Liquid formulation containing golimumab and poloxamer 188

Abstract

The aqueous liquid formulation with improved stability comprises golimumab and a poloxamer, and preferably a histidine buffer, a sugar and / or a sugar alcohol. Uses and methods of using 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

[Technical Field]

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

[0002] Any discussion of prior art throughout this specification should not be taken in any way as an admission that such prior art is widely known or forms part of the common general knowledge in the art.

[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 (TNFα). In the United States, there are two commercially available golimumab products: Simponi® and Simponi Aria® (Janssen Biotech, Inc.), which contain 100 mg / ml and 12.5 mg / mL of golimumab, respectively. Both Simponi® and Simponi Aria® are parenteral formulations suitable for administration by subcutaneous (SC) or intravenous (IV) injection, respectively.

[0004] The subcutaneous golimumab product, Simponi®, is indicated (in the United States) for the treatment of moderate to severe rheumatoid arthritis (RA) in combination with methotrexate; for the treatment of active psoriatic arthritis (PsA) alone or in combination with methotrexate; for the treatment of active ankylosing spondylitis (AS); and for the treatment of moderately to severely active ulcerative colitis (UC). For RA, PsA, and AS, the Simponi® dosing schedule is 50 mg given as a subcutaneous injection once monthly. For UC, the Simponi® dosing schedule is three start-up subcutaneous injections (two 100 mg injections on day 1 of treatment, followed by one 100 mg injection two weeks later), then one 100 mg injection every four weeks thereafter. Subcutaneous Simponi® injections can be self-administered by patients.

[0005] The intravenous golimumab product, Simponi Aria®, is indicated (in the United States) in combination with methotrexate for the treatment of moderate to severe rheumatoid arthritis (RA) in adults; for the treatment of active psoriatic arthritis (PsA) in people aged 2 years and older; for the treatment of active ankylosing spondylitis (AS) in adults; and for the treatment of active polyarticular juvenile idiopathic arthritis (pJIA) in people aged 2 years and older. Simponi Aria® is typically administered by intravenous injection (infusion) four weeks after the first treatment and every eight weeks thereafter.

[0006] In Europe, Simponi® is approved for rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), psoriatic arthritis (PsA), axial spondyloarthritis (AS), and ulcerative colitis (UC) as a 50 mg or 100 mg pen or PFS for RA, PsA, AS, and UC, and as a pre-filled variable-dose pen (45 mg / 0.45 mL) delivering 0.1 to 0.45 mL in 0.05 mL increments 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 in water for injection (pH adjusted to 5.5). 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 in water for injection (pH adjusted to 5.5).

[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 biologics, which are prone to aggregation, degradation, oxidation, isomerization, adsorption, and denaturation, which can be accelerated by agitation and environmental stresses such as changes in pH and temperature.

[0009] Surfactants play a vital role in the stabilization of biopharmaceuticals, which may include protection from interfacial stresses, such as interface-induced aggregation, precipitation, and adsorption, resulting from exposure to liquid-air interfaces and contact with purification and other processing, storage, and delivery equipment. Summary of the Invention [Problem to be solved by the invention]

[0010] One object of the present invention is to provide a stable formulation of golimumab. [Means for solving the problem]

[0011] Polyoxyethylene (PEO) surfactants, including polysorbates, have been identified as promising surfactants for use in biologics. However, the inventors surprisingly found that polysorbates can be unstable and apparently caused particulates and opacity during the identification and evaluation of golimumab formulations, particularly when co-formulated with histidine buffers. The inventors have discovered that stable golimumab formulations can be produced using poloxamer surfactants, optionally in combination with histidine buffers.

[0012] The present invention relates to a liquid formulation comprising an anti-TNFα antibody, and more particularly to a stable liquid formulation comprising golimumab.

[0013] In a first aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: golimumab 5–200 mg / mL; 20-50 mg / mL sugar and / or sugar alcohol; 0.6 to 1.6 mg / mL histidine buffer; and 0.005–0.1% (w / v) poloxamer; Including, An aqueous liquid formulation having a pH of 5.0 to 6.0 is provided.

[0014] In a second aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: golimumab 5–200 mg / mL; 20-50 mg / mL sugar and / or sugar alcohol; 0.6–1.6 mg / mL histidine buffer; 0.005 to 0.1% (w / v) poloxamer; and water; consists essentially of An aqueous liquid formulation having a pH of 5.0 to 6.0 is provided.

[0015] In a third aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: about 12.5 mg / mL golimumab or about 100 mg / mL golimumab; sorbitol at approximately 40–50 mg / mL; about 0.8 to 1.5 mg / mL histidine buffer; and approximately 0.015% (w / v) poloxamer; Including, An aqueous liquid formulation having a pH of about 5.0 to about 6.0 is provided.

[0016] In a fourth aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: about 12.5 mg / mL golimumab or about 100 mg / mL golimumab; sorbitol at approximately 41–45 mg / mL; about 0.8 to 1.5 mg / mL histidine buffer; and approximately 0.015% (w / v) poloxamer 188; Including, An aqueous liquid formulation is provided having a pH of about 5.5.

[0017] In a fifth aspect, the present invention provides a method for producing a pharmaceutical composition comprising: (1) about 12.5 mg / mL of golimumab; and (2) a) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer and about 0.015% (w / v) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having a pH of about 5.8 One of The present invention provides an aqueous liquid formulation comprising:

[0018] In a sixth aspect, the present invention provides a method for producing a pharmaceutical composition comprising: (1) about 100 mg / mL of golimumab; and (2) a) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer, and about 0.015% (w / v) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188 having 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) poloxamer 188, having a pH of about 5.8 One of The present invention provides an aqueous liquid formulation comprising:

[0019] In a seventh aspect, the present invention provides an aqueous liquid formulation comprising golimumab and a surfactant, wherein the formulation exhibits a decrease in surfactant concentration of no more than 40% when stored for one month at 25°C and / or a decrease in surfactant concentration of no more than 50% when stored for one month at 40°C.

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

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

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

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

[0024] In a twelfth aspect, the present 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 present invention provides a liquid formulation of the invention for use in the treatment or prevention of rheumatoid arthritis or active psoriatic arthritis in combination with methotrexate.

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

[0027] In a fifteenth aspect, the present invention provides the 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 aspects 1 to 15 above.

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

[0030] [Figure 1] 1 is a graph showing surfactant (polysorbate 80) concentration over time under various storage conditions for several comparative formulations. [Figure 2] 1 is a graph showing surfactant (poloxamer 188) concentration over time under various storage conditions for several inventive formulations. DETAILED DESCRIPTION OF THE INVENTION

[0031] definition 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 otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0032] Unless the context clearly requires otherwise, throughout this specification and the claims, the words "comprise," "comprising," and the like are to be construed in an inclusive sense; that is, in the sense of "including, but not limited to," as opposed to an exclusive or exhaustive sense.

[0033] 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."

[0034] Unless otherwise specified, "%" means [100 × m x / v tot ](m x is the mass of component x in g, and v tot is the total volume of all components in mL).

[0035] As used herein, the term "substantially" shall mean, where appropriate, including more than 50% by weight, unless otherwise indicated.

[0036] The recitation of numerical ranges using endpoints includes those endpoints and all numbers subsumed within the range (e.g., 1 to 10 includes 1, 1.5, 2, 5, 5.75, 7.1, 8.5, 9, 10, etc.).

[0037] As used in this specification and claims, the singular forms "a," "an," and "the" may include plural references unless the context clearly dictates otherwise.

[0038] As used herein, the terms "about" and "approximately" are used interchangeably. Both terms are intended to cover any normal fluctuations or variations understood by one of ordinary skill in the art. In some embodiments, "about" and "approximately" refer to ±10% of a reference value, or ±5%, or ±2%, or ±1%, or ±0.1% of a reference value.

[0039] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of golimumab that elicits a biological or medical response in a subject, e.g., inhibits the disease and its progression (e.g., inhibits the disease, condition, or disorder, e.g., prevents further development of the disease symptoms and / or symptomology in an individual experiencing or exhibiting the disease, condition, or disorder's symptoms or symptomology); and / or ameliorates the disease (e.g., ameliorates the disease, condition, or disorder, e.g., reduces the symptoms, reverses the disease symptoms and / or symptomology in an individual experiencing or exhibiting the disease, condition, or disorder's symptoms or symptomology).

[0040] As used herein, the phrases "treating," "treat," and "treatment" and the like include inhibiting the disease and / or its progression (e.g., inhibiting the disease, condition, or disorder, e.g., arresting further onset of the disease symptoms and / or symptomology, in an individual experiencing or exhibiting the disease, condition, or disorder's symptoms or symptomology); and / or ameliorating the disease (e.g., ameliorating the disease, condition, or disorder, e.g., reducing the symptoms, reversing the disease symptoms and / or symptomology, in an individual experiencing or exhibiting the disease, condition, or disorder's symptoms or symptomology).

[0041] As used herein, the terms "preventing," "prevent," and "prevention," etc., include the prevention of the recurrence and / or onset of one or more symptoms of a disorder or disease, particularly in a subject analyzed as being susceptible to or likely to develop the disease.

[0042] As used herein, the phrase "subject in need thereof" means that the subject has been identified as in need of a treatment described herein.

[0043] As used herein, the terms "subject" and "patient" are interchangeable and can be taken to mean any living organism that can be treated with the compounds of the invention. Thus, the terms "patient" and "subject" can include human adults or children.

[0044] Detailed Description All references cited herein, including patents, patent applications, publications, and databases, whether or not previously specifically incorporated, are hereby incorporated by reference in their entirety.

[0045] Those skilled in the art will appreciate that the liquid formulations described herein include the embodiments and features disclosed herein and all combinations and / or permutations of the disclosed embodiments and features.

[0046] The inventors have surprisingly found that golimumab formulations containing poloxamer instead of polysorbate as a surfactant exhibit improved stability (particularly surfactant stability) over extended periods, particularly at somewhat elevated temperatures. This allows for the production of golimumab formulations that are stable over the course of treatment. The inventors believe that surfactant stability in golimumab formulations may be positively affected by the use of a poloxamer surfactant in conjunction with a histidine buffer. Furthermore, the surfactant stability of the golimumab formulations described herein may result in part from increased resistance to oxidation and hydrolysis, both of which are enzymatic from residual host cell proteins (e.g., lipases) and / or histidine (e.g., along with trace metals) that are not removed during clarification and purification.

[0047]

[0003] Described herein is an aqueous liquid formulation comprising golimumab and a surfactant. The formulation preferably comprises 5-200 mg / mL golimumab; 20-50 mg / mL sugar and / or sugar alcohol; 0.6-1.6 mg / mL histidine buffer; and 0.005-0.1% (w / v) surfactant, which is a poloxamer; the liquid formulation has a pH of 5.0-6.0. In one embodiment, described herein is an aqueous liquid formulation consisting essentially of 5-200 mg / mL golimumab; 20-50 mg / mL sugar and / or sugar alcohol; 0.6-1.6 mg / mL histidine buffer; and 0.005-0.1% (w / v) poloxamer; the liquid formulation has a pH of 5.0-6.0. In another embodiment, described herein is a liquid formulation comprising about 12.5 mg / mL golimumab or about 100 mg / mL golimumab, about 40-50 mg / mL sorbitol, about 0.8-1.5 mg / mL histidine buffer, and about 0.015% (w / v) poloxamer; the liquid formulation has a pH of 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 41-45 mg / mL sorbitol, about 0.8-1.5 mg / mL histidine buffer, and about 0.015% (w / v) poloxamer 188; the liquid formulation has a pH of about 5.5.

[0048] The present invention is based, in part, on the discovery that golimumab formulations that include poloxamer instead of polysorbate as a surfactant have improved stability, particularly at somewhat elevated temperatures and over extended periods of time. More particularly, the formulations exhibit improved surfactant stability.

[0049] The liquid formulations described herein are suitable for pharmaceutical administration, e.g., parenteral administration, particularly subcutaneous injection, e.g., by pre-filled disposable syringe or auto-injector.

[0050] water The primary component (or carrier) of the liquid formulation is pharmaceutical grade water. "Pharmaceutical grade water" refers to water that meets at least the purity and quality requirements suitable for making parenteral liquid formulations as set forth in the USP for "Water for Injection" (or "WFI"). As will be understood by those skilled in the art, WFI is potable water that has been purified to remove chemicals and microorganisms by distillation or a purification method equivalent to or superior to distillation. WFI contains no additives. Pharmaceutical grade water can be sterilized before and / or after being combined with the other components of the liquid formulation, but sterilization is not required.

[0051] The liquid formulations herein contain several ingredients dissolved and / or dispersed, typically completely dissolved, in pharmaceutical grade water, including golimumab, a sugar and / or sugar alcohol, a histidine buffer, and a poloxamer.

[0052] Anti-TNFα antibody The antibody used in the liquid formulation is the antibody golimumab, the encoded amino acid sequence of which comprises 1342 amino acids, including any accepted variants or biosimilars thereof. In one embodiment, the golimumab has the light chain sequence of golimumab:

[0053] [ka]

[0054] and the heavy chain sequence of golimumab:

[0055] [ka]

[0056] The amino acid sequence is generated from one or more vectors encoding the amino acid sequence comprising:

[0057] In another embodiment, golimumab has the variable light chain sequence of golimumab:

[0058] [ka]

[0059] and the variable heavy chain sequence of golimumab:

[0060] [ka]

[0061] The amino acid sequence is generated from one or more vectors encoding the amino acid sequence comprising:

[0062] Because golimumab is produced by a biological process, certain minor variations may occur from batch to batch, including, but not limited to, "lysine clipping," in which the C-terminal lysine of the heavy chain constant region is clipped; this variation is considered golimumab and has no clinically meaningful impact. As understood by those skilled in the art, a biosimilar refers to a biological product that is highly similar to a reference product (in this case, golimumab produced by Janssen Biotech) and has no clinically meaningful differences in efficacy and safety. The high degree of similarity between a biosimilar and a reference product generally includes physical, chemical, and biological properties, and minor differences that are tolerated are clinically insignificant. This understanding is used by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), as well as by pharmaceutical companies seeking marketing authorization for biosimilars of reference products. In the United States, biosimilars may be designated by an extension following the name of the reference product. For the avoidance of doubt, in the disclosure herein, all such extensions 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 5 mg / mL to 200 mg / mL, for example, 10 mg / mL to 110 mg / mL, in particular, 12.5 mg / mL or 100 mg / mL.

[0063] Sugars and sugar alcohols The liquid formulations described herein may contain 20-50 mg / mL of a sugar or sugar alcohol. The primary purpose of the sugar or sugar alcohol is to stabilize the protein and / or change the osmolality of the formulation to an isotonic level. The sugar or sugar alcohol can be any suitable sugar or sugar alcohol. In some embodiments, the sugar or sugar alcohol is selected from sucrose, trehalose, maltose, lactose, or sorbitol, individually or in any suitable combination of two or more. In one embodiment, the sugar alcohol is sorbitol.

[0064] The sugar or sugar alcohol can be present in the liquid formulations described herein at any suitable concentration between 20 and 50 mg / mL. In some embodiments, the sugar or sugar alcohol is present at a concentration between 30 and 50 mg / mL, or between 40 and 50 mg / mL, or between 41 and 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 about 45 mg / mL.

[0065] Poloxamer The liquid formulations described herein contain a poloxamer as a surfactant. Poloxamers are nonionic triblock copolymers consisting of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)). Poloxamers can protect protein formulations from agitation-induced stress and / or exposure of proteins to surfaces and / or air-liquid interfaces. The term poloxamer as used herein is not intended to be particularly limiting. In certain embodiments, the poloxamer may be poloxamer 188, also known as P188, where the first two digits (18) are multiplied by 100 to obtain the approximate molecular mass of the polyoxypropylene core (i.e., 1800) and the last digit (8) is multiplied by 10 to obtain the percentage of polyoxyethylene content (i.e., 80%).

[0066] As outlined above, the commercially available Simponi® and Simponi Aria® formulations do not contain poloxamer. Instead, they utilize polysorbate 80 (polyoxyethylene (80) sorbitan monolaurate) as a surfactant at a concentration of 0.15 mg / mL, i.e., 0.015% (w / v).

[0067] The liquid formulations described herein preferably contain poloxamer in an amount of 0.005-0.1% (w / v) based on the total formulation. In some embodiments, the poloxamer is present in an amount of 0.005-0.05% (w / v), or 0.01-0.05% (w / v), or 0.015-0.1% (w / v), or 0.0075-0.02% (w / v), or 0.01-0.075% (w / v), or 0.01-0.04% (w / v), or about 0.005% (w / v).

[0033] In some embodiments, the soluble ...

[0068] Osmotic pressure The liquid formulations described herein have an osmolality within the parenterally acceptable range, generally between 200 and 600 mOsm / kg. Typically, the osmolality of the liquid formulations described herein is within the range of 240 to 420 mOsm / kg. In some embodiments, the liquid formulations have an osmolality within the range of 300 to 400 mOsm / kg, typically between 330 and 380 mOsm / kg. In other embodiments, the osmolality is within the range of 270 to 325 mOsm / kg. Values ​​within these ranges can be achieved by balancing the type and amount of stabilizer, the type and amount of buffer, and, to a lesser extent, the type and amount of poloxamer, taking into account the amount of golimumab in pharmaceutical-grade water. Osmolality can also be adjusted by adding additional agents, such as salts (e.g., NaCl).

[0069] pH The liquid formulations described herein preferably have a pH in the range of 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, about 5.5, or about 5.8. The pH can be adjusted, if necessary, by adding a pH adjuster. In some embodiments, the pH adjuster can be an acid or a base. In some embodiments, the acid is HCl or acetic acid. In some embodiments, the base is NaOH.

[0070] Histidine Buffer The liquid formulations herein may include a buffer, preferably a histidine buffer, preferably a 0.6-1.6 mg / mL histidine buffer. The concentration of the histidine buffer does not necessarily refer to the concentration of the starting components used to make the buffer. Instead, it refers to the concentration of histidine in the buffer after the starting components have been added and undergone ionic dissociation in the equilibration buffer. For example, the Simponi Aria® product contains L-histidine and L-histidine monohydrochloride monohydrate as starting components at concentrations of 0.285 and 1.605 mg / mL, respectively. Upon dissociation in the buffer, these concentrations of components 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 buffer can be obtained by including as ingredients 0.148 mg / mL L-histidine and 0.974 mg / mL L-histidine monohydrochloride monohydrate at a pH of 5.5.

[0071] In some embodiments, the liquid formulations herein contain 0.6-1.6 mg / mL histidine buffer. In other embodiments, the formulations contain 0.8-1.5 mg / mL histidine buffer. In other embodiments, the formulations contain 1.3-1.6 mg / mL histidine buffer. In some embodiments, the formulations contain 1.30 mg / mL, 1.47 mg / mL, or 1.60 mg / mL histidine buffer. As noted above, a histidine buffer concentration of 1.473 mg / mL can be obtained by including L-histidine and L-histidine monohydrochloride monohydrate as ingredients at concentrations of 0.285 and 1.605 mg / mL, respectively. Similarly, a histidine buffer solution at a concentration of 0.87 mg / mL can be obtained by including as components L-histidine and L-histidine monohydrochloride monohydrate at concentrations of 0.148 and 0.974 mg / mL, respectively. Finally, it will be appreciated that antibodies such as golimumab can contribute to the buffering capacity of liquid formulations.

[0072] formulation In one embodiment, an aqueous liquid formulation described herein may comprise 5-200 mg / mL golimumab; 20-50 mg / mL sugar and / or sugar alcohol; 0.6-1.6 mg / mL histidine buffer; and 0.005-0.1% (w / v) poloxamer; and the liquid formulation has a pH of 5.0-6.0.

[0073] In another embodiment, the aqueous liquid formulations described herein may consist essentially of 5-200 mg / mL golimumab; 20-50 mg / mL sugar and / or sugar alcohol; 0.6-1.6 mg / mL histidine buffer; and 0.005-0.1% (w / v) poloxamer; the liquid formulation has a pH of 5.0-6.0. "Consisting essentially of" in this context serves to exclude the addition of other buffers or salts, but would allow for the addition of minor agents, such as pH adjusters, antioxidants, or preservatives.

[0074] In further embodiments, the aqueous liquid formulations described herein may consist of water, 5-200 mg / mL golimumab; 20-50 mg / mL sugar and / or sugar alcohol; 0.6-1.6 mg / mL histidine buffer; and 0.005-0.1% (w / v) poloxamer; the liquid formulation has a pH of 5.0-6.0. In this context, "consisting of" excludes all other pharmaceutical excipients, and thus excludes additional buffers and salts, as well as antioxidants and preservatives. For clarity, impurities at levels sufficiently low to be pharmaceutically acceptable are not excluded.

[0075] An exemplary stabilized liquid formulation of golimumab is one comprising the following in combination with about 12.5 mg / mL of golimumab: a) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer and about 0.015% (w / v) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having a pH of about 5.8.

[0076] An exemplary stabilized liquid formulation of golimumab is one comprising the following in combination with about 100 mg / mL of golimumab: a) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer and about 0.015% (w / v) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188 having 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) poloxamer 188, having a pH of about 5.8.

[0077] stability The liquid formulations described herein are relatively stable. Typically, the formulations have 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. Generally, such stability includes the chemical and physical stability of golimumab, such that only minor fragmentation and aggregation of the antibody is observed, and the stability of the surfactant, such that only minor degradation of the surfactant is observed.

[0078] The golimumab formulations described herein exhibit remarkable surfactant concentration stability, or, alternatively, resistance to surfactant degradation. In embodiments, the golimumab formulations exhibit minimal decrease in surfactant concentration during storage. The decrease in surfactant concentration can be expressed as a percentage of the original surfactant concentration, determined by comparing the surfactant concentration after storage under specified conditions with the concentration of the as-prepared golimumab formulation. The surfactant concentration can be measured after storage, for example, by ultra-performance liquid chromatography coupled with evaporative light scattering detection (UPLC / ELSD).

[0079] By way of non-limiting illustrative example, the surfactant stability of the golimumab formulations described herein may result in part from increased resistance to oxidation and hydrolysis, both of which are enzymatic from residual host cell proteins (e.g., lipases) and / or histidine (e.g., along with trace metals) that are not removed during clarification and purification.

[0080] In embodiments, the golimumab formulation exhibits a decrease in surfactant concentration of 15% or less after storage at 5° C. for 1 month. In embodiments, the golimumab formulation exhibits a decrease in surfactant concentration of 40% or less, 35% or less, 25% or less, 20% or less, 15% or less, or 10% or less after storage at 25° C. for 1 month. In embodiments, the golimumab formulation exhibits a decrease in surfactant concentration 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 after storage at 40° C. The decrease in surfactant concentration can be measured, for example, as described in the Examples below.

[0081] Manufacturing of pharmaceutical preparations The liquid formulations of the present invention can be made by combining golimumab, stabilizer, poloxamer, and histidine buffer in pharmaceutical-grade water to form a solution and / or suspension. The order of addition and method of combination are generally not particularly critical. For convenience and commercial practicality, golimumab can be formulated into the formulations described herein using well-known ultrafiltration / diafiltration (UF / DF) techniques. Generally, expressed golimumab is captured and purified by various methods and then subjected to UF / DF for further purification, concentration, and modification of the liquid medium. The golimumab solution obtained by the previous purification process step can be exchanged by diafiltration, as is well known in the art. In making the formulations described herein, poloxamer can be added during or after the UF / DF process is completed, and golimumab can be diafiltered with a solution of stabilizer and histidine buffer in WFI. The poloxamer can be added as a solution in WFI or the diafiltration solution. If necessary, the pH can be adjusted before, during, or after the UF / DF operation, such as by the introduction of HCl or other pH adjusting agents suitable for parenteral formulations. However, the liquid formulations described herein are not limited to the use of UF / DF, and any suitable method or means for combining the listed ingredients at the desired concentrations can be used to make the liquid formulations described herein.

[0082] Use of the formulation The liquid formulations described herein are useful for treating various diseases and disorders or their symptoms that respond to golimumab or anti-TNFα 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). Dosages and regimens are known, for example, from the administration of Simponi® and Simponi Aria®, as approved by the U.S. FDA or EMA. The liquid formulations herein can be loaded into pre-filled syringes to provide 0.5 mL of a 100 mg / mL formulation, equivalent to a 50 mg dose of golimumab, or can be provided in injection vials in an amount of 1.0 mL of a 12.5 mg / mL formulation, equivalent to a 12.5 mg dose of golimumab.

[0083] In various exemplary embodiments, the present disclosure relates to the following and all combinations thereof: 1. Golimumab 5–200 mg / mL; 20-50 mg / mL sugar and / or sugar alcohol; 0.6 to 1.6 mg / mL histidine buffer; and 0.005–0.1% (w / v) poloxamer; Including, An aqueous liquid formulation having a pH of 5.0 to 6.0. 2. Golimumab 5–200 mg / mL; 20-50 mg / mL sugar and / or sugar alcohol; 0.6–1.6 mg / mL histidine buffer; 0.005 to 0.1% (w / v) poloxamer; and water; consists essentially of Item 1. An aqueous liquid formulation having a pH of 5.0 to 6.0. 3. The aqueous liquid formulation of item 1 or 2, which contains a sugar alcohol including 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, having a pH of 5.2 to 5.8. 6. The aqueous liquid formulation of any one of items 1 to 5, having a pH of about 5.5. 7. about 12.5 mg / mL golimumab or about 100 mg / mL golimumab; sorbitol at approximately 40–50 mg / mL; about 0.8 to 1.5 mg / mL histidine buffer; and approximately 0.015% (w / v) poloxamer; Including, 4. The aqueous liquid formulation of any one of items 1 to 3, having a pH of 5.0 to 6.0. 8. (i) about 12.5 mg / mL golimumab; and (ii) a) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer and about 0.015% (w / v) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having a pH of about 5.8 One of 6. The aqueous liquid formulation of any one of items 1 to 5, comprising: 9. (i) about 100 mg / mL golimumab; and (ii) a) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer and about 0.015% (w / v) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188 having 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) poloxamer 188, having a pH of about 5.8 One of 6. The aqueous liquid formulation of any one of items 1 to 5, comprising: 10. An aqueous liquid formulation comprising golimumab and a surfactant, which exhibits a decrease in surfactant concentration of 40% or less when stored at 25°C for 1 month. 11. The aqueous liquid formulation of item 10, wherein the surfactant concentration is reduced by 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. Golimumab 5–200 mg / mL; 20-50 mg / mL sugar and / or sugar alcohol; 0.6 to 1.6 mg / mL histidine buffer; and 0.005–0.1% (w / v) poloxamer; Including, 14. The aqueous liquid formulation of any one of items 10 to 13, having a pH of 5.0 to 6.0. 15. Golimumab 5–200 mg / mL; 20-50 mg / mL sugar and / or sugar alcohol; 0.6–1.6 mg / mL histidine buffer; 0.005 to 0.1% (w / v) poloxamer; and water; consists essentially of 15. The aqueous liquid formulation of any one of items 10 to 14, having a pH of 5.0 to 6.0. 16. An aqueous liquid formulation comprising golimumab and poloxamer. 17. An aqueous liquid formulation of item 16 containing 5 to 200 mg / mL of golimumab. 18. The aqueous liquid formulation of item 16 or 17, wherein the poloxamer is poloxamer 188. 19. An 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 containing 0.6 to 1.6 mg / mL 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 including sorbitol. 24. The aqueous liquid formulation of item 22 or 23, comprising 20 to 50 mg / mL of sugar and / or sugar alcohol. 25. An aqueous liquid formulation of any one of items 16 to 24 having a pH of 5.0 to 6.0. 26. A golimumab formulation for parenteral injection comprising a sugar and / or sugar alcohol, a buffer and a surfactant, wherein the surfactant is a poloxamer. 27. A golimumab formulation from item 26 containing 5 to 200 mg / mL of golimumab. 28. The golimumab formulation of item 26 or 27, wherein the poloxamer is poloxamer 188. 29. Any one of the golimumab formulations of items 26 to 28 containing 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 containing 0.6 to 1.6 mg / mL histidine buffer. 32. The golimumab formulation of any one of items 26 to 31, comprising a sugar alcohol, including sorbitol. 33. The golimumab formulation of any one of items 26 to 32, comprising 20 to 50 mg / mL of a sugar and / or sugar alcohol. 34. Any one of the golimumab formulations of items 26 to 33 having a pH of 5.0 to 6.0. 35. An aqueous liquid formulation containing golimumab and a surfactant, which exhibits a decrease in surfactant concentration of 50% or less when stored at 40°C for 1 month. 36. The aqueous liquid formulation of item 35, wherein the surfactant concentration is reduced by 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. Golimumab 5–200 mg / mL; 20-50 mg / mL sugar and / or sugar alcohol; 0.6 to 1.6 mg / mL histidine buffer; and 0.005–0.1% (w / v) poloxamer; Including, 39. The aqueous liquid formulation of any one of items 35 to 38, having a pH of 5.0 to 6.0. 40. Golimumab 5–200 mg / mL; 20-50 mg / mL sugar and / or sugar alcohol; 0.6–1.6 mg / mL histidine buffer; 0.005 to 0.1% (w / v) poloxamer; and water; consists essentially of 39. The aqueous liquid formulation of any one of items 35 to 39, having a pH of 5.0 to 6.0. 41. A formulation of any one of items 1 to 40 for use in the treatment or prevention of rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, moderately to severely active ulcerative colitis or active polyarticular juvenile idiopathic arthritis. 42. A method for 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 a 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. [Example]

[0084] The present invention will now be described with reference to the following examples, which are to be considered in all respects as illustrative and non-limiting.

[0085] The surfactant concentration over time was measured at various storage temperatures for the following inventive and comparative formulations in Table 1:

[0086] [Table 1]

[0087] 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 that Poloxamer 188 is used as the surfactant instead of Polysorbate 80. Similarly, Inventive Example 2 corresponds to Comparative Example 2 except that Poloxamer 188 is used as the surfactant instead of Polysorbate 80.

[0088] The surfactant concentrations of these four example formulations were monitored over three months of storage at 5°C, 25°C, and 40°C. Figure 1 shows the results of the comparative examples. After three months of storage at 25°C (green line) and 40°C (red line), the polysorbate 80 concentrations in these comparative formulations were substantially reduced (approximately 24-62% of the surfactant remained). After three months of storage at 5°C (blue line), the polysorbate 80 concentrations were somewhat more stable, with approximately 93% of the surfactant remaining.

[0089] Figure 2 shows the results of the inventive examples. After 3 months of storage at 5°C (blue line), 25°C (green line), and 40°C (red line), the poloxamer 188 concentration in these inventive formulations remained remarkably stable (approximately 87-100% of the surfactant remained).

[0090] As can be seen from Figures 1 and 2, the liquid formulations described herein containing poloxamer surfactants exhibited improved surfactant stability compared to formulations containing polysorbate surfactants, an effect that was particularly evident at storage temperatures of 25°C and 40°C.

[0091] Although the present invention has been described with reference to particular embodiments, it will be understood by those skilled in the art that the present invention may be embodied in many other forms, and in particular, the features of any one of the various described embodiments may be provided in any combination in any of the other described embodiments.

Claims

1. An aqueous liquid formulation comprising golimumab and poloxamer.

2. 10. The aqueous liquid formulation of claim 1, comprising 5 to 200 mg / mL of golimumab.

3. 3. The aqueous liquid formulation of claim 1, wherein the poloxamer is poloxamer 188.

4. 4. The aqueous liquid formulation according to any one of claims 1 to 3, comprising 0.005 to 0.1% (w / v) of poloxamer.

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

6. 6. An aqueous liquid formulation according to any one of claims 1 to 5, further comprising a sugar and / or a sugar alcohol, preferably including sorbitol.

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

8. 8. The aqueous liquid formulation according to any one of claims 1 to 7, having a pH of 5.0 to 6.

0.

9. golimumab at approximately 12.5 mg / mL; about 40-50 mg / mL sorbitol, preferably 45 mg / mL sorbitol; about 0.8 to 1.5 mg / mL histidine buffer; and about 0.015% (w / v) poloxamer, preferably poloxamer 188; Including, 10. The aqueous liquid formulation of claim 1, having a pH of 5.0 to 6.

0.

10. golimumab at approximately 100 mg / mL; about 40-50 mg / mL sorbitol, preferably 41 mg / mL sorbitol; about 0.8 to 1.5 mg / mL histidine buffer; and about 0.015% (w / v) poloxamer, preferably poloxamer 188; Including, 10. The aqueous liquid formulation of claim 1, having a pH of 5.0 to 6.

0.

11. (i) about 12.5 mg / mL of golimumab; and (ii) a) about 45 mg / mL sorbitol, about 1.47 mg / mL histidine buffer and about 0.015% (w / v) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having a pH of about 5.8 One of 10. The aqueous liquid formulation according to any one of claims 1 to 9, comprising:

12. (i) about 100 mg / mL golimumab; and (ii) a) about 41 mg / mL sorbitol, about 0.87 mg / mL histidine buffer and about 0.015% (w / v) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188, having 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) poloxamer 188 having 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) poloxamer 188, having a pH of about 5.8 One of 11. The aqueous liquid formulation of any one of claims 1 to 8 or 10, comprising:

13. 13. The aqueous liquid formulation according to claim 1, which exhibits a decrease in surfactant concentration of 40% or less when stored at 25°C for 1 month, preferably a decrease in surfactant concentration of 15% or less.

14. 14. The aqueous liquid formulation according to claim 1, which exhibits a decrease in surfactant concentration of 50% or less when stored at 40°C for 1 month, preferably a decrease in surfactant concentration of 15% or less.

15. 15. A formulation according to any one of claims 1 to 14 for use in the treatment or prevention of rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, moderately to severely active ulcerative colitis or active polyarticular juvenile idiopathic arthritis.

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