Liquid formulations comprising golimumab and poloxamer 188

Abstract

An aqueous liquid formulation having improved stability includes golimumab and a poloxamer and preferably a histidine buffer, sugar and / or sugar alcohol. Uses and methods of use of the aqueous liquid formulation for treating or preventing rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, moderately to severely active ulcerative colitis, or active polyarticular juvenile idiopathic arthritis.

Description

LIQUID FORMULATIONS COMPRISING GOLIMUMAB AND POLOXAMER 188FIELD

[0001] The present invention relates to liquid formulations comprising a protein and methods of preparing same, which are useful in, for example, therapeutic applications. However, it will be appreciated that the invention is not limited to this particular field of use. More particularly, the invention relates to liquid formulations comprising an anti-TNFa antibody, in particular golimumab, a histidine buffer, and a poloxamer.BACKGROUND

[0002] Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

[0003] Golimumab is a fully human monoclonal IgG antibody that binds with high affinity and specificity to both soluble and transmembrane forms of tumor necrosis factor alpha (TNFa). In the US, there are two commercial golimumab products, Simponi® and Simponi Aria® (Janssen Biotech, Inc.), which contain 100 mg / ml and 12.5 mg / mL of golimumab, respectively. Simponi® and Simponi Aria® are both parenteral formulations suitable for administration by subcutaneous (SC) injection or intravenous (IV) injection, respectively.

[0004] The subcutaneous golimumab product, Simponi®, is indicated (in the US) for treatment of: moderate to severe rheumatoid arthritis (RA) in combination with methotrexate; active psoriatic arthritis (PsA), alone or in combination with methotrexate; active ankylosing spondylitis (AS); and moderately to severely active ulcerative colitis (UC). For RA, PsA and AS, the dosing schedule for Simponi® is 50 mg given as a subcutaneous injection once a month. For UC, the dosing schedule for Simponi® is three starter subcutaneous injections (two 100-mg injections on the first day of treatment, followed by one 100-mg injection two weeks later), then one 100-mg injection every four weeks afterward. The subcutaneous injection of Simponi® may be self-administered by the patient.

[0005] The intravenous golimumab product, Simponi Aria®, is indicated (in the US) for treatment of: moderate to severe rheumatoid arthritis (RA) in adults, in combination withmethotrexate; active psoriatic arthritis (PsA) in people two years of age and older; active ankylosing spondylitis (AS) in adults; and active polyarticular juvenile idiopathic arthritis (pJIA) in people two years of age and older. Simponi Aria® is administered by intravenous injection (infusion), typically four weeks after the first treatment, and every eight weeks after that.

[0006] In Europe, Simponi® is approved for rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), psoriatic arthritis (PsA), axial spondyloarthritis (AS) and ulcerative colitis (UC). The RA, PsA, AS and UC as 50 mg or 100 mg pens or PFS and as a pre-filled variable dose pen (45 mg / 0.45 mL) delivering 0.1 - 0.45 mL in increments of 0.05 mL for JIA.

[0007] Each 1 mL dose of Simponi® contains 100 mg golimumab, 41 mg sorbitol, 0.87 mg L-histidine, and 0.15 mg polysorbate 80, pH adjusted to pH 5.5 in water for injection.Each 1 mL dose of Simponi Aria® contains 12.5 mg golimumab, 45 mg sorbitol, 0.285 mg L- histidine, 1.605 mg L-histidine monohydrochloride monohydrate, and 0.15 mg polysorbate 80, pH adjusted to pH 5.5 in water for injection.

[0008] Product stability is an essential quality attribute for pharmaceutical formulations that is important for both efficacy and safety and is a regulatory requirement for approval by health authorities. It refers to the retention of chemical, physical and biological properties and characteristics after manufacture, formulation, transportation, storage, and administration. Stability can be particularly challenging for biologies which are prone to aggregation, degradation, oxidation, isomerization, adsorption, and denaturation, which can be accelerated by environmental stresses such as agitation, and variations in pH and temperature.

[0009] Surfactants perform a vital role in stabilizing biologies. This role can include protection from interfacial stresses such as interface-induced aggregation, precipitation and adsorption from exposure to a liquid-air interface and contact with purification and other processing, storage, and delivery equipment.

[0010] It is an object of the present invention to provide stable formulations of golimumab.SUMMARY

[0011] Polyoxyethylene (PEO) surfactants, including polysorbates, have been identified as promising surfactants to use in biological formulations. However, the present inventors have found that, surprisingly, polysorbates can be unstable and were seemingly the source of particulates and cloudiness during identification and evaluation of golimumab formulations, especially when co-formulated with a histidine buffer. The present inventors have discovered that stable golimumab formulations can be made with a poloxamer surfactant, optionally in combination with a histidine buffer.

[0012] The present invention relates to liquid formulations comprising an anti-TNFa antibody and more specifically stable liquid formulations comprising golimumab.

[0013] In a first aspect, the invention provides an aqueous liquid formulation comprising: from 5 to 200 mg / mL of golimumab; from 20 to 50 mg / mL of a sugar and / or a sugar alcohol; from 0.6 to 1.6 mg / mL of a histidine buffer; and from 0.005 to 0.1 % (w / v) of a poloxamer; wherein the liquid formulation has a pH of from 5.0 to 6.0.

[0014] In a second aspect, the invention provides an aqueous liquid formulation consisting essentially of: from 5 to 200 mg / mL of golimumab; from 20 to 50 mg / mL of a sugar and / or a sugar alcohol; from 0.6 to 1.6 mg / mL of a histidine buffer; from 0.005 to 0.1 % (w / v) of a poloxamer; and water; wherein the liquid formulation has a pH of from 5.0 to 6.0.

[0015] In a third aspect, the invention provides an aqueous liquid formulation comprising: about 12.5 mg / mL golimumab or about 100 mg / mL golimumab; about 40 to 50 mg / mL sorbitol; about 0.8 to 1.5 mg / mL of a histidine buffer; and about 0.015 % (w / v) of a poloxamer; wherein the liquid formulation has a pH from about 5.0 to about 6.0.

[0016] In a fourth aspect, the invention provides an aqueous liquid formulation comprising: about 12.5 mg / mL golimumab or about 100 mg / mL golimumab; about 41 to 45 mg / mL sorbitol; about 0.8 to 1.5 mg / mL of a histidine buffer; and about 0.015 % (w / v) of poloxamer 188; wherein the liquid formulation has a pH of about 5.5.

[0017] In a fifth aspect, the invention provides an aqueous liquid formulation comprising:(1) about 12.5 mg / mL golimumab; and(2) one of the following: a) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2; b) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; c) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8; d) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.2; e) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.5; f) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.8; g) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.2; h) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.5; i) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.8; j) about 45 mg / mL sorbitol, about 1.30 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2;k) about 45 mg / mL sorbitol, about 1.30 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; l) about 45 mg / mL sorbitol, about 1.30 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8; m) about 45 mg / mL sorbitol, about 1.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2; n) about 45 mg / mL sorbitol, about 1.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; or o) about 45 mg / mL sorbitol, about 1.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8.

[0018] In a sixth aspect, the invention provides an aqueous liquid formulation comprising:(1) about 100 mg / ml golimumab; and(2) one of the following: a) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2; b) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; c) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8; d) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.2; e) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.5; f) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.8; g) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.2; h) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.5;i) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.8; j) about 41 mg / mL sorbitol, about 0.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2; k) about 41 mg / mL sorbitol, about 0.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; l) about 41 mg / mL sorbitol, about 0.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8; m) about 41 mg / mL sorbitol, about 1.00 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2; n) about 41 mg / mL sorbitol, about 1.00 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; or o) about 41 mg / mL sorbitol, about 1.00 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8.

[0019] In a seventh aspect, the invention provides an aqueous liquid formulation comprising golimumab and a surfactant. The formulation exhibits a loss of surfactant concentration of 40% or less when stored for one month at 25°C and / or a loss of surfactant concentration of 50% or less when stored for one month at 40°C.

[0020] In an eighth aspect, the invention provides an aqueous liquid formulation comprising golimumab and a poloxamer.

[0021] In a ninth aspect, the invention provides a golimumab formulation for parenteral injection, comprising a sugar and / or a sugar alcohol, a buffer, and a surfactant, where the surfactant is a poloxamer.

[0022] In a tenth aspect, the invention provides a liquid formulation of the invention for use in treating or preventing rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, active ulcerative colitis, or active polyarticular juvenile idiopathic arthritis.

[0023] In an eleventh aspect, the invention provides a method of treating or preventing rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, active ulcerative colitis, or active polyarticular juvenile idiopathic arthritis in a subject, comprising administering to the subject a liquid formulation of the invention.

[0024] In a twelfth aspect, the invention provides use of a liquid formulation of the invention in the manufacture of a medicament for treating or preventing rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, active ulcerative colitis, or active polyarticular juvenile idiopathic arthritis.

[0025] In a thirteenth aspect, the invention provides a liquid formulation of the invention for use in treating or preventing rheumatoid arthritis or active psoriatic arthritis, in combination with methotrexate.

[0026] In a fourteenth aspect, the invention provides a method of treating or preventing rheumatoid arthritis or active psoriatic arthritis, in combination with administration of methotrexate.

[0027] In a fifteenth aspect, the invention provides use of a liquid formulation of the invention in the manufacture of a medicament for treating or preventing rheumatoid arthritis or active psoriatic arthritis, in combination with methotrexate.

[0028] The following features may be used alone or in combination with the first through fifteenth aspects above.BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Preferred embodiments of the invention will now be described, by way of example only, with reference to the accompanying drawings in which:

[0030] FIG. 1 shows the concentration of surfactant (polysorbate 80) over time under different storage conditions, for several comparative formulations.

[0031] FIG. 2 shows the concentration of surfactant (poloxamer 188) over time under different storage conditions, for several inventive formulations.DEFINITIONS

[0032] In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one having ordinary skill in the art to which the invention pertains.

[0033] Unless the context clearly requires otherwise, throughout the description and the claims, the words ‘comprise’, ‘comprising’, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of ‘including, but not limited to’.

[0034] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein are to be understood as modified in all instances by the term ‘about’ .

[0035] In what follows, unless otherwise indicated, ‘%’ will mean ‘% (w / v)’, calculated as [100 x nix / vtot], where mxis the mass of component x in g and vtot is the total volume of all components in mL.

[0036] The term ‘substantially’ as used herein shall mean comprising more than 50% by weight, where relevant, unless otherwise indicated.

[0037] The recitation of a numerical range using endpoints includes the endpoints and all numbers subsumed within that range (e.g., from 1 to 10 includes 1, 1.5, 2, 5, 5.75, 7.1, 8.5, 9, 10, etc.).

[0038] As used herein and in the claims, the singular form of “a”, “an”, and “the” may include the plural references unless the context clearly dictates otherwise.

[0039] As used herein, the terms “about” and “approximately” are used synonymously. Both terms are meant to cover any normal fluctuations or variations understood by those skilled in the art. In some embodiments, “about” and “approximately” refer to ± 10% of the reference value, or ± 5%, or ± 2%, or ± 1%, or ± 0.1% of the reference value.

[0040] As used herein, the term “an effective amount” or “therapeutically effective amount” refers to an amount of golimumab that a will elicit a biological or medical response in a subject, for example, inhibiting a disease and its progression (for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder, including arresting further development of the pathology and / or symptomatology of the disease); and / or ameliorating a disease (for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition ordisorder, such as reducing the pathology, reversing the pathology and / or symptomatology of the disease).

[0041] As used herein, the phrase “treating”, “treat”, and “treatment” and the like includes inhibiting a disease and / or its progression (for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder, including arresting further development of the pathology and / or symptomatology of the disease); and / or ameliorating a disease (for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder, such as reducing the pathology, reversing the pathology and / or symptomatology of the disease).

[0042] As used herein, the term “preventing”, “prevent”, and “prevention” and the like, includes the prevention of the recurrence and / or the onset of one or more symptoms of a disorder or disease, especially in a subject who has been analyzed to be susceptible or likely to develop the disease.

[0043] As used herein, the phrase “a subject in need thereof’ means that the subject has been identified as having a need for the herein described treatment.

[0044] As used herein, the term “subject” and “patient” are interchangeable and may be taken to mean any living organism, which may be treated with compounds of the present invention. As such, the terms “patient” and “subject” may include a human adult or child.DETAILED DESCRIPTION

[0045] All references cited herein, including patents, patent applications, publications, and databases, are hereby incorporated by reference in their entireties, whether previously specifically incorporated or not.

[0046] The skilled addressee will understand that the liquid formulations described herein comprise the embodiments and features as disclosed herein as well as all combinations and / or permutations of the disclosed embodiments and features.

[0047] The present inventors surprisingly found that golimumab formulations containing a poloxamer instead of a polysorbate as a surfactant had improved stability (in particular surfactant stability) over extended periods of time, especially at somewhat elevated temperatures. This enables the production of golimumab formulations that are stable overperiods of time during which a treatment is to be administered. The inventors believe that surfactant stability in golimumab formulations may be positively influenced by the use of a poloxamer surfactant together with a histidine buffer. Furthermore, surfactant stability of the golimumab formations described herein, may result in part from increased resistance to oxidation and hydrolysis, both enzymatically from residual host cell proteins (e.g., lipases) which are not removed during clarification and purification and / or histidine (e.g, in combination with trace metals).

[0048] Described herein is an aqueous liquid formulation comprising golimumab and a surfactant. The formulation preferably comprises: from 5 to 200 mg / mL of golimumab; from 20 to 50 mg / mL of a sugar and / or a sugar alcohol; from 0.6 to 1.6 mg / mL of a histidine buffer; and from 0.005 to 0.1 % (w / v) of a surfactant that is a poloxamer; wherein the liquid formulation has a pH of from 5.0 to 6.0. In one embodiment, described herein is an aqueous liquid formulation consisting essentially of: from 5 to 200 mg / mL of golimumab; from 20 to 50 mg / mL of a sugar and / or a sugar alcohol; from 0.6 to 1.6 mg / mL of a histidine buffer; and from 0.005 to 0.1 % (w / v) of a poloxamer; wherein the liquid formulation has a pH of from 5.0 to 6.0. In another embodiment, described herein is a liquid formulation comprising: about 12.5 mg / mL golimumab or about 100 mg / mL golimumab; about 40 to 50 mg / mL sorbitol; about 0.8 to 1.5 mg / mL of a histidine buffer; and about 0.015 % (w / v) of a poloxamer; wherein the liquid formulation has a pH from about 5.0 to about 6.0. In another embodiment, described herein is a liquid formulation comprising: about 12.5 mg / mL golimumab or about 100 mg / mL golimumab; about 41 to 45 mg / mL sorbitol; about 0.8 to 1.5 mg / mL of a histidine buffer; and about 0.015 % (w / v) of poloxamer 188; wherein the liquid formulation has a pH of about 5.5.

[0049] The present invention is based in part on the discovery that golimumab formulations containing a poloxamer instead of a polysorbate as a surfactant had improved stability over extended periods of time, especially at somewhat elevated temperatures. More particularly, the formulation shows improved surfactant stability.

[0050] The liquid formulations described herein are suitable for pharmaceutical administration, such as parenteral administration, and especially for subcutaneous injection such as by a pre-filled single-use syringe or auto-injector.Water

[0051] The main component (or carrier) of the liquid formulations is water of pharmaceutical grade. ‘Pharmaceutical-grade water’ refers to water meeting at least the purity and quality requirements suitable for making a parenteral liquid formulation as set forth in the USP for ‘water for injection’ (or “WFI”). As is understood by workers skilled in the art, WFI is drinking water purified by distillation, or a purification process equivalent or superior to distillation, resulting in the removal of chemicals and microorganisms. WFI contains no added substances. The pharmaceutical-grade water may be sterilized prior to and / or after being combined with other components of the liquid formulation, but sterilization is not required.

[0052] The liquid formulations herein comprise several components that are dissolved and / or dispersed, but typically fully dissolved, in the pharmaceutical-grade water. These include: golimumab, a sugar and / or a sugar alcohol, a histidine buffer, and a poloxamer.Anti-TNFa Antibody

[0053] The antibody used in the liquid formulations is the antibody golimumab, whose encoded amino acid sequence contains 1342 amino acids, including any accepted variations or biosimilars thereof. In one embodiment, golimumab is produced from one or more vectors encoding amino acid sequences comprising the light chain sequence of golimumab:EIVLTQSPATLSLSPGERATLSCRASQSVYSYLAWYQQKPGQAPRLLIYDASNR ATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPFTFGPGTKVDIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1) and the heavy chain sequence of golimumab:QVQLVESGGGVVQPGRSLRLSCAASGFIFSSYAMHWVRQAPGNGLEWVAFMS YDGSNKKYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRGIAA GGNYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 2).

[0054] In another embodiment, golimumab is produced from one or more vectors encoding amino acid sequences comprising the variable light chain sequence of golimumab:EIVLTQSPATLSLSPGERATLSCRASQSVYSYLAWYQQKPGQAPRLLIYDASNRA TGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPFTFGPGTKVDIK (SEQ ID NO: 3) and the variable heavy chain sequence of golimumab: QVQLVESGGGVVQPGRSLRLSCAASGFIFSSYAMHWVRQAPGNGLEWVAFMS YDGSNKKYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRGIAAG GNYYYYGMDVWGQGTTVTVSS (SEQ ID NO: 4)

[0055] Because golimumab is produced by a biological process, certain minor variations can occur from batch to batch, including but not limited to “lysine clipping” wherein the C- terminal lysine of the heavy chain constant region is clipped off, which variations are considered golimumab and have no clinically meaningful effect. A biosimilar, as is understood by workers skilled in the art, refers to a biologic that is highly similar to the reference product (in this case to the golimumab produced by Janssen Biotech, Inc.) and has no clinically meaningful differences therefrom in terms of efficacy and safety. The high degree of similarity between the biosimilar and reference product generally includes the physical, chemical, and biological properties and the minor differences permitted are not clinically meaningful. This understanding is used by the United States Food and Drug Administration (U.S. FDA) and the European Medicines Agency (EMA) as well as by pharmaceutical companies seeking permission to market a biosimilar of a reference product. In the U.S., a biosimilar may be denoted with an extension after the reference product name. In the context of the disclosure herein, for the avoidance of doubt, all such extension names of golimumab should be considered within the scope of the term ‘golimumab’ as used herein. The concentration of golimumab in the liquid formulations described herein may be from 5 mg / mL to 200 mg / mL, such as from 10 mg / mL to 110 mg / mL, and in particular, may be 12.5 mg / mL or may be 100 mg / mL.Sugar and Sugar Alcohol

[0056] The liquid formulations described herein may comprise from 20 to 50 mg / mL of a sugar or a sugar alcohol. The primary purpose of sugar or sugar alcohol is to stabilize the protein and / or modify the osmolality of the formulations to an iso-osmotic level. The sugar or sugar alcohol may be any suitable sugar or sugar alcohol. In some embodiments, the sugar or sugar alcohol is selected from sucrose, trehalose, maltose, lactose, or sorbitol, either individually or in any suitable combination of two or more. In one embodiment, the sugar alcohol is sorbitol.

[0057] The sugar or sugar alcohol may be present in the liquid formulations described herein at any suitable concentration from 20 to 50 mg / mL. In some embodiments, the sugar or sugar alcohol is present at a concentration of 30 to 50 mg / mL, or 40 to 50 mg / mL, or 41 to 45 mg / mL. In some embodiments, the sugar is present in the liquid formulations described herein at a concentration of about 41 mg / mL, or at a concentration of about 45 mg / mL.Poloxamer

[0058] The liquid formulations described herein comprise a poloxamer as a surfactant. Poloxamers are nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly (ethylene oxide)). Poloxamers may protect protein formulations against agitation induced stress and / or exposure of proteins to surfaces and / or air-liquid interfaces. The poloxamer used herein is not intended to be particularly limited. In a particular embodiment, the poloxamer may be poloxamer 188, otherwise known as Pl 88, where the first two digits (18) multiplied by 100 give the approximate molecular mass of the polyoxypropylene core (i.e., 1800), and the last digit (8) multiplied by 10 gives the percentage of polyoxyethylene content (i.e., 80%).

[0059] As outlined above, the commercial Simponi® and Simponi Aria® formulations do not include a poloxamer. Instead, those formulations utilise polysorbate 80(polyoxy ethylene(80) sorbitan monolaurate) as a surfactant, at a concentration of 0.15 mg / mL, i.e., 0.015 % (w / v).

[0060] The liquid formulations described herein preferably comprise a poloxamer in an amount of from 0.005 to 0.1 % (w / v) based on the total formulation. In some embodiments, the poloxamer is present in an amount of from 0.005 to 0.05 % (w / v), or from 0.01 to 0.05 %(w / v), or from 0.015 to 0.1 % (w / v), or from 0.0075 to 0.02 % (w / v), or from 0.01 to 0.075 % (w / v), or from 0.01 to 0.04 % (w / v), or an amount of about 0.005 % (w / v), 0.0075 % (w / v), 0.01 % (w / v), 0.015 % (w / v), 0.02 % (w / v), 0.03 % (w / v), 0.04 % (w / v), 0.05 % (w / v), 0.06 % (w / v), 0.07 % (w / v), 0.08 % (w / v), 0.09 % (w / v), or 0.1 % (w / v).Osmolality

[0061] The liquid formulations described herein have an osmolality within a parenterally acceptable range, generally between 200 and 600 mOsm / kg. Typically, the osmolality of the liquid formulations described herein is within the range of between 240 and 420 mOsm / kg. In some embodiments, the liquid formulations have an osmolality within the range of 300 to 400 mOsm / kg, and typically between 330 and 380 mOsm / kg. In other embodiments, the osmolality is within the range of 270-325 mOsm / kg. Values within these ranges can be attained by balancing the kind and amount of the stabiliser, the kind and amount of buffer, and to a lesser extent, the kind and amount of poloxamer, given the amount of golimumab in pharmaceutical-grade water. Osmolality may also be adjusted by adding additional agents such as salts (e.g., NaCl). pH

[0062] The liquid formulations described herein preferably have a pH in the range of from 5.0 to 6.0. In some embodiments, the pH is in the range of 5.2 to 5.8. In some embodiments, the pH is about 5.2, or about 5.5, or about 5.8. The pH can be adjusted, if necessary, by the addition of pH adjustment agents. In some embodiments, the pH adjustment agents may be an acid or a base. In some embodiments, the acid is HC1 or acetic acid. In some embodiments, the base is NaOH.Histidine Buffer

[0063] The liquid formulations herein may comprise a buffer, preferably a histidine buffer, and preferably from 0.6 to 1.6 mg / mL of a histidine buffer. The concentration of histidine buffer does not necessarily refer to the concentration of starting ingredients used to make the buffered solution. Instead, it refers to the concentration of histidine in the buffered solution, after the starting ingredients have been added and have undergone ionic dissociation in the equilibrated buffered solution. For example, the Simponi Aria® product includes as starting ingredients L-histidine and L-histidine monohydrochloride monohydrate, inconcentrations of 0.285 and 1.605 mg / mL, respectively. Upon dissociation in the buffered solution, these concentrations of ingredients result in a histidine buffer concentration of 1.473 mg / mL. Similarly, the Simponi® product has a reported histidine concentration of 0.87 mg / mL. This histidine concentration in the buffered solution can be obtained by including as ingredients 0.148 mg / mL of L-histidine and 0.974 mg / mL of L-histidine monohydrochloride monohydrate, at a pH of 5.5.

[0064] In some embodiments, the liquid formulations herein comprise from 0.6 to 1.6 mg / mL of the histidine buffer. In other embodiments, the formulations comprise 0.8 to 1.5 mg / mL of the histidine buffer. In other embodiments, the formulations comprise 1.3 to 1.6 mg / mL of the histidine buffer. In some embodiments, the formulations comprise 1.30 mg / mL, or 1.47 mg / mL, or 1.60 mg / mL of the histidine buffer. As noted above, a histidine buffer concentration of 1.473 mg / mL can be obtained by including as ingredients L-histidine and L- histidine monohydrochloride monohydrate, in concentrations of 0.285 and 1.605 mg / mL, respectively. Similarly, a histidine buffer concentration of 0.87 mg / mL can be obtained by including as ingredients L-histidine and L-histidine monohydrochloride monohydrate, in concentrations of 0.148 and 0.974 mg / mL, respectively. Finally, it is understood that an antibody such as golimumab may contribute to the buffering capacity of a liquid formulation. Formulations

[0065] In one embodiment, the aqueous liquid formulations described herein may comprise from 5 to 200 mg / mL of golimumab; from 20 to 50 mg / mL of a sugar and / or a sugar alcohol; from 0.6 to 1.6 mg / mL of a histidine buffer; and from 0.005 to 0.1 % (w / v) of a poloxamer; wherein the liquid formulation has a pH of from 5.0 to 6.0.

[0066] In another embodiment, the aqueous liquid formulations described herein may consist essentially of from 5 to 200 mg / mL of golimumab; from 20 to 50 mg / mL of a sugar and / or a sugar alcohol; from 0.6 to 1.6 mg / mL of a histidine buffer; and from 0.005 to 0.1 % (w / v) of a poloxamer; wherein the liquid formulation has a pH of from 5.0 to 6.0. “Consisting essentially of’ in this context serves to exclude the addition of other buffers or salts, but would permit the addition of minor agents such as a pH adjusting agents, antioxidants, or preservatives.

[0067] In a further embodiment, the aqueous liquid formulation described herein may consist of water, from 5 to 200 mg / mL of golimumab; from 20 to 50 mg / mL of a sugar and / or a sugar alcohol; from 0.6 to 1.6 mg / mL of a histidine buffer; and from 0.005 to 0.1 % (w / v) of a poloxamer; wherein the liquid formulation has a pH of from 5.0 to 6.0. In this context, “consist of’ excludes all other pharmaceutical excipients and thus additional buffer or salt are excluded as well as antioxidants and preservatives. For clarity, impurities of sufficiently low level so as to be pharmaceutically acceptable are not excluded.

[0068] Exemplary stabilizing liquid formulations of golimumab are formulations that comprise the following, in combination with about 12.5 mg / mL golimumab: a) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2; b) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; c) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8; d) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.2; e) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.5; f) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.8; g) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.2; h) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.5; i) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.8; j) about 45 mg / mL sorbitol, about 1.30 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2;k) about 45 mg / mL sorbitol, about 1.30 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; l) about 45 mg / mL sorbitol, about 1.30 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8; m) about 45 mg / mL sorbitol, about 1.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2; n) about 45 mg / mL sorbitol, about 1.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; o) about 45 mg / mL sorbitol, about 1.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8.

[0069] Exemplary stabilizing liquid formulations of golimumab are formulations that comprise the following, in combination with about 100 mg / mL golimumab: a) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2; b) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; c) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8; d) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.2; e) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.5; f) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.8; g) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.2; h) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.5; i) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.8;j) about 41 mg / mL sorbitol, about 0.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2; k) about 41 mg / mL sorbitol, about 0.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; l) about 41 mg / mL sorbitol, about 0.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8; m) about 41 mg / mL sorbitol, about 1.00 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2; n) about 41 mg / mL sorbitol, about 1.00 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; or o) about 41 mg / mL sorbitol, about 1.00 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8.Stability

[0070] The liquid formulations described herein are relatively stable. Typically, the formulation has satisfactory bulk stability for at least 36 months, or at least 24 months, or at least 12 months, or at least 6 months, or at least 3 months. In general, such stability includes chemical and physical stability of golimumab such that only minor amounts of both fragmentation and aggregation of the antibody are observed, as well as surfactant stability such that only minor amounts of surfactant degradation are observed.

[0071] The golimumab formulations described herein exhibit remarkable stability in surfactant concentration or, put another way, resistance to surfactant degradation. In embodiments, a golimumab formulation exhibits minimal loss of surfactant concentration during storage. Loss of surfactant concentration can be expressed as a percentage of original surfactant concentration, determined by comparing the surfactant concentration after storage under specified conditions to the concentration of the golimumab formulation as prepared. Surfactant concentration can be measured after storage, e.g., by ultra-performance liquid chromatography coupled with evaporative light scattering detection (UPLC / ELSD).

[0072] As a non-limiting, exemplary explanation, surfactant stability of the golimumab formulations described herein may result, in part, from increased resistance to oxidation and hydrolysis, both enzymatically from residual host cell proteins (e.g., lipases) which are notremoved during clarification and purification and / or from histidine (e.g., in combination with trace metals).

[0073] In embodiments, the golimumab formulations exhibit a loss of surfactant concentration after storage at 5°C for 1 month of 15% or less. In embodiments, the golimumab formulations exhibit a loss of surfactant concentration after storage at 25°C for 1 month of 40% or less, 35% or less, 25% or less, 20% or less, 15% or less, or 10% or less. In embodiments, the golimumab formulations exhibit a loss of surfactant concentration after storage at 40°C for 1 month of 55% or less, 50% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, or 15% or less. Loss of surfactant concentration may be measured, e.g., as described in the examples below.Manufacture of formulation

[0074] The liquid formulation of the present invention can be made by combining golimumab, stabilizer, poloxamer, and histidine buffer, in a pharmaceutical-grade water to form a solution and / or suspension. The order of addition and method of combining is normally not of particular importance. For convenience and commercial practicality, golimumab may be formulated into the formulations described herein using well known ultrafiltration / diafiltration (UF / DF) techniques. In general, the expressed golimumab is captured and purified by various processes and then subjected to UF / DF for additional purification, concentration, and modification of the liquid media. The golimumab solution resulting from the previous purification process steps can be replaced using diafiltration, as is well known in the art. In making the formulations herein described, golimumab can be diafiltered with a solution of stabilizer, and histidine buffer, in WFI, with the poloxamer being added during or after the completion of the UF / DF process. The poloxamer may be added as a solution in WFI or in the diafiltering solution. The pH can be adjusted, if needed, before, during, or after UF / DF operations such as by the introduction of HC1 or other pH adjusting agent that is suitable for a parenteral formulation. The liquid formation is not, however, limited to the use of UF / DF and any suitable process or means for combining the recited ingredients in the desired concentrations can be used to make the liquid formulations described herein.Uses of Formulation

[0075] The liquid formulations described herein are useful for treating a variety of diseases and disorders or symptoms thereof that respond to golimumab or anti-TNFa antibody treatment. These include rheumatoid arthritis (RA), active psoriatic arthritis (PsA), active ankylosing spondylitis (AS), moderately to severely active ulcerative colitis (UC), and active polyarticular juvenile idiopathic arthritis (pJIA). The dosing amount and regimen are well known from the administration of Simponi® and Simponi Aria® as, for example, approved by the U.S. FDA or EMA. The liquid formulations herein may be loaded into a prefilled syringe to provide 0.5 mL of a 100 mg / mL formulation, corresponding to a golimumab dose of 50 mg, or may be provided in a vial for injection in an amount of 1.0 mL of a 12.5 mg / mL formulation, corresponding to a golimumab dose of 12.5 mg.

[0076] In various exemplary embodiments, the present disclosure relates to the following items and all combinations thereof:1. An aqueous liquid formulation comprising: from 5 to 200 mg / mL of golimumab; from 20 to 50 mg / mL of a sugar and / or a sugar alcohol; from 0.6 to 1.6 mg / mL of a histidine buffer; and from 0.005 to 0.1 % (w / v) of a poloxamer; wherein the liquid formulation has a pH of from 5.0 to 6.0.2. The aqueous liquid formulation of item 1, consisting essentially of: from 5 to 200 mg / mL of golimumab; from 20 to 50 mg / mL of a sugar and / or a sugar alcohol; from 0.6 to 1.6 mg / mL of a histidine buffer; from 0.005 to 0.1 % (w / v) of a poloxamer; and water; wherein the liquid formulation has a pH of from 5.0 to 6.0.3. The aqueous liquid formulation of item 1 or item 2, comprising a sugar alcohol comprising sorbitol.4. The aqueous liquid formulation of any one of items 1 to 3, wherein the poloxamer comprises poloxamer 188.5. The aqueous liquid formulation of any one of items 1 to 4, wherein the pH is from 5.2 to 5.8.6. The aqueous liquid formulation of any one of items 1 to 5, wherein the pH is about 5.5.7. The aqueous liquid formulation of any one of items 1 to 3, comprising about 12.5 mg / mL golimumab or about 100 mg / mL golimumab; about 40 to 50 mg / mL sorbitol; about 0.8 to 1.5 mg / mL of a histidine buffer; and about 0.015 % (w / v) of a poloxamer; wherein the liquid formulation has a pH of from 5.0 to 6.0.8. The aqueous liquid formulation of any one of items 1 to 5, comprising:(i) about 12.5 mg / mL golimumab; and(ii) one of the following: a) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2; b) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; c) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8;d) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.2; e) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.5; f) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.8; g) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.2; h) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.5; i) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.8; j) about 45 mg / mL sorbitol, about 1.30 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2; k) about 45 mg / mL sorbitol, about 1.30 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; l) about 45 mg / mL sorbitol, about 1.30 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8; m) about 45 mg / mL sorbitol, about 1.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2;n) about 45 mg / mL sorbitol, about 1.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; or o) about 45 mg / mL sorbitol, about 1.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8. The aqueous liquid formulation of any one of items 1 to 5, comprising:(i) about 100 mg / mL golimumab; and(ii) one of the following: a) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2; b) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; c) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8; d) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.2; e) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.5; f) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.8;g) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.2; h) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.5; i) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.8; j) about 41 mg / mL sorbitol, about 0.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2; k) about 41 mg / mL sorbitol, about 0.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; l) about 41 mg / mL sorbitol, about 0.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8; m) about 41 mg / mL sorbitol, about 1.00 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2; n) about 41 mg / mL sorbitol, about 1.00 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; or o) about 41 mg / mL sorbitol, about 1.00 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8.10. An aqueous liquid formulation comprising golimumab and a surfactant, wherein the formulation exhibits a loss of surfactant concentration of 40% or less when stored for one month at 25 °C.11. The aqueous liquid formulation of item 10, wherein the loss of surfactant concentration is 15% or less.12. The aqueous liquid formulation of item 10 or 11, wherein the surfactant comprises a poloxamer.13. The aqueous liquid formulation of any one of items 10 to 12, further comprising a histidine buffer.14. The aqueous liquid formulation of any one of items 10 to 13, comprising: from 5 to 200 mg / mL of golimumab; from 20 to 50 mg / mL of a sugar and / or a sugar alcohol; from 0.6 to 1.6 mg / mL of a histidine buffer; and from 0.005 to 0.1 % (w / v) of a poloxamer; wherein the liquid formulation has a pH of from 5.0 to 6.0.15. The aqueous liquid formulation of any one of items 10 to 14, consisting essentially of: from 5 to 200 mg / mL of golimumab; from 20 to 50 mg / mL of a sugar and / or a sugar alcohol; from 0.6 to 1.6 mg / mL of a histidine buffer; from 0.005 to 0.1 % (w / v) of a poloxamer; and water; wherein the liquid formulation has a pH of from 5.0 to 6.0.16. An aqueous liquid formulation, comprising golimumab and a poloxamer.17. The aqueous liquid formulation of item 16, comprising 5 to 200 mg / mL golimumab.18. The aqueous liquid formulation of item 16 or 17, wherein the poloxamer is poloxamer 188.19. The aqueous liquid formulation of any one of items 16 to 18, comprising 0.005 to 0.1 % (w / v) poloxamer.20. The aqueous liquid formulation of any one of items 16 to 19, further comprising a histidine buffer.21. The aqueous liquid formulation of item 20, comprising 0.6 to 1.6 mg / mL of histidine buffer.22. The aqueous liquid formulation of any one of items 16 to 21, further comprising a sugar and / or a sugar alcohol.23. The aqueous liquid formulation of item 22, comprising a sugar alcohol comprising sorbitol.24. The aqueous liquid formulation of item 22 or 23, comprising 20 to 50 mg / mL of the sugar and / or sugar alcohol.25. The aqueous liquid formulation of any one of items 16 to 24, having a pH of from 5.0 to 6.0.26. A golimumab formulation for parenteral injection, comprising a sugar and / or a sugar alcohol, a buffer, and a surfactant, where the surfactant is a poloxamer.27. The golimumab formulation of item 26, comprising 5 to 200 mg / mL golimumab.28. The golimumab formulation of item 26 or 27, wherein the poloxamer is poloxamer 188.29. The golimumab formulation of any one of items 26 to 28, comprising 0.005 to 0.1 % (w / v) poloxamer.30. The golimumab formulation of any one of items 26 to 29, wherein the buffer is a histidine buffer.31. The golimumab formulation of item 30, comprising 0.6 to 1.6 mg / mL of histidine buffer.32. The golimumab formulation of any one of items 26 to 31, comprising a sugar alcohol comprising sorbitol.33. The golimumab formulation of any one of items 26 to 32, comprising 20 to 50 mg / mL of the sugar and / or sugar alcohol.34. The golimumab formulation of any one of items 26 to 33, having a pH of from 5.0 to 6.0.35. An aqueous liquid formulation comprising golimumab and a surfactant, wherein the formulation exhibits a loss of surfactant concentration of 50% or less when stored for one month at 40°C.36. The aqueous liquid formulation of item 35, wherein the loss of surfactant concentration is 15% or less.37. The aqueous liquid formulation of item 35 or 36, wherein the surfactant comprises a poloxamer.38. The aqueous liquid formulation of any one of items 35 to 37, further comprising a histidine buffer.39. The aqueous liquid formulation of any one of items 35 to 38, comprising: from 5 to 200 mg / mL of golimumab; from 20 to 50 mg / mL of a sugar and / or a sugar alcohol; from 0.6 to 1.6 mg / mL of a histidine buffer; and from 0.005 to 0.1 % (w / v) of a poloxamer; wherein the liquid formulation has a pH of from 5.0 to 6.0.40. The aqueous liquid formulation of any one of items 35 to 39, consisting essentially of: from 5 to 200 mg / mL of golimumab; from 20 to 50 mg / mL of a sugar and / or a sugar alcohol; from 0.6 to 1.6 mg / mL of a histidine buffer; from 0.005 to 0.1 % (w / v) of a poloxamer; and water; wherein the liquid formulation has a pH of from 5.0 to 6.0.41. The formulation of any one of items 1 to 40, for use in treating or preventing rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, moderately to severely active ulcerative colitis, or active polyarticular juvenile idiopathic arthritis.42. A method of treating or preventing rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, moderately to severely active ulcerative colitis, or active polyarticular juvenile idiopathic arthritis, in a subject, comprising administering to the subject the formulation of any one of items 1 to 41. 43. Use of a formulation of any one of items 1 to 41 in the manufacture of a medicament for treating or preventing rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, moderately to severely active ulcerative colitis, or active polyarticular juvenile idiopathic arthritis.EXAMPLES

[0077] The present invention will now be described with reference to the following examples which should be considered in all respects as illustrative and non-restrictive.

[0078] The concentration of surfactant over time, under a range of storage temperatures, was measured for the following inventive and comparative formulations in Table 1:* The concentration of L-histidine and L-histidine monohydrochloride monohydrate of the Simponi® formulation is reported collectively as 0.87 mg / mL. It is assumed that the value refers to the total concentration of L-histidine from both components of the histidine buffering system. The concentration of each component ingredient was calculated according to the target pH.

[0079] In these examples, Comparative Example 1 corresponds to the Simponi® formulation, and Comparative Example 2 corresponds to the Simponi Aria® formulation.Inventive Example 1 corresponds to Comparative Example 1, except for using poloxamer 188 instead of polysorbate 80 as surfactant. Similarly, Inventive Example 2 corresponds to Comparative Example 2, except for using poloxamer 188 instead of polysorbate 80 as surfactant.

[0080] The surfactant concentrations for these four example formulations were monitored at storage conditions of 5°C, 25°C and 40°C for three months. FIG. 1 shows the results for the comparative examples. After three months of storage at 25°C (green lines) and 40°C (red lines), the concentration of polysorbate 80 of these comparative formulations decreased substantially (about 24 to 62% of surfactant remaining). After three months of storage at 5°C (blue lines), the concentration of polysorbate 80 was somewhat more stable, with about 93% of surfactant remaining.

[0081] FIG. 2 shows the results for the inventive examples. After three months of storage at 5°C (blue lines), 25°C (green lines) and 40°C (red lines), the concentration of poloxamer 188 of these inventive formulations remained remarkably stable (about 87 to 100% of surfactant remaining).

[0082] As can be seen from FIGS. 1 and 2, liquid formulations as described herein, comprising a poloxamer surfactant, showed improved surfactant stability compared to formulations comprising a polysorbate surfactant. This effect was particularly pronounced at storage temperatures of 25°C and 40°C.

[0083] Although the invention has been described with reference to specific examples, it will be appreciated by those skilled in the art that the invention may be embodied in many other forms in particular features of any one of the various described examples may be provided in any combination in any of the other described examples.

Claims

CLAIMS1. An aqueous liquid formulation, comprising golimumab and a poloxamer.

2. The aqueous liquid formulation as claimed in claim 1, comprising 5 to 200 mg / mL golimumab.

3. The aqueous liquid formulation as claimed in claim 1-2, wherein the poloxamer is poloxamer 188.

4. The aqueous liquid formulation as claimed in any of claims 1-3, comprising 0.005 to 0.1 % (w / v) poloxamer.

5. The aqueous liquid formulation as claimed in any of claims 1-4, further comprising a histidine buffer, preferably comprising 0.6 to 1.6 mg / mL of histidine buffer.

6. The aqueous liquid formulation as claimed in any of claims 1-5, further comprising a sugar and / or a sugar alcohol which preferably comprises sorbitol.

7. The aqueous liquid formulation as claimed in claim 6, comprising the sugar and / or sugar alcohol in an amount of 20 to 50 mg / mL.

8. The aqueous liquid formulation as claimed in any one of claims 1-7, having a pH of from 5.0 to 6.0.

9. The aqueous liquid formulation as claimed in claim 1 , comprising about 12.5 mg / mL golimumab; about 40 to 50 mg / mL sorbitol, preferably 45 mg / mL sorbitol; about 0.8 to 1.5 mg / mL of a histidine buffer; and about 0.015 % (w / v) of a poloxamer, preferably poloxamer 188; wherein the liquid formulation has a pH of from 5.0 to 6.0.

10. The aqueous liquid formulation as claimed in claim 1, comprisingabout 100 mg / mL golimumab; about 40 to 50 mg / mL sorbitol, preferably 41 mg / mL sorbitol; about 0.8 to 1.5 mg / mL of a histidine buffer; and about 0.015 % (w / v) of a poloxamer, preferably poloxamer 188; wherein the liquid formulation has a pH of from 5.0 to 6.0.

11. The aqueous liquid formulation as claimed in any one of claims 1-9, comprising:(i) about 12.5 mg / mL golimumab; and(ii) one of the following: a) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2; b) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; c) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8; d) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.2; e) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.5; f) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.8; g) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.2; h) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.5; i) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.8; j) about 45 mg / mL sorbitol, about 1.30 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2; k) about 45 mg / mL sorbitol, about 1.30 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; l) about 45 mg / mL sorbitol, about 1.30 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8;m) about 45 mg / mL sorbitol, about 1.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2; n) about 45 mg / mL sorbitol, about 1.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; or o) about 45 mg / mL sorbitol, about 1.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8.

12. The aqueous liquid formulation as claimed in any of the claims 1-8 or 10, comprising:(i) about 100 mg / mL golimumab; and(ii) one of the following: a) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2; b) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; c) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8; d) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.2; e) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.5; f) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.010 % (w / v) of poloxamer 188, with a pH of about 5.8; g) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.2; h) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.5; i) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.020 % (w / v) of poloxamer 188, with a pH of about 5.8; j) about 41 mg / mL sorbitol, about 0.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2; k) about 41 mg / mL sorbitol, about 0.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5;l) about 41 mg / mL sorbitol, about 0.60 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8; m) about 41 mg / mL sorbitol, about 1.00 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.2; n) about 41 mg / mL sorbitol, about 1.00 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.5; or o) about 41 mg / mL sorbitol, about 1.00 mg / mL histidine buffer, and about 0.015 % (w / v) of poloxamer 188, with a pH of about 5.8.

13. The aqueous liquid formulation as claimed in any of the claims 1-12, wherein the formulation exhibits a loss of surfactant concentration of 40% or less when stored for one month at 25 °C, preferably a loss of surfactant concentration is 15% or less.

14. The aqueous liquid formulation as claimed in any of the claims 1-13, wherein the formulation exhibits a loss of surfactant concentration of 50% or less when stored for one month at 40°C, preferably a loss of surfactant concentration is 15% or less.

15. The formulation as claimed in any one of claims 1-14, for use in treating or preventing rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, moderately to severely active ulcerative colitis, active polyarticular juvenile idiopathic arthritis.

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