Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
  • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39591—Stabilisation, fragmentation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
  • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
  • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
  • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
  • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
  • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
  • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

• the present invention relates to a novel protein formulation.
• the invention relates to a liquid pharmaceutical composition of an antibody directed to lnterleukin-6 receptor, a method of manufacturing the composition, a kit including the composition, a package including the composition and to methods of treatment using the composition and/or package.
• autoimmune diseases such as rheumatoid arthritis, juvenile arthritis and other autoimmune diseases.
• drugs targeting Tumor Necrosis Factor-a such as Etanercept (marketed as Enbrel®), Adalimumab (marketed as Humira®) or Infliximab (marketed as Remicade®) as well as lnterleukin-6 receptor (IL-6R)(such as tocilizumab (marketed as ROACTEMRA® or Actemra®)
• IL-6R lnterleukin-6 receptor
• Other drugs targeting IL- 6R for the treatment of these disorders are under development or already in pre-registration before the health authorities, such as sapelizumab, vobarilizumab or sarilumab.
• Tocilizumab for instance is generally delivered to a patient either via intravenous or subcutaneous injection, and is provided in a liquid form, typically in packages such as vials, prefilled syringes, or prefilled "pen devices”.
• Current commercial formulations of tocilizumab comprise the following ingredients:
• composition comprising a bioactive protein, such as an antibody
• said composition When preparing a pharmaceutical composition comprising a bioactive protein, such as an antibody, said composition must be formulated in such a way that the activity of the protein is maintained for an appropriate period of time.
• a loss in activity / stability of the protein may result from chemical or physical instabilities of the protein notably due to denaturation, aggregation or oxidation.
• the resulting products may thus be pharmaceutically unacceptable, especially after storage for a long time.
• excipient(s) is known to increase the stability of a given protein, the stabilizing effects of these excipients is highly dependent of the nature of the excipients and of the bioactive protein itself.
• the antibodies are formulated with different excipients when they are market with different strengths (e.g. 20 mg/mL versus 180 mg/mL) or with different presentations (intravenous versus subcutaneous).
• a liquid pharmaceutical composition comprising an antibody directed to interleunkin-6 receptor (IL-6R) (such as tocilizumab, sapelizumab, vobarilizumab or sarilumab), a histidine buffer and a polyol (such as a sugar alcohol).
• IL-6R interleunkin-6 receptor
• Said composition further comprises a free amino acid, a surfactant and optionally a salt.
• Said composition is (substantially or entirely) free of arginine (suitably L-arginine).
• a method of manufacturing a liquid pharmaceutical composition comprising mixing together an antibody against IL-6R (such as tocilizumab, sapelizumab, vobarilizumab or sarilumab), an histidine buffer, a polyol (such as a sugar alcohol), a free amino acid, a surfactant and optionally a salt.
• an antibody against IL-6R such as tocilizumab, sapelizumab, vobarilizumab or sarilumab
• an histidine buffer such as a polyol (such as a sugar alcohol)
• a polyol such as a sugar alcohol
• a free amino acid such as a surfactant and optionally a salt.
• a liquid pharmaceutical composition obtainable by, obtained by, or directly obtained by a method of manufacturing a liquid pharmaceutical composition as defined herein.
• a drug delivery device e.g. pre-filled syringe or pen, or intravenous bag
• a liquid pharmaceutical composition as defined herein.
• kits of parts 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 with directions regarding the administration (e.g. intravenous or subcutaneous) of the liquid pharmaceutical composition.
• a package e.g. pre-filled syringe, pen, intravenous bag, or a package/container containing any of the aforementioned
• a method of manufacturing a package or a drug delivery device comprising incorporating a liquid pharmaceutical composition as defined herein within a package or drug delivery device.
• a package or a drug delivery device obtainable by, obtained by, or directly obtained by a method of manufacturing a package or a drug delivery device as defined herein.
• liquid pharmaceutical composition as defined herein for use in therapy.
• Figure 1 buffer selection step. A) Light stress, High Molecular Weight (HMW) %, SEC data; B) Light stress, DLS (monomer radius), C) Thermal stress at 50°C, aggregates radius; D) Thermal stress at 50°C, HMW %, SEC data.
• HMW High Molecular Weight
• Figure 2 buffer selection step. A) Oxidation stress, Monomer %, SEC data; B) Oxidation stress, High molecular weight %, SEC data; C) Mechanical stress, High molecular weight %, SEC data.
• Figure 3 behaviour of the formulations under thermal stress - results on main peak variations (CE- SDS).
• antibody and its plural form “antibodies”, as used herein includes, inter alia, polyclonal antibodies, affinity-purified polyclonal antibodies, monoclonal antibodies, and antigen-binding fragments, such as nanobodies, F(ab')2, Fab proteolytic fragments, and single chain variable region fragments (scFvs). It refers both to one-armed (monovalent) or two-armed (bivalent) antibody.
• recombinant antibody is intended to include an antibody prepared, expressed, produced or isolated using a recombinant method.
• anti-IL-6R antibody refers to an antibody directed to interleukin-6 receptor (i.e. IL-6R). Preferably, it is an antibody which does not only bind to its target, i.e. the IL-6R, but also neutralise it (alternatively inhibit it or antagonise it).
• tocilizumab includes the originator drug substance (as commercially available), as defined in W09219759 (particularly hPM-1 therein) and elsewhere in the art, and also 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. It has a molecular weight of about 145 kDa.
• LCVR light chain variable region
• HCVR heavy chain variable region
• sapelizumab has 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.
• Vobarilizumab refers to an anti-IL6R nanobody linked to an anti-human serum albumin nanobody, currently under development also named ALX-0061 , as well as biosimilars thereof.
• Vobarilizumab comprises an amino acid sequence as defined in SEQ ID NO: 5. It has a molecular weight of about 257 kDa.
• Sarilumab refers to an anti-IL6R antibody currently in pre-registration before health authorities also named REGN-88 or SAR-153191 , as well as biosimilars thereof.
• 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. It has a molecular weight of about 144 kDa.
• biosimilar refers to a drug substance which share full protein sequence identity with any one of drug substances on the market (i.e. approved by health authorities). It is noted that a biosimilar may have a (slightly) different glycosylation profile. Such "biosimilars” would need to be officially approved as a “biosimilar” for marketing before said “biosimilar” is sold on the market.
• buffer or “buffer solution” refers to solutions of compounds that are known to be safe in formulations for pharmaceutical or veterinary use and that have the effect of maintaining or controlling the pH of the formulation in the pH range desired for the formulation.
• Acceptable buffers for controlling pH at a moderately acidic pH to a moderately basic pH include, but are not limited to, phosphate, acetate, lactate, citrate, arginine, TRIS, and histidine, salts and/or acidic forms thereof, and/or any combination thereof.
• TRIS refers to 2-amino-2-hydroxymethyl-1 ,3, -propanediol, and to any pharmacologically acceptable salt thereof.
• the compound(s) making the buffer are also called "buffering agent(s)". According to the present invention, preferable buffers are histidine buffers.
• a given concentration of a histidine buffer generally relates to the combined concentration of histidine and the imidazolium form (or protonated histidine salt) of histidine.
• concentrations are usually straightforward to calculate by reference to the input quantities of histidine or a salt thereof.
• the overall pH of the composition is generally a reflection of the equilibrium concentration of each of the relevant buffering species (i.e. the balance of buffering agent(s) to acid/base conjugate(s) thereof).
• buffering agent refers to an acid or base component (usually a weak acid or weak base) of a buffer or buffer solution.
• a buffering agent helps maintain the pH of a given solution at or near to a pre-determined value, and the buffering agents are generally chosen to complement the pre-determined value.
• a buffering agent is suitably a single compound which gives rise to a desired buffering effect, especially when said buffering agent is mixed with (and suitably capable of proton exchange with) an appropriate amount (depending on the pre-determined pH desired) of its corresponding "acid/base conjugate", or if the required amount of its corresponding "acid/base conjugate” is formed in situ - this may be achieved by adding strong acid or base until the required pH is reached.
• references herein to an "amino acid” or “amino acids”, whether specific (e.g. arginine, histidine) or general (e.g. any amino acid), in the context of their presence or otherwise within compositions (especially pharmaceutical liquid compositions of the invention) relate to the corresponding free amino acid(s) (regardless of its/their protonation state and/or salt form, though for consistency amounts are suitably calculated by reference to the free amino acid per se). This may suitably include natural and/or artificial amino acids.
• substantially free when used in relation to a given component of a composition, refers to a composition to which essentially none of said component has been added. As explained above, such references have no bearing on the presence of amino acid residue(s) within a protein structure.
• composition When a composition is "substantially free" of a given component, said composition suitably comprises no more than 0.001 wt.% of said component, suitably no more than 0.0001 wt.% of said component, suitably no more than 0.00001 wt.%, suitably no more than 0.000001 wt.%, suitably no more than 0.0000001 wt.% thereof, most suitably no more than 0.0001 parts per billion (by weight).
• stability refers to the physical, chemical, and conformational stability of tocilizumab in the formulations according to the present invention (and including maintenance of biological potency). Instability of a protein formulation may be caused by chemical degradation or aggregation of the protein molecules to form higher order polymers, deglycosylation, modification of glycosylation, oxidation or any other structural modification that reduces at least one biological activity of an antibody of the present invention.
• stable solution or formulation is one solution or formulation wherein the degree of degradation, modification, aggregation, loss of biological activity and the like, of proteins therein is acceptably controlled, and does not increase unacceptably with time. It thus generally refers to the physical stability and/or chemical stability and/or biological stability of a component, typically an active or composition thereof, during preservation/storage.
• the formulation retains at least more than 80% of the antibody activity over a period of at least 12 months at room temperature and/or at lower temperatures (such as from 2 to 8°C).
• the stabilized antibody formulation of the present invention has preferably a shelf-life of at least about 12 months, 18 months, more preferably at least 20 months, still more preferably about 24 months, when stored at room temperature, and/or at lower temperatures (such as from 2 to 8°C).
• Methods for monitoring the stability of the antibody formulation of the present invention are available in the art, and include the methods described in the examples disclosed herein.
• stabilizing agent or "stabilizer”, as used herein, is a compound that is physiologically tolerated and imparts a suitable stability/tonicity to a formulation. It prevents notably the net flow of water across cell membranes that are in contact with the formulation. Compounds such as glycerin, are commonly used for such purposes.
• 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).
• the preferred stabilizing agent is a polyol, even more preferably a sugar alcohol such as mannitol.
• surfactant refers to a soluble compound that can be used notably 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, notably in order to modify the absorption of the drug or its delivery to the target tissues.
• Well known surfactants include polysorbates (polyoxyethylene derivatives; Tween) as well as poloxamers (i.e. copolymers based on ethylene oxide and propylene oxide, also known as Pluronics®).
• the preferred surfactant is a polysorbate surfactant and even more preferably is polysorbate 80.
• isotonicity agent or "tonicifier”, as used herein, is a compound that is physiologically tolerated and imparts a suitable tonicity to a formulation. It prevents notably the net flow of water across cell membranes that are in contact with 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 NaCI.
• references to specific amounts of a given component of a composition, especially a buffering agent suitably relate to the amounts of the pure anhydrous form of the relevant component (or compositions formed by using said amounts of the pure anhydrous form), even though such a component may be used in a non-anhydrous form when forming the composition.
• Amounts of any corresponding non-anhydrous forms e.g. monohydrates, dihydrates, etc.
• amounts stipulated in relation to histidine refer to the anhydrous form of histidine which has a molecular weight of about 155 g/mol.
• the skilled person would readily understand how to judiciously adjust the quantity of diluent/water depending on the form of the components used, in order to derive the target concentrations.
• references to “treating” or “treatment” include prophylaxis as well as the alleviation of established symptoms of a condition.
• Treating” or “treatment” of a state, disorder or condition therefore includes: (1 ) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e.
• composition is said to comprise a plurality of ingredients (optionally in specific amounts of concentrations or in specific ranges of concentrations), said composition may optionally include additional ingredients other than those specifically mentioned.
• the main object of the present invention is a liquid pharmaceutical composition
• a liquid pharmaceutical composition comprising an anti- IL-6R antibody, said antibody being able to neutralise (alternatively inhibit or antagonise) IL-6R activity.
• the liquid pharmaceutical composition comprises an anti-IL-6R antibody such as tocilizumab, sapelizumab, vobarilizumab or sarilumab, including any biosimilar thereof.
• the composition preferably comprises a histidine buffer, keeping the pH in the range of 5.5 to 7.5, as well as a polyol.
• the composition is preferably (substantially or entirely) free of arginine.
• the composition may include any one or more additional components defined herein in relation to a liquid pharmaceutical composition (e.g.
• the liquid pharmaceutical composition according to the invention comprises an anti-IL6-R antibody, a histidine buffer keeping the pH in the range of 5.5 to 7.5, a polyol, a polysorbate surfactant, a free amino acid and optionally a salt.
• the liquid pharmaceutical composition is (substantially or entirely) free of arginine (such as L-arginine).
• the liquid pharmaceutical composition according to the present invention as a whole comprises the anti-IL-6R antibody at a concentration of or of about 10 to or to about 250 mg/ml, preferably of or of about 15 to or to about 200 mg/mL.
• the anti-IL-6R antibody may be present in the formulation at a concentration of or of about 15, 20, 30, 40, 50, 60, 80, 100, 120, 140, 160, 180 or 200 mg/ml.
• the anti-IL-6R antibody can be any known anti-IL6R antibody such as tocilizumab, sapelizumab, vobarilizumab or sarilumab (as defined herein).
• the formulations of the invention retain at least 80% of the anti-IL-6R biological activity at the time of formulation and/or packaging over a period of at least 12 months (before the first use). Anti-IL-6R activity may be measured by any known methods.
• the liquid pharmaceutical composition according to the present invention as a whole has a pH in the range of or of about 5.5 to or to about 7.5.
• the liquid pharmaceutical composition has a pH in the range of or of about 6.0 to or to about 7.0.
• the liquid pharmaceutical composition has a pH of or of about 6.0 or 6.5.
• the buffer according to the present invention is a histidine buffer and is at a concentration of or of about 2 to or to about 50 mM.
• the histidine buffer is present at a concentration of or of about 5 to or to about 30 mM, preferably at a concentration of or of about 10 to or to about 25 mM, even preferably at a concentration of or of about 20 mM.
• the liquid pharmaceutical composition comprises the buffering species (suitably histidine buffering species - e.g. histidine itself) at a concentration of or of about 0.1 to or to about 10 mg/mL.
• the buffering species is present at a concentration of or of about 0.5 to or to about 5 mg/mL, more preferably of or of about 2 to or to about 4 mg/mL.
• the buffering species may be present in the formulation at a concentration of or of about 2.0 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75 or 4.0 mg/mL.
• the buffer system/buffering agent is present at a concentration of or of about 3.10 mg/mL.
• the liquid pharmaceutical composition comprises the buffer in a molar ratio of buffer to anti-IL6R antibody of about 5: 1 to about 200: 1 , and will mainly depend on the concentration of antibody in the formulation. For instance, when the anti-IL6R antibody is tocilizumab or sarilumab at 20 mg/mL the molar ratio is most suitably about 145: 1 and when the anti-IL6R antibody is tocilizumab or sarilumab at 180 mg/mL the molar ratio is most suitably about 16: 1.
• the liquid pharmaceutical composition according to the invention as a whole comprises a stabiliser, most preferably a polyol.
• a stabiliser most preferably a polyol.
• a component facilitates maintenance of the structural integrity of the biopharmaceutical drug, particularly during freezing and/or lyophilisation (if needed) and/or storage.
• the liquid pharmaceutical composition may comprise one or more polyols.
• the polyol is a sugar polyol, such as a sugar alcohol.
• the sugar alcohol is selected from the group consisting of mannitol, sorbitol, xylitol, arabitol, erythritol, lactitol, maltitol or inositol.
• the polyol e.g. the sugar alcohol
• Mannitol was indeed identified by the inventors as a particularly advantageous polyol stabiliser for use together with a histidine buffer in liquid anti-IL-6R antibody formulations.
• the liquid pharmaceutical composition comprises the polyol(s) (such as mannitol) at a concentration of or of about 50 to or to about 400 mM, preferably from or from about 100 to or to about 300 mM, more preferably from or from of about 150 to or to about 250 mM.
• the polyol(s) is/are present at a concentration of between 190 and 210 mM, most preferably at or at about 200 mM.
• the polyol is mannitol and is present in the liquid pharmaceutical composition at a concentration of or of about 200 mM.
• the liquid pharmaceutical composition comprises the polyol(s) (such as mannitol) at a concentration of or of about 1 mg/mL to or to about 100 mg/mL, more preferably of or of about 10 mg/mL to or to about 75 mg/mL, even more preferably of or of about 25 mg/mL to or to about 50 mg/mL.
• the polyol(s) is/are present at a concentration of between 30 mg/mL and 40 mg/mL, most suitably about 36 mg/mL.
• the polyol(s) may be present in the formulation at a concentration of or of about 25, 27.5, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 42.5, 45, 47.5 or 50 mg/mL
• the polyol is mannitol and is present in the liquid pharmaceutical composition at a concentration of or of about 36 mg/mL.
• the liquid pharmaceutical composition comprises the polyol(s) (such as mannitol) in a molar ratio of sugar stabilizer(s) to anti-IL-6R antibody of about 100: 1 to about 1500: 1 , and will mainly depend on the concentration of antibody in the formulation.
• the molar ratio is most suitably about 1450: 1 and when the anti-IL6R antibody is tocilizumab or sarilumab at 180 mg/mL the molar ratio is most suitably about 161 : 1.
• the liquid pharmaceutical composition according to the present invention as a whole comprises at least one free amino acid other than histidine and arginine.
• said free amino acid contains a sulphur element, such as cysteine or methionine. Even preferably, the free amino acid is methionine. Said component has been shown to be a good anti-oxidant.
• the liquid pharmaceutical composition comprises the at least one free amino acid (such as methionine) at a concentration of or of about 0.1 to 5 mM, preferably of or of about 0.2 to or to about 2 mM, more preferably of or of about 0.4 to or to about 0.6 mM.
• the free amino acid(s) is/are present at a concentration of or of about 0.400, 0.425, 0.450, 0.475, 0.500, 0.550, 0.575 or 0.600 mM.
• the at least one free amino acid is methionine and is present in the liquid pharmaceutical composition at a concentration of or of about 0.5 mM.
• the liquid pharmaceutical composition comprises the at least one free amino acid (such as methionine) at a concentration of or of about 0.01 mg/mL to or to about 1 mg/mL, preferably of or of about 0.025 mg/mL to or to about 0.5 mg/mL, more preferably of or of about 0.05 mg/mL to or to about 0.2 mg/mL, even preferably of or of about 0.06 mg/mL to or to about 0.1 mg/mL.
• the at least one free amino acid(s) is/are present at a concentration of or of 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.
• the at least one free amino acid is methionine and is present in the liquid pharmaceutical composition at a concentration of or of about 0.075 mg/mL.
• the liquid pharmaceutical composition comprises the at least one amino acid (such as methionine) in a molar ratio of sugar stabilizer(s) to anti-IL-6R antibody of about 1 :5 to about 5:1 , and will mainly depend on the concentration of antibody in the formulation. For instance, when the anti-IL6R antibody is tocilizumab or sarilumab at 20 mg/mL the molar ratio is preferably about 36:10 and when the anti-IL6R antibody is tocilizumab or sarilumab at 180 mg/mL the molar ratio is most suitably about 2:5.
• the liquid pharmaceutical composition according to the present invention as a whole contains surfactants.
• 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).
• the surfactant is polysorbate 80.
• the liquid pharmaceutical composition comprises the surfactant, such as polysorbate 80, at a concentration of or of about 0.1 to or to about 5 mM, preferably from or from about 0.2 to or to about 2 mM, more preferably of or of about 0.4 to or to about 0.9 mM.
• the surfactant is present at a concentration of or of about 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85 or 0.90 mM.
• the surfactant is polysorbate 80 and is present in the liquid pharmaceutical composition at a concentration of or of about 0.75 or 0.80 mM.
• the liquid pharmaceutical composition comprises the surfactant, such as polysorbate 80, at a concentration of or of about 0.1 to or to about 10 mg/mL, preferably of or of about 0.25 to or to 5 mg/mL, more preferably of or of about 0.5 to or to about 2 mg/mL.
• the surfactant is present at a concentration of or of about 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.
• the surfactant is polysorbate 80 and is present in the liquid pharmaceutical composition at a concentration of or of about 1.0 mg/mL.
• the liquid pharmaceutical composition comprises the surfactant (such as polysorbate 80) in a molar ratio of surfactant to anti-IL-6R antibody of about 1 :2 to about 60: 1 , and will mainly depend on the concentration of antibody in the formulation. For instance, when the anti-IL6R antibody is tocilizumab or sarilumab at 20 mg/mL the molar ratio is preferably about 56:10 and when the anti-IL6R antibody is tocilizumab or sarilumab at 180 mg/mL the molar ratio is most suitably about 6: 10.
• the surfactant such as polysorbate 80
• the liquid pharmaceutical compositions of the invention may include any one or more pharmaceutically acceptable diluents, or mixture thereof.
• the liquid pharmaceutical composition is an aqueous pharmaceutical composition.
• the diluent is water, and suitably water alone.
• the water is suitably water for injection (WFI).
• WFI water for injection
• the diluent may constitute the balance of ingredients in any liquid pharmaceutical composition, for instance so that the weight percentages total 100%.
• Any concentrations given herein in relation to any component of the liquid pharmaceutical composition represent concentrations of said component in (and suitably dissolved in) the diluent in admixture with any other components.
• the liquid pharmaceutical composition of the invention is suitably a solution, and is suitably (substantially or entirely) free of particulates or precipitates.
• the liquid pharmaceutical composition according to the present invention as a whole may further comprise one or more excipients such as a salt.
• excipients such as a salt.
• the tonicifier is or comprises sodium chloride (NaCI).
• NaCI sodium chloride
• Sodium chloride is a particularly advantageous stabiliser for use together with the histidine buffer in liquid anti-IL-6R antibody formulations.
• the liquid pharmaceutical composition comprises the salt (such as sodium chloride) at a concentration of or of about 20 to or to about 200 mM, preferably of or of about 50 to or to about 150 mM, more preferably of or of about 75 to or to about 125 mM.
• the salt is present at a concentration of or of about 100 mM.
• the salt is sodium chloride and is present at a concentration of or of about 100 mM.
• the liquid pharmaceutical composition comprises the salt (such as NaCI) at a concentration of or of about 0.5 mg/mL to or to about 25 mg/mL, preferably of or of about 1.0 mg/mL to or to about 10 mg/mL, more suitably of or of about 3 mg/mL to or to about 7 mg/mL.
• the salt is present at a concentration of between 5 mg/mL and 6 mg/mL, most suitably about 5.84 mg/mL.
• the salt is sodium chloride and is present at a concentration of about 5.84 mg/mL.
• the liquid pharmaceutical composition comprises the salt (such as NaCI) in a molar ratio of salt to anti-IL-6R antibody of about 50: 1 to about 800:1 , and will mainly depend on the concentration of antibody in the formulation. For instance, when the anti-IL6R antibody is tocilizumab or sarilumab at 20 mg/mL the molar ratio is preferably about 725:1 and when the anti- IL6R antibody is tocilizumab or sarilumab at 180 mg/mL the molar ratio is most suitably about 80:1.
• the salt such as NaCI
• the present invention also provides a method of stabilising liquid anti-IL-6R antibody compositions, comprising mixing the anti-IL-6R antibody with any relevant components required to form a liquid pharmaceutical composition as defined herein. Therefore, herein provided is a method of manufacturing a liquid pharmaceutical composition, the method comprising mixing together an antibody against IL-6R, such as tocilizumab, an histidine buffer, a polyol (such as a sugar alcohol), and optionally any one or more additional components defined herein in relation to a liquid pharmaceutical composition, optionally in any amount, concentration, or form stipulated; and optionally adjusting any one or more parameters given herein in relation to a liquid pharmaceutical composition (e.g. pH, osmolality).
• an antibody against IL-6R such as tocilizumab, an histidine buffer, a polyol (such as a sugar alcohol)
• a polyol such as a sugar alcohol
• any one or more additional components defined herein in relation to a liquid pharmaceutical composition optionally in any amount, concentration, or form stipulated
• Other relevant components can include at least one free amino acid (such as methionine), a surfactant (such as polysorbate 80) and optionally a salt (such as NaCI).
• a free amino acid such as methionine
• a surfactant such as polysorbate 80
• a salt such as NaCI
• Each of these compounds i.e. anti-IL-6R antibody, the histidine buffer, the polyol, the surfactant, the at least one free amino acid, and/or the salt
• the method involves mixing together the relevant components in a diluent (e.g. water), so that all of the components are (substantially or entirely) dissolved in the diluent.
• a diluent e.g. water
• liquid pharmaceutical composition obtainable by, obtained by, or directly obtained by a method of manufacturing a liquid pharmaceutical composition as defined herein.
• the liquid pharmaceutical compositions of the invention have a shelf life of at least 6 months, suitably at least 12 months, suitably at least 18 months, more suitably at least 24 months.
• the liquid pharmaceutical compositions of the invention have 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.
• the buffering agent and/or the buffer is pre-formed as a separate mixture, and the buffer is transferred to a precursor of the liquid pharmaceutical composition (comprising some or all components except the buffer) via buffer exchange (e.g. using diafiltration until the relevant concentrations or osmolality is reached). Additional excipients may be added thereafter if necessary in order to produce the final liquid pharmaceutical composition.
• the pH may be adjusted once or before all the components are present.
• the final liquid pharmaceutical composition may be filtered, suitably to remove particulate matter.
• filtration is through filters sized at or below 1 ⁇ , suitably at 0.22 ⁇ .
• filtration is mode through PES filters or PVDF filters at 0.22 ⁇ .
• the present invention provides a drug delivery device comprising a liquid pharmaceutical composition as defined herein.
• the drug delivery device comprises a chamber within which the pharmaceutical composition resides. More preferably, the drug delivery device is sterile.
• the drug delivery device may a vial, ampoule, syringe, injection pen (e.g. essentially incorporating a syringe), or intravenous bag.
• injection pen e.g. essentially incorporating a syringe
• intravenous bag e.g. a vial, ampoule, syringe, injection pen (e.g. essentially incorporating a syringe), or intravenous bag.
• the drug delivery device is a syringe, it is preferably an injection pen.
• the syringe is a glass syringe.
• the present invention provides a kit of parts 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 directions regarding the administration (e.g. sub-cutaneous or intravenous) 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 such like) prior to administration.
• a package comprising a liquid pharmaceutical composition as defined herein.
• the package comprises a drug delivery device as defined herein, suitably a plurality of drug delivery devices.
• the package may comprise any suitably container for containing one or more drug delivery devices.
• the present invention provides, in a sixth aspect, a method of manufacturing a drug delivery device, suitably as defined herein, the method comprising incorporating a liquid pharmaceutical composition as defined herein within a drug delivery device.
• manufacture typically involves charging the liquid pharmaceutical composition as defined herein to a syringe, suitably via a needle affixed thereto. The needle may thereafter be removed, replaced, or remain.
• a drug delivery device obtainable by, obtained by, or directly obtained by a method of manufacture defined herein.
• a method of manufacturing a package comprising incorporating a liquid pharmaceutical composition as defined herein within a package.
• a liquid pharmaceutical composition as defined herein within a package.
• this is achieved by incorporating said liquid pharmaceutical composition within one or more drug delivery devices, and thereafter incorporating the one or more pre-filled drug delivery devices into a container present within the package.
• the present invention provides, in addition, a package obtainable by, obtained by, or directly obtained by a method of manufacture defined herein.
• liquid pharmaceutical compositions defined herein may be used to treat any one or more of the aforementioned diseases or medical disorders.
• the liquid pharmaceutical compositions are used to treat rheumatoid arthritis and juvenile idiopathic arthritis.
• the liquid pharmaceutical compositions are used to treat other diseases such as giant cell arteritis or systemic sclerosis.
• liquid pharmaceutical compositions are suitably parenterally administered, either via intravenous injection or via sub-cutaneous injection.
• liquid pharmaceutical composition comprises:
• An anti-IL-6R antibody (such as tocilizumab, sapelizumab, vobarilizumab or sarilumab); histidine buffer keeping the pH between about 5.5 to 7.5;
• a polyol e.g. mannitol
• a free amino acid e.g. methionine
• a surfactant e.g. polysorbate 80
• a salt e.g. NaCI.
• liquid pharmaceutical composition comprises:
• An anti-IL-6R antibody (such as tocilizumab, sapelizumab, vobarilizumab or sarilumab), wherein the antibody is at a concentration of 10 to 250 mg/mL;
• histidine buffer keeping the pH between about 5.5 to 7.5;
• a polyol e.g. mannitol
• a surfactant e.g. polysorbate 80
• a salt e.g. NaCI.
• liquid pharmaceutical composition comprises:
• An anti-IL-6R antibody (such as tocilizumab, sapelizumab, vobarilizumab or sarilumab); histidine buffer keeping the pH between about 5.5 to 7.5, wherein the buffer is at a concentration of 2 to 50 mM, or alternatively at a concentration of 0.1 to 10 mg/mL or alternatively at a molar ratio buffer to antibody of 5: 1 to 200:1 ;
• a polyol e.g. mannitol
• a surfactant e.g. polysorbate 80
• a salt e.g. NaCI.
• the liquid pharmaceutical composition comprises: An anti-IL-6R antibody (such as tocilizumab, sapelizumab, vobarilizumab or sarilumab); histidine buffer keeping the pH between about 5.5 to 7.5;
• An anti-IL-6R antibody such as tocilizumab, sapelizumab, vobarilizumab or sarilumab
• histidine buffer keeping the pH between about 5.5 to 7.5;
• polyol e.g. mannitol
• the polyol is at a concentration of 50 to 400 mM, or alternatively at a concentration of 1 to 100 mg/mL or alternatively at a molar ratio polyol to antibody of 100:1 to 1500:1 ;
• a free amino acid e.g. methionine
• a surfactant e.g. polysorbate 80
• a salt e.g. NaCI.
• liquid pharmaceutical composition comprises:
• An anti-IL-6R antibody (such as tocilizumab, sapelizumab, vobarilizumab or sarilumab); histidine buffer keeping the pH between about 5.5 to 7.5;
• a polyol e.g. mannitol
• a free amino acid e.g. methionine
• the free amino acid is at a concentration of 0.1 to 5 mM, or alternatively at a concentration of 0.01 to 1 mg/mL or alternatively at a molar ratio free amino acid to antibody of 1 :5 to 5: 1 ;
• a surfactant e.g. polysorbate 80
• a salt e.g. NaCI.
• liquid pharmaceutical composition comprises:
• An anti-IL-6R antibody (such as tocilizumab, sapelizumab, vobarilizumab or sarilumab); histidine buffer keeping the pH between about 5.5 to 7.5
• a polyol e.g. mannitol
• a free amino acid e.g. methionine
• a surfactant e.g. polysorbate 80
• the free amino acid is at a concentration of 0.1 to 5 mM, or alternatively at a concentration of 0.1 to 10 mg/mL or alternatively at a molar ratio surfactant to antibody of 1 :2 to 60:1 ;
• a salt e.g. NaCI.
• liquid pharmaceutical composition comprises:
• An anti-IL-6R antibody (such as tocilizumab, sapelizumab, vobarilizumab or sarilumab); histidine buffer keeping the pH between about 5.5 to 7.5
• a polyol e.g. mannitol
• a free amino acid e.g. methionine
• a surfactant e.g. polysorbate 80
• the liquid pharmaceutical composition comprises:
• An anti-IL-6R antibody (such as tocilizumab, sapelizumab, vobarilizumab or sarilumab), wherein the antibody is at a concentration of 10 to 250 mg/mL;
• histidine buffer keeping the pH between about 5.5 to 7.5; wherein the buffer is at a concentration of 2 to 50 mM, or alternatively at a concentration of 0.1 to 10 mg/mL or alternatively at a molar ratio buffer to antibody of 5:1 to 200:1 ;
• polyol e.g. mannitol
• the polyol is at a concentration of 50 to 400 mM, or alternatively at a concentration of 1 to 100 mg/mL or alternatively at a molar ratio polyol to antibody of 100:1 to 1500: 1 ;
• a free amino acid e.g. methionine
• the free amino acid is at a concentration of 0.1 to 5 mM, or alternatively at a concentration of 0.01 to 1 mg/mL or alternatively at a molar ratio free amino acid to antibody of 1 :5 to 5: 1 ;
• a surfactant e.g. polysorbate 80
• the free amino acid is at a concentration of 0.1 to 5 mM, or alternatively at a concentration of 0.1 to 10 mg/mL or alternatively at a molar ratio surfactant to antibody of 1 :2 to 60:1 ;
• a salt e.g. NaCI
• the free amino acid is at a concentration of 20 to 200 mM, or alternatively at a concentration of 0.5 to 25 mg/mL or alternatively at a molar ratio salt to antibody of 50: 1 to 800: 1.
• Exposure was conducted at 765 Wh/m2. The samples exposed to irradiation were placed alongside with required amount of control samples (to be kept in the same chamber but without being irradiated). After exposure, at each time point, the required amount of samples was withdrawn to be tested immediately or stored at -80°C before testing.
• Each sample (100 ⁇ _) was added with 100 ⁇ _ of H202 2% v/v to get the final concentration of 1 %.
• the solution was incubated at 25°C. In case the solution becomes cloudy, the plate was spin down at 10000 g for 25 min at RT°C.
• the study aimed to develop one new liquid formulation of anti-IL-6R antibody, for both subcutaneous and/or intravenous use.
• the formulation development was composed of the following phases:
• DS buffer screen was executed using a DoE approach. From an initial high number of buffers, through a combined approach of thermodynamic and kinetic parameters a final buffer was selected, as well as one back up.
• the anti-IL-6R antibody that was used in this example is tocilizumab. After purification, the antibody was exchanged by centrifugation with 4 different buffers:
• the DS was composed only of the mAb and the buffer, the aim of this step was to evaluate the single interaction of the two components.
• the experimental matrix was as followed (see Table 2 below):
• the antibody target concentration was above 210 img/mL
• DSF Differential Scanning Fluorimetry
• SyproOrange dye was used to preselect the buffers. Stress tests phase was run with the buffers having the higher Th and the lower aggregation percentage, as per DSF:
• Fig. 1 A and 1 B show the results respectively on high molecular weight species (HMW) and on monomer radius. Histidine buffer, 20 mM, at pH 6.0 as well as phosphate buffer, 20 mM, at pH 6.2, presented the lowest increase of HMW %, as well as the lowest increase of monomer radius. It is noted that TRIS buffer gave slightly more protection against light stress than phosphate buffer.
• Fig. 1 C and 1 B show the results respectively on aggregates radius and high molecular weight species (HMW). Very low increase of aggregate radius was observed for all the samples except for phosphate pH 7.2. Histidine buffer, 20 mM, at pH 6.0 as well as phosphate buffer, 20 mM, at pH 6.2, presented the lowest increase of HMW. Most aggregated samples were the ones with phosphate buffer pH 7.2.
• Oxidation stress Fig. 2A and 2B show the results respectively on monomer % and high molecular weight species (HMW). Very low HMW increase of aggregate radius was observed for all the samples.
• Viscosity The data underlined that phosphate buffers had a higher viscosity than either histidine or TRIS buffer (see table 3 below)
• the selected buffers were: Histidine buffer, 20 mM, at pH 6.0 (as the lead buffer) as well as TRIS buffer, 20 mM, at pH 7.1 (as the backup).
• buffer 1
• High throughput excipients screening by SE-HPLC about 40 different formulations
• stress tests on the selected formulations
• selection of one lead formulation and one (or two) back-ups The formulations stability will then by tested for several months.
• the experimental matrix for the DoE is reported in Table 4:
• Osmolality was adjusted with an isotonicity agent (Sodium Chloride to adjust the osmolality to 300 mOsm/Kg).
• the selected formulations were stressed with the same conditions described for the buffer selection. From the stress tests, the resulting 1 lead formulation (TOM 4) was selected and put in stability for several months in the final primary container.
• Fig. 3 shows the results on main peak variations (CE-SDS).
• Formulations TOM 4, TOM 1 1 , TOM 17, TOM 29, TOM 34 and TOM 35 presented the lowest variation compared to RoActemra. They are all formulated in histidine 20 mM.
• Fig. 4 shows the results on main peak variations (CE-SDS).
• Formulations TOM 4, TOM 26, TOM 27, TOM 29, TOM 34, TOM 35 presented the lowest variation compared to RoActemra. They are all formulated in histidine 20 mM.
• Table 4 experimental matrix for the DoE of example 2.
• arginine is mentioned in this table as a bulking agent, it is to be understood as arginine monohydrate; TRIS, in the buffer column, refers to TRIS 20 mM pH 7.1 and histidine, in the buffer column, refers to Histidine 20 mM pH 6.0.
• the 1-year stability was assessed for the lead formulation.
• Various criteria have been monitored including pH, protein content (assessed by optical density), HMW species (assessed by SE-HPLC) and main peak (assessed by IEX-HPLC).
• the results are shown in Table 5 below, confirming stability of the lead formulation over at least one year.

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