Therapeutic antibody formulations

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 is in the field of medicine. More specifically, the present invention relates to a method for the treatment of subcutaneous ("SC"), intramuscular and / or intraperitoneal ("IP") administration. More particularly, the present invention relates to pharmaceutical formulations of anti-IL-23p19 antibodies. These anti-IL-23p19 antibody pharmaceutical preparations are effective in treating at least psoriasis (Ps), psoriatic arthritis, and Treatment of PsA, ulcerative colitis (UC), Crohn's disease (CD) and / or ankylosing spondylitis It is expected to be useful for

[0002] Anti-IL-23 is used to treat patients with Ps, PsA UC, CD, and / or ankylosing spondylitis. There is a need for pharmaceutical formulations of p19 antibodies. The administration of therapeutic antibodies is common and advantageous. Such an administration route allows therapeutic antibodies to be administered for short periods of time. allowing patients to self-administer therapeutic antibodies without visiting a physician The antibodies can be delivered to patients SC, IP and / or IM in pharmaceutical preparations. The agent requires a specific concentration of anti-IL-23p19 antibody. These pharmaceutical formulations containing the p19 antibody have the following properties: physical and chemical stability of the anti-IL-23p19 antibody; However, therapeutic antibodies can be administered SC, IM, and / or IP. Formulating suitable aqueous pharmaceutical formulations for these purposes can be difficult and unpredictable.

[0003] With the formulation of therapeutic antibodies into aqueous pharmaceutical formulations suitable for SC, IM, and / or IP administration The difficulties and unpredictability are, in part, due to the nature of the drugs that must be present for a pharmaceutical formulation to be therapeutically viable. This is due to a number of properties that must be in place. Pharmaceutical formulations are believed to provide stability to therapeutic antibodies in solution. At the same time, functional characteristics of therapeutic antibodies, such as target affinity, selectivity and efficacy, which are essential for therapeutic efficacy, are being investigated. In addition, the aqueous pharmaceutical formulation must also be safe for administration to patients. It must be stable, well tolerated by the patient and suitable for manufacture and storage.

[0004] Formulation of high concentration therapeutic antibodies is much more complicated. For example, the increased rate of antibody release Solution, cleavage, clipping, high molecular weight aggregation, dimerization, trimerization, precipitation pH shift, turbidity, Changes in solution color, charge change, isomerization, oxidation and / or deamination (all of which may contribute to the treatment) This has implications for the formulation of highly concentrated therapeutic antibodies. Another known challenge in formulating therapeutic antibodies at high concentrations is the drug formulation. The increased viscosity can adversely affect SC, IM, and / or IP administration of the drug.

[0005] Mirikizumab, CAS Registry Number 1884201-71-1, binds to p19 of human IL-23. Subunit-targeted humanized immunoglobulin (Ig) G4 variant monoclonal Mirikizumab is an antibody that is described in U.S. Patent No. 9,023,358. It has been evaluated for the treatment of patients with mild to severe plaque psoriasis, UC and CD. Mabs can be administered subcutaneously to patients in highly concentrated (75-150 mg / mL) pharmaceutical formulations. In reformulation studies, mirikizumab was shown to be effective at lower and higher pH values ​​( It has been found that stability in formulations is reduced at pH < 5.0 and pH > 7.0. Mirikizumab samples formulated at low concentrations were assayed at low concentrations as determined by SEC. The samples formulated at least Certain formulations of mirikizumab at a concentration of 50 mg / mL showed significant protein cryoprecipitation. To circumvent these observed problems, specific concentrations of anti-IL-23p19 antibodies were There is a need for pharmaceutical formulations of the body. The pharmaceutical formulations provided herein meet the aforementioned need. More specifically, the pharmaceutical formulations provided herein are capable of inhibiting the functions of mirikizumab that are essential for therapeutic efficacy. Suitable for SC, IM and / or IP administration of high concentrations of mirikizumab while maintaining therapeutic characteristics It is.

[0006] therefore, (i) 50 mg / mL to 150 mg / mL of an IL-23p19 antibody; (ii) 8 mM to 12 mM citrate buffer; (iii) 100-200 mM sodium chloride (NaCl); (iv) 0.01% w / v to 0.05% w / v of a surfactant, and a pharmaceutical formulation comprising the same. And, The pH of the formulation is 5.0 to 6.0; Anti-IL-23p19 antibody binds the light chain variable region (LCVR) and 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: The number is 7.

[0007] In certain embodiments of the invention, 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 It is.

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

[0009] In an alternative embodiment of the invention, the pharmaceutical formulation comprises an anti-IL-23p19 antibody. The p19 antibody comprises an LCVR and an HCVR, and the LCVR has the amino acid sequence LCDR1, LCDR2, LCDR3, LCDR4, LCDR5, LCDR6, LCDR7, LCDR8, LCDR9, LCDR10, LCDR11, LCDR12, LCDR13, LCDR14, LCDR15, LCDR16, LCDR17, LCDR18, LCDR19 ... HCVR comprises the amino acid sequences HCDR1, HCDR2, and LCDR3; CDR3, LCDR1 is SEQ ID NO: 4, LCDR2 is SEQ ID NO: 5, DR3 is SEQ ID NO:6, HCDR1 is SEQ ID NO:1, and HCDR2 is SEQ ID NO:2 and HCDR3 is SEQ ID NO:3.

[0010] In a further embodiment of the invention, the concentration of the anti-IL-23p19 antibody is about 75 mg / mL to The concentration of the anti-IL-23p19 antibody is about 100 mg / mL. The concentration of the anti-IL-23p19 antibody is preferably about 100 mg / mL to about 150 mg / mL. is about 100 mg / mL. Alternatively, preferably, the concentration of anti-IL-23p19 antibody is is approximately 125 mg / mL.

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

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

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

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

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

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

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

[0018] In a further aspect of the invention, the present invention relates to a method for treating psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis and / or Also provided is a method of treating and / or preventing ankylosing spondylitis, comprising administering to a patient a therapeutically effective amount of The method includes administering a pharmaceutical formulation of the present invention.

[0019] In yet a further aspect of the invention, the present invention relates to a method for treating psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis and / or or a pharmaceutical formulation according to the invention for use in the treatment and / or prevention of ankylosing spondylitis. .

[0020] In yet a further aspect of the invention, the present invention relates to a method for treating psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis and / or or the use of the pharmaceutical formulation of the present invention in the manufacture of a medicament for use in the treatment of ankylosing spondylitis. is provided.

[0021] In addition to the difficulties of formulating therapeutic antibodies mentioned above, there is also the undesirable tendency for the antibody to remain in the blood even after the needle is removed. Unusual injection-associated pain has been reported with this route of administration, which may affect patient perception of treatment. Injection pain has been reported with formulations with increased viscosity. Pain associated with injections of pharmaceutical preparations, including therapeutic antibodies, is a complex and multifactorial problem. For example, The individual components of the aqueous pharmaceutical formulation and / or their concentrations, proportions and properties may be determined in accordance with the therapeutic context. Similarly, the individual components (and / or their concentrations, proportions and characteristics) may affect the injection pain. The stability, functional properties, manufacturability and / or stability of the formulated therapeutic antibody in the aqueous pharmaceutical formulation are Therefore, certain formulation adjustments may be beneficial for given properties of the formulation. While adjustments may have a significant effect on the formulation, the same adjustments may also have adverse effects on other properties of the formulation. To add to the complexity, there is an almost limitless number of different formulation components (e.g., buffers, and excipients) and their concentrations and proportions. Correlations to predict the effect of agents on various properties and characteristics of a given therapeutic antibody have been scarce. Little or no existence.

[0022] Thus, it is suitable for SC, IM and / or IP administration and provides therapeutically beneficial levels of injectable There is also a need for pharmaceutical formulations of therapeutic antibodies that exhibit associated pain and are well tolerated by patients. More particularly, it is suitable for SC, IM and / or IP administration and is more effective than alternative formulations of mirikizumab. The drug was shown to have improved levels of injection-associated pain and was well tolerated by patients. There is a need for formulations. Such pharmaceutical formulations also provide stability to therapeutic antibodies and provide therapeutic The properties of the therapeutic antibody that are essential for its therapeutic effect must be maintained. It should also be manufacturable and preferably have an extended shelf life. The pharmaceutical formulation is suitable for SC, IM, and / or IP administration via a prefilled syringe or autoinjector. It is also necessary that the temperature is suitable.

[0023] The pharmaceutical formulations provided herein satisfy the aforementioned needs. More particularly, The provided pharmaceutical formulations maintain the functional characteristics of mirikizumab essential for its therapeutic efficacy while: High concentrations of mirikizumab (e.g., suitable viscosity) suitable for SC, IM and / or IP administration The pharmaceutical formulations provided herein are also well tolerated by patients and are an alternative to mirikizumab. It exhibits improved levels of injection-associated pain compared to alternative pharmaceutical formulations, and provides a therapeutically favorable level of injection pain. It can cause associated pain.

[0024] therefore, (i) 50 mg / mL to 150 mg / mL of an IL-23p19 antibody; (ii) 3 mM to 12 mM histidine buffer; (iii) 25 to 75 mM NaCl; (iv) 2 to 5% w / v of an isotonicity agent; (iv) 0.01% w / v to 0.05% w / v of a surfactant, and a pharmaceutical formulation comprising the same. And, The pH of the formulation is 5.0 to 6.0; Anti-IL-23p19 antibody binds the light chain variable region (LCVR) and 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: The number is 7.

[0025] In certain embodiments of the invention, 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 It is.

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

[0027] In an alternative embodiment of the invention, the pharmaceutical formulation comprises an anti-IL-23p19 antibody. The p19 antibody comprises an LCVR and an HCVR, and the LCVR has the amino acid sequence LCDR1, LCDR2, LCDR3, LCDR4, LCDR5, LCDR6, LCDR7, LCDR8, LCDR9, LCDR10, LCDR11, LCDR12, LCDR13, LCDR14, LCDR15, LCDR16, LCDR17, LCDR18, LCDR19 ... HCVR comprises the amino acid sequences HCDR1, HCDR2, and LCDR3; CDR3, LCDR1 is SEQ ID NO: 4, LCDR2 is SEQ ID NO: 5, DR3 is SEQ ID NO:6, HCDR1 is SEQ ID NO:1, and HCDR2 is SEQ ID NO:2 and HCDR3 is SEQ ID NO:3.

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

[0029] In yet a further embodiment of the invention, the concentration of the histidine buffer is about 5 mM.

[0030] In yet a further embodiment of the invention, the tonicity agent is mannitol.

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

[0032] In yet a further embodiment of the invention the surfactant is Polysorbate 20 or Polysorbate The rating 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 yet a further embodiment of the invention, the concentration of NaCl is about 50 mM.

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

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

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

[0039] In a further aspect of the invention, the present invention relates to a method for treating psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis and / or A method for treating and / or preventing ankylosing spondylitis is provided, the method comprising administering to a patient a therapeutically effective amount of The method includes administering a pharmaceutical formulation of the present invention.

[0040] In yet a further aspect of the invention, the present invention relates to a method for treating psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis and / or or a pharmaceutical formulation according to the invention for use in the treatment and / or prevention of ankylosing spondylitis. .

[0041] In yet a further aspect of the invention, the present invention relates to a method for treating psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis and / or or the use of the pharmaceutical formulation of the present invention in the manufacture of a medicament for use in the treatment of ankylosing spondylitis. is provided.

[0042] Yet a further aspect of the invention relates to the administration of a pharmaceutical formulation comprising an anti-IL-23p19 antibody by SC, IP or The present invention provides a method for reducing injection-associated pain experienced by a patient during or immediately following IM and / or intramuscular administration. The method includes administering to a patient a pharmaceutical formulation of the present invention, the administering step comprising , providing a therapeutically favorable level of injection-associated pain.

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

[0044] In yet a further aspect of the invention, a patient in need of SC administration of an anti-IL-23p19 antibody is Improved methods for doing so, the improvement comprising administering to a patient a pharmaceutical product comprising an anti-IL-23p19 antibody. and a method for administering the pharmaceutical formulation of the present invention to a subject comprising administering the pharmaceutical formulation of the present invention to a subject in need thereof. administering, wherein the administering step provides an improved level of injection-associated pain; and / or provide a therapeutically favorable level of injection-associated pain. Poor levels of injection pain include a VAS score of less than 30 mm or less than 20 mm.

[0045] In yet a further aspect of the invention, the present invention relates to a method for treating psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis, and An improved method of treating at least one of the ankylosing spondylitis, wherein the improvement is an anti-IL-1 inhibitor. Methods are provided that include reducing injection-associated pain upon SC administration of a pharmaceutical formulation comprising an -23p19 antibody. wherein the method comprises administering a pharmaceutical formulation as described herein, provides improved levels of injection pain and / or provides a therapeutically favorable level of injection pain Preferably, the therapeutically desirable level of injection pain is less than 30 mm or includes VAS scores less than 20 mm.

[0046] As used herein, the expression "pharmaceutical preparation" refers to a pharmaceutical agent that exerts a biological effect in humans. at least one therapeutic antibody capable of delivering to humans when combined with a therapeutic antibody; At least one inactive ingredient (e.g., a buffer, an excipient, a boundary layer) that is suitable for therapeutic administration of the The pharmaceutical formulation of the present disclosure refers to a solution having a therapeutic antibody in the formulation. The extent of degradation, modification, aggregation, loss of biological activity, etc. is controlled within acceptable limits and decreases over time. It is a suitable formulation that does not increase beyond the above range.

[0047] As used herein, the term "antibody" refers to an antibody that is bound to one another by disulfide bonds. Immunoglobulin G (IgG) is a globulin that contains two combined heavy chains ("HC") and two light chains ("LC"). Each heavy chain comprises a heavy chain variable region ("HCVR") and a heavy chain constant region ("CVR"). Each light chain is composed of a light chain variable region ("LCVR") and a light chain constant region (" HCVR and LCVR each consist of a framework region ("FR" ), interspersed with more conserved regions called complementarity determining regions ("CDRs"). The HCVR and LCVR are each divided into the following regions of hypervariability: , FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4, from the amino terminus to the It is composed of three CDRs and four FRs arranged toward the carboxy terminus. The variable region of the LC contains the 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 q) may mediate the binding of immunoglobulins to host tissues or factors.

[0048] As used interchangeably herein, "binding to the p19 subunit of human IL-23" refers to "Anti-IL-23p19 antibody" or "anti-IL-23p19 antibody" refers to an antibody that binds to the p19 subunit of human IL-23. It refers to an antibody that binds to the p40 subunit of human IL-23 but does not bind to the p40 subunit of human IL-23. Exemplary antibodies include mirikizumab, guselkumab, tildrakizumab, and risankizumab. Some examples include:

[0049] Guselkumab, CAS Registry Number 1350289-85-8, is used for the treatment of plaque psoriasis. A fully human IgG1 label that binds to the p19 subunit of human IL-23, approved by the National Institutes of Health. The antibody and the method for producing it are disclosed in U.S. Patent No. 7,935. ,344.

[0050] Tildrakizumab, CAS Registry Number 1326244-10-3, is used to treat moderate to severe chronic myelopathy. Approved for the treatment of chronic psoriasis, targeting the p19 subunit of human IL-23 The antibody and the method for producing it are As described in U.S. Patent No. 8,293,883.

[0051] Risankizumab, CAS Registry Number 1612838-76-2, binds human IL-23 p1 It is a humanized IgG1 kappa monoclonal antibody that targets the 9 subunit. A method for making it is described in U.S. Patent No. 8,778,346. Mab is approved for the treatment of moderate to severe plaque psoriasis.

[0052] Brazikumab, CAS Registry Number 1610353-18-8, binds to p19 of human IL-23. It is a humanized IgG2 lambda monoclonal antibody that targets the IgG2 subunit. Methods for making it are described in U.S. Patent No. 8,722,033. is being evaluated for the treatment of CD and UC.

[0053] As used herein, the terms "about" or "approximately" refer to the amount of the When used in reference to a listed value or range of values, the value shall be 10% less than the listed value. This means that the value may vary by no more than (e.g., + / - 10%). When used in a quantitative analysis, the expression "about 100" includes 90 and 110 and all values ​​therebetween (e.g. For example, 91, 92, 93, 94, etc.

[0054] As used herein, the phrase "injection site pain" refers to the pain that occurs upon injection of a liquid formulation subcutaneously. Pain is localized at the injection site due to pain. Pain can be measured, for example, on a visual analog scale (VAS). Any method known in the art, including pain assessment, pain quality assessment, or acupuncture pain assessment, may be used. Any type of pain assessment that is available in the art can be used to assess pain. For example, the pain perceived by the subject can be assessed using any type of pain assessment that is available in the art. Pain at the injection site can be assessed using a visual analogue scale (VAS). The VAS is a pain measurement instrument that allows pain to be expressed as a continuous value (e.g., no pain, no pain). The VAS is measured using a water bottle approximately 100 mm long. A flat line with numeric and / or word descriptors (e.g., 0 or 10, or "no pain" or "unbearable pain") and, if necessary, additional options between the two extremes. a word or numeric descriptor, e.g., mild, moderate, severe; or a number between 1 and 9 (e.g., L ee JS, et al. (2000) AcadEmerg Med 7:550, also Singer and Thods (1998) Academic Emergence (See, for example, Epstein-Barr Medicine, 5:1007.) Pain may occur once or twice after administration of the formulation. is assessed at various time points, e.g., immediately after injection, approximately 1, 2, 3, 4, 5, 6, 7 , 8, 9, 10, 15, 20, 25, 30, 35, 40, or 45 minutes later. Pain severity was assessed according to the VAS tool as mild pain (≤30 mm), moderate pain (> It can be classified into mild pain (30mm~≦70mm) and severe pain (>70mm). The desirable properties of an agent include that it is well tolerated by the patient, e.g., that it has a therapeutically favorable therapeutic effect. 3. Give pain associated with injection (e.g., VAS score of <30mm and / or <20mm) As is known, the components of a pharmaceutical formulation and their concentrations and / or proportions may vary. This may affect the injection-associated pain experienced by the patient.

[0055] As used interchangeably herein, "treatment" and / or "treatment" refer to "Treating" and / or "treat" means complete disappearance, slowing or disappearance of may delay, reduce the severity or frequency (e.g., of flares or episodes), reduce the severity of, or improve the course of, a disease and / or condition. The term is intended to refer to any process in which there may be an interruption or cessation of the progression of the disease symptoms, but Complete disappearance of all disease symptoms is not required. Treatment is in accordance with the methods disclosed herein for the treatment of disease in humans. and may benefit from at least one of the above processes, comprising: (a) administering an aqueous pharmaceutical formulation of Inhibiting further progression of the symptoms and effects of the disease, i.e., arresting the onset of the disease and (b) alleviating the disease, i.e., eliminating or reducing the disease, symptoms of the disease, or complications of the disease. (c) causing regression, and (c) preventing or reducing the frequency of episodes or flares of the disease. According to certain embodiments, the pharmaceutical formulations provided herein are for the treatment of psoriasis, ulcers, and the like. At least one of ulcerative colitis, Crohn's disease, psoriatic arthritis and / or ankylosing spondylitis It can be used in the treatment of.

[0056] As used interchangeably herein, the terms "patient," "subject," and "individual" Unless otherwise specified, a subject is a person who has a medical condition that is caused by administration of the pharmaceutical formulations disclosed herein. Those who have, are at risk of developing, or experience symptoms of a disease that would benefit It can be further characterized as:

[0057] As used interchangeably herein, an "effective amount" or a "therapeutically effective amount" of a pharmaceutical formulation of the present disclosure. " refers to the amount (dose, frequency of administration, and specific means of administration) necessary to achieve the desired therapeutic result. The effective amount of the pharmaceutical formulation of the present disclosure depends on the disease state, age, sex, and weight of the subject. as well as the ability of the pharmaceutical formulation of the present disclosure to elicit a desired response in a subject. An effective amount also refers to an amount that is therapeutically beneficial and outweighs any toxic or detrimental effects of the pharmaceutical formulations of the present disclosure. It is an amount that has a greater effect.

[0058] The pharmaceutical formulation of the present invention may be administered to a patient via parenteral administration. As understood in the art, a sterile syringe or some other device, including an automatic injector or infusion pump, may be used. This refers to the injection of a dose into the body by any of a number of different drug delivery systems, including the pharmaceutical formulations of the present disclosure. Exemplary drug delivery systems for use in are described in the following references: The disclosure of which is expressly incorporated herein by reference in its entirety: The patent application, entitled "Infusion Pump Assembly," was filed in U.S. Patent Publication No. 2014 / 0054883, filed February 3, 2006, by N. et al. Medication Dispensing Apparatus with Tri ple Screw Threads for Mechanical Advanta U.S. Patent No. 7,291,132 to DeRuntz et al., entitled "U.S. Patent No. 7,291,132, issued September 2006 ... The Medication Dispensing Apparatus was filed on the 18th. s with Spring-Driven Locking Feature Ena "Blown by Administration of Final Dose" No. 7,517,334 to Jacobs et al., issued on August 24, 2012. The Automatic Injection Device with Del ay Mechanism Including Dual Functioning Adams et al., U.S. Patent No. 8,734,399, entitled "Biasing Member" No. 4. Parenteral routes include IM, SC, and IP routes of administration. [Brief description of the drawings]

[0059] [Figure 1] FIG. 1 is a contour plot of mirikizumab concentration versus pH, showing the relationship of target pH to antibody concentration for expected monomeric purity. [Diagram 2] Glide force data for Formulation 1 and Formulations 21-29 are shown. EXAMPLES

[0060] Example 1: Antibody Production Anti-IL-23p19 antibodies can be produced and purified as follows. In an expression system for antibody secretion using a fixed HC:LC vector ratio, or using both LC and and both HC (e.g., each LC is SEQ ID NO: 10 and each HC is SEQ ID NO: 9). A single vector system that transduces suitable host cells, such as CHO, either transiently or stably. The clarified medium into which the antibody is secreted can be transfected by any of a number of commonly used techniques. For example, the medium may be purified using a suitable buffer, such as phosphate buffered saline. The protein A or G Sepharose FF column was equilibrated with saline (pH 7.4) The column is washed to remove non-specifically bound components. The bound antibody is then For example, the antibody fragments are eluted by a pH gradient. Depending on the intended use, further purification is optional. Antibodies are typically purified using Soluble aggregates and multimers may be isolated by size exclusion and / or concentration using techniques such as those described herein. including removal, hydrophobic interaction, ion exchange, or hydroxyapatite chromatography Antibodies after these chromatography steps can be effectively removed by common techniques. The purity of the product is greater than 99%. The product can be rapidly dissolved in the formulation matrix of the present invention at -70°C. It may be frozen or lyophilized. Exemplary Antibody Amino Acid and Nucleic Acid Sequences The sequence is shown below.

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

[0062] Antibody concentrations were 20, 85, 100, 125, and 150 mg / mL in formulations 1 to 20. The wide range of antibody concentrations explains the multiple possible presentations of mirikizumab drug. were chosen to provide a clear correlation between some forms of degradation (e.g., aggregation) and concentration. The formulation data was based on the three The effect of NaCl on the solubility of 0.01, 0.03, and 0.05% w / v was studied. Concentrations of 100, 150, and 200 mM were investigated. Biophysical screening revealed that the region of optimal overall stability was between pH 5.5 and 6. 0, so the effect of pH was studied over a range from 5.0 to 6.0.

[0063] Based on preformulation data, there is no significant effect on stability with different container closure types. No significant effects were observed. Therefore, a 1 mL prefilled syringe (PFS) was used. To ensure consistency in study design, vials were used for formulations 17 to 19. 20 (with 2 mL PFS) was included as a direct comparison with formulation 16 and was It was determined whether there was a significant contribution from the syringe.

[0064] Formulations 1-20 were prepared independently in the order specified. The materials for each formulation were The dialyzed solution was then diluted with an appropriate amount of The samples were diluted to the desired antibody concentrations with formulation buffer. Filter through a 2 μm filter and aseptically fill into the indicated container closure system.

[0065] The buffer excipient composition consisted of anhydrous citric acid (QD514N, lot number C490136), Sodium enoate dihydrate (QD517A, Lot No. C487212), Sodium chloride (QD515R, Lot No. C481616), Polysorbate 80 (QD513DV IE, Lot No. C457300).

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

[0067] Selected analyses and characterizations to determine the chemical and physical stability and properties of the formulation Methods include size exclusion chromatography (SEC) HPLC, imaging capillary isoelectric Spot electrophoresis iCIEF, reduced and non-reduced CESDS, HIAC, microflow imaging sizing (MFI), appearance, pH (USP <921> ) and protein concentration by UV absorbance Measure syringe function and test the device.

[0068] The samples were stored at four temperature conditions (5°C, 15°C, 25°C, and 35°C) with the syringe held horizontally. The vials were then stored upside down in a 200°C tube. This temperature range allowed for the Arrhenius kinetics to be Assuming that the activation energy for each analytical response variable can be estimated, This allowed early prediction of optimal formulation conditions, accelerating the drug development process. .

[0069] The sampling schedule for Formulations 1-14 is outlined in Table 2. The schedule is and 35°C at four time points over a three-month period, and at three time points for the other storage conditions. This sampling frequency allows the data to be applied to predictive models. After the three-month time point, we have enough information to calculate the activation energy (Ea) 3 Calculated using Arrhenius kinetics model, the results at accelerated temperature were predicted 5°C. The Ea value of 21.5 kcal / mol was used to determine the SEC (monomer, polymer, and post-monomer), iCIEF (main peak, total acidic and total basic The CE-SDS (antibody), as well as the non-reduced and reduced forms, were adapted. This adaptation was due in part to Based on what has been observed with other IgG4 antibodies. Time points indicated with X indicate that samples were By EC, iCIEF, reduced and non-reduced CE-SDS, pH, UV content, and appearance. These are the conditions analyzed. Tests by HIAC and MFI were performed less frequently. I did. [Table 2]

[0070] The sampling schedule for formulations 15 to 20 is shown in Table 3. These formulations are shown in the associated containers as formulations that can be evaluated in clinical trials in human patients. These formulations were then placed in a stopper system (containing a vial and a 2.25 mL syringe). To determine the stability of these potential drug products and the effect of the type of container closure on stability. It was evaluated to understand whether [Table 3]

[0071] Formulation Study 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-4d. The data for 35°C is displayed for 3 months. The data for 25°C is displayed for 6 months, and the data for 5°C is displayed for 10 months. Data are presented for up to 18 months (formulations 15 and 20 only). As temperature increases, The proportion of monomers has decreased. The maximum change in this data set is <2%. The percentage was 98.4% for samples tested at 5°C for 18 months, except for one result at 9 months. It remains above .6%.

[0072] The monomer and polymer values ​​(not shown) are inversely related to each other and are consistent with the results observed by SEC. The degradation was mainly due to the formation of soluble aggregates (polymers).

[0073] The predicted effect of each input variable on SEC monomer purity over 24 months at 5°C was The model is based on the results from data up to 1000 Hz. Using all four temperatures, Modified Arrhenius kinetics was modeled. To generate these predictions, The activation energy (Ea) in cal / mol was used. The percentage prediction was >98%, with the maximum predicted change being >1.3%, and the is stable across the design domain, as shown in Tables 4a-4d. This is in close agreement with the experimental data presented. This relationship is related to the probability of intermolecular interactions between antibodies. This may be a function of increased Studies have observed a slight increase in stability at lower pH conditions. Polysorbate 80 The concentration of HCl, the concentration of NaCl, and the container closure do not appear to have a significant effect. For two given factors (antibody concentration, pH), the best and worst positions in the design space The difference was <1.0%.

[0074] Figure 1 shows the relationship of target pH to antibody concentration for expected monomer purity. Contour plot of pH Target*Concentration Target The Prob>F Effect Test value for is 0.0130, and the interaction The effect of pH on purity was statistically significant at higher antibody concentrations. It becomes much stronger. [Table 4] [Table 5] [Table 6] [Table 7]

[0075] Formulation Study A: Results - Charge Heterogeneity - iCIEF a) Main peak ratio The percentage values ​​of the main peak of iCIEF at 5°C, 15°C, 25°C and 35°C are shown in Tables 5a to 5c. The initial values ​​for the main peak conditions are shown in Fig. d. The initial values ​​for the main peak conditions are 76.2 to 77. The main peak decomposition rate correlates with increasing temperature. Decomposition occurred over 18 months at 5°C. It has been kept to a minimum for the month, with the main peak remaining at over 75%.

[0076] An apparent Ea estimate of 21.5 kcal / mol was used for the prediction. Monthly peak predictions were made for the rate of change as a function of five input variables (up to 3 months). The effect of the five input variables was greatest for pH, but the difference was still <2%. The only two input variables that showed a statistically significant effect were pH and NaCl concentration. Increasing NaCl concentration appears to result in an increase in the proportion of the main peak. Optimal pH stability occurs at 5.5-6.0. Polysorbate 80, Mirikizumab Concentration and container closure showed no clear effect across the areas 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-6d. The total basic variant values ​​at 15°C, 25°C and 35°C are shown in Tables 6e to 6h.

[0078] The acidic variants increased over the 18 months of collected data, except at 35°C. Only slight changes in basic variants were observed over time. The trend of the peaks reflects the behavior of the main peak with increasing temperature, and the shape of the acidic variants. The acidic variant may result primarily from deamidation.

[0079] Changes in acidic and basic variants over 24 months, as well as the main peak data The effect of all input variables on the prediction is <1%. The largest effect comes from pH, but the trend The affinity of the variant differs between the two forms. The acidic variant is more stable at pH levels approaching 5.5. Although it appears that the proportion of basic variants is most stable at pH 6.0, These two different trends combine to make the pH environment of pH 5.5 to 6.0 the best 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 Study A: Results - CE-SDS Table 7a-CE-SDS reduced percent purity values ​​at 5°C, 15°C, 25°C and 35°C Shown in 7d.

[0081] For formulations 15, 16, 19, and 20, no significant changes were observed from the first to 3 months at 5°C. Increases in purity were observed, which may be due to variability between formulations. suggests that the changes at 35°C may be somewhat masked by the same systematic variations. Nonetheless, no significant changes were observed at 5°C for 18 months, and at 35°C for 18 months. After 3 months at 25°C, the overall change was <3%. At the high purity level, fragments and aggregates Both aggregates declined over the course of the study.

[0082] Prediction of percent purity change with reduced CE-SDS after 24 months storage at 5°C The measurements have a large uncertainty compared to the trends of the input variables. All predictions of purity over the study range of 24 months at 5°C were consistent with the initial The difference from the baseline value was <1%.

[0083] Table 7e-CE-SDS non-reduced percent purity values ​​at 5°C, 15°C, 25°C and 35°C Shown in 7h.

[0084] Similar to reduced CE-SDS, there was a clear increase at 5°C and 25°C, resulting in systematic variation. This increase appears to be due to the same systematic variation as the change at 35°C. Nonetheless, the 5°C No significant changes were observed over 18 months at 35°C, with an overall change of <2% after 3 months at 35°C. The results were similar to those of the reduced CE-SDS. The aggregates did not show any tendency during the course of the study. Although not shown, the fragments increased at 35°C in proportion to the decrease in purity. Among the input variables that affect percent purity by SDS are antibody concentration and container closure. The highest expected purity was at pH 5.5. The effect of force variables was <1.2% difference in 24-month prediction. [Table 20] [Table 21] [Table 22] [Table 23] [Table 24] [Table 25] [Table 26] [Table 27]

[0085] Formulation Study A: Results - Subvisible Particles a) HIAC Data from the HIAC insoluble particulate test at 5°C, 15°C, 25°C and 35°C are shown in Table 8a. Shown in ~8d.

[0086] Most formulations up to 3 months at 25°C have counts below 5000, which is The insoluble particulate count in prefilled syringes is within the acceptable range. 0, 11 and 13 are well above this count. These formulations are 150 mg / The five formulations had a target concentration of antibody of 1000 µg / mL. The next closest with counts below 2 µg / mL The formulation with the highest antibody concentration was formulation no. 16, which had an antibody concentration of 125 mg / mL. The highest values ​​are beyond the tolerance of the instrument, so they are not completely reliable. The insoluble microparticle counts at 150 mg / mL antibody concentration were also significantly higher than other runs at 5°C. The tendency is more pronounced at 25°C. and 13 were USP 10000-10000-10000 throughout the study, except for the 3-month 35°C time point. <788> Cowne Complies with packaging / container requirements. [Table 28] [Table 29] [Table 30] [Table 31]

[0087] b) MFI Data from the MFI insoluble particulate test at 5°C, 15°C, 25°C and 35°C are shown in Table 8e. Shown in 8g.

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

[0089] Formulation Study A: Conclusions The objective of Formulation Study A is to identify formulations suitable for administration to human patients and to evaluate the stability of the formulations. By systematically optimizing the key formulation parameters, the robustness of the formulation can be monitored. This study investigated the relationship between mirikizumab concentration, pH, NaCl, and polysorbate 80. The physical and chemical stability was evaluated as a function of time. Some formulations were stable for 24 months at 5°C. In terms of chemical and physical stability over the entire range studied, with all predicted changes being <5% The optimum stability by SEC is near pH 5.0 ( However, after 24 months at 5°C, the change over the entire pH range was <2%.) iCIEF results showed that the optimum stability is between pH 5.5 and pH 6.0. Considering these predictions, pH 5.5 is the most important factor in determining whether the This appears to be the optimal pH because it balances the observations from both assays. As the protein concentration increases, the proportion of monomers in the SEC decreases, and the proportion of non-reduced C E-SDS purity decreased, but the difference between 20 mg / mL and 150 mg / mL was <1%. No significant trends were observed with respect to changes in NaCl or polysorbate 80 concentration. Additionally, no significant effects were observed between types of container closure in this study. Insoluble particulate counts were higher in formulations targeting 150 mg / mL mirikizumab. Additional studies are being conducted to better understand the cause of this observation. Based on the results described in, the preferred formulation is 10 mM citrate buffer at pH 5.5. 150 mM NaCl, 0.03% w / v polysorbate 80 (for IV administration) For intravenous administration from a vial, the concentration is 0.05% w / v. The preferred concentration of 0 is 0.05% w / v.

[0090] Example 3: Formulation Study B the purpose The presence of sodium chloride and / or citrate may increase the potential for injection site discomfort. It is hypothesized that there may be a benefit to the use of morphine in the injection formulation. The objective of Formulation Study B is to provide a well-tolerated injection experience. The objective of this study was to identify alternative formulations of mirikizumab that are likely to provide a therapeutic benefit to patients with ≥ 18 months of pain after injection. In addition to improvement, other objectives of this study include: meet standard bioequivalence criteria and the safety benefits provided by the preferred formulation. These include maintaining and / or minimizing quality, manufacturability, and deliverability.

[0091] Formulation Research B: Research design and preparation of anti-IL-23p19 antibody pharmaceutical formulations Part I of the study consisted of the design and evaluation of a number of formulations, as shown in Table 9a. There are. [Table 35]

[0092] With the exception of formulation 1 (preferred formulation from formulation study A), samples were taken from drug substance lot EL01. 685-056-F-Fill (C1 Demo #2) with the matrix (Po The buffer-exchanged samples were prepared by buffer exchange into 100% ethanol (without resolvate 80). Concentrate and / or dilute the solution to 125 mg / mL mirikizumab with buffer and add polysorbate Polysorbate 80 (PS80) was added to a final concentration of 0.03% w / v. The formulation was then sterile filtered. The solution was filtered and loaded into a 2.25 mL syringe and the appropriate plunger was inserted. The samples were stored and removed from the chamber as shown in Table 9b. [Table 36]

[0093] The results from the evaluation of the formulations shown in Table 9a support the design of further formulations shown in Table 10a. and led to evaluation (Part II of the study). [Table 37]

[0094] With the exception of formulation 1 (preferred formulation from formulation study A), samples were taken from drug substance lot EL01. Buffer exchange of 685-056-F-Fill (C1 Demo #2) to 0.3M NaCl The mixture was then converted (initially to 0.3M NaCl) and then to the matrices listed in Table 10a. The buffer was then exchanged into 100% ethanol (without polysorbate 80) in the same manner as in Example 1. The first dialysis approach limits the amount of residual citrate in the final drug sample. The buffer-exchanged sample was concentrated to 125 mg / mL mirikizumab in buffer. and / or diluted and PS80 was added to a final concentration of 0.03% w / v. The agent was sterile filtered and loaded into a 2.25 mL syringe and the appropriate plunger was inserted. Representative drug samples were stored and removed from the chamber as shown in Table 10b. [Table 38]

[0095] The results from the evaluation of the formulations shown in Tables 9a and 10a were used to evaluate further formulations shown in Table 11a. This led to the design and evaluation of a novel anti-cancer drug (Part III of the study). [Table 39]

[0096] With the exception of formulation 1 (preferred formulation from formulation study A), the samples were Prepared by buffer exchange or dilution of drug substance into a matrix containing 0.1% polysorbate 80 Formulation 38 was first dialyzed against 0.3 M NaCl. The sample was then washed with buffer. Concentrate and / or dilute mirikizumab to 125 mg / mL and add PS80 to 0.03 The formulation was then sterile filtered and loaded into 2.25 mL syringes. The appropriate plunger was inserted. The final drug product samples were stored as shown in Table 11b. and removed from the chamber. [Table 40]

[0097] Formulation Study B: Part I Results - Purity Both SEC and both CE-SDS methods demonstrated that the purity of mirikizumab varies with time and temperature. All test formulations performed as well as or better than formulation 1. The histidine-free matrices (formulations 1, 21, and 29) were used in stability studies. The maximum decrease in purity was observed during the course of the reaction. The decrease in SEC monomer purity at 25°C and 40°C The results are shown in Table 12. The matrices without histidine (formulations 1, 21, and 29) The fastest decomposition rates were observed at 25°C and 40°C. Formulations 23 and 24 showed the highest decomposition rates under refrigerated conditions. The solubility was not maintained. [Table 41]

[0098] Formulation Study B: Part I Results - Aggregates SEC data showed a time- and temperature-dependent increase in mirikizumab aggregates. The formulation performed as well as or better than Formulation 1. Histidine-free matrix (Formulations 1, 21, and 29) showed the greatest increase in aggregates over the course of the stability study.25 The SEC aggregate formation rates at 40°C and 40°C are shown in Table 13. The sucrose (formulations 1, 21, and 29) showed the fastest degradation rates at 25°C and 40°C. . [Table 42]

[0099] Formulation Study B: Results of Part I - Fragments The CE-SDS reduced fragment values ​​are shown in Table 14a. The time and time-dependent values ​​for the mirikizumab fragments are shown in Table 14b. All formulations performed as well as or better than formulation 1. . [Table 43] [Table 44]

[0100] Formulation Study B: Part I Results - Charge Variants The icIEF main peak decomposition rates at 25°C and 40°C are shown in Table 15. The mirikizumab charge variant main peak showed a time- and temperature-dependent decrease This was mainly due to the formation of acidic variants. After 8 weeks at 40°C, A slight increase (approximately <2%) in the solubility of 100 mg / kg ... Formulations 1, 25, and 26, which contain sodium chloride, delayed the formation of charge variants. This appears to offer the advantage of [Table 45]

[0101] Formulation Study B: Part I Results - Insoluble Microparticles Insoluble particulate data showed that particle counts of ≥ 2 μm at 5°C indicated refrigerated solubility issues. With the exception of formulations 23 and 24, which were The samples stored at 25°C, and especially at 40°C, consistently had more grains. Some formulations stored at elevated temperatures produced particulate matter with increasing storage time. Some studies have shown a tendency for the number of cases to increase.

[0102] Formulation Study B: Part I Results-Viscosity and Glide Force Viscosity can be improved by using enhanced prefilled syringe (ePFS) or autoinjector (AI) delivery systems. Viscosity is an important attribute of a formulation when it is delivered by an AI device. The dose must be low enough for the chair to deliver the full dose, and in the case of ePFS, The viscosity of the formulations prepared for Formulation Study B-Part I is not very high. The concentrations (at 15°C and 20°C) are shown in Table 16. Mirikizumab concentrations were consistent across samples. Formulations 21-24 and 27-29 were significantly higher than formulation 1 (approximately 125 mg / mL). Formulations 25 and 26, which contain NaCl and have a lower pH, are 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 results of a formulation study. The formulations in Research Part B had two different glide force profiles: The results show that ionic species such as NaCl are removed from the formulation. Removal of the tungsten leads to an increase in glide force. This change in acceleration conditions ultimately leads to a decrease in glide force after long-term storage. This was due to the gradual loss of silicone oil in the syringe barrel. The inclusion of ionic species improved this loss of silicone oil and resulted in a consistent A formulation that maintains the desired glide force is obtained.

[0104] The viscosity of formulations 21-24 and 27-29 was significantly high, and the effect of the syringe glide force was Considering the effect of citrate buffer and NaCl excipients to reduce pain at the injection site Replacement of must be balanced against the impact on viscosity and glide force. Therefore, additional formulations were designed and evaluated in Formulation Study B: Part II.

[0105] Formulation Study B: Part II Results - Purity SEC, CE-SDS reduction for formulations 1 and 30-36 at 5°C, 25°C and 35°C The original and CE-SDS non-reduced monomer purity values ​​are shown in Tables 17a-17c. Both CE-SDS methods showed a time- and temperature-dependent decrease in mirikizumab purity. All test formulations performed equal to or better than formulation 1. 32 and 34 showed the least decrease in purity at elevated temperature during the course of the stability study. [Table 47] [Table 48] [Table 49]

[0106] Formulation Study B: Part II Results - Aggregates Table 1 shows the SEC total aggregate values ​​for formulations 1 and 30-36 at 5°C, 25°C and 35°C. 8. SEC showed a time- and temperature-dependent increase in mirikizumab aggregates. Formulations 30, 32, and 34 performed similarly to formulation 1. The results showed minimal increase in aggregates at 100°C. [Table 50]

[0107] Formulation Study B: Results of Part II - Fragments CE-SDS reduced and stoichiometric analysis of formulations 1 and 30-36 at 5°C, 25°C and 35°C The fragment values ​​of the CE-SDS non-reduced form are shown in Tables 19a and 19b. The S method showed a time- and temperature-dependent increase in mirikizumab fragments. All formulations showed performance equal to or better than that of formulation 1. [Table 51] [Table 52]

[0108] Formulation Study B: Part II Results - Charge Variants icIEF charge balance for formulations 1 and 30-36 at 5°C, 25°C and 35°C The anthraquinone peak values ​​are shown in Table 20a. Total acidic variant values ​​for 36 are shown in Table 20b. Formulations at 5°C, 25°C and 35°C Total basic variant values ​​for 1 and 30-36 are shown in Table 20c.

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

[0110] Formulation Study B: Part II Results - Viscosity Figure 1 shows the viscosity (at 15°C and 20°C) of the formulations prepared for Formulation Study B-Part II. 21. Mirikizumab concentrations are fairly constant across samples (approximately 125 mg / mL). This was observed in Part I of Formulation Study B, where removal or reduction of NaCl concentration The data in Table 21 show that lowering pH reduces viscosity. This shows that it is possible to [Table 56]

[0111] Data from Formulation Study B, Parts I and II were evaluated and favorable results were obtained in Formulation Study B, Part III. A suitable formulation was designed and evaluated.

[0112] Formulation Study B: Part III Results - Purity SEC, CE-SDS reduction for formulations 1 and 37-40 at 5°C, 25°C and 35°C The original and CE-SDS non-reduced monomer purity values ​​are shown in Tables 22a-22c. Both CE-SDS methods showed a time- and temperature-dependent decrease in mirikizumab purity. All test formulations performed equal to or better than Formulation 1. [Table 57] [Table 58] [Table 59]

[0113] Formulation Study B: Part III Results - Aggregates Table 2 shows the SEC total aggregate values ​​for formulations 1 and 37-40 at 5°C, 25°C and 35°C. 3. SEC showed a time- and temperature-dependent increase in mirikizumab aggregates. The formulation performed similarly to formulation 1. [Table 60]

[0114] Formulation Study B: Results of Part III - Fragments CE-SDS reduced and stoichiometric analysis of formulations 1 and 37-40 at 5°C, 25°C and 35°C The fragment values ​​of the CE-SDS non-reduced form are shown in Tables 24a and 24b. The S method showed a time- and temperature-dependent increase in mirikizumab fragments. All formulations showed performance equal to or better than that of formulation 1. [Table 61] [Table 62]

[0115] Formulation Study B: Part III Results - Charge Variants icIEF charge balance for formulations 1 and 37-40 at 5°C, 25°C and 35°C The anthraquinone peak values ​​are shown in Table 25a. Total acidic variant values ​​for 40 are shown in Table 25b. Formulations at 5°C, 25°C and 35°C Total basic variant values ​​for 1 and 37-40 are shown in Table 25c.

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

[0117] Formulation Study B: Conclusions The objective of Formulation Study B is to verify the superior stability properties of the preferred formulation identified in Formulation Study Part A. While maintaining the potential for The aim of this study was to identify a highly concentrated mirikizumab formulation that could reduce the discomfort of injection pain. Through the above series of studies, the preferred formulations were (i) mirikizumab, (ii) 5 mM (iii) 50 mM NaCl; (iv) 3.3% w / v Mannix buffer. (v) 0.03% w / v polysorbate 80, and the pH of the formulation was 5. It is .5.

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

[0119] Example 4: Clinical Study - Evaluation of Mirikizumab Formulations in Healthy Subjects overview Preferred formulation from formulation study A (mirikizumab, 10 mM citrate buffer, 150 mM M NaCl, 0.05% w / v polysorbate 80, pH 5.5) (hereinafter referred to as formulation A- P) and the preferred formulation from formulation study B (mirikizumab, 5 mM histidine buffer Buffer solution: 50 mM NaCl, 3.3% w / v mannitol, 0.03% w / v polyisobutene. The efficacy and safety of the formulation (BP) was investigated in clinical trials in human patients and the relative and the overall bioavailability and injection site reaction profile, particularly the injection site pain profile. The files were compared.

[0120] This study was a phase 1, subject-blinded, investigator-blinded, two-arm, randomized, single-dose, healthy This is a parallel design study in eligible subjects. Eligible subjects will be admitted to the Clinical Research Unit (CRU) on Day 1. ) and were randomized 1:1 to one of two possible treatments, The assigned code was used to identify the three possible injection sites within the treatment (arm, thigh, or abdomen). Subjects were randomized 1:1:1 to either the primary or secondary control group at 4:00 p.m. on Day 1, at the discretion of the investigator. After completing the interim safety evaluation, patients were allowed to leave the CRU and were administered the drug for up to 12 weeks after treatment. Patients will be seen at regular outpatient visits for pharmacokinetic sampling and safety evaluations. Safety and tolerability were assessed by clinical laboratory tests, vital sign measurements, adverse event records, and physical examinations. was assessed by physical examination.

[0121] Formulations AP and BP were designed to deliver 100 mg of mirikizumab. The doses were prefilled, disposable, manual syringes containing 1 mL of each drug. The study period was 16 weeks, including a 4-week screening period, intervention on day 1, and follow-up. The study included a 12-week post-treatment evaluation period with a randomization schedule. Therefore, subjects received 2 x 1 mL subcutaneous (SC) injections of PFS in the arm, thigh, or abdomen.

[0122] the purpose The specific objectives of this study are: i) A single 200mg SC dose of mirikizumab formulation BP compared with mirikizumab formulation AP To evaluate the relative bioavailability of the doses (2 x 1 mL PFS injections) -Endpoint is C max , AUC(0~∞), and AUC(0~t last ) (AUC(0~∞) = area under the concentration versus time curve from time 0 to infinity; AUC(0~t l ast ) = area under the concentration versus time curve from time zero to time t, where t is the measurable concentration (Cmax = maximum observed drug concentration). ii) A single 200mg dose of mirikizumab formulation BP compared with mirikizumab formulation AP To evaluate the safety and tolerability of the C dose (2 × 1 mL PFS injections); -Endpoints were treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). SAE). iii) To assess injection site reactions (ISR), including pain -Endpoints were severity, duration, and severity of erythema, bruising, induration, pain, pruritus, and edema. The subjects were the time and location of injection, as well as VAS pain scores and bleeding immediately after injection.

[0123] method Subjects were apparently healthy men or women aged 18 to 75 years who were obese at screening. The fullness index had to be between 18.0 and 32.0 kg / m2 (both ends included). Of the 60 subjects enrolled, 19 were men and 41 were women. Their ages ranged from 19 to 74.

[0124] Mirikizumab AP and Mirikizumab BP are delivered in the form of 100 mg of Mirikizumab. Supplied as a 1 mL, single-dose, pre-filled, disposable manual syringe designed to deliver It was done.

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

[0126] Subjects randomized to arm or thigh injection sites included: : (a) the first injection was administered in the left limb, and (b) A second injection is administered into the corresponding (contralateral) right limb.

[0127] Subjects randomized to the abdominal injection site included: (a) the first injection was administered in the left lower quadrant; and (b) The second injection is administered in the right lower quadrant. The second injection is administered 20 (± 2) It needs to be administered after 2 minutes.

[0128] Outpatient visits were on days 3, 5, 8, 11, 15, 22, 29, 43, 57, 71, and 85. Pharmacokinetic (PK) samples were collected on days 1 (pre-dose), 3, 5, 8, 11, 15, and 20. Data were collected on days 22, 29, 43, 57, 71, and 85. AEs and concomitant medications were assessed at -1 , 1, 3, 5, 8, 11, 15, 22, 29, 36, 43, 50, 57, 64, 71, and Safety assessment telephone calls were conducted on days 36, 50, and 64. The injection site was assessed for erythema, induration, pruritus, edema, pain (initial injection site only), and bruising. Site evaluations were 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 Calculations were performed using noncompartmental methods using nlin version 8.1. [Table 66]

[0130] Arithmetic mean concentration-time profiles were plotted using nominal time points per protocol. The average concentration was calculated based on the data obtained for 2 / 3 of the individual data points within the sampling window (±10%). ), were plotted at that time point.

[0131] Statistical analysis of PK parameters between mirikizumab formulation AP and mirikizumab formulation BP Log-transformed C max , AUC(0~t last ), and AUC(0~∞) parameters Data were evaluated using a linear fixed-effects model with fixed effects for treatment formulation and injection site location. The difference between the AP and BP formulations was back transformed to obtain the geometric mean squared ... The LS mean ratios and corresponding 90% CIs are presented. Parameters varied by therapeutic formulation. It was stopped.

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

[0133] Overall, Cma was significantly higher after administration of mirikizumab AP and mirikizumab BP. No statistically significant differences were observed in x, AUC(0 ∞), and AUC(0 tlast). No significant difference was observed, and the 90% CI for the ratio of geometric LS means includes a value of 1 (Table 27). [Table 68]

[0134] There were no statistically significant differences in median tmax of mirikizumab between the formulations. The serum concentration of mirikizumab decreased after tmax, and the mirikizumab formulation AP and mirikizumab formulation The geometric mean t values ​​after administration of BP were similar, 11.5 days (276 hours), respectively. ) and 11.8 days (283 hours). AUC(0~tlast), AUC(0 ∞ ), and the intersubject variability (CV%) estimates of Cmax were moderate to high for the mirikizumab formulation AP. The median response rate was 48% to 56% for the mirikizumab BP and 45% to 46% for the mirikizumab BP.

[0135] (b) Safety analysis TEAE The incidence of all TEAEs reported during the study was The results were similar among subjects receiving mab BP (Table 28). Injection site data were prospective. events related to the injection site were recorded as study endpoints related to ISR. and was not recorded as an AE unless the event was qualified as an SAE. [Table 69]

[0136] Overall, 3 (10.0%) subjects who received mirikizumab-AP had a total Five TEAEs were reported in 3 patients (10.0%) who received mirikizumab BP compared with 16 patients (10.0%) who received mirikizumab BP. Subjects reported a total of seven TEAEs (Tables 29a and 29b). The following TEAEs were reported: a) Mirikizumab-based AP (4 events in 2 [6.7%] subjects) - One subject had a single event of mild nausea, moderate vomiting, and moderate headache. Ta. - 1 subject had a single event of mild nausea. b) Mirikizumab BP (2 events in 1 subject [3.3%]) - 1 subject had a single event of mild nausea and mild headache.

[0137] All except one TEAE, moderate heel fracture, thought to be related to another medical condition TEAEs resolved by the end of the study, with the majority resolving without treatment. The two TEAEs of headache required paracetamol, and the heel fracture required apixaba. The patient required methamphetamine, hydrocodone, and paracetamol. [Table 70] [Table 71]

[0138] Deaths, SAEs, and Discontinuations No deaths occurred during the study. No SAEs occurred during the study. No AEs occurred during the study. There were no interruptions.

[0139] Injection site evaluation Injection site bleeding occurred in 3 (10.0%) subjects receiving mirikizumab AP. 2 in the arm and 1 in the abdomen) and 3 (10.0%) who received mirikizumab BP. reported in subjects (two on the arm, one on the thigh).

[0140] Each subject's initial injection site was prospectively evaluated for ISR at the time points listed above. The site was assessed for erythema, edema, induration, pruritus, and pain, and any category was scored at each time point. Each positive reaction at the first or second injection site was counted as an event. Spontaneously reported ISRs were evaluated as described above.

[0141] Injection site reaction data are summarized in Tables 30a and 30b, which include planned prospective evaluations. Data from titers and one subject receiving formulation AP (arm) at each injection site on Day 9 It includes an evaluation of spontaneously reported ISRs. [Table 72-1] [Table 72-2] [Table 73-1] [Table 73-2]

[0142] Overall, 23 (76.7%) subjects (7 reported 47 ISRs (1 in the arm, 8 in the thigh, and 8 in the abdomen) and Fifteen subjects (50.0%) received the drug (six in the arm, six in the thigh, and six in the abdomen) for 20 minutes. The number of ISRs was 100% for mirikizumab formulation AP or 100% for mirikizumab formulation B- The reported IS The majority of Rs consisted of mild reactions. Most responses (82.1%) occurred within 30 days of treatment administration. It occurred within minutes.

[0143] Pain by classification During the ISR assessment, subjects were asked whether they had any pain at the injection site ("Yes / No"). After administration of the mirikizumab formulation AP, 22 (73.3%) subjects (6 in the arm, 8 in the left arm) Twenty-five events of pain were reported in 20 patients (thigh pain in 10 patients and abdominal pain in 8 patients). -After administration of P, 11 (36.7%) subjects (4 in the arm, 3 in the thigh, and 4 in the abdomen) Thus, 13 events of pain were reported.

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

[0145] The mean VAS pain score within one minute of administration was 26. 1 and 12.6 after administration of mirikizumab BP. This difference was statistically significant. and the 90% CI for the difference in geometric LS means does not include the value of 1 (Table 32). [Table 76]

[0146] At 5 minutes after administration, the mean VAS pain score was 6.0 after administration of the mirikizumab formulation AP. and after administration of mirikizumab BP it was 1.9.

[0147] Similar findings were observed when the thigh injection sites were examined separately, but the mirikizumab formulation Mean VAS pain scores at the injection site in the arm and abdomen between AP and mirikizumab BP There were no statistically significant differences in the core. The majority of pain reported was mild in severity. Severe pain was reported by two subjects receiving mirikizumab AP (thigh). Only reported.

[0148] Sequence Listing Heavy Chain CDRs Sequence number 1 GYKFTRYVMH Sequence number 2 YINPYNDGTNYNEKFKG SEQ ID NO:3 ARNWDTGL

[0149] Light Chain CDRs SEQ ID NO: 4 KASDHILKFLT SEQ ID NO:5 GATSLET Sequence number 6 QMYWSTPFT

[0150] Heavy chain variable region SEQ ID NO:7 QVQLVQSGAEVKKPGSSVKVSCKASGYKFTRYVMHWVRQA PGQGLEWMGYINPYNDGTNYNEKFKGRVTITADKSTSTAY MELSSLRSEDTAVYYCARNWDTGLWGQGTTVTVSS

[0151] Light chain variable region SEQ ID NO:8 DIQMTQSPSSLSASVGDRVTITCKASDHILKFLTWYQQKP GKAPKLLIYGATSLETGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCQMYWSTPFTFGGGTKVEIK

[0152] Complete heavy chain SEQ ID NO:9 QVQLVQSGAEVKKPGSSVKVSCKASGYKFTRYVMHWVRQA PGQGLEWMGYINPYNDGTNYNEKFKGRVTITADKSTSTAY MELSSLRSEDTAVYYCARNWDTGLWGQGTTVTVSSASTKG PSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV DHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPP KPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPSSIEKTISKAKGQPREPQVYTLPSQEEMTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSL G

[0153] Complete light chain SEQ ID NO:10 DIQMTQSPSSLSASVGDRVTITCKASDHILKFLTWYQQKP GKAPKLLIYGATSLETGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCQMYWSTPFTFGGGGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSSTLTLSKADYEKHKVYACEVTHQG LSSPVTKSFNRGEC

Claims

1. 1. A pharmaceutical formulation comprising: (i) 50 mg / mL to 150 mg / mL of an IL-23p19 antibody; (ii) 8 mM to 12 mM citrate buffer; (iii) 100-200 mM sodium chloride (NaCl); (iv) 0.01% w / v to 0.05% w / v of a surfactant; the pH of the formulation is 5.0 to 6.0; The anti-IL-23p19 antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR) 8, and the amino acid sequence of the LCVR is SEQ ID NO: 8, and the amino acid sequence of the HCVR is A pharmaceutical formulation, wherein the sequence is SEQ ID NO:

7.

2. The anti-IL-23p19 antibody comprises a light chain (LC) and a heavy chain (HC), the amino acid sequence of said HC is SEQ ID NO: 9, The pharmaceutical formulation according to claim 1.

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

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

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

6. 6. The method of claim 1, wherein the concentration of the anti-IL-23p19 antibody is about 100 mg / mL.

2. The pharmaceutical formulation according to any one of claims 1 to 11.

7. 6. The method of claim 1, wherein the concentration of the anti-IL-23p19 antibody is about 125 mg / mL.

2. The pharmaceutical formulation according to any one of claims 1 to 11.

8. The method according to any one of claims 1 to 7, wherein the concentration of the citrate buffer is about 10 mM. A pharmaceutical composition comprising:

9. 9. The method according to claim 1, wherein the citrate buffer is a sodium citrate buffer. Item 1. The pharmaceutical preparation according to item 1.

10. 10. The method according to claim 1, wherein the surfactant is polysorbate 20 or polysorbate 80.

2. The pharmaceutical formulation according to any one of claims 1 to 11.

11. 11. The pharmaceutical formulation of claim 10, wherein the surfactant is polysorbate 80.

12. 12. Any of claims 1 to 11, wherein the concentration of the surfactant is about 0.03% (w / v). The pharmaceutical formulation according to claim 1.

13. The medicament according to any one of claims 1 to 12, wherein the concentration of NaCl is about 150 mM. formulation.

14. The medicament according to any one of claims 1 to 13, wherein the pH of the formulation is about 5.

5. formulation.

15. The formulation comprises: (i) 100 mg / mL or 125 mg / mL mirikizumab; (ii) 10 mM sodium citrate buffer; (iii) 150 mM NaCl; (iv) 0.03% w / v polysorbate 80, 4. The pharmaceutical formulation of claim 3, wherein the pH of the formulation is about 5.

5.

16. 16. The pharmaceutical formulation of claim 15, wherein the formulation comprises 100 mg / mL mirikizumab.

17. 16. The pharmaceutical formulation of claim 15, wherein the formulation comprises 125 mg / mL mirikizumab.

18. 1. A pharmaceutical formulation comprising: (i) 50 mg / mL to 150 mg / mL of an IL-23p19 antibody; (ii) a 3 mM to 12 mM histidine buffer; and (iii) 25 to 75 mM NaCl; and (iv) 2-5% w / v of an isotonicity agent; and (iv) 0.01% w / v to 0.05% w / v of a surfactant; the pH of the formulation is 5.0 to 6.0; The anti-IL-23p19 antibody contains a light chain variable region (LCVR) and a heavy chain variable region (HCVR). The amino acid sequence of the LCVR is SEQ ID NO: 8, and the amino acid sequence of the HCVR is 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 heavy chain is SEQ ID NO: 9, 20. The pharmaceutical formulation of claim 18.

20. The pharmaceutical composition according to claim 18 or 19, wherein the anti-IL-23p19 antibody is mirikizumab. formulation.

21. The concentration of the anti-IL-23p19 antibody is about 75 mg / mL to about 150 mg / mL. The pharmaceutical formulation according to any one of claims 18 to 20.

22. The concentration of the anti-IL-23p19 antibody is about 100 mg / mL to about 150 mg / mL The pharmaceutical formulation according to any one of claims 18 to 21,

23. 18 to 20. The method according to claim 17, wherein the concentration of the anti-IL-23p19 antibody is about 100 mg / mL.

23. The pharmaceutical formulation according to any one of claims 22.

24. 18 to 20. The method of claim 17, wherein the concentration of the anti-IL-23p19 antibody is about 125 mg / mL.

23. The pharmaceutical formulation according to any one of claims 22.

25. The method according to any one of claims 18 to 24, wherein the concentration of the histidine buffer is about 5 mM. The pharmaceutical composition described.

26. The medicament according to any one of claims 18 to 25, wherein the isotonicity agent is mannitol. composition.

27. 27. The pharmaceutical composition of claim 26, wherein the concentration of mannitol is 3.3% w / v.

28. The surfactant is polysorbate 20 or polysorbate 80.

28. The pharmaceutical formulation according to any one of claims 27.

29. 30. The pharmaceutical formulation of claim 28, wherein the surfactant is polysorbate 80.

30. 30. The method according to claim 18, wherein the concentration of the surfactant is about 0.03% (w / v).

3. The pharmaceutical formulation according to claim 1 .

31. The medicament according to any one of claims 18 to 30, wherein the concentration of NaCl is about 50 mM. formulation.

32. The pharmaceutical composition according to any one of claims 18 to 31, wherein the pH of the formulation is about 5.

5. Drug preparations.

33. (i) 100 mg / mL or 125 mg / mL mirikizumab; (ii) 5 mM histidine buffer; (iii) 50 mM NaCl; (iv) 3.3% w / v mannitol; (v) 0.03% w / v of polysorbate 80, 21. The pharmaceutical formulation of claim 20, wherein the pH of the formulation is 5.

5.

34. 33. The pharmaceutical formulation of claim 32, wherein the formulation comprises 100 mg / mL mirikizumab.

35. 33. The pharmaceutical formulation of claim 32, wherein the formulation comprises 125 mg / mL mirikizumab.

36. Treating and / or Treating Psoriasis, Ulcerative Colitis, Crohn's Disease, Psoriatic Arthritis and / or Ankylosing Spondylitis or a method for preventing said disease, said method comprising administering to said subject a therapeutically effective amount of a compound according to any one of claims 1 to 35. A method comprising administering to a patient the pharmaceutical formulation described.

37. Treatment and / or management of psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis and / or ankylosing spondylitis A pharmaceutical formulation according to any one of claims 1 to 35 for use in the treatment, prevention or prophylaxis of a disease.

38. For use in the treatment of psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis and / or ankylosing spondylitis Use of a pharmaceutical formulation according to any one of claims 1 to 35 in the manufacture of a medicament for For.

39. Upon SC, IP and / or IM administration of a pharmaceutical formulation comprising an anti-IL-23p19 antibody, or 18. A method for reducing injection-associated pain experienced by a patient immediately after injection, said method comprising: 35 to a patient, comprising administering to said patient a pharmaceutical formulation according to any one of claims 1 to 35, The method of claim 1, wherein the injection patch provides a therapeutically favorable level of injection-associated pain.

40. The therapeutically preferred level of injection-associated pain is a VAS score of less than 30 mm or less than 20 mm.

40. The method of claim 39, comprising a score.

41. Improved methods for administering anti-IL-23p19 antibodies SC to patients in need thereof The method, wherein the improvement is achieved by administering a pharmaceutical formulation comprising an anti-IL-23p19 antibody to an injection site via SC administration. and reducing pain associated with pain, said method comprising administering a pharmaceutical formulation according to any one of claims 18 to 35. administering to a subject in need of an injection, the administering step providing an improved level of injection-associated pain; and / or improved methods of providing a therapeutically favorable level of injection-associated pain.

42. The therapeutically preferred level of injection-associated pain is a VAS score of less than 30 mm or less than 20 mm.

42. An improved method for SC administration of an anti-IL-23p19 antibody according to claim 41, comprising: How it was done.

43. At least one of the following conditions: psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis, and ankylosing spondylitis and an improved method of treating another disease, said improvement comprising an anti-IL-23p19 antibody. The method comprises reducing injection-associated pain upon SC administration of the pharmaceutical formulation, the method comprising any one of claims 18 to 35.

20. The method of claim 19, further comprising administering to said patient a pharmaceutical formulation ... and / or providing a therapeutically favorable level of injection-associated pain. An improved method for

44. The therapeutically preferred level of injection-associated pain is a VAS score of less than 30 mm or less than 20 mm.

44. The method of claim 43, comprising administering to the patient a psoriasis, ulcerative colitis, Crohn's disease, psoriatic arthritis, or and ankylosing spondylitis.

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