the high PS20 loading of 0.5 g / L compared to the lower loadings. The 0 g / L loading showed the smallest increase in sliding equilibrium stress, while the intermediate concentration of 0.2 g / L showed a good compromise between high and low sliding equilibrium stress. Notably, essentially no differences were observed between the formulations with respect to sliding yield stress.

[0490] 2.3. Further Analysis and Results

[0491] Further analysis was also performed on the seven formulations tested, with the following results: Storage times and temperatures were as described above. The contents of the main peak, APG, and BGP in IEC remained constant over 24 and 36 months at 5°C. No differences between the formulations were observed for the main peak, APG, and BGP. The HIC main peak content remained constant at 5°C for 24 months, ranging from 96.5 to 97.3%, with 1.4 to 1.7% for the pre-peak and 1.4 to 1.9% for the post-peak. Over 36 months at 5°C, HIC main peak contents ranging from 95.9 to 97.3%, with 1.4 to 1.7% for the pre-peak and 1.4 to 2.4% for the post-peak, were obtained. Over storage times up to 12 months at 25°C, main peak contents between 93.9 and 96.8%, with 1.4 to 3.0% for the pre-peak and 1.7 to 2.7% for the post-peak, were obtained. Over storage times up to 3 months at 40°C, main peak contents between 90.3 and 95.2%, with 2.5 to 6.0% for the pre-peak and 2.3 to 3.7% for the post-peak, were obtained. No differences between the formulations were observed for the main peak, pre-peak, and post-peak. Specific binding activity remained essentially constant up to 24 and 36 months of storage at the different storage temperatures tested. Specific binding activity ranged from 97 to 101%. Protein concentrations remained essentially constant up to 24 and 36 months of storage at the different storage temperatures tested. Small deviations in protein concentrations were attributed to analytical variability, leading to ranges of 147-155 mg / ml (24 months) and 147-159 mg / ml (36 months). The pH values ​​remained essentially constant up to 24 and 36 months of storage time at the different storage temperatures tested. The pH ranged from 5.7 to 5.9. Osmolality remained essentially constant up to 24 and 36 months of storage at the different storage temperatures tested. Tested values ​​ranged from 305 to 322 mOsm / kg. Dynamic viscosity remained essentially constant up to 24 and 36 months of storage time at the different storage temperatures tested. Dynamic viscosity ranged from 9.2 to 11.0 mPas. Protein-associated particles and foreign particles remained essentially consistently low over storage time at the different storage temperatures tested.

[0492] 2.4. Summary of Results

[0493] In summary, the tested formulations were stable over long-term storage periods of up to 24 and 36 months at temperatures ranging from 5°C to 40°C. In particular, formulations containing surfactants, such as PS20, were found to be stable, whereas formulations lacking PS20 showed some formation of subvisible particles and an increase in opalescence. LMW content also increased slightly for formulations lacking PS20. A particularly suitable content of surfactants, such as the nonionic surfactant PS20, appeared to be 0.2 g / L under the test conditions.

[0494] 3. Variation in trehalose content

[0495] In this example, trehalose concentrations were varied from 145, 165, 185, 205, and 225 mM, analyzed over different time points, and stored at three different temperatures (5° C., 25° C., and 40° C.). The formulations prepared are shown in Table 65. [Table 67]

[0496] 3.1.Analysis

[0497] Measurements were performed on samples at 1, 3, 6, 9, 12, 18, 24, and 36 months of storage, as well as initially before storage. Further details regarding the analytical methods utilized are provided below.

[0498] 3.2.Results

[0499] 3.2.1. Determination of Monomer Content

[0500] The stability of formulations containing varying amounts of trehalose was assessed by measuring the monomer content using UP-SEC analysis, revealing the results shown below. [Table 68]

[0501] Results and Discussion

[0502] Monomer measurements showed that the formulations were stable over a range of trehalose contents, indicating stability over a range of trehalose contents.

[0503] 3.2.2. Measurement of HMW content

[0504] The HMW content of the formulations was measured using UP-SEC and the results of the analysis are shown below. [Table 69]

[0505] Results and Discussion

[0506] Measurement of HMW content indicates that the formulation is stable over a range of trehalose contents.

[0507] 3.2.3. Determination of LMW content

[0508] LMW content was also measured via UP-SEC for formulations containing varying amounts of trehalose, and the results are shown below. [Table 70]

[0509] Results and Discussion

[0510] LMW measurements show that the formulations are stable over a range of trehalose contents.

[0511] 3.2.4. Measurement of binding activity

[0512] The binding activity of risankizumab contained in formulations according to the present disclosure was measured. Antigen binding measurements show high binding activity to IL-23 for all tested formulations, ranging from 92-122% binding activity and 96-100% specific binding activity. These results support the advantageous stability of the tested formulations and demonstrate that formulations containing various concentrations of trehalose are applicable according to the present disclosure.

[0513] 3.2.5. Osmolality Measurement

[0514] Osmolality was measured to ensure that the formulations tested had suitable osmolality for injection, and the results are shown below: [Table 71]

[0515] Results and Discussion

[0516] Osmolality values ​​range from about 245 to 380 mOsm / kg for trehalose concentrations of 145 to 225 mM. Since the optimal osmolality is about 310 mOsm / kg, it may be advantageous to provide a formulation with such an osmolality. This can be achieved, for example, by using a trehalose concentration of 185 mM in combination with the formulation according to this example.

[0517] 3.3. Further Analysis and Results

[0518] Further analysis was also performed on the five formulations tested (storage times and temperatures as described above). The contents of the main peak, APG, and BGP of IEC remained constant over 24 and 36 months at 5°C. No differences were observed between the formulations for the main peak, APG, and BGP. The HIC main peak content was constant over 24 months at 5°C, ranging from 96.4 to 97.4%, with a pre-peak content of 1.4 to 1.8% and a post-peak content of 1.2 to 2.0%. Over 36 months at 5°C, HIC main peak contents ranged from 96.0 to 97.4%, with a pre-peak content of 1.4 to 1.8% and a post-peak content of 1.2 to 2.3%. At 25°C, main peak contents between 94.2 and 97.4%, with a pre-peak content of 1.4 to 3.0% and a post-peak content of 1.2 to 2.8%, were obtained over storage times up to 12 months. At 40°C, main peak contents between 90.3 and 97.4%, with a pre-peak content of 1.4 to 5.9% and a post-peak content of 1.2 to 3.7%, were obtained over storage times up to 3 months. No differences between the formulations were observed for the main peak, pre-peak, and post-peak. Protein concentrations remained essentially constant up to 24 and 36 months of storage time at the different storage temperatures tested. Small deviations in protein concentrations were attributed to analytical variability, leading to ranges of 145-153 mg / ml (24 months) and 148-158 mg / ml (36 months). pH values ​​remained essentially constant up to 24 and 36 months of storage time at the different storage temperatures tested. The pH ranged from 5.7 to 5.9. Opalescence remained essentially constant up to 24 and 36 months of storage at the different storage temperatures tested. Opalescence ranged from 5 to 9 FNU. Dynamic viscosity remained essentially constant up to 24 and 36 months of storage time at the different storage temperatures tested. Dynamic viscosity ranged from 8.9 to 10.3 mPas. The sliding equilibrium stress remained constant over 24 months at 5°C, ranging from 6.5 to 7.7 N (maximum) and 5.8 to 7.4 N (average), with the sliding yield stress ranging from 3.9 to 5.0 N. Over 36 months at 5°C, the sliding equilibrium stress remained constant over 6.1 to 8.5 N (maximum) and 5.8 to 7.7 N (average), with the sliding yield stress ranging from 3.9 to 5.0 N. Over storage times up to 12 months at 25°C, the sliding equilibrium stress ranged between 6.7 to 15.7 N (maximum) and 6.2 to 12.4 N (average), with the sliding yield stress ranging from 3.9 to 5.6 N. At 40°C, over storage times up to 3 months, the sliding equilibrium stress ranged between 8.7-23.1 N (maximum) and 7.3-16.4 N (average), and for the sliding yield stress it was 5.1-6.6 N. Protein-related particles and foreign particles remained essentially constant low over storage time at the different storage temperatures tested.

[0519] 3.4. Summary of results

[0520] In summary, all tested formulations were stable, demonstrating that the trehalose concentration can be varied while maintaining high stability. Thus, the trehalose concentrations shown can be flexibly applied to produce stable protein formulations of 150 mg / ml risankizumab.

[0521] V. Example 4: Analysis of Additional Parameters of Specific Formulations

[0522] In view of the results of the previous examples, particularly suitable formulations include the following compounds: - 150mg / ml risankizumab, - 10 mM acetate buffer, 185mM trehalose, and - 0.2mg / ml PS20; Therein the pH of the formulation is 5.7.

[0523] The formulation has a clear to slightly opalescent appearance and is essentially free of foreign particles. The osmolality is approximately 310 mOsm / kg. This formulation is particularly suitable for injection, especially subcutaneous injection. Furthermore, a viscosity of approximately 9.6 mPas has been measured, making it suitable for injection using a syringe. The conductivity at 20°C is approximately 1.53 mS / cm, and the density at 20°C is approximately 1.067 g / cm. 3 and its density at 4°C is approximately 1.071 g / cm 3 It was.

[0524] This 150 mg / ml risankizumab formulation may be provided as follows: [Table 72] [Table 73]

Claims

1. A stable liquid aqueous pharmaceutical formulation, 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 a viscosity of the formulation of less than 20.0 mPas when measured at 20°C after storage of the formulation at 5°C for 12 months.

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

3. A stable liquid aqueous pharmaceutical formulation as described in claim 1, wherein the pH of the formulation is 5.

5.

4. A stable liquid aqueous pharmaceutical formulation as described in claim 1, wherein the pH of the formulation is 5.

7.

5. A stable liquid aqueous pharmaceutical formulation as described in claim 1, wherein the pH of the formulation is 5.

9.

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

5.

7. A stable liquid aqueous pharmaceutical formulation as described in claim 2, wherein the pH of the formulation is 5.

7.

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