Therapeutic antibody preparations

Abstract

To provide stable pharmaceutical formulations for therapeutic anti-IL-23p19 antibodies and methods of using such stable pharmaceutical formulations.SOLUTION: A pharmaceutical formulation comprises (i) 50 mg / mL-150 mg / mL of an antibody IL-23p19 antibody, (ii) 3 mM-12 mM of a histidine buffer, (iii) 25-75 mM of NaCl, (iv) 2-5%w / v of an isotonizing agent, and (iv) 0.01%w / v-0.05%w / v of a surfactant, where the formulation has a pH of 5.0-6.0, the anti-IL-23p19 antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), the amino acid sequence of the LCVR is a specific sequence, and the amino acid sequence of the HCVR is another specific sequence.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention belongs to the field of medicine. More specifically, the present invention relates to an aqueous pharmaceutical preparation containing a therapeutic antibody suitable for subcutaneous ("SC"), intramuscular ("IM"), and / or intraperitoneal ("IP") administration. Even more specifically, the present invention relates to a pharmaceutical preparation of an anti-IL-23p19 antibody . These anti-IL-23p19 antibody pharmaceutical preparations are expected to be useful for the treatment of at least psoriasis (Ps), psoriatic arthritis (PsA), ulcerative colitis (UC), Crohn's disease (CD) and / or ankylosing spondylitis . For the treatment of patients with Ps, PsA UC, CD, and / or ankylosing spondylitis, pharmaceutical preparations of anti-IL-23

[0002] p19 antibodies are needed. Administration of such therapeutic antibodies via SC, IP and / or IM administration is common and advantageous. Such administration routes allow the therapeutic antibody to be delivered in a short period of time and allow the patient to self-administer the therapeutic antibody without visiting a physician . To enable delivery of the antibody to the patient by SC, IP and / or IM, the pharmaceutical preparation requires a specific concentration of anti-IL-23p19 antibody. These pharmaceutical preparations containing a certain concentration of anti-IL-23 p19 antibody need to maintain the physical and chemical stability of the anti-IL-23p19 antibody. However, formulating a therapeutic antibody into an aqueous pharmaceutical preparation suitable for SC, IM, and / or IP administration is difficult and unpredictable. <{0000025}>

[0003] The difficulties and unpredictability associated with formulating a therapeutic antibody into an aqueous pharmaceutical preparation suitable for SC, IM, and / or IP administration are, in part, due to the requirements for the pharmaceutical preparation to be therapeutically viable This is due to numerous unavoidable characteristics. Pharmaceutical formulations provide stability to therapeutic antibodies in solution. At the same time, the functional characteristics of therapeutic antibodies, which are essential for therapeutic effect such as target affinity, selectivity, and efficacy, The properties must be maintained. Furthermore, aqueous pharmaceutical formulations are also safe for administration to patients. It must be readily tolerable by patients and suitable for manufacture and storage.

[0004] Formulating high concentrations of therapeutic antibodies is even more complex. For example, the rate at which antibodies are divided... Dissolution, cleavage, clipping, high molecular weight aggregation, dimerization, trimerization, precipitation pH shift, turbidity, Changes in the color of the solution, changes in charge, isomerization, oxidation and / or deamination (all of these are therapeutic (This affects the concentration, functionality, and efficacy of the antibody used) in high-concentration therapeutic antibody preparations. It has been reported that another known challenge in formulating high concentrations of therapeutic antibodies is the pharmaceutical formulation process. This is an increase in viscosity that can adversely affect the administration of SC, IM, and / or IP.

[0005] Millikizumab, with CAS registry number 1884201-71-1, is a human IL-23 p19 Humanized immunoglobulin (Ig) G4 variant monoclonals targeting subunits It is an antibody and is listed in U.S. Patent No. 9,023,358. Mirikizumab is moderate It is being evaluated for the treatment of patients with psoriasis vulgaris ranging from mild to severe, as well as ulcerative colitis and cardiomyopathy (CD). Mab can be administered subcutaneously to patients in high concentrations (75-150 mg / mL) of pharmaceutical formulations. In the reformulation study, mirikizumab was found to be more effective at lower and higher pH values. It has been found that the stability of the formulation decreases at pH < 5.0 and pH > 7.0. Samples of mirikizumab formulated at a concentration are low-concentration, as determined by SEC. Compared to samples formulated at a lower concentration, it showed more soluble aggregates. Furthermore, at Certain formulations of mirikizumab at a concentration of 50 mg / mL exhibit a marked protein cold precipitation reaction. This was shown. To avoid these observed problems, a specific concentration of anti-IL-23p19 anti A medical preparation for the body is needed. The medical preparations provided herein satisfy the aforementioned need. More specifically, the pharmaceutical formulations provided herein contain the mechanism of mirikizumab, which is essential for therapeutic efficacy. Suitable for high-concentration mirikizumab administration via SC, IM, and / or IP while maintaining functional characteristics. That is the case.

[0006] therefore, (i) IL-23p19 antibody in a concentration of 50 mg / mL to 150 mg / mL, (ii) 8 mM to 12 mM citrate buffer, (iii) 100-200 mM sodium chloride (NaCl) and (iv) A pharmaceutical formulation containing a surfactant of 0.01% w / v to 0.05% w / v is provided. And so, The pH of the formulation is 5.0 to 6.0. Anti-IL-23p19 antibodies affect the light chain variable region (LCVR) and heavy chain variable region (HCVR). Including, the amino acid sequence of LCVR is SEQ ID NO: 8, and the amino acid sequence of HCVR is SEQ ID NO: The answer is 7.

[0007] In one embodiment of the present invention, the anti-IL-23p19 antibody comprises a light chain (LC) and a heavy chain (HC). ) contains, the amino acid sequence of LC is SEQ ID NO: 10, and the amino acid sequence of the heavy chain is SEQ ID NO: 9 That is the case.

[0008] In a preferred embodiment of the present invention, the anti-IL-23p19 antibody is mirikizumab.

[0009] In an alternative embodiment of the present invention, the pharmaceutical preparation comprises an anti-IL-23p19 antibody, and the anti-IL-23 p19 antibody comprises an LCVR and an HCVR, the LCVR comprises the amino acid sequences LCDR1, LCD R2, and LCDR3, the HCVR comprises the amino acid sequences HCDR1, HCDR2, and H CDR3, LCDR1 is SEQ ID NO: 4, LCDR2 is SEQ ID NO: 5, LC DR3 is SEQ ID NO: 6, HCDR1 is SEQ ID NO: 1, HCDR2 is SEQ ID NO: 2 and HCDR3 is SEQ ID NO: 3.

[0010] In a further embodiment of the present invention, the concentration of the anti-IL-23p19 antibody is from about 75 mg / mL to about 150 mg / mL. Preferably, the concentration of the anti-IL-23p19 antibody is from about 100 m g / mL to about 150 mg / mL. More preferably, the concentration of the anti-IL-23p19 antibody is about 100 mg / mL. Alternatively, preferably, the concentration of the anti-IL-23p19 antibody is about 125 mg / mL.

[0011] In yet a further embodiment of the present invention, the concentration of the citrate buffer is about 10 mM. Preferably the citrate buffer is a sodium citrate buffer.

[0012] In yet a further embodiment of the present invention, the surfactant is polysorbate 20 or polysorbate 80. Preferably, the surfactant is polysorbate 80. More preferably the concentration of the surfactant is about 0.03% (w / v).

[0013] In yet a further embodiment of the present invention, the concentration of NaCl is about 150 mM.

[0014] In yet a further embodiment of the present invention, the pH of the preparation is about 5.5.

[0015] In a preferred embodiment of the present invention, the formulation is (i) 100 mg / mL or 125 mg / mL of mirikizumab, (ii) 10 mM sodium citrate buffer, (iii) 150 mM NaCl and (iv) containing 0.03% w / v polysorbate 80, The pH of the formulation is approximately 5.5.

[0016] Preferably, the formulation contains 100 mg / mL of mirikizumab.

[0017] Alternatively, preferably, the formulation contains 125 mg / mL of mirikizumab.

[0018] In further aspects of the present invention, psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis and / or Methods for treating and / or preventing ankylosing spondylitis are also provided, and these methods provide the patient with a therapeutically effective dose. This includes administering the pharmaceutical formulation of the present invention.

[0019] Further embodiments of the present invention include psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis and / Alternatively, the present invention provides a pharmaceutical formulation for use in the treatment and / or prevention of ankylosing spondylitis. .

[0020] Further embodiments of the present invention include psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis and / or use of the pharmaceutical formulation of the present invention in the manufacture of pharmaceuticals for use in the treatment of ankylosing spondylitis. It will be provided.

[0021] In addition to the difficulties in formulating the antibody drugs mentioned above, even after the injection needle is removed, the desired Undesirable injection-related pain has been reported with this route of administration, and it affects the patient's treatment. It may compromise safety. Pain associated with injection has been reported with formulations of increased viscosity. Pain associated with injections of pharmaceutical preparations containing therapeutic antibodies is a complex and multifactorial problem. For example, The individual components of an aqueous pharmaceutical preparation, and / or their concentration, proportion, and properties, are relevant to the treatment. It may affect the pain associated with injection. Similarly, the individual components (and / or their concentration, proportion and characteristics) may also be affected. (Sex) refers to the stability, functional properties, manufacturability, and / or properties of formulated therapeutic antibodies in aqueous pharmaceutical formulations. Or it may affect tolerability. Therefore, certain formulation modifications are beneficial to the given properties of the formulation. While this may have some effect, the same adjustment may also adversely affect other properties of the formulation. Yes. It would become even more complex, but there are almost an infinite number of different formulation components (for example, buffers). The excipients, as well as their concentrations and proportions, have been reported. However, in certain manufacturing processes, The correlation for predicting the effects of a drug on various properties and characteristics of a given therapeutic antibody is, They hardly exist or don't exist at all.

[0022] Therefore, it is suitable for SC, IM, and / or IP administration, and is administered at therapeutically beneficial levels. There is also a need for therapeutic antibody pharmaceutical formulations that cause accompanying pain and are well tolerated by patients. More specifically, it is suitable for SC, IM, and / or IP administration, and is a substitute for mirikizumab. Mirikizumab is a drug that exhibits an improved level of injection-related pain and is well tolerated by patients. A formulation is needed. Such a pharmaceutical formulation also provides stability to therapeutic antibodies and cure The properties of therapeutic antibodies, which are essential for therapeutic effects, must be maintained. Such pharmaceutical formulations are Furthermore, it must be possible to manufacture it, and preferably it has an extended shelf life. Pharmaceutical preparations are administered via SC, IM, and / or IP via pre-filled syringes or auto-injectors. It also needs to be suitable.

[0023] The pharmaceutical formulations provided herein satisfy the aforementioned needs. For more details, see herein. The pharmaceutical formulations provided maintain the functional characteristics of mirikizumab, which are essential for therapeutic efficacy. Suitable for SC, IM, and / or IP administration of high concentrations of mirikizumab (e.g., with appropriate viscosity). Yes. The pharmaceutical formulations provided herein are also well tolerated by patients and are a substitute for mirikizumab. It exhibits an improved level of injection-related pain compared to alternative drug formulations, and provides a therapeutically favorable level of injection. It can cause accompanying pain.

[0024] therefore, (i) IL-23p19 antibody in a concentration of 50 mg / mL to 150 mg / mL, (ii) 3 mM to 12 mM histidine buffer, (iii) 25-75 mM NaCl and (iv) 2-5% w / v isotonic agent, (iv) A pharmaceutical formulation containing a surfactant of 0.01% w / v to 0.05% w / v is provided. And so, The pH of the formulation is 5.0 to 6.0. Anti-IL-23p19 antibodies affect the light chain variable region (LCVR) and heavy chain variable region (HCVR). Including, the amino acid sequence of LCVR is SEQ ID NO: 8, and the amino acid sequence of HCVR is SEQ ID NO: The answer is 7.

[0025] In one embodiment of the present invention, the anti-IL-23p19 antibody comprises a light chain (LC) and a heavy chain (HC). ) contains, the amino acid sequence of LC is SEQ ID NO: 10, and the amino acid sequence of the heavy chain is SEQ ID NO: 9 That is the case.

[0026] In a preferred embodiment of the present invention, the anti-IL-23p19 antibody is mirikizumab.

[0027] In an alternative embodiment of the present invention, the pharmaceutical formulation comprises an anti-IL-23p19 antibody, and anti-IL-23 The p19 antibody contains LCVR and HCVR, and LCVR has the amino acid sequence LCDR1, LCD It contains R2 and LCDR3, and HCVR has the amino acid sequences HCDR1, HCDR2, and H It includes CDR3, LCDR1 is sequence number 4, LCDR2 is sequence number 5, LC DR3 is sequence number 6, HCDR1 is sequence number 1, and HCDR2 is sequence number 2. Yes, HCDR3 is sequence number 3.

[0028] In a further embodiment of the present invention, the concentration of the anti-IL-23p19 antibody is approximately 75 mg / mL. The concentration is approximately 150 mg / mL. Preferably, the concentration of anti-IL-23p19 antibody is approximately 100 mg / mL. The concentration is g / mL to approximately 150 mg / mL. More preferably, the concentration of the anti-IL-23p19 antibody This is approximately 100 mg / mL. Alternatively, preferably, the concentration of the anti-IL-23p19 antibody. This is approximately 125 mg / mL.

[0029] In a further embodiment of the present invention, the concentration of the histidine buffer solution is approximately 5 mM.

[0030] In further embodiments of the present invention, the isotonic agent is mannitol.

[0031] Preferably, the mannitol concentration is 3.3% w / v.

[0032] In further embodiments of the present invention, the surfactant is polysorbate 20 or polysorbate It is 80.

[0033] Preferably, the surfactant is polysorbate 80.

[0034] More preferably, the concentration of the surfactant is about 0.03% (w / v).

[0035] In a further embodiment of the present invention, the concentration of NaCl is approximately 50 mM.

[0036] In a further embodiment of the present invention, the pH of the formulation is approximately 5.5.

[0037] In a preferred embodiment of the present invention, the formulation is (i) 100 mg / mL or 125 mg / mL of mirikizumab, (ii) 5 mM histidine buffer, (iii) 50 mM NaCl and (iv) 3.3% w / v mannitol and (v) Contains 0.03% w / v polysorbate 80, The pH of the formulation is 5.5.

[0038] Preferably, the formulation contains 100 mg / mL of mirikizumab. Alternatively, preferably, The formulation contains 125 mg / mL of mirikizumab.

[0039] In further aspects of the present invention, psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis and / or A method is provided for treating and / or preventing ankylosing spondylitis, the method being used to provide the patient with a therapeutically effective dose. This includes administering the pharmaceutical formulation of the present invention.

[0040] Further embodiments of the present invention include psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis and / Alternatively, the present invention provides a pharmaceutical formulation for use in the treatment and / or prevention of ankylosing spondylitis. .

[0041] Further embodiments of the present invention include psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis and / or use of the pharmaceutical formulation of the present invention in the manufacture of pharmaceuticals for use in the treatment of ankylosing spondylitis. It will be provided.

[0042] In a further aspect of the present invention, the SC, IP and Methods have been proposed to reduce the injection-related pain experienced by patients during or immediately after administration of IM. The method comprises administering the pharmaceutical formulation of the present invention to a patient, wherein the step of administering is It provides a therapeutically favorable level of injection-related pain.

[0043] Preferably, a therapeutically favorable level of injection-related pain is less than 30 mm or less than 20 mm. Includes the VAS score.

[0044] In a further aspect of the present invention, patients requiring SC administration of anti-IL-23p19 antibody An improved method for doing so, the improvement being a pharmaceutical product containing an anti-IL-23p19 antibody. A method is provided, including the reduction of injection-related pain during SC administration of the agent, and the method is provided for the pharmaceutical formulation of the present invention. The administration step includes providing an improved level of parainjection pain, And / or provides a therapeutically favorable level of injection-related pain. Preferably, therapeutically favorable A significant level of injection-related pain includes VAS scores of less than 30 mm or less than 20 mm.

[0045] Further embodiments of the present invention include psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis, and An improved method for treating at least one of the conditions of ankylosing spondylitis, wherein the improvement is anti-IL A method is provided that includes reducing injection-related pain during SC administration of a pharmaceutical product containing the -23p19 antibody. The method includes administering a pharmaceutical preparation described herein, and the step of such administration It provides an improved level of parainjection pain and / or a therapeutically favorable level of parainjection pain. Provides accompanying pain. Preferably, the therapeutically favorable level of accompanying pain from injection is less than 30 mm or This includes VAS scores of less than 20mm.

[0046] As used herein, the term "pharmaceutical preparation" refers to a product that exerts a biological effect in humans. At least one therapeutic antibody that can be used in combination with a therapeutic antibody to reach humans. Suitable for therapeutic administration of [the substance], containing at least one inactive component (e.g., buffer, excipient, [the substance]). This refers to a solution containing surfactants, etc. The pharmaceutical formulation of this disclosure contains a fraction of the therapeutic antibody in the formulation. The degree of dissolution, modification, aggregation, and loss of biological activity is controlled within an acceptable range over time. This is a suitable formulation that will not increase beyond a certain limit.

[0047] As used herein, the term “antibody” refers to two entities connected by disulfide bonds. Immunoglobulin G containing two bound heavy chains ("HC") and two light chains ("LC") This refers to the IgG molecule. Each heavy chain consists of a variable heavy chain region ("HCVR") and a constant heavy chain region ("C"). Each light chain consists of a light chain variable region ("LCVR") and a light chain steady region (" It consists of CL). HCVR and LCVR each consist of a framework area (FR). Complementarity-determining regions ("CDRs") are scattered along with more conserved regions called ). It is further subdivided into a region of hypervariability called HCVR. HCVR and LCVR are in the following order, respectively. FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 are from the amino terminus. It consists of three CDRs and four FRs positioned at the ruboxy terminus. Each HC and The variable region of the LC contains a binding domain that interacts with the antigen. The constant region of the antibody is Various cells of the immune system (e.g., effector cells) and the first component of the classical complement system (Cl It may mediate the binding of immunoglobulins to host tissues or factors, including q).

[0048] When used interchangeably in this specification, "conjugates to the p19 subunit of human IL-23" Antibodies that bind to the p19 subunit of human IL-23, or "anti-IL-23p19 antibodies," are antibodies that bind to the p19 subunit of human IL-23. This refers to antibodies that bind to other substances but do not bind to the p40 subunit of human IL-23. Examples of antibodies include mirikizumab, guselkumab, tildrakizumab, and risankizumab. It can be listed.

[0049] Guselkumab, with CAS registry number 1350289-85-8, is used for the treatment of psoriasis vulgaris. Approved to bind to the p19 subunit of human IL-23, fully human IgG1 This is a useless monoclonal antibody. The antibody and the method for producing it are permitted under U.S. Law No. 7,935. It is described in issue 344.

[0050] Childrakizumab, CAS registry number 1326244-10-3, is used for moderate to severe cases of phlebotomy. Approved for the treatment of plaque psoriasis, targeting the p19 subunit of human IL-23 This is a humanized IgG1 kappa monoclonal antibody. The antibody and the method for producing it are as follows: It is described in U.S. Patent No. 8,293,883.

[0051] Risankizumab, CAS registry number 1612838-76-2, is a human IL-23 p1 This is a humanized IgG1 kappa monoclonal antibody that targets 9 subunits. The method for producing it is described in U.S. Patent No. 8,778,346. Mab is approved for the treatment of moderate to severe plaque psoriasis.

[0052] Brazicumab, with CAS registry number 1610353-18-8, is a human IL-23 p19 This is a humanized IgG2 lambda monoclonal antibody that targets a subunit. The method for producing this is described in U.S. Patent No. 8,722,033. (Brazicumb) It is being evaluated for the treatment of CD and UC.

[0053] Where used herein, the terms “about” or “approximately” are specifically listed below. When used in relation to a given number or range of values, the values ​​listed are 10% different from the values ​​listed. This means that the following (e.g., + / - 10%) may differ. For example, used in this specification. In this case, the expression "approximately 100" includes 90 and 110, as well as all values ​​in between (e.g., For example, this includes 91, 92, 93, 94, etc.

[0054] As used herein, the term "pain at the injection site" refers to pain that occurs when a liquid formulation is injected subcutaneously. This refers to pain localized at the injection site. Pain can be measured, for example, using a visual analog scale (V AS), qualitative assessment of pain, or acupuncture pain assessment, including those known in the art. It can be assessed using any type of pain assessment available. For example, the subject perceives Pain at the injection site can be assessed using a Visual Analog Scale (VAS). VAS is a measuring instrument that measures pain, and pain is a continuous value (for example, when there is no pain). It is measured when the pain ranges from mild to extreme. Operationally, the VAS is measured in water approximately 100 mm long. It is a flat line and a numeric and / or word descriptor (e.g., 0 or 10, or "no pain"). Alternatively, "unbearable pain" is incorporated, and additional options between the two extremes are available as needed. A word or number descriptor, e.g., mild, moderate, severe; or a number from 1 to 9 (e.g., L ee JS, et al. (2000) AcadEmerg Med 7:550, also Singer and Thods (1998) Academic Emergence (See y Medicine, 5:1007). Pain may subside once after administration of the preparation. It is evaluated at various points in time, for example, immediately after injection, and approximately 1, 2, 3, 4, 5, 6, and 7 days after injection. It may be evaluated after 8, 9, 10, 15, 20, 25, 30, 35, 40, or 45 minutes. The severity of pain is classified according to the VAS tool as mild pain (≤30mm) and moderate pain (> It can be classified into 30mm to ≤70mm and severe pain (>70mm). Stable pharmaceutical production A desirable property of the agent is that it is well tolerated by the patient, for example, therapeutically favorable. Bell's injection-related pain (e.g., a VAS score of <30 mm and / or <20 mm) is administered. This is the case. As is well known, the components of a pharmaceutical preparation, as well as their concentrations and / or proportions, This can affect the pain associated with injections experienced by patients.

[0055] Where used interchangeably in this specification, “treatment” and / or “cure” "Treatment" and / or "treatment" means complete disappearance, slowing down or This includes delay, a decrease in the severity or frequency (e.g., of flares or episodes), disease and / or illness. It is intended to refer to all processes in which the progression of the patient's symptoms may be interrupted or stopped, but all Complete disappearance of disease symptoms is not required. Treatment is for the treatment of the disease in humans. (a) The administration of an aqueous pharmaceutical preparation, and the benefit of at least one of the above processes is obtained. To inhibit the further progression of the symptoms and effects of the disease, that is, to prevent the onset of the disease. (b) to alleviate the disease, that is, to eliminate the disease, the symptoms of the disease or complications of the disease or (c) to cause regression and to prevent or reduce the frequency of disease episodes or flares. This includes, according to certain embodiments, the pharmaceutical formulations provided herein are for treating psoriasis, ulcers, and other skin conditions. At least one of the following: cerebral colitis, Crohn's disease, psoriatic arthritis, and / or ankylosing spondylitis. It can be used to treat [condition].

[0056] Where used interchangeably in this specification, the terms “patient,” “subject,” and “individual” are not interchangeable. , refers to humans. Unless otherwise specified, the subjects are those who have received the pharmaceutical preparations disclosed herein. Those who have, are at risk of developing, or experience symptoms of a disease that would benefit them. It can be further characterized as follows.

[0057] Where used interchangeably in this specification, “effective dose” or “therapeutic effective dose” of the pharmaceutical formulations in this disclosure "The amount (dose, frequency of administration, and specific means of administration) required to achieve the desired treatment outcome" This refers to the period of time. The effective dose of the pharmaceutical formulation in this disclosure depends on the patient's condition, age, sex, and weight. Furthermore, it varies depending on factors such as the ability of the pharmaceutical formulation of this disclosure to induce a desired response in the subject. The effective dose may also be more therapeutically beneficial than the toxic or adverse effects of the pharmaceutical formulations of this disclosure. The amount is sufficient to outweigh the effect.

[0058] The pharmaceutical formulation of the present invention can be administered to a patient via parenteral administration. Parenteral administration is a medical treatment As understood in the field, several sterile syringes or automatic injectors or infusion pumps are used. This refers to the injection of doses into the body via several other drug delivery systems, along with the pharmaceutical formulations of this disclosure. An example drug delivery system for use is described in the following references, and The disclosure is expressly incorporated herein in its entirety by reference: March 7, 2013 A patent application was filed, titled "Infusion Pump Assembly" by Laniga n et al., U.S. Patent Publication No. 2014 / 0054883, filed on February 3, 2006, " Medication Dispensing Apparatus with Tri ple Screw Threads for Mechanical Advanta DeRuntz et al., U.S. Patent No. 7,291,132, September 2006, titled "ge" The application was filed on the 18th, and the "Medication Dispensing Apparatus" was submitted. s with Spring-Driven Locking Feature Ena Titled "Bleed by Administration of Final Dose" Jacobs et al.'s U.S. Patent No. 7,517,334, and the publication dated August 24, 2012. Requested, "Automatic Injection Device with Del ay Mechanism Including Dual Functioning Adams et al., in a U.S. publication titled "Biasing Member," published 8,734,39 No. 4. Parenteral routes include the administration routes of IM, SC, and IP. [Brief explanation of the drawing]

[0059] [Figure 1] This is a contour plot of mirikizumab concentration versus pH, showing the relationship between antibody concentration and target pH for expected monomer purity. [Figure 2] The glide force data for formulation 1 and formulations 21-29 are shown. [Examples]

[0060] Example 1: Antibody production Anti-IL-23p19 antibodies can be prepared and purified as follows. An expression system for secreting antibodies using a fixed HC:LC vector ratio, or both LC and Both HCs (for example, each LC is sequence number 10 and each HC is sequence number 9) A single vector system that transiently or stably transduces suitable host cells such as CHO. To septice, the clarified medium containing the secreted antibody is subjected to many commonly used techniques. Purify using one of the following: For example, the culture medium is purified using a suitable buffer, such as phosphate-buffered diet. Protein A or G, equilibrated with saline solution (pH 7.4), is then subjected to a Sepharose FF column. It can be applied in a suitable manner. Wash the column to remove nonspecific binding components. The bound antibody is then removed. For example, it elutes due to a pH gradient. Antibody fragments are detected by SDS-PAGE, etc. The antibodies are pooled. Further purification is optional, depending on the intended use. It can be concentrated and / or sterile filtered using various techniques. Soluble aggregates and polymers can be removed by size. Includes removal, hydrophobic interaction, ion exchange, or hydroxyapatite chromatography. These can be effectively removed by common techniques. Antimicrobial residues after these chromatography steps The purity of the product exceeds 99%. The product is rapidly processed at -70°C in the formulation matrix of the present invention. The material may be frozen or freeze-dried. Exemplary antibody amino acid sequence and nucleic acid. The array is shown below.

[0061] Example 2: Formulation Research A Research design and preparation of anti-IL-23p19 antibody drug formulations The study design involved the concentration of the anti-IL-23p19 antibody (mirikizumab) and sodium chloride. The effects of four factors were evaluated: the concentration of [substance name], the concentration of polysorbate 80, and pH. The formulations are shown in Table 1. [Table 1]

[0062] Antibody concentrations were measured at 20, 85, 100, 125, and 150 mg / mL using formulations 1-20. The broad range of antibody concentrations explains the multiple possible presentations of the mirikizumab drug. Selected for this purpose, and demonstrating a clear correlation between several forms of decomposition (such as aggregation) and concentration. It was based on the pre-formulation data provided. Polysorbate 80 has three The study was conducted at concentrations of 0.01, 0.03, and 0.05% w / v. The effect of NaCl was: The study was conducted at concentrations of 100, 150, and 200 mM. Preformulation study and Biophysical screening revealed that the optimal overall stability range is pH 5.5 to 6. Since the effect was shown to be 0, the effect of pH was studied in the range of 5.0 to 6.0.

[0063] Based on pre-formulation data, the stability of various container lid types is affected. No significant effects were observed. Therefore, use a 1 mL pre-filled syringe (PFS). This ensured consistency in the research design. Vials were used for formulations 17-19. Formula 20 (using 2 mL of PFS) is included for direct comparison with formulation 16, and is different. We determined whether the syringe made a significant contribution.

[0064] Formulations 1-20 were prepared independently in the specified order. The materials for each formulation were the active pharmaceutical ingredient. It was prepared by dialysis under specific formulation conditions. Then, an appropriate amount was added to the dialyzed solution. The polysorbate was added and diluted to the specified antibody concentration with formulation buffer. The sample was then divided into 0.2 The mixture was filtered through a 2μm filter and aseptically filled into the indicated container stopper system.

[0065] The buffering excipient composition is anhydrous citric acid (QD514N, lot number C490136), Sodium enoate dihydrate (QD517A, lot number C487212), sodium chloride Mu (QD515R, lot number C481616), Polysorbate 80 (QD513DV It consists of IE (lot number C457300).

[0066] The anti-IL-23p19 antibody is mirikizumab, and is the LC of SEQ ID NO: 10 and SEQ ID NO: 9 Includes HC (demo lot number EL01685-039-F-Fill).

[0067] Selected analyses and characterizations to measure the chemical and physical stability and properties of the formulation. The techniques include size exclusion chromatography (SEC) HPLC and imaging capillary isoelectric testing. Point electrophoresis iCIEF, reduced and unreduced CESDS, HIAC, microflow imaging Gating (MFI), appearance, pH (USP <921> ), UV absorbance is used to determine protein concentration Measure the syringe function and test the device.

[0068] The samples were collected under four temperature conditions (5°C, 15°C, 25°C, and 35°C), and the syringe was kept horizontal. The vials were stored upside down. This temperature range allows for the Arrhenius reaction kinetics. Assuming this, the activation energy of each analytical response variable can be estimated. Furthermore, high-temperature storage This allowed us to predict optimal formulation conditions early on and accelerate the drug development process. .

[0069] Table 2 outlines the sampling schedule for formulations 1-14. The schedule is 25°C. For 35°C and 35°C, data was collected at four points over a three-month period; for other storage conditions, data was collected at three points over a three-month period. It is designed to record data. This sampling frequency allows the data to be used appropriately in the predictive model. Sufficient information is obtained to match. After 3 months, the activation energy (Ea) The results at the accelerating temperature were calculated using the Arrhenius reaction kinetics model, and the predicted result was 5°C lower. Qualitative analysis was performed and correlated. Using the Ea value of 21.5 kcal / mol, SEC (monomer, Polymers and post-monomers), iCIEF (main peak, total acid and total basic thresholds) Ant), as well as non-reducing and reduced CE-SDS, were made compliant. This compliance is in part This is based on observations made with other IgG4 antibodies. The time points indicated by X are when the sample is S Based on EC, iCIEF, reduced and non-reduced CE-SDS, pH, UV content, and appearance. These are the conditions that were analyzed. Tests using HIAC and MFI were not performed very frequently. . [Table 2]

[0070] Table 3 shows the sampling schedule for formulations 15-20. Formulations 15-20 are This represents formulations that can be evaluated in clinical trials in human patients. These formulations are in the associated containers. The mixture was placed in a stoppering system (including a vial and a 2.25 mL syringe). To confirm the stability of these potential pharmaceuticals, and to determine the effect of container stopper type on stability. We evaluated it to understand whether or not it was true. [Table 3]

[0071] Formulation Research A - Results - Size Exclusion Chromatography The SEC percent monomer values ​​at 5°C, 15°C, 25°C, and 35°C are shown in Tables 4a to 4d. It shows that data at 35°C is displayed for 3 months, data at 25°C is displayed for 6 months, and 5°C The data is shown for up to 18 months (formulations 15 and 20 only). As the temperature rises, The monomer percentage decreased. The maximum change in this dataset is <2%. The proportion was 98% for samples tested at 5°C for 18 months, with the exception of one result at 9 months. It remains above 0.6%.

[0072] The monomer and polymer values ​​(not shown) are inversely related to each other, as observed in SEC. The decomposition was mainly due to the formation of soluble aggregates (polymers).

[0073] The predictive effect of each input variable on SEC monomer purity over 24 months at 5°C is 3 months. The model is created using the results obtained from the data up to that point. All four temperatures are used. We modeled the modified Arrhenius reaction kinetics. To generate these predictions, we used 21.5k The activation energy (Ea) in cal / mol was used for all cases of the monomer. The predicted percentage is >98%, and the maximum predicted change is >1.3%, for mirikizumab. This indicates that it is stable across the entire design domain. This is shown in Tables 4a-4d. This closely matches the experimental data we have seen. In the scope of our study, increasing the mirikizumab concentration... This resulted in greater monomer loss. This relationship is related to the probability of intermolecular interactions between antibodies. It may be a function of the increase. This is consistent with preformation studies. The study observed a slight increase in stability under lower pH conditions. Polysorbate 80 The concentration of the substance, the concentration of NaCl, and the container stopper do not appear to have a significant effect. For the two factors given (antibody concentration, pH), the best and worst positions in the design region. The difference was <1.0%.

[0074] Figure 1 shows the relationship between antibody concentration and target pH for expected monomer purity. This is a contour map. pH Target * Concentration Target The Prob>F Effect Test value for this is 0.0130, and the interaction This shows that it is statistically significant. The effect of pH on purity is greater at higher antibody concentrations. I will become incredibly strong. [Table 4] [Table 5] [Table 6] [Table 7]

[0075] Formulation Research A: Results - Charge Heterogeneity - iCIEF a) Percentage of main peaks Tables 5a-5 show the percentage values ​​of the main peaks of iCIEF at 5°C, 15°C, 25°C, and 35°C. As shown in d, the initial values ​​for the main peak condition are 76.2 to 77 for all formulations. The figure was 9%. The main peak decomposition rate correlates with increasing temperature. Decomposition occurred at 5°C with 18 cells. Monthly peaks were kept to a minimum, and the survival rate of the main peaks exceeds 75%.

[0076] An apparent Ea estimate of 21.5 kcal / mol was used for the prediction. 24 months at 5°C The monthly peak forecast was performed as a function of the rate of change of five input variables (up to 3 months). (Based on data). The effect of the five input variables is greatest at pH, but even then the difference is less than 2%. The results are satisfactory. Only two input variables, pH and NaCl concentration, showed a statistically significant effect. Yes, it was. It appears that increasing the NaCl concentration leads to an increase in the proportion of the main peak. The optimal pH stability occurs between 5.5 and 6.0. Polysorbate 80, mirikizumab Concentration and container closure did not show a clear effect across the entire area studied. [Table 8] [Table 9] [Table 10] [Table 11]

[0077] b) Acidic and basic variants The total acidic variant values ​​at 5°C, 15°C, 25°C, and 35°C are shown in Tables 6a to 6d. The total basic variant values ​​at 15°C, 25°C, and 35°C are shown in Tables 6e to 6h.

[0078] Acidic variants increased over the 18 months of collected data, except at 35°C. Therefore, only a very slight change in the basic variant over time was observed. The trend reflects the behavior of the main peak as temperature increases, and the shape of the acidic variant. It increases the compound. Acidic variants can mainly arise from deamidation.

[0079] Similar to the main peak data, the 24-month changes in acidic and basic variants are shown. The influence of all input variables on the prediction is <1%. The greatest influence comes from pH, but the gradient The direction differs between the two variant forms. The acidic variant becomes more stable as the pH approaches 5.5. Although it appears that way, the proportion of basic variants is most stable at pH 6.0. These two different tendencies combine to make a pH environment of 5.5-6.0 suitable for antibodies. It is the most chemically stable. [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18] [Table 19]

[0080] Formulation Research A: Results - CE-SDS Table 7a~ shows the CE-SDS reduced percentage purity values ​​at 5°C, 15°C, 25°C, and 35°C. This is shown in 7d.

[0081] For formulations 15, 16, 19, and 20, clear results were observed from the beginning to the 3-month period at 5°C. An increase in purity was observed, which may be due to variability between formulations. This suggests that the changes at 35°C may be somewhat masked by the same systematic fluctuations. This suggests that, nevertheless, no significant changes were observed at 5°C for 18 months, and 35 The overall change after 3 months at °C was <3%. At high purity levels, fragments and coagulations were observed. Both aggregate values ​​decreased during the research process.

[0082] Prediction of the change in percentage purity using reduced CE-SDS when stored at 5°C for 24 months. The measurement has significant uncertainty compared to the trend of the input variable. Protein concentration is statistically... It was the only significant effect. All predictions of purity over the 24-month study period at 5°C were the first. The difference from the period value was <1%.

[0083] Table 7e~ shows the CE-SDS non-reduced percentage purity values ​​at 5°C, 15°C, 25°C, and 35°C. This is shown at 7h.

[0084] Similar to reduced CE-SDS, it shows a clear increase at 5°C and 25°C, indicating systematic variation. It appears to be affecting the results. This increase is due to the same systematic fluctuations as the change at 35°C. This suggests that there may be some hidden aspects. Nevertheless, 5℃ No significant changes were observed over 18 months, and the overall change after 3 months at 35°C was <2%. The results were similar to those for reduced CE-SDS. The aggregates showed no particular trend during the research process. Although not shown, the amount of fragments increased at 35°C in proportion to the decrease in purity. Non-reducing CE -Among the input variables that affect the purity percentage by SDS, antibody concentration and container stopper The amount was important. The expected highest purity is at pH 5.5. In all cases, The influence of the force variables resulted in a difference of <1.2% in the 24-month forecast. [Table 20] [Table 21] [Table 22] [Table 23] [Table 24] [Table 25] [Table 26] [Table 27]

[0085] Formulation Research A: Results - Subvisible Particles a) HIAC Table 8a shows data from HIAC-insoluble particulate matter tests at 5°C, 15°C, 25°C, and 35°C. This is shown in ~8d.

[0086] Most formulations for up to 3 months at 25°C have a count of less than 5000, which means The insoluble particulate count in the pre-filled syringe is within the acceptable range. Formulation numbers 4, 7, 1 0, 11, and 13 are significantly higher than this count. These formulations contain 150 mg / These are five formulations with target antibody concentrations in mL. The next closest is a count of less than 2 μm / mL. The formulation is formulation number 16 and has an antibody concentration of 125 mg / mL. Formulation number 4 is the maximum It contains a large number of particles, and the highest value exceeds the instrument's tolerance, so it is not completely reliable. No. Insoluble particle count at an antibody concentration of 150 mg / mL is also better than other runs at 5°C. The trend is increasing, but it is more pronounced at 25°C. In particular, formulation numbers 4, 7, 10, and 11. And 13, except for the point at 35°C at 3 months, throughout the study, USP <788> counseling It complies with the requirements for containers. [Table 28] [Table 29] [Table 30] [Table 31]

[0087] b) MFI Table 8e~ shows data from MFI insoluble particulate matter tests at 5°C, 15°C, 25°C, and 35°C. This is shown in 8g.

[0088] A similar trend was observed in the MFI results compared to the HIAC results. At 25°C, The highest count for all formulations corresponds to an antibody concentration of 150 mg / mL. Unlike the IAC results, the count for formulation number 16 was for formulations with lower antibody concentrations. They were equivalent. Formulation number 4 again showed the highest count (almost an order of magnitude higher than the other formulations). stomach). [Table 32] [Table 33] [Table 34]

[0089] Formulation Research A: Conclusion The purpose of formulation study A is to identify a formulation composition suitable for administration to human patients and to prioritize stability. By systematically optimizing essential formulation parameters, the robustness of the formulation can be monitored. This study investigated the relationship between mirikizumab concentration, pH, NaCl, and polysorbate 80. Physical and chemical stability were evaluated. Several formulations were stable at 5°C for 24 months. All predicted changes were <5%, and from the perspective of chemical and physical stability across the entire area studied. It appears robust. Optimal stability according to SEC is approaching pH 5.0. However, the overall change in the pH range after 24 months at 5°C was <2%). iCIEF results This showed that the optimal stability lies between pH 5.5 and pH 6.0. Another method showed that p No clear trend was observed for H. Considering these predictions, pH 5.5 is related. The observations from both assays are balanced, so it is considered to be the optimal pH. This occurs. As the protein concentration increases, the proportion of SEC monomers decreases, and non-reduced C Although the purity of E-SDS decreased, the difference between 20 mg / mL and 150 mg / mL was <1%. Yes. A significant trend was observed regarding the change in the concentration of NaCl or polysorbate 80. No significant effect was observed between different types of container stoppers in this study. Insoluble particulate count is higher in formulations targeting 150 mg / mL of mirikizumab. Further research is being conducted to better understand the cause of this observation. Based on the results described, the preferred formulation is one with a pH of 5.5 and a 10 mM citrate buffer. Solution, 150 mM NaCl, 0.03% w / v polysorbate 80 (for IV administration) It is 0.05% w / v in alcohol. When administered intravenously from a vial, polysorbate 8 The preferred concentration for 0 is 0.05% w / v.

[0090] Example 3: Formulation Research B the purpose The presence of sodium chloride and / or citrate increases the likelihood of discomfort at the injection site. It has been hypothesized that there is a reason for this. The purpose of formulation study B is to provide a highly tolerable injection experience. The goal is to identify alternative formulations to mirikizumab that are likely to be used. In addition to improvement, another objective of this study is to compare the preferred formulation identified in Formulation Study A with the to meet standard bioequivalence criteria and the safety provided by the preferred formulation This includes maintaining and / or minimizing qualitative properties, manufacturability, and deliverability.

[0091] Pharmaceutical Research B: Research design and preparation of anti-IL-23p19 antibody drug formulations Part I of the study consists of the design and evaluation of numerous formulations, as shown in Table 9a. Yes, they are. [Table 35]

[0092] Except for Formulation 1 (the preferred formulation from Formulation Study A), the samples were the API lot EL01 685-056-F-Fill (C1 Demo #2) was buffer-exchanged into the matrices listed in Table 9 (without polysorbate 80). The buffer-exchanged samples were concentrated and / or diluted with buffer to 125 mg / mL of mirikizumab and polysorbate 80 (PS80) was added to a final concentration of 0.03% w / v. The formulations were then sterile filtered and filled into 2.25 mL syringes with appropriate plungers inserted. The final pharmaceutical samples were stored as shown in Table 9b and removed from the chamber.

Table 36

[0093] The results from the evaluation of the formulations shown in Table 9a led to the further formulation design and evaluation shown in Table 10a (Part II of the study).

Table 37

[0094] Except for Formulation 1 (the preferred formulation from Formulation Study A), the samples were the API lot EL01 buffer-exchanged against 0.3 M NaCl of 685-056-F-Fill (C1 Demo #2) (initially against 0.3 M NaCl) and then further buffer-exchanged into the matrices listed in Table 10a (without polysorbate 80). This two-step dialysis approach was used to limit the amount of residual citrate in the final pharmaceutical samples ​​It was used for this purpose. The buffer-exchanged sample was concentrated with buffer to 125 mg / mL of mirikizumab. And / or diluted, and PS80 was added to obtain a final concentration of 0.03% w / v. Then, the preparation The solution was sterile filtered, filled into a 2.25 mL syringe, and an appropriate plunger was inserted. Typical pharmaceutical samples were stored as shown in Table 10b and then removed from the chamber. [Table 38]

[0095] The results from the evaluation of the formulations shown in Tables 9a and 10a indicate further development as shown in Table 11a. This led to the design and evaluation of the agent (Part III of the study). [Table 39]

[0096] With the exception of Formulation 1 (preferred formulation from Formulation Study A), the samples are listed in Table 11a. The preparation is carried out by exchanging the buffer solution into the prepared matrix (without polysorbate 80) or by diluting the active ingredient. Prepared. Formulation 38 was first dialyzed with 0.3M NaCl. The sample was then in buffer. 125 mg / mL of mirikizumab is concentrated and / or diluted, and PS80 is added to make 0.03 The final concentration was adjusted to %w / v. Then, the preparation was sterile filtered and filled into a 2.25 mL syringe. Then, the appropriate plunger was inserted. The final drug sample was stored as shown in Table 11b. It was then removed from the chamber. [Table 40]

[0097] Formulation Research B: Results of Part I - Purity Both the SEC and both the CE - SDS methods showed that the purity of mirikizumab decreased depending on time and temperature. All test formulations showed performance equal to or better than that of Formulation 1. The matrices without histidine (Formulations 1, 21, and 29) showed the greatest decrease in purity during the stability test. The rates of decrease in SEC monomer purity at 25 °C and 40 °C are shown in Table 12. The matrices without histidine (Formulations 1, 21, and 29) showed the fastest degradation rates at 25 °C and 40 °C. Formulations 23 and 24 did not maintain solubility under refrigerated conditions.

Table 41

[0098] Formulation Research B: Results of Part I - Aggregates The SEC data showed an increase in mirikizumab aggregates that was dependent on time and temperature. All formulations showed performance equal to or better than that of Formulation 1. The matrices without histidine (Formulations 1, 21, and 29) showed the greatest increase in aggregates during the stability test. The rates of SEC aggregate formation at 25 °C and 40 °C are shown in Table 13. The matrices without histidine (Formulations 1, 21, and 29) showed the fastest degradation rates at 25 °C and 40 °C.

Table 42

[0099] Formulation Research B: Results of Part I - Fragment The CE - SDS reduced fragment values are shown in Table 14a, and the CE - SDS reduced fragment values are shown in Table 14b. Both CE - SDS methods showed the time and ​​It showed increased temperature dependence. All formulations performed at or above the level of formulation 1. . [Table 43] [Table 44]

[0100] Formulation Research B: Part I Results - Charge Variants Table 15 shows the icIEF main peak resolution at 25°C and 40°C. icIEF is, The mirikizumab charge variant showed a decrease in time and temperature dependence at the main peak. This was mainly due to the formation of acidic variants. After 8 weeks at 40°C, basic variants were formed. A slight increase (approximately <2%) was observed. All formulations showed performance equivalent to formulation 1. Formulations 1, 25, and 26 containing sodium chloride delayed the formation of charge variants. It appears to offer the advantage of providing that benefit. [Table 45]

[0101] Formulation Research B: Results of Part I - Insoluble Microparticles The data for insoluble fine particles showed that the count of particles ≥2μm at 5°C indicated a problem with refrigeration solubility. Except for formulations 23 and 24, the particle count remains at approximately 5000 particles / mL throughout the 6-month period. (This was revealed.) Samples stored at 25°C, and especially at 40°C, consistently had more particles. It produced offspring. Some formulations stored at high temperatures showed increased particle size as storage time increased. Some have shown an increasing trend in the number of units.

[0102] Formulation Research B: Part I Results - Viscosity and Glide Force Viscosity is measured in enhanced pre-filled syringes (ePFS) or automated syringe (AI) delivery systems. Viscosity is an important attribute of a formulation when it is delivered by AI. The chair needs to be low enough so that the dose can be fully delivered, and in the case of ePFS, manually Discharge by this method is not so difficult. The viscosity of the formulations prepared for Formulation Research B-Part I The temperatures (at 15°C and 20°C) are shown in Table 16. The mirikizumab concentration was constant throughout the sample. Yes (approximately 125 mg / mL). Formulations 21-24 and 27-29 are very different from formulation 1. It has high viscosity. Formulations 25 and 26, which contain NaCl and have a lower pH, are manufactured It has only a slightly higher viscosity than agent 1. [Table 46]

[0103] Glide force is another parameter that helps differentiate between formulations. Figure 2 shows the Pharmaceutical Research Institute. The formulation of Part B has two different glide force profiles: it does not change with respect to acceleration stability. This illustrates the process of showing substances and changes. It also illustrates the extraction of ionic species such as NaCl from a formulation. Removing it results in an increase in glide force. This change under acceleration conditions ultimately leads to long-term storage. It appeared at 5°C. This is due to the gradual loss of silicone oil in the syringe barrel. It is possible. By including ionic species, the loss of this silicone oil is improved and consistent. A formulation that maintains the glide force can be obtained.

[0104] The viscosity of formulations 21-24 and 27-29 is remarkably high, and the glide force of the syringe is Considering the effects, citrate buffer and NaCl excipients are used to reduce pain at the injection site. Replacing it must be done in consideration of the impact on viscosity and glide force. Therefore, further formulations were designed and evaluated in Formulation Study B: Part II.

[0105] Formulation Research B: Results of Part II - Purity SEC and CE-SDS reactions of formulations 1 and 30-36 at 5°C, 25°C, and 35°C. The purity values ​​of the original and CE-SDS non-reducing monomers are shown in Tables 17a to 17c. SEC and Both CE-SDS methods show that the purity of mirikizumab decreases in a time and temperature-dependent manner. This was shown. All test formulations showed performance equivalent to or better than formulation 1. Formulation 30, Samples 32 and 34 showed the least decrease in purity at high temperatures during the stability study. [Table 47] [Table 48] [Table 49]

[0106] Formulation Research B: Results of Part II - Aggregates Table 1 shows the total SEC aggregate values ​​for formulations 1 and 30-36 at 5°C, 25°C, and 35°C. As shown in 8, SEC showed a time and temperature-dependent increase in myrikizumab aggregates. Formulation 1 showed performance equivalent to Formulation 1. Formulations 30, 32, and 34 showed excessive stability in the stability study. The smallest increase in aggregates was observed at this point. [Table 50]

[0107] Formulation Research B: Results of Part II - Fragment CE-SDS reduced form and The fragment values ​​for the non-reduced CE-SDS are shown in Tables 19a and 19b. Method S showed a time- and temperature-dependent increase in mirikizumab fragments. All formulations It demonstrated performance equivalent to or better than formulation 1. [Table 51] [Table 52]

[0108] Formulation Research B: Part II Results - Charge Variant icIEF charge validation for formulations 1 and 30-36 at 5°C, 25°C, and 35°C. The antmain peak values ​​are shown in Table 20a. Formulations 1 and 30 at 5°C, 25°C, and 35°C. Table 20b shows the total acidic variant values ​​for 36. Formulations at 5°C, 25°C, and 35°C. The total basicity variant values ​​for 1 and 30-36 are shown in Table 20c.

[0109] icIEF depends on the time and temperature of the main peak of the myrikizumab charge variant. A decrease was observed. This was mainly due to the formation of acidic variants. After 8 weeks at 35°C, the salt A slight increase (approximately <2%) in the base variant was observed. All formulations were equivalent to formulation 1. The performance was demonstrated. [Table 53] [Table 54] [Table 55]

[0110] Formulation Research B: Results of Part II - Viscosity The viscosity of the formulations prepared for Formulation Research B-Part II (at 15°C and 20°C) is shown. As shown in 21, the mirikizumab concentration remained nearly constant throughout the sample (approximately 125 mg / mL). This was observed in Part I of Formulation Study B, in which the removal or reduction of NaCl concentration occurred. We confirmed that this leads to an increase in viscosity. The data in Table 21 shows that a decrease in pH leads to a decrease in viscosity. This indicates that it is possible. [Table 56]

[0111] We evaluated the data from Parts I and II of Formulation Study B, and found that Part III of Formulation Study B was favorable. We designed and evaluated effective formulations.

[0112] Formulation Research B: Results of Part III - Purity SEC and CE-SDS reactions of formulations 1 and 37-40 at 5°C, 25°C, and 35°C. The purity values ​​of the original and CE-SDS non-reducing monomers are shown in Tables 22a to 22c. SEC and Both CE-SDS methods show that the purity of mirikizumab decreases in a time and temperature-dependent manner. This was demonstrated. All test formulations showed performance equivalent to or better than formulation 1. [Table 57] [Table 58] [Table 59]

[0113] Formulation Research B: Results of Part III - Aggregates Table 2 shows the total SEC aggregate values ​​for formulations 1 and 37-40 at 5°C, 25°C, and 35°C. As shown in 3, SEC showed a time and temperature-dependent increase in myrikizumab aggregates. The formulation showed performance equivalent to that of formulation 1. [Table 60]

[0114] Formulation Research B: Results of Part III - Fragment CE-SDS reduced form and The fragment values ​​for the non-reduced CE-SDS are shown in Tables 24a and 24b. Method S showed a time- and temperature-dependent increase in mirikizumab fragments. All formulations It demonstrated performance equivalent to or better than formulation 1. [Table 61] [Table 62]

[0115] Formulation Research B: Part III Results - Charge Variants icIEF charge validation for formulations 1 and 37-40 at 5°C, 25°C, and 35°C. The antmain peak values ​​are shown in Table 25a. Formulations 1 and 37 at 5°C, 25°C, and 35°C. Table 25b shows the total acidic variant values ​​for 40. Formulations at 5°C, 25°C, and 35°C. The total basicity variant values ​​for 1 and 37-40 are shown in Table 25c.

[0116] icIEF depends on the time and temperature of the main peak of the myrikizumab charge variant. A decrease was observed. This was mainly due to the formation of acidic variants. After 8 weeks at 35°C, the salt A slight increase (approximately <2%) in the base variant was observed. All formulations were equivalent to formulation 1. The performance was demonstrated. [Table 63] [Table 64] [Table 65]

[0117] Formulation Research B: Conclusion The objective of Formulation Study B is to obtain the superior stability characteristics of the preferred formulation identified in Formulation Study Part A. While maintaining the potential of formulations containing NaCl and / or citrate buffer, By identifying a high-concentration mirikizumab formulation that can reduce the discomfort of injection pain, Through the above series of studies, the preferred formulations were (i) mirikizumab, (ii) 5 mM (iii) Histidine buffer, (iii) 50 mM NaCl, (iv) 3.3% w / v mannidine This formulation contains toll and (v) 0.03% w / v polysorbate 80, and the pH of this formulation is 5 It is 0.5.

[0118] The formulations described herein can be evaluated in clinical trials in human patients.

[0119] Example 4: Clinical study - Evaluation of mirikizumab formulation in healthy subjects overview Preferred formulation from formulation study A (mirikizumab, 10 mM citrate buffer, 150 ml) M NaCl, 0.05% w / v polysorbate 80, pH 5.5) (Hereafter, Formulation A- (referred to as P) and preferred formulations from formulation study B (mirikizumab, 5 mM histidine saturates) Combolic juice, 50 mM NaCl, 3.3% w / v mannitol, 0.03% w / v polysorbate The relative performance of Rubate 80 (pH 5.5) (formulation BP) was investigated in clinical trials in human patients. Target bioavailability and injection site reaction profile, in particular, injection site pain profile I compared the files.

[0120] This study is a Phase 1, subject-blinded, investigator-blinded, two-group, randomized, single-dose, healthy study. This is a parallel design study in eligible subjects. Eligible subjects are those who meet the criteria on day 1 of the Clinical Research Unit (CRU). They are hospitalized and randomized 1:1 to one of two possible treatments, and their lives are monitored by computer. Using the assigned code, three possible injection sites (arm, thigh, or abdomen) can be selected within the treatment. Participants were randomized in a 1:1:1 ratio to the department. At the discretion of the principal investigator, participants were selected for 4 hours on day 1. After completing the safety evaluation, patients are permitted to leave the CRU, up to 12 weeks after administration. During your regular outpatient visit, you will be asked to come to the hospital for pharmacokinetic sampling and safety evaluation. Safety and tolerability were assessed through clinical tests, vital sign measurements, adverse event recording, and body The assessment was based on a physical examination.

[0121] Formulation AP and Formulation BP are designed to deliver mirikizumab 100 mg. The study consisted of a pre-filled, disposable manual syringe for a single 1 mL dose. The study period for each participant was the longest possible duration. The program lasts 16 weeks, and includes a 4-week screening period, an intervention on day 1, and follow-up. The study included a 12-week post-treatment evaluation period with a stoppage. On day 1, according to the randomization schedule, The subjects received 2 x 1 mL PFS subcutaneous (SC) injections in the arm, thigh, or abdomen.

[0122] the purpose The specific objectives of this study are as follows: i) Comparison of mirikizumab preparation AP with mirikizumab preparation BP (200 mg single dose) Evaluate the relative bioavailability of the dosage (2 x 1 mL PFS injection). -The endpoint is C max , AUC(0~∞), and AUC(0~t last ) (AUC(0~∞) = Area under the concentration-time curve from time 0 to infinity; AUC(0~t l ast ) = Area under the concentration-time curve from time zero to time t, where t is the measurable concentration. This is the final point in time, where Cmax = the maximum observed drug concentration. ii) Comparison of mirikizumab preparation AP with mirikizumab preparation BP (200 mg single dose) Evaluate the safety and tolerability of the C dose (2 x 1 mL PFS injection); -The endpoints are the therapeutic adverse reactions (TEAEs) and serious adverse reactions ( It is SAE. iii) Evaluate injection site reactions (ISR), including pain. - Endpoints include the severity, duration, and severity of erythema, bruising, induration, pain, itching, and edema. The factors considered are the injection site, the VAS pain score immediately after injection, and bleeding.

[0123] method The subjects were clearly healthy men or women aged 18 to 75 years old, with obesity levels at the time of screening. The saturation index needed to be between 18.0 and 32.0 kg / m2 (including both endpoints). Of the 60 people registered, 19 were male and 41 were female. The age range of the participants was The age range was from 19 to 74 years old.

[0124] Sending mirikizumab preparations AP and mirikizumab preparations BP, and mirikizumab 100mg. Designed for precise delivery, supplied as a 1 mL single-dose, pre-filled, disposable manual syringe. It was done.

[0125] On day 1, subjects received 2 x 1 mL PFS SC injections in their arm, thigh, or abdomen.

[0126] The subjects randomly assigned to receive injections in either the arm or thigh include the following: : (a) The first injection was administered to the left limb, and (b) The second injection is administered to the corresponding (contralateral) right limb.

[0127] The subjects randomly assigned to receive injections in the abdomen include the following: (a) The first injection is administered to the lower left abdomen, and (b) The second injection is administered to the right lower abdomen. The second injection should be administered 20 (±) from the first injection. 2) It needs to be administered after 2 minutes.

[0128] Outpatient visits will be scheduled on the 3rd, 5th, 8th, 11th, 15th, 22nd, 29th, 43rd, 57th, 71st, and 85th days. The study was conducted. Pharmacokinetic (PK) samples were taken on day 1 (before administration), 3, 5, 8, 11, and 15. Data was collected on the 22nd, 29th, 43rd, 57th, 71st, and 85th. Evaluation of adverse events and concomitant medications was -1. , 1, 3, 5, 8, 11, 15, 22, 29, 36, 43, 50, 57, 64, 71, and It was conducted on day 85. Telephone contact for safety assessment was made on days 36, 50, and 64. The injection caused erythema, induration, itching, edema, pain (only at the initial injection site), and bruising. Site evaluation was performed at 1, 5, 15, 30, 60, 120, and 240 minutes after administration on day 1. Ta.

[0129] result (a) Pharmacokinetic analysis The following PK parameter estimates for mirikizumab are from Phoenix WinNo. The calculation was performed using the non-compartmental method with NLIN version 8.1. [Table 66]

[0130] The arithmetic mean concentration-time profile was plotted using the nominal time point for each protocol. The average density is calculated by considering that 2 / 3 of the individual data points at that time fall within the sampling window (±10%). If quantifiable measurements were available within the given range, they were plotted at that point.

[0131] Statistical analysis of PK parameters between mirikizumab formulation AP and mirikizumab formulation BP Logarithmically transformed C max , AUC(0~t last ), and the AUC(0~∞) parameter The results were evaluated using a linear fixation effect model that provides a fixation effect on the therapeutic agent and the injection site location. The difference between the mirikizumab formulation AP and the mirikizumab formulation BP was inversely transformed, and the geometry was The mean ratio of LS and the corresponding 90% CI are shown. The parameters vary depending on the therapeutic formulation. I was stopped.

[0132] Summary of PK parameters for mirikizumab preparations AP and mirikizumab preparations BP The results are shown in Table 26. [Table 67]

[0133] Overall, after administration of mirikizumab preparations AP and mirikizumab preparations BP, Cma No statistically significant differences were observed in x, AUC(0 ∞), and AUC(0 tlast). Undetected, the 90% confidence interval for the geometric LS mean ratio includes a value of 1 (Table 27). [Table 68]

[0134] There was no statistically significant difference in the median tmax of mirikizumab between the formulations. Serum concentrations of zumab decreased after tmax, and mirikizumab preparation AP and mirikizumab preparation The geometric mean t1 / 2 values ​​after BP administration were similar, at 11.5 days (276 hours) each. ) and 11.8 days (283 hours). AUC(0~tlast), AUC(0 ∞ ), and the estimated inter-subject variation (CV%) of Cmax were moderate with the mirikizumab preparation AP. The prevalence rates were high, ranging from 48% to 56%, compared to 45% to 46% with mirikizumab BP.

[0135] (b) Safety analysis TEAE The incidence of all TEAEs reported during the study was for mirikizumab preparations AP and mirikizumab. Similar results were observed among subjects who received mab bisphosphonate (Table 28). Injection site data were prospective. Events related to the injection site were evaluated and recorded as ISR-related research endpoints. Therefore, unless the event was certified as an SAE, it was not recorded as an AE. [Table 69]

[0136] Overall, the 3 patients (10.0%) who received the mirikizumab drug AP were, Of the 5 TEAEs reported, 3 patients (10.0%) who received mirikizumab BP were compared. The elephant reported a total of seven TEAEs (Tables 29a and 29b), all related to mirikizumab. The following TEAEs were reported as being among the suspected TEAEs. a) Millikizumab AP (four events in 2 subjects [6.7%]) -One subject experienced a single event consisting of mild nausea, moderate vomiting, and moderate headache. Ta. -One participant experienced a single event of mild nausea. b) Mirikizumab BP (2 events in one patient [3.3%]) -One subject experienced a single event: mild nausea and mild headache.

[0137] All moderate heel fractures except one TEAE thought to be related to other medical conditions TEAEs resolved by the end of the study, with the majority resolving without treatment. Paracetamol is needed for the two TEAE headaches, and apixaba is needed for heel fractures. Hydrocodone and paracetamol were required. [Table 70] [Table 71]

[0138] Death, SAE, and interruption No deaths occurred during the study. No SAEs occurred during the study. No AEs occurred during the study. There were no interruptions.

[0139] Evaluation of the injection site Bleeding at the injection site occurred in 3 patients (10.0%) who received the mirikizumab preparation AP. Two patients received treatment in the arms, one in the abdomen, and three patients (10.0%) received treatment with the mirikizumab drug BP. The results were reported for the arms of two subjects and the thigh of one subject.

[0140] The initial injection site for each subject was prospectively evaluated for ISR at the above time point. The position is evaluated for erythema, edema, induration, itching, and pain, and any category at each point in time. Each positive Lee reaction was counted as an event. In addition, self-injection at the first or second injection site The initially reported ISRs were evaluated as described above.

[0141] Injection site reaction data are summarized in Tables 30a and 30b. This includes planned prospective evaluations. Data from the values, and from one subject who received the AP (arm) formulation, at each injection site on day 9. This includes evaluations of voluntarily reported ISRs. [Table 72-1] [Table 72-2] [Table 73-1] [Table 73-2]

[0142] Overall, among the 23 patients (76.7%) who received the mirikizumab drug AP, 7 patients (8 people reported ISR in the arms, 8 in the thighs, and 8 in the abdomen) and 47 ISRs were reported using mirikizumab BP. Of the 15 subjects (50.0%) who received the treatment (6 in the arm, 6 in the thigh, and 6 in the abdomen), 20 The number of ISRs was reported for either the mirikizumab preparation AP or the mirikizumab preparation B- Similar results were observed among the injection sites (arm, thigh, abdomen) of subjects who received P. The majority of R responses were mild. Most responses (82.1%) occurred after 30 minutes of treatment administration. It occurred within minutes.

[0143] Pain by classification During the ISR assessment, participants were asked if they experienced pain at the injection site ("Yes / Good"). (Eh). After administration of the mirikizumab preparation AP, 22 subjects (73.3%) (6 of whom had their arms examined, 8 Twenty-five events of pain were reported (in the thigh in one person and in the abdomen in eight). Mirikizumab formulation B - After administration of P, 11 subjects (36.7%) (4 in the arm, 3 in the thigh, and 4 in the abdomen) Therefore, 13 pain-related events were reported.

[0144] Pain Visual Analog Scale Pain at the injection site was further evaluated using the VAS pain scale. A summary of the VAS pain score data is shown in Tables 31a and 31b. [Table 74] [Table 75]

[0145] The average VAS pain score within 1 minute after administration was 26 after administration of the mirikizumab preparation AP. The initial value was 1, and after administration of the mirikizumab preparation BP, it was 12.6. This difference was statistically significant. Therefore, the 90% confidence interval of the difference in geometric LS means does not include a value of 1 (Table 32). [Table 76]

[0146] Five minutes after administration, the average VAS pain score was 6.0 after administration of the mirikizumab preparation AP. Yes, and after administration of the mirikizumab preparation BP, the value was 1.9.

[0147] Similar findings were observed when the thigh injection sites were examined separately, but the mirikizumab preparation Between AP and mirikizumab BP, the mean VAS pain level at injection sites in the arm and abdomen was There were no statistically significant differences in the core. The majority of reported pain was mild in severity. Severe pain was observed in two subjects who received the mirikizumab drug AP (thigh). Only this was reported.

[0148] Sequence List Heavy-chain CDR Sequence ID 1: GYKFTRYVMH Sequence ID 2: YINPYNDGTNYNEKFKG Sequence ID 3 ARNWDTGL

[0149] Light Chain CDR Sequence ID 4: KASDHILKFLT Sequence ID 5: GATSLET Sequence ID 6 QMYWSTPFT

[0150] Heavy chain variable region Sequence ID 7 QVQLVQSGAEVKKPGSSVKVSCKASGYKFTRYVMHWVRQA PGQGLEWMGYINPYNDGTNYNEKFKGRVTITADKSTSTAY MELSSLRSEDTAVYYCARNWDTGLWGQGTTVTVSS

[0151] Light chain variable region Sequence ID 8 DIQMTQSPSSLSASVGDRVTITCKASDHILKFLTWYQQKP GKAPKLLIYGATSLETGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCQMYWSTPFTFGGGTKVEIK

[0152] Fully heavy chain Sequence ID 9 QVQLVQSGAEVKKPGSSVKVSCKASGYKFTRYVMHWVRQA PGQGLEWMGYINPYNDGTNYNEKFKGRVTITADKSTSTAY MELSSLRSEDTAVYYCARNWDTGLWGQGTTVTVSSASTKG PSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV DHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPP KPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPSSIEKTISKAKGQPREPQVYTLPSQEEMTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSL G

[0153] Complete light chain Sequence ID 10 DIQMTQSPSSLSASVGDRVTITCKASDHILKFLTWYQQKPGKAPKLLIYGATSLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQMYWSTPFTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC The present invention includes the following embodiments. <1> It is a pharmaceutical preparation, (i) IL-23p19 antibody in a concentration of 50 mg / mL to 150 mg / mL, (ii) 8 mM to 12 mM citrate buffer, (iii) 100-200 mM sodium chloride (NaCl) and (iv) containing a surfactant of 0.01% w / v to 0.05% w / v, The pH of the aforementioned formulation is 5.0 to 6.0. A pharmaceutical formulation wherein the anti-IL-23p19 antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), the amino acid sequence of the LCVR being SEQ ID NO: 8, and the amino acid sequence of the HCVR being SEQ ID NO: 7. <2> The anti-IL-23p19 antibody comprises a light chain (LC) and a heavy chain (HC), wherein the amino acid sequence of the LC is SEQ ID NO: 10, and the amino acid sequence of the HC is SEQ ID NO: 9. <1> The pharmaceutical preparations described above. <3> The aforementioned anti-IL-23p19 antibody is mirikizumab. <1> or <2> The pharmaceutical preparations described above. <4> The concentration of the aforementioned anti-IL-23p19 antibody is approximately 75 mg / mL to approximately 150 mg / mL. <1> ~ <3> A pharmaceutical preparation described in any of the following. <5> The concentration of the anti-IL-23p19 antibody is approximately 100 mg / mL to approximately 150 mg / mL. <1> ~ <4> A pharmaceutical preparation described in any of the following. <6> The concentration of the anti-IL-23p19 antibody is approximately 100 mg / mL. <1> ~ <5> A pharmaceutical preparation described in any of the following. <7> The concentration of the anti-IL-23p19 antibody is approximately 125 mg / mL. <1> ~ <5> A pharmaceutical preparation described in any of the following. <8> The concentration of the citrate buffer solution is approximately 10 mM. <1> ~ <7> A pharmaceutical composition as described in any of the following. <9> The citrate buffer is a sodium citrate buffer. <1> ~ <8> A pharmaceutical preparation described in any of the following. <10> The surfactant is polysorbate 20 or polysorbate 80. <1> ~ <9> A pharmaceutical preparation described in any of the following. <11> The surfactant is polysorbate 80. <10> The pharmaceutical preparations described above. <12> The concentration of the surfactant is approximately 0.03% (w / v). <1> ~ <11> A pharmaceutical preparation described in any of the following. <13> The concentration of NaCl is approximately 150 mM. <1> ~ <12> A pharmaceutical preparation described in any of the following. <14> The pH of the aforementioned formulation is approximately 5.5. <1> ~ <13> A pharmaceutical preparation described in any of the following. <15> The aforementioned formulation, (i) 100 mg / mL or 125 mg / mL of mirikizumab, (ii) 10 mM sodium citrate buffer, (iii) 150 mM NaCl and (iv) containing 0.03% w / v polysorbate 80, The pH of the aforementioned formulation is approximately 5.5. <3> The pharmaceutical preparations described above. <16> The aforementioned formulation contains 100 mg / mL of mirikizumab, <15> The pharmaceutical preparations described above. <17> The aforementioned preparation contains 125 mg / mL of mirikizumab, <15> The pharmaceutical preparations described above. <18> It is a pharmaceutical preparation, (i) IL-23p19 antibody in concentrations of 50 mg / mL to 150 mg / mL, (ii) 3 mM to 12 mM histidine buffer, (iii) 25-75 mM NaCl and (iv) 2-5% w / v isotonic agent, (iv) containing a surfactant of 0.01% w / v to 0.05% w / v, The pH of the aforementioned formulation is 5.0 to 6.0. A pharmaceutical formulation comprising an anti-IL-23p19 antibody containing a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the amino acid sequence of the LCVR is SEQ ID NO: 8 and the amino acid sequence of the HCVR is SEQ ID NO: 7. <19> The anti-IL-23p19 antibody comprises a light chain (LC) and a heavy chain (HC), the amino acid sequence of the LC is SEQ ID NO: 10, and the amino acid sequence of the heavy chain is SEQ ID NO: 9. <18> The pharmaceutical preparations described above. <20> The aforementioned anti-IL-23p19 antibody is mirikizumab. <18> or <19> The pharmaceutical preparations described above. <21> The concentration of the aforementioned anti-IL-23p19 antibody is approximately 75 mg / mL to approximately 150 mg / mL. <18> ~ <20> A pharmaceutical preparation described in any of the following. <22> The concentration of the anti-IL-23p19 antibody is approximately 100 mg / mL to approximately 150 mg / mL. <18> ~ <21> A pharmaceutical preparation described in any of the following. <23> The concentration of the anti-IL-23p19 antibody is approximately 100 mg / mL. <18> ~ <22> A pharmaceutical preparation described in any of the following. <24> The concentration of the anti-IL-23p19 antibody is approximately 125 mg / mL. <18> ~ <22> A pharmaceutical preparation described in any of the following. <25> The concentration of the histidine buffer solution is approximately 5 mM. <18> ~ <24> A pharmaceutical composition as described in any of the following. <26> The isotonic agent is mannitol. <18> ~ <25> A pharmaceutical composition as described in any of the following. <27> The concentration of mannitol is 3.3% w / v. <26> The pharmaceutical composition described above. <28> The surfactant is polysorbate 20 or polysorbate 80. <18> ~ <27> A pharmaceutical preparation described in any of the following. <29> The surfactant is polysorbate 80. <28> The pharmaceutical preparations described above. <30> The concentration of the surfactant is approximately 0.03% (w / v). <18> ~ <29> A pharmaceutical preparation described in any of the following. <31> The concentration of NaCl is approximately 50 mM. <18> ~ <30> A pharmaceutical preparation described in any of the following. <32> The pH of the aforementioned formulation is approximately 5.5. <18> ~ <31> A pharmaceutical preparation described in any of the following. <33> (i) 100 mg / mL or 125 mg / mL of mirikizumab, (ii) 5 mM histidine buffer, (iii) 50 mM NaCl and (iv) 3.3% w / v mannitol and (v) Contains 0.03% w / v polysorbate 80, The pH of the aforementioned formulation is 5.5. <20> The pharmaceutical preparations described above. <34> The aforementioned formulation contains 100 mg / mL of mirikizumab, <32> The pharmaceutical preparations described above. <35> The aforementioned preparation contains 125 mg / mL of mirikizumab, <32> The pharmaceutical preparations described above. <36> A method for treating and / or preventing psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis and / or ankylosing spondylitis, wherein the method comprises a therapeutically effective amount <1> ~ <35> A method comprising administering to a patient any of the pharmaceutical preparations described in any of the above. <37> For use in the treatment and / or prevention of psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis and / or ankylosing spondylitis, <1> ~ <35> A pharmaceutical preparation described in any of the following. <38> In the manufacture of pharmaceuticals for use in the treatment of psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis and / or ankylosing spondylitis, <1> ~ <35> Use of any of the pharmaceutical preparations listed. <39> A method for reducing parainjection pain experienced by a patient during or immediately after administration of a pharmaceutical preparation containing an anti-IL-23p19 antibody, wherein the method is <18> ~ <35> A method comprising administering to a patient a pharmaceutical preparation described in any of the above, wherein the step of administration provides a therapeutically preferred level of injection-related pain. <40> The aforementioned therapeutically favorable level of injection-related pain includes a VAS score of less than 30 mm or less than 20 mm. <39> The method for reducing injection-related pain described above. <41> An improved method for administering an anti-IL-23p19 antibody via saccharinization (SC) to a patient requiring such administration, wherein the improvement includes reducing the parainjection pain associated with the SC administration of a pharmaceutical formulation containing the anti-IL-23p19 antibody, and the method is <18> ~ <35> An improved method comprising administering a pharmaceutical preparation described in any of the above, wherein the step of administration provides an improved level of parainjection pain and / or a therapeutically preferred level of parainjection pain. <42> The aforementioned therapeutically favorable level of injection-related pain includes a VAS score of less than 30 mm or less than 20 mm. <41> An improved method for SC administration of the anti-IL-23p19 antibody described in [reference]. <43> An improved method for treating at least one of psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis, and ankylosing spondylitis, wherein the improvement includes reducing the injection-related pain during SC administration of a pharmaceutical formulation containing an anti-IL-23p19 antibody, and the method is <18> ~ <35> An improved method comprising administering a pharmaceutical preparation described in any of the above, wherein the step of administration provides an improved level of parainjection pain and / or a therapeutically preferred level of parainjection pain. <44> The aforementioned therapeutically favorable level of injection-related pain includes a VAS score of less than 30 mm or less than 20 mm. <43> An improved method for treating at least one of the following conditions: psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis, and ankylosing spondylitis.

Claims

1. It is a pharmaceutical preparation, (i) IL-23p19 antibody in a concentration of 50 mg / mL to 150 mg / mL, (ii) 3 mM to 12 mM histidine buffer, (iii) 25-75 mM NaCl, (iv) 2-5% w / v isotonic agent, (iv) containing a surfactant of 0.01% w / v to 0.05% w / v, The pH of the aforementioned formulation is 5.0 to 6.

0. A pharmaceutical preparation comprising an anti-IL-23p19 antibody containing a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the amino acid sequence of the LCVR is SEQ ID NO: 8 and the amino acid sequence of the HCVR is SEQ ID NO:

7.

2. The pharmaceutical formulation according to claim 1, wherein the anti-IL-23p19 antibody comprises a light chain (LC) and a heavy chain (HC), the amino acid sequence of the LC is SEQ ID NO: 10, and the amino acid sequence of the heavy chain is SEQ ID NO:

9.

3. The pharmaceutical formulation according to claim 1 or 2, wherein the anti-IL-23p19 antibody is mirikizumab.

4. The pharmaceutical preparation according to any one of claims 1 to 3, wherein the concentration of the anti-IL-23p19 antibody is approximately 75 mg / mL to approximately 150 mg / mL.

5. The pharmaceutical preparation according to any one of claims 1 to 4, wherein the concentration of the anti-IL-23p19 antibody is about 100 mg / mL to about 150 mg / mL.

6. The pharmaceutical preparation according to any one of claims 1 to 5, wherein the concentration of the anti-IL-23p19 antibody is approximately 100 mg / mL.

7. The pharmaceutical formulation according to any one of claims 1 to 5, wherein the concentration of the anti-IL-23p19 antibody is approximately 125 mg / mL.

8. The pharmaceutical preparation according to any one of claims 1 to 5, wherein the concentration of the anti-IL-23p19 antibody is about 150 mg / mL.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the concentration of the histidine buffer is about 5 mM.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the isotonic agent is mannitol.

11. The pharmaceutical composition according to claim 10, wherein the concentration of mannitol is 3.3% w / v.

12. The pharmaceutical formulation according to any one of claims 1 to 11, wherein the surfactant is polysorbate 20 or polysorbate 80.

13. The pharmaceutical formulation according to claim 12, wherein the surfactant is polysorbate 80.

14. The pharmaceutical formulation according to any one of claims 1 to 13, wherein the concentration of the surfactant is about 0.03% (w / v).

15. A pharmaceutical preparation according to any one of claims 1 to 14, wherein the concentration of NaCl is approximately 50 mM.

16. The pharmaceutical preparation according to any one of claims 1 to 15, wherein the pH of the preparation is approximately 5.

5.

17. (i) Mirikizumab at 50 mg / mL to 150 mg / mL, (ii) 5 mM histidine buffer, (iii) 50 mM NaCl and (iv) 3.3% w / v mannitol and (v) Contains 0.03% w / v polysorbate 80, The pharmaceutical preparation according to claim 3, wherein the pH of the preparation is 5.0 to 6.

0.

18. The pharmaceutical formulation according to claim 17, wherein the formulation comprises 50 mg / mL of mirikizumab.

19. The pharmaceutical formulation according to claim 17, wherein the formulation comprises 100 mg / mL of mirikizumab.

20. The pharmaceutical formulation according to claim 17, wherein the formulation comprises 125 mg / mL of mirikizumab.

21. The pharmaceutical formulation according to claim 17, wherein the formulation comprises 150 mg / mL of mirikizumab.

22. A pharmaceutical preparation according to any one of claims 1 to 21, for use in the treatment and / or prevention of psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis and / or ankylosing spondylitis.

23. Use of a pharmaceutical preparation according to any one of claims 1 to 21 in the manufacture of a pharmaceutical product for use in the treatment of psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis and / or ankylosing spondylitis.

24. A pharmaceutical formulation according to any one of claims 1 to 21, for use in a method of reducing parainjection pain experienced by a patient during or immediately after SC, IP and / or IM administration of a pharmaceutical formulation containing an anti-IL-23p19 antibody, wherein the method comprises administering the pharmaceutical formulation according to any one of claims 1 to 21 to a patient, wherein such administration provides a therapeutically preferred level of parainjection pain.

25. The pharmaceutical formulation according to claim 24, wherein the therapeutically preferred level of injection-related pain includes a VAS score of less than 30 mm or less than 20 mm.

26. A pharmaceutical formulation according to any one of claims 1 to 21, for use in an improved method for administering an anti-IL-23p19 antibody via saccharinization (SC) to a patient requiring such administration, wherein the improvement comprises reducing parainjection pain during SC administration of the pharmaceutical formulation comprising the anti-IL-23p19 antibody, and the method comprises administering the pharmaceutical formulation according to any one of claims 1 to 21, wherein the administration provides an improved level of parainjection pain and / or a therapeutically preferable level of parainjection pain.

27. The pharmaceutical formulation according to claim 26, wherein the therapeutically preferred level of injection-related pain includes a VAS score of less than 30 mm or less than 20 mm.

28. A pharmaceutical formulation according to any one of claims 1 to 21, for use in an improved method for treating at least one of psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis, and ankylosing spondylitis, wherein the improvement comprises reducing parainjection pain during SC administration of the pharmaceutical formulation comprising an anti-IL-23p19 antibody, and the method comprises administering the pharmaceutical formulation according to any one of claims 1 to 21, wherein the administration provides an improved level of parainjection pain and / or a therapeutically preferred level of parainjection pain.

29. The pharmaceutical formulation according to claim 28, wherein the therapeutically preferred level of injection-related pain includes a VAS score of less than 30 mm or less than 20 mm.

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