Liquid pharmaceutical composition

Abstract

To provide a novel protein formulation, in particular, a liquid pharmaceutical composition for an antibody specific to Interleukin-6 receptor.SOLUTION: A liquid pharmaceutical composition comprises: (a) tocilizumab; (b) 5 to 30 mM of a histidine buffer; (c) 50 to 250 mM of a polyol; (d) free amino acids; (e) 0.1 to 2 mg / mL of polysorbate 80; (f) water for injection; and (g) optionally sodium chloride. The composition has a pH between 6.0 and 6.5.SELECTED DRAWING: None

Description

[Technical field]

[0001] Introduction The present invention relates to novel protein formulations. In particular, the present invention relates to liquid pharmaceutical compositions of antibodies specific for the interleukin-6 receptor, methods for producing the compositions, kits containing the compositions, packages containing the compositions, and methods of treatment using the compositions and / or packages. [Background technology]

[0002] background Several biologics have been approved since the 90s to treat autoimmune diseases such as rheumatoid arthritis, juvenile arthritis, and other autoimmune diseases. Among others, tumor necrosis factor-alpha (etanercept, marketed as Enbrel®, adalimumab (marketed as Humira®), or infliximab (marketed as Remicade®) and interleukin-6 receptor (IL-6R) (tocilizumab (ROACTEMRA®)). There are drugs that target the inflammatory bowel disease, such as those marketed as rituximab or Actemra. Other drugs targeting IL-6R for the treatment of these disorders are in development or already preregistered before health authorities, such as sapelizumab, vobarilizumab, or sarilumab.

[0003] For example, tocilizumab is generally delivered to patients via either intravenous or subcutaneous injection and is typically provided in a package, such as a vial, a pre-filled syringe, or a pre-filled "pen device", in liquid form. Current commercial formulations of tocilizumab include the following components:

[0004] [Table 1]

[0005] These formulations were described, respectively, in WO 03068260 and WO 2009084659. Other formulations specific for anti-IL-6R antibodies were described, such as those in WO 0213860, WO 2011085158, or even WO 2013063510.

[0006] When preparing pharmaceutical compositions containing biologically active proteins such as antibodies, the compositions must be formulated in such a way that the activity of the protein is maintained for an appropriate period of time. Loss of protein activity / stability can be due to chemical or physical instability of the protein, especially due to denaturation, aggregation, or oxidation. The resulting product is therefore particularly suitable for long-term storage. The latter may be pharma- ceutical unacceptable. The use of additives is known to increase the stability of certain proteins, but the stabilizing effect of these additives is highly dependent on the nature of the additive and the bioactive protein itself.

[0007] As clearly demonstrated by tocilizumab, antibodies are generally formulated with different excipients when they are marketed in different strengths (e.g., 20 mg / mL vs. 180 mg / mL) or in different dosing methods (intravenous vs. subcutaneous).

[0008] There remains a need for further formulations containing anti-IL-6R antibodies such as tocilizumab, sapelizumab, vovalilizumab, or sarilumab as active ingredients, which are stable for a suitable period of time and suitable for use in injections, preferably in any type of injection.The formulations may be useful for administration in the treatment of autoimmune diseases such as rheumatoid arthritis and juvenile idiopathic arthritis.Alternative formulations that are useful, but relatively effective, even if they cannot exceed the overall efficacy of the commercially available formulations, whatever the concentration of the antibody or its dosage method, would represent a highly desirable alternative to the commercially available formulations.Desirably, the problems of the prior art may be solved while reducing the complexity of the formulation. Summary of the Invention [Means for solving the problem]

[0009] Summary of the Invention According to a first aspect of the present invention, there is provided a liquid pharmaceutical composition comprising an antibody specific for the interleukin-6 receptor (IL-6R) (such as tocilizumab, sapelizumab, vovalizumab, or sarilumab), a histidine buffer, and a polyol (such as a sugar alcohol). The composition further comprises free amino acids, a surfactant, and optionally a salt. The composition is (substantially or completely) free of arginine (suitably L-arginine).

[0010] According to a second aspect of the present invention, there is provided a method for producing a liquid pharmaceutical composition, comprising mixing together an antibody against IL-6R (such as tocilizumab, sapelizumab, vovalizumab, or sarilumab), a histidine buffer, a polyol (such as a sugar alcohol), a free amino acid, a surfactant, and optionally a salt. Also provided is a liquid pharmaceutical composition obtainable by, obtained by, or directly obtained by the method for producing a liquid pharmaceutical composition as defined herein.

[0011] According to a third aspect of the present invention there is provided a drug delivery device (such as a pre-filled syringe or pen or an intravenous bag) comprising a liquid pharmaceutical composition as defined herein.

[0012] According to a fourth aspect of the present invention there is provided a kit of components comprising a drug delivery device, a liquid pharmaceutical composition as defined herein (optionally contained in a package or container), and optionally a set of instructions having directions for administration (e.g. intravenously or subcutaneously) of the liquid pharmaceutical composition.

[0013] In a fifth aspect of the invention, there is provided a package (e.g. a pre-filled syringe, a pen, an intravenous bag, or a package / container containing any of the foregoing) comprising a liquid pharmaceutical composition as defined herein.

[0014] According to a sixth aspect of the present invention there is provided a method for manufacturing a package or drug delivery device comprising incorporating within the package or drug delivery device a liquid pharmaceutical composition as defined herein. A package or drug delivery device obtained by, or directly obtained by, the method is also provided.

[0015] According to a seventh aspect of the present invention there is provided a liquid pharmaceutical composition as defined herein for use in therapy. [Brief description of the drawings]

[0016] [Figure 1] Figure 14. Buffer selection steps: A) Light stress, high molecular weight (HMW)%, SEC data; B) Light stress, DLS (monomer radius); C) Heat stress at 50°C, aggregate radius; D) Heat stress at 50°C, HMW%, SEC data. [Diagram 2] Figure 3. Buffer selection steps: A) Oxidative stress, % monomer, SEC data; B) Oxidative stress, % polymer, SEC data; C) Mechanical stress, % polymer, SEC data. [Diagram 3] FIG. 2: Behavior of formulations under heat stress—results regarding changes in main peaks (CE-SDS). [Figure 4] FIG. 2: Behavior of formulations under light stress—results concerning changes in main peaks (CE-SDS). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] definition Any feature, including any suitable and preferred feature, described with respect to any particular aspect of the invention may also be a feature, including any suitable and preferred feature, of any other aspect of the invention.

[0018] Unless otherwise stated, the following terms used in the specification and claims have the following meanings, as explained below.

[0019] The term "antibody" and its plural form "antibodies" as used herein include, inter alia, polyclonal antibodies, affinity purified polyclonal antibodies, monoclonal antibodies, as well as nanobodies, F(ab')2, Fab proteolytes, and the like. The term "antibody" includes both single-armed (monovalent) or two-armed (bivalent) antibodies, and antigen-binding fragments, such as single-chain variable fragments (scFv).

[0020] The term "recombinant antibody" is intended to include antibodies that are prepared, expressed, produced, or isolated using recombinant methods.

[0021] The term "anti-IL-6R antibody" refers to an antibody specific for the interleukin 6 receptor (i.e., IL-6R). Preferably, an anti-IL-6R antibody is an antibody that not only binds to its target, i.e., IL-6R, but also neutralizes it (instead inhibits or antagonizes it).

[0022] The term "tocilizumab" includes the originator's drug substance (commercially available) as defined in WO 9219759 (especially hPM-1 therein) and elsewhere in the art, as well as biosimilars thereof. Tocilizumab has a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2. Tocilizumab has a molecular weight of approximately 145 kDa.

[0023] The term "saperizumab" refers to an investigational anti-IL6R antibody also known as SA-237 and its biosimilars. Saperizumab is a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:3 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:4. ).

[0024] The term "vovalilizumab" refers to an anti-IL6R nanobody linked to an anti-human serum albumin nanobody, also named ALX-0061, currently in development, and its biosimilars. Vovalilizumab comprises the amino acid sequence defined in SEQ ID NO: 5. Vovalilizumab has a molecular weight of approximately 257 kDa.

[0025] The term "sarilumab" refers to an anti-IL6R antibody, also named REGN-88 or SAR-153191, currently being preregistered before health authorities, and its biosimilars. Sarilumab has a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:6 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:7. Sarilumab has a molecular weight of about 144 kDa.

[0026] The term "biosimilar" refers to a drug substance that shares complete protein sequence identity with any one of the drug substances on the market (i.e. approved by a health authority). Note that a biosimilar may have a (slightly) different glycosylation profile. Such a "biosimilar" needs to be officially approved as a "biosimilar" for sale before said "biosimilar" can be marketed and sold.

[0027] As used herein, the term "buffer" or "buffer solution" refers to a solution of a compound known to be safe in a formulation for pharmaceutical or veterinary use and effective in maintaining or controlling the pH of the formulation in the range of pH desired for the formulation. Acceptable buffers for controlling pH from moderately acidic to moderately basic pH include, but are not limited to, phosphate, acetate, lactate, citrate, arginine, TRIS, and histidine, its salts and / or acidic forms, and / or any combination thereof. "TRIS" refers to 2-amino-2-hydroxymethyl-1,3-propanediol and any pharmacologically acceptable salts thereof. Compounds that make up a buffer are also referred to as "buffering agents." According to the present invention, the preferred buffer is a histidine buffer. The pH of the "buffer solution" will change only slightly upon the addition of small amounts of strong acid or base due to the "buffering effect" provided by the "buffering agent." It should be noted that a particular concentration of a histidine buffer generally refers to a combination of the concentrations of histidine and the imidazolium form of histidine (or a protonated histidine salt). In the case of histidine, however, such a concentration is usually easy to calculate by reference to the input amount of histidine or its salt. The overall pH of a composition is generally a reflection of the equilibrium concentrations of each of the relevant buffer species (i.e., the balance of the buffer to its acid / base conjugate).

[0028] As used herein, the term "buffer" refers to an acid or base component (usually a weak acid or weak base) of a buffer or buffer solution. A buffer helps maintain the pH of a particular solution at or near a predetermined value, and buffers are generally chosen to complement the predetermined value. A buffer is suitably a single compound that produces the desired buffering effect, which may be achieved by adding a strong acid or strong base until the required pH is reached, especially if the buffer is mixed with (and can be properly proton-exchanged with) an appropriate amount (depending on the desired, predetermined pH) of its corresponding "acid / base conjugate" or if the required amount of the corresponding "acid / base conjugate" is formed in situ.

[0029] Unless otherwise specified, references herein to an "amino acid" in the context of an amino acid present or otherwise within a composition (particularly a pharmaceutical liquid composition of the present invention) refer to either a specific (e.g., arginine, histidine) or generally (e.g., any amino acid). The amounts in the formula (I) refer to the corresponding free amino acids (for consistency, the amounts are calculated by reference to the free amino acids as such, as appropriate, but regardless of their / their protonation state and / or salt form). This may include naturally occurring and / or artificial amino acids, as appropriate. Unless otherwise specified, such reference is not intended to relate to amino acid residues that are covalently incorporated as part of a larger compound (rather than a composition comprising multiple compounds), such as a peptide or protein (where such amino acid residues are linked via peptide bonds). Thus, for example, although tocilizumab contains amino acid residues as a protein, tocilizumab is not considered to contain any "free amino acids". As an example, a composition defined as "free of arginine" does not contain any free arginine, although the composition may still contain one or more proteins (e.g., tocilizumab) where the protein itself contains an arginine residue. Unless otherwise specified, reference herein to any one or more "amino acids", whether specific or general, refers to the L-stereoisomer or racemate thereof, as appropriate, most suitably L-amino acids.

[0030] The term "substantially free", when used in reference to a particular component of a composition (e.g., "liquid pharmaceutical composition substantially free of arginine"), refers to a composition to which essentially none of the component has been added. As explained above, such a reference is unrelated to the presence of amino acid residues in protein structures. When a composition is "substantially free" of a particular component, the composition suitably contains 0.001% by weight or less of the component, suitably 0.0001% by weight or less of the component, suitably 0.00001% by weight or less, suitably 0.000001% by weight or less, suitably 0.0000001% by weight or less of the component, most suitably 0.0001 parts per billion (by weight) or less.

[0031] The term "completely free," when used in reference to a particular component of a composition (e.g., a "liquid pharmaceutical composition substantially free of arginine"), refers to a composition that does not contain any of said components. As explained above, such a reference is unrelated to the presence of the amino acid residue in a protein structure.

[0032] The term "stability" as used herein refers to the physical, chemical, and conformational stability of tocilizumab in a formulation according to the invention (and includes maintenance of biological potency). Instability of a protein formulation may be caused by chemical degradation or aggregation of protein molecules to form higher order polymers, deglycosylation, modified glycosylation, oxidation, or any other structural modification that reduces at least one biological activity of the antibody of the invention.

[0033] The term "stable" solution or formulation, as used herein, is one in which the degree of protein degradation, modification, aggregation, loss of biological activity, and the like, is somewhat controlled and does not increase unacceptably over time. It therefore generally refers to the physical and / or chemical and / or biological stability of the components, typically the active agent or composition, during storage / keeping.

[0034] Preferably, the formulation retains at least greater than 80% of antibody activity over a period of at least 12 months at room temperature and / or at lower temperatures (such as 2-8° C.). The stabilized antibody formulations of the invention preferably have a shelf life of at least about 12 months, 18 months, more preferably at least 20 months, and even more preferably about 24 months when stored at room temperature and / or at lower temperatures (such as 2-8° C.). Methods for monitoring the stability of the antibody formulations of the invention are available in the art and include the methods described in the Examples disclosed herein.

[0035] The term "stabilizer" or "stabilizer" as used herein is a compound that is physiologically tolerable and provides suitable stability / tonicity to the formulation. It particularly prevents net water flow across cell membranes bordering the formulation. Compounds such as glycerin are commonly used for such purposes. Other suitable stability agents include, but are not limited to, amino acids or proteins (e.g., glycine or albumin), salts (e.g., sodium chloride), and sugars (e.g., dextrose, mannitol, sucrose, and lactose). According to the present invention, preferred stabilizers are polyols, even more preferably sugar alcohols such as mannitol.

[0036] The term "surfactant" as used herein refers to a soluble compound that can be used to increase the water solubility of hydrophobic oily substances, or otherwise increase the miscibility of two substances with different hydrophobicities. For this reason, these polymers are commonly used in industrial applications, cosmetics, and pharmaceuticals. They are also used as model systems for drug delivery applications, particularly to modify the absorption of drugs or their delivery to target tissues. Well-known surfactants include polysorbates (polyoxyethylene derivatives; Tween) and poloxamers (i.e., copolymers based on ethylene oxide and propylene oxide, also known as Pluronics®). According to the present invention, the preferred surfactant is a polysorbate surfactant, even more preferably polysorbate 80.

[0037] The term "isotonicity agent" or "tonicifier", as used herein, is a compound that confers a physiologically tolerable and suitable tonicity to a formulation. It specifically prevents the net flow of water across cell membranes bordering the formulation. Compounds such as glycerin are commonly used for such purposes. According to the present invention, the preferred isotonicity agent is a salt, even more preferably NaCl.

[0038] Reference herein to a specific amount of a particular component of a composition, particularly a buffer, appropriately refers to the amount of the pure anhydrous form of the relevant component (or the composition formed by using said amount of the pure anhydrous form), although such component may be used in a non-anhydrous form when forming the composition. The amount of any corresponding non-anhydrous form (e.g., monohydrate, dihydrate, etc.) may be easily calculated by simply using the appropriate multiplier. For example, unless otherwise specified (following the examples, the amounts refer to histidine), the amount specified for histidine refers to the anhydrous form of histidine having a molecular weight of about 155 g / mol. It will be practical for a person skilled in the art to easily understand how to adjust the amount of diluent / water depending on the form of the component used to obtain the target concentration.

[0039] It should be appreciated that references to "treating" or "treatment" include prophylactic treatment and the alleviation of established symptoms of a condition. "Treating" a condition, disorder, or condition or its "treatment" includes (1) preventing or delaying the appearance of clinical symptoms of the condition, disorder, or condition occurring in a human who may be afflicted by or susceptible to the condition, disorder, or condition, but who has not yet experienced or displayed clinical or subclinical symptoms of the condition, disorder, or condition, (2) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying the onset or recurrence of the disease (in the case of maintenance therapy) or at least one clinical or subclinical symptom thereof, or (3) palliating or attenuating the disease, i.e., causing regression of the condition, disorder, or condition or at least one clinical or subclinical symptom thereof.

[0040] When a composition is said to contain a plurality of ingredients (at any selected specific amount or concentration), In particular, in the range of concentrations specified, the composition may optionally contain additional ingredients other than those specifically mentioned.

[0041] Detailed Description of the Invention The main object of the present invention is a liquid pharmaceutical composition comprising an anti-IL-6R antibody, said antibody being capable of neutralizing (instead inhibiting or antagonizing) IL-6R activity. Preferably, the liquid pharmaceutical composition comprises an anti-IL-6R antibody, such as tocilizumab, sapelizumab, vovalizumab, or sarilumab, including any biosimilars thereof. The composition preferably comprises a histidine buffer and a polyol, maintaining a pH in the range of 5.5 to 7.5. The composition is preferably (substantially or completely) free of arginine. Moreover, the composition may optionally comprise any one or more further components defined herein for the liquid pharmaceutical composition (including, for example, isotonicity agents, surfactants, etc.) in any amount, concentration, or form specified herein, and the composition optionally exhibits any one or more parameters or characteristics indicated herein for the liquid pharmaceutical composition (e.g., pH, osmolality). Preferably, the liquid pharmaceutical composition according to the present invention comprises an anti-IL6-R antibody, a histidine buffer that maintains a pH in the range of 5.5 to 7.5, a polyol, a polysorbate surfactant, a free amino acid, and optionally a salt.

[0042] In accordance with the present invention, the liquid pharmaceutical composition as a whole is (substantially or completely) free of arginine (such as L-arginine).

[0043] The liquid pharmaceutical composition according to the present invention contains an anti-IL-6R antibody at a concentration of 10 to 250 mg / ml or about 10 to about 250 mg / ml, preferably 15 to 200 mg / ml or about 15 to about 200 mg / ml. For example, the anti-IL-6R antibody may be present in the formulation at a concentration of 15, 20, 30, 40, 50, 60, 80, 100, 120, 140, 160, 180, or 200 mg / ml or about 15, about 20, about 30, about 40, about 50, about 60, about 80, about 100, about 120, about 140, about 160, about 180, or about 200 mg / ml. The anti-IL-6R antibody can be any known anti-IL6R antibody, such as tocilizumab, sapelizumab, vovalizumab, or sarilumab (as defined herein).

[0044] Preferably, the formulations of the present invention retain at least 80% of their anti-IL-6R biological activity at the time of formulation and / or packaging over a period of at least 12 months (prior to the first use). Anti-IL-6R activity may be measured by any known method.

[0045] The liquid pharmaceutical composition according to the present invention has an overall pH in the range of 5.5 to 7.5 or about 5.5 to about 7.5. Preferably, the liquid pharmaceutical composition has a pH in the range of 6.0 to 7.0 or about 6.0 to about 7.0. Suitably, the liquid pharmaceutical composition has a pH of 6.0 or 6.5 or about 6.0 or about 6.5.

[0046] The buffer according to the present invention is a histidine buffer and is at a concentration of 2 to 50 mM or about 2 to about 50 mM. In one embodiment, the histidine buffer is present at a concentration of 5 to 30 mM or about 5 to about 30 mM, preferably at a concentration of 10 to 25 mM or about 10 to about 25 mM, and more preferably at a concentration of 20 mM or about 20 mM.

[0047] In another aspect, the liquid pharmaceutical composition comprises a buffer species (suitably a histidine buffer species - e.g. histidine itself) at a concentration of 0.1-10 mg / mL or about 0.1-10 mg / mL. In one embodiment, the buffer species is present at a concentration of 0.5-5 mg / mL or about 0.5-5 mg, more preferably 2-4 mg / mL or about 2-4 mg / mL. For example, the buffer species is , 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, or 4.0 mg / mL or about 2.0, about 2.25, about 2.5, about 2.75, about 3.0, about 3.25, about 3.5, about 3.75, or about 4.0 mg / mL. In one embodiment, the buffer system / buffering agent is present in a concentration of 3.10 mg / mL or about 3.10 mg / mL.

[0048] In another embodiment, the liquid pharmaceutical composition comprises a buffer in a molar ratio of buffer to anti-IL6R antibody of about 5:1 to about 200:1, which will depend primarily on the concentration of the antibody in the formulation. For example, if the anti-IL6R antibody is tocilizumab or sarilumab at 20 mg / mL, the molar ratio is most suitably about 145:1, and if the anti-IL6R antibody is tocilizumab or sarilumab at 180 mg / mL, the molar ratio is most suitably about 16:1.

[0049] The liquid pharmaceutical composition according to the present invention as a whole comprises a stabilizer, most preferably a polyol. Suitably, such a component promotes the maintenance of the structural integrity of the biological preparation, especially during freezing and / or lyophilization (if necessary) and / or storage. The liquid pharmaceutical composition may comprise one or more polyols. Preferably, the polyol is a sugar polyol, such as a sugar alcohol. More preferably, the sugar alcohol is selected from the group consisting of mannitol, sorbitol, xylitol, arabitol, erythritol, lactitol, maltitol, or inositol. More preferably, the polyol (e.g., sugar alcohol) is mannitol. Mannitol has indeed been identified by the present inventors as a particularly advantageous polyol stabilizer for use together with a histidine buffer in liquid anti-IL-6R antibody formulations.

[0050] The liquid pharmaceutical composition comprises a polyol (such as mannitol) at a concentration of 50-400 mM or about 50-400 mM, preferably 100-300 mM or about 100-300 mM, more preferably 150-250 mM or about 150-250 mM. In one embodiment, the polyol is present at a concentration between 190-210 mM, most preferably 200 mM or about 200 mM. In one particular embodiment, the polyol is mannitol and is present in the liquid pharmaceutical composition at a concentration of 200 mM or about 200 mM.

[0051] In another aspect, the liquid pharmaceutical composition comprises a polyol (such as mannitol) at a concentration of 1 mg / mL to 100 mg / mL or about 1 mg / mL to about 100 mg / mL, more preferably 10 mg / mL to 75 mg / mL or about 10 mg / mL to about 75 mg / mL, even more preferably 25 mg / mL to 50 mg / mL or about 25 mg / mL to about 50 mg / mL. In one embodiment, the polyol is present in a concentration between 30 mg / mL to 40 mg / mL, most suitably about 36 mg / mL. For example, the polyol (such as mannitol) may be present in the formulation at a concentration of, or about, 25, 27.5, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 42.5, 45, 47.5, or 50 mg / mL. In one particular embodiment, the polyol is mannitol and is present in the liquid pharmaceutical composition at a concentration of, or about, 36 mg / mL.

[0052] In another embodiment, the liquid pharmaceutical composition comprises a polyol (such as mannitol) in a molar ratio of sugar stabilizer to anti-IL-6R antibody of about 100:1 to about 1500:1, which will depend primarily on the concentration of the antibody in the formulation. For example, if the anti-IL6R antibody is tocilizumab or sarilumab at 20 mg / mL, the molar ratio is most suitably about 1450:1, and if the anti-IL6R antibody is tocilizumab or sarilumab at 180 mg / mL, the molar ratio is most suitably about 161:1.

[0053] The liquid pharmaceutical composition according to the present invention as a whole comprises at least one free amino acid other than histidine and arginine. Preferably, said free amino acid contains a sulfur element, such as cysteine ​​or methionine. More preferably, said free amino acid is methionine. Said components have been shown to be good antioxidants.

[0054] The liquid pharmaceutical composition comprises at least one free amino acid (such as methionine) at a concentration of 0.1 to 5 mM or about 0.1 to about 5 mM, preferably 0.2 to 2 mM or about 0.2 to about 2 mM, more preferably 0.4 to 0.6 mM or about 0.4 to about 0.6 mM. For example, the free amino acid is present at a concentration of 0.400, 0.425, 0.450, 0.475, 0.500, 0.550, 0.575, or 0.600 mM or about 0.400, about 0.425, about 0.450, about 0.475, about 0.500, about 0.550, about 0.575, or about 0.600 mM. In a particular embodiment, the at least one free amino acid is methionine and is present in the liquid pharmaceutical composition at a concentration of 0.5 mM or about 0.5 mM.

[0055] In another embodiment, the liquid pharmaceutical composition comprises at least one free amino acid (such as methionine) at a concentration of 0.01 mg / mL to 1 mg / mL or about 0.01 mg / mL to about 1 mg / mL, preferably 0.025 mg / mL to 0.5 mg / mL or about 0.025 mg / mL to about 0.5 mg / mL, more preferably 0.05 mg / mL to 0.2 mg / mL or about 0.05 mg / mL to about 0.2 mg / mL, and even more preferably 0.06 mg / mL to 0.1 mg / mL or about 0.06 to about 0.1 mg / mL. For example, the at least one free amino acid is present at a concentration of, or about, 0.050, 0.055, 0.060, 0.065, 0.070, 0.075, 0.080, 0.085, 0.090, 0.095, or 0.1 mg / mL. In one particular embodiment, the at least one free amino acid is methionine and is present in the liquid pharmaceutical composition at a concentration of, or about, 0.075 mg / mL.

[0056] In another embodiment, the liquid pharmaceutical composition comprises at least one amino acid (such as methionine) in a molar ratio of glucose stabilizer to anti-IL-6R antibody of about 1:5 to about 5:1, which will depend primarily on the concentration of the antibody in the formulation. For example, if the anti-IL6R antibody is tocilizumab or sarilumab at 20 mg / mL, the molar ratio is preferably about 36:10, and if the anti-IL6R antibody is tocilizumab or sarilumab at 180 mg / mL, the molar ratio is most suitably about 2:5.

[0057] The liquid pharmaceutical composition according to the invention as a whole contains a surfactant. Preferred surfactants are polysorbates such as polysorbate 20 (alternative name: polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (alternative name: polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (alternative name: polyoxyethylene (20) sorbitan monostearate) or polysorbate 80 (alternative name: polyoxyethylene (20) sorbitan monooleate). Preferably, the surfactant is polysorbate 80.

[0058] The liquid pharmaceutical composition contains a surfactant such as polysorbate 80 at a concentration of 0.1 to 5 mM or about 0.1 to about 5 mM, preferably 0.2 to 2 mM or about 0.2 to about 2 mM, more preferably 0.4 to 0.9 mM or about 0.4 to about 0.9 mM. For example, the surfactant may be 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, or 0.90 mM or about 0.40, about 0.45, about 0.50, about 0.55, about 0.60, about 0.65, about 0.70, about 0.75, about 0.80, about 0.85 In one particular embodiment, the surfactant is polysorbate 80 and is present in the liquid pharmaceutical composition at a concentration of, or about, 0.75 or 0.80 mM.

[0059] In another embodiment, the liquid pharmaceutical composition comprises a surfactant such as polysorbate 80 at a concentration of 0.1 to 10 mg / mL or about 0.1 to about 10 mg / mL, preferably 0.25 to 5 mg / mL or about 0.25 to about 5 mg / mL, more preferably 0.5 to 2 mg / mL or about 0.5 to about 2 mg / mL. For example, the surfactant is present at a concentration of 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.75, or 2 mg / mL or about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.75, or about 2 mg / mL. In one particular embodiment, the surfactant is polysorbate 80 and is present in the liquid pharmaceutical composition at a concentration of at or about 1.0 mg / mL.

[0060] In another embodiment, the liquid pharmaceutical composition comprises a surfactant (such as polysorbate 80) in a molar ratio of surfactant to anti-IL-6R antibody of about 1:2 to about 60:1, which will depend primarily on the concentration of the antibody in the formulation. For example, if the anti-IL6R antibody is tocilizumab or sarilumab at 20 mg / mL, the molar ratio is preferably about 56:10, and if the anti-IL6R antibody is tocilizumab or sarilumab at 180 mg / mL, the molar ratio is most suitably about 6:10.

[0061] The liquid pharmaceutical composition of the present invention may contain any one or more pharma- ceutically acceptable diluents or mixtures thereof. However, most suitably, the liquid pharmaceutical composition is an aqueous pharmaceutical composition. Most suitably, the diluent is water, suitably only water. The water is suitably water for injection (WFI). The diluent may, for example, balance the components in any liquid pharmaceutical composition so that the weight percentage is 100%. Any concentration given herein for any component of the liquid pharmaceutical composition corresponds to the concentration of said component (suitably dissolved) in the diluent mixed with any other components.

[0062] Liquid pharmaceutical compositions of the present invention are suitably solutions and are suitably free (substantially or completely) of particles or precipitates.

[0063] The liquid pharmaceutical composition according to the present invention may further comprise one or more additives, such as salts, as a whole. In one particular embodiment, there is at least one further additive that is a tonicity agent. Preferably, when present, the tonicity agent is or comprises sodium chloride (NaCl). Sodium chloride is a particularly advantageous stabilizer for use together with histidine buffers in liquid anti-IL-6R antibody formulations.

[0064] Suitably, the liquid pharmaceutical composition comprises a salt (such as sodium chloride) at a concentration of 20 to 200 mM or about 20 to about 200 mM, preferably 50 to 150 mM or about 50 to about 150 mM, more preferably 75 to 125 mM or about 75 to about 125 mM. In one embodiment, the salt is present at a concentration of 100 mM or about 100 mM. In one particular embodiment, the salt is sodium chloride and is present at a concentration of 100 mM or about 100 mM. In another aspect, the liquid pharmaceutical composition comprises a salt (such as NaCl) at a concentration of 0.5 mg / mL to 25 mg / mL or about 0.5 mg / mL to about 25 mg / mL, preferably 1.0 mg / mL to 10 mg / mL or about 1.0 mg / mL to about 10 mg / mL, more suitably 3 mg / mL to 7 mg / mL or about 3 mg / mL to about 7 mg / mL. In one embodiment, the salt is present in a concentration between 5 mg / mL and 6 mg / mL, most suitably about 5.84 mg / mL. In one particular embodiment, the salt is sodium chloride and is present in a concentration of about 5.84 mg / mL.

[0065] In another embodiment, the liquid pharmaceutical composition comprises a salt (such as NaCl) in a molar ratio of salt to anti-IL-6R antibody of about 50:1 to about 800:1, which will depend primarily on the concentration of the antibody in the formulation. For example, if the anti-IL6R antibody is tocilizumab or sarilumab at 20 mg / mL, the molar ratio is preferably about 725:1, and if the anti-IL6R antibody is tocilizumab or sarilumab at 180 mg / mL, the molar ratio is most suitably about 80:1.

[0066] In a further aspect, the present invention also provides a method for stabilizing a liquid anti-IL-6R antibody composition, comprising mixing an anti-IL-6R antibody with any relevant components required to form a liquid pharmaceutical composition as defined herein.Therefore, a method for producing a liquid pharmaceutical composition is provided herein, comprising mixing together an antibody against IL-6R, such as tocilizumab, a histidine buffer, a polyol (such as a sugar alcohol), and optionally any one or more further components as defined herein for liquid pharmaceutical compositions, optionally in any amount, concentration, or form as specified; and optionally adjusting any one or more parameters as indicated herein for liquid pharmaceutical compositions (e.g., pH, osmolality).Other relevant components may include at least one free amino acid (such as methionine), a surfactant (such as polysorbate 80), and optionally a salt (such as NaCl). Each of these compounds (i.e., anti-IL-6R antibody, histidine buffer, polyol, surfactant, at least one free amino acid, and / or salt) can be used according to the concentrations, pH, and / or ratios described herein. If necessary, a person skilled in the art may refer to the examples or techniques well known in the art to form a liquid pharmaceutical composition (especially one for injection by syringe).

[0067] In one embodiment, the method comprises mixing the relevant components together in a diluent (eg, water) such that all of the components are dissolved (substantially or completely) in the diluent.

[0068] Also provided is a liquid pharmaceutical composition obtainable by, obtained by or directly obtained by the process for producing a liquid pharmaceutical composition as defined herein.

[0069] Suitably, the liquid pharmaceutical composition of the present invention has a shelf life of at least 6 months, suitably at least 12 months, suitably at least 18 months, more suitably at least 24 months. Suitably, the liquid pharmaceutical composition of the present invention has a shelf life of at least 6 months, suitably at least 12 months, suitably at least 18 months, more suitably at least 24 months at a temperature of 2-8°C.

[0070] In some embodiments, the buffering agent and / or buffer are preformed as a separate mixture, and the buffer is transferred to the precursor of the liquid pharmaceutical composition (containing some or all of the components other than the buffer) via buffer exchange (e.g., using diafiltration until the appropriate concentration or osmolality is reached). Additional additives may then be added, if necessary, to produce the final liquid pharmaceutical composition. The pH may be adjusted once or before all components are present.

[0071] The final liquid pharmaceutical composition may suitably be filtered to remove particulate matter. Suitably, the filtration is through a filter of size 1 μm or less, suitably 0.22 μm. For example, the mode of filtration is through a 0.22 μm PES or PVDF filter.

[0072] In a third aspect, the present invention provides a drug delivery device comprising a liquid pharmaceutical composition as defined herein. Preferably, the drug delivery device comprises a chamber in which the pharmaceutical composition is present. More preferably, the drug delivery device is sterile.

[0073] The drug delivery device may be a vial, an ampoule, a syringe, an injection pen (e.g., inherently incorporating a syringe), or an intravenous bag. When the drug delivery device is a syringe, it is preferably an injection pen. Suitably, the syringe is a glass syringe.

[0074] In a fourth aspect, the present invention provides a kit of elements comprising a drug delivery device, (without the liquid pharmaceutical composition incorporated therein), a liquid pharmaceutical composition as defined herein (optionally contained in a separate package or container), and optionally a set of instructions with instructions for administration (e.g. subcutaneously or intravenously) of the liquid pharmaceutical composition. The user may then fill the drug delivery device with the liquid pharmaceutical composition (which may be provided in a vial or ampoule or the like) prior to administration.

[0075] As a fifth aspect, a package is also described that contains the liquid pharmaceutical composition defined herein.Compatibly, the package contains a drug delivery device defined herein, and suitably, a plurality of drug delivery devices.The package may contain any suitable container for containing one or more drug delivery devices.

[0076] The present invention provides in a sixth aspect a method for manufacturing a drug delivery device suitably as defined herein, comprising incorporating a liquid pharmaceutical composition as defined herein into the drug delivery device. Such manufacturing typically comprises loading a liquid pharmaceutical composition as defined herein into a syringe, suitably via a needle attached thereto. The needle may then be removed, replaced or left in place. Also disclosed is a drug delivery device obtainable by, obtained by or directly obtained by the method of manufacturing as defined herein.

[0077] Also described is a method for manufacturing a package, comprising incorporating a liquid pharmaceutical composition defined herein into the package.Suitably, this is achieved by incorporating said liquid pharmaceutical composition into one or more drug delivery devices, and then incorporating one or more pre-filled drug delivery devices into a container present in the package.The present invention further provides a package obtainable by, obtained by, or directly obtained by the method of manufacture defined herein.

[0078] The liquid pharmaceutical composition defined herein may be used to treat any one or more of the aforementioned diseases or medical disorders. In a particular embodiment, the liquid pharmaceutical composition is used to treat rheumatoid arthritis and juvenile idiopathic arthritis. In another aspect, the liquid pharmaceutical composition is used to treat other diseases, such as giant cell arteritis or systemic sclerosis.

[0079] Liquid pharmaceutical compositions are suitably administered parenterally via intravenous or subcutaneous injection.

[0080] Specific Embodiments In one embodiment, the liquid pharmaceutical composition comprises - Anti-IL-6R antibody (tocilizumab, sapelizumab, vovalilizumab, or sarilumab) Bu et al.); - Histidine buffer that maintains a pH between approximately 5.5 and 7.5; - polyols (e.g. mannitol); - free amino acids (e.g. methionine); - surfactants (e.g. polysorbate 80); - Water for injections; and - Optionally a salt (e.g. NaCl) Includes.

[0081] In one embodiment, the liquid pharmaceutical composition comprises - Anti-IL-6R antibodies (such as tocilizumab, sapelizumab, vovalilizumab, or sarilumab) at a concentration of 10-250 mg / mL; - Histidine buffer that maintains a pH between approximately 5.5 and 7.5; - polyols (e.g. mannitol); - free amino acids (e.g. methionine); - surfactants (e.g. polysorbate 80); - Water for injections; and - Optionally a salt (e.g. NaCl) Includes.

[0082] In one embodiment, the liquid pharmaceutical composition comprises - Anti-IL-6R antibodies (such as tocilizumab, sapelizumab, vovalilizumab, or sarilumab); - histidine buffer at a concentration between 2 and 50 mM, or at a concentration between 0.1 and 10 mg / mL, or at a molar ratio of buffer to antibody between 5:1 and 200:1, with a pH between about 5.5 and 7.5; - polyols (e.g. mannitol); - free amino acids (e.g. methionine); - surfactants (e.g. polysorbate 80); - Water for injections; and - Optionally a salt (e.g. NaCl) Includes.

[0083] In one embodiment, the liquid pharmaceutical composition comprises - Anti-IL-6R antibodies (such as tocilizumab, sapelizumab, vovalilizumab, or sarilumab); - Histidine buffer that maintains a pH between approximately 5.5 and 7.5; - a polyol (e.g. mannitol) in a concentration of 50-400 mM, or in a concentration of 1-100 mg / mL, or in a molar ratio of polyol to antibody of 100:1 to 1500:1; - free amino acids (e.g. methionine); - surfactants (e.g. polysorbate 80); - Water for injections; and - Optionally a salt (e.g. NaCl) Includes.

[0084] In one embodiment, the liquid pharmaceutical composition comprises - Anti-IL-6R antibodies (such as tocilizumab, sapelizumab, vovalilizumab, or sarilumab); - Histidine buffer that maintains a pH between approximately 5.5 and 7.5; - polyols (e.g. mannitol); - a free amino acid (e.g. methionine) at a concentration of 0.1 to 5 mM, or at a concentration of 0.01 to 1 mg / mL, or at a molar ratio of free amino acid to antibody of 1:5 to 5:1; - surfactants (e.g. polysorbate 80); - Water for injections; and - Optionally a salt (e.g. NaCl) Includes.

[0085] In one embodiment, the liquid pharmaceutical composition comprises - Anti-IL-6R antibodies (such as tocilizumab, sapelizumab, vovalilizumab, or sarilumab); - Histidine buffer that maintains a pH between approximately 5.5 and 7.5 - polyols (e.g. mannitol); - free amino acids (e.g. methionine); - detergent (e.g. polysorbate 80), free amino acid at a concentration of 0.1-5 mM, or at a concentration of 0.1-10 mg / mL, or a molar ratio of detergent to antibody of 1:2 to 60:1; - Water for injections; and - Optionally a salt (e.g. NaCl) Includes.

[0086] In one embodiment, the liquid pharmaceutical composition comprises - Anti-IL-6R antibodies (such as tocilizumab, sapelizumab, vovalilizumab, or sarilumab); - Histidine buffer that maintains a pH between approximately 5.5 and 7.5 - polyols (e.g. mannitol); - free amino acids (e.g. methionine); - surfactants (e.g. polysorbate 80); - Water for injections; and - Optionally salt (e.g. NaCl), free amino acids at a concentration of 20-200 mM, or at a concentration of 0.5-25 mg / mL, or a molar ratio of salt to antibody of 50:1-800:1 Includes.

[0087] In one embodiment, the liquid pharmaceutical composition comprises - Anti-IL-6R antibodies (such as tocilizumab, sapelizumab, vovalilizumab, or sarilumab) at a concentration of 10-250 mg / mL; - histidine buffer at a concentration between 2 and 50 mM, or at a concentration between 0.1 and 10 mg / mL, or at a molar ratio of buffer to antibody between 5:1 and 200:1, with a pH between about 5.5 and 7.5; - a polyol (e.g. mannitol) in a concentration of 50-400 mM, or in a concentration of 1-100 mg / mL, or in a molar ratio of polyol to antibody of 100:1 to 1500:1; - a free amino acid (e.g. methionine) at a concentration of 0.1 to 5 mM, or at a concentration of 0.01 to 1 mg / mL, or at a molar ratio of free amino acid to antibody of 1:5 to 5:1; - detergent (e.g. polysorbate 80), free amino acid at a concentration of 0.1-5 mM, or at a concentration of 0.1-10 mg / mL, or a molar ratio of detergent to antibody of 1:2 to 60:1; - Water for injections; and - Optionally salt (e.g. NaCl), free amino acids at a concentration of 20-200 mM, or at a concentration of 0.5-25 mg / mL, or a molar ratio of salt to antibody of 50:1-800:1 Includes. EXAMPLES

[0088] Materials and Equipment The following materials were used in preparing the formulations described in the Examples below.

[0089] [Table 2]

[0090] The following disposable equipment and materials were used in the following examples and screening experiments:

[0091] [Table 3]

[0092] The following equipment was used in the following examples and screening experiments:

[0093] [Table 4]

[0094] Analytical techniques and protocols The following analytical method protocols were used in the following examples and screening experiments for the reasons stated in the table below.

[0095] [Table 5]

[0096] The individual protocols for each of the above analytical methods are described in order below, and in the Examples and screening experiments where any such analytical method is mentioned these protocols were used.

[0097] 1. Heat Stress Each sample was incubated at 50° C. At each time point, the required amount of sample was removed and either analyzed immediately or stored at −80° C. before testing.

[0098] 2. Mechanical Stress Each sample was placed in a 10 ml Nalgene square bottle and incubated for 14 days. At each time point, the relevant container was either tested immediately or removed for storage at -80°C prior to testing.

[0099] 3. Light Stress Exposure was at 765Wh / m2. The light-exposed samples were placed alongside the required amount of control samples (kept in the same chamber but not irradiated). After exposure, at each time point, the required amount of sample was either tested immediately or removed for storage at -80°C before testing.

[0100] 4. Oxidative Stress To each sample (100 μL), 100 μL of H2O2 2% v / v was added to obtain a final concentration of 1%. The solutions were incubated at 25° C. If the solutions became turbid, the plates were spun down at 10000 g for 25 min at RT° C.

[0101] 5. Other methods The standard method, - visible particles, - protein content, - SE-HPLC, - CE-SDS, - CEX-HPLC - pH, - Osmolality (time 0 only) Used for.

[0102] The study aimed to develop a new liquid formulation of one anti-IL-6R antibody for both subcutaneous and / or intravenous use. The formulation development consisted of the following phases: 1. Buffer Selection (DS DoE) 2. Additive Selection (DP DoE)

[0103] Formal stability studies were performed as follows (Table 1).

[0104] [Table 6]

[0105] Example 1 - Buffer Screening DS buffer screening was performed using a DoE approach. From an initial number of buffers, one final buffer and one reserve were selected by a combination of thermodynamic and kinetic parameter approaches. The anti-IL-6R antibody used in this example is tocilizumab. After purification, the antibody was exchanged into four different buffers by centrifugation: Phosphate buffer pKa=7.2, Phosphate citrate buffer pKa=6.40, TRIS buffer pKa=8.1, Histidine pKa=6.0.

[0106] The DS consisted only of mAb and buffer, and the goal of this step was to evaluate a single interaction between the two components. The experimental matrix was as follows (see Table 2 below):

[0107] [Table 7]

[0108] Exchange and concentration by concentration are well within the knowledge of one of ordinary skill in the art and therefore will not be detailed herein. The antibody target concentration was 210 mg / mL or higher. Differential scanning fluorimetry (DSF) technology (High throughput thermostability screening of monoclonal antibody formulations. J Pharm Sci. 2010 Apr;99(4):1707-20) was used with SyproOrange dye. Buffers were used to preselect. A stress test phase was performed with buffers with higher Th and lower aggregation percentage according to DSF: - Histidine 20mM, pH 6.0, - TRIS 20mM pH 6.2, - Phosphate 20mM pH 6.2, - Phosphate 20mM pH 7.2.

[0109] The stress tests used were as follows: - Heat stress, - mechanical stress, - Light stress, - Oxidation.

[0110] Light stress: Figures 1A and 1B show the results for high molecular weight species (HMW) and monomer radius, respectively. Histidine buffer, 20 mM, pH 6.0 and phosphate buffer, 20 mM, pH 6.2 showed the least increase in HMW% and the least increase in monomer radius. Note that TRIS buffer showed slightly more protection against light stress than phosphate buffer.

[0111] Heat stress: Figures 1C and 1B show the results for aggregate radius and high molecular weight species (HMW). Figure 1 shows the aggregate radius of each sample. A very low increase in aggregate radius was observed for all samples except for phosphate pH 7.2. Histidine buffer, 20 mM, pH 6.0 and phosphate buffer, 20 mM, pH 6.2 showed the lowest increase in HMW. The most aggregated sample was from phosphate buffer pH 7.2.

[0112] Oxidative Stress: Figures 2A and 2B show the results for % monomer and high molecular weight species (HMW), respectively. A very small HMW increase in aggregate radius was observed for all samples.

[0113] Mechanical stress: Figure 2C shows the results for high molecular weight species (HMW). The smallest increase in HMW% was observed for phosphate buffer, pH 6.2 and histidine buffer, pH 6.0.

[0114] Viscosity: The data clearly showed that the phosphate buffer had a higher viscosity than either the histidine or TRIS buffers (see Table 3 below).

[0115] [Table 8]

[0116] Conclusion: Based on the results of the buffer screening, the buffers selected were: histidine buffer, 20 mM, pH 6.0 (as the first buffer) and TRIS buffer, 20 mM, pH 7.1 (as the reserve).

[0117] Example 2 - Additive Screening The goal was to develop a formulation made of five components: buffer, antioxidant, surfactant, tonicity, and stabilizer. The same approach used for buffer selection was used for excipient screening: 1) high throughput excipient screening by SE-HPLC (for about 40 different formulations), 2) stress testing on selected formulations, 3) one primary formulation and one (or two) back-up selection. Formulation stability was then tested for several months. The experimental matrix for the DoE is reported in Table 4.

[0118] Osmolality was adjusted with an isotonicity agent (sodium chloride to adjust osmolality to 300 mOsm / Kg).

[0119] The selected formulations were stressed under the same conditions as described for buffer selection. From the stress test, one resulting first formulation (TOM 4) was selected and stabilized in the final primary container for several months.

[0120] Heat stress: Figure 3 shows the results for the main peak changes (CE-SDS). OM 4, TOM 11, TOM 17, TOM 29, TOM 34, and TOM 35 showed the least changes compared to RoActemra. They all showed the lowest changes in the histidine 20m Formulated in M.

[0121] Light stress: Figure 4 shows the results for the main peak changes (CE-SDS). Formulations TOM 4, TOM 26, TOM 27, TOM 29, TOM 34, and TOM 35 showed the lowest changes compared to RoActemra. They all had a histidine concentration of 20 mM. It is formulated in

[0122] [Table 9]

[0123] Example 3 - 1-year stability The one-year stability was determined for the first formulation. Various criteria were monitored, including pH, protein content (as determined by optical density), HMW species (as determined by SE-HPLC), and major peaks (as determined by IEX-HPLC). The results are shown in Table 5 below and confirm the stability of the first formulation for at least one year.

[0124] [Table 10]

[0125] Abbreviation DoE Design of Experiments DP Drug Products DS API DSF Differential Scanning Fluorescence OD optical density PES Polyethersulfone rpm Revolutions per minute RT room temperature SE-HPLC Size Exclusion High Performance Liquid Chromatography HMW High molecular weight

[0126] References 1) International Publication No. 03 / 068260 2) International Publication No. 2009 / 084659 3) International Publication No. 0213860 4) International Publication No. 2011085158 5) International Publication No. 2013063510 6)High throughput thermostability screening of monoclonal antibody formulations. J Pharm Sci. 2010 Apr;99(4):1707-20

Claims

1. 1. A liquid pharmaceutical composition comprising: (a) Anti-IL-6 receptor (anti-IL-6R) antibody; (b) histidine buffer; (c) polyol; (d) free amino acids; (e) a surfactant; (f) water for injection; and (g) optionally, salt Including, A liquid pharmaceutical composition having a pH between 5.5 and 7.

5.

2. 2. The liquid pharmaceutical product of claim 1 having a pH between 6.0 and 6.

5.

3. The liquid pharmaceutical composition according to claim 1 or 2, wherein the polyol is mannitol.

4. The liquid pharmaceutical composition according to any one of claims 1 to 3, wherein the free amino acid is methionine.

5. The liquid pharmaceutical composition according to any one of claims 1 to 4, wherein the surfactant is a polysorbate.

6. The liquid pharmaceutical composition of claim 5 , wherein the polysorbate is polysorbate 80.

7. The liquid pharmaceutical composition according to any one of claims 1 to 6, wherein said optional salt is sodium chloride.

8. The liquid pharmaceutical composition of any one of claims 1 to 7, wherein the anti-IL6R antibody is selected from the group consisting of tocilizumab, sapelizumab, vovalizumab, or sarilumab.

9. The composition - 15-200 mg / ml anti-IL-6R; - 10 and 25 mM histidine (or histidine buffer system); - 190-210 mM mannitol; - 0.4 to 0.6 mM methionine; - 0.4-0.9 mM polysorbate 80; - Water (for injection); - 75-125 mM sodium chloride The liquid pharmaceutical composition according to any one of claims 1 to 8, comprising:

10. A drug delivery device comprising a liquid pharmaceutical composition according to any one of claims 1 to 9.

11. A liquid pharmaceutical composition according to any one of claims 1 to 9 for use in the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, giant cell arteritis or systemic sclerosis.

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