OA19780A - Stabilized formulations containing antiinterleukin-6 receptor (IL-6R) antibodies. - Google Patents
Stabilized formulations containing antiinterleukin-6 receptor (IL-6R) antibodies. Download PDFInfo
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- OA19780A OA19780A OA1201800488 OA19780A OA 19780 A OA19780 A OA 19780A OA 1201800488 OA1201800488 OA 1201800488 OA 19780 A OA19780 A OA 19780A
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- mab1
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Abstract
The present invention provides pharmaceutical formulations comprising a human antibody that specifically binds to human interleukin-6 receptor (hlL-6R). The formulations may contain, in addition to an anti-hlL-6R antibody, at least one amino acid, at least one sugar, and/or at least one non-ionic surfactant. The pharmaceutical formulations of the present invention exhibit a substantial degree of antibody stability after storage for several months.
Description
STABILIZED FORMULATIONS CONTAINING ANTI-INTERLEUKIN-6 RECEPTOR (IL-6R) ANTIBODIES
FIELD OF THE INVENTION
The présent invention relates to the field of therapeutic antibody formulations. More specifically, the présent invention relates to the field of pharmaceutical formulations comprising a human antibody that specifically binds to human interleukin-6 receptor.
SEQUENCE LISTING
An ASCII compilant textfile of a sequence listing is filed concurrently with the présent spécification. The contents of the text file are herein incorporated by reference. The text file containing the sequence listing is named IL6RAbFormulationSeqList, was created on January 7, 2010, and contains 37,387 bytes.
BACKGROUND .Therapeutic macromolecules (e.g., antibodies) must be formulated in a manner that not only makes the molécules suitable for administration to patients, but also maintains their stability during storage. For example, therapeutic antibodies in liquid solution are prone to dégradation, aggregation and/or undesired Chemical modifications unless the solution is formulated properly. The stability of an antibody in liquid formulation dépends not only on the kinds of excipients used in the formulation, but also on the amounts and proportions of the excipients relative to one another. Furthermore, other considérations aside from stability must be taken into account when preparing a liquid antibody formulation. Examples of such additional considérations include the viscosity of the solution and the concentration of 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 adéquate concentration of antibody, and possesses a suitable viscosity as well as other properties which enable the formulation to be conveniently administered to patients.
Antibodies to the human interleukin-6 receptor (hlL-6R) are one example of a therapeutically relevant macromolecule that requires proper formulation. Anti-hlL-6R antibodies are clinically uséful for the treatment and/or prévention of diseases such as rheumatoid arthritis, ankylosing spondylitis, and other conditions. Exemplary anti-IL-6R antibodies are described, inter alia, in US 7,582,298; 6,410,691; 5,817,790; 5,795,695; and 6,670,373. A particularly important anti-hlL-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).
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Although anti-hlL-6R antibodies are known, there remains a need in the art for novel pharmaceutical formulations comprising anti-hlL-6R antibodies which are sufficiently stable and also suitable for administration to patients.
BRIEF SUMMARY OF THE INVENTION
The présent invention satisfies the aforementioned need by providing pharmaceutical formulations comprising a human antibody that specifically binds to human interleukin-6 receptor (hlL-6R). The formulations of the invention may 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, e.g., histidine and/or arginine. The carbohydrate can be a sugar such as, e.g., sucrose, glucose, mannitol, lactose or trehalose.
According to certain embodiments of the présent invention, the formulation further comprises a non-ionic surfactant. The non-ionic surfactant can be, e.g., polysorbate 20, polysorbate 80, polyoxyethylene sorbitan monooleate, polyethylene glycol, etc.
The antibody contained within the pharmaceutical formulations of the présent invention can be any antibody which specifically binds to hlL-6R. Exemplary antibodies that may be contained within the formulations of the invention are antibodies comprising a heavy Chain variable région (HCVR) and a light chain variable région (LCVR), wherein the HCVR comprises a heavy chain complementary determining région (HCDR) 1 having the amino acid sequence of SEQ ID NO: 20, a HCDR2 having the amino acid sequence of SEQ ID NO:22, and a HCDR3 having the amino acid sequence of SEQ ID NO:24; and wherein the LCVR comprises a light chain complementary determining région (LCDR) 1 having the amino acid sequence of SEQ ID NO: 28, a LCDR2 having the amino acid sequence of SEQ ID NO:30, and a LCDR3 having the amino acid sequence of SEQ ID NO:32. In certain embodiments, the antibody contained within the formulations of the présent invention are antibodies comprising a HCVR having the amino acid sequence of SEQ ID NO: 18 and a LCVR having the amino acid sequence of SEQ ID NO:26.
The antibody formulations of the présent invention may be contained within any suitable container useful for storing pharmaceutical formulations. Examples of such suitable containers include, e.g., glass or plastic vials, syringes and cartridges. The container may be clear or opaque (e.g., amber colored).
According to certain aspects of the présent invention, the pharmaceutical formulations remain relatively stable following storage for several days, months or years at a given
-219780 température. For example, in certain exemplary embodiments of the présent invention, a high percentage of the antibody (e.g., 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 native form of the antibody may be measured, e.g., by SE-HPLC, or by any other method known in the art. The storage température at which stability of the antibody is maintained can be, e.g., -80°C, -40°C, -20°C, 0°C, 5°C, 25°C, 45°C, or higher.
Other embodiments of the présent invention will become apparent from a review of the ensuing detailed description.
BR1EF DESCRIPTION OF THE FIGURES
Figure 1 shows the percent of native mAb1 remaining, as measured by SE-HPLC, following various amounts of time of storage at -20°C (filled triangles), -30°C (filled squares), and -80°C (filled diamonds).
Figure 2 shows the percent of acidic species of mAb1, as measured by CEX-HPLC, following various amounts of time of storage at -20°C (filled triangles), -30°C (filled squares), and -80°C (filled diamonds).
Figure 3 shows the percent of native mAb1 remaining in various minimal excipient formulations, as measured by SE-HPLC, following various amounts of time of storage at 30°C. Filled diamonds represent formulation 1 (80 mg/mL mAb1, 0.13% polysorbate 20, 6% sucrose, 10 mM histidine); filled squares represent formulation 2 (80 mg/mL mAb1, 0.13% polysorbate 20,10 mM histidine); filled triangles represent formulation 3 (80 mg/mL mAb, 1% sucrose, 10 mM histidine); open 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); filled circles represent formulation 6 (80 mg/mL mAb1, 6% sucrose, 10 mM histidine); crosses represent formulation 7 (80 mg/mL antibody, 10 mM histidine); and open circles represent formulation 8 (65 mg/mL antibody, 10 mM histidine). Ail formulations are set out in Table 6 (see Example 2, below).
Figure 4 shows the percent of native mAb1 remaining in various minimal excipient formulations, as measured by SE-HPLC, following various amounts of time of storage at 20°C. Filled diamonds represent formulation 1 (80 mg/mL mAb1, 0.13% polysorbate 20, 6% sucrose, 10 mM histidine); filled squares represent formulation 2 (80 mg/mL mAb1, 0.13% polysorbate 20,10 mM histidine); filled triangles represent formulation 3 (80 mg/mL mAb, 1% sucrose, 10 mM histidine); open 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); filled circles represent formulation 6 (80 mg/mL mAb1, 6% sucrose, 10 mM
-319780 histidine); crosses represent formulation 7 (80 mg/mL antibody, 10 mM histidine); and open circles represent formulation 8 (65 mg/mL antibody, 10 mM histidine). Ali formulations are set out in Table 6 (see Example 2, below).
DETA1LED DESCRIPTION
Before the présent invention is described, it is to be understood thatthis invention is not limited to particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the présent invention will be limited only by the appended daims.
Unless defined otherwise, ail technical and scientific terms used herein hâve the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the term about, when used in reference to a particular recited numerical value, means that the value may vary from the recited value by no more than 1%. For example, as used herein, the expression about 100 includes 99 and 101 and ail values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
Although any methods and materials similar or équivalent to those described herein can be used in the practice ortesting of the présent invention, the preferred methods and materials are now described. Ail publications mentioned herein are incorporated herein by reference to describe in their entirety.
PHARMACEUTICAL FORMULATIONS
As used herein, the expression pharmaceutical formulation means a combination of at least one active ingrédient (e.g., a small molécule, macromolecule, compound, etc. which is capable of exerting a biological effect in a human or non-human animal), and at least one inactive ingrédient which, when combined with the active ingrédient and/or one or more additional inactive ingrédients, is suitable for therapeutic administration to a human or nonhuman animal. The term formulation, as used herein, means pharmaceutical formulation unless specifically indicated otherwise. The présent invention provides pharmaceutical formulations comprising at least one therapeutic polypeptide. According to certain embodiments of the présent invention, the therapeutic polypeptide is an antibody that binds specifically to human interleukin-6 receptor (hlL-6R) or an antigen-binding fragment thereof. More specifically, the présent invention includes pharmaceutical formulations that comprise:
-419780 (i) a human antibody that specifically binds to hlL-6R; (ii) histidine; and (iii) a carbohydrate. Additional components may be included in the formulations of the présent invention such as, e.g., at least one non-ionic surfactant, and at least one additional amino acid. Spécifie exemplary components and formulations included within the présent invention are described in detail below.
The pharmaceutical formulations of the présent invention may, in certain embodiments, be fluid formulations. As used herein, the expression fluid formulation means a mixture of at least two components that exists predominantly in the fluid State at about 5°C to about 45°C. Fluid formulations include, inter alia, liquid formulations. Fluid formulations may be of low, moderate or high viscosity depending on their particular constituents.
ANTIBODIES THAT BIND SPECIFICALLY TO hlL-6R
The pharmaceutical formulations of the présent invention may comprise a human antibody, or an antigen-binding fragment thereof, that binds specifically to hlL-6R. As used herein, the term hlL-6R means a human cytokine receptor that specifically binds interleukin-6 (IL-6). In certain embodiments, the antibody contained within the pharmaceutical formulations of the présent invention binds specifically to the extracellular domain of hlL-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 generally intended to refer to immunoglobulin molécules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as multimers thereof (e.g., IgM); however, immunoglobulin molécules consisting of only heavy chains (i.e., lacking light chains) are also encompassed within the définition of the term antibody. Each heavy chain comprises a heavy chain variable région (abbreviated herein as HCVR or VH) and a heavy chain constant région. The heavy chain constant région comprises three domains, CH1, CH2 and CH3. Each light chain comprises a light chain variable région (abbreviated herein as LCVR or VL) and a light chain constant région. The light chain constant région comprises one domain (CL1). The VH and VL régions can be further subdivided into régions of hypervariability, termed complementary determining régions (CDRs), interspersed with régions that are more conserved, termed framework régions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
Unless specifically indicated otherwise, the term antibody, as used herein, shall be understood to encompass complété antibody molécules as well as antigen-binding fragments thereof. The term antigen-binding portion or antigen-binding fragment of an
-519780 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 to hIL-6R.
An isolated antibody, as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds hlL-6R is substantially free of antibodies that specifically bind antigens other than hlL-6R).
The term specifically binds, or the like, means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiologie conditions. Spécifie binding can be characterized by a dissociation constant of at least about IxlO6 M or greater. Methods for determining whether two molécules specifically bind are well known in the art and include, for example, equilibrium dialysis, surface plasmon résonance, and the like. An isolated antibody that specifically binds hlL-6R may, however, hâve cross-reactivity to other antigens, such as IL-6R molécules from other species. In the context of the présent invention, multispecific (e.g., bispecific) antibodies that bind to hlL-6R as well as one or more additional antigens are deemed to specifically bind hlL-6R. Moreover, an isolated antibody may be substantially free of other cellular material and/or Chemicals.
Exemplary anti-hlL-6R antibodies that may be included in the pharmaceutical formulations of the présent invention are setforth in US 7,582,298, the disclosure of which is incorporated by référencé in its entirety.
According to certain embodiments of the présent invention, the anti-hlL-6R antibody, or antigen-binding fragment thereof, comprises a heavy chain complementary determining région (HCDR) 1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 4, 20, 36 and 52; a HCDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO:6, 22, 38 and 54; and a 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 antigen-binding fragment thereof, comprises HCDR1-HCDR2HCDR3 domains, respectively, selected from the group consisting of: (i) SEQ ID NOs:4 - 6 8; (ii) SEQ ID NOs:20 - 22 - 24; (iii) SEQ ID NOs:36 - 38 - 40; and (iv) SEQ ID NOs:52 54 - 56.
According to certain embodiments of the présent invention, the anti-hlL-6R antibody, or antigen-binding fragment thereof, comprises a light chain complementary determining région (LCDR) 1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 12, 28, 44 and 60; a LCDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO:14, 30, 46 and 62; and a LCDR3 having an amino acid sequence
-619780 selected from the group consisting of SEQ ID NO:16, 32, 48 and 64. In certain embodiments, the anti-hlL-6R antibody, or antigen-binding fragment thereof, comprises LCDR1-LCDR2-LCDR3 domains, respectively, selected from the group consisting of: (i) SEQ ID NOs:12 - 14-16; (ii) SEQ ID NOs:28 - 30 - 32; (iii) SEQ ID NOs:44 - 46 - 48; and (iv) SEQ ID NQs:60 - 62 - 64.
In certain embodiments, the anti-hIL-6R antibody, or antigen-binding fragment thereof, comprises HCDR1-HCDR2-HCDR3 / LCDR1-LCDR2-LCDR3 domains, respectively, selected from the group consisting of: (i) SEQ ID NOs:4 - 6 - 8 / SEQ ID NOs:12 - 14-16; (ii) SEQ ID NQs:20 - 22 - 24 / SEQ ID NOs:28 - 30 - 32; (iii) SEQ ID NOs:36 - 38 - 40 / SEQ ID NOs:44 - 46 - 48; and (iv) SEQ ID NOs:52 - 54 - 56 / SEQ ID NQs:60 - 62 - 64.
In certain embodiments, the anti-hlL-6R antibody, or antigen-binding fragment thereof, comprises a heavy chain variable région (HCVR) having an amino acid sequence selected from the group consisting of SEQ ID NO:2,18, 34 and 50. In certain embodiments, the antihlL-6R antibody, or antigen-binding fragment thereof, comprises a light chain variable région (LCVR) having an amino acid sequence selected from the group consisting of SEQ ID NQ:10, 26, 42 and 58. In certain embodiments, the anti-hlL-6R antibody, or antigen-binding fragment thereof, comprises a HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NO:2/10; 18/26; 34/42 and 50/58.
The non-limiting, exemplary antibody used in the Examples herein is referred to as mAb1. This antibody is also referred to in US 7,582,298 as VQ8F11-21. mAb1 (VQ8F1121) comprises an HCVR/LCVR amino acid sequence pair having SEQ ID NOs:18/26, and HCDR1-HCDR2-HCDR3 / LCDR1-LCDR2-LCDR3 domains represented by SEQ ID NQs:20 - 22 - 24 / SEQ ID NOs:28 - 30 - 32.
The amount of antibody, or antigen-binding fragment thereof, contained within the pharmaceutical formulations of the présent invention may vary depending on the spécifie properties desired of the formulations, as well as the particular circumstances and purposes for which the formulations are intended to be used. In certain embodiments, the pharmaceutical formulations may contain about 1 mg/mL to about 500 mg/mL of antibody; about 5 mg/mL to about 400 mg/mL of antibody; about 5 mg/mL to about 200 mg/mL of antibody; about 25 mg/mL to about 180 mg/mL of antibody; about 25 mg/mL to about 150 mg/mL of antibody; or about 50 mg/mL to about 180 mg/mL of antibody. For example, the formulations of the présent invention may 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
-719780 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; about 190 mg/mL; about 195 mg/mL; or about 200 mg/mL of an antibody or an antigen-binding fragment thereof, that binds specifically to hIL-6R.
EXCIPIENTS and pH
The pharmaceutical formulations of the présent 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 présent invention include, inter alia, arginine and/or histidine.
The amount of amino acid contained within the pharmaceutical formulations of the présent invention may vary depending on the spécifie properties desired of the formulations, as well as the particular circumstances and purposes for which the formulations are intended to be used. In certain embodiments, the formulations may 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 présent invention may 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 mM; about 20.5 mM; about 21 mM; about 21.5 mM; about 22 mM; about 22.5 mM; about mM; about 23.5 mM; about 24 mM; about 24.5 mM; about 25 mM; about 25.5 mM; about mM; about 26.5 mM; about 27 mM; about 27.5 mM; about 28 mM; about 28.5 mM; about 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 (e.g., histidine and/or arginine).
The pharmaceutical formulations of the présent invention may also comprise one or more carbohydrate, e.g., one or more sugar. The sugar can be a reducing sugar or a non
-819780 reducing sugar. Reducing sugars include, e.g., sugars with a ketone or aldéhyde group and contain a reactive hemiacetal group, which allows the sugar to act as a reducing agent. Spécifie 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. Spécifie examples of nonreducing sugars include sucrose, trehalose, sorbose, sucralose, melezitose and raffinose. Sugar acids include, for example, saccharic acids, gluconate and other polyhydroxy sugars and salts thereof.
The amount of sugar contained within the pharmaceutical formulations of the présent invention will vary depending on the spécifie circumstances and intended purposes for which the formulations are used. In certain embodiments, the formulations may 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 présent invention may 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 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 (e.g., sucrose).
The pharmaceutical formulations of the présent invention may also comprise one or more surfactant. As-used herein, the term surfactant means a substance which 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 présent invention include, e.g., alkyl poly(ethylene oxide), alkyl polyglucosides (e.g., octyl glucoside and decyl maltoside), fatty alcohols such as cetyl alcohol and oleyl alcohol, cocamide MEA, cocamide DEA, and cocamide TEA. Spécifie non-ionic surfactants that can be included in the formulations of the présent invention include, e.g., 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; polyethylenepolypropylene glycol; or polyethylene glycol (PEG). Polysorbate 20 is also known as TWEEN 20, sorbitan monolaurate and polyoxyethylenesorbitan monolaurate.
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The amount of surfactant contained within the pharmaceutical formulations of the présent invention may vary depending on the spécifie properties desired of the formulations, as well as the particular circumstances and purposes for which the formulations are intended to be used. In certain embodiments, the formulations may contain about 0.05% to about 5% surfactant; or about 0.1% to about 0.2% surfactant. For example, the formulations of the présent invention may comprise about 0.05%; about 0.06%; about 0.07%; about 0.08%; about 0.09%; about 0.10%; about 0.11%; about 0.12%; about 0.13%; about 0.14%; 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 (e.g., polysorbate 20).
The pharmaceutical formulations of the présent invention may hâve a pH of from about 5.0 to about 8.0. For example, the formulations of the présent invention may hâve 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.
EXEMPLARY FORMULATIONS
According to one aspect of the présent invention, the pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hlL-6R (e.g., mAb1); (ii) an amino acid (e.g., histidine); and (iii) a sugar (e.g., sucrose). Spécifie, non-limiting exemplary embodiments encompassed by this aspect of the invention are set forth in Table 1.
Table 1: Exemplary Pharmaceutical Formulations Comprising mAb1, Histidine and Suc rose__
| mAb1 (mg/ml) | 2 5 | 5 0 | 10 0 | 15 0 | 2 5 | 5 0 | 10 0 | 15 0 | 2 5 | 5 0 | 10 0 | 15 0 | 2 5 | 5 0 | 10 0 | 15 0 |
| histidin e (mM) | 1 0 | 1 0 | 10 | 10 | 1 0 | 1 0 | 10 | 10 | 1 0 | 1 0 | 10 | 10 | 1 0 | 1 0 | 10 | 10 |
| sucrose (%) | 1 | 1 | 1 | 1 | 2 | 2 | 2 | 2 | 4 | 4 | 4 | 4 | 6 | 6 | 6 | 6 |
According to another aspect of the présent invention, the pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hlL-6R (e.g., mAb1); (ii) an amino acid (e.g., histidine); (iii) a sugar (e.g., sucrose); and (iv) a surfactant (e.g., polysorbate 20). Spécifie, non-limiting exemplary embodiments encompassed by this aspect of the invention are set forth in Tables 2A and 2B.
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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 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 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 |
According to another aspect of the présent invention, the pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hlL-6R (e.g., mAb1); (ii) a first amino acid (e.g., histidine); (iii) a sugar (e.g., sucrose); (iv) a surfactant (e.g., polysorbate 20); and (v) a second amino acid (e.g., arginine). Spécifie, non-limiting exemplary embodiments encompassed by this aspect of the invention are setforth in Tables 3A, 3B, 3C, 3D, 3E and 3F.
Table 3A: Exemplary Pharmaceutical Formulations Comprising mAb1, Histidine, Sucrose, Polysorbate 20 and Arginine
| 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) | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
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Table 3B: Exemplary Pharmaceutical Formulations Comprising mAb1, Histidine, Sucrose, Polysorbate 20 and Arginine
| 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 Arginine
| 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 |
Table 3D: Exemplary Pharmaceutical Formulations Comprising mAb1, Histidine, Sucrose, Polysorbate 20 and Arginine
| 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) | 25 | 25 | 25 | 25 | 25 | 25 | 25 | 25 | 25 | 25 | 25 | 25 |
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Table 3E: Exemplary Pharmaceutical Formulations Comprising mAb1, Histidine, Sucrose, Polysorbate 20 and Arginine
| 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) | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 | 50 |
Table 3F: Exemplary Pharmaceutical Formulations Comprising mAb1, Histidine, Sucrose, Polysorbate 20 and Arginine
| mAb1 (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 présent invention are set forth elsewhere herein, including the working Examples presented 5 below.
STABILITY AND VISCOSITY OF THE PHARMACEUTICAL FORMULATIONS
The pharmaceutical formulations of the présent invention typically exhibit high levels of stability. The term stable, as used herein in référencé to the pharmaceutical formulations, means that the antibodies within the pharmaceutical formulations retain an acceptable 10 degree of structure and/or function and/or biological activity after storage for a defined amount of time. A formulation may be stable even though the antibody contained therein does not maintain 100% of its structure and/or function and/or biological activity after storage for a defined amount of time. Under certain circumstances, maintenance of about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% of an 15 antibody's structure and/or function and/or biological activity after storage for a defined amount of time may be regarded as stable.
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Stability can be measured, inter alia, by determining the percentage of native antibody remaining in the formulation after storage for a defined amount of time at a given température. The percentage of native antibody can be determined by, inter alia, size exclusion chromatography (e.g., size exclusion high performance liquid chromatography [SE-HPLC]). An acceptable degree of stability, as that phrase is used herein, means that at least 90% of the native form of the antibody can be detected in the formulation after storage for a defined amount of time at a given température. 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 amount of time at a given température. The defined amount of time 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 more. The température at which the pharmaceutical formulation may be stored when assessing stability can be any température from about -80°C to about 45°C, e.g., 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 may be deemed stable if after 3 months of storage at 5°C, greater than about 90%, 95%, 96% or 97% of native antibody is detected by SE-HPLC. A pharmaceutical formulation may also be deemed stable if after 6 months of storage at 5°C, greater than about 90%, 95%, 96% or 97% of native antibody is detected by SE-HPLC. A pharmaceutical formulation may also be deemed stable if after 9 months of storage at 5°C, greater than about 90%, 95%, 96% or 97% of native antibody is detected by SE-HPLC. A pharmaceutical formulation may also be deemed stable if after 3 months of storage at 25°C, greater than about 90%, 95%, 96% or 97% of native antibody is detected by SE-HPLC. A pharmaceutical formulation may also be deemed stable if after 6 months of storage at 25°C, greater than about 90%, 95%, 96% or 97% of native antibody is detected by SE-HPLC. A pharmaceutical formulation may also be deemed stable if after 9 months of storage at 25°C, greater than about 90%, 95%, 96% or 97% of native antibody is detected by SE-HPLC.
Other methods may be used to assess the stability of the formulations of the présent invention such as, e.g., differential scanning calorimetry (DSC) to détermine thermal stability, controlled agitation to détermine mechanical stability, and absorbance at about 350 nm or about 405 nm to détermine solution turbidities. For example, a formulation of the présent invention may be considered stable if, after 6 or more months of storage at about 5°C to about 25°C, the change in OD405 of the formulation is less than about 0.05 (e.g., 0.04, 0.03, 0.02, 0.01, or less) from the OD405 of the formulation at t=0.
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Stability may also be assessed by measuring the biological activity and/or binding affinity of the antibody to its target. For example, a formulation of the présent invention may be regarded as stable if, after storage at e.g., 5°C, 25°C, 45°C, etc. for a defined amount of time (e.g., 1 to 12 months), the anti-IL-6R antibody contained within the formulation binds to IL-6R with an affinity that is at least 50%, 60%, 70%, 80%, 90%, 95%, or more of the binding affinity of the antibody prior to said storage. Additional methods for assessing the stability of an antibody in formulation are demonstrated in the Examples presented below.
In the fluid form, the pharmaceutical formulations of the présent invention may, in certain embodiments, exhibit low to moderate levels of viscosity. Viscosity as used herein may be kinematic viscosity or absolute viscosity. Kinematic viscosity is a measure of the résistive flow of a fluid under the influence of gravity. When two fluids of equal volume are placed in identical capillary viscometers and allowed to flow by gravity, a viscous fluid takes longer than a less viscous fluid to flow through the capillary. For example, if one fluid takes 200 seconds to complété 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 kinematic viscosity is L2/T where L is a length and T is a time. Commonly, kinematic viscosity is expressed in centistokes (cSt). The SI unit of kinematic viscosity is mm2/s, which is 1 cSt. Absolute viscosity is expressed in units of centipoise (cP). The SI unit of absolute viscosity is the milliPascal-second (mPa-s), where 1 cP = 1 mPa-s.
As used herein, a low level of viscosity, in reference to a fluid formulation of the présent invention, will exhibit an absolute viscosity of less than about 20 cPoise (cP). For example, a fluid formulation of the invention will be deemed to hâve low viscosity, 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 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, in reference to a fluid formulation of the présent invention, will exhibit an absolute viscosity of between about 30 cP and about 20 cP. For example, a fluid formulation of the invention will be deemed to hâve 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 présent inventors hâve made the surprising discovery that low to moderate viscosity fluid formulations comprising high concentrations of
-1519780 an anti-hlL-6R antibody (e.g., 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 decreased to an even greater extent by adjusting the sucrose content to less than 10%.
CONTAINERS FOR THE PHARMACEUTICAL FORMULATIONS AND METHODS OF ADMINISTRATION
The pharmaceutical formulations of the présent invention may be contained within any container suitable for storage of medicines and other therapeutic compositions. For example, the pharmaceutical formulations may be contained within a sealed and sterilized plastic or glass container having a defined volume such as a vial, ampule, syringe, cartridge, or bottle. Different types of vials can be used to contain the formulations of the présent invention including, e.g., clear and opaque (e.g., amber) glass or plastic vials. Likewise, any type of syringe can be used to contain and/or administer the pharmaceutical formulations of the présent invention.
The pharmaceutical formulations of the présent invention may be contained within normal tungsten syringes or low tungsten syringes. As will be appreciated by persons of ordinary skill in the art, the process of making glass syringes generally involves the use of a hot tungsten rod which functions to pierce the glass thereby creating a hole from which liquids can be drawn and expelled from the syringe. This process results in the déposition of trace amounts of tungsten on the interior surface of the syringe. Subséquent 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 greater 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 présent 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 fewer ppb of tungsten.
The rubber plungers used in syringes, and the rubber stoppers used to close the openings of vials, may be coated to prevent contamination of the médicinal contents of the syringe or vial and/or to preserve their stability. Thus, pharmaceutical formulations of the présent invention, according to certain embodiments, may be contained within a syringe that comprises a coated plunger, or within a vial that is sealed with a coated rubber stopper. For example, the plunger or stopper may be coated with a fluorocarbon film. Examples of coated stoppers and/or plungers suitable for use with vials and syringes containing the pharmaceutical formulations of the présent invention are mentioned in, e.g., U.S. Patent
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Nos. 4,997,423; 5,908,686; 6,286,699; 6,645,635; and 7,226,554, the contents of which are incorporated by reference herein in their entireties. Particular exemplary coated rubber stoppers and plungers that can be used in the context of the présent invention are commercially available under the tradename FluroTec®, available from West Pharmaceutical Services, Inc. (Lionville, PA).
According to certain embodiments of the présent invention, the pharmaceutical formulations may be contained within a lowtungsten syringe that comprises a fluorocarboncoated plunger. As discussed in the Examples section below, the combination of a low tungsten syringe and a fluorocarbon-coated plunger was observed to yield surprising stability characteristics with regard to the pharmaceutical formulations of the présent invention.
The pharmaceutical formulations can be administered to a patient by parentéral routes such as injection (e.g., subcutaneous, intravenous, intramuscular, intraperitoneal, etc.) or percutaneous, mucosal, nasal, pulmonary and/or oral administration. Numerous reusable pen and/or autoinjector delivery devices can be used to subcutaneously deliver the pharmaceutical formulations of the présent invention. Examples include, but are not limited to AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), D1SETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25™ pen, HUMALOG™ pen, HUMALIN 70/30™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN™ I, Il and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (sanofi-aventis, Frankfurt, Germany), to name only a few. Examples of disposable pen and/or autoinjector delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the présent invention include, but are not limited to the SOLOSTAR™ pen (sanofi-aventis), the FLEXPEN™ (Novo Nordisk), and the KW1KPEN™ (Eli Lilly), the SURECLICK™ Autoinjector (Amgen, Thousand Oaks, CA), the PENLET™ (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, L.P.), and the HUMIRA™ Pen (Abbott Labs, Abbott Park, IL), to name only a few.
The use of a microinfusor to deliver the pharmaceutical formulations of the présent invention is also contemplated herein. As used herein, the term microinfusor means a subcutaneous delivery device designed to slowly administer large volumes (e.g., up to about 2.5 mL or more) of a therapeutic formulation over a prolonged period of time (e.g., about 10, 15, 20, 25, 30 or more minutes). See, e.g., U.S. 6,629,949; US 6,659,982; and Meehan et al., J. Controlled Release 46:107-116 (1996). Microinfusors are particularly useful for the
-1719780 delivery of large doses of therapeutic proteins contained within high concentration (e.g., about 100, 125, 150, 175, 200 or more mg/mL) and/or viscous solutions.
THERAPEUTIC USES OF THE PHARMACEUTICAL FORMULATIONS
The pharmaceutical formulations of the présent invention are useful, inter alia, for the treatment, prévention and/or amelioration of any disease or disorder associated with IL-6 activity, including diseases or disorders mediated by activation of the IL-6 receptor. Exemplary, non-limiting diseases and disorders that can be treated and/or prevented by the administration of the pharmaceutical formulations of the présent invention include, e.g., rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, pancreatitis, juvénile idiopathic arthritis, vasculitis, Kawasaki disease, systemic lupus erythematosis, psoriasis, psoriatic arthritis, Sjogren syndrome, Still's disease, Castleman's disease, multiple sclerosis, diseases associated with abnormal blood coagulation or fibrinolysis (e.g., thrombosis), cancer (e.g., breast cancer, leukemia, ovarian cancer, melanoma, prostate cancer, pancreatic cancer, lymphoma, lung cancer, rénal cell carcinoma, colorectal cancer, multiple myeloma, etc.), cachexia, chronic rejection of transplanted organs and cells, cardiopathy, viral infection (e.g., HIV infection, EBV infection, etc.), plasmacytosis, hyperimmunoglobulinemia, anémia, nephritis, mesothelioma, and hearing loss and other inner ear disorders.
Thus, the présent invention includes methods of treating, preventing, and/or ameliorating any disease or disorder associated with IL-6 activity or IL-6R activation (including any of the above mentioned exemplary diseases, disorders and conditions). The therapeutic methods of the présent invention comprise administering to a subject any formulation comprising an anti-hlL-6R antibody as disclosed herein. The subject to which the pharmaceutical formulation is administered can be, e.g., any human or non-human animal that is in need of such treatment, prévention and/or amelioration, or who would otherwise benefit from the inhibition or atténuation of IL-6 and/or IL-6R-mediated activity. For example, the subject can be an individual that is diagnosed with, or who is deemed to be at risk of being afflicted by any of the aforementioned diseases or disorders. The présent invention further includes the use of any of the pharmaceutical formulations disclosed herein in the manufacture of a médicament for the treatment, prévention and/or amelioration of any disease or disorder associated with IL-6 activity or IL-6R activation (including any of the above mentioned exemplary diseases, disorders and conditions).
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EXAMPLES
The following examples are put forth so as to provide those of ordinary skill in the art with a complété disclosure 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 regard as their invention. Efforts hâve been made to ensure accuracy with respect to numbers used (e.g., amounts, température, etc.) but some experimental errors and déviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, température is in degrees Centigrade, and pressure is at or near atmospheric.
Example 1. Stability of a Fully Human Anti-Human lnterleukin-6 Receptor (IL-6R) Antibody (mAb1) After Storage at Low Températures
In this Example, various formulations were created containing an anti-human IL-6R antibody without excipients. The exemplary antibody used in this and ail subséquent Examples set forth below is an antibody comprising a heavy chain variable région (HCVR) with the amino acid sequence of SEQ ID NO:18, and a light chain variable région (LCVR) with the amino acid sequence of SEQ ID NO:26. This antibody is rëferred to herein as mAb1.
As a preliminary experiment, the stability of mAb1 in liquid solution was determined 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 by cation exchange high performance liquid chromatography (CEX-HPLC). Stability was assessed based on the percentage of native mAb1 remaining in the sample (by SE-HPLC; Table 4) and by the percentage of acidic species observed in the sample (by CEX-HPLC; Table 5) (An increase in percent acidic species is consistent with deamidation of the antibody and is thus considered an undesired phenomenon with respect to the pharmaceutical formulations of the présent invention).
Table 4: % Native mAb1 Remaining (SE-HPLC)
| Time (months) | Storage Température | ||
| -80°C | -30°C | -20°C | |
| 0 | 95.9 | 95.9 | 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 |
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Table 5: % Acidic Species (CEX-HPLC)
| Time (months) | Storage Température | ||
| -80°C | -30°C | -20°C | |
| 0 | 28.6 | 28.6 | 28.6 |
| 1 | 27.3 | 28.0 | 28.1 |
| 3 | 27.3 | 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 depicted in Figures 1 and 2, 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 Minimal Excipients
Eight different formulations containing mAb1 and minimal excipients as shown in Table 6 were prepared.
Table 6: mAb1 Minimal 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 |
| Ail formulations contain 10 mM histidine, pH 6.0 |
The formulations were tested for stability by SE-HPLC after various amounts of time at 10 30°C and -20°C. The results, expressed in percent of native mAb1 remaining, are shown in
Tables 7 (-30°C storage) and 8 (-20°C).
Table 7: % Native mAb1 Remaining (SE-HPLC) After Storage at -30°C_______
| Time (months) | 1 | 2 | Formulation # (see Tab | e6) 6 | 7 | 8 | ||
| 3 | 4 | 5 | ||||||
| 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 |
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Table 8: % Native mAb1 Remaining (SE-HPLC) After Storage at -20°C
| Time (months) | 1 | 2 | Forr 3 | nulation # 4 | (see Tab . 5 | e6) 6 | 7 | 8 |
| 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 Ί | 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 depicted 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 enhanced by the addition of 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, designated Formulation A, is shown in Table 9.
Table 9: Stabilized mAb1 Formulation 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 mAb1 was tested for stability after several months of storage at 5°C in clear vials. Stability was assessed by the following parameters: (a) visual appearance; (b) turbidity (OD 405 nm); (c) pH; (d) percent total mAb1 recovered (as measured by RP-HPLC); (d) percent native mAb1 recovered (as measured by SE-HPLC); (e) percent main peak mAb1 recovered (as measured by CEXHPLC); and (f) percent acidic species mAb1 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.
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Table 10: Stability of Formulation A Containing 25 mg/mL mAb1 After Storage at 5°C in Clear Vials
| Parameter | 0 | Length of 5°C Storage (months) | 12 | ||||
| 1 | 2 | 3 | 6 | 9 | |||
| Visual Appearance | Pass | Pass | Pass | Pass | Pass | Pass | Pass |
| 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 |
| % Native mAb1 Recovered | 97.5 | 98.0 | 97.5 | 97.6 | 97.5 | 97.5 | 97.8 |
| % Main Peak mAb1 Recovered | 58.4 | 57.9 | 58.7 | 58.1 | 57.9 | 57.9 | 58.4 |
| % Acidic Species mAb1 Recovered | 26.5 | 28.0 | 26.5 | 28.0 | 27.3 | 28.0 | 27.9 |
Table 11 A: Stability of Formulation A Containing 50 mg/mL mAb1 After Storage at 5°C in Clear Vials (0-9 months)
| Parameter | 0 | Length of 5°C S | torage (months) | 9 | ||
| 1 | 2 | 3 | 6 | |||
| Visual Appearance | Pass | Pass | Pass | Pass | Pass | Pass |
| 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 mAb1 Recovered | 100 | 99 | 104 | 106 | 100 | 109 |
| % Native mAb1 Recovered | 97.4 | 97.5 | 97.3 | 97.2 | 97.3 | 97.2 |
| % Main Peak mAb1 Recovered | 57.1 | 56.7 | 58.0 | 54.2 | 53.3 | 57.9 |
| % Acidic Species mAb1 Recovered | 27.6 | 26.7 | 27.6 | 28.5 | 26.8 | 26.9 |
Table 11 B: Stability of Formulation A Containing 50 mg/mL mAb1 After Storage at 5°C in Clear Vials (12-24 months)
| Parameter | Length of 5°C Storage (months) | ||
| 12 | 18 | 24 | |
| Visual Appearance | Pass | Pass | Pass |
| Turbidity (OD 405 nm) | 0.00 | 0.00 | 0.00 |
| pH | 5.9 | 6.0 | 5.9 |
| % Total mAb1 Recovered | 103 | 107 | 105 |
| % Native mAb1 Recovered | 97.1 | 97.1 | 96.9 |
| % Main Peak mAb1 Recovered | 56.4 | 57.1 | 56.4 |
| % Acidic Species mAb1 Recovered | 28.1 | 28.3 | 29.0 |
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Table 12A: Stability of Formulation A Containing 100 mg/mL mAb1 After Storage at 5°C in Clear Vials (0-9 months)
| Parameter | 0 | Length of 5°C S | torage (months) | 9 | ||
| 1 | 2 | 3 | 6 | |||
| Visual Appearance | Pass | Pass | Pass | Pass | Pass | Pass |
| 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 mAbl Recovered | 100 | 99 | 100 | 107 | 101 | 106 |
| % Native mAbl Recovered | 97.3 | 97.0 | 97.0 | 97.1 | 96.9 | 96.9 |
| % Main Peak mAbl Recovered | 55.1 | 55.5 | 57.9 | 55.9 | 55.4 | 56.8 |
| % Acidic Species mAbl Recovered | 27.6 | 26.9 | 27.4 | 29.6 | 27.4 | 27.4 |
Table 12B: Stability of Formulation A Containing 100 mg/mL mAb1 After ____________Storage at 5°C in Clear Vials (12-24 months)____________
| Parameter | Length of 5°C Storage (months) | ||
| 12 | 18 | 24 | |
| Visual Appearance | Pass | Pass | Pass |
| Turbidity (OD 405 nm) | 0.00 | 0.00 | 0.00 |
| pH | 6.0 | 6.0 | 6.0 |
| % Total mAbl Recovered | 101 | 102 | 103 |
| % Native mAbl Recovered | 96.8 | 96.7 | 96.5 |
| % Main Peak mAbl Recovered | 57.3 | 57.5 | 56.7 |
| % Acidic Species mAbl Recovered | 27.3 | 28.1 | 28.7 |
The results of this Example demonstrate that Formulation A containing 25, 50 or 100 mg/mL mAbl remained stable after at least 9 months of storage, at 5°C in clear vials, with 5 about 97% or more of native mAbl remaining in ail samples after 9 months of storage under such conditions. For the 50 and 100 mg/mL formulations, 96.9% and 96.5% of native mAbl, respectively, was detected after up to 24 months of storage at 5°C. In addition, the percent acidic species remained at 29% or lowerfor ail time points analyzed, thus confirming the stability of the formulations.
Similar stability studies were also carried out using Formulation A containing 75 mg/mL mAbl following storage at 2-8°C. No significant dégradation was observed for any of the concentrations tested after 24 months of 2-8°C storage as determined by SE-HPLC and CEX-HPLC (data not shown).
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Table 13: Stability of Formulation A Containing 25 mg/mL mAb1 After Storage at 5°C in 5 mL clear Vials
| Parameter | t=0 0 | 1 | Stc 2 | rage at 5°C 3 | (months) 6 | 9 | 12 |
| Visual Appearance | Pass | Pass | Pass | Pass | Pass | Pass | Pass |
| 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 mAb1 Recovered | 100 | 106 | 103 | 98 | 100 | 100 | 101 |
| % Native mAb1 Recovered | 97.1 | 97.0 | 96.9 | 96.9 | 97.0 | 96.4 | 96.6 |
| % Main Peak mAb1 Recovered | 57.8 | 56.8 | 56.2 | 54.2 | 56.4 | 56.4 | 56.8 |
| % Acidic Species mAb1 Recovered | 27.9 | 30.7 | 30.8 | 33.0 | 30.6 | 29.8 | 30.1 |
Example 5. Stability of Formulation A Manufactured in Clear and Amber Glass Vials
Additional experiments were conducted to compare the stability of Formulation A (see
Example 3) containing 25 and 100 mg/mL mAb1 manufactured in amber glass vials to the same formulation manufactured in clear vials. Two types of amber vials were used in this Example: 5 mL and 20 mL amber vials. Stability was assessed following storage at 5°C, 25°C or 45°C based on the same 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 mAb1 After Storage at 5°C in 5 mL Clear Vials
| Parameter | Storage at 5°C (months) | ||||||
| t=0 0 | 1 | 2 | 3 | 6 | 9 | 12 | |
| Visual Appearance | Pass | Pass | Pass | Pass | Pass | Pass | Pass |
| 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 mAb1 Recovered | 100 | 106 | 104 | 97 | 100 | 99 | 100 |
| % Native mAb1 Recovered | 96.2 | 96.3 | 96.1 | 96.0 | 95.9 | 95.5 | 95.4 |
| % Main Peak mAb1 Recovered | 57.6 | 57.3 | 57.9 | 55.5 | 56.2 | 56.4 | 55.4 |
| % Acidic Species mAb1 Recovered | 28.2 | 30.2 | 29.4 | 31.1 | 30.7 | 30.0 | 32.2 |
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Table 15: Stability of Formulation A Containing 25 mg/mL mAb1 After Storage at 5°C in 5 mL Amber Vials
| Parameter | t=0 0 | 1 | Stc 2 | rage at 5°C 3 | (months) 6 | 9 | 12 |
| Visual Appearance | Pass | Pass | Pass | Pass | Pass | Pass | Pass |
| 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 mAb1 Recovered | 100 | 104 | 104 | 98 | 99 | 97 | 101 |
| % Native mAb1 Recovered | 97.1 | 97.4 | 96.8 | 96.7 | 96.7 | 96.1 | 96.3 |
| % Main Peak mAb1 Recovered | 57.8 | 56.4 | 56.3 | 56.1 | 55.7 | 55.9 | 55.2 |
| % Acidic Species mAb1 Recovered | 27.9 | 30.4 | 30.6 | 31.8 | 31.0 | 30.5 | 32.9 |
Table 16: Stability of Formulation A Containing 100 mg/mL mAb1 After Storage at 5°C 5 in 5 mL Amber Vials
| Parameter ' | Storage at 5°C (months) | ||||||
| 0 | 1 | 2 | 3 | 6 | 9 | 12 | |
| Visual Appearance | Pass | Pass | Pass | Pass | Pass | Pass | Pass |
| 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 mAb1 Recovered | 100 | 102 | 104 | 97 | 101 | 100 | 100 |
| % Native mAb1 Recovered | 96.2 | 95.0 | 96.0 | 96.0 | 95.8 | 95.0 | 95.3 |
| % Main Peak mAb1 Recovered | 57.6 | 56.9 | 58.0 | 55.6 | 56.3 | 56.5 | 55.1 |
| % Acidic Species mAb1 Recovered | 28.2 | 30.1 | 29.4 | 31.4 | 30.4 | 30.0 | 32.3 |
Table 17: Stability of Formulation A Containing 25 mg/mL mAb1 After Storage at 5°C in 20 mL Amber Vials
| Parameter | 0 | 1 | Stora 2 | ge at 5°C (i 3 | nonths) 6 | 9 | 12 |
| Visual Appearance | Pass | Pass | Pass | Pass | Pass | Pass | Pass |
| 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 |
-2519780
Table 17, contStability of Formulation A Containing 25 mg/mL mAb1 After Storage at 5°C in 20 mL Amber Vials
| Storage at 5°C (months) _________ | |||||||
| Parameter | 0 | 1 | 2 | 3 | 6 | 9 | 12 |
| % Total mAb1 Recovered | 100 | 105 | 103 | 97 | 101 | 98 | 101 |
| % Native mAb1 Recovered | 97.1 | 96.9 | 97.0 | 96.8 | 97.0 | 96.2 | 96.6 |
| % Main Peak mAb1 Recovered | 57.8 | 56.4 | 57.1 | 55.9 | 55.6 | 56.1 | 55.2 |
| % Acidic Species mAb1 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 Vials
| Parameter | Storage at 5°C (months) | ||||||
| 0 | 1 | 2 | 3 | 6 | 9 | 12 | |
| Visual Appearance | Pass | Pass | Pass | Pass | Pass | Pass | Pass |
| 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 mAb1 Recovered | 100 | 105 | 103 | 97 | 99 | 98 | 100 |
| % Native mAb1 Recovered | 96.2 | 96.2 | 96.0 | 96.0 | 95.8 | 95.4 | 95.5 |
| % Main Peak mAb1 Recovered | 57.6 | 57.9 | 56.3 | 56.5 | 56.5 | 56.4 | 55.3 |
| % Acidic Species mAb1 Recovered | 28.2 | 29.8 | 30.4 | 30.3 | 30.6 | 30.0 | 30.9 |
Table 19: Stability of Formulation A Containing 100 mg/mL mAb1 After Storage at 25°C and 45°C in Clear Vials_______________________
| Parameter | 0 | Storage at 45°C (days) | Storage at 25°C (months) | |||||
| 7 | 14 | 28 | 1 | 2 | 3 | 6 | ||
| Visual Appearance | Pass | Pass | Pass | Pass | Pass | Pass | Pass | Pass |
| Turbidity (OD 405 nm) | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 |
| pH | 6.0 | 6.1 | 6.1 | 6.1 | 6.1 | 6.1 | 6.1 | 6.1 _ |
| % Total mAb1 Recovered | 100 | 101 | 97 | 105 | 105 | 102 | 97 | 101 |
| % Native mAb1 Recovered | 95.6 | 94.8 | 93.8 | 91.2 | 94.6 | 93.7 | 93.1 | 93.4 |
| % Main Peak mAb1 Recovered | 57.6 | 45.7 | 34.9 | 22.3 | 53.1 | 49.0 | 43.0 | 37.9 |
| % Acidic Species mAb1 Recovered | 28.2 | 37.3 | 49.8 | 70.8 | 32.5 | 36.8 | 42.4 | 53.8 |
-2619780
Table 20: Stability of Formulation A Containing 100 mg/mL mAb1 After Storage . at 25°C and 45°C in 5 mL Amber Vials
| Parameter | t=0 0 | Storage at 45°C (days) | 1 | Storage at 25°C (months) | 6 | |||
| 7 | 14 | 28 | ||||||
| 2 | 3 | |||||||
| Visual Appearance | Pass | Pass | Pass | Pass | Pass | Pass | Pass | Pass |
| Turbidity (OD 405 nm) | 0.00 | 0.00 | 0.01 | 0.02 | 0.00 | 0.00 | 0.01 | 0.02 |
| pH | 6.0 | 6.1 | 6.1 | 6.1 | 6.1 | 6.1 | 6.1 | 6.0 |
| % Total mAb1 Recovered | 100 | 101 | 100 | 105 | 106 | 103 | 97 | 100 |
| % Native mAb1 Recovered | 95.6 | 94.6 | 93.6 | 90.9 | 94.5 | 93.7 | 93.4 | 92.7 |
| % Main Peak mAb1 Recovered | 57.6 | 46.1 | 35.2 | 21.6 | 52.7 | 46.3 | 42.0 | 34.2 |
| % Acidic Species mAb1 Recovered | 28.2 | 37.3 | 50.1 | 70.9 | 32.8 | 39.6 | 43.4 | 57.3 |
Table 21: Stability of Formulation A Containing 100 mg/mL mAb1 After Storage at 25°C and 45°C in 20 mL Amber Vials
| Parameter | t=0 0 | Storage at 45°C (days) | 1 | Storage at 25°C (months) | 6 | |||
| 7 | 14 | 28 | ||||||
| 2 | 3 | |||||||
| Visual Appearance | Pass | Pass | Pass | Pass | Pass | Pass | Pass | Pass |
| Turbidity (OD 405 nm) | 0.00 | 0.01 | 0.00 | 0.02 | 0.00 | 0.01 | 0.00 | 0.02 |
| PH | 6.0 | 6.0 | 6.1 | 6.1 | 6.0 | 6.0 | 6.0 | 6.0 |
| % Total mAb1 Recovered | 100 | 101 | 101 | 105 | 104 | 103 | 96 | 100 |
| % Native mAb1 Recovered | 95.6 | 94.9 | 93.8 | 91.5 | 94.3 | 94.0 | 93.6 | 93.5 |
| % Main Peak mAb1 Recovered | 57.6 | 45.7 | 34.2 | 23.3 | 52.7 | 49.3 | 43.5 | 36.7 |
| % Acidic Species mAb1 Recovered | 28.2 | 36.7 | 51.1 | 68.6 | 32.5 | 35.8 | 41.3 | 55.0 |
As shown in this Example, Formulation A containing 25 mg/mL or 100 mg/mL mAb1 exhibited équivalent stability profiles when stored in either clear or amber vials. Moreover, 5 as demonstrated in Example 4 for storage in clear vials, relatively high stability of mAb1 was maintained in Formulation A when stored in either clear or amber vials at 5°C for up to 12 months.
-2719780
Example 6. Effect of Arginine, Histidine and Sucrose Concentrations on Viscosity and Stability of Formulations Containing 150 mg/mL mAb1
Several formulations were prepared containing 150 mg/mL, 175 mg/mL and 200 mg/mL mAb1 and various quantifies of histidine, arginine and sucrose. Viscosity and osmolality were measured for each formulation. Additionally, the stability of the 150 mg/mL formulations after 4 weeks of storage at 45°C was assessed in terms of percent native mAb1 remaining (by SE-HPLC) and percent main peak remaining (by CEX-HPLC). The results are summarized in Table 22.
Table 22: Effect of Arginine, Histidine and Sucrose on Viscosity and Stability of mAb1 Formulations
| mAb1 (mg/mL) | [Histidine] (mM) | [Arginine] (mM) | [Sucrose] (%) | Viscosity (cPoise) | Osmolality (mOsm) | % native mAb1 remaining* | % 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 | ||
| 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 |
* Initial % native mAb1 = 96.5% (SE-HPLC)
The results presented in Table 16 indicate that increasing the histidine concentration to 25 mM or 100 mM and adding arginine to the formulation (25 mM or 50 mM) significantly reduced the viscosity of the formulation as compared to formulations containing only 10 mM histidine and no arginine. Furthermore, reducing the sucrose concentration from 10% to 5% 15 with the added histidine and arginine decreased the viscosity of the formulation to an even greater extent.
Based at least in part on the foregoing, the following Formulations (designated Formulation B and Formulation C) set forth in Table 23 were prepared.
-2819780
Table 23: Stabilized mAb1 Formulations 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 mAb1 When Manufactured in a Vial and Syringes
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 préparations were stored at 5, 25 and 45°C forvarious amounts of time. The stability of mAb1 following storage was measured by SE-HPLC and CEX-HPLC. The results are shown in Table 24. (An increase in percent acidic species is consistent with deamidation of the antibody and is 10 thus considered an undesired phenomenon with respect to the pharmaceutical formulations of the présent invention).
Table 24: Stability of Formulation B Containing 150 mg/mL mAb1 in Vial and Syringe
| 2 mL Glass Vial | Regular Syringe | LowTungsl | en Syringe | ||||
| Temp | Time | % Native (SE-HPLC) | % Acidic (CEX-HPLC) | % Native (SE-HPLC) | % Acidic (CEX-HPLC) | % Native (SE-HPLC) | % Acidic (CEX-HPLC) |
| 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 | 28 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 month | 95.3 | 34.6 | 94.7 | 37.4 | 96.0 | 36.3 |
| 25°C | 3 month | 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 month | 96.3 | 29.3 | 96.4 | 29.0 | 96.4 | 29.1 |
| 5°C | 3 month | 95.7 | 29.4 | 95.8 | 29.6 | 95.8 | 29.6 |
As shown in this table, Formulation B containing 150 mg/mL mAb1, stored at 5°C in a glass vial or syringe, remained relatively stable for at least 3 months.
-2919780
Example 8: Stability of mAb1 Formulations in Prefilled Syringes
A sériés of experiments was carried out to assess the stability of different mAb1 formulations in prefilled syringes. For these experiments various luer and staked needle, 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 prefilled syringes at 45°C, 25°C and 5°C for various amounts of time (ranging from 14 days to 12 months, depending on the conditions tested).
Six different formulations of mAb1 were tested for stability in prefilled syringes in this Example: (1) Formulation A (see Table 9) containing 100 mg/mL mAb1; (2) Formulation A (see Table 9) containing 25 mg/mL mAb1; (3) Formulation B (see Table 23) containing 150 mg/mL mAb1; (4) Formulation B (see Table 23) containing 25 mg/mL mAb1; (5) Formulation C (see Table 23) containing 175 mg/mL of mAb1 ; and (6) Formulation C (see Table 23) containing 25 mg/mL of mAb1.
Stability was assessed by the following parameters: (a) Visual analysis; (b) turbidity (OD405nm); (c) percent recovery by RP-HPLC; (d) percent native mAb1 by SE-HPLC; (e) percent main peak mAb1 by CEX-HPLC; and (f) percent acidic species by CEX-HPLC.
The results from a représentative experiment assessing the stability of Formulation A, containing 100 mg/mL mAb1 in two different syringes (Syringe #1 and Syringe #2) are shown in Tables 25 and 26 below.
Table 25: Stability of Formulation A containing 100 mg/mL mAb1 in Staked Needle Prefilled
| Syringe #1 Description: _________________________________________________________ | |||||||
| Syringe: | BD 1 mL long 29ga x 1/2 Physiolis, LowTungsten | ||||||
| Plunger: | West FluroTec® 4023/50 | ||||||
| Tip Cap: | BD 260 | ||||||
| Siliconization: | Sprayed | ||||||
| Temp | Time | Visual Analysis | Turbidity (OD405 nm) | % Recovery | % Native mAb1 | % Main Peak | % Acidic Species |
| — | Start | Pass | 0.00 | 100 | 96.6 | 56.9 | 28.7 |
| 45°C | 14 days | Pass | 0.00 | 99 | 95.1 | 32.7 | 50.7 |
| 45°C | 28 days | Pass | 0.01 | 103 | 92.6 | 20.9 | 66.1 |
| 45°C | 56 days | Pass | 0.03 | 105 | 88.8 | 9.9 | 80.9 |
| 25°C | 1 month | Pass | 0.00 | 106 | 95.6 | 52.4 | 32.0 |
| 25°C | 2 months | Pass | 0.00 | 107 | 95.2 | 48.0 | 37.0 |
| 25°C | 3 months | Pass | 0.00 | 106 | 94.2 | 44.8 | 41.8 |
| 25°C | 6 months | Pass | 0.01 | 101 | 93.7 | 34.8 | 53.9 |
| 25°C | 9 months | Pass | 0.03 | 98 | 91.4 | 26.1 | 64.6 |
| 25°C | 12 months | Pass | 0.03 | 101 | 89.9 | 21.3 | 69.4 |
-3019780
| Table 25 cont...: Stability of Formulation A containing 100 mg/mL mAb1 in Staked Needle Prefilled Syringe #1 | |||||||
| Syringe #1 Description: ________________________________________________ | |||||||
| Syringe: | BD 1 mL long 29ga x 1/2 Physiolis, Low Tungsten | ||||||
| Plunger: | West FluroTec® 4023/50 | ||||||
| Tip Cap: | BD 260 | ||||||
| Si | iconization: | Sprayed | |||||
| 5°C | 1 month | Pass | 0.00 | 110 | 96.4 | 56.8 | 29.9 |
| 5°C | 2 months | Pass | 0.00 | 108 | 96.2 | 55.7 | 31.1 |
| 5°C | 3 months | Pass | 0.00 | 104 | 96.0 | 56.3 | 30.0 |
| 5°C | 6 months | Pass | 0.00 | 100 | 96.5 | 55.0 | 31.3 |
| 5°C | 9 months | Pass | 0.00 | 98 | 96.2 | 56.7 | 30.3 |
| 5°C | 12 months | Pass | 0.00 | 101 | 95.4 | 57.3 | 30.2 |
| Table 26: Stability of Formulation A containing 100 mg/mL mAb1 in Staked Needle Prefilled Syringe #2 | |||||||
| Syringe #2 Description: _______________________________________________________________ | |||||||
| Syringe: | Schott 1 mL Long SN CF 29ga x 1/2 | ||||||
| Plunger: | West FluroTec® 4023/50 . | ||||||
| Tip Cap: | Stelmi 4800 w/RNS | ||||||
| Siliconization: | Sprayed | ||||||
| Temp | Time | Visual Analysis | Turbidity (OD405 nm) | % Recovery | % Native mAb1 | % Main Peak | % Acidic Species |
| Start | Pass | 0.00 | 100 | 96.3 | 57.5 | 28.0 | |
| 45°C | 14 days | Pass | 0.00 | 100 | 95.2 | 33.7 | 49.6 |
| 45°C | 28 days | Pass | 0.00 | 103 | 93.3 | 22.8 | 64.7 |
| 45°C | 56 days | Pass | 0.03 | 107 | 88.0 | 9.9 | 81.1 |
| 25°C | 1 month | Pass | 0.00 | 108 | 95.5 | 52.5 | 31.8 |
| 25°C | 2 months | Pass | 0.00 | 107 | 95.2 | 49.2 | 35.7 |
| 25°C | 3 months | Fail | 0.00 | 106 | 93.9 | 43.1 | 42.0 |
| 25°C | 6 months | Fait | 0.00 | 102 | 92.9 | 34.4 | 54.0 __ |
| 25°C | 9 months | Pass | 0.02 | 100 | 92.3 | 26.9 | 63.5 |
| 25°C | 12 months | Pass | 0.03 | 103 | 90.0 | 20.0 | 70.2 |
| 5°C | 1 month | Pass | 0.00 | 111 | 96.3 | 56.7 | 29.9 |
| 5°C | 2 months | Pass | 0.00 | 112 | 95.6 | 55.9 | 31.1 |
| 5°C | 3 months | Pass | 0.00 | 106 | 96.1 | 57.2 | 29.4 |
| 5°C | 6 months | Pass | 0.00 | 102 | 96.0 | 54.9 | 31.6 |
| 5°C | 9 months | Pass | 0.00 | 100 | 95.9 | 56.7 | 30.2 |
| 5°C | 12 months | Pass | 0.00 | 102 | 95.4 | 56.0 | 30.7 |
The results from another représentative experiment assessing the stability of Formulation C, containing 175 mg/mL mAb1 in two different syringes (Syringe #1 and 5 Syringe #3) are shown in Tables 27 and 28 below.
The results from this set of experiments demonstrate that the different formulations remain relatively stable in prefilled syringes, especially when stored at températures of 25°C and below, for one month or greater. Moreover, the various formulations of the invention
-3119780 appeared to hâve enhanced stability when contained in low tungsten syringes containing fluorocarbon-coated plungers.
Table 27: Stability of Formulation C containing 175 mg/mL mAb! in Staked Needle Prefilled
| Syrinqe #1 Description: _______________________________________________________ | |||||||
| Syringe: | BD 1 mL long 29ga x 1/2 Physiolis, Low Tungsten | ||||||
| Plunger: | West FluroTec® 4023/50 | ||||||
| Tip Cap: | BD 260 | ||||||
| Si | iconization: | Sprayed | |||||
| Temp | Time | Visual Analysis | Turbidity (OD405 nm) | % Recovery | % Native mAb1 | % Main Peak | % Acidic Species |
| — | Start | Pass | 0.00 | 100 | 96.7 | 59.7 | 32.4 |
| 45°C | 7 days | Pass | 0.01 | 102 | 96.1 | 48.6 | 39.5 |
| 45°C | 14 days | Pass | 0.03 | 97 | 95.0 | 36.9 | 50.0 |
| 45°C | 28 days | Pass | 0.03 | 98 | 91.9 | 24.7 | 66.0 |
| 45°C | 56 days | Pass | 0.05 | 97 | 91.9 | 12.3 | 83.3 |
| 25°C | 1 month | Pass | 0.02 | 99 | 95.4 | 56.9 | 33.8 |
| 25°C | 2 months | Pass | 0.00 | 100 | 95.0 | 51.1 | 39.8 |
| 5°C | 1 month | Pass | 0.00 | 98 | 96.1 | 59.5 | 32.7 |
| 5°C | 2 months | Pass | 0.00 | 101 | 96.4 | 56.3 | 37.1 |
Table 28: Stability of Formulation C containing 175 mg/mL mAb1 in Staked Needle Prefilled
| Syrinqe #1 Description: _______________________________________________________ | |||||||
| Syringe: | Daikyo Seiko CZ 1 mL std 30ga x 1/2 | ||||||
| Plunger: | Daikyo D-21-6-1 FluroTec® Coated | ||||||
| Tip Cap: | 7028 | ||||||
| Si | iconization: | N/A | |||||
| Temp | Time | Visual Analysis | Turbidity (OD405 nm) | % Recovery | % Native mAb1 | % Main Peak | % Acidic Species |
| -- | Start | Pass | 0.00 | 100 | 96.4 | 58.2 | 33.6 |
| 45°C | 7 days | Pass | 0.00 | 101 | 95.7 | 45.4 | 40.4 |
| 45°C | 14 days | Pass | 0.01 | 101 | 94.8 | 37.5 | 48.8 |
| 45°C | 28 days | Pass | 0.04 | 96 | 94.0 | 29.4 | 59.4 |
| 45°C | 56 days | Pass | 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 | Pass | 0.00 | 100 | 96.4 | 56.7 | 34.0 __ |
| 5°C | 2 months | Pass | 0.00 | 101 | 96.2 | 54.7 | 34.0 |
The présent invention is not to be limited in scope by the spécifie embodiments describe herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended daims.
Claims (12)
- What is claimed is:1. A pharmaceutical formulation comprising:(i) a human antibody that specifically binds to human interleukin-6 receptor (hlL-6R), wherein the antibody is at a concentration of from 5 mg/ml to 200 mg/ml and comprises a heavy chain variable région having the amino acid sequence of SEQ ID NO: 18 and a light chain variable région having the amino acid sequence of SEQ ID NO:26;(ii) histidine at a concentration of from 10 mM to 25 mM;(iii) arginine at a concentration of from 25 mM to 50 mM;(iv) sucrose in an amount of from 5% to 10% w/v; and (v) polysorbate 20 in an amount of from 0.1% to 0.2% w/v.
- 2. The pharmaceutical formulation of daim 1, wherein the formulation has a pH of about 6. .
- 3. The pharmaceutical formulation of any one of daims 1 or 2, 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 exdusion-high performance liquid chromatography (SE-HPLC).
- 4. The pharmaceutical formulation of any one of daims 1 or 2, 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 exdusion-high performance liquid chromatography (SE-HPLC).
- 5. The pharmaceutical formulation of any one of daims 1 or 2, 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).
- 6. The pharmaceutical formulation of any one of daims 1 to 5, which is contained in a glass vial.
- 7. The pharmaceutical formulation of any one of daims 1 to 5, which is contained in a syringe.
- 8. The pharmaceutical formulation of claim 7, wherein the syringe comprises a fluorocarbon-coated plunger, or the syringe is a low tungsten syringe.-3319780
- 9. The pharmaceutical formulation of any one of daims 1 to 5, which is contained in a microinfusor.
- 10. The pharmaceutical formulation of claim 1, comprising:(i) 25 to 200 mg/mL of a human antibody that specifically binds to human interleukin-6 receptor (hIL-6R), wherein the antibody comprises a heavy chain variable région having the amino acid sequence of SEQ ID NO: 18 and a light chain variable région having the amino acid sequence of SEQ ID NO:26;(ii) about 25 mM histidine;(iii) about 5% w/v sucrose; and (iv) about 0.2% w/v polysorbate 20; and (v) about 50 mM arginine.
- 11. The pharmaceutical formulation of claim 1, comprising:(i) about 175 mg/mL of a human antibody that specifically binds to human interleukin-6 receptor (h!L-6R), wherein the antibody comprises a heavy chain and light chain variable région (HCVR / LCVR) amino acid sequence pair of SEQ ID NOs: 18/26;(ii) about 25 mM histidine;(iii) about 5% sucrose;(iv) about 0.2% polysorbate 20; and (v) about 50 mM arginine.
- 12. The pharmaceutical formulation of claim 11, wherein the formulation is contained in a staked needle prefilled syringe.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US61/293,227 | 2010-01-08 | ||
| US12/986,223 | 2011-01-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA19780A true OA19780A (en) | 2021-04-30 |
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