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    • 专利摘要:
    stabilized formulations containing anti-interleukin-6 (il-6r) receptor antibodies. the present invention relates to pharmaceutical formulations comprising a human antibody that specifically binds to a human interleukin-6 (hil-6r) receptor. the formulations may additionally contain and / or at least one nonionic surfactant. the pharmaceutical formulations of the present invention exhibit a considerable degree of stability of antibodies after storage for several months.
    公开号:BR112012016618A2
    申请号:R112012016618-2
    申请日:2011-01-07
    公开日:2020-06-02
    发明作者:B. Dix Daniel；S. Graham Kenneth；E. Kamen Douglas；M. Walsh Scott
    申请人:Regeneron Pharmaceuticals, Inc.；
    IPC主号:
    专利说明:

    Invention Patent Descriptive Report for STABILIZED FORMULATIONS CONTAINING ANTI-INTERLEUCIN-6 RECEPTOR ANTIBODIES (IL-6R).
    FIELD OF THE INVENTION
    The present invention relates to the field of therapeutic antibody formulations. More specifically, the present invention relates to the field of pharmaceutical formulations comprising a human antibody that specifically binds to a human interleukin-6 receptor. SEQUENCE LISTING
    A file with a text according to the WIPO ST 25 standard of a sequence listing is deposited concurrently with this specification. The contents of the text file are hereby incorporated by reference. The text file containing the sequence listing is called IL6RAbFormulationSeqList, was created on January 7, 2010, and contains 37,387 bytes.
    BACKGROUND
    Therapeutic macromolecules (eg antibodies) must be formulated in a way that not only makes the molecules suitable for administration to patients, but also maintains their stability during storage. For example, therapeutic antibodies in liquid solution are prone to degradation, aggregation and / or unwanted chemical modifications unless the solution is formulated appropriately. The stability of an antibody in liquid formulation depends not only on the types of excipients used in the formulation, but also on the quantities and proportions of the excipients in relation to each other. Furthermore, considerations other than stability must be taken into account when preparing a liquid antibody formulation. Examples of such additional considerations include the viscosity of the solution and the concentration of the antibody that can be accommodated by a given formulation. Thus, when formulating a therapeutic antibody, great care must be taken to arrive at a formulation that remains stable, contains an appropriate concentration of the antibody, and has an adequate vision and other properties that allow the formulation to be conveniently administered to patients.
    Human interleukin-6 receptor (NL-6R) antibodies are an example of a therapeutically relevant macromolecule that requires adequate formulation. Anti-hl L-6R antibodies are useful clinically for the treatment and / or prevention of diseases such as rheumatoid arthritis, ankylosing spondylitis, and other conditions. Exemplary anti-IL-6R antibodies are described, among others, in US 7,582,298; 6,410,691; 5,817,790; 5,795,695; and 6,670,373. A particularly important anti-hl L-6R antibody with great therapeutic potential is the antibody referred to in US 7,582,298 as VQ8F11-21 (also referred to herein as mAb1).
    Although Anti-hl L-6R antibodies are known, there remains a need in the art for new pharmaceutical formulations comprising anti-hl L-6R antibodies that are sufficiently stable and also suitable for administration to patients.
    BRIEF SUMMARY OF THE INVENTION
    The present invention satisfies the need mentioned above by providing pharmaceutical formulations comprising a human antibody that specifically binds to a human interleukin-6 (hlL6R) receptor. The formulations of the invention can comprise excipients in addition to the anti-hLL-6R antibody. For example, in certain embodiments, the formulation may comprise (i) a human antibody that specifically binds to hLL-6R; (ii) at least one amino acid; and (iii) at least one carbohydrate. The amino acid can be, for example, histidine and / or arginine. The carbohydrate can be a sugar such as, for example, sack rose, glucose, mannitol, lactose or trehalose.
    According to certain embodiments of the present invention, the formulation further comprises a non-ionic surfactant. The nonionic surfactant can be, for example, polysorbate 20, polysorbate 80, poly (ethylene oxide) sorbitan monooleate, polyethylene glycol, etc.
    The antibody contained in the pharmaceutical formulations of the present invention can be any antibody that specifically binds to hl L-6R.
    3/45
    Exemplary antibodies that can be contained in the formulations of the invention are antibodies comprising a heavy chain variable region (HCVR) and a light chain variable region (LCVR), where HCVR comprises a complementary heavy chain determining region (HCDR) 1 having the amino acid sequence of SEQ ID NO: 20, an HCDR2 having the amino acid sequence of SEQ ID NO: 22, and an HCDR3 having the amino acid sequence of SEQ ID NO: 24; and where the LCVR comprises a complementary light chain determining region (LCDR) 1 having an amino acid sequence of SEQ ID NO: 28, an LCDR2 having an amino acid sequence of SEQ ID NO: 30, and an LCDR3 having an amino acid sequence SEQ ID NO: 32. In certain embodiments, the antibody contained in the formulations of the present invention are antibodies comprising an HCVR having the amino acid sequence of SEQ ID NO: 18 and an LCVR having an amino acid sequence of SEQ ID NO: 26.
    The antibody formulations of the present invention can be contained within any suitable containers useful for storing pharmaceutical formulations. Examples of such suitable containers include, for example, glass or plastic vials, syringes and cartridges. The container can be transparent or opaque (for example, amber colored).
    According to certain aspects of the present invention, pharmaceutical formulations remain relatively stable following storage for several days, months or years at a given temperature. For example, in certain exemplary embodiments of the present invention, a high percentage of the antibody (for example, 90%, 95%, 96% or more) is maintained in its native form following at least 3, 6, 9 or more months of storage. The percentage of the native form of the antibody can be measured, for example, by SE-HPLC, or by any other method known in the art. The storage temperature at which antibody stability is maintained can be, for example, -80 ° C, -40 ° C, -20 ° C, 0 ° C, 5 ° C, 25 ° C, 45 ° C, or higher.
    Other embodiments of the present invention will become apparent from a review of the detailed description that follows.
    4/45
    BRIEF DESCRIPTION OF THE FIGURES
    Figure 1 shows the percentage of the remaining native mAb1, as measured by SE-HPLC, followed by several storage times at -20X (filled triangles), -SO'O (filled squares), and -80 ° C ( filled rhombuses).
    Figure 2 shows the percentage of acidic species of mAb1, as measured by CEX-HPLC, followed by several storage times at -2 ° C (filled triangles), -30 ° C (filled squares), and -80 ° C (filled diamonds).
    Figure 3 shows the percentage of native mAb1 remaining in various minimal excipient formulations, as measured by SEHPLC, following various storage times at -30 D C. The filled lozenges represent formulation 1 (80 mg / mL mAb1, 0, 13% polysorbate 20, 6% sucrose, 10 mM histidine); the filled squares represent formulation 2 (80 mg / ml mAb1, 0.13% polysorbate 20, 10 mM hystidine); the filled triangles represent formulation 3 (80 mg / ml mAb1, 1% sucrose, 10 mM histidine); the blank squares represent formulation 4 (80 mg / ml mAb1, 2% sucrose, 10 mM histidine); asterisks represent formulation 5 (80 mg / ml mAb1, 4% sucrose, 10 mM histidine); the filled circles represent formulation 6 (80 mg / ml mAb1, 6% sucrose, 10 mM histidine); the crosses represent formulation 7 (80 mg / ml antibody, 10 mM histidine); and blank circles represent formulation 8 (65 mg / ml antibody, 10 mM histidine). All formulations are set out in Table 6 (see Example 2, below).
    Figure 4 shows the percentage of native mAb1 remaining in various minimal excipient formulations, as measured by SEHPLC, followed by several storage times at -20 ° C. The filled diamonds represent formulation 1 (80 mg / ml mAb1, 0.13% polysorbate 20, 6% sucrose, 10 mM histidine); the filled squares represent formulation 2 (80 mg / ml mAb1, 0.13% polysorbate 20, 10 mM histidine); the filled triangles represent formulation 3 (80 mg / ml mAb, 1% sucrose, 10 mM histidine); the blank squares represent the
    5/45 formulation 4 (80 mg / ml mAb1, 2% sucrose, 10 mM histidine); asterisks represent formulation 5 (80 mg / ml mAb1, 4% sucrose, 10 mM histidine); the filled circles represent formulation 0 (80 mg / ml mAb1, 6% sucrose, 10 mM histidine); the crosses represent formulation 7 (80 mg / ml antibody, 10 mM histidine); and the blank circles represent formulation 8 (65 mg / ml antibody, 10 mM histidine). All formulations are set out in table 6 (see Example 2, below).
    DETAILED DESCRIPTION
    Before the present invention is described, it should be understood that that invention is not limited to the particular methods and experimental conditions described, as such methods and conditions may vary. It should also be understood that the terminology used here is for the purpose of only describing particular modalities, and is not intended to be limiting, since the scope of the present invention will only be limited by the appended claims.
    Unless otherwise defined, all scientific and technical terms used herein have the same meaning as nominally understood by the person of ordinary knowledge in the technique to which this invention belongs. As used herein, the term about, when used in reference to a particular reported numeric value, means that the value can vary from the reported value by no more than 1%. For example, as used herein, the expression about 100 includes 99 and 101 and all intermediate values (for example, 99.1,99.2, 99.3, 99.4, etc.).
    Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are hereby incorporated by reference for a full description.
    PHARMACEUTICAL FORMULATIONS
    As used herein, the term pharmaceutical formulation means a combination of at least one active ingredient (for example, a small molecule, macromolecule, compound, etc. that is capable of having a biological effect on a human or non-animal. human), and at least one active ingredient which, when combined with the active ingredient and / or one or more additional active ingredients, is suitable for therapeutic administration to a human or non-human animal. The term formulation, as used herein, means pharmaceutical formulation unless specifically indicated otherwise. The present invention provides pharmaceutical formulations comprising at least one therapeutic polypeptide. According to certain embodiments of the present invention, the therapeutic polypeptide is an antibody that specifically binds to a human interleukin-6 (hiL-6R) receptor or an antigen-binding fragment thereof. More specifically, the present invention includes pharmaceutical formulations that comprise:
    (i) a human antibody that specifically binds hIL-SR; (il) histidine; and (iii) a carbohydrate. Additional components can be included in the formulations of the present invention such as, for example, at least one nonionic surfactant, and at least one additional amino acid. Specific exemplary components and formulations included in the present invention are described in detail below.
    The pharmaceutical formulations of the present invention can, in certain embodiments, be fluid formulations. As used herein, the term fluid formulation means a mixture of at least two components that exist predominantly in the fluid state from about 5 D C to about 45 “C. Fluid formulations include, among others, liquid formulations. Fluid formulations can be low, moderate or high viscosity depending on their particular constituents. ANTIBODIES THAT SPECIFICALLY CONNECT TO hlL-6R
    The pharmaceutical formulations of the present invention can comprise a human antibody, or an antigen binding fragment thereof, which specifically binds to hLL-6R. As used herein, □ hlL-6R means a human cytosine receptor that specifically binds to interleukin-6 (IL-6). In certain embodiments, the antibody contained in the pharmaceutical formulations of the present invention specifically binds to the extracellular domain of h! L-6R. The extracellular domain of hlL-6R is represented by the amino acid sequence of SEQ ID NO: 74.
    The term antibody, as used herein, is intended to refer generically to immunoglobulin molecules comprising four polypeptide chains, two heavy chains (H) and two light chains (L) interconnected by disulfide bonds, as well as their multimers (for example, IgM); however, immunoglobulin molecules consisting solely of heavy chains (i.e., with missing light chains) are also included within the definition of the term antibody. Each heavy chain comprises a heavy chain variable region (hereinafter abbreviated as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2 and CH3. Each light chain comprises a light chain variable region (here abbreviated as LCVR or VL) and a light chain constant region. The light chain constant region comprises a domain (CL1). The VH and VL regions can be further subdivided into hypervariable regions, called complementary determinant regions (CDRs), interspersed with regions that are more conserved, called structural regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from the amino termination to the carboxy termination in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
    Unless specifically indicated otherwise, the term antibody, as used herein, is to be understood to encompass entire antibody molecules as well as their antigen-binding fragments. The term antigen binding portion or antigen binding fragment of an antibody (or simply antibody portion or antibody fragment), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind hlL-6R.
    An isolated antibody, as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigen specificities (for example, a
    8/45 Isolated antibody that specifically binds hll_-6R is substantially free of antibodies that specifically bind antigen (other than hLL-6R).
    The term specifically binds, or similar, means that an antibody or an antigen-binding fragment forms a complex with an antigen that is relatively stable under physiological conditions. The specific bond can be characterized by a dissociation constant of at least about 1x10 s M or greater. Methods for determining whether two molecules specifically bind are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. An isolated antibody that specifically binds hlL-6R may, however, cross-react with other antigens, such as IL-6R molecules from other species. In the context of the present invention, it is believed that multispecific (e.g., bispecific) antibodies that bind hlL-6R as well as one or more additional antigens specifically bind hlL-6R. In addition, an isolated antibody can be substantially free of other cellular materials and / or chemicals.
    Exemplary anti-hLL-6R antibodies that can be included in the pharmaceutical formulations of the present invention are presented in US 7,582,298, the disclosure of which is incorporated herein in its entirety by reference.
    In accordance with certain embodiments of the present invention, the anti-hLL-6R antibody, or its antigen-binding fragment, comprises a complementary heavy chain determining region (HCDR) 1 having an amino acid sequence selected from the group consisting of SEQ ID NO : 4, 20, 30 and 52; an HCDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 22, 38 and 54; and an HCDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 18, 34 and 50. In certain embodiments, the anti-hlL-6R antibody, or an antigen binding fragment thereof, comprises the HCDR1 domains -HCDR2- HCDR3, respectively 9/45, selected from the group consisting of: (i) SEQ ID No. s: 4-6-8; (ii) SEQ ID NO: 20 - 22 - 24; (iii) SEQ 1D No. s: 36 - 38 - 40; and (iv) C SEQ ID Nos: 52 -54 - 56.
    According to certain embodiments of the present invention, the anti-hLL-6R antibody, or its antigen-binding fragment, comprises a complementary light chain determining region (LCDR) 1 having an amino acid sequence selected from the group consisting of SEQ ID NO : 12, 28, 44 and 60; LCDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 14, 30, 46 and 62; and an LCDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 16, 32, 48 and 64. In certain embodiments, the anti-hlL-6R antibody, or its antigen binding fragment, comprises the LCDR1 LCDR2 domains LCDR3, respectively, selected from the group consisting of: (i) SEQ ID No. s: 12-14-16; (ii) SEQ ID NO: 28 - 30 - 32; (iii) SEQ ID NO: 44 - 46 - 48; and (iv) SEQ ID NO: 60 - 62 - 64.
    In certain embodiments, the anti-hlL-6R antibody, or its antigen-binding fragment, comprises the HCDR1-HCDR2HCDR3 / LCDR1-LCDR2-LCDR3 domains, respectively, selected from the group consisting of: (i) SEQ ID NO: s : 4 - 6 - 8 / SEQ ID NO: 12 - 14 - 16; (ii) SEQ ID NO: 20 - 22 - 24 / SEQ ID NO: 28 - 30 - 32; (iii) SEQ ID NO: 36 - 38 - 40 / SEQ ID NO: 44 - 46 - 48; and (iv) SEQ ID NO: 52 - 54 - 56 / SEQ ID NO: 60 - 62 - 64.
    In certain embodiments, the anti-hlL-6R antibody, or its antigen-binding fragment, comprises a heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 18, 34 and 50, In certain embodiments, the anti-hlL-6R antibody, or its antigen-binding fragment, comprises a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of SEQ ID NO: 10, 26, 42 and 58. In certain embodiments, the anti-hLL-6R antibody, or its antigen-binding fragment, comprises a selected pair of HCVR / LCVR amino acid sequence from the group consisting of
    10/45
    SEQ ID NO; 2/10; 18/26; 34/42 and 50/58.
    The exemplary, non-limiting antibody used in the Examples is referred to herein as mAb1. This antibody is also referred to in US 7,582,298 as VQ8F11-21. MAb1 (VQ8F11-21) comprises a pair of HCVR / LCVR amino acid sequences having SEQ ID NO: 18/26, and the HCDR1-HCDR2-HCDR3 / LCDR1-LCDR2-LCDR3 domains represented by SEQ ID NO: 20 - 22 - 24 / SEQ ID NO: 28 - 30 - 32.
    The amount of antibody, or its antigen-binding fragment, contained in the pharmaceutical formulations of the present invention can vary depending on the specific properties desired from the formulations, as well as the particular circumstances and purposes for which the formulations are intended to be used. In certain embodiments, pharmaceutical formulations can contain about 1 mg / ml to about 500 mg / ml of antibody; about 5 mg / ml to about 400 mg / ml antibody; about 5 mg / ml to about 200 mg / ml antibody; about 25 mg / ml to about 180 mg / ml antibody; about 25 mg / ml to about 150 mg / ml antibody; or about 50 mg / ml to about 180 mg / ml antibody. For example, the formulations of the present invention can comprise about 1 mg / ml; about 2 mg / ml; about 5 mg / ml; about 10 mg / ml; about 15 mg / ml; about 20 mg / ml; about 25 mg / ml; about 30 mg / ml; about 35 mg / ml; about 40 mg / ml; about 45 mg / ml; about 50 mg / ml; about 55 mg / ml; about 60 mg / ml; about 65 mg / ml; about 70 mg / ml; about 75 mg / ml; about 80 mg / ml; about 85 mg / ml; about 86 mg / ml; about 87 mg / ml; about 88 mg / ml; about 89 mg / ml; about 90 mg / ml; about 95 mg / ml; about 100 mg / ml; about 105 mg / ml; about 110 mg / ml; about 115 mg / ml; about 120 mg / ml; about 125 mg / ml; about 130 mg / ml; about 131 mg / ml; about 132 mg / ml; about 133 mg / ml; about 134 mg / ml; about 135 mg / ml; about 140 mg / ml; about 145 mg / ml; about 150 mg / ml; about 155 mg / ml; about 160 mg / ml; about 165 mg / ml; about 170 mg / ml; about 175 mg / ml; about 180 mg / ml; about 185 mg / ml;
    11/45 about 190 mg / ml; about 195 mg / ml; or about 200 mg / ml of an antibody or antigen-binding fragment thereof, which specifically binds to hLL-6R.
    EXCIPIENTS and pH
    The pharmaceutical formulations of the present invention comprise one or more excipients. The term excipient, as used herein, means any non-therapeutic agent added to the formulation to provide a desired consistency, viscosity or stabilizing effect.
    In certain embodiments, the pharmaceutical formulation of the invention comprises at least one amino acid. Exemplary amino acids suitable for use in the formulations of the present invention include, inter alia, arginine and / or histidine.
    The amount of amino acid contained in the pharmaceutical formulations of the present invention can vary depending on the specific properties desired from the formulations, as well as the particular circumstances and purposes for which the formulations are intended to be used. In certain embodiments, the formulations can contain about 1 mM to about 200 mM of an amino acid; about 2 mM to about 100 mM of an amino acid; about 5 mM to about 50 mM of an amino acid; or about 10 mM to about 25 mM of an amino acid. For example, the pharmaceutical formulations of the present invention can comprise about 1 mM; about 1.5 mM; about 2 mM; about 2.5 mM; about 3 mM; about 3.5 mM; about 4 mM; about 4.5 mM; about 5 mM; about 5.5 mM; about 6 mM; about 6.5 mM; about 7 mM; about 7.5 mM; about 8 mM; about 8.5 mM; about 9 mM; about 9.5 mM; about 10 mM; about 10.5 mM; about 11 mM; about 11.5 mM; about 12 mM; about 12.5 mM; about 13 mM; about 13.5 mM; about 14 mM; about 14.5 mM; about 15 mM; about 15.5 mM; 16 mM; about 16.5 mM; about 17 mM; about 17.5 mM; about 18 mM; about 18.5 mM; about 19 mM; about 19.5 mM; about 20 mM; about 20.5 mM; about 21
    12/45 mM; about 21.5 mM; about 22 mM; about 22.5 mM; about 23 mM; about 23.5 mM; about 24 mM; about 24.5 mM; about 25 mM; about 25.5 mM; about 2S mM; about 26.5 mM; about 27 mM; about 27.5 mM; about 28 mM; about 28.5 mM; about 29 mM; about 29.5 mM; about 30 mM; about 35 mM; about 40 mM; about 45 mM; or about 50 mM of an amino acid (for example, histidine and / or arginine).
    The pharmaceutical formulations of the present invention can also comprise one or more carbohydrates, for example, one or more sugars. Sugar can be a reducing sugar or a non-reducing sugar. Drafting sugars include, for example, sugars with a ketone or aldehyde group and contain a reactive hemiacetal group, which allows the sugar to act as a reducing agent. Specific examples of reducing sugars include fructose, glucose, glyceraldehyde, lactose, arabinose, mannose, xylose, ribose, rhamnose, galactose and maltose. Non-reducing sugars can comprise an anomeric carbon that is an acetal and is not substantially reactive with amino acids or polypeptides to initiate a Maillard reaction. Specific examples of non-reducing sugars include sucrose, trehalose, sorbose, sucralose, melezitosis and raftnose. Sugar acids include, for example, saccharic acids, gluconate and other polyhydroxide sugars and their salts.
    The amount of sugar contained in the pharmaceutical formulations of the present invention will vary depending on the specific circumstances and intended purposes for which the formulations are used. In certain embodiments, the formulations can contain about 0.1% to about 20% sugar; about 0.5% to about 20% sugar; about 1% to about 20% sugar; about 2% to about 15% sugar; about 3% to about 10% sugar; about 4% to about 10% sugar; or about 5% to about 10% sugar. For example, the pharmaceutical formulations of the present invention can comprise about 0.5%; about 1.0%; about 1.5%; about 2.0%; about 2.5%; about 3.0%; about 3.5%; about 4.0%; about 4.5%; about
    13/45
    5.0%; about 5.5%; about 6.0%; 6.5%; about 7.0%; about 7.5%; about 8.0%; about 8.5%; about 9.0%; about 9.5%; about 10.0%; about 10.5%; about 11.0%; about 11.5%; about 12.0%; about 12.5%; about 13.0%; about 13.5%; about 14.0%; about 14.5%; about 15.0%; about 15.5%; about 16.0%; 16.5%; about 17.0%; about 17.5%; about 18.0%; about 18.5%; about 19.0%; about 19.5%; or about 20.0% sugar (for example, sucrose).
    The pharmaceutical formulations of the present invention can also comprise one or more surfactants. As used herein, □ surfactant means a substance that reduces the surface tension of a fluid in which it is dissolved and / or reduces the interfacial tension between oil and water. Surfactants can be ionic or non-ionic. Exemplary non-ionic surfactants that can be included in the formulations of the present invention include, for example, alkyl (poly) ethylene oxide, alkyl polyglycosides (for example, octyl glycoside and decyl maltoside), fatty alcohols such as cetyl alcohol and oleyl alcohol , cocamide MEA, cocamide DEA, and cocamide TEA, Specific non-ionic surfactants that can be included in the formulations of the present invention include, for example, polysorbates such as polysorbate 20, polysorbate 28, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80 , polysorbate 81, and polysorbate 85; poloxamers such as poloxamer 188, poloxamer 407; polyethylene propylene glycol; or polyethylene glycol (PEG). Polysorbate 20 is also known as TWEEN 20, sorbitan monolaurate and polyoxyethylene sorbitan monolaurate.
    The amount of surfactant contained in the pharmaceutical formulations of the present invention can vary depending on the specific properties desired from the formulations, as well as the particular circumstances and purposes for which the formulations are intended to be used. In certain embodiments, formulations can contain about 0.05% to about 5% surfactant; or about 0.1% to about 0.2% of so14 / 45 soative. For example, the formulations of the present invention can comprise about 0.05%; about 0.06%; about 0.07%; about 0.08%; about 0.09 ') / 0; about 0.10 ° A; about 0.11) 70; about 0.12 ° A; about 0.13 ° A; about 0.14 ° A; about 0.15%; about 0.16%; about 0.17%; about 0.18%; about 0.19%; about 0.20%; about 0 „21%; about 0.22%; about 0.23%; about 0.24%; about 0.25%; about 0.26%; about 0.27%; about 0.28%; about 0.29%; or about 0.30% surfactant (for example, polysorbate 20).
    The pharmaceutical formulations of the present invention can have a pH of about 5.0 to about 8.0. For example, the formulations of the present invention can have a pH of about 5.0; about 5.2; about 5.4; about 5.6; about 5.8; about 6.0; about 6.2; about 6.4; about 6.6; about 6.8; about 7.0; about 7.2; about 7.4; about 7.6; about 7.8; or about 8.0.
    EXAMPLE FORMULATIONS
    According to one aspect of the present invention, the pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hLL-6R (for example, mAb1); (ii) an amino acid (for example, histidine); and (iii) a sugar (for example, sucrose). Exemplary specific and non-limiting modalities encompassed by this aspect of the invention are shown in Table 1.
    Table 1: Exemplary Pharmaceutical Formulations Comprising mAb1,
    Histidine and Sucrose
    mAb1 (mg / ml) 25 50 10 150 25 50 100 150 25 50 100 150 25 50 100 150 histidine(mM) 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 got itknow%) 1 1 1 1 2 2 2 2 4 4 4 4 6 6 6 6
    In accordance with another aspect of the present invention, the pharmaceutical formulation comprises: (i) a human antibody that specifically binds h! L-6R (for example, mAb1); (ii) an amino acid (for example, histidine); (iii) a sugar (for example, sucrose); and (iv) a surfactant (for example, polysorbate 20). Exemplary specific and non-limiting modalities encompassed by this aspect of the invention are shown in Tables 2A and 2B.
    According to another aspect of the present invention, the pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hLL-6R (for example, mAb1); (ü) a first amino acid (for example, histidine); (iii) a sugar (for example, sucrose); (iv) a surfactant (for example, polysorbate 20); and (v) a second amino acid (for example, arginine). Exemplary specific and non-limiting modalities encompassed by this aspect of the invention are shown in tables 3A, 3B, 30, 3D, 3E and 3F.
    Table 2A: Exemplary Pharmaceutical Formulations Comprising mAb1,
    Histidine, Sucrose and Polysorbate 20
    mAb1 (mg / ml) 25 50 100 150 25 50 100 150 25 50 100 150 histidine(mM) 10 10 10 10 10 10 10 10 10 10 10 10 sucrose (%) 2 2 2 2 5 5 5 5 10 10 10 10 polysorbate 20 (%) 0.1 0.1 0.1 o, 1 0.1 0.1 0.1 0.1 o, 1 0.1 0.1 0.1
    Table 2B: Exemplary Pharmaceutical Formulations Comprising mAb1,
    Histidine, Sucrose and Polysorbate 20
    mAb1 (mg / ml) 25 50 100 150 25 50 100 150 25 50 100 150 histidine(mM) 10 10 10 10 10 10 10 10 10 10 10 10 sucrose(%) 2 2 2 2 5 5 5 5 10 10 10 10 polysorbate 20 <%> 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2
    16/45
    Table 3A: Exemplary Pharmaceutical Formulations Comprising mAb1,
    Histidine, Sucrose, Polysorbate 20 and Arqinina
    mAb1 (mg / ml) 25 50 100 150 25 50 100 150 25 50 10 150 histidine (mM) 10 10 10 10 10 10 10 10 10 10 10 10 sucrose (%) 2 2 2 2 2 2 2 2 2 2 2 2 polysorbate 20 (%) 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Arginine (mM) 10 10 10 10 10 10 10 10 10 10 10 10
    Table 3B: Exemplary Pharmaceutical Formulations Comprising mAb1,
    Histidine, Sucrose, Polysorbate 20 and Arqinina
    mAb1 (mg / ml) 25 50 100 150 25 50 100 150 25 50 100 150 histidine (mM) 10 10 10 10 10 10 10 10 10 10 10 10 sucrose(%) 2 2 2 2 5 5 5 5 10 10 10 10 polysorbate 20 (%) 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Arginine (mM) 25 25 25 25 25 25 25 25 25 25 25 25
    Table 3C: Exemplary Pharmaceutical Formulations Comprising mAb1,
    Histidine, Sucrose, Polysorbate 20 and Arqinina
    mAb1 (mg / ml) 25 50 100 150 25 50 100 150 25 50 100 150 histidine (mM) 25 25 25 25 25 25 25 25 25 25 25 25 sucrose(%) 2 2 2 2 5 5 5 5 10 10 10 10 polysorbate 20 (%) 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Arginine (mM) 10 10 10 10 10 10 10 10 10 10 10 10
    17/45
    Table 3D: Exemplary Pharmaceutical Formulations Comprising mAb1
    Histidine, Sucrose, Polysorbate 20 and Arginine
    mAbl (mg / ml) 25 50 100 150 25 50 100 150 25 50 100 150 histidine (mM) 25 25 25 25 25 25 25 25 25 25 25 25 sucrose(%) 2 2 2 2 5 5 5 5 10 10 10 10 polysorbate 20 (%) 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Arginine (mM) 25 25 25 25 25 25 25 25 25 25 25 25
    Table 3E: Exemplary Pharmaceutical Formulations Comprising mAb1,
    Histidine, Sucrose, Polysorbate 20 and Arginine
    mAbl (mg / ml) 25 50 100 150 25 50 100 150 25 50 100 150 histidine (mM) 25 25 25 25 25 25 25 25 25 25 25 25 sucrose(%) 2 2 2 2 5 5 5 5 10 10 10 10 polysorbate 20 (%> 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Arginine (mM) 50 50 50 50 50 50 50 50 50 50 50 50
    Table 3R Exemplary Pharmaceutical Formulations Comprising mAbl,
    Histidine. Sucrose, Polysorbate 20 and Arginine
    mAbl (mg / ml) 160 170 175 180 160 170 175 180 160 170 175 180 histidine(mM) 25 25 25 25 25 25 25 25 25 25 25 25 sucrose(%) 2 2 2 2 5 5 5 5 10 10 10 10 polysorbate 20 (%) 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Arginine(mM) 50 50 50 50 50 50 50 50 50 50 50 50
    Additional non-limiting examples of pharmaceutical formulations encompassed by the present invention are presented elsewhere herein, including the functional examples presented below.
    STABILITY AND VISCOSITY OF PHARMACEUTICAL FORMULATIONS
    18/45
    The pharmaceutical formulations of the present invention typically exhibit high levels of stability. The term stable, as used herein in reference to pharmaceutical formulations, means that antibodies in pharmaceutical formulations retain an acceptable degree of structure and / or function and / or biological activity after storage for a defined period of time. The formulation can be stable even if the antibody contained therein does not maintain 100% of its structure and / or function and / or biological activity after storage for a defined period of time. Under certain circumstances, the maintenance of about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% of a structure antibody and / or function and / or biological activity after storage for a defined period of time can be seen as stable.
    Stability can be measured, among other means, by determining the percentage of native antibodies remaining in the formulation after storage for a defined period of time at a given temperature. The percentage of native antibodies can be determined by, among other means, size exclusion chromatography (for example, size exclusion high performance liquid chromatography [SE-HPLC]). An acceptable degree of stability, as the phrase is used here, means that at least 90% of the native form of the antibody can be detected in the formulation after storage for a defined period of time at a given temperature. In certain embodiments, at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the native form of the antibody can be detected in the formulation after storage for a defined period of time at a given temperature. The time interval defined after which stability is measured can be at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, or
    19/45 more. The temperature at which the pharmaceutical formulation can be stored when assessing stability can be any temperature from about -80 ° C to about 45 ° C, for example, storage at about -30 ° C, about -20 ° C, about 0 ° C, about 5 ° C, about 25 ° C, or about 45 ° C. For example, a pharmaceutical formulation can be considered stable if after 3 months of storage at 5 ° C, more than about 90%, 95%, 96% or 97% of native antibodies is detected by SEHPLC. The pharmaceutical formulation can also be considered stable if, after 6 months of storage at 5 ° C, more than about 90%, 95%, 96% of 97% of native antibodies are detected by SE-HPLC. The pharmaceutical formulation can also be considered stable if, after 9 months of storage at 5 ° C, it is detected by SE-HPLC more than about 90%, 95%, 96% or 97% of native antibodies. The pharmaceutical formulation can also be considered stable if after 3 months of storage at 25 ° C, it is detected by SE-HPLC more than about 90%, 95%, 96% or 97% of native antibodies. The pharmaceutical formulation can also be considered stable if, after 6 months of storage at 25 ° C, it is detected by SE-HPLC more than about 90%, 95%, 96% or 97% of native antibodies. The pharmaceutical formulation can also be considered stable if after 9 months of storage at 25 ° C, it is detected by SE-HPLC more than about 90%, 95%, 96% or 97% of native antibodies.
    Other methods can be used to assess the stability of the formulations of the present invention such as, for example, differential scanning calorimetry (DSC) to determine thermal stability, controlled agitation to determine mechanical stability, and absorbance at about 350 nm or about 405 nm to determine the turbidity of the solution. For example, the formulation of the present invention can be considered stable if, after 6 or more months of storage at about 5 ° C to about 25 ° C, the change in the formulation's 0D405 is less than about 0.05 ( for example, 0.04, 0.03, 0.02, 0.01, or less) of OD405 of the formulation at = 0,
    Stability can also be assessed by measuring biological activity and / or antibody binding affinity to its target. For example, a formulation of the present invention can be seen as stable if, after storage at, for example, 5 D C, 25 ° C, 45 D C, etc. for a defined period of time (for example, 1 to 12 months), the anti-IL-6R antibody contained in the formulation binds to IL-6R with an affinity that is at least 50%, 60%, 70%, 80% , 90%, 95%, or more of the antibody binding affinity prior to said storage. Additional methods for assessing the stability of an antibody in the formulation are demonstrated in the Examples presented below.
    In fluid form, the pharmaceutical formulations of the present invention may, in certain embodiments, exhibit low to moderate viscosity levels. Viscosity as used here can be kinematic viscosity or absolute viscosity. Kinematic Viscosity ”is a measure of the resistive flow of a fluid under the influence of gravity. When two fluids of the same volume are placed in viscometers of identical capillarity and allowed to flow by gravity, a viscous fluid takes longer than a less viscous fluid to flow through the capillaries. For example, if one fluid takes 200 seconds to complete its flow and another fluid takes 400 seconds, the second fluid is twice as viscous as the first on a kinematic viscosity scale. Absolute viscosity, sometimes called dynamic or simple viscosity, is the product of kinematic viscosity and fluid density (Absolute viscosity = Kinematic viscosity x Density). The dimension of the kinematic viscosity is 12 / T where L is a length and T is a time. Generally, kinematic viscosity is expressed in centistokes (cSt). The SI unit of kinematic viscosity is mm 2 / s, which is 1 cSt. The absolute viscosity is expressed in units of centipoise (cP). The SI unit of absolute viscosity is milliPascal-second (mPa-s), where 1 cP = 1 mPa-s.
    As used herein, a low viscosity level, with reference to a fluid formulation of the present invention, will exhibit an absolute viscosity of less than about 20 ePoise (cP). For example, a fluid formulation of the invention will be evaluated as having low viscosity,
    21/45 if, when measured using standard viscosity measurement techniques, the formulation exhibits an absolute viscosity of about 19 cP, about 18 cP, about 17 cP, about 16 cP, about 15 cP, about about 14 cP, about 13 cP, about 12 cP, about 11 cP, about 10 cP, about 9 cP, about 8 cP, about 7 cP, about 6 cP, about 5 cP, about 4 cP or less. As used herein, a moderate level of viscosity, with reference to a fluid formulation of the present invention, will exhibit an absolute viscosity between about 30 cP and about 20 cP. For example, a fluid formulation of the invention will be assessed as having moderate viscosity, if, when measured using standard viscosity measurement techniques, the formulation exhibits an absolute viscosity of about 30 cP, about 29 cP, about 28 cP , about 27 cP, about 26 cP, about 25 cP, about 24 cP, about 23 cP, about 22 cP, about 21 cP or about 20 cP.
    As illustrated in example 6 below, the present inventors have made the surprising discovery that fluid formulations with low to moderate viscosity comprising high concentrations of an anti-hL L-6R antibody (for example, up to at least 175 mg / ml) can be obtained by formulating the antibody with 25 mM to 100 mM histidine and 25 mM to 50 mM arginine. In addition, it was further discovered that the viscosity of the formulation could be further reduced by adjusting the sucrose content to less than 10%.
    CONTAINERS FOR PHARMACEUTICAL FORMULATIONS AND METHODS OF ADMINISTRATION
    The pharmaceutical formulations of the present invention can be contained within any container suitable for storing medications and other therapeutic compositions. For example, pharmaceutical formulations can be contained within sterile glass or plastic containers having a defined volume such as a vial, ampoule, syringe, cartridge, or bottle. Different types of bottles can be used to contain formulations of the present invention including, for example, transparent or opaque glass or plastic bottles (for example, amber). I22 / 45 likewise, any type of syringe can be used to contain and / or administer the pharmaceutical formulations of the present invention.
    The pharmaceutical formulations of the present invention can be contained within normal tungsten syringes or low tungsten syringes. As will be judged by people of ordinary skill in the art, the glass syringe manufacturing process usually involves the use of a hot tungsten bar that works to pierce the glass therein creating a hole through which the liquid can be pulled and expelled from the syringe . This process results in the deposition of tiny amounts of tungsten on the inner surface of the syringe. Subsequent washing and other processing steps can be used to reduce the amount of tungsten in the syringe. As used herein, the term normal tungsten means that the syringe contains more than 500 parts per billion (ppb) of tungsten. The term low tungsten means that the syringe contains less than 500 ppb of tungsten. For example, a low tungsten syringe, according to the present invention, can contain less than about 490, 480, 470, 460, 450, 440, 430, 420, 410, 390, 350, 300, 250, 200, 150, 100, 90, 80, 70, 60, 50.40, 30, 20, 10 or less ppb of tungsten.
    The rubber plungers used in the syringes, and the rubber stoppers used to close the vial openings, can be coated to prevent contamination of the syringe or vial's medicinal contents and / or to preserve its stability. Thus, the pharmaceutical formulations of the present invention, according to certain modalities, can be contained in a syringe comprising a coated plunger, or in a bottle that is sealed with a coated rubber stopper. For example, the plunger or lock can be coated with a fluorocarbon film. Examples of coated plugs and / or plungers suitable for use with vials and syringes containing the pharmaceutical formulations of the present invention are mentioned in, for example, U.S. Patent Nos. 4,997,423; 5,908,686; 6.2S6.699; 6,645,635; and 7,226,554, the contents of which are incorporated herein by reference in their entirety. Exemplary coated rubber latches and plungers in particular that can be used in the context of
    The present invention is commercially available under the trademark FluroTec®, available from West Pharmaceutical Services, Inc. (Lionville, PA).
    In accordance with certain embodiments of the present invention, pharmaceutical formulations can be contained in a low tungsten syringe comprising a plunger coated with fluorocarbon. As discussed in the Examples section below, the combination of a low tungsten syringe and a fluorocarbon-coated plunger has been observed to produce surprising stability characteristics with respect to the pharmaceutical formulations of the present invention.
    Pharmaceutical formulations can be administered to a patient via parenteral routes such as injection (for example, subcutaneous, intravenous, intramuscular, intraperitoneal, etc.) or percutaneous, mucous, nasal, pulmonary and / or oral administration. In moist, reusable pens and / or self-injecting delivery devices can be used to deliver the pharmaceutical formulations of the present invention subcutaneously. Examples include, but are not limited to AUTOPEN ™ (Owen Mumford, Inc., Woodstock, UK), DISETRONICTM pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25 ™ pen, HUMALOGTM pen, HUMALIN 70 / pen 30 ™ (Eli Lilly and Co., Indianapolis, IN), NOVOPEN I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR ™ (Novo Nordisk, Cocanetahagen, Denmark), BD ™ pen (Becton Dickinson, Franklin Lakes , NJ), OPTIPEN, OPTIPEN PRO ™, OPTIPEN STARLET ™, and OPTiCLIK ™ (sanofi-aventis, Frankfurt, Germany), just to mention a few. Examples of disposable pens and / or self-injecting delivery devices having applications in the subcutaneous delivery of a pharmaceutical composition of the present invention include, but are not limited to SOLOSTAR pen (sanofi-aventis), FLEXPEN ™ (Novo Nordisk), and KWIKPEN ™ (Eli Lilly), the SURECLICK ™ Autoinjector (Amgen, Thousand Oaks, CA), PENLET ™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA ™ pen (Abbott Labs, Abbott Park , IL), just to mention a few.
    24/45
    The use of a microinfuser to deliver the pharmaceutical formulations of the present invention is also contemplated here. As used herein, the microinfuser stubborn ' 1 means a subcutaneous delivery device designed to slowly deliver large volumes (for example, up to about 2.5 mL or more) of a therapeutic formulation over an extended period of time (for example, about 10 , 15, 20, 25, 30 or more minutes). See, for example, US 6,629,949; US 6,659,982; and Meehan et al., J. Controlled Release 46: 107-116 (1996). Microfusers are particularly useful for delivering large doses of therapeutic proteins contained in high concentration solutions (for example, about 100, 125, 150, 175, 200 or more mg / mL) and / or viscous.
    THERAPEUTIC USES OF PHARMACEUTICAL FORMULATIONS
    The pharmaceutical formulations of the present invention are useful, inter alia, for the treatment, prevention and / or amelioration of any disease or disorder associated with IL-6 activity, including diseases or disorders mediated by the activation of the IL-6 Receptor Exemplary diseases and disorders and non-limiting factors that can be treated and / or avoided by administering the pharmaceutical formulations of the present invention include, for example, rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, pancreatitis, juvenile idiopathic arthritis, vasculitis, Kawasaki disease, lupus systemic erythromatous, psoriasis, psoriatic attrition, Sjogren's syndrome, Still's disease, Castleman's disease, multiple sclerosis, diseases associated with abnormal blood clotting or fibrinolysis (for example, thrombosis), cancer (for example, breast cancer, leukemia, cancer ovarian, melanoma, prostate cancer, pancreatic cancer, lymphoma, lung cancer, kidney cell carcinoma, colorectal cancer, multiple myeloma, etc.), cachexia, chronic rejection of transplanted organs and cells, heart disease, viral infection (e.g., H1V infection, EBV infection, etc.), plasmacytosis, hyperimmunoglobulinsmia, anemia, nephritis, mesothelioma, and hearing loss and others inner ear disorders.
    Thus, the present invention includes methods for the treatment, prevention, and / or amelioration of any disease or disorder associated with
    25/45 IL-6 activity or IL-6R activation (including any of the exemplary diseases mentioned above, disorders and conditions). The therapeutic methods of the present invention comprise administering to a subject any formulation comprising an anti-hLL-6R antibody as set forth herein. The subject to which the pharmaceutical formulation is administered can be, for example, any human or non-human animal that needs such treatment, prevention and / or improvement, or who would otherwise benefit from inhibiting or mitigating IL-mediated Activity 6 and / or IL6R. For example, the subject may be an individual who is diagnosed with, or who is believed to be at risk of being afflicted by any of the diseases or disorders mentioned above. The present invention further includes the use of any of the pharmaceutical formulations as set forth herein in the manufacture of a medicament for the treatment, prevention and / or amelioration of any disease or disorder associated with IL6 activity or IL-6R activation (including any exemplary diseases mentioned above, disorders and conditions).
    EXAMPLES
    The following examples are advanced in order to provide those of ordinary skill in the art with a complete exposition and description of how to make and use the methods and compositions of the invention, and are not intended to limit the scope of what the inventors see as their invention. Efforts have been made to ensure accuracy with respect to the numbers used (eg quantities, temperature, etc.), but some experimental errors and deviations must be taken into account. Unless otherwise stated, the parts are parts by weight, the molecular weight is the average molecular weight, the temperature is in degrees centigrade, and the pressure is atmospheric or close to that.
    Example 1. Stability of a fully human antibody (mAb1) to the anti-human Interleukin-6 (1L-6R) receptor after storage at low temperatures
    In this example, several formulations were created containing an anti-human IL-6R antibody without excipients. The exemplary antibody used
    26/45 in that and the subsequent examples advanced below is an antibody comprising a heavy chain variable region (HCVR) with the amino acid sequence of SEQ ID NO: 18, and a light chain variable region (LCVR) with the amino acid sequence SEQ ID NO: 26. Such an antibody is referred to herein as mAb1.
    As a preliminary experiment, the stability of mAb1 in liquid solution was determined by following various amounts of time in frozen storage at -20 ° C, -30 ° C and -80'C. The concentration of mAb1 used in this example was 128 mg / ml. At various time points, the stability of mAb1 was determined by size exclusion high performance liquid chromatography (SE-HPLC) and cation exchange-based high performance liquid chromatography (CEX-HPLC). Stability was assessed based on a percentage of native mAb1 remaining in the sample (by SE-HPLC; Table 4) and by a percentage of acidic species observed in the sample (by CEX-HPLC; Table 5) (A percentage increase in acidic species is consistent with the deamination of the antibody and is thus considered an undesirable phenomenon with respect to the pharmaceutical formulations of the present invention).
    Table 4:% native mAb1 remaining (SE-HPLC)
    Time (months) Storage Temperature -80’C -30 C -20’C 0 95.9 55.9 95.9 1 95.7 94.3 93.2 3 95.6 93.6 89.3 6 96.1 96.0 88.9 9 95.6 91.6 87.9
    Table 5:% Acidic species (CEX-HPLC)
    Time (months) Storage Temperature -80 ° C -30 ° C -20 ° C 0 28.6 28.6 28.6 1 27.3 28.0 28.1 3 27.3 Ί 27.7 28.3 6 28.6 29.6 29.3 9 29.0 28.8 29.0
    The results of Tables 3 and 4 are described in figures 1 and 2,
    27145 respectively. These results show that mAb1 can remain stable at a concentration of 128 mg / mL for at least 9 months when stored at -80 ° C.
    Example 2. Stability of mAb1 Formulations Containing Mini Exposients 5 mos
    Eight different formulations were prepared containing mAb1 and minimal excipients as shown in table 6. The formulations were tested for stability by SE-HPLC at various time intervals at -30 ° C and -20 ° C. The results, expressed as a percentage of native native 10 mAb1, are shown in Tables 7 (-3CTC storage) and 8 (20 ° C).
    Table 6: mAb1 Minimum Excipient Formulations
    Formulation Excipient mAb1 (mg / mL) 1 0.13% polysorbate 20 6% sucrose 80 2 0.13% polysorbate 20 80 3 1% sucrose 80 4 2% sucrose 80 5 4% sucrose 80 6 6% sucrose 80 7 none 80 8 none 65 All formulations contain 10 mM histidine, pH 6.0
    Table 7:% mAb1 Native Remnant (SE-HPLC) After Storage at -30 ° C
    Time(months) 1 2 Formulation No. (see table 6) 7 8 3 4 5 6 0 96.4 96.2 96.4 96.5 96.5 96.6 96.2 96.5 1 96.4 95.1 96.3 96.3 96.4 96.6 95.1 95.3 2 96.4 94.7 96.0 96.4 96.5 96.0 95.0 95.4 3 96.5 94.7 96.3 96.7 96.7 96.7 94.4 94.9 4 97.2 95.2 96.7 97.4 97.3 97.3 95.1 95.7 6 97.0 94.2 96.2 96.8 97.1 96.9 94.0 94.5 9 96.7 93.6 96.0 96.6 96.5 96.9 93.4 93.8
    28/45
    Table 8:% native mAb1 remaining (SE-HPLC) After storage at -20 ^ 0
    Time (months) 1 2 Formulation No. (see table 6) 7 8 3 4 5 s 0 96.4 96.2 96.4 96.5 96.5 96.6 96.2 96.5 1 96.7 94.5 96.0 96.8 96.5 96.3 94.1 94.5 2 96.4 90.9 95.3 96.4 96.4 96.4 90.9 91.8 3 96.9 90.1 95.1 96.6 96.6 96.7 90.5 90.9 4 97.2 90.7 95.8 97.4 97.1 97.1 91.4 91.8 6 96.9 86.9 94.1 96.9 96.9 97.1 87.5 88.5 9 96.5 86.0 93.3 96.6 96.6 96.7 86.7 87.5
    The results of Tables 7 and 8 are described in figures 3 and 4, respectively. As shown in this example, the stability of mAb1 was maintained to a significant extent in formulations 1, 4, 5 and 6 after several months of storage at -20 ° C and -30 ° C. These results indicate that the stability of mAb1 at -20 ° C and -30 ° C can be improved by adding at least 2% sucrose.
    Example 3. Stabilized formulation of mAb1
    A stabilized formulation containing various concentrations of mAb1 was prepared for use in Examples 4 and 5 below. This formulation, called Formulation A, is shown in table 9.
    Table 9: Stabilized formulation of mAb1 A
    Component Formulation A mAb1 25- 100 mg / mL Histidine 10 mM Polysorbate 20 0.2% Sucrose 10%
    pH adjusted to 6.0
    Example 4. Stability of Formulation A After Storage at 5 ° C
    Formulation A (see Example 3) containing 25, 50 or 100 mg / ml of mAb1 was tested for stability after several months of storage at 5 ° C in clear vials. Stability was
    29/45 assessed by the following parameters: (a) visual appearance; (b) turbidity (OD 405 nm); (c) pH; (d) total percentage of mAb1 recovered (as measured by RP-HPLC); (d) percentage of native mAb1 recovered (as measured by SE-HPLC); (e) percentage of main peak mAb1 recovered (as measured by CEXHPLC); and (f) percentage of acidic mAb1 species recovered (as measured by CEX-HPLC). The stability results for Formulation A containing 25, 50 and 100 mg / ml of mAb1 are summarized in tables 10, 11 and 12, respectively.
    Table 10: Stability of Formulation A Containing 25 mg / mL of mAb1
    After Storage at 5 ° C in Transparent Bottles
    Parameter Storage Life at 5 ° C (months) 0 1 2 3 6 9 12 Visual appearance Passouu Passed Passed Passed Passed Pas-souou Passed Turbidity (OD 405 nm) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 pH 6.0 6.1 6.1 6.1 6.1 6.1 6.1 % Total mAb1 recovered 100 99 101 112 103 94 101 % of native mAb1 recovered 97.5 98.0 97.5 97.6 97.5 97.5 97.8 % of main peak mAb1 recovered 58.4 57.9 58.7 58.1 57.9 57.9 58.4 % of acidic mAb1 species recovered 26.5 28.0 26.5 28.0 27.3 28.0 27.9
    30/45
    Table 11A: Stability of Formulation A Containing 50 mq / mL of mAb1
    After Storage at 5 ° C in Transparent Bottles (0-9 months)
    Parameter Storage life at 5 ° C (months) 0 1 2 3 6 9 Visual appearance Passed u Pas-I'm u P ro u Pas-I know Pas-I know Pas-scuu Turbidity (OD 405 nm) 0.00 0.00 0.00 0.00 0.00 0.00 pH 5.8 5.9 5.8 5.9 5.9 6.0 Total% of mAb1 recovered 100 99 104 106 100 109 % of native mAb1 recovered 97.4 97.5 97.3 97.2 97.3 97.2 % of main peak mAbl recovered 57.1 56.7 58.0 54.2 53.3 57.9 % of acidic mAbl species recovered) 27.6 26.7 27.6 28.5 26.8 26.9
    Table 11B: Stability of Formulation A Containing 50 mg / mL of mAb1
    After Storage at 5 ° C in Transparent Bottles (12 - 24 months)
    Parameter Storage life at 5 ° C 12 (months)18 24 Visual appearance Passouu Passouu Passouu Turbidity (OD 405 nm) 0.00 0.00 0.00 pH 5.9 6.0 5.9 Total% of mAbl recovered 103 107 105 % of native recovered mAbl 97.1 97.1 96.9 % of main peak mAbl recovered 56.4 57.1 56.4 % of acidic mAbl species recovered) 28.1 28.3 29.0
    31/45
    Table 12A: Stability of Formulation A Containing 100 mq / mL of mAb1
    After storage at 5 ° C in transparent bottles (0-9 months)
    Parameter Storage life at 5 ° C (months) 0 1 2 3 6 9 Visual appearance Passed u Passouu Passouu Passouu Pas-I know Passouu Turbidity (OD 405 nm) 0.00 0.00 0.00 0.00 0.00 0.00 pH 5.9 6.0 5.9 5.9 5.9 5.9 Total% of mAb1 recovered 100 99 100 107 101 106 % of native mAb1 recovered 97.3 97.0 97.0 97.1 96.9 96.9 % of main peak mAb1 recovered 55.1 55.5 57.9 55.9 55.4 58.6 % of acidic mAb1 species recovered) 27.6 26.9 27.4 29.6 27.4 27.4
    Table 12B: Stability of Formulation A Containing 100 mq / mL of mAb1 After Storage at 5 ° C in transparent Flasks (12 - 24 months)
    Parameter Storage life at 5 ° C 12 (months)18 24 Visual appearance Passouu Passouu Passouu Turbidity (OD 405 nm) 0.00 0.00 0.00 pH 6.0 6.0 60 Total% of mAb1 recovered 101 102 103 % of native mAb1 recovered 96.8 96.7 96.5 % of main peak mAb1 recovered 57.3 57.5 56.7 % of acidic mAb1 species recovered) 27.3 28.1 28.7
    The results of this Example demonstrate that the Formulation
    The one containing 25, 50 or 100 mg / mL of mAb1 remained stable after at least 9 months of storage, at 5 D C in transparent vials, with about 97% or more of native mAb1 remaining in all samples after 9 months of storage under such conditions
    3> 21A5 tions. For the 50 and 100 mg / ml formulations, 96.9% and 96.5% of native mAb1 was detected, respectively, after up to 24 months of storage at 5'C. In addition, a percentage of acidic species remained at 29% or less for all time points 5 analyzed, thus confirming the stability of the formulations.
    Similar stability studies were also performed using Formulation A containing 75 mg / ml of mAb1 following storage at 2-8 ° C. No significant degradation was observed for any of the concentrations tested after 24 months 10 of storage at 2-8 ° C as determined by SE-HPLC and CEXHPLC (data not shown).
    Table 13: Stability of Formulation A Containing 25 mq / ml_ of mAb1 After storage at 5 ° C in transparent 5 ml bottles
    Parameter Storage life at 5 ° C (months) t = 00 1 2 3 6 9 12 Visual appearance Passed u Passouu Passouu Passouu Passed u Passouu Passouu Turbidity (OD 405 nm) 0.0 0.0 0.0 0.0 0.0 0.0 0.0 PH 6.0 6.0 6.0 6.0 6.0 6.0 6.1 Total% of mAb1 recovered 100 106 103 98 100 100 101 % of native mAb1 recovered 97.1 97.0 96.9 96.9 97.0 96.4 96.6 % of main peak mAb1 recovered 57.8 56.8 56.2 54.2 56.4 56.4 56.8 % of acidic mAb1 species recovered) 27.9 30.7 30.8 33.0 30.6 29.8 30.1
    Example 5. Stability of Formulation A Made in clear and amber glass bottles
    Additional experiments were conducted to compare the stability of Formulation A (see Example 3) containing 25 and 100
    33/45 mg / mL of mAb1 made in amber glass bottles to the same formulation made in transparent bottles. Two types of amber bottles were used in this example: 5 ml and 20 ml amber bottles. Stability was assessed following storage at 5 ° C, 25 D C or 45 ° G based on the same 5 parameters as used in Example 4. The results for the 25 mg / mL and 100 mg / mL formulations are summarized in tables 13 through 21.
    Table 14: Stability of Formulation A Containing 100 mg / mL of mAb1
    After storage at 5 ° C in transparent 5 mL bottles
    Parameter Storage life at 5 ° C (months) t = 00 1 2 3 6 9 12 Visual appearance Passauu Passed u Pas-I know Pas-I'm u Passouu Passouu Passouu Turbidity (OD 405 nm) 0.0 0.0 0.0 0.0 0.0 0.0 0.0 PH 6.0 6.1 6.0 6.1 6.0 6.1 6.1 Total% of mAb1 recovered 100 106 104 97 100 99 100 % of native mAb1 recovered 96.2 96.3 96.1 96.0 95.9 95.5 95.4 % of main peak mAb1 recovered 57.6 57.3 57.9 55.5 56.2 56.4 55.4 % of acidic mAb1 species recovered) 28.2 30.2 29.4 31.1 30.7 30.0 32.2
    34/45
    Table 15: Stability of Formulation A Containing 25 mq / mL of mAb1
    After storage at 5 ° C in 5 ml amber bottles
    Parameter Storage life at 5 ° C (months) t = 00 1 2 3 6 9 12 Visual appearance Passouu Passouu Passed u Passouu Passed u Passouu Passouu Turbidity (OD 405 nm) 0.0 0.0 0.0 0.0 0.0 0.0 0.0 pH 6.0 6.0 6.0 6.0 6.0 6.0 6.0 Total% of mAb1 recovered 100 104 104 98 99 97 101 % of native mAb1 recovered 97.1 97.4 96.8 96.7 96.7 96.1 96.3 % of main peak mAb1 recovered 57.8 56.4 56.3 56.1 55.7 55.9 55.2 % of acidic mAb1 species recovered) 27.9 30.4 30.6 31.8 31.0 30.5 32.9
    Table 16: Stability of Formulation A Containing 100 mq / mL of mAb1
    After storage at 5 ° C in 5 ml amber bottles
    Parameter Storage life at 5 ° C (months) t = 00 1 2 3 6 9 12 Visual appearance Passed u Passouu Passouu Pas-I'm u Pas-I know Passouu Passouu Turbidity (OD 405 nm) 0.0 0.0 0.0 o.o 0.0 0.0 0.0 pH 6.0 6.0 6.0 6.0 6.0 6.0 6.1 Total% of mAb1 recovered 100 102 104 97 101 100 100 % of native mAb1 recovered 96.2 95.0 96.0 96.0 95.8 95.0 95.3 % of main peak mAb1 recovered 57.6 56.9 58.0 55.6 56.3 56.5 55.1 % of acidic mAb1 species recovered) 28.2 30.1 29.4 31.4 30.4 30.0 32.3
    35/45
    Table 17: Stability of Formulation A Containing 25 mg / mL of mAb1
    After storage at 5 ° C in 20 ml amber bottles
    Parameter Storage life at 5 ° C (months) 0 1 2 3 6 9 12 Visual appearance Pas-I'm u Passouu Passouu Passed u Passed u Pas-I know Passouu Turbidity (OD 405 nm) 0.0 0.0 0.0 0.0 0.0 0.0 0.0 PH 8.0 6.0 6.0 6.0 6.0 6.0 6.0 Total% of mAb1 recovered 100 105 103 97 101 98 101 % of native mAb1 recovered 97.1 96.9 97.0 96.8 97.0 96.2 96.6 % of main peak mAb1 recovered 57.8 56.4 57.1 55.9 55.6 56.1 55.2 % of acidic mAb1 species recovered) 27.9 20.9 30.2 30.5 30.7 30.0 31.9
    Table 18; Stability of Formulation A Containing 100 mg / mL mAb1
    After storage at 5 ° C in 20 ml amber bottles
    Parameter Storage life at 5 ° C (months) 0 1 2 3 6 9 12 Visual appearance Passouu Passouu Passouu Passouu Passouu Passouu Passouu Turbidity (OD 405 nm) 0.0 0.0 0.0 0.0 0.0 0.0 0.0 PH 6.0 6.0 6.0 6.0 6.0 6.0 6.0 Total% of mAb1 recovered 100 105 103 97 99 98 100 % of native mAb1 recovered 96.2 96.2 96.0 96.0 95.8 95.4 95.5 % of main peak mAb1 recovered 57.6 57.9 56.3 56.5 56.5 56.4 55.3 % of mAb1 acid species recovered) 28.2 29.8 30.4 30.3 30.6 30.0 30.9
    36/45
    Table 19: Stability of Formulation A Containing 100 mti / mL of mAb1 After storage at 25 ° C and 45 ° C in
    Transparent bottles
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    37/45
    Table 21: Stability of Formulation A Containing 100 mg / ml of mAb1 After storage at 25 ° C and 45 ° C in 20 ml amber bottles
    ΦCfl ΦTHETheLO CM¢ 0THEÇΦAND<ü cΦN <0< <0 Passouu CM O o 6 ^ [100 I 93.5 | 36.7 55.0 CO □TheCOCOCD D_ 0.00 6 ^ 96 CD00CD 43.5 41.3 CM 32 OCOCONUTCQ CL 0.01 I 6.0 J 103 94.0 oo σί 35.8 y - Passouu I o.oo | Cl · CD 104 I 94.3 52.7 32.5CO 1 00 S. CN O O Passouu 0.02 CD | 105 LDCXf 00 CM CM 68.6 ASS3 7AND4>AND Passouu 00'0 T<0 THE 0000 CMTHE T - IO c a> NΠ5Ξ Passouu 0.01 I 6.0 I TheT— I 94.9 45.7 36.7 THE □COWith the CL 0.00 I 6 1 o I I ioo I 95.6 57.6 28.2 Parameter Visual appearance I Turbidity (OD 405 nm) I Q. Total% of mAb1 recovered I % of native mAb1 recovered I % of main peak mAb1 recovered _________ % of acidic mAb1 species recovered)
    38/45
    As shown in this example, Formulation A containing 25 mg / ml or 100 mg / ml of mAb1 exhibited equivalent stability profiles when stored in either clear or amber bottles. In addition, as shown in Example 4 for storage in clear bottles, the relatively high stability of mAb1 was maintained in Formulation A when stored in either clear or amber bottles at 5 ° C for up to 12 months.
    Example 6, Effect of Arginine, Histidine and Sucrose concentrations on Viscosity and Stability of Formulations Containing 150 mg / mL of mAb1
    Several formulations were prepared containing 150 mg / ml, 175 mg / ml and 200 mg / ml of mAb1 and various amounts of histidine, arginine and sucrose. Viscosity and osmolality were measured for each formulation. In addition, the stability of the 150 mg / ml formulations after 4 weeks of storage at 45 ° C was evaluated in terms of percentage of remaining native mAb1 (by SE-HPLC) and percentage of remaining main peak (by CEXHPLC). The results are summarized in table 22.
    Table 22: Effect of Arginine, Histidine and Sucrose on the Viscosity and Stability of the mAb1 Formulations
    mAbí (mg / ml) [histidine] (mM) [arginine] (mM) [sucrose] (%) Viscosity (cPoise) OsmolaI age (mOsm) % mAbí native remnant * % acidic species 150 10 0 10 -15 375 90.8 19.9 150 25 25 10 -11.5 500 91.6 19.5 150 25 25 5 -8.5 305 91.8 19.8 150 25 25 2.5 -8.0 220 91.1 19.9 150 25 25 0 -8.5 115 90.3 20.6 175 10 0 10 -27 395
    39/45
    mAb1(mg / ml) [histidine](mM) [arginine] (mM) [sucrose](%) Viscosity (cPoise) Osmolality (mOsm) 175 25 25 10 -20.5 415 175 25 25 5 -19 300 175 25 50 5 -14.5 390 175 100 0 5 -12.5 415 175 100 50 5 -10 515 200 10 0 10 -44 410 200 25 25 10 -35 480 200 25 25 5 -30 300 200 25 25 0 -28 130 200 100 0 10 -27 570 200 100 50 10 -21 670
    *% of native native mAb1 = 96.5% (SE-HPLC)
    The results presented in table 16 indicate that increasing the concentration of histidine to 25 mM or 100 mM and adding arginine to the formulation (25 mM or 50 mM) significantly reduced the viscosity of the formulation compared to formulations containing only 10 mM histidine and arginine. In addition, reducing the sucrose concentration from 10% to 5% with the added histidine and arginine decreased the formulation viscosity even further.
    Based at least in part on the preceding, the following formulations (designated Formulation B and Formulation C'j shown in table 23) were prepared.
    Table 23: Formulations r stabilized nAb1 B and C Component Formulation B Formulation C mAb1 25 -200 mg / mL 25 - 200 mg / mL Histidine 25 mM 25 mM Polysorbate 20 0.2% 0.2% Sucrose 5% 5% Arginine 25 mM 50 mM
    pH adjusted to 6.0
    Example 7. Stability of Formulation B Containing 150 mg / mL of mAb1 when Manufactured in a vial and Syringes
    40/45
    A Formulation B (see Table 23) containing 150 mg / ml mAb1 was prepared in a 2 ml glass vial and in two different syringes: regular and low tungsten. The preparations were stored at 5, 25 and 45 ° C for several time intervals. The stability of mAb1 following storage was measured by SE-HPLC and CEX-HPLC. The results are shown in Table 24. (A percentage increase in acidic species is consistent with deamination of the antibody and is thus considered an undesirable phenomenon with respect to the pharmaceutical formulations of the present invention).
    Table 24: Stability of Formulation B Containing 150 ma / mL of mAb1 in Vial and Syringe
    2 ml glass bottle_ Regular Syringe Low tungsten syringe Temperature Time % Native(SE-HPLC) % Acrylic(CEX-HPLC) % Native (SE-HPLC) % Acrylic (CEXHPLC) % Native (SE-HPLC) % Acidic (CEXHPLC) - Start 96.7 32.2 96.5 32.3 96.7 31.7 45 ° C 14 days 94.1 52.7 94.3 54.5 94.3 56.1 45 ° C 14 days 92.7 69.7 92.7 69.7 92.5 70.8 45 ° C 56 days 86.7 84.7 87.8 82.6 86.9 83.5 25'C 1 month 95.1 31.2 95.7 30.6 95.6 31.1 25 ° C 2 months 95.3 34.6 94.7 37.4 96.0 36.3 25 ° C 3 months 94.3 40.6 93.9 43.7 94.1 42.6 5’C 1 month 96.2 30.2 96.5 29.1 96.4 29.3 5'C 2 months 96.3 29.3 96.4 29.0 96.4 29.1 5’C 3 months 95.7 29.4 95.8 29.6 95.8 29.6
    As shown in this table, Formulation B containing
    150 mg / mL of mAb1, stored at 5 ° C in a glass vial or syringe, remained relatively stable for at least 3 months.
    Example 8: Stability of mAb1 formulations in pre-filled syringes
    A series of experiments was performed to evaluate the stability of different mAb1 formulations in pre-filled syringes. For these experiments, several luer and fixed needles, regular tungsten and low tungsten syringes were used in combination with different types of plungers (coated and uncoated) and tip caps. The formulations were tested for stability after storage in serin
    41/45 gas pre-filled at 45 ° C, 25 ° C and 5 ° C for various time intervals (ranging from 14 days to 12 months, depending on the conditions tested).
    Six different mAb1 formulations were tested for stability in pre-filled syringes in this example: (1) Formulation A (see Table 5) containing 100 mg / ml mAb1; (2) Formulation A (see Table 9) containing 25 mg / ml of mAb1; (3) Formulation B (see Table 23) containing 150 mg / ml of mAb1; (4) Formulation B (see Table 23) containing 25 mg / nnL of mAb1; (5) Formulation C (see Table 23) containing 175 mg / ml mAb1; and (6) Formulation C (see Table 23) containing 25 mg / ml mAb1.
    Stability was assessed by the following parameters: (a) visual analysis; (b) turbidity (01D405nm); (c) percentage of recovery by RP-HPLC; (d) percentage of native mAb1 by SE-HPLC; (e) percentage of the main peak of mAb1 by CEX-HPLC; and (f) percentage of acidic species by CEX-HPLC.
    The results of a representative experiment evaluating the stability of Formulation A, containing 100 mg / ml of mAb1 in two different syringes (Syringe No.1 and Syringe No. 2) are shown in tables 25 and 26 below.
    42/45
    Table 25: Stability of Formulation A containing 100 mg / mL of mAb1 in a pre-filled Syringe with No. 1 fixed needle
    Description of Syringe No. 1
    Syringe: BD 1 mL long 29ga x 1/2 Physiolis, Low tungsten Piston: West FluroTec® 4023/50 Tip cover: BD 260 Siliconization: Sprayed Temperatu-frog Time Visual analysis Turbidity (Οϋ 405Β ιη) % recovery % of native mAb1 % of Main Peak % of Acidic Species - Start passed on 0.00 100 96.6 56.9 28.7 45 ° C 14 days passed on 0.00 99 95.1 32.7 50.7 45 ° C 28 days passed on 0.01 103 92.6 20.9 66.1 45 ° C 56 days passed on 0.03 105 88.8 9.9 80.9 25 ° C 1 month passed on 0.00 106 95.6 52.4 32.0 25 ° C 2 months passed on 0.00 107 95.2 48.0 37.0 25 ° C 3 months passed on 0.00 106 94.2 44.8 41.8 25'C 6 months passed on 0.01 101 93.7 34.8 53.9 25 ° C 9 months passed on 0.03 98 91.4 26.1 64.6 25 ° C 12 months passed on 0.03 101 89.9 21, .3 69.4 5 ° C 1 month passed on 0.00 110 96.4 56.8 29.9 5 ° C 2 months passed on 0.00 108 96.2 55.7 31.1 5 ° C 3 months passed on 0.00 104 96.0 56.3 30.0 5’C δ months passed on 0.00 100 96.5 55.0 31.3 5 ° C 9 months passed on 0.00 98 96.2 56.7 30.3 5 ° C 12 months passed on 0.00 101 95.4 57.3 30.2
    43/45
    Table 26: Stability of Formulation A containing 100 mq / mL of mAbl in a Pre-filled Syringe with fixed needle No.2 ____________________________________
    Syringe Description No.2; Syringe: Schott 1 mL Long SNCF 29ga x 1/2 Piston: West FiuroTec® 4023/50 Tip cover: Stelmi 4800 w / RNS Siliconization: Sprayed Temperature Time Visual analysis Turbidity(OD ^ osnm} % recovery % of native mAbl % of Main Peak % Acidic Species - In ugly passed on 0.00 100 96.3 57.5 28.0 45 ° C 14 days passed on 0.00 100 95.2 33.7 49.6 45’C 23 days passed on 0.00 103 93.3 22.8 64.7 45 ° C 56 days passed on 0.03 107 88.0 9.9 81.1 25 ° C 1 month passed on 0.00 108 95.5 52.5 31.8 25 ° C 2 months passed on 0.00 107 95.2 49.2 35.7 25 ° C 3 months Failed 0.00 106 93.9 43.1 42.0 25 ° C 6 months Failed 0.00 102 92.9 34.4 54.0 25 ° C 9 months passed on 0.02 100 92.3 26.9 63.5 25 "C 12 months passed on 0.03 103 90.0 20.0 70.2 5 ° C 1 month passed on 0.00 111 96.3 56.7 29.9 5 ° C 2 months passed on 0.00 112 95.6 55.9 31.1 5 ° C 3 months passed on 0.00 106 96.1 57.2 29.4 5 ° C 6 months passed on 0.00 102 96.0 54.9 31.6 5 ° C 9 months passed on 0.00 100 95.9 56.7 30.2 5 ° C 12 months passed on 0.00 102 95.4 56.0 30.7
    The results of another representative experiment evaluating the stability of Formulation C, containing 175 mg / mL of mAbl in two different syringes (Syringe No. 1 and Syringe No.3) are shown in tables 27 and 28 below.
    The results of this set of experiments demonstrate that the different formulations remain relatively stable in pre-filled syringes, especially when stored at temperatures of 25 ° C and below, for a month or more. In addition, the various formulations of the invention appear to have improved stability when contained in low tungsten syringes containing a fluorocarbon-coated plunger.
    44/45
    Table 27: Stability of Formulation C containing 175 mq / mL of mAb1 in a pre-filled Syringe with No.1 fixed needle
    Description of Syringe No. 1:
    Syringe: BD 1 mL long 29ga x 1/2 Physiolis, Low tungsten Piston: West FluroTec® 4023 / 5D Tip cover: BD 260 Siliconization: SprayedTemp Time Visual analysis Turbidity (0 D 4.35 nrin ) % recovery % of native mAb1 % of Main Peak % of Acidic Species - In ugly passed on 0.00 100 96.7 59.7 32.4 45 ° C 7 days passed on 0.01 102 96.1 48.6 39.5 45 ° C 14 days passed on 0.03 97 95.0 36.9 50.0 45’C 28 days passed on 0.03 98 91.9 24.7 66.0 45 C 55 days passed on 0.05 97 91.9 12.3 83.3 25 S C 1 month passed on 0.02 99 95.4 56.9 33.8 25 ° C 2 months passed on 0.00 100 95.0 51.1 39.8 5 ° C 1 month passed on 0.00 98 96.1 59.5 32.7 5 ° C 2 months passed on 0.00 101 96.4 56.3 37.1
    Table 28: Stability of Formulation C containing 175 mq / mL of mAb1 in a pre-filled Syringe with fixed needle No.3
    Description of Syringe No.1:
    Syringe: Daikyo Seiko CZ 1 mL std 30ga x 1/2 Piston: Daikyo D-21-6-1 Coated FiuroTec® Tip cover: 7028 Siliconization: AT Temp Time Visual analysis Turbidity(OD4o5nm} % recovery % of native mAb1 % of Main Peak % of Acidic Species - start passed on 0.00 100 96.4 58.2 33.6 45 ° G 7 days passed on 0.00 101 95.7 45.4 40.4 45 * 0 14 days passed on 0.01 101 94.8 37.5 48.8 45 "C 28 days passed on 0.04 96 94.0 29.4 59.4 45 ° C 56 days passed on 0.06 99 85.9 7.8 87.0 25 ’C 1 month N / D N / D N / D N / D N / D N / D 5 ° C 1 month passed on 0.00 100 96.4 56.7 34.0 5 ° C 2 months passed on 0.00 101 96.2 54.7 34.0
    45/45
    The present invention should not be limited in scope by the specific modalities described herein. In fact, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the preceding description and the attached figures5. Such modifications are intended to fall within the scope of the appended claims.
    权利要求:
    Claims (33)
    [1]
    1. A pharmaceutical formulation comprising: (i> a human antibody that specifically binds to a human interleukin-6 (hLL-6R) receptor; (ii) histidine; and (iii) a carbohydrate.
    [2]
    2. Pharmaceutical formulation according to claim 1, wherein the carbohydrate is a sugar selected from the group consisting of sucrose, glucose, mannitol, lactose and realose.
    [3]
    Pharmaceutical formulation according to claim 1, wherein the carbohydrate is sucrose.
    [4]
    A pharmaceutical formulation according to any one of claims 1 to 3, wherein said human antibody that specifically targets hlL-6R comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), where HCVR comprises complementary determining regions of light and heavy chain (HCDR1-HCDR2-HCDR3 / LCDR1-LCDR2- LCDR3) having the amino acid sequences of: (i) SEQ ID NO: 4 - 6 - 8 / SEQ ID No. s: 12 -14 - 16; (ii) SEQ ID NO: 20 - 22 - 24 / SEQ ID NO: 28 - 30 - 32; (iii) SEQ ID NO: 36 - 38 - 40 / SEQ ID NO: 44 - 46 - 48; or (iv) SEQ ID NO: 52 - 54 - 56 / SEQ ID NO: 60 - 62 - 64.
    [5]
    A pharmaceutical formulation according to claim 4, wherein said human antibody that specifically binds to hlL-6R comprises pairs of amino acid sequences from variable regions of heavy and light chain (HCVR / LCVR) selected from the group consisting of in; (i) SEQ ID NO: 2/10; (ii) SEQ ID NO: 18/26; (iii) SEQ ID No. s; 34/42; and (iv) SEQ ID NO: 50/58.
    [6]
    A pharmaceutical formulation according to any one of claims 1 to 5, wherein said human antibody that specifically binds to a human interleukin-6 receptor (hLL-6R) is in a concentration of about 5 to 200 mg / ml .
    [7]
    Pharmaceutical formulation according to any one of claims 1 to 6, wherein the histidine is in a concentration of about 5 to 50 mM.
    2/4
    [8]
    Pharmaceutical formulation according to any one of claims 1 to 7, wherein the carbohydrate is in a concentration of about 1 to 20%.
    [9]
    Pharmaceutical formulation according to any one of claims 1 to 8, further comprising a non-ionic surfactant.
    [10]
    A pharmaceutical formulation according to claim 9, wherein said nonionic surfactant is selected from the group consisting of polysorbate 20, polysorbate 80 and polyoxyethylene sorbitan monooleate.
    [11]
    A pharmaceutical formulation according to claim 9, wherein said nonionic surfactant is polysorbate 20.
    [12]
    Pharmaceutical formulation according to any one of claims 9 to 11, wherein said nonionic surfactant is in a concentration of about 0.01 to 1%.
    [13]
    Pharmaceutical formulation according to any one of claims 9 to 12, comprising: (i) about 25 to 200 mg / ml of said human antibody that specifically binds h! L-6R; (ii) about 10 to 25 mM histidine; (iii) about 5 to 10% sucrose; and (iv) about 0.1 to 0.2% polysorbate 20.
    [14]
    A pharmaceutical formulation according to any one of claims 9 to 12, comprising: (i) about 100 mg / ml of a human antibody that specifically binds to hLL-6R; (ii) about 10 mM histidine; (iii) about 10% sucrose; and (iv) about 0.2% of polysorbate 20.
    [15]
    Pharmaceutical formulation according to any one of claims 9 to 14, further comprising arginine.
    [16]
    The pharmaceutical formulation according to claim 15, wherein the arginine is in a concentration of about 5 to 100 mM.
    [17]
    A pharmaceutical formulation according to claim 15, wherein the arginine is in a concentration of about 25 to 50 mM.
    [18]
    A pharmaceutical formulation according to claim 15, comprising: (i) about 150 mg / ml of said human antibody which is
    3/4 specifically binds to hlL-6R; (ii) about 25 mM histidine; (iii) about 5% sucrose; (iv) about 0.2% polysorbate 20; and (v) about 25 mM arginine.
    [19]
    A pharmaceutical formulation according to claim 15, comprising: (i) about 175 mg / ml of said human antibody that specifically binds to hLL-6R; (ii) about 25 mM histidine; (iii) about 5% sucrose; (iv) about 0.2% of polysorbate 20; and (v) about 50 mM arginine.
    [20]
    A pharmaceutical formulation according to claim 19, wherein said human antibody that specifically binds to a human interleukin-6 receptor (hLL-6R) comprises a pair of amino acid sequences of SEQ ID NO: 18 / 26 of variable region of light chain and heavy chain (HCVR / LCVR).
    [21]
    21. The pharmaceutical formulation according to claim 19 or 20, wherein at least 90% of the native form of said antibody is recovered after nine months of storage at 5 ° C, as determined by size exclusion high performance liquid chromatography (SE-HPLC).
    [22]
    22. The pharmaceutical formulation according to claim 19 or 20, wherein at least 95% of the native form of said antibody is recovered after nine months of storage at 5 ° C, as determined by size exclusion high performance liquid chromatography ( SE-HPLC).
    [23]
    23. The pharmaceutical formulation according to claim 19 or 20, wherein at least 96% of the native form of said antibody is recovered after nine months of storage at 5 ° C, as determined by size exclusion high performance liquid chromatography (SE-HPLC).
    [24]
    24. The pharmaceutical formulation according to any one of claims 19 to 23, wherein the formulation exhibits a viscosity of less than about 15 cPoise.
    [25]
    25. Pharmaceutical formulation according to any one
    4/4 of claims 19 to 23, wherein the formulation exhibits a viscosity of less than about 12 cPoise.
    [26]
    26. The pharmaceutical formulation according to any one of claims 19 to 23, wherein the formulation exhibits a viscosity of less than about 9 cPoise.
    [27]
    27. The pharmaceutical formulation according to any one of claims 16 to 26, contained in a glass bottle.
    [28]
    28. A pharmaceutical formulation according to any one of claims 16 to 26, contained in a syringe.
    [29]
    29. The pharmaceutical formulation according to any one of claims 16 to 26, contained in a microinfuser.
    [30]
    A pharmaceutical formulation according to claim 28, wherein said syringe comprises a plunger coated with fluorocarbon.
    [31]
    The pharmaceutical formulation according to claim 28, wherein said syringe is a low tungsten syringe.
    [32]
    32. Pharmaceutical formulation comprising: (i) about 5 to 200 mg / ml of a human antibody that specifically binds to a human interleukin-6 (hLL-6R) receptor; (ii) about 5 to 50 mM histidine; (iii) about 1 to 20% sucrose; and (iv) about 0.01 to 1% of polysorbate 20.
    [33]
    33. A pharmaceutical formulation comprising: (i) about 175 mg / ml of a human antibody that specifically binds to a human interleukin-6 receptor (hlL-6R), wherein said antibody comprises a pair of amino acid sequences of SEQ ID NO: 18/26 of light and heavy chain variable region (HCVR / LCVR); (ii) about 25mM histidine; (iii) about 5% sucrose; (iv) about 0.2% of polysorbate 20; and (v) about 50 mM arginine.
    类似技术:
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    法律状态:
    2020-06-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2020-06-23| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2020-07-14| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2020-09-01| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|
    2021-01-05| B09B| Patent application refused [chapter 9.2 patent gazette]|
    2021-03-23| B12B| Appeal against refusal [chapter 12.2 patent gazette]|
    2021-10-19| B350| Update of information on the portal [chapter 15.35 patent gazette]|
    优先权:
    申请号 | 申请日 | 专利标题
    US29322710P| true| 2010-01-08|2010-01-08|
    US61/293,227|2010-01-08|
    US12/986,223|2011-01-07|
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    PCT/US2011/020457|WO2011085158A2|2010-01-08|2011-01-07|Stabilized formulations containing anti-interleukin-6 receptorantibodies|
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