U.S. patent application number 16/471492 was filed with the patent office on 2020-03-19 for anti-tnf alpha antibody formulations.
This patent application is currently assigned to AMGEN INC.. The applicant listed for this patent is AMGEN INC.. Invention is credited to Joy BRENNAN, William J. CALLAHAN, Rahul Rajan KAUSHIK.
Application Number | 20200087390 16/471492 |
Document ID | / |
Family ID | 61006357 |
Filed Date | 2020-03-19 |
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United States Patent
Application |
20200087390 |
Kind Code |
A1 |
CALLAHAN; William J. ; et
al. |
March 19, 2020 |
ANTI-TNF ALPHA ANTIBODY FORMULATIONS
Abstract
Stable adalimumab formulations are disclosed.
Inventors: |
CALLAHAN; William J.;
(Thousand Oaks, CA) ; KAUSHIK; Rahul Rajan;
(Newbury Park, CA) ; BRENNAN; Joy; (Thousand Oaks,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AMGEN INC. |
Thousand Oaks |
CA |
US |
|
|
Assignee: |
AMGEN INC.
Thousand Oaks
CA
|
Family ID: |
61006357 |
Appl. No.: |
16/471492 |
Filed: |
December 20, 2017 |
PCT Filed: |
December 20, 2017 |
PCT NO: |
PCT/US2017/067723 |
371 Date: |
June 19, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62437640 |
Dec 21, 2016 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/08 20130101; A61K
47/10 20130101; A61K 47/183 20130101; A61K 39/39591 20130101; C07K
16/241 20130101; A61K 9/0019 20130101 |
International
Class: |
C07K 16/24 20060101
C07K016/24; A61K 47/10 20060101 A61K047/10; A61K 47/18 20060101
A61K047/18 |
Claims
1. A stable aqueous formulation comprising about 180 mg/mL
adalimumab, about 20 mM glutamate, and about 160 mM
monoethanolamine (MEA), wherein the formulation has a pH of about
5.2, and demonstrates less than about a 2.1-fold increase in acidic
species as measured by cation-exchange high-performance liquid
chromatography (CEX-HPLC) after storage for 28 days at 40.degree.
C.
Description
REFERENCE TO PRIOR APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 62/437,640, filed Dec. 21, 2016, which is hereby
incorporated by reference.
[0002] The present application is being filed along with a sequence
listing in electronic format. The sequence listing is provided as a
file entitled A-2102-WO-PCT_SeqListing_122017.txt, created Dec. 19,
2017, which is 8 kb in size. The information in the electronic
format of the sequence listing is incorporated herein by reference
in its entirety.
BACKGROUND
[0003] Elevated levels of tumor necrosis factor alpha (TNF.alpha.)
have been associated with a number of human disorders such as
arthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing
spondylitis, axial spondyloarthritis, juvenile idiopathic
arthritis, enthesitis related arthritis, osteoarthritis, peripheral
spondyloarthritis, acute disc prolapse, inflammatory bowel disease,
Crohn's disease, ulcerative colitis, intestinal Behcet's disease,
chronic pouchitis, small bowel lesions, Hermansky-Pudlak syndrome,
psoriasis, psoriasis vulgaris, psoriasis arthropica, plaque
psoriasis, hidradenitis suppurativa, interstitial cystitis, sleep
apnea, sarcoidosis, retinal vascular disorders, uveitis, choroidal
neovascularization, Pyoderma Gangrenosum, giant cell arteritis,
Netherton syndrome, anaplastic thyroid cancers, asthma, and
refractory asthma. TNF.alpha. inhibitors are frequently used to
treat these disorders. One such inhibitor is adalimumab, also known
as D2E7, a recombinant human IgG1 monoclonal antibody specific for
human TNF.alpha..
SUMMARY
[0004] The present disclosure is directed to stable aqueous
adalimumab formulations, to methods of making stable aqueous
adalimumab formulations, to use of a formulation as disclosed
herein, and to methods of treating a disease comprising
administering to a patient a formulation as disclosed herein.
[0005] In one aspect, the disclosure includes a stable aqueous
formulation comprising about 180 mg/mL adalimumab, about 20 mM
glutamate, and about 160 mM monoethanolamine (MEA), wherein the
formulation has a pH of about 5.2, and demonstrates less than about
a 2.1-fold increase in acidic species as measured by
cation-exchange high-performance liquid chromatography (CEX-HPLC)
after storage for 28 days at 40.degree. C.
[0006] In another aspect, the disclosure provides a stable
adalimumab formulation as described in the Tables provided herein.
In some aspects, the stable adalimumab formulation provided herein
demonstrates one or more of the following parameters: (i) less than
about a 2.1-fold increase in acidic species, as measured by
cation-exchange high-performance liquid chromatography (CEX-HPLC)
after storage for 28 days at 40.degree. C.; (ii) less than about a
5-fold increase in high molecular weight species (HMWS) species, as
measured by size-exclusion chromatography (SE-HPLC) after storage
for 28 days at 40.degree. C.; and/or (iii) less than about 500
nephelometric turbidity units (NTUs) after stirring at room
temperature for 5 days.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1 is a bar graph of stability of adalimumab
formulations as determined by cation-exchange high-performance
liquid chromatography (CEX-HPLC).
[0008] FIG. 2 is a bar graph of stability of adalimumab
formulations as determined by size-exclusion high-performance
liquid chromatography (SE-HPLC).
[0009] FIG. 3 is a bar graph of stability of adalimumab
formulations as determined by CEX-HPLC.
[0010] FIG. 4 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0011] FIG. 5 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0012] FIG. 6 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0013] FIG. 7 is a bar graph of stability of adalimumab
formulations as determined by CEX-HPLC.
[0014] FIG. 8 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC. The symbol " . . . "
indicates a value above the maximum shown on the y-axis.
[0015] FIG. 9 is a bar graph of stability of adalimumab
formulations as determined by CEX-HPLC.
[0016] FIG. 10 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0017] FIG. 11 is a bar graph of stability of adalimumab
formulations as determined by CEX-HPLC.
[0018] FIG. 12 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0019] FIG. 13 is a bar graph of stability of adalimumab
formulations as determined by CEX-HPLC.
[0020] FIG. 14 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0021] FIG. 15 is a bar graph of stability of adalimumab
formulations as determined by CEX-HPLC.
[0022] FIG. 16 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0023] FIG. 17 is a bar graph of stability of adalimumab
formulations as determined by CEX-HPLC.
[0024] FIG. 18 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0025] FIG. 19 is a bar graph of stability of adalimumab
formulations as determined by CEX-HPLC.
[0026] FIG. 20 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0027] FIG. 21 is a bar graph of stability of adalimumab
formulations as determined by opalescence measurement.
[0028] FIG. 22 is a bar graph of stability of adalimumab
formulations as determined by CEX-HPLC.
[0029] FIG. 23 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0030] FIG. 24 is a bar graph of stability of adalimumab
formulations as determined by CEX-HPLC.
[0031] FIG. 25 is a bar graph of stability of adalimumab
formulations as determined by CEX-HPLC.
[0032] FIG. 26 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0033] FIG. 27 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0034] FIG. 28 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0035] FIG. 29 is a bar graph of stability of adalimumab
formulations as determined by CEX-HPLC.
[0036] FIG. 30 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0037] FIG. 31 is a bar graph of stability of adalimumab
formulations as determined by micro-flow imaging (MFI).
[0038] FIG. 32 is a bar graph of stability of adalimumab
formulations as determined by MFI. The symbol " . . . " indicates a
value above the maximum shown on the y-axis.
[0039] FIG. 33 is a bar graph of stability of adalimumab
formulations as determined by MFI.
[0040] FIG. 34 is a bar graph of stability of adalimumab
formulations as determined by MFI. The symbol " . . . " indicates a
value above the maximum shown on the y-axis.
[0041] FIG. 35 is a bar graph of stability of adalimumab
formulations as determined by MFI.
[0042] FIG. 36 is a bar graph of stability of adalimumab
formulations as determined by MFI. The symbol " . . . " indicates a
value above the maximum shown on the y-axis.
[0043] FIG. 37 is a bar graph of stability of adalimumab
formulations as determined by CEX-HPLC.
[0044] FIG. 38 is a bar graph of stability of adalimumab
formulations as determined by CEX-HPLC.
[0045] FIG. 39 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0046] FIG. 40 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0047] FIG. 41 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0048] FIG. 42 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0049] FIG. 43 is a bar graph of stability of adalimumab
formulations as determined by CEX-HPLC.
[0050] FIG. 44 is a bar graph of stability of adalimumab
formulations as determined by CEX-HPLC.
[0051] FIG. 45 is a bar graph of stability of adalimumab
formulations as determined by CEX-HPLC.
[0052] FIG. 46 is a bar graph of stability of adalimumab
formulations as determined by CEX-HPLC.
[0053] FIG. 47 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0054] FIG. 48 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0055] FIG. 49 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0056] FIG. 50 is a bar graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0057] FIG. 51 is a line graph of stability of adalimumab
formulations as determined by CEX-HPLC.
[0058] FIG. 52 is a line graph of stability of adalimumab
formulations as determined by CEX-HPLC.
[0059] FIG. 53 is a line graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0060] FIG. 54 is a line graph of stability of adalimumab
formulations as determined by SE-HPLC.
[0061] FIG. 55 is a bar graph of stability of adalimumab
formulations as determined by MFI.
[0062] FIG. 56 is a bar graph of stability of adalimumab
formulations as determined by MFI.
[0063] FIG. 57 is a bar graph of stability of adalimumab
formulations as determined by MFI.
[0064] FIG. 58 is a bar graph of stability of adalimumab
formulations (non-transport at 4.degree. C.) as determined by
CEX-HPLC.
[0065] FIG. 59 is a bar graph of stability of adalimumab
formulations (transport at 4.degree. C.) as determined by
CEX-HPLC.
[0066] FIG. 60 is a bar graph of stability of adalimumab
formulations (non-transport at 25.degree. C.) as determined by
CEX-HPLC.
[0067] FIG. 61 is a bar graph of stability of adalimumab
formulations (transport at 25.degree. C.) as determined by
CEX-HPLC.
[0068] FIG. 62 is a bar graph of stability of adalimumab
formulations (non-transport at 40.degree. C.) as determined by
CEX-HPLC.
[0069] FIG. 63 is a bar graph of stability of adalimumab
formulations (transport at 40.degree. C.) as determined by
CEX-HPLC.
[0070] FIG. 64 is a bar graph of stability of adalimumab
formulations (non-transport at 4.degree. C.) as determined by
SE-HPLC.
[0071] FIG. 65 is a bar graph of stability of adalimumab
formulations (transport at 4.degree. C.) as determined by
SE-HPLC.
[0072] FIG. 66 is a bar graph of stability of adalimumab
formulations (non-transport at 25.degree. C.) as determined by
SE-HPLC.
[0073] FIG. 67 is a bar graph of stability of adalimumab
formulations (transport at 25.degree. C.) as determined by
SE-HPLC.
[0074] FIG. 68 is a bar graph of stability of adalimumab
formulations (non-transport at 40.degree. C.) as determined by
SE-HPLC.
[0075] FIG. 69 is a bar graph of stability of adalimumab
formulations (transport at 40.degree. C.) as determined by
SE-HPLC.
[0076] FIGS. 70A-B are a bar graph of stability of adalimumab
formulations as determined by MFI. FIG. 70B is the same data
presented in FIG. 70A but graphed at a different scale.
[0077] FIGS. 71A-B are a bar graph of stability of adalimumab
formulations as determined by MFI. FIG. 71B is the same data
presented in FIG. 71A but graphed at a different scale.
[0078] FIGS. 72A-B are a bar graph of stability of adalimumab
formulations as determined by determined by MFI. FIG. 72B is the
same data presented in FIG. 72A but graphed at a different
scale.
[0079] FIG. 73 is a bar graph of stability of adalimumab
formulations (non-transport at 4.degree. C.) as determined by
CEX-HPLC.
[0080] FIG. 74 is a bar graph of stability of adalimumab
formulations (transport at 4.degree. C.) as determined by
CEX-HPLC.
[0081] FIG. 75 is a bar graph of stability of adalimumab
formulations (non-transport at 25.degree. C.) as determined by
CEX-HPLC.
[0082] FIG. 76 is a bar graph of stability of adalimumab
formulations (transport at 25.degree. C.) as determined by
CEX-HPLC.
[0083] FIG. 77 is a bar graph of stability of adalimumab
formulations as (non-transport at 40.degree. C.) determined by
CEX-HPLC.
[0084] FIG. 78 is a bar graph of stability of adalimumab
formulations (transport at 40.degree. C.) as determined by
CEX-HPLC.
[0085] FIG. 79 is a bar graph of stability of adalimumab
formulations (non-transport at 4.degree. C.) as determined by
SE-HPLC.
[0086] FIG. 80 is a bar graph of stability of adalimumab
formulations (transport at 4.degree. C.) as determined by
SE-HPLC.
[0087] FIG. 81 is a bar graph of stability of adalimumab
formulations (non-transport at 25.degree. C.) as determined by
SE-HPLC.
[0088] FIG. 82 is a bar graph of stability of adalimumab
formulations (transport at 25.degree. C.) as determined by
SE-HPLC.
[0089] FIG. 83 is a bar graph of stability of adalimumab
formulations (non-transport at 40.degree. C.) as determined by
SE-HPLC.
[0090] FIG. 84 is a bar graph of stability of adalimumab
formulations (transport at 40.degree. C.) as determined by
SE-HPLC.
[0091] FIG. 85 is a bar graph of stability of adalimumab
formulations as determined by MFI.
[0092] FIG. 86 is a bar graph of stability of adalimumab
formulations as determined by MFI.
[0093] FIG. 87 is a bar graph of stability of adalimumab
formulations as determined by MFI.
DETAILED DESCRIPTION
[0094] The present disclosure provides stable aqueous adalimumab
formulations and related methods of making stable aqueous
adalimumab formulations. Also provided are lyophilized forms of the
aqueous adalimumab formulations disclosed herein. The present
disclosure also provides related uses of the formulations disclosed
herein and related methods of administering these formulations to
treat diseases such as arthritis, rheumatoid arthritis, psoriatic
arthritis, ankylosing spondylitis, axial spondyloarthritis,
juvenile idiopathic arthritis, enthesitis related arthritis,
osteoarthritis, peripheral spondyloarthritis, acute disc prolapse,
inflammatory bowel disease, Crohn's disease, ulcerative colitis,
intestinal Behcet's disease, chronic pouchitis, small bowel
lesions, Hermansky-Pudlak syndrome, psoriasis, psoriasis vulgaris,
psoriasis arthropica, plaque psoriasis, hidradenitis suppurativa,
interstitial cystitis, sleep apnea, sarcoidosis, retinal vascular
disorders, uveitis, choroidal neovascularization, Pyoderma
Gangrenosum, giant cell arteritis, Netherton syndrome, anaplastic
thyroid cancers, asthma, and refractory asthma.
[0095] The stable aqueous adalimumab formulations include
adalimumab and one or more excipients selected such that the
formulation demonstrates characteristics suitable for use as a
pharmaceutical composition. A formulation suitable for use as a
pharmaceutical composition generally exhibits a low amount of high
molecular weight species (HMWS), such as aggregates and dimers,
and/or also exhibits a low degree of oxidation over time. For
example, a suitable adalimumab formulation may exhibit minimal
oxidation of residues TRP 53, MET 34, MET 256, and MET 432. A
suitable formulation may also exhibit a minimal amount of
sub-visible particles (e.g., particles having a diameter of
.gtoreq.10 .mu.m or .gtoreq.25 .mu.m) and/or non-spherical
particles (e.g., particles having an aspect ratio of .gtoreq.5
.mu.m). High amounts of HMWS, oxidation, and/or particles may
impact the shelf-life, safety and/or potency of a formulation.
Stable aqueous adalimumab formulations are described in the
embodiments set forth below.
[0096] In some cases, the stable aqueous adalimumab formulations
include adalimumab, calcium chloride, and optionally one or more
(typically one, two, or three) additional excipients as described
herein.
[0097] In some cases, the stable aqueous adalimumab formulations
include adalimumab, a buffer, and optionally one or more (typically
one, two, or three) additional excipients as described herein.
Suitable buffers include glutamate/glutamic acid buffers
("glutamate buffer"), adipate/adipic acid buffers ("adipate
buffer"), glucuronate/glucuronic acid buffers ("glucuronate
buffer"), acetate/acetic acid buffers ("acetate buffer"),
benzoate/benzoic acid buffers ("benzoate buffer"),
glycolate/glycolic acid buffers ("glycolate buffer"),
lactate/lactic acid buffers ("lactate buffer"), and histidine
buffers.
[0098] In some cases, the stable aqueous adalimumab formulations
include adalimumab and do not include a buffer. Optionally, these
adalimumab formulations additionally include one or more (typically
one, two, or three) excipients as described herein.
[0099] In some cases, the stable aqueous adalimumab formulation
includes adalimumab, a buffer (e.g., lactate buffer), calcium
chloride, and optionally one or more (typically one, two, or three)
additional excipients as described herein.
[0100] As used herein, a "stable" formulation demonstrates
stability sufficient to permit administration to a patient. For
example, a stable formulation may demonstrate long-term stability,
such as stability upon storage for 6 months or 1 year. Stability of
a formulation may, for example, be assessed by growth of acidic
species over time, growth of high molecular weight species over
time, or increase in opalescence over time. When stability is
assessed by growth of acidic species over time, a stable
formulation may demonstrate less than about a 4-fold increase
(e.g., less than about a 3.5-fold increase, less than about a
3-fold increase, less than about a 2.5-fold increase, less than
about a 2.4-fold increase, less than about a 2.3-fold increase,
less than about a 2.25-fold increase, less than about a 2.2-fold
increase, less than about a 2.15-fold increase, less than about a
2.1-fold increase, less than about a 2.05-fold increase, or less
than about a 2-fold increase) in acidic species as measured by
CEX-HPLC after storage for 28 days at 40.degree. C. When stability
is assessed by growth of high molecular weight species over time, a
stable formulation may demonstrate less than about a 5-fold
increase (e.g., less than about a 4.5-fold increase, less than
about a 4-fold increase, less than about a 3.9-fold increase, less
than about a 3.8-fold increase, less than about a 3.7-fold
increase, less than about a 3.6-fold increase, less than about a
3.5-fold increase, less than about a 3.4-fold increase, less than
about a 3.3-fold increase, less than about a 3.2-fold increase,
less than about a 3.15-fold increase, less than about a 3.1-fold
increase, less than about a 3.05-fold increase, less than about a
3-fold increase, less than about a 2.95-fold increase, or less than
about a 2.9-fold increase) in HMWS species as measured by SE-HPLC
after storage for 28 days at 40.degree. C. When stability is
assessed by increase in opalescence over time, a stable formulation
may demonstrate less than about 500 nephelometric turbidity units
(NTUs) (e.g., less than about 400 NTUs, less than about 350 NTUs,
less than about 300 NTUs, less than about 250 NTUs, less than about
200 NTUs, less than about 150 NTUs, less than about 140 NTUs, less
than about 130 NTUs, less than about 125 NTUs, less than about 120
NTUs, less than about 115 NTUs, less than about 110 NTUs, less than
about 100 NTUs, less than about 90 NTUs, less than about 80 NTUs,
or less than about 70 NTUs) after stirring at room temperature for
5 days.
[0101] As used herein, an "aqueous" formulation contains water.
Aqueous formulations can be in a liquid state or a frozen state,
and preferably are liquid formulations.
[0102] As used herein, an "excipient" is a component of a
formulation other than water and the active agent (e.g., adalimumab
or biosimilar thereof) added to the formulation. Examples of
excipients include buffers; stabilizers such as amino acids and
amino acid derivatives, polyethylene glycols and polyethylene
glycol derivatives, polyols, acids, amines, polysaccharides or
polysaccharide derivatives, salts, and surfactants; and
pH-adjusting agents.
[0103] As used herein, a "biosimilar," particularly an adalimumab
biosimilar, is a biological product that is highly similar to
HUMIRA (also known as adalimumab or D2E7) notwithstanding minor
differences in clinically inactive components; and there are no
clinically meaningful differences between the biological product
and HUMIRA in terms of safety, purity, and potency of the
product.
[0104] As used herein, the term "about," when used to modify a
particular value or range, generally means within 20 percent, e.g.,
within 10 percent, 5 percent, 4 percent, 3 percent, 2 percent, or 1
percent of the stated value or range.
[0105] Adalimumab is a fully human monoclonal antibody of the
immunoglobulin G1 (IgG1) subclass expressed in the Chinese hamster
ovary (CHO) cell line and consists of 2 heavy chains (HC), and 2
light chains (LC) of the kappa subclass. Adalimumab contains 32
total cysteine residues involved in both intrachain and interchain
disulfide bonds. Each HC contains 451 amino acids with 4 intrachain
disulfides. Each LC contains 214 amino acids with 2 intrachain
disulfides. Each HC contains an N-linked glycan at the consensus
glycosylation site on Asn301. The amino acid sequences of the
adalimumab variable LC and variable HC are set out at SEQ ID NO: 1
and 2, respectively and the full length LC and HC are set out as
SEQ ID NO: 3 and 4; respectively. In addition, the adalimumab LC
CDRs are set out as SEQ ID NO: 5 (LC CDR1), SEQ ID NO: 6 (LC CDR2)
and SEQ ID NO: 7 (LC CDR3). Adalimumab HC CDRs are set out as SEQ
ID NO: 8 (HC CDR1), SEQ ID No: 9 (HC CDR2), and SEQ ID NO: 10 (HC
CDR3). Adalimumab has been described and claimed in U.S. Pat. No.
6,090,382, the disclosure of which is hereby incorporated by
reference in its entirety. As used herein, the term "adalimumab"
includes biosimilars of adalimumab.
Formulations of Adalimumab with Calcium Chloride
[0106] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 200
mg/mL, such as about 90 to about 120 mg/mL, about 80 to about 120
mg/mL, about 90 to about 110 mg/mL, about 160 to about 190 mg/mL,
about 40 to about 60 mg/mL, about 50 mg/mL, about 100 mg/mL, or
about 170 mg/mL, calcium chloride at a concentration of about 1 to
about 150 mM, such as about 5 to about 50 mM, about 5 to about 30
mM, about 10 to about 30 mM, about 12.5 to about 17.5 mM about 20
to about 40 mM, about 30 to about 50 mM, about 40 to about 80 mM,
about 50 to about 100 mM, about 10 mM, about 15 mM, about 20 mM,
about 25 mM, or about 30 mM, and one or more excipients as
discussed below. The presence of calcium chloride in the
formulations advantageously and unexpectedly provides improved
stability over time as compared to other salts, particularly with
respect to levels of acidic species at 40.degree. C. as detected by
cation-exchange high-performance liquid chromatography (CEX-HPLC).
Further, the presence of calcium chloride at low concentrations
(e.g., about 20 to about 25 mM, about 10 mM to about 20 mM, about
12.5 mM to about 17.5 mM, or about 15 mM) advantageously lowers the
rate of growth of acidic species without significantly increasing
the growth of high molecular weight species (HMWS) at 40.degree. C.
as detected by size-exclusion high-performance liquid
chromatography (SE-HPLC).
[0107] Increased levels of acidic species over time are generally
due to protein deamidation. It is therefore beneficial for the
stable aqueous adalimumab formulations to demonstrate minimal
growth of acidic species over time. Similarly, it is beneficial for
the stable aqueous adalimumab formulations to demonstrate minimal
growth over time of HMWS because HMWS provide a measure of soluble
aggregation.
[0108] Further still, the presence of calcium chloride at low
concentrations (e.g., about 10 mM to about 20 mM, about 12.5 mM to
about 17.5 mM or about 15 mM) advantageously minimizes formation of
sub-visible and/or non-spherical particles in a formulation, as
detected by micro-flow imaging ("MFI") even if the formulation has
been subjected to transport conditions.
[0109] Suitable excipients for combination with the calcium
chloride-containing adalimumab formulations include certain
buffers, and certain stabilizers such as certain amino acids and
amino acid derivatives, certain polyethylene glycols and
polyethylene glycol derivatives, certain polyols, certain acids,
certain amines, certain polysaccharides or polysaccharide
derivatives, and certain surfactants. Examples of suitable buffers
include glutamate (e.g., at a concentration of about 5 mM to about
50 mM, about 10 mM to about 25 mM, about 15 mM to about 20 mM,
about 10 mM, about 15 mM, about 20 mM, and/or about 25 mM), adipate
(e.g., at a concentration of about 5 mM to about 50 mM, about 10 mM
to about 25 mM, about 15 mM to about 20 mM, about 10 mM, about 15
mM, about 20 mM, and/or about 25 mM), glucuronate (e.g., at a
concentration of about 5 mM to about 50 mM, about 10 mM to about 30
mM, about 10 mM, about 15 mM, about 20 mM, and/or about 25 mM),
acetic acid and/or acetate (e.g., at a concentration of about 0.1
mM to about 300 mM, about 2 mM to about 30 mM, about 5 mM to about
50 mM, about 5 mM to about 15 mM, about 10 mM to about 20 mM, about
10 mM to about 30 mM, about 15 mM to about 25 mM, about 30 mM to
about 40 mM, about 35 mM to about 45 mM, about 40 mM to about 50
mM, about 10 mM, about 15 mM, about 20 mM, and/or about 25 mM),
benzoate (e.g., at a concentration of about 5 mM to about 50 mM,
about 10 mM to about 30 mM, about 10 mM, about 15 mM, about 20 mM,
and/or about 25 mM), glycolate (e.g., at a concentration of about 5
mM to about 50 mM, about 10 mM to about 30 mM, about 10 mM, about
15 mM, about 20 mM, and/or about 25 mM), lactic acid and/or lactate
(e.g., at a concentration of about 0.1 mM to about 300 mM, about 2
mM to about 30 mM, about 10 mM to about 30 mM, about 5 mM to about
15 mM, about 7 mM to about 12 mM, about 9 mM to about 11 mM, about
10 mM, about 15 mM, about 20 mM, and/or about 25 mM), and histidine
(e.g., at a concentration of about 5 mM to about 50 mM, about 5 mM
to about 15 mM, about 10 mM, about 15 mM, about 20 mM, and/or about
25 mM). Examples of suitable amino acids and amino acid derivatives
include proline (e.g., at a concentration of about 0.1 to about 450
mM, about 50 to about 320 mM, and/or about 50 to about 300 mM),
N-acetyl arginine (e.g., at a concentration of about 0.1 to about
450 mM or about 90 to about 150 mM), citruline (e.g., at a
concentration of about 0.1 to about 450 mM or about 100 to about
150 mM), sarcosine (e.g., at a concentration of about 0.1 to about
450 mM or about 100 to about 150 mM), N-acetyl proline (e.g., at a
concentration of about 0.1 to about 450 mM or about 100 to about
150 mM), N-acetyl ornithine (e.g., at a concentration of about 0.1
to about 450 mM or about 100 to about 150 mM), ornithine (e.g., at
a concentration of about 0.1 to about 450 mM or about 100 to about
150 mM), beta-alanine (e.g., at a concentration of about 0.1 to
about 450 mM or about 100 to about 150 mM), alanine (e.g., at a
concentration of about 0.1 to about 450 mM or about 80 to about 120
mM), asparagine (e.g., at a concentration of about 0.1 to about 450
mM or about 80 to about 120 mM), isoleucine (e.g., at a
concentration of about 0.1 to about 450 mM or about 80 to about 120
mM), serine (e.g., at a concentration of about 0.1 to about 450 mM
or about 80 to about 120 mM), aspartic acid (e.g., at a
concentration of about 0.1 to about 450 mM or about 10 to about 30
mM), creatine (e.g., at a concentration of about 0.1 to about 450
mM or about 15 to about 35 mM), glutamine (e.g., at a concentration
of about 0.1 to about 450 mM or about 40 to about 60 mM),
phenylalanine (e.g., at a concentration of about 0.1 to about 450
mM or about 40 to about 60 mM), tryptophan (e.g., at a
concentration of about 0.1 to about 450 mM or about 15 to about 35
mM), and arginine-HCl (e.g., at a concentration of about 0.1 to
about 450 mM or about 80 to about 120 mM). Examples of suitable
polyethylene glycols and polyethylene glycol derivatives include
PEG 15 hydroxystearate (e.g., at a concentration of about 0.1%
(w/v) to about 20% (w/v) or about 3% (w/v) to about 6% (w/v)), PEG
3350 (e.g., at a concentration of about 0.1% (w/v) to about 30%
(w/v) or about 1% (w/v) to about 7% (w/v)), PEG 200 (e.g., at a
concentration of about 0.1% (w/v) to about 10% (w/v) or about 0.6%
(w/v) to about 4.8% (w/v)), PEG 600 (e.g., at a concentration of
about 0.1% (w/v) to about 30% (w/v) or about 1.2% (w/v) to about
14.5% (w/v)), and PEG 400 (e.g., at a concentration of about 0.1%
(w/v) to about 20% (w/v) or about 0.3% (w/v) to about 1.5% (w/v)).
Examples of suitable polyols include inositol (e.g., at a
concentration of about 0.1 to about 450 mM or about 150 to about
210 mM), glycerol (also referred to as glycerin) (e.g., at a
concentration of about 0.1% (w/v) to about 15% (w/v) or about 0.5%
(w/v) to about 1% (w/v)), sucrose (e.g., at a concentration of
about 0.1% (w/v) to about 15% (w/v), about 4% (w/v) to about 10%
(w/v), about 6% (w/v) to about 8.5% (w/v), about 6.2% (w/v) to
about 7.3% (w/v), about 4% (w/v) to about 9% (w/v), about 6.5%
(w/v), about 6.8% (w/v), about 6.9% (w/v), about 7.4% (w/v), or
about 9% (w/v)), and sorbitol (e.g., at a concentration of about
0.1% (w/v) to about 10% (w/v), about 3% (w/v) to about 5% (w/v),
and/or about 4% (w/v)). Examples of suitable acids include glycolic
acid (e.g., at a concentration of about 0.1 to about 300 mM or
about 50 to about 70 mM), pyrollidone carboxylic acid (PCA) (e.g.,
at a concentration of about 0.1% (w/v) to about 15% (w/v) or about
0.05% (w/v) to about 2% (w/v)), medronic acid (e.g., at a
concentration of about 0.1 to about 450 mM or about 100 to about
150 mM), benzene sulfonic acid (e.g., at a concentration of about
0.1 to about 300 mM or about 60 to about 90 mM), and methane
sulfonic acid (MSA) (e.g., at a concentration of about 0.1 to about
150 mM, about 0.1 to about 50 mM, and/or about 10 to about 30 mM).
Examples of suitable amines include monoethanolamine hydrochloride
(MEA-HCl) (e.g., at a concentration of about 0.1 to about 150 mM or
about 0.1 to about 40 mM), monoethanolamine (MEA) (e.g., at a
concentration of about 0.1 to about 300 mM, about 0.1 to about 50
mM, and/or about 30 to about 160 mM), and triethanolamine (TEA)
(e.g., at a concentration of about 0.1 to about 170 mM or about 30
to about 150 mM). Examples of suitable polysaccharides or
polysaccharide derivatives include hyaluronic acid (e.g., at a
concentration of about 0.05% (w/v) to about 2.5% (w/v) or about
0.1% (w/v) to about 0.05% (w/v)), sodium carboxymethylcellulose
(NaCMC) (e.g., at a concentration of about 0.1% (w/v) to about 15%
(w/v) or about 0.1% (w/v) to about 2% (w/v)), and dextran (e.g., at
a concentration of about 0.1% (w/v) to about 15% (w/v) or about 8%
(w/v) to about 12% (w/v)). Examples of suitable surfactants include
Pluronic F68 (e.g., at a concentration of about 0.001% (w/v) to
about 10% (w/v), about 0.005% (w/v) to about 1% (w/v), about 0.05%
(w/v) to about 0.4% (w/v), about 0.05% (w/v) to about 0.1% (w/v),
about 0.01% (w/v) to about 0.2% (w/v), about 0.03% (w/v) to about
0.06% (w/v), about 0.01% (w/v), about 0.05% (w/v), about 0.06%
(w/v), and/or about 0.1% (w/v)), Polysorbate 80 (e.g., at a
concentration of about 0.001% (w/v) to about 2% (w/v), about 0.005%
(w/v) to about 0.1% (w/v), about 0.03% (w/v) to about 0.1% (w/v),
about 0.04% (w/v) to about 0.1% (w/v), about 0.03% (w/v), about
0.04% (w/v), and/or about 0.1% (w/v)), Polysorbate 20 (e.g., at a
concentration of about 0.001% (w/v) to about 2% (w/v) or about
0.005% (w/v) to about 0.1% (w/v)), Docusate sodium (e.g., at a
concentration of about 0.001% (w/v) to about 1% (w/v) or about
0.005% (w/v) to about 0.05% (w/v)), benzalkonium chloride (e.g., at
a concentration of about 0.001% (w/v) to about 1% (w/v) or about
0.05% (w/v) to about 0.5% (w/v)), Span 40 (sorbitan monopalmitate)
(e.g., at a concentration of about 0.001% (w/v) to about 1% (w/v)
or about 0.05% (w/v) to about 0.5% (w/v)), and Triton X-100 (e.g.,
at a concentration of about 0.001% (w/v) to about 1% (w/v) or about
0.005% (w/v) to about 0.1% (w/v)). Examples of other suitable
excipients include imidazole (e.g., at a concentration of about
0.1% (w/v) to about 15% (w/v) or about 0.5% (w/v) to about 2%
(w/v)), taurine (e.g., at a concentration of about 0.1 to about 450
mM or about 100 to about 150 mM), betaine (e.g., at a concentration
of about 0.1 to about 450 mM or about 100 to about 150 mM), gelatin
(e.g., at a concentration of about 0.1% (w/v) to about 15% (w/v) or
about 0.5% (w/v) to about 2% (w/v)), niacinamide (e.g., at a
concentration of about 0.1 to about 450 mM or about 100 to about
120 mM), polyvinylpyrrolidone (PVP), for example, 10K PVP, (e.g.,
at a concentration of about 0.001% (w/v) to about 10% (w/v) or
about 0.05% (w/v) to about 2% (w/v)), guanidine hydrochloride
(GnHCl) (e.g., at a concentration of about 0.1 to about 150 mM or
about 10 to about 30 mM), and ethanol (e.g., at a concentration of
about 0.05% (w/v) to about 2.5% (w/v) or about 0.25% (w/v) to about
1% (w/v)). Optionally, the calcium chloride-containing stable
aqueous adalimumab formulation has a pH of about 4.8 to about 5.7,
for example, about 4.9 to about 5.6, about 5.0 to about 5.5, about
5.1 to about 5.4, about 5.1 to about 5.3, about 5.1 to about 5.2,
about 5.2 to about 5.3, and/or about 5.2. Optionally, the pH of the
stable aqueous adalimumab formulation is adjusted using a strong
acid and/or a strong base including, but not limited to,
hydrochloric acid, sodium hydroxide, calcium hydroxide, MSA, and/or
MEA.
[0110] Suitable excipients for combination with the calcium
chloride-containing adalimumab formulations also include, but are
not limited to, glutamate at a concentration of about 5 mM to about
50 mM (e.g., about 10 mM to about 25 mM, about 15 mM to about 20
mM, about 10 mM, about 15 mM, about 20 mM, and/or about 25 mM),
adipate at a concentration of about 5 mM to about 50 mM (e.g.,
about 10 mM to about 25 mM, about 15 mM to about 20 mM, about 10
mM, about 15 mM, about 20 mM, and/or about 25 mM), glucuronate at a
concentration of about 5 mM to about 50 mM (e.g., about 10 mM to
about 30 mM, about 10 mM, about 15 mM, about 20 mM, and/or about 25
mM), acetic acid and/or acetate at a concentration of about 0.1 mM
to about 300 mM (e.g., about 2 mM to about 30 mM, about 5 mM to
about 50 mM, about 5 mM to about 15 mM, about 10 mM to about 20 mM,
about 10 mM to about 30 mM, about 15 mM to about 25 mM, about 30 mM
to about 40 mM, about 35 mM to about 45 mM, about 40 mM to about 50
mM, about 10 mM, about 15 mM, about 20 mM, and/or 25 mM), benzoate
at a concentration of about 5 mM to about 50 mM (e.g., about 10 mM
to about 30 mM, about 10 mM, about 15 mM, about 20 mM, and/or about
25 mM), glycolate at a concentration of about 5 mM to about 50 mM
(e.g., about 10 mM to about 30 mM, about 10 mM, about 15 mM, about
20 mM, and/or about 25 mM), lactic acid and/or lactate at a
concentration of about 0.1 mM to about 300 mM (e.g., about 2 mM to
about 30 mM, about 10 mM to about 30 mM, about 5 mM to about 15 mM,
about 10 mM, about 15 mM, about 20 mM, and/or about 25 mM),
histidine at a concentration of about 5 mM to about 50 mM (e.g.,
about 5 mM to about 15 mM, about 10 mM, about 15 mM, about 20 mM,
and/or about 25 mM), proline at a concentration of about 0.1 to
about 450 mM (e.g., about 50 to about 320 mM and/or about 50 to
about 300 mM), N-acetyl arginine at a concentration of about 0.1 to
about 450 mM (e.g., about 90 to about 150 mM), citruline at a
concentration of about 0.1 to about 450 mM (e.g., about 100 to
about 150 mM), sarcosine at a concentration of about 0.1 to about
450 mM (e.g., about 100 to about 150 mM), N-acetyl proline at a
concentration of about 0.1 to about 450 mM (e.g., about 100 to
about 150 mM), N-acetyl ornithine at a concentration of about 0.1
to about 450 mM (e.g., about 100 to about 150 mM), ornithine at a
concentration of about 0.1 to about 450 mM (e.g., about 100 to
about 150 mM), beta-alanine at a concentration of about 0.1 to
about 450 mM (e.g., about 100 to about 150 mM), alanine at a
concentration of about 0.1 to about 450 mM (e.g., about 80 to about
120 mM), asparagine at a concentration of about 0.1 to about 450 mM
(e.g., about 80 to about 120 mM), isoleucine at a concentration of
about 0.1 to about 450 mM (e.g., about 80 to about 120 mM), serine
at a concentration of about 0.1 to about 450 mM (e.g., about 80 to
about 120 mM), aspartic acid at a concentration of about 0.1 to
about 450 mM (e.g., about 10 to about 30 mM), creatine at a
concentration of about 0.1 to about 450 mM (e.g., about 15 to about
35 mM), glutamine at a concentration of about 0.1 to about 450 mM
(e.g., about 40 to about 60 mM), phenylalanine at a concentration
of about 0.1 to about 450 mM (e.g., about 40 to about 60 mM),
tryptophan at a concentration of about 0.1 to about 450 mM (e.g.,
about 15 to about 35 mM), arginine-HCl at a concentration of about
0.1 to about 450 mM (e.g., about 80 to about 120 mM), PEG 15
hydroxystearate at a concentration of about 0.1% (w/v) to about 20%
(w/v) (e.g., about 3% (w/v) to about 6% (w/v)), PEG 3350 at a
concentration of about 0.1% (w/v) to about 30% (w/v) (e.g., about
1% (w/v) to about 7% (w/v)), PEG 200 at a concentration of about
0.1% (w/v) to about 10% (w/v) (e.g., about 0.6% (w/v) to about 4.8%
(w/v)), PEG 600 at a concentration of about 0.1% (w/v) to about 30%
(w/v) (e.g., about 1.2% (w/v) to about 14.5% (w/v)), PEG 400 at a
concentration of about 0.1% (w/v) to about 20% (w/v) (e.g., about
0.3% (w/v) to about 1.5% (w/v)), inositol at a concentration of
about 0.1 to about 450 mM (e.g., about 150 to about 210 mM),
glycerol (also referred to as glycerin) at a concentration of about
0.1% (w/v) to about 15% (w/v) (e.g., about 0.5% (w/v) to about 1%
(w/v)), sucrose at a concentration of about 0.1% (w/v) to about 15%
(w/v) (e.g., about 4% (w/v) to about 10% (w/v), about 6.2% (w/v) to
about 7.3% (w/v), about 4% (w/v) to about 9% (w/v), about 6.5%
(w/v), about 6.8% (w/v), about 6.9% (w/v), or about 9% (w/v)),
sorbitol at a concentration of about 0.1% (w/v) to about 10% (w/v)
(e.g., about 3% (w/v) to about 5% (w/v) and/or about 4% (w/v)),
glycolic acid at a concentration of about 0.1 to about 300 mM
(e.g., about 50 to about 70 mM), PCA at a concentration of about
0.1% (w/v) to about 15% (w/v) (e.g., about 0.05% (w/v) to about 2%
(w/v)), medronic acid at a concentration of about 0.1 to about 450
mM (e.g., about 100 to about 150 mM), benzene sulfonic acid at a
concentration of about 0.1 to about 300 mM (e.g., about 60 to about
90 mM), methane sulfonic acid (MSA) at a concentration of about 0.1
to about 150 mM (e.g., about 0.1 to about 50 mM and/or about 10 to
about 30 mM), monoethanolamine hydrochloride (MEA-HCl) at a
concentration of about 0.1 to about 150 mM (e.g., about 0.1 to
about 40 mM), monoethanolamine (MEA) at a concentration of about
0.1 to about 300 mM (e.g., about 0.1 to about 50 mM and/or about 30
to about 160 mM), triethanolamine (TEA) at a concentration of about
0.1 to about 170 mM (e.g., about 30 to about 150 mM), hyaluronic
acid at a concentration of about 0.05% (w/v) to about 2.5% (w/v)
(e.g., about 0.1% (w/v) to about 0.05% (w/v)), sodium
carboxymethylcellulose (NaCMC) at a concentration of about 0.1%
(w/v) to about 15% (w/v) (e.g., about 0.1% (w/v) to about 2%
(w/v)), dextran at a concentration of about 0.1% (w/v) to about 15%
(w/v) (e.g., about 8% (w/v) to about 12% (w/v)), Pluronic F68 at a
concentration of about 0.001% (w/v) to about 10% (w/v) (e.g., about
0.005% (w/v) to about 1% (w/v), about 0.05% (w/v) to about 0.4%
(w/v), about 0.05% (w/v) to about 0.1% (w/v), about 0.01% (w/v),
about 0.05% (w/v), and/or about 0.1% (w/v)), Polysorbate 80 at a
concentration of about 0.001% (w/v) to about 2% (w/v) (e.g., about
0.005% (w/v) to about 0.1% (w/v), about 0.03% (w/v) to about 0.1%
(w/v), about 0.04% (w/v) to about 0.1% (w/v), about 0.03% (w/v),
about 0.04% (w/v), and/or about 0.1% (w/v)), Polysorbate 20 at a
concentration of about 0.001% (w/v) to about 2% (w/v) (e.g., about
0.005% (w/v) to about 0.1% (w/v)), Docusate sodium at a
concentration of about 0.001% (w/v) to about 1% (w/v) (e.g., about
0.005% (w/v) to about 0.05% (w/v)), benzalkonium chloride at a
concentration of about 0.001% (w/v) to about 1% (w/v) (e.g., about
0.05% (w/v) to about 0.5% (w/v)), Span 40 (sorbitan monopalmitate)
at a concentration of about 0.001% (w/v) to about 1% (w/v) (e.g.,
about 0.05% (w/v) to about 0.5% (w/v)), Triton X-100 at a
concentration of about 0.001% (w/v) to about 1% (w/v) (e.g., about
0.005% (w/v) to about 0.1% (w/v)), imidazole at a concentration of
about 0.1% (w/v) to about 15% (w/v) (e.g., about 0.5% (w/v) to
about 2% (w/v)), taurine at a concentration of about 0.1 to about
450 mM (e.g., about 100 to about 150 mM), betaine at a
concentration of about 0.1 to about 450 mM (e.g., about 100 to
about 150 mM), gelatin at a concentration of about 0.1% (w/v) to
about 15% (w/v) (e.g., about 0.5% (w/v) to about 2% (w/v)),
niacinamide at a concentration of about 0.1 to about 450 mM (e.g.,
about 100 to about 120 mM), polyvinylpyrrolidone (PVP), for
example, 10K PVP, at a concentration of about 0.001% (w/v) to about
10% (w/v) (e.g., about 0.05% (w/v) to about 2% (w/v)), guanidine
hydrochloride (GnHCl) at a concentration of about 0.1 to about 150
mM (e.g., about 10 to about 30 mM), and ethanol at a concentration
of about 0.05% (w/v) to about 2.5% (w/v) (e.g., about 0.25% (w/v)
to about 1% (w/v)). Optionally, the calcium chloride-containing
stable aqueous adalimumab formulation has a pH of about 4.8 to
about 5.7, for example, about 4.9 to about 5.6, about 5.0 to about
5.5, about 5.1 to about 5.4, about 5.1 to about 5.3, about 5.1 to
about 5.2, about 5.2 to about 5.3, and/or about 5.2. Optionally,
the pH of the stable aqueous adalimumab formulation is adjusted
using a strong acid and/or a strong base including, but not limited
to, hydrochloric acid, sodium hydroxide, calcium hydroxide, MSA,
and/or MEA.
[0111] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 3350 at a concentration of about 5% (w/v) to about 10% (w/v),
calcium chloride at a concentration of about 30 to about 60 mM, and
has a pH of about 5.0 to about 5.5.
[0112] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 140
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
dextran at a concentration of about 5% (w/v) to about 15% (w/v),
calcium chloride at a concentration of about 30 to about 60 mM, and
has a pH of about 5.0 to about 5.5.
[0113] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 200 at a concentration of about 0.5% (w/v) to about 2% (w/v),
calcium chloride at a concentration of about 30 to about 60 mM, and
has a pH of about 5.0 to about 5.5.
[0114] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 600 at a concentration of about 1.5% (w/v) to about 4% (w/v),
calcium chloride at a concentration of about 30 to about 60 mM, and
has a pH of about 5.0 to about 5.5.
[0115] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
calcium chloride at a concentration of about 50 mM to about 100 mM,
proline at a concentration of about 50 mM to about 150 mM, and has
a pH of about 5.0 to about 5.5.
[0116] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
ethanol at a concentration of about 0.3% (w/v) to about 0.8% (w/v),
calcium chloride at a concentration of about 30 mM to about 60 mM,
and has a pH of about 5.0 to about 5.5.
[0117] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
ethanol at a concentration of about 0.3% (w/v) to about 0.8% (w/v),
PEG 3350 at a concentration of about 0.7% (w/v) to about 1.5%
(w/v), calcium chloride at a concentration of about 30 mM to about
60 mM, and has a pH of about 5.0 to about 5.5.
[0118] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
TEA at a concentration of about 100 mM to about 200 mM, calcium
chloride at a concentration of about 30 mM to about 60 mM, and has
a pH of about 5.0 to about 5.5.
[0119] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
TEA at a concentration of about 20 mM to about 40 mM, calcium
chloride at a concentration of about 60 mM to about 90 mM, and has
a pH of about 5.0 to about 5.5.
[0120] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
alanine at a concentration of about 80 mM to about 120 mM, calcium
chloride at a concentration of about 30 mM to about 60 mM, and has
a pH of about 5.0 to about 5.5.
[0121] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
asparagine at a concentration of about 80 mM to about 120 mM,
calcium chloride at a concentration of about 30 mM to about 60 mM,
and has a pH of about 5.0 to about 5.5.
[0122] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
isoleucine at a concentration of about 80 mM to about 120 mM,
calcium chloride at a concentration of about 30 mM to about 60 mM,
and has a pH of about 5.0 to about 5.5.
[0123] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
serine at a concentration of about 80 mM to about 120 mM, calcium
chloride at a concentration of about 30 mM to about 60 mM, and has
a pH of about 5.0 to about 5.5.
[0124] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
aspartic acid at a concentration of about 10 mM to about 30 mM,
proline at a concentration of about 60 mM to about 100 mM, calcium
chloride at a concentration of about 30 mM to about 60 mM, and has
a pH of about 5.0 to about 5.5.
[0125] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
creatine at a concentration of about 15 mM to about 35 mM, proline
at a concentration of about 60 mM to about 90 mM, calcium chloride
at a concentration of about 30 mM to about 60 mM, and has a pH of
about 5.0 to about 5.5.
[0126] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
glutamine at a concentration of about 40 mM to about 60 mM, proline
at a concentration of about 40 mM to about 60 mM, calcium chloride
at a concentration of about 30 mM to about 60 mM, and has a pH of
about 5.0 to about 5.5.
[0127] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
leucine at a concentration of about 40 mM to about 60 mM, proline
at a concentration of about 40 mM to about 60 mM, calcium chloride
at a concentration of about 30 mM to about 60 mM, and has a pH of
about 5.0 to about 5.5.
[0128] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
phenylalanine at a concentration of about 40 mM to about 60 mM,
proline at a concentration of about 40 mM to about 60 mM, calcium
chloride at a concentration of about 30 mM to about 60 mM, and has
a pH of about 5.0 to about 5.5.
[0129] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 80 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
tryptophan at a concentration of about 10 mM to about 40 mM,
proline at a concentration of about 60 mM to about 90 mM, calcium
chloride at a concentration of about 30 mM to about 60 mM, and has
a pH of about 5.0 to about 5.5.
[0130] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0131] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
proline at a concentration of about 80 to about 120 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0132] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 15 hydroxystearate at a concentration of about 3% (w/v) to
about 8% (w/v), calcium chloride at a concentration of about 30 to
about 60 mM, and optionally Pluronic F68 at a concentration of
about 0.05% (w/v) to about 0.4% (w/v) or Polysorbate 80 at a
concentration of about 0.005% (w/v) to about 0.1% (w/v), and has a
pH of about 5.0 to about 5.5.
[0133] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 15 hydroxystearate at a concentration of about 3% (w/v) to
about 8% (w/v), calcium chloride at a concentration of about 30 to
about 60 mM, proline at a concentration of about 80 to about 120
mM, and optionally Pluronic F68 at a concentration of about 0.05%
(w/v) to about 0.4% (w/v) or Polysorbate 80 at a concentration of
about 0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0
to about 5.5.
[0134] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
imidazole at a concentration of about 0.7% (w/v) to about 1.5%
(w/v), calcium chloride at a concentration of about 30 to about 60
mM, and optionally Pluronic F68 at a concentration of about 0.05%
(w/v) to about 0.4% (w/v) or Polysorbate 80 at a concentration of
about 0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0
to about 5.5.
[0135] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
N-acetyl arginine at a concentration of about 100 to about 150 mM,
calcium chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0136] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
inositol at a concentration of about 200 to about 300 mM, calcium
chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0137] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 3350 at a concentration of about 0.7% (w/v) to about 1.5%
(w/v), calcium chloride at a concentration of about 30 to about 60
mM, and optionally Pluronic F68 at a concentration of about 0.05%
(w/v) to about 0.4% (w/v) or Polysorbate 80 at a concentration of
about 0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0
to about 5.5.
[0138] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
taurine at a concentration of about 100 to about 150 mM, calcium
chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0139] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
citruline at a concentration of about 100 to about 150 mM, calcium
chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0140] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
betaine at a concentration of about 100 to about 150 mM, calcium
chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0141] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
sarcosine at a concentration of about 100 to about 150 mM, calcium
chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0142] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
glycolic acid at a concentration of about 40 to about 80 mM,
calcium chloride at a concentration of about 60 to about 90 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0143] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PCA at a concentration of about 0.7% (w/v) to about 1.5% (w/v),
calcium chloride at a concentration of about 60 to about 90 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0144] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
gelatin at a concentration of about 0.7% (w/v) to about 1.5% (w/v),
calcium chloride at a concentration of about 60 to about 90 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0145] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
hyaluronic acid at a concentration of about 0.1% (w/v) to about
0.5% (w/v), calcium chloride at a concentration of about 60 to
about 90 mM, and optionally Pluronic F68 at a concentration of
about 0.05% (w/v) to about 0.4% (w/v) or Polysorbate 80 at a
concentration of about 0.005% (w/v) to about 0.1% (w/v), and has a
pH of about 5.0 to about 5.5.
[0146] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
N-acetyl proline at a concentration of about 100 to about 150 mM,
calcium chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0147] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
N-acetyl ornithine at a concentration of about 100 to about 150 mM,
calcium chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0148] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
ornithine at a concentration of about 100 to about 150 mM, calcium
chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0149] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
beta-alanine at a concentration of about 100 to about 150 mM,
calcium chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0150] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
niacinamide at a concentration of about 100 to about 150 mM,
calcium chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0151] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
medronic acid at a concentration of about 100 to about 150 mM,
calcium chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0152] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 200 at a concentration of about 0.7% (w/v) to about 1.5% (w/v),
calcium chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0153] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 600 at a concentration of about 1.5% (w/v) to about 4% (w/v),
and calcium chloride at a concentration of about 30 to about 60 mM,
and has a pH of about 5.0 to about 5.5.
[0154] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
niacinamide at a concentration of about 80 to about 120 mM, calcium
chloride at a concentration of about 60 to about 100 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0155] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
benzene sulfonic acid at a concentration of about 60 to about 90
mM, calcium chloride at a concentration of about 25 to about 75 mM,
and optionally Pluronic F68 at a concentration of about 0.05% (w/v)
to about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0156] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 400 at a concentration of about 0.25% (w/v) to about 0.75%
(w/v), calcium chloride at a concentration of about 40 to about 80
mM, glycerin at a concentration of about 0.5% (w/v) to about 1%
(w/v), and optionally Pluronic F68 at a concentration of about
0.05% (w/v) to about 0.4% (w/v) or Polysorbate 80 at a
concentration of about 0.005% (w/v) to about 0.1% (w/v), and has a
pH of about 5.0 to about 5.5.
[0157] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, adipate at a concentration of about 10 mM to about 25 mM,
N-acetyl arginine at a concentration of about 100 to about 150 mM,
calcium chloride at a concentration of about 30 to about 50 mM, and
MSA at a concentration of about 10 to about 30 mM, and has a pH of
about 5.0 to about 5.5.
[0158] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, adipate at a concentration of about 10 mM to about 25 mM,
calcium chloride at a concentration of about 60 to about 90 mM, PEG
400 at a concentration of about 0.1% (w/v) to about 0.5% (w/v), and
10K PVP at a concentration of about 0.5% (w/v) to about 2% (w/v),
and has a pH of about 5.0 to about 5.5.
[0159] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, adipate at a concentration of about 10 mM to about 25 mM,
PEG 400 at a concentration of about 0.5% (w/v) to about 2% (w/v),
and calcium chloride at a concentration of about 30 to about 50 mM,
and has a pH of about 5.0 to about 5.5.
[0160] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, adipate at a concentration of about 10 mM to about 25 mM,
PEG 3350 at a concentration of about 0.5% (w/v) to about 2% (w/v),
and calcium chloride at a concentration of about 60 to about 90 mM,
and has a pH of about 5.0 to about 5.5.
[0161] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, adipate at a concentration of about 10 mM to about 25 mM,
PEG 3350 at a concentration of about 0.5% (w/v) to about 2% (w/v),
PEG 400 at a concentration of about 1% (w/v) to about 3% (w/v), and
calcium chloride at a concentration of about 10 to about 30 mM, and
has a pH of about 5.0 to about 5.5.
[0162] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, adipate at a concentration of about 10 mM to about 25 mM,
PEG 3350 at a concentration of about 0.5% (w/v) to about 2% (w/v),
PEG 400 at a concentration of about 0.5% (w/v) to about 2% (w/v),
and calcium chloride at a concentration of about 30 to about 50 mM,
and has a pH of about 5.0 to about 5.5.
[0163] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Polysorbate 20 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3.
[0164] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Polysorbate 80 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3.
[0165] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3.
[0166] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Docusate sodium at a concentration of about 0.005% (w/v) to about
0.05% (w/v), and has a pH of about 5.1 to 5.3.
[0167] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
benzalkonium chloride at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3.
[0168] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Span 40 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3.
[0169] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Triton X-100 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3.
[0170] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM, and
arginine-HCl at a concentration of about 80 to about 120 mM, and
has a pH of about 5.1 to 5.3.
[0171] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Polysorbate 80 at a concentration of about 0.0025% (w/v) to about
0.025% (w/v), and has a pH of about 5.1 to 5.3.
[0172] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Polysorbate 80 at a concentration of about 0.005% (w/v) to about
0.05% (w/v), and has a pH of about 5.1 to 5.3.
[0173] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Polysorbate 80 at a concentration of about 0.025% (w/v) to about
0.25% (w/v), and has a pH of about 5.1 to 5.3.
[0174] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Polysorbate 20 at a concentration of about 0.0025% (w/v) to about
0.025% (w/v), and has a pH of about 5.1 to 5.3.
[0175] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Polysorbate 20 at a concentration of about 0.005% (w/v) to about
0.05% (w/v), and has a pH of about 5.1 to 5.3.
[0176] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Polysorbate 20 at a concentration of about 0.025% (w/v) to about
0.25% (w/v), and has a pH of about 5.1 to 5.3.
[0177] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Triton X-100 at a concentration of about 0.0025% (w/v) to about
0.025% (w/v), and has a pH of about 5.1 to 5.3.
[0178] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Triton X-100 at a concentration of about 0.005% (w/v) to about
0.05% (w/v), and has a pH of about 5.1 to 5.3.
[0179] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Triton X-100 at a concentration of about 0.025% (w/v) to about
0.25% (w/v), and has a pH of about 5.1 to 5.3.
[0180] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Pluronic F68 at a concentration of about 0.025% (w/v) to about
0.25% (w/v), and has a pH of about 5.1 to 5.3.
[0181] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3.
[0182] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Pluronic F68 at a concentration of about 0.2% (w/v) to about 0.6%
(w/v), and has a pH of about 5.1 to 5.3.
[0183] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 50
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.5% (w/v) to about 7.1% (w/v),
calcium chloride at a concentration of about 15 to about 35 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3.
[0184] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 50
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.0% (w/v) to about 6.5% (w/v),
calcium chloride at a concentration of about 15 to about 35 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3.
[0185] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 50
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.7% (w/v) to about 7.3% (w/v),
calcium chloride at a concentration of about 5 to about 15 mM,
guanidine hydrochloride (GnHCl) at a concentration of about 10 to
about 30 mM, and Pluronic F68 at a concentration of about 0.05%
(w/v) to about 0.5% (w/v), and has a pH of about 5.1 to 5.3.
[0186] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 50
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.7% (w/v) to about 7.3% (w/v),
calcium chloride at a concentration of about 5 to about 15 mM,
NaCMC at a concentration of about 0.2% (w/v) to about 1% (w/v), and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3.
[0187] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.4% (w/v) to about 7.2% (w/v),
calcium chloride at a concentration of about 15 to about 35 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with HCl, NaOH, and/or
Ca(OH).sub.2.
[0188] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
proline at a concentration of about 190 to about 250 mM, calcium
chloride at a concentration of about 15 to about 35 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with HCl, NaOH, and/or
Ca(OH).sub.2.
[0189] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.4% (w/v) to about 7.2% (w/v),
calcium chloride at a concentration of about 15 to about 35 mM, and
Polysorbate 80 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
and/or Ca(OH).sub.2.
[0190] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 110
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.6% (w/v) to about 7% (w/v),
calcium chloride at a concentration of about 20 to about 30 mM, and
Polysorbate 80 at a concentration of about 0.05% (w/v) to about
0.2% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
and/or Ca(OH).sub.2.
[0191] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
proline at a concentration of about 190 to about 250 mM, calcium
chloride at a concentration of about 15 to about 35 mM, and
Polysorbate 80 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
and/or Ca(OH).sub.2.
[0192] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.4% (w/v) to about 7.2% (w/v),
calcium chloride at a concentration of about 15 to about 35 mM, and
Polysorbate 80 at a concentration of about 0.01% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
and/or Ca(OH).sub.2.
[0193] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
proline at a concentration of about 190 to about 250 mM, calcium
chloride at a concentration of about 15 to about 35 mM, and
Polysorbate 80 at a concentration of about 0.01% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
and/or Ca(OH).sub.2.
[0194] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
proline at a concentration of about 190 to about 240 mM, calcium
chloride at a concentration of about 15 to about 35 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MSA and/or MEA.
[0195] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
proline at a concentration of about 200 to about 250 mM, calcium
chloride at a concentration of about 10 to about 30 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MSA and/or MEA.
[0196] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, lactate at a concentration of about 5 mM to about 15 mM, PEG
600 at a concentration of about 11% (w/v) to about 15% (w/v),
calcium chloride at a concentration of about 20 to about 40 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MSA and/or MEA.
[0197] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, lactate at a concentration of about 5 mM to about 15 mM, PEG
600 at a concentration of about 11% (w/v) to about 15% (w/v),
calcium chloride at a concentration of about 10 to about 30 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MSA and/or MEA.
[0198] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, lactate at a concentration of about 5 mM to about 15 mM, PEG
600 at a concentration of about 8% (w/v) to about 9% (w/v), calcium
chloride at a concentration of about 10 to about 30 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MSA and/or MEA.
[0199] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, lactate at a concentration of about 5 mM to about 15 mM, PEG
600 at a concentration of about 3% (w/v) to about 5% (w/v), PEG 200
at a concentration of about 1.2% (w/v) to about 2% (w/v), calcium
chloride at a concentration of about 10 to about 30 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MSA and/or MEA.
[0200] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, lactate at a concentration of about 5 mM to about 15 mM, PEG
200 at a concentration of about 3.5% (w/v) to about 4.2% (w/v),
calcium chloride at a concentration of about 10 to about 30 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MSA and/or MEA.
[0201] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, lactate at a concentration of about 5 mM to about 15 mM, PEG
600 at a concentration of about 5% (w/v) to about 5.7% (w/v),
calcium chloride at a concentration of about 10 to about 30 mM,
proline at a concentration of about 90 to about 130 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MSA and/or MEA.
[0202] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
calcium chloride at a concentration of about 10 to about 30 mM,
proline at a concentration of about 190 to about 250 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MSA and/or MEA.
[0203] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
calcium chloride at a concentration of about 15 to about 35 mM,
proline at a concentration of about 190 to about 250 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with HCl, NaOH, and/or
Ca(OH).sub.2.
[0204] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, histidine at a concentration of about 5 mM to about 15 mM,
proline at a concentration of about 270 to about 370 mM, and
calcium chloride at a concentration of about 10 to about 30 mM, and
has a pH of about 6.7 to 6.9. Optionally, the pH of the formulation
is adjusted within this range with MEA and/or MSA.
[0205] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 600 at a concentration of about 8% (w/v) to about 10%
(w/v), calcium chloride at a concentration of about 10 to about 30
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0206] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 600 at a concentration of about 6.5% (w/v) to about 7.3%
(w/v), PEG 200 at a concentration of about 0.3% (w/v) to about 1%
(w/v), calcium chloride at a concentration of about 10 to about 30
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0207] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 600 at a concentration of about 4% (w/v) to about 5%
(w/v), PEG 200 at a concentration of about 1.5% (w/v) to about 2.1%
(w/v), calcium chloride at a concentration of about 10 to about 30
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0208] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 600 at a concentration of about 0.9% (w/v) to about 1.5%
(w/v), PEG 200 at a concentration of about 2.5% (w/v) to about 3.5%
(w/v), calcium chloride at a concentration of about 10 to about 30
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0209] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 200 at a concentration of about 3% (w/v) to about 5%
(w/v), calcium chloride at a concentration of about 10 to about 30
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0210] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 600 at a concentration of about 6.9% (w/v) to about 7.7%
(w/v), proline at a concentration of about 40 to about 80 mM,
calcium chloride at a concentration of about 10 to about 30 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MEA and/or MSA.
[0211] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 600 at a concentration of about 5% (w/v) to about 6%
(w/v), proline at a concentration of about 90 to about 150 mM,
calcium chloride at a concentration of about 10 to about 30 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MEA and/or MSA.
[0212] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 600 at a concentration of about 2% (w/v) to about 3%
(w/v), proline at a concentration of about 150 to about 210 mM,
calcium chloride at a concentration of about 10 to about 30 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MEA and/or MSA.
[0213] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, proline at a concentration of about 200 to about 300 mM,
calcium chloride at a concentration of about 10 to about 30 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MEA and/or MSA.
[0214] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, sorbitol at a concentration of about 3% (w/v) to about 5%
(w/v), calcium chloride at a concentration of about 15 to about 35
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with HCl and/or
NaOH.
[0215] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, sucrose at a concentration of about 5% (w/v) to about 8%
(w/v), calcium chloride at a concentration of about 15 to about 35
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0216] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, proline at a concentration of about 200 to about 250 mM,
calcium chloride at a concentration of about 15 to about 35 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MEA and/or MSA.
[0217] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 600 at a concentration of about 11% (w/v) to about 15%
(w/v), calcium chloride at a concentration of about 20 to about 40
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0218] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, sucrose at a concentration of about 5% (w/v) to about 8%
(w/v), calcium chloride at a concentration of about 15 to about 35
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0219] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, sucrose at a concentration of about 6.9% (w/v) to about 7.7%
(w/v), calcium chloride at a concentration of about 10 to about 30
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0220] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 200 at a concentration of about 4.5% (w/v) to about 5.1%
(w/v), calcium chloride at a concentration of about 10 to about 30
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0221] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, sorbitol at a concentration of about 3% (w/v) to about 5%
(w/v), calcium chloride at a concentration of about 15 to about 35
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with HCl.
[0222] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 600 at a concentration of about 13% (w/v) to about 16%
(w/v), calcium chloride at a concentration of about 10 to about 30
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0223] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 600 at a concentration of about 3% (w/v) to about 3.6%
(w/v), calcium chloride at a concentration of about 10 to about 30
mM, proline at a concentration of about 150 to about 210 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MEA and/or MSA.
[0224] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL, PEG 600 at a concentration of about 8% (w/v) to about 9%
(w/v), and calcium chloride at a concentration of about 15 to about
35 mM, and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MEA and/or MSA.
[0225] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL, PEG 600 at a concentration of about 6% (w/v) to about 7%
(w/v), and calcium chloride at a concentration of about 40 to about
60 mM, and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MEA and/or MSA.
[0226] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL, PEG 600 at a concentration of about 3.4% (w/v) to about 4%
(w/v), and calcium chloride at a concentration of about 65 to about
85 mM, and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MEA and/or MSA.
[0227] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL and calcium chloride at a concentration of about 80 to about
120 mM, and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MEA and/or MSA.
[0228] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL, proline at a concentration of about 200 to about 250 mM, and
calcium chloride at a concentration of about 15 to about 35 mM, and
has a pH of about 5.1 to 5.3. Optionally, the pH of the formulation
is adjusted within this range with MEA and/or MSA.
[0229] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL, proline at a concentration of about 120 to about 180 mM, and
calcium chloride at a concentration of about 40 to about 60 mM, and
has a pH of about 5.1 to 5.3. Optionally, the pH of the formulation
is adjusted within this range with MEA and/or MSA.
[0230] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL, proline at a concentration of about 60 to about 90 mM, and
calcium chloride at a concentration of about 65 to about 85 mM, and
has a pH of about 5.1 to 5.3. Optionally, the pH of the formulation
is adjusted within this range with MEA and/or MSA.
[0231] In an embodiment, a lyophilized form of any one of the
foregoing calcium chloride-containing adalimumab formulations is
provided.
[0232] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 mg/ml to about
200 mg/ml, or about 160 mg/ml to about 190 mg/mL, or about 80 mg/ml
to about 120 mg/ml, or about 90 mg/ml to about 110 mg/ml, or about
95 mg/ml to about 105 mg/ml, or about 40 mg/ml, or about 45 mg/ml,
or about 50 mg/ml, or about 55 mg/ml, or about 60 mg/ml, or about
65 mg/ml, or about 70 mg/ml, or about 75 mg/ml, or about 80 mg/ml,
or about 85 mg/ml, or about 90 mg/ml, or about 95 mg/ml, or about
100 mg/ml, or about 105 mg/ml, or about 110 mg/ml, or about 115
mg/ml, or about 120 mg/ml, or about 125 mg/ml, or about 130 mg/ml,
or about 135 mg/ml, or about 140 mg/ml, or about 145 mg/ml, or
about 150 mg/ml, or about 155 mg/ml, or about 160 mg/ml, or about
165 mg/ml, or about 170 mg/ml, or about 175 mg/ml, or about 180
mg/ml, or about 185 mg/ml, or about 190 mg/mL, with the following
excipients:
(a) lactate buffer at a concentration of about 5 mM to about 15 mM,
or about 7 mM to about 12 mM, or about 9 mM to about 11 mM, or
about 5 mM, or about 6 mM, or about 7 mM, or about 8 mM, or about 8
mM, or about 9 mM, or about 10 mM, or about 11 mM, or about 12 mM,
or about 13 mM, or about 14 mM, or about 15 mM; (b) calcium
chloride at a concentration of about 5 to about 30 mM, about 10 to
about 20 mM, or about 12.5 mM to about 17.5 mM, or about 14 mM to
about 16 mM, or about 10 mM, or about 10.5 mM, or about 11 mM, or
about 11.5 mM, or about 12 mM, or about 12.5 mM, or about 13 mM, or
about 13.5 mM, or about 14 mM, or about 14.5 mM, or about 15 mM, or
about 15.5 mM, or about 16 mM, or about 16.5 mM, or about 17 mM, or
about 17.5 mM, or about 18 mM, or about 18.5 mM, or about 19 mM, or
about 19.5 mM, or about 20 mM; (c) sucrose at a concentration of
about 4% (w/v) to about 10% (w/v), or about 6% (w/v) to about 8.5%
(w/v), or about 4% (w/v), or about 4.5% (w/v), or about 5% (w/v),
or about 5.5% (w/v), or about 6% (w/v), or about 6.5% (w/v), or
about 7% (w/v), or about 7.1% (w/v), or about 7.2% (w/v), or about
7.3% (w/v), or about 7.4% (w/v), or about 7.5% (w/v), or about 7.6%
(w/v), or about 7.7% (w/v), or about 7.8% (w/v), or about 8% (w/v),
or about 8.5% (w/v); (d) Pluronic F68 at a concentration of about
0.03% (w/v) to about 0.09% (w/v), or about 0.03% (w/v) to about
0.06% (w/v), about 0.01% (w/v) to about 0.2% (w/v), about 0.01%
(w/v) to about 0.1% (w/v), about 0.03% (w/v) to about 0.1% (w/v),
or about 0.05% (w/v) to about 0.07% (w/v), or about 0.03% (w/v), or
about 0.04% (w/v), or about 0.05% (w/v), or about 0.06% (w/v), or
about 0.07% (w/v), or about 0.08% (w/v), about 0.09% (w/v), or
about 0.1% (w/v); and (e) has a pH of about 3.5 to about 8, or
about 4 to about 7, or about 4.5 to about 6, or about 5 to about
5.5, or about 3.5, or about 4, or about 4.5, or about 4.6, or about
4.7, or about 4.8, or about 4.9, or about 5.0, or about 5.1, or
about 5.2, or about 5.3, or about 5.4, or about 5.5, or about 5.6,
or about 5.7, or about 5.8, or about 5.9, or about 6.0, or about
6.5, or about 7.0, or about 7.5, or about 8.0.
[0233] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration or about 40 mg/ml to 200
mg/ml, lactate buffer at a concentration of about 5 mM to about 15
mM, sucrose at a concentration of about 4% (w/v) to about 10%
(w/v), calcium chloride at a concentration of about 5 to about 30
mM, and Pluronic F68 at a concentration of about 0.03% (w/v) to
about 0.1% (w/v), and has a pH of about 3.5 to 8.
[0234] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration or about 40 mg/ml to 200
mg/ml, lactate buffer at a concentration of about 1 mM to about 15
mM, sucrose at a concentration of about 4% (w/v) to about 10%
(w/v), calcium chloride at a concentration of about 10 to about 20
mM, and Pluronic F68 at a concentration of about 0.03% (w/v) to
about 0.1% (w/v), and has a pH of about 3.5 to 8.
[0235] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 80 mg/ml to about
120 mg/mL, lactate buffer at a concentration of about 7 mM to about
12 mM, sucrose at a concentration of about 4% (w/v) to about 10%
(w/v), calcium chloride at a concentration of about 12.5 to about
17.5 mM, and Pluronic F68 at a concentration of about 0.03% (w/v)
to about 0.07% (w/v), and a pH of about 4 to about 7.
[0236] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 mg/ml to about
110 mg/mL, lactate buffer at a concentration of about 9 mM to about
11 mM, sucrose at a concentration of about 6% (w/v) to about 8.5%
(w/v), calcium chloride at a concentration of about 14 to about 16
mM, and Pluronic F68 at a concentration of about 0.03% (w/v) to
about 0.07% (w/v), and a pH of about 5.0 to about 5.5.
[0237] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 100 mg/mL, lactate
buffer at a concentration of about 10 mM, sucrose at a
concentration of about 7.4% (w/v), calcium chloride at a
concentration of about 15 mM, and Pluronic F68 at a concentration
of about 0.06% (w/v), and a pH of about 5.2.
[0238] In an embodiment, the stable aqueous adalimumab formulation
is one of the lactate buffer formulations described in Tables G, H,
I, 1, 11, 12, 13, 15, 16 or 17 provided herein.
[0239] In an embodiment, the stable aqueous adalimumab formulations
described above, which include lactate buffer, calcium chloride,
and Pluronic F68, are in lyophilized form. In an embodiment, the
stable aqueous adalimumab formulations described above, which
include lactate, calcium chloride, and Pluronic F68, are not in
lyophilized form (e.g., are hydrated).
[0240] In an embodiment, the pH of the stable aqueous adalimumab
formulations described above, which include lactate buffer, calcium
chloride, and Pluronic F68, can be adjusted using HCl/Ca(OH).sub.2.
In an embodiment, the pH of the stable aqueous adalimumab
formulations described above, which include lactate buffer, calcium
chloride, and Pluronic F68, is not adjusted using a pH adjusting
agent.
[0241] The stable aqueous adalimumab formulations described above,
which include lactate buffer, calcium chloride, and Pluronic F68,
exhibit a conductivity of less than about 4 mS/cm, or less than
about 3.5 mS/cm, or less than about 3 mS/cm, or less than about 2.5
mS/cm, or less than about 2 mS/cm, or less than about 1.5 mS/cm, or
less than about 1 mS/cm, or less than about 0.5 mS/cm, or about 0.5
mS/cm to about 3.5 mS/cm at ambient room temperature.
[0242] The stable aqueous adalimumab formulations described above,
which include lactate buffer, calcium chloride, and Pluronic F68,
exhibit an osmolality of 270-330 mOsM, or about 300 mOsM.
[0243] Aqueous adalimumab formulations having the specific
combination of about 5 to about 30 mM (e.g., 12.5 mM to about 17.5
mM, or about 15 mM) calcium chloride, about 5 mM to about 15 mM
(e.g., about 7 mM to about 12 mM, or about 9 mM to about 11 mM, or
about 10 mM) lactate buffer, and Pluronic F68 surfactant (e.g.,
about 0.03% (w/v) to about 0.1% (w/v); about 0.03% (w/v) or about
0.06% (w/v)), advantageously exhibit a lowered growth rate of
acidic species, as detected by CEX-HPLC), a lowered growth rate of
HMWS, as detected by SE-HPLC, and a minimal amount of sub-visible
and/or non-spherical particles, as detected by MFI. See, e.g.,
Examples 15-17 below.
Formulations of Adalimumab with Glutamate Buffer
[0244] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 200
mg/mL, such as about 90 to about 120 mg/mL, about 160 to about 190
mg/mL, about 40 to about 60 mg/mL, about 50 mg/mL, about 100 mg/mL,
or about 170 mg/mL, glutamate at a concentration of about 5 mM to
about 50 mM (e.g., about 5 mM to about 30 mM, about 10 mM to about
25 mM, about 15 mM to about 20 mM, about 10 mM, about 15 mM, about
20 mM, and/or about 25 mM), and one or more excipients. Suitable
excipients include certain stabilizers such as certain amino acids
and amino acid derivatives, certain polyethylene glycols and
polyethylene glycol derivatives, certain polyols, certain acids,
certain amines, certain polysaccharides or polysaccharide
derivatives, certain salts, and certain surfactants. Examples of
suitable amino acids and amino acid derivatives include proline
(e.g., at a concentration of about 0.1 to about 450 mM or about 50
to about 300 mM), arginine (e.g., at a concentration of about 0.1
to about 450 mM or about 60 to about 90 mM), N-acetyl arginine
(e.g., at a concentration of about 0.1 to about 450 mM or about 90
to about 150 mM), citruline (e.g., at a concentration of about 0.1
to about 450 mM or about 100 to about 150 mM), sarcosine (e.g., at
a concentration of about 0.1 to about 450 mM or about 100 to about
150 mM), N-acetyl proline (e.g., at a concentration of about 0.1 to
about 450 mM or about 100 to about 150 mM), N-acetyl ornithine
(e.g., at a concentration of about 0.1 to about 450 mM or about 100
to about 150 mM), ornithine (e.g., at a concentration of about 0.1
to about 450 mM or about 100 to about 150 mM), beta-alanine (e.g.,
at a concentration of about 0.1 to about 450 mM or about 100 to
about 150 mM), alanine (e.g., at a concentration of about 0.1 to
about 450 mM or about 80 to about 120 mM), asparagine (e.g., at a
concentration of about 0.1 to about 450 mM or about 80 to about 120
mM), isoleucine (e.g., at a concentration of about 0.1 to about 450
mM or about 80 to about 120 mM), serine (e.g., at a concentration
of about 0.1 to about 450 mM or about 80 to about 120 mM), aspartic
acid (e.g., at a concentration of about 0.1 to about 450 mM or
about 10 to about 30 mM), creatine (e.g., at a concentration of
about 0.1 to about 450 mM or about 15 to about 35 mM), glutamine
(e.g., at a concentration of about 0.1 to about 450 mM or about 40
to about 60 mM), leucine (e.g., at a concentration of about 0.1 to
about 450 mM or about 40 to about 60 mM), phenylalanine (e.g., at a
concentration of about 0.1 to about 450 mM or about 40 to about 60
mM), and tryptophan (e.g., at a concentration of about 0.1 to about
450 mM or about 15 to about 35 mM). Examples of suitable
polyethylene glycols and polyethylene glycol derivatives include
PEG 15 hydroxystearate (e.g., at a concentration of about 0.1%
(w/v) to about 20% (w/v) or about 2.5% (w/v) to about 5% (w/v)),
PEG 3350 (e.g., at a concentration of about 0.1% (w/v) to about 30%
(w/v), about 0.5% (w/v) to about 2% (w/v), about 1% (w/v) to about
7% (w/v), about 5% (w/v) to about 10% (w/v), and/or about 6% (w/v)
to about 8% (w/v)), PEG 600 (e.g., at a concentration of about 0.1%
(w/v) to about 30% (w/v), about 1% (w/v) to about 4% (w/v), and/or
about 1% (w/v) to about 2% (w/v)), PEG 400 (e.g., at a
concentration of about 0.1% (w/v) to about 20% (w/v), about 0.5%
(w/v) to about 10% (w/v), about 0.2% (w/v) to about 2% (w/v),
and/or about 6% (w/v) to about 12% (w/v)), and PEG 200 (e.g., at a
concentration of about 0.1% (w/v) to about 10% (w/v), about 1%
(w/v) to about 4% (w/v), and/or about 0.05% (w/v) to about 5%
(w/v)). Examples of suitable polyols include glycerol (also
referred to as glycerin) (e.g., at a concentration of about 0.1%
(w/v) to about 15% (w/v), about 0.7% (w/v) to about 2.5% (w/v),
and/or about 0.5% (w/v) to about 4% (w/v)), inositol (e.g., at a
concentration of about 0.1 to about 450 mM or about 180 to about
250 mM), sucrose (e.g., at a concentration of about 0.1% (w/v) to
about 15% (w/v), about 4% (w/v) to about 10% (w/v), about 4% (w/v)
to about 9% (w/v), about 6.5% (w/v), about 6.8% (w/v), about 6.9%
(w/v), or about 9% (w/v)), and sorbitol (e.g., at a concentration
of about 0.1% (w/v) to about 10% (w/v), about 3% (w/v) to about 5%
(w/v), and/or about 4% (w/v)). Examples of suitable acids include
glycolic acid (e.g., at a concentration of about 0.1 to about 300
mM or about 50 to about 70 mM), PCA (e.g., at a concentration of
about 0.1% (w/v) to about 15% (w/v) or about 0.05% (w/v) to about
2% (w/v)), medronic acid (e.g., at a concentration of about 0.1 to
about 450 mM or about 100 to about 150 mM), methane sulfonic acid
(MSA) (e.g., at a concentration of about 0.1 to about 150 mM, about
0.1 to about 50 mM, and/or about 20 to about 125 mM), benzene
sulfonic acid (e.g., at a concentration of about 0.1 to about 300
mM or about 75 to about 150 mM), and adipic acid (e.g., at a
concentration of about 0.1 to about 300 mM or about 120 to about
180 mM). Examples of suitable amines include triethanolamine (TEA)
(e.g., at a concentration of about 0.1 to about 170 mM or about 30
to about 150 mM), monoethanolamine hydrochloride (MEA-HCl) (e.g.,
at a concentration of about 0.1 to about 150 mM or about 0.1 to
about 40 mM), monoethanolamide (MEA) (e.g., at a concentration of
about 0.1 to about 300 mM, about 0.1 to about 50 mM, about 0.1 to
about 170 mM, and/or about 30 to about 160 mM). Examples of
suitable polysaccharides or polysaccharide derivatives include
dextran (e.g., at a concentration of about 0.1% (w/v) to about 15%
(w/v) or about 2% (w/v) to about 10% (w/v)) and hyaluronic acid
(e.g., at a concentration of about 0.05% (w/v) to about 2.5% (w/v)
or about 0.1% (w/v) to about 0.05% (w/v)). Examples of suitable
salts include calcium chloride (e.g., at a concentration of about 1
to about 150 mM, about 5 to about 50 mM, about 10 to about 30 mM,
about 20 to about 40 mM, about 30 to about 50 mM, about 40 to about
80 mM, about 50 to about 100 mM, or about 25 mM), sodium borate
(e.g., at a concentration of about 0.1 to about 150 mM or about 60
to about 90 mM), sodium bicarbonate (e.g., at a concentration of
about 0.1 to about 150 mM or about 60 to about 90 mM), sodium
sulfate (e.g., at a concentration of about 0.1 to about 150 mM or
about 60 to about 90 mM), calcium sulfate (e.g., at a concentration
of about 0.1 to about 150 mM or about 10 to about 30 mM), ammonium
sulfate (e.g., at a concentration of about 0.1 to about 150 mM or
about 60 to about 90 mM), sodium chloride (e.g., at a concentration
of about 10 to about 100 mM, about 60 to about 90 mM, about 15 to
about 50 mM, and/or about 35 mM), and magnesium chloride (e.g., at
a concentration of about 0.1 to about 150 mM or about 60 to about
90 mM). Examples of suitable surfactants include benzalkonium
chloride (e.g., at a concentration of about 0.001% (w/v) to about
1% (w/v) or about 0.005% (w/v) to about 0.05% (w/v)), guanidine HCl
(e.g., at a concentration of about 0.001% (w/v) to about 1% (w/v)
or about 0.005% (w/v) to about 0.05% (w/v)), lecithin (e.g., at a
concentration of about 0.001% (w/v) to about 1% (w/v) or about
0.005% (w/v) to about 0.05% (w/v)), oleic acid (e.g., at a
concentration of about 0.001% (w/v) to about 1% (w/v) or about
0.005% (w/v) to about 0.05% (w/v)), Pluronic F68 (e.g., at a
concentration of about 0.001% (w/v) to about 10% (w/v), about
0.005% (w/v) to about 1% (w/v), about 0.05% (w/v) to about 0.4%
(w/v), about 0.05% (w/v) to about 0.1% (w/v), about 0.01% (w/v),
about 0.05% (w/v), and/or about 0.1% (w/v)), Polysorbate 20 (e.g.,
at a concentration of about 0.001% (w/v) to about 2% (w/v) or about
0.005% (w/v) to about 0.1% (w/v)), Polysorbate 80 (e.g., at a
concentration of about 0.001% (w/v) to about 2% (w/v), about 0.005%
(w/v) to about 0.1% (w/v), about 0.005% (w/v) to about 0.05% (w/v),
about 0.03% (w/v) to about 0.1% (w/v), about 0.04% (w/v) to about
0.1% (w/v), about 0.03% (w/v), about 0.04% (w/v), and/or about 0.1%
(w/v)), polyvinyl alcohol, for example, 31K or 205 K polyvinyl
alcohol, (e.g., at a concentration of about 0.01% (w/v) to about
10% (w/v) or about 0.05% (w/v) to about 0.5% (w/v)),
polyvinylpyrrolidone (PVP), for example, 10K PVP, (e.g., at a
concentration of about 0.001% (w/v) to about 10% (w/v), about 0.01%
(w/v) to about 1% (w/v), and/or about 0.005% (w/v) to about 2%
(w/v)), and protamine sulfate (e.g., at a concentration of about
0.001% (w/v) to about 2% (w/v) or about 0.005% (w/v) to about 0.05%
(w/v)). Examples of other suitable excipients include imidazole
(e.g., at a concentration of about 0.1% (w/v) to about 15% (w/v) or
about 1% (w/v) to about 2% (w/v)), taurine (e.g., at a
concentration of about 0.1 to about 450 mM or about 100 to about
150 mM), betaine (e.g., at a concentration of about 0.1 to about
450 mM or about 100 to about 150 mM), gelatin (e.g., at a
concentration of about 0.1% (w/v) to about 15% (w/v) or about 0.5%
(w/v) to about 2% (w/v)), niacinamide (e.g., at a concentration of
about 0.1 to about 450 mM, about 100 to about 270 mM, and/or about
100 to about 150 mM), and ethanol (e.g., at a concentration of
about 0.05% (w/v) to about 2.5% (w/v) or about 0.25% (w/v) to about
1.4% (w/v)). Optionally, the glutamate-containing stable aqueous
adalimumab formulation has a pH of about 4.8 to about 5.7, for
example, about 4.9 to about 5.6, about 5.0 to about 5.5, about 5.1
to about 5.4, about 5.1 to about 5.3, about 5.1 to about 5.2, about
5.2 to about 5.3, and/or about 5.2. Optionally, the pH of the
stable aqueous adalimumab formulation is adjusted using a strong
acid and/or a strong base including, but not limited to,
hydrochloric acid, sodium hydroxide, calcium hydroxide, MSA, and/or
MEA.
[0245] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 200
mg/mL, such as about 90 to about 120 mg/mL, about 160 to about 190
mg/mL, about 40 to about 60 mg/mL, about 50 mg/mL, about 100 mg/mL,
or about 170 mg/mL, glutamate at a concentration of about 5 mM to
about 50 mM (e.g., about 5 mM to about 30 mM, about 10 mM to about
25 mM, about 15 mM to about 20 mM, about 10 mM, about 15 mM, about
20 mM, and/or about 25 mM), and one or more excipients selected
from the group consisting of PEG 3350 at a concentration of about
0.1% (w/v) to about 30% (w/v) (e.g., about 0.5% (w/v) to about 2%
(w/v), about 1% (w/v) to about 7% (w/v), about 5% (w/v) to about
10% (w/v), and/or about 6% (w/v) to about 8% (w/v)), PEG 600 at a
concentration of about 0.1% (w/v) to about 30% (w/v) (e.g., about
1% (w/v) to about 4% (w/v) and/or about 1% (w/v) to about 2%
(w/v)), PEG 400 at a concentration of about 0.1% (w/v) to about 20%
(w/v) (e.g., about 0.5% (w/v) to about 10% (w/v), about 0.2% (w/v)
to about 2% (w/v) and/or about 6% (w/v) to about 12% (w/v)), PEG
200 at a concentration of about 0.1% (w/v) to about 10% (w/v)
(e.g., about 1% (w/v) to about 4% (w/v) and/or about 0.05% (w/v) to
about 5% (w/v)), glycerol (also referred to as glycerin) at a
concentration of about 0.1% (w/v) to about 15% (w/v) (e.g., about
0.7% (w/v) to about 2.5% (w/v) and/or about 0.5% (w/v) to about 4%
(w/v)), polyvinylpyrrolidone (PVP), for example, 10K PVP, at a
concentration of about 0.001% (w/v) to about 10% (w/v) (e.g., about
0.01% (w/v) to about 1% (w/v) and/or about 0.005% (w/v) to about 2%
(w/v)), calcium chloride at a concentration of about 1 to about 150
mM (e.g., about 5 to about 50 mM, about 10 to about 30 mM, about 20
to about 40 mM, about 30 to about 50 mM, about 40 to about 80 mM,
about 50 to about 100 mM, or about 25 mM), proline at a
concentration of about 0.1 to about 450 mM (e.g., about 50 to about
300 mM), PEG 15 hydroxystearate at a concentration of about 0.1%
(w/v) to about 20% (w/v) (e.g., about 2.5% (w/v) to about 5%
(w/v)), arginine at a concentration of about 0.1 to about 450 mM
(e.g., about 60 to about 90 mM), dextran at a concentration of
about 0.1% (w/v) to about 15% (w/v) (e.g., about 2% (w/v) to about
10% (w/v)), imidazole at a concentration of about 0.1% (w/v) to
about 15% (w/v) (e.g., about 1% (w/v) to about 2% (w/v)), N-acetyl
arginine at a concentration of about 0.1 to about 450 mM (e.g.,
about 90 to about 150 mM), inositol at a concentration of about 0.1
to about 450 mM (e.g., about 180 to about 250 mM), taurine at a
concentration of about 0.1 to about 450 mM (e.g., about 100 to
about 150 mM), citruline at a concentration of about 0.1 to about
450 mM (e.g., about 100 to about 150 mM), betaine at a
concentration of about 0.1 to about 450 mM (e.g., about 100 to
about 150 mM), sarcosine at a concentration of about 0.1 to about
450 mM (e.g., about 100 to about 150 mM), glycolic acid at a
concentration of about 0.1 to about 300 mM (e.g., about 50 to about
70 mM), PCA at a concentration of about 0.1% (w/v) to about 15%
(w/v) (e.g., about 0.05% (w/v) to about 2% (w/v)), gelatin at a
concentration of about 0.1% (w/v) to about 15% (w/v) (e.g., about
0.5% (w/v) to about 2% (w/v)), hyaluronic acid at a concentration
of about 0.05% (w/v) to about 2.5% (w/v) (e.g., about 0.1% (w/v) to
about 0.05% (w/v)), N-acetyl proline at a concentration of about
0.1 to about 450 mM (e.g., about 100 to about 150 mM), N-acetyl
ornithine at a concentration of about 0.1 to about 450 mM (e.g.,
about 100 to about 150 mM), ornithine at a concentration of about
0.1 to about 450 mM (e.g., about 100 to about 150 mM), beta-alanine
at a concentration of about 0.1 to about 450 mM (e.g., about 100 to
about 150 mM), niacinamide at a concentration of about 0.1 to about
450 mM (e.g., about 100 to about 270 mM and/or about 100 to about
150 mM), medronic acid at a concentration of about 0.1 to about 450
mM (e.g., about 100 to about 150 mM), methane sulfonic acid (MSA)
at a concentration of about 0.1 to about 150 mM (e.g., about 0.1 to
about 50 mM and/or about 20 to about 125 mM), triethanolamine (TEA)
at a concentration of about 0.1 to about 170 mM (e.g., about 30 to
about 150 mM), monoethanolamide hydrochloride (MEA-HCl) at a
concentration of about 0.1 to about 150 mM (e.g., about 0.1 to
about 40 mM), monoethanolamide (MEA) at a concentration of about
0.1 to about 300 mM (e.g., about 0.1 to about 50 mM, about 0.1 to
about 170 mM, and/or about 30 to about 160 mM), ethanol at a
concentration of about 0.05% (w/v) to about 2.5% (w/v) (e.g., about
0.25% (w/v) to about 1.4% (w/v)), benzene sulfonic acid at a
concentration of about 0.1 to about 300 mM (e.g., about 75 to about
150 mM), adipic acid at a concentration of about 0.1 to about 300
mM (e.g., about 120 to about 180 mM), sodium borate at a
concentration of about 0.1 to about 150 mM (e.g., about 60 to about
90 mM), sodium bicarbonate at a concentration of about 0.1 to about
150 mM (e.g., about 60 to about 90 mM), sodium sulfate at a
concentration of about 0.1 to about 150 mM (e.g., about 60 to about
90 mM), calcium sulfate at a concentration of about 0.1 to about
150 mM (e.g., about 10 to about 30 mM), ammonium sulfate at a
concentration of about 0.1 to about 150 mM (e.g., about 60 to about
90 mM), sodium chloride at a concentration of about 10 to about 100
mM (e.g., about 60 to about 90 mM, about 15 to about 50 mM, and/or
about 35 mM), magnesium chloride at a concentration of about 0.1 to
about 150 mM (e.g., about 60 to about 90 mM), alanine at a
concentration of about 0.1 to about 450 mM (e.g., about 80 to about
120 mM), asparagine at a concentration of about 0.1 to about 450 mM
(e.g., about 80 to about 120 mM), isoleucine at a concentration of
about 0.1 to about 450 mM (e.g., about 80 to about 120 mM), serine
at a concentration of about 0.1 to about 450 mM (e.g., about 80 to
about 120 mM), aspartic acid at a concentration of about 0.1 to
about 450 mM (e.g., about 10 to about 30 mM), creatine at a
concentration of about 0.1 to about 450 mM (e.g., about 15 to about
35 mM), glutamine at a concentration of about 0.1 to about 450 mM
(e.g., about 40 to about 60 mM), leucine at a concentration of
about 0.1 to about 450 mM (e.g., about 40 to about 60 mM),
phenylalanine at a concentration of about 0.1 to about 450 mM
(e.g., about 40 to about 60 mM), tryptophan at a concentration of
about 0.1 to about 450 mM (e.g., about 15 to about 35 mM),
benzalkonium chloride at a concentration of about 0.001% (w/v) to
about 1% (w/v) (e.g., about 0.005% (w/v) to about 0.05% (w/v)),
guanidine HCl at a concentration of about 0.001% (w/v) to about 1%
(w/v) (e.g., about 0.005% (w/v) to about 0.05% (w/v)), lecithin at
a concentration of about 0.001% (w/v) to about 1% (w/v) (e.g.,
about 0.005% (w/v) to about 0.05% (w/v)), oleic acid at a
concentration of about 0.001% (w/v) to about 1% (w/v) (e.g., about
0.005% (w/v) to about 0.05% (w/v)), sucrose at a concentration of
about 0.1% (w/v) to about 15% (w/v) (e.g., about 4% (w/v) to about
10% (w/v), about 4% (w/v) to about 9% (w/v), about 6.5% (w/v),
about 6.8% (w/v), about 6.9% (w/v), or about 9% (w/v)), sorbitol at
a concentration of about 0.1% (w/v) to about 10% (w/v) (e.g., about
3% (w/v) to about 5% (w/v) and/or about 4% (w/v)), Pluronic F68 at
a concentration of about 0.001% (w/v) to about 10% (w/v) (e.g.,
about 0.005% (w/v) to about 1% (w/v), about 0.05% (w/v) to about
0.4% (w/v), about 0.05% (w/v) to about 0.1% (w/v), about 0.01%
(w/v), about 0.05% (w/v), and/or about 0.1% (w/v)), Polysorbate 20
at a concentration of about 0.001% (w/v) to about 2% (w/v) (e.g.,
about 0.005% (w/v) to about 0.1% (w/v)), Polysorbate 80 at a
concentration of about 0.001% (w/v) to about 2% (w/v) (e.g., about
0.005% (w/v) to about 0.1% (w/v), about 0.005% (w/v) to about 0.05%
(w/v), about 0.03% (w/v) to about 0.1% (w/v), about 0.04% (w/v) to
about 0.1% (w/v), about 0.03% (w/v), about 0.04% (w/v), and/or
about 0.1% (w/v)), polyvinyl alcohol, for example, 31K or 205 K
polyvinyl alcohol, at a concentration of about 0.01% (w/v) to about
10% (w/v) (e.g., about 0.05% (w/v) to about 0.5% (w/v)), and
protamine sulfate at a concentration of about 0.001% (w/v) to about
2% (w/v) (e.g., about 0.005% (w/v) to about 0.05% (w/v)).
Optionally, the glutamate-containing stable aqueous adalimumab
formulation has a pH of about 4.8 to about 5.7, for example, about
4.9 to about 5.6, about 5.0 to about 5.5, about 5.1 to about 5.4,
about 5.1 to about 5.3, about 5.1 to about 5.2, about 5.2 to about
5.3, and/or about 5.2. Optionally, the pH of the stable aqueous
adalimumab formulation is adjusted using a strong acid and/or a
strong base including, but not limited to, hydrochloric acid,
sodium hydroxide, calcium hydroxide, MSA, and/or MEA.
[0246] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
proline at a concentration of about 250 mM to about 350 mM, and has
a pH of about 5.0 to about 5.5. Optionally, the pH of the stable
aqueous adalimumab formulation is adjusted within this range with
MEA or sodium hydroxide.
[0247] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 3350 at a concentration of about 5% (w/v) to about 10% (w/v),
and has a pH of about 5.0 to about 5.5.
[0248] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 3350 at a concentration of about 5% (w/v) to about 10% (w/v),
calcium chloride at a concentration of about 30 to about 60 mM, and
has a pH of about 5.0 to about 5.5.
[0249] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 140
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
dextran at a concentration of about 5% (w/v) to about 15% (w/v),
and has a pH of about 5.0 to about 5.5.
[0250] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 140
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
dextran at a concentration of about 5% (w/v) to about 15% (w/v),
calcium chloride at a concentration of about 30 to about 60 mM, and
has a pH of about 5.0 to about 5.5.
[0251] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 200 at a concentration of about 0.5% (w/v) to about 2% (w/v),
and has a pH of about 5.0 to about 5.5.
[0252] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 200 at a concentration of about 0.5% (w/v) to about 2% (w/v),
calcium chloride at a concentration of about 30 to about 60 mM, and
has a pH of about 5.0 to about 5.5.
[0253] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 600 at a concentration of about 1.5% (w/v) to about 4% (w/v),
and has a pH of about 5.0 to about 5.5.
[0254] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 600 at a concentration of about 1.5% (w/v) to about 4% (w/v),
calcium chloride at a concentration of about 30 to about 60 mM, and
has a pH of about 5.0 to about 5.5.
[0255] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 140
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
proline at a concentration of about 200 to about 300 mM, and has a
pH of about 5.0 to about 5.5.
[0256] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 3350 at a concentration of about 0.5% (w/v) to about 2% (w/v),
and has a pH of about 5.0 to about 5.5.
[0257] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
MSA at a concentration of about 50 mM to about 150 mM, TEA at a
concentration of about 25 mM to about 75 mM, and has a pH of about
5.0 to about 5.5.
[0258] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
sodium borate at a concentration of about 50 mM to about 100 mM,
proline at a concentration of about 50 mM to about 150 mM, and has
a pH of about 5.0 to about 5.5.
[0259] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
sodium bicarbonate at a concentration of about 50 mM to about 100
mM, proline at a concentration of about 50 mM to about 150 mM, and
has a pH of about 5.0 to about 5.5.
[0260] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
sodium sulfate at a concentration of about 50 mM to about 100 mM,
proline at a concentration of about 50 mM to about 150 mM, and has
a pH of about 5.0 to about 5.5.
[0261] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
calcium sulfate at a concentration of about 10 mM to about 30 mM,
proline at a concentration of about 50 mM to about 150 mM, and has
a pH of about 5.0 to about 5.5.
[0262] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
ammonium sulfate at a concentration of about 50 mM to about 100 mM,
proline at a concentration of about 50 mM to about 150 mM, and has
a pH of about 5.0 to about 5.5.
[0263] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
calcium chloride at a concentration of about 50 mM to about 100 mM,
proline at a concentration of about 50 mM to about 150 mM, and has
a pH of about 5.0 to about 5.5.
[0264] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
sodium chloride at a concentration of about 50 mM to about 100 mM,
proline at a concentration of about 50 mM to about 150 mM, and has
a pH of about 5.0 to about 5.5.
[0265] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 200
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
magnesium chloride at a concentration of about 50 mM to about 100
mM, proline at a concentration of about 50 mM to about 150 mM, and
has a pH of about 5.0 to about 5.5.
[0266] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
MEA at a concentration of about 20 mM to about 50 mM, and has a pH
of about 5.0 to about 5.5.
[0267] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
MEA at a concentration of about 70 mM to about 90 mM, and has a pH
of about 5.0 to about 5.5.
[0268] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
MEA at a concentration of about 100 mM to about 130 mM, and has a
pH of about 5.0 to about 5.5.
[0269] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
ethanol at a concentration of about 1% (w/v) to about 2% (w/v), and
has a pH of about 5.0 to about 5.5.
[0270] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
ethanol at a concentration of about 0.3% (w/v) to about 0.8% (w/v),
calcium chloride at a concentration of about 30 mM to about 60 mM,
and has a pH of about 5.0 to about 5.5.
[0271] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
ethanol at a concentration of about 0.3% (w/v) to about 0.8% (w/v),
PEG 3350 at a concentration of about 0.7% (w/v) to about 1.5%
(w/v), calcium chloride at a concentration of about 30 mM to about
60 mM, and has a pH of about 5.0 to about 5.5.
[0272] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
TEA at a concentration of about 100 mM to about 200 mM, calcium
chloride at a concentration of about 30 mM to about 60 mM, and has
a pH of about 5.0 to about 5.5.
[0273] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
TEA at a concentration of about 20 mM to about 40 mM, calcium
chloride at a concentration of about 60 mM to about 90 mM, and has
a pH of about 5.0 to about 5.5.
[0274] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
ethanol at a concentration of about 0.3% (w/v) to about 0.8% (w/v),
and has a pH of about 5.0 to about 5.5.
[0275] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
ethanol at a concentration of about 0.3% (w/v) to about 0.8% (w/v),
PEG 200 at a concentration of about 1.5% (w/v) to about 4% (w/v),
and has a pH of about 5.0 to about 5.5.
[0276] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
ethanol at a concentration of about 0.1% (w/v) to about 0.4% (w/v),
PEG 200 at a concentration of about 1.5% (w/v) to about 4% (w/v),
and has a pH of about 5.0 to about 5.5.
[0277] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
ethanol at a concentration of about 0.3% (w/v) to about 0.8% (w/v),
MSA at a concentration of about 80 mM to about 120 mM, and has a pH
of about 5.0 to about 5.5.
[0278] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
ethanol at a concentration of about 0.3% (w/v) to about 0.8% (w/v),
10K PVP at a concentration of about 0.3% (w/v) to about 0.8% (w/v),
MSA at a concentration of about 80 mM to about 120 mM, and has a pH
of about 5.0 to about 5.5.
[0279] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
ethanol at a concentration of about 0.3% (w/v) to about 0.8% (w/v),
MEA at a concentration of about 80 mM to about 120 mM, and has a pH
of about 5.0 to about 5.5.
[0280] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
alanine at a concentration of about 80 mM to about 120 mM, calcium
chloride at a concentration of about 30 mM to about 60 mM, and has
a pH of about 5.0 to about 5.5.
[0281] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
asparagine at a concentration of about 80 mM to about 120 mM,
calcium chloride at a concentration of about 30 mM to about 60 mM,
and has a pH of about 5.0 to about 5.5.
[0282] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
isoleucine at a concentration of about 80 mM to about 120 mM,
calcium chloride at a concentration of about 30 mM to about 60 mM,
and has a pH of about 5.0 to about 5.5.
[0283] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
serine at a concentration of about 80 mM to about 120 mM, calcium
chloride at a concentration of about 30 mM to about 60 mM, and has
a pH of about 5.0 to about 5.5.
[0284] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
aspartic acid at a concentration of about 10 mM to about 30 mM,
proline at a concentration of about 60 mM to about 100 mM, calcium
chloride at a concentration of about 30 mM to about 60 mM, and has
a pH of about 5.0 to about 5.5.
[0285] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
creatine at a concentration of about 15 mM to about 35 mM, proline
at a concentration of about 60 mM to about 90 mM, calcium chloride
at a concentration of about 30 mM to about 60 mM, and has a pH of
about 5.0 to about 5.5.
[0286] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
glutamine at a concentration of about 40 mM to about 60 mM, proline
at a concentration of about 40 mM to about 60 mM, calcium chloride
at a concentration of about 30 mM to about 60 mM, and has a pH of
about 5.0 to about 5.5.
[0287] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
leucine at a concentration of about 40 mM to about 60 mM, proline
at a concentration of about 40 mM to about 60 mM, calcium chloride
at a concentration of about 30 mM to about 60 mM, and has a pH of
about 5.0 to about 5.5.
[0288] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
phenylalanine at a concentration of about 40 mM to about 60 mM,
proline at a concentration of about 40 mM to about 60 mM, calcium
chloride at a concentration of about 30 mM to about 60 mM, and has
a pH of about 5.0 to about 5.5.
[0289] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 80 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
tryptophan at a concentration of about 10 mM to about 40 mM,
proline at a concentration of about 60 mM to about 90 mM, calcium
chloride at a concentration of about 30 mM to about 60 mM, and has
a pH of about 5.0 to about 5.5.
[0290] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 80 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
benzalkonium chloride at a concentration of about 0.005% (w/v) to
about 0.05% (w/v), proline at a concentration of about 250 mM to
about 350 mM, and has a pH of about 5.0 to about 5.5.
[0291] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 80 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
guanidine HCl at a concentration of about 0.005% (w/v) to about
0.05% (w/v), proline at a concentration of about 250 mM to about
350 mM, and has a pH of about 5.0 to about 5.5.
[0292] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 80 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
lecithin at a concentration of about 0.005% (w/v) to about 0.05%
(w/v), proline at a concentration of about 250 mM to about 350 mM,
and has a pH of about 5.0 to about 5.5.
[0293] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 80 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
oleic acid at a concentration of about 0.005% (w/v) to about 0.05%
(w/v), proline at a concentration of about 250 mM to about 350 mM,
and has a pH of about 5.0 to about 5.5.
[0294] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 80 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
Polysorbate 80 at a concentration of about 0.005% (w/v) to about
0.05% (w/v), proline at a concentration of about 250 mM to about
350 mM, and has a pH of about 5.0 to about 5.5.
[0295] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 80 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
polyvinyl alcohol 205K at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), proline at a concentration of about 250 mM to
about 350 mM, and has a pH of about 5.0 to about 5.5.
[0296] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 80 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
polyvinyl alcohol 31K at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), proline at a concentration of about 250 mM to
about 350 mM, and has a pH of about 5.0 to about 5.5.
[0297] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 80 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PVP at a concentration of about 0.005% (w/v) to about 0.05% (w/v),
proline at a concentration of about 250 mM to about 350 mM, and has
a pH of about 5.0 to about 5.5.
[0298] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 80 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
protamine sulfate at a concentration of about 0.005% (w/v) to about
0.05% (w/v), proline at a concentration of about 250 mM to about
350 mM, and has a pH of about 5.0 to about 5.5.
[0299] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 400 at a concentration of about 5% (w/v) to about 12% (w/v),
glycerol at a concentration of about 0.7% (w/v) to about 1.5%
(w/v), and optionally Pluronic F68 at a concentration of about
0.05% (w/v) to about 0.4% (w/v) or Polysorbate 80 at a
concentration of about 0.005% (w/v) to about 0.1% (w/v), and has a
pH of about 5.0 to about 5.5.
[0300] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 400 at a concentration of about 2% (w/v) to about 6% (w/v),
glycerol at a concentration of about 0.7% (w/v) to about 1.5%
(w/v), and optionally Pluronic F68 at a concentration of about
0.05% (w/v) to about 0.4% (w/v) or Polysorbate 80 at a
concentration of about 0.005% (w/v) to about 0.1% (w/v), and has a
pH of about 5.0 to about 5.5.
[0301] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 400 at a concentration of about 0.5% (w/v) to about 2% (w/v),
glycerol at a concentration of about 1.5% (w/v) to about 4% (w/v),
and optionally Pluronic F68 at a concentration of about 0.05% (w/v)
to about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0302] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 400 at a concentration of about 8% (w/v) to about 12% (w/v),
and optionally Pluronic F68 at a concentration of about 0.05% (w/v)
to about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0303] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PVP at a concentration of about 0.7% (w/v) to about 1.5% (w/v), and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0304] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0305] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
proline at a concentration of about 80 to about 120 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0306] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 15 hydroxystearate at a concentration of about 1.5% (w/v) to
about 4% (w/v), and optionally Pluronic F68 at a concentration of
about 0.05% (w/v) to about 0.4% (w/v) or Polysorbate 80 at a
concentration of about 0.005% (w/v) to about 0.1% (w/v), and has a
pH of about 5.0 to about 5.5.
[0307] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 15 hydroxystearate at a concentration of about 1.5% (w/v) to
about 4% (w/v), arginine at a concentration of about 60 to about 90
mM, and optionally Pluronic F68 at a concentration of about 0.05%
(w/v) to about 0.4% (w/v) or Polysorbate 80 at a concentration of
about 0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0
to about 5.5.
[0308] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 15 hydroxystearate at a concentration of about 3% (w/v) to
about 8% (w/v), calcium chloride at a concentration of about 30 to
about 60 mM, and optionally Pluronic F68 at a concentration of
about 0.05% (w/v) to about 0.4% (w/v) or Polysorbate 80 at a
concentration of about 0.005% (w/v) to about 0.1% (w/v), and has a
pH of about 5.0 to about 5.5.
[0309] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 15 hydroxystearate at a concentration of about 3% (w/v) to
about 8% (w/v), calcium chloride at a concentration of about 30 to
about 60 mM, proline at a concentration of about 80 to about 120
mM, and optionally Pluronic F68 at a concentration of about 0.05%
(w/v) to about 0.4% (w/v) or Polysorbate 80 at a concentration of
about 0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0
to about 5.5.
[0310] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
dextran at a concentration of about 1.5% (w/v) to about 4% (w/v),
and optionally Pluronic F68 at a concentration of about 0.05% (w/v)
to about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0311] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
imidazole at a concentration of about 1.5% (w/v) to about 4% (w/v),
and optionally Pluronic F68 at a concentration of about 0.05% (w/v)
to about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0312] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
imidazole at a concentration of about 0.7% (w/v) to about 1.5%
(w/v), calcium chloride at a concentration of about 30 to about 60
mM, and optionally Pluronic F68 at a concentration of about 0.05%
(w/v) to about 0.4% (w/v) or Polysorbate 80 at a concentration of
about 0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0
to about 5.5.
[0313] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
N-acetyl arginine at a concentration of about 100 to about 150 mM,
and optionally Pluronic F68 at a concentration of about 0.05% (w/v)
to about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0314] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
N-acetyl arginine at a concentration of about 100 to about 150 mM,
calcium chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0315] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
inositol at a concentration of about 200 to about 300 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0316] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
inositol at a concentration of about 200 to about 300 mM, calcium
chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0317] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 3350 at a concentration of about 0.7% (w/v) to about 1.5%
(w/v), calcium chloride at a concentration of about 30 to about 60
mM, and optionally Pluronic F68 at a concentration of about 0.05%
(w/v) to about 0.4% (w/v) or Polysorbate 80 at a concentration of
about 0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0
to about 5.5.
[0318] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
taurine at a concentration of about 100 to about 150 mM, calcium
chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0319] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
citruline at a concentration of about 100 to about 150 mM, calcium
chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0320] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
betaine at a concentration of about 100 to about 150 mM, calcium
chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0321] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
sarcosine at a concentration of about 100 to about 150 mM, calcium
chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0322] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 400 at a concentration of about 1% (w/v) to about 1.5% (w/v),
glycolic acid at a concentration of about 40 to about 80 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0323] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
glycolic acid at a concentration of about 40 to about 80 mM,
calcium chloride at a concentration of about 60 to about 90 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0324] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PCA at a concentration of about 0.7% (w/v) to about 1.5% (w/v), and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0325] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PCA at a concentration of about 0.7% (w/v) to about 1.5% (w/v),
calcium chloride at a concentration of about 60 to about 90 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0326] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
gelatin at a concentration of about 0.7% (w/v) to about 1.5% (w/v),
calcium chloride at a concentration of about 60 to about 90 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0327] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
hyaluronic acid at a concentration of about 0.1% (w/v) to about
0.5% (w/v), and optionally Pluronic F68 at a concentration of about
0.05% (w/v) to about 0.4% (w/v) or Polysorbate 80 at a
concentration of about 0.005% (w/v) to about 0.1% (w/v), and has a
pH of about 5.0 to about 5.5.
[0328] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
hyaluronic acid at a concentration of about 0.1% (w/v) to about
0.5% (w/v), calcium chloride at a concentration of about 60 to
about 90 mM, and optionally Pluronic F68 at a concentration of
about 0.05% (w/v) to about 0.4% (w/v) or Polysorbate 80 at a
concentration of about 0.005% (w/v) to about 0.1% (w/v), and has a
pH of about 5.0 to about 5.5.
[0329] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
N-acetyl proline at a concentration of about 100 to about 150 mM,
calcium chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0330] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
N-acetyl ornithine at a concentration of about 100 to about 150 mM,
calcium chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0331] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
ornithine at a concentration of about 100 to about 150 mM, calcium
chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0332] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
beta-alanine at a concentration of about 100 to about 150 mM,
calcium chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0333] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
niacinamide at a concentration of about 100 to about 150 mM,
calcium chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0334] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
medronic acid at a concentration of about 100 to about 150 mM,
calcium chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0335] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 200 at a concentration of about 0.7% (w/v) to about 1.5% (w/v),
and optionally Pluronic F68 at a concentration of about 0.05% (w/v)
to about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0336] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 200 at a concentration of about 0.7% (w/v) to about 1.5% (w/v),
calcium chloride at a concentration of about 30 to about 60 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0337] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 600 at a concentration of about 1.5% (w/v) to about 4% (w/v),
and optionally Pluronic F68 at a concentration of about 0.05% (w/v)
to about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0338] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 600 at a concentration of about 1.5% (w/v) to about 4% (w/v),
and calcium chloride at a concentration of about 30 to about 60 mM,
and has a pH of about 5.0 to about 5.5.
[0339] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
MSA at a concentration of about 80 to about 120 mM, TEA at a
concentration of about 30 to about 70 mM, and optionally Pluronic
F68 at a concentration of about 0.05% (w/v) to about 0.4% (w/v) or
Polysorbate 80 at a concentration of about 0.005% (w/v) to about
0.1% (w/v), and has a pH of about 5.0 to about 5.5.
[0340] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
MSA at a concentration of about 110 to about 140 mM, and optionally
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.4%
(w/v) or Polysorbate 80 at a concentration of about 0.005% (w/v) to
about 0.1% (w/v), and has a pH of about 5.0 to about 5.5.
[0341] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
niacinamide at a concentration of about 250 to about 300 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0342] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
niacinamide at a concentration of about 80 to about 120 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0343] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
niacinamide at a concentration of about 80 to about 120 mM, calcium
chloride at a concentration of about 60 to about 100 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0344] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
niacinamide at a concentration of about 80 to about 120 mM, MSA at
a concentration of about 60 to about 100 mM, and optionally
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.4%
(w/v) or Polysorbate 80 at a concentration of about 0.005% (w/v) to
about 0.1% (w/v), and has a pH of about 5.0 to about 5.5.
[0345] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
niacinamide at a concentration of about 80 to about 120 mM, PEG 200
at a concentration of about 0.7% (w/v) to about 1.5% (w/v), and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0346] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
ethanol at a concentration of about 0.25% (w/v) to about 0.75%
(w/v), and optionally Pluronic F68 at a concentration of about
0.05% (w/v) to about 0.4% (w/v) or Polysorbate 80 at a
concentration of about 0.005% (w/v) to about 0.1% (w/v), and has a
pH of about 5.0 to about 5.5.
[0347] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
ethanol at a concentration of about 0.25% (w/v) to about 0.75%
(w/v), PEG 200 at a concentration of about 1.5% (w/v) to about 4%
(w/v), and optionally Pluronic F68 at a concentration of about
0.05% (w/v) to about 0.4% (w/v) or Polysorbate 80 at a
concentration of about 0.005% (w/v) to about 0.1% (w/v), and has a
pH of about 5.0 to about 5.5.
[0348] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
ethanol at a concentration of about 0.1% (w/v) to about 0.4% (w/v),
PEG 200 at a concentration of about 1.5% (w/v) to about 4% (w/v),
and optionally Pluronic F68 at a concentration of about 0.05% (w/v)
to about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0349] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
ethanol at a concentration of about 0.1% (w/v) to about 0.4% (w/v),
PEG 200 at a concentration of about 1.5% (w/v) to about 4% (w/v),
MSA at a concentration of about 80 to about 120 mM, and optionally
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.4%
(w/v) or Polysorbate 80 at a concentration of about 0.005% (w/v) to
about 0.1% (w/v), and has a pH of about 5.0 to about 5.5.
[0350] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
ethanol at a concentration of about 0.25% (w/v) to about 0.75%
(w/v), MSA at a concentration of about 80 to about 120 mM, 10K PVP
at a concentration of about 0.25% (w/v) to about 0.75% (w/v), and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0351] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
ethanol at a concentration of about 0.25% (w/v) to about 0.75%
(w/v), MEA at a concentration of about 80 to about 120 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0352] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
benzene sulfonic acid at a concentration of about 100 to about 200
mM, and optionally Pluronic F68 at a concentration of about 0.05%
(w/v) to about 0.4% (w/v) or Polysorbate 80 at a concentration of
about 0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0
to about 5.5. Optionally, the pH of the formulation is adjusted
within this range with sodium hydroxide or calcium hydroxide.
[0353] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
benzene sulfonic acid at a concentration of about 60 to about 90
mM, and optionally Pluronic F68 at a concentration of about 0.05%
(w/v) to about 0.4% (w/v) or Polysorbate 80 at a concentration of
about 0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0
to about 5.5.
[0354] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
benzene sulfonic acid at a concentration of about 60 to about 90
mM, calcium chloride at a concentration of about 25 to about 75 mM,
and optionally Pluronic F68 at a concentration of about 0.05% (w/v)
to about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0355] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
benzene sulfonic acid at a concentration of about 60 to about 90
mM, MEA at a concentration of about 60 to about 90 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0356] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
adipic acid at a concentration of about 100 to about 200 mM, and
optionally Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.4% (w/v) or Polysorbate 80 at a concentration of about
0.005% (w/v) to about 0.1% (w/v), and has a pH of about 5.0 to
about 5.5.
[0357] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, glutamate at a concentration of about 10 mM to about 25 mM,
PEG 400 at a concentration of about 0.25% (w/v) to about 0.75%
(w/v), calcium chloride at a concentration of about 40 to about 80
mM, glycerin at a concentration of about 0.5% (w/v) to about 1%
(w/v), and optionally Pluronic F68 at a concentration of about
0.05% (w/v) to about 0.4% (w/v) or Polysorbate 80 at a
concentration of about 0.005% (w/v) to about 0.1% (w/v), and has a
pH of about 5.0 to about 5.5.
[0358] Exemplary aqueous adalimumab formulations are provided in
Table A. Each formulation in Table A may optionally include
Pluronic F68 at a concentration of about 0.001% (w/v) to about 10%
(w/v) (e.g., about 0.005% (w/v) to about 1% (w/v), about 0.05%
(w/v) to about 0.4% (w/v), about 0.05% (w/v) to about 0.1% (w/v),
about 0.01% (w/v), about 0.05% (w/v), and/or about 0.1% (w/v)),
Polysorbate 20 at a concentration of about 0.001% (w/v) to about 2%
(w/v) (e.g., about 0.005% (w/v) to about 0.1% (w/v)), or
Polysorbate 80 at a concentration of about 0.001% (w/v) to about 2%
(w/v) (e.g., about 0.005% (w/v) to about 0.1% (w/v), about 0.03%
(w/v) to about 0.1% (w/v), about 0.04% (w/v) to about 0.1% (w/v),
about 0.03% (w/v), about 0.04% (w/v), and/or about 0.1% (w/v)).
Each formulation in Table A has a pH of about 5.0 to about 5.5,
e.g., about 5.1 to about 5.3 and/or about 5.2. Optionally, the pH
of each formulation in Table A is adjusted using a strong acid
and/or strong base including, but not limited to, hydrochloric
acid, sodium hydroxide, calcium hydroxide, MSA, and/or MEA.
TABLE-US-00001 TABLE A Protein conc. Buffer Excipient(s).sup.1 100
mg/mL 15 mM glutamate 8% PEG 400 1% glycerol 100 mg/mL 15 mM
glutamate 4% PEG 200 1% glycerol 100 mg/mL 15 mM glutamate 1% PEG
400 2.5% glycerol 100 mg/mL 15 mM glutamate 10% PEG 400 100 mg/mL
15 mM glutamate 1% PVP 110 mg/mL 20 mM glutamate 45 mM CaCl.sub.2
110 mg/mL 20 mM glutamate 45 mM CaCl.sub.2 100 mM proline 110 mg/mL
20 mM glutamate 2.5% PEG 15 hydroxystearate 110 mg/mL 20 mM
glutamate 2.5% PEG 15 hydroxystearate 75 mM arginine 110 mg/mL 20
mM glutamate 5% PEG 15 hydroxystearate 45 mM CaCl.sub.2 110 mg/mL
20 mM glutamate 5% PEG 15 hydroxystearate 45 mM CaCl.sub.2 100 mM
proline 110 mg/mL 20 mM glutamate 2% dextran 110 mg/mL 20 mM
glutamate 2% imidazole 110 mg/mL 20 mM glutamate 1% imidazole 45 mM
CaCl.sub.2 110 mg/mL 20 mM glutamate 120 mM N-acetyl arginine 110
mg/mL 20 mM glutamate 120 mM N-acetyl arginine 45 mM CaCl.sub.2 105
mg/mL 20 mM glutamic acid 250 mM inositol 105 mg/mL 20 mM glutamic
acid 180 mM inositol 40 mM CaCl.sub.2 105 mg/mL 20 mM glutamic acid
1% PEG 3350 40 mM CaCl.sub.2 105 mg/mL 20 mM glutamic acid 120 mM
taurine 40 mM CaCl.sub.2 105 mg/mL 20 mM glutamic acid 120 mM
citruline 40 mM CaCl.sub.2 105 mg/mL 20 mM glutamic acid 120 mM
betaine 40 mM CaCl.sub.2 105 mg/mL 20 mM glutamic acid 120 mM
sarcosine 40 mM CaCl.sub.2 105 mg/mL 20 mM glutamic acid 1.2% PEG
400 60 mM glycolic acid 105 mg/mL 20 mM glutamic acid 60 mM
glycolic acid 75 mM CaCl.sub.2 105 mg/mL 20 mM glutamic acid 1% PCA
105 mg/mL 20 mM glutamic acid 1% PCA 75 mM CaCl.sub.2 110 mg/mL 20
mM glutamic acid 1% Type B gelatin 75 mM CaCl.sub.2 110 mg/mL 20 mM
glutamic acid 0.25% hyaluronic acid 110 mg/mL 20 mM glutamic acid
0.25% hyaluronic acid 75 mM CaCl.sub.2 110 mg/mL 20 mM glutamic
acid 120 mM N-acetyl proline 40 mM CaCl.sub.2 110 mg/mL 20 mM
glutamic acid 120 mM N-acetyl ornithine 40 mM CaCl.sub.2 110 mg/mL
20 mM glutamic acid 120 mM ornithine 40 mM CaCl.sub.2 110 mg/mL 20
mM glutamic acid 120 mM beta-alanine 40 mM CaCl.sub.2 110 mg/mL 20
mM glutamic acid 120 mM niacinamide 40 mM CaCl.sub.2 110 mg/mL 20
mM glutamic acid 120 mM medronic acid 40 mM CaCl.sub.2 110 mg/mL 20
mM glutamic acid 1% PEG 200 110 mg/mL 20 mM glutamic acid 1% PEG
200 40 mM CaCl.sub.2 110 mg/mL 20 mM glutamic acid 2% PEG 600 110
mg/mL 20 mM glutamic acid 2% PEG 600 40 mM CaCl2 110 mg/mL 20 mM
glutamic acid 100 mM MSA 50 mM TEA 110 mg/mL 20 mM glutamic acid
125 mM MSA 110 mg/mL 20 mM glutamic acid 270 mM niacinamide 110
mg/mL 20 mM glutamic acid 100 mM niacinamide 110 mg/mL 20 mM
glutamic acid 100 mM niacinamide 80 mM CaCl.sub.2 110 mg/mL 20 mM
glutamic acid 100 mM niacinamide 80 mM MSA 110 mg/mL 20 mM glutamic
acid 100 mM niacinamide 1% PEG 200 110 mg/mL 20 mM glutamic acid
0.5% ethanol 110 mg/mL 20 mM glutamic acid 0.5% ethanol 2% PEG 200
110 mg/mL 20 mM glutamic acid 0.25% ethanol 2% PEG 200 110 mg/mL 20
mM glutamic acid 0.25% ethanol 2% PEG 200 100 mM MSA 110 mg/mL 20
mM glutamic acid 0.5% ethanol 100 mM MSA 0.5% 10K PVP 110 mg/mL 20
mM glutamic acid 0.5% ethanol 100 mM MEA 110 mg/mL 20 mM glutamic
acid 150 mM benzene sulfonic acid (adjust pH with NaOH) 110 mg/mL
20 mM glutamic acid 150 mM benzene sulfonic acid (adjust pH with
Ca(OH).sub.2) 110 mg/mL 20 mM glutamic acid 75 mM benzene sulfonic
acid 110 mg/mL 20 mM glutamic acid 75 mM benzene sulfonic acid 50
mM CaCl.sub.2 110 mg/mL 20 mM glutamic acid 75 mM benzene sulfonic
acid 75 mM MEA 110 mg/mL 20 mM glutamic acid 150 mM adipic acid 180
mg/mL 20 mM glutamic acid 0.5% PEG 400 60 mM CaCl.sub.2 0.7%
glycerin .sup.1All percentages are (w/v).
[0359] In an embodiment, a lyophilized form of any one of the
foregoing glutamate-containing adalimumab formulations is
provided.
Formulations of Adalimumab with Adipate Buffer
[0360] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 200
mg/mL, such as about 170 to about 190 mg/mL, about 90 to about 120
mg/mL, about 160 to about 190 mg/mL, about 40 to about 60 mg/mL,
about 50 mg/mL, about 100 mg/mL, or about 170 mg/mL, adipate at a
concentration of about 5 mM to about 50 mM (e.g., about 10 mM to
about 25 mM, about 15 mM to about 20 mM, about 10 mM, about 15 mM,
about 20 mM, and/or about 25 mM), and one or more excipients.
Suitable excipients include certain stabilizers such as certain
amino acids and amino acid derivatives, certain polyethylene
glycols and polyethylene glycol derivatives, certain polyols,
certain acids, certain amines, certain salts, and certain
surfactants. Examples of suitable amino acids and amino acid
derivatives include proline (e.g., at a concentration of about 0.1
to about 450 mM or about 50 to about 300 mM) and N-acetyl arginine
(e.g., at a concentration of about 0.1 to about 450 mM or about 100
to about 150 mM). Examples of suitable polyethylene glycols and
polyethylene glycol derivatives include PEG 400 (e.g., at a
concentration of about 0.1% (w/v) to about 20% (w/v) or about 0.3%
(w/v) to about 1.5% (w/v)) and PEG 3350 (e.g., at a concentration
of about 0.1% (w/v) to about 30% (w/v) or about 0.5% (w/v) to about
2% (w/v)). Examples of suitable polyols include glycerol (e.g., at
a concentration of about 0.1% (w/v) to about 15% (w/v) or about 1%
(w/v) to about 2% (w/v)), sucrose (e.g., at a concentration of
about 0.1% (w/v) to about 15% (w/v), about 4% (w/v) to about 10%
(w/v), about 4% (w/v) to about 9% (w/v), about 6.5% (w/v), about
6.8% (w/v), about 6.9% (w/v), or about 9% (w/v)), and sorbitol
(e.g., at a concentration of about 0.1% (w/v) to about 10% (w/v),
about 3% (w/v) to about 5% (w/v), and/or about 4% (w/v)). Examples
of suitable acids include MSA (e.g., at a concentration of about
0.1 to about 150 mM, about 0.1 to about 50 mM, and/or about 10 to
about 40 mM). Examples of suitable amines include monoethanolamine
hydrochloride (MEA-HCl) (e.g., at a concentration of about 0.1 to
about 150 mM, about 0.1 to about 40 mM, or about 50 to about 100
mM) and methanolamine (MEA) (e.g., at a concentration of about 0.1
to about 150 mM, about 0.1 to about 50 mM, or about 50 to about 100
mM). Examples of suitable salts include calcium chloride (e.g., at
a concentration of about 1 to about 150 mM, about 20 to about 75
mM, about 5 to about 50 mM, about 10 to about 30 mM, about 20 to
about 40 mM, about 30 to about 50 mM, about 40 to about 80 mM,
about 50 to about 100 mM, or about 25 mM) and sodium chloride
(e.g., at a concentration of about 10 to about 100 mM, about 60 to
about 90 mM, about 15 to about 50 mM, and/or about 35 mM). Examples
of suitable surfactants Pluronic F68 (e.g., at a concentration of
about 0.001% (w/v) to about 10% (w/v), about 0.005% (w/v) to about
1% (w/v), about 0.05% (w/v) to about 0.4% (w/v), about 0.05% (w/v)
to about 0.1% (w/v), about 0.01% (w/v), about 0.05% (w/v), and/or
about 0.1% (w/v)), Polysorbate 20 (e.g., at a concentration of
about 0.001% (w/v) to about 2% (w/v) or about 0.005% (w/v) to about
0.1% (w/v)), and Polysorbate 80 (e.g., at a concentration of about
0.001% (w/v) to about 2% (w/v), about 0.005% (w/v) to about 0.1%
(w/v), about 0.005% (w/v) to about 0.05% (w/v), about 0.03% (w/v)
to about 0.1% (w/v), about 0.04% (w/v) to about 0.1% (w/v), about
0.03% (w/v), about 0.04% (w/v), and/or about 0.1% (w/v)). Examples
of other suitable excipients include imidazole (e.g., at a
concentration of about 0.1% (w/v) to about 15% (w/v) or about 1%
(w/v) to about 1.5% (w/v)) and PVP, for example, 10K PVP, (e.g., at
a concentration of about 0.1% (w/v) to about 10% (w/v) or about
0.5% (w/v) to about 2% (w/v)). Optionally, the adipate-containing
stable aqueous adalimumab formulation has a pH of about 4.8 to
about 5.7, for example, about 4.9 to about 5.6, about 5.0 to about
5.5, about 5.1 to about 5.4, about 5.1 to about 5.3, about 5.1 to
about 5.2, about 5.2 to about 5.3, and/or about 5.2. Optionally,
the pH of the stable aqueous adalimumab formulation is adjusted
using a strong acid and/or a strong base including, but not limited
to, hydrochloric acid, sodium hydroxide, calcium hydroxide, MSA,
and/or MEA.
[0361] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 200
mg/mL, such as about 170 to about 190 mg/mL, about 90 to about 120
mg/mL, about 160 to about 190 mg/mL, about 40 to about 60 mg/mL,
about 50 mg/mL, about 100 mg/mL, or about 170 mg/mL, adipate at a
concentration of about 5 mM to about 50 mM (e.g., about 10 mM to
about 25 mM, about 15 mM to about 20 mM, about 10 mM, about 15 mM,
about 20 mM, and/or about 25 mM), and one or more excipients
selected from the group consisting of N-acetyl arginine at a
concentration of about 0.1 to about 450 mM (e.g., about 100 to
about 150 mM), PEG 400 at a concentration of about 0.1% (w/v) to
about 20% (w/v) (e.g., about 0.3% (w/v) to about 1.5% (w/v)), MSA
at a concentration of about 0.1 to about 150 mM (e.g., about 0.1 to
about 50 mM and/or about 10 to about 40 mM), calcium chloride at a
concentration of about 1 to about 150 mM (e.g., about 20 to about
75 mM, about 5 to about 50 mM, about 10 to about 30 mM, about 20 to
about 40 mM, about 30 to about 50 mM, about 40 to about 80 mM,
about 50 to about 100 mM, or about 25 mM), monoethanolamide
hydrochloride (MEA-HCl) at a concentration of about 0.1 to about
150 mM (e.g., about 0.1 to about 40 mM or about 50 to about 100
mM), monoethanolamide (MEA) at a concentration of about 0.1 to
about 150 mM (e.g., about 0.1 to about 50 mM or about 50 to about
100 mM), glycerol at a concentration of about 0.1% (w/v) to about
15% (w/v) (e.g., about 1% (w/v) to about 2% (w/v)), imidazole at a
concentration of about 0.1% (w/v) to about 15% (w/v) (e.g., about
1% (w/v) to about 1.5% (w/v)), PVP, for example, 10K PVP, at a
concentration of about 0.1% (w/v) to about 10% (w/v) (e.g., about
0.5% (w/v) to about 2% (w/v)), PEG 3350 at a concentration of about
0.1% (w/v) to about 30% (w/v) (e.g., about 0.5% (w/v) to about 2%
(w/v)), sodium chloride at a concentration of about 10 to about 100
mM (e.g., about 60 to about 90 mM, about 15 to about 50 mM, and/or
about 35 mM), proline at a concentration of about 0.1 to about 450
mM (e.g., about 50 to about 300 mM), sucrose at a concentration of
about 0.1% (w/v) to about 15% (w/v) (e.g., about 4% (w/v) to about
10% (w/v), about 4% (w/v) to about 9% (w/v), about 6.5% (w/v),
about 6.8% (w/v), about 6.9% (w/v), or about 9% (w/v)), sorbitol at
a concentration of about 0.1% (w/v) to about 10% (w/v) (e.g., about
3% (w/v) to about 5% (w/v) and/or about 4% (w/v)), Pluronic F68 at
a concentration of about 0.001% (w/v) to about 10% (w/v) (e.g.,
about 0.005% (w/v) to about 1% (w/v), about 0.05% (w/v) to about
0.4% (w/v), about 0.05% (w/v) to about 0.1% (w/v), about 0.01%
(w/v), about 0.05% (w/v), and/or about 0.1% (w/v)), Polysorbate 20
at a concentration of about 0.001% (w/v) to about 2% (w/v) (e.g.,
about 0.005% (w/v) to about 0.1% (w/v)), and Polysorbate 80 at a
concentration of about 0.001% (w/v) to about 2% (w/v) (e.g., about
0.005% (w/v) to about 0.1% (w/v), about 0.005% (w/v) to about 0.05%
(w/v), about 0.03% (w/v) to about 0.1% (w/v), about 0.04% (w/v) to
about 0.1% (w/v), about 0.03% (w/v), about 0.04% (w/v), and/or
about 0.1% (w/v)). Optionally, the adipate-containing stable
aqueous adalimumab formulation has a pH of about 4.8 to about 5.7,
for example, about 4.9 to about 5.6, about 5.0 to about 5.5, about
5.1 to about 5.4, about 5.1 to about 5.3, about 5.1 to about 5.2,
about 5.2 to about 5.3, and/or about 5.2. Optionally, the pH of the
stable aqueous adalimumab formulation is adjusted using a strong
acid and/or a strong base including, but not limited to,
hydrochloric acid, sodium hydroxide, calcium hydroxide, MSA, and/or
MEA.
[0362] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, adipate at a concentration of about 10 mM to about 25 mM,
N-acetyl arginine at a concentration of about 100 to about 150 mM,
PEG 400 at a concentration of about 0.5% (w/v) to about 1% (w/v),
and MSA at a concentration of about 10 to about 30 mM, and has a pH
of about 5.0 to about 5.5.
[0363] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, adipate at a concentration of about 10 mM to about 25 mM,
N-acetyl arginine at a concentration of about 100 to about 150 mM,
calcium chloride at a concentration of about 30 to about 50 mM, and
MSA at a concentration of about 10 to about 30 mM, and has a pH of
about 5.0 to about 5.5.
[0364] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, adipate at a concentration of about 10 mM to about 25 mM,
N-acetyl arginine at a concentration of about 100 to about 150 mM,
MEA-HCl at a concentration of about 30 to about 70 mM, and MSA at a
concentration of about 5 to about 15 mM, and has a pH of about 5.0
to about 5.5.
[0365] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, adipate at a concentration of about 10 mM to about 25 mM,
glycerol at a concentration of about 1% (w/v) to about 2% (w/v),
and MSA at a concentration of about 30 to about 50 mM, and has a pH
of about 5.0 to about 5.5.
[0366] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, adipate at a concentration of about 10 mM to about 25 mM,
PEG 400 at a concentration of about 0.5% (w/v) to about 2% (w/v),
and MSA at a concentration of about 30 to about 50 mM, and has a pH
of about 5.0 to about 5.5.
[0367] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, adipate at a concentration of about 10 mM to about 25 mM,
and imidazole at a concentration of about 1% (w/v) to about 1.5%
(w/v), and has a pH of about 5.0 to about 5.5.
[0368] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, adipate at a concentration of about 10 mM to about 25 mM,
calcium chloride at a concentration of about 60 to about 90 mM, PEG
400 at a concentration of about 0.1% (w/v) to about 0.5% (w/v), and
10K PVP at a concentration of about 0.5% (w/v) to about 2% (w/v),
and has a pH of about 5.0 to about 5.5.
[0369] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, adipate at a concentration of about 10 mM to about 25 mM,
MEA-HCl at a concentration of about 80 to about 120 mM, PEG 400 at
a concentration of about 0.1% (w/v) to about 0.5% (w/v), and 10K
PVP at a concentration of about 0.5% (w/v) to about 2% (w/v), and
has a pH of about 5.0 to about 5.5.
[0370] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, adipate at a concentration of about 10 mM to about 25 mM,
PEG 400 at a concentration of about 0.5% (w/v) to about 2% (w/v),
and calcium chloride at a concentration of about 30 to about 50 mM,
and has a pH of about 5.0 to about 5.5.
[0371] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, adipate at a concentration of about 10 mM to about 25 mM,
PEG 3350 at a concentration of about 0.5% (w/v) to about 2% (w/v),
and calcium chloride at a concentration of about 60 to about 90 mM,
and has a pH of about 5.0 to about 5.5.
[0372] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, adipate at a concentration of about 10 mM to about 25 mM,
PEG 3350 at a concentration of about 0.5% (w/v) to about 2% (w/v),
PEG 400 at a concentration of about 1% (w/v) to about 3% (w/v), and
calcium chloride at a concentration of about 10 to about 30 mM, and
has a pH of about 5.0 to about 5.5.
[0373] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 170 to about 190
mg/mL, adipate at a concentration of about 10 mM to about 25 mM,
PEG 3350 at a concentration of about 0.5% (w/v) to about 2% (w/v),
PEG 400 at a concentration of about 0.5% (w/v) to about 2% (w/v),
and calcium chloride at a concentration of about 30 to about 50 mM,
and has a pH of about 5.0 to about 5.5.
[0374] Exemplary aqueous adalimumab formulations are provided in
Table B. Each formulation in Table B may optionally include
Pluronic F68 at a concentration of about 0.001% (w/v) to about 10%
(w/v) (e.g., about 0.005% (w/v) to about 1% (w/v), about 0.05%
(w/v) to about 0.4% (w/v), about 0.05% (w/v) to about 0.1% (w/v),
about 0.01% (w/v), about 0.05% (w/v), and/or about 0.1% (w/v)),
Polysorbate 20 at a concentration of about 0.001% (w/v) to about 2%
(w/v) (e.g., about 0.005% (w/v) to about 0.1% (w/v)), or
Polysorbate 80 at a concentration of about 0.001% (w/v) to about 2%
(w/v) (e.g., about 0.005% (w/v) to about 0.1% (w/v), about 0.03%
(w/v) to about 0.1% (w/v), about 0.04% (w/v) to about 0.1% (w/v),
about 0.03% (w/v), about 0.04% (w/v), and/or about 0.1% (w/v)).
Each formulation in Table B has a pH of about 5.0 to about 5.5,
e.g., about 5.1 to about 5.3 and/or about 5.2. Optionally, the pH
of each formulation in Table B is adjusted using a strong acid
and/or strong base including, but not limited to, hydrochloric
acid, sodium hydroxide, calcium hydroxide, MSA, and/or MEA.
TABLE-US-00002 TABLE B Protein conc. Buffer Excipient(s) 180 mg/mL
15 mM adipate 120 mM N-acetyl arginine 0.7% PEG 400 20 mM MSA 180
mg/mL 15 mM adipate 120 mM N-acetyl arginine 40 mM CaCl.sub.2 20 mM
MSA 180 mg/mL 15 mM adipate 120 mM N-acetyl arginine 50 mM MEA-HCl
10 mM MSA 180 mg/mL 15 mM adipate 1.4% glycerol 40 mM MSA 180 mg/mL
15 mM adipate 1% PEG 400 40 mM MSA 180 mg/mL 15 mM adipate 1.2%
imidazole 180 mg/mL 20 mM adipate 75 mM CaCl.sub.2 0.3% PEG 400 1%
PVP 10K 180 mg/mL 20 mM adipate 100 mM MEA-HCl 0.3% PEG 400 1% PVP
10K 180 mg/mL 20 mM adipate 1% PEG 400 40 mM CaCl.sub.2 180 mg/mL
20 mM adipate 1% PEG 3350 75 mM CaCl.sub.2 180 mg/mL 20 mM adipate
1% PEG 3350 1.5% PEG 400 20 mM CaCl2 180 mg/mL 20 mM adipate 1% PEG
3350 1% PEG 400 40 mM CaCl.sub.2
[0375] In an embodiment, a lyophilized form of any one of the
foregoing adipate-containing adalimumab formulations is
provided.
Formulations of Adalimumab with Glucuronate Buffer
[0376] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 200
mg/mL, such as about 170 to about 190 mg/mL, about 90 to about 120
mg/mL, about 160 to about 190 mg/mL, about 40 to about 60 mg/mL,
about 50 mg/mL, about 100 mg/mL, or about 170 mg/mL, glucuronate at
a concentration of about 5 mM to about 50 mM (e.g., about 10 mM to
about 30 mM, about 10 mM, about 15 mM, about 20 mM, and/or about 25
mM), and one or more excipients. Suitable excipients include
certain stabilizers such as certain amino acids and amino acid
derivatives, certain polyols, certain acids, certain amines,
certain salts, and certain surfactants. Examples of suitable amino
acids and amino acid derivatives include proline (e.g., at a
concentration of about 0.1 to about 450 mM, about 250 to about 350
mM, or about 50 to about 300 mM). Examples of suitable polyols
include sucrose (e.g., at a concentration of about 0.1% (w/v) to
about 15% (w/v), about 4% (w/v) to about 10% (w/v), about 4% (w/v)
to about 9% (w/v), about 6.5% (w/v), about 6.8% (w/v), about 6.9%
(w/v), or about 9% (w/v)) and sorbitol (e.g., at a concentration of
about 0.1% (w/v) to about 10% (w/v), about 3% (w/v) to about 5%
(w/v), and/or about 4% (w/v)). Examples of suitable acids include
methane sulfonic acid (MSA) (e.g., at a concentration of about 0.1
to about 150 mM or about 0.1 to about 50 mM). Examples of suitable
amines include monoethanolamide hydrochloride (MEA-HCl) (e.g., at a
concentration of about 0.1 to about 150 mM or about 0.1 to about 40
mM) and monoethanolamide (MEA) (e.g., at a concentration of about
0.1 to about 300 mM or about 0.1 to about 50 mM). Examples of
suitable salts include sodium chloride (e.g., at a concentration of
about 10 to about 100 mM, about 60 to about 90 mM, about 15 to
about 50 mM, and/or about 35 mM) and calcium chloride (e.g., at a
concentration of about 1 to about 150 mM, about 5 to about 50 mM,
about 10 to about 30 mM, about 20 to about 40 mM, about 30 to about
50 mM, about 40 to about 80 mM, about 50 to about 100 mM, or about
25 mM). Examples of suitable surfactants include Pluronic F68
(e.g., at a concentration of about 0.001% (w/v) to about 10% (w/v),
about 0.005% (w/v) to about 1% (w/v), about 0.05% (w/v) to about
0.4% (w/v), about 0.05% (w/v) to about 0.1% (w/v), about 0.01%
(w/v), about 0.05% (w/v), and/or about 0.1% (w/v)), Polysorbate 20
(e.g., at a concentration of about 0.001% (w/v) to about 2% (w/v)
or about 0.005% (w/v) to about 0.1% (w/v)), and Polysorbate 80
(e.g., at a concentration of about 0.001% (w/v) to about 2% (w/v),
about 0.005% (w/v) to about 0.1% (w/v), about 0.005% (w/v) to about
0.05% (w/v), about 0.03% (w/v) to about 0.1% (w/v), about 0.04%
(w/v) to about 0.1% (w/v), about 0.03% (w/v), about 0.04% (w/v),
and/or about 0.1% (w/v)). Optionally, the glucuronate-containing
stable aqueous adalimumab formulation has a pH of about 4.8 to
about 5.7, for example, about 4.9 to about 5.6, about 5.0 to about
5.5, about 5.1 to about 5.4, about 5.1 to about 5.3, about 5.1 to
about 5.2, about 5.2 to about 5.3, and/or about 5.2. Optionally,
the pH of the stable aqueous adalimumab formulation is adjusted
using a strong acid and/or a strong base including, but not limited
to, hydrochloric acid, sodium hydroxide, calcium hydroxide, MSA,
and/or MEA.
[0377] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 200
mg/mL, such as about 170 to about 190 mg/mL, about 90 to about 120
mg/mL, about 160 to about 190 mg/mL, about 40 to about 60 mg/mL,
about 50 mg/mL, about 100 mg/mL, or about 170 mg/mL, glucuronate at
a concentration of about 5 mM to about 50 mM (e.g., about 10 mM to
about 30 mM, about 10 mM, about 15 mM, about 20 mM, and/or about 25
mM), and one or more excipients selected from the group consisting
of proline at a concentration of about 0.1 to about 450 mM (e.g.,
about 250 to about 350 mM or about 50 to about 300 mM), sodium
chloride at a concentration of about 10 to about 100 mM (e.g.,
about 60 to about 90 mM, about 15 to about 50 mM, and/or about 35
mM), calcium chloride at a concentration of about 1 to about 150 mM
(e.g., about 5 to about 50 mM, about 10 to about 30 mM, about 20 to
about 40 mM, about 30 to about 50 mM, about 40 to about 80 mM,
about 50 to about 100 mM, or about 25 mM), sucrose at a
concentration of about 0.1% (w/v) to about 15% (w/v) (e.g., about
4% (w/v) to about 10% (w/v), about 4% (w/v) to about 9% (w/v),
about 6.5% (w/v), about 6.8% (w/v), about 6.9% (w/v), or about 9%
(w/v)), sorbitol at a concentration of about 0.1% (w/v) to about
10% (w/v) (e.g., about 3% (w/v) to about 5% (w/v) and/or about 4%
(w/v)), methane sulfonic acid (MSA) at a concentration of about 0.1
to about 150 mM (e.g., about 0.1 to about 50 mM), monoethanolamide
hydrochloride (MEA-HCl) at a concentration of about 0.1 to about
150 mM (e.g., about 0.1 to about 40 mM), monoethanolamide (MEA) at
a concentration of about 0.1 to about 300 mM (e.g., about 0.1 to
about 50 mM), Pluronic F68 at a concentration of about 0.001% (w/v)
to about 10% (w/v) (e.g., about 0.005% (w/v) to about 1% (w/v),
about 0.05% (w/v) to about 0.4% (w/v), about 0.05% (w/v) to about
0.1% (w/v), about 0.01% (w/v), about 0.05% (w/v), and/or about 0.1%
(w/v)), Polysorbate 20 at a concentration of about 0.001% (w/v) to
about 2% (w/v) (e.g., about 0.005% (w/v) to about 0.1% (w/v)), and
Polysorbate 80 at a concentration of about 0.001% (w/v) to about 2%
(w/v) (e.g., about 0.005% (w/v) to about 0.1% (w/v), about 0.005%
(w/v) to about 0.05% (w/v), about 0.03% (w/v) to about 0.1% (w/v),
about 0.04% (w/v) to about 0.1% (w/v), about 0.03% (w/v), about
0.04% (w/v), and/or about 0.1% (w/v)). Optionally, the
glucuronate-containing stable aqueous adalimumab formulation has a
pH of about 4.8 to about 5.7, for example, about 4.9 to about 5.6,
about 5.0 to about 5.5, about 5.1 to about 5.4, about 5.1 to about
5.3, about 5.1 to about 5.2, about 5.2 to about 5.3, and/or about
5.2. Optionally, the pH of the stable aqueous adalimumab
formulation is adjusted using a strong acid and/or a strong base
including, but not limited to, hydrochloric acid, sodium hydroxide,
calcium hydroxide, MSA, and/or MEA.
[0378] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glucuronate at a concentration of about 10 mM to about 30
mM, and proline at a concentration of about 250 to about 350 mM,
and has a pH of about 5.0 to about 5.5.
[0379] Exemplary aqueous adalimumab formulations are provided in
Table C. Each formulation in Table C may optionally include
Pluronic F68 at a concentration of about 0.001% (w/v) to about 10%
(w/v) (e.g., about 0.005% (w/v) to about 1% (w/v), about 0.05%
(w/v) to about 0.4% (w/v), about 0.05% (w/v) to about 0.1% (w/v),
about 0.01% (w/v), about 0.05% (w/v), and/or about 0.1% (w/v)),
Polysorbate 20 at a concentration of about 0.001% (w/v) to about 2%
(w/v) (e.g., about 0.005% (w/v) to about 0.1% (w/v)), or
Polysorbate 80 at a concentration of about 0.001% (w/v) to about 2%
(w/v) (e.g., about 0.005% (w/v) to about 0.1% (w/v), about 0.03%
(w/v) to about 0.1% (w/v), about 0.04% (w/v) to about 0.1% (w/v),
about 0.03% (w/v), about 0.04% (w/v), and/or about 0.1% (w/v)).
Each formulation in Table C has a pH of about 5.0 to about 5.5,
e.g., about 5.1 to about 5.3 and/or about 5.2. Optionally, the pH
of each formulation in Table C is adjusted using a strong acid
and/or strong base including, but not limited to, hydrochloric
acid, sodium hydroxide, calcium hydroxide, MSA, and/or MEA.
TABLE-US-00003 TABLE C Protein conc. Buffer Excipient(s) 105 mg/mL
20 mM MEA glucuronate 300 mM proline 105 mg/mL 20 mM Na glucuronate
300 mM proline
[0380] In an embodiment, a lyophilized form of any one of the
foregoing glucuronate-containing adalimumab formulations is
provided.
Formulations of Adalimumab with Acetate Buffer
[0381] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 200
mg/mL, such as about 90 to about 120 mg/mL, about 90 to about 110
mg/mL, about 100 to about 110 mg/mL, about 120 to about 160 mg/mL,
about 130 to about 150 mg/mL, about 160 to about 190 mg/mL, about
160 to about 180 mg/mL, about 170 to about 180 mg/mL, about 40 to
about 60 mg/mL, about 40 to about 50 mg/mL, about 50 mg/mL, about
100 mg/mL, or about 170 mg/mL, acetic acid and/or acetate at a
concentration of about 0.1 mM to about 300 mM (e.g., about 2 mM to
about 30 mM, about 5 mM to about 50 mM, about 5 mM to about 15 mM,
about 10 mM to about 20 mM, about 10 mM to about 30 mM, about 15 mM
to about 25 mM, about 30 mM to about 40 mM, about 35 mM to about 45
mM, about 40 mM to about 50 mM, about 10 mM, about 15 mM, about 20
mM, and/or about 25 mM), and one or more excipients. Suitable
excipients include certain stabilizers such as certain amino acids
and amino acid derivatives, certain polyols, certain acids, certain
amines, certain salts, certain polysaccharides or polysaccharide
derivatives, and certain surfactants. Examples of suitable amino
acids and amino acid derivatives include arginine-HCl (e.g., at a
concentration of about 0.1 to about 450 mM, about 20 to about 200
mM, about 50 to about 150 mM, about 80 to about 120 mM, and/or
about 100 mM) and proline (e.g., at a concentration of about 0.1 to
about 450 mM, about 20 to about 400 mM, about 50 to about 350 mM,
about 50 to about 300 mM, about 80 to about 300 mM, about 100 to
about 250 mM, about 150 to about 230 mM, about 100 to about 140 mM,
about 130 to about 170 mM, about 160 to about 200 mM, about 190 to
about 230 mM, about 220 to about 260 mM, about 250 to about 290 mM
and/or about 220 mM). Examples of suitable polyols include sucrose
(e.g., at a concentration of about 0.1% (w/v) to about 15% (w/v)
about 4% (w/v) to about 12% (w/v), about 4% (w/v) to about 10%
(w/v), about 4% (w/v) to about 9% (w/v), about 5% (w/v) to about
10% (w/v), about 6% (w/v) to about 8% (w/v), about 8% (w/v) to
about 10% (w/v), about 8.5% (w/v) to about 9.5% (w/v), about 9%
(w/v), about 5.8% (w/v) to about 6.6% (w/v), about 6% (w/v) to
about 6.4% (w/v), about 6.2% (w/v), about 6.1% (w/v) to about 6.9%
(w/v), about 6.3% (w/v) to about 6.7% (w/v), about 6.5% (w/v),
about 6.4% (w/v) to about 7.2% (w/v), about 6.6% (w/v) to about 7%
(w/v), about 6.8% (w/v), about 6.5% (w/v) to about 7.3% (w/v),
about 6.7% (w/v) to about 7.1% (w/v), about 6.9% (w/v), about 6.6%
(w/v) to about 7.4% (w/v), about 6.8% (w/v) to about 7.2% (w/v),
about 7% (w/v), about 6.9% (w/v) to about 7.7% (w/v), about 7.1%
(w/v) to about 7.5% (w/v), and/or about 7.3% (w/v)) and sorbitol
(e.g., at a concentration of about 0.1% (w/v) to about 10% (w/v),
about 3% (w/v) to about 5% (w/v), and/or about 4% (w/v)). Examples
of suitable acids include MSA (e.g., at a concentration of about
0.1 to about 150 mM, about 0.1 to about 50 mM, about 10 to about 50
mM, about 20 to about 40 mM, about 30 mM, about 30 to about 50 mM,
about 40 to about 60 mM, about 50 to about 70 mM, about 60 to about
80 mM, about 70 to about 90 mM, and/or about 80 to about 100 mM).
Examples of suitable amines include MEA-HCl (e.g., at a
concentration of about 0.1 to about 150 mM, about 0.1 to about 40
mM, about 10 to about 50 mM, about 20 to about 40 mM, about 30 mM,
about 30 to about 50 mM, about 40 to about 60 mM, about 50 to about
70 mM, about 60 to about 80 mM, about 70 to about 90 mM, and/or
about 80 to about 100 mM) and MEA (e.g., at a concentration of
about 0.1 to about 300 mM, about 0.1 to about 50 mM, about 10 to
about 50 mM, about 20 to about 40 mM, about 30 mM, about 30 to
about 50 mM, about 40 to about 60 mM, about 50 to about 70 mM,
about 60 to about 80 mM, about 70 to about 90 mM, and/or about 80
to about 100 mM). Examples of suitable salts include calcium
chloride (e.g., at a concentration of about 1 to about 150 mM,
about 5 to about 50 mM, about 5 to about 15 mM, about 10 to about
40 mM, about 10 to about 30 mM, about 15 to about 35 mM, about 20
to about 30 mM, about 20 to about 40 mM, about 30 to about 50 mM,
about 40 to about 50 mM, about 40 to about 60 mM, about 40 to about
80 mM, about 50 to about 100 mM, about 10 mM, about 25 mM, and/or
about 45 mM) and sodium chloride (e.g., at a concentration of about
10 to about 100 mM, about 60 to about 90 mM, about 15 to about 50
mM, and/or about 35 mM). Examples of suitable polysaccharides or
polysaccharide derivatives include sodium carboxymethylcellulose
(NaCMC) (e.g., at a concentration of about 0.1% (w/v) to about 15%
(w/v), about 0.1% (w/v) to about 5% (w/v), about 0.1% (w/v) to
about 2% (w/v), about 0.1% (w/v) to about 1% (w/v), and/or about
0.1% (w/v) to about 0.5% (w/v)). Examples of suitable surfactants
include guanidine hydrochloride (GnHCl) (e.g., at a concentration
of about 0.1 to about 150 mM, 5 to about 50 mM, about 10 to about
40 mM, about 15 to about 30 mM, and/or 20 mM), Pluronic F68 (e.g.,
at a concentration of about 0.001% (w/v) to about 10% (w/v), about
0.005% (w/v) to about 1% (w/v), about 0.01% (w/v) to about 0.1%
(w/v), about 0.01% (w/v) to about 1% (w/v), about 0.05% (w/v) to
about 0.1% (w/v), about 0.05% (w/v) to about 0.4% (w/v), about
0.05% (w/v) to about 0.5% (w/v), about 0.1% (w/v) to about 2%
(w/v), about 0.2% (w/v) to about 1% (w/v), about 0.01% (w/v), about
0.05% (w/v), about 0.1% (w/v), and/or about 0.4% (w/v)), Docusate
sodium (e.g., at a concentration of about 0.001% (w/v) to about 1%
(w/v) or about 0.005% (w/v) to about 0.05% (w/v)), benzalkonium
chloride (e.g., at a concentration of about 0.001% (w/v) to about
1% (w/v) or about 0.05% (w/v) to about 0.5% (w/v)), Span 40 (e.g.,
at a concentration of about 0.001% (w/v) to about 1% (w/v) or about
0.05% (w/v) to about 0.5% (w/v)), Triton X-100 (e.g., at a
concentration of about 0.001% (w/v) to about 1% (w/v), about 0.002%
(w/v) to about 0.01% (w/v), about 0.005% (w/v) to about 0.05%
(w/v), about 0.02% (w/v) to about 0.1% (w/v), and/or about 0.05%
(w/v) to about 0.2% (w/v)), Polysorbate 20 (e.g., at a
concentration of about 0.001% (w/v) to about 2% (w/v), about 0.002%
(w/v) to about 0.01% (w/v), about 0.005% (w/v) to about 0.05%
(w/v), about 0.005% (w/v) to about 0.1% (w/v), about 0.02% (w/v) to
about 0.1% (w/v), and/or about 0.05% (w/v) to about 0.2% (w/v)),
and Polysorbate 80 (e.g., at a concentration of about 0.001% (w/v)
to about 2% (w/v), about 0.002% (w/v) to about 0.01% (w/v), about
0.005% (w/v) to about 0.1% (w/v), about 0.005% (w/v) to about 0.05%
(w/v), about 0.02% (w/v) to about 0.1% (w/v), about 0.03% (w/v) to
about 0.1% (w/v), 0.04% (w/v) to about 0.1% (w/v), about 0.05%
(w/v) to about 0.2% (w/v), about 0.03% (w/v), about 0.04% (w/v),
and/or about 0.1% (w/v)). Optionally, the acetate-containing stable
aqueous adalimumab formulation has a pH of about 4.8 to about 5.7,
for example, about 4.9 to about 5.6, about 5.0 to about 5.5, about
5.1 to about 5.4, about 5.1 to about 5.3, about 5.1 to about 5.2,
about 5.2 to about 5.3, and/or about 5.2. Optionally, the pH of the
stable aqueous adalimumab formulation is adjusted using a strong
acid and/or a strong base including, but not limited to,
hydrochloric acid, sodium hydroxide, calcium hydroxide, MSA, and/or
MEA.
[0382] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 200
mg/mL, such as about 90 to about 120 mg/mL, about 90 to about 110
mg/mL, about 100 to about 110 mg/mL, about 120 to about 160 mg/mL,
about 130 to about 150 mg/mL, about 160 to about 190 mg/mL, about
160 to about 180 mg/mL, about 170 to about 180 mg/mL, about 40 to
about 60 mg/mL, about 40 to about 50 mg/mL, about 50 mg/mL, about
100 mg/mL, or about 170 mg/mL, acetic acid and/or acetate at a
concentration of about 0.1 mM to about 300 mM (e.g., about 2 mM to
about 30 mM, about 5 mM to about 50 mM, about 5 mM to about 15 mM,
about 10 mM to about 20 mM, about 10 mM to about 30 mM, about 15 mM
to about 25 mM, about 30 mM to about 40 mM, about 35 mM to about 45
mM, about 40 mM to about 50 mM, about 10 mM, about 15 mM, about 20
mM, and/or about 25 mM), and one or more excipients selected from
the group consisting of sucrose at a concentration of about 0.1%
(w/v) to about 15% (w/v) (e.g., about 4% (w/v) to about 12% (w/v),
about 4% (w/v) to about 10% (w/v), about 4% (w/v) to about 9%
(w/v), about 5% (w/v) to about 10% (w/v), about 6% (w/v) to about
8% (w/v), about 8% (w/v) to about 10% (w/v), about 8.5% (w/v) to
about 9.5% (w/v), about 9% (w/v), about 5.8% (w/v) to about 6.6%
(w/v), about 6% (w/v) to about 6.4% (w/v), about 6.2% (w/v), about
6.1% (w/v) to about 6.9% (w/v), about 6.3% (w/v) to about 6.7%
(w/v), about 6.5% (w/v), about 6.4% (w/v) to about 7.2% (w/v),
about 6.6% (w/v) to about 7% (w/v), about 6.8% (w/v), about 6.5%
(w/v) to about 7.3% (w/v), about 6.7% (w/v) to about 7.1% (w/v),
about 6.9% (w/v), about 6.6% (w/v) to about 7.4% (w/v), about 6.8%
(w/v) to about 7.2% (w/v), about 7% (w/v), about 6.9% (w/v) to
about 7.7% (w/v), about 7.1% (w/v) to about 7.5% (w/v), and/or
about 7.3% (w/v)), sorbitol at a concentration of about 0.1% (w/v)
to about 10% (w/v) (e.g., about 3% (w/v) to about 5% (w/v) and/or
about 4% (w/v)), calcium chloride at a concentration of about 1 to
about 150 mM (e.g., about 5 to about 50 mM, about 5 to about 15 mM,
about 10 to about 40 mM, about 10 to about 30 mM, about 15 to about
35 mM, about 20 to about 30 mM, about 20 to about 40 mM, about 30
to about 50 mM, about 40 to about 50 mM, about 40 to about 60 mM,
about 40 to about 80 mM, about 50 to about 100 mM, about 10 mM,
about 25 mM, and/or about 45 mM), sodium chloride at a
concentration of about 10 to about 100 mM (e.g., about 60 to about
90 mM, about 15 to about 50 mM, and/or about 35 mM), MSA at a
concentration of about 0.1 to about 150 mM (e.g., about 0.1 to
about 50 mM, about 10 to about 50 mM, about 20 to about 40 mM,
about 30 mM, about 30 to about 50 mM, about 40 to about 60 mM,
about 50 to about 70 mM, about 60 to about 80 mM, about 70 to about
90 mM, and/or about 80 to about 100 mM), MEA-HCl at a concentration
of about 0.1 to about 150 mM (e.g., about 0.1 to about 40 mM, about
10 to about 50 mM, about 20 to about 40 mM, about 30 mM, about 30
to about 50 mM, about 40 to about 60 mM, about 50 to about 70 mM,
about 60 to about 80 mM, about 70 to about 90 mM, and/or about 80
to about 100 mM), MEA at a concentration of about 0.1 to about 300
mM (e.g., about 0.1 to about 50 mM, about 10 to about 50 mM, about
20 to about 40 mM, about 30 mM, about 30 to about 50 mM, about 40
to about 60 mM, about 50 to about 70 mM, about 60 to about 80 mM,
about 70 to about 90 mM, and/or about 80 to about 100 mM),
guanidine hydrochloride (GnHCl) at a concentration of about 0.1 to
about 150 mM (e.g., 5 to about 50 mM, about 10 to about 40 mM,
about 15 to about 30 mM, and/or 20 mM), sodium
carboxymethylcellulose (NaCMC) at a concentration of about 0.1%
(w/v) to about 15% (w/v) (e.g., about 0.1% (w/v) to about 5% (w/v),
about 0.1% (w/v) to about 2% (w/v), about 0.1% (w/v) to about 1%
(w/v), and/or about 0.1% (w/v) to about 0.5% (w/v)), arginine-HCl
at a concentration of about 0.1 to about 450 mM (e.g., about 20 to
about 200 mM, about 50 to about 150 mM, about 80 to about 120 mM,
and/or about 100 mM), proline at a concentration of about 0.1 to
about 450 mM (e.g., about 20 to about 400 mM, about 50 to about 350
mM, about 50 to about 300 mM, about 80 to about 300 mM, about 100
to about 250 mM, about 150 to about 230 mM, about 100 to about 140
mM, about 130 to about 170 mM, about 160 to about 200 mM, about 190
to about 230 mM, about 220 to about 260 mM, about 250 to about 290
mM and/or about 220 mM), Pluronic F68 at a concentration of about
0.001% (w/v) to about 10% (w/v) (e.g., about 0.005% (w/v) to about
1% (w/v), about 0.01% (w/v) to about 0.1% (w/v), about 0.01% (w/v)
to about 1% (w/v), about 0.05% (w/v) to about 0.1% (w/v), about
0.05% (w/v) to about 0.4% (w/v), about 0.05% (w/v) to about 0.5%
(w/v), about 0.1% (w/v) to about 2% (w/v), about 0.2% (w/v) to
about 1% (w/v), about 0.01% (w/v), about 0.05% (w/v), about 0.1%
(w/v), and/or about 0.4% (w/v)), Docusate sodium at a concentration
of about 0.001% (w/v) to about 1% (w/v) (e.g., about 0.005% (w/v)
to about 0.05% (w/v)), benzalkonium chloride at a concentration of
about 0.001% (w/v) to about 1% (w/v) (e.g., about 0.05% (w/v) to
about 0.5% (w/v)), Span 40 at a concentration of about 0.001% (w/v)
to about 1% (w/v) (e.g., about 0.05% (w/v) to about 0.5% (w/v)),
Triton X-100 at a concentration of about 0.001% (w/v) to about 1%
(w/v) (e.g., about 0.002% (w/v) to about 0.01% (w/v), about 0.005%
(w/v) to about 0.05% (w/v), about 0.02% (w/v) to about 0.1% (w/v),
and/or about 0.05% (w/v) to about 0.2% (w/v)), Polysorbate 20 at a
concentration of about 0.001% (w/v) to about 2% (w/v) (e.g., about
0.002% (w/v) to about 0.01% (w/v), about 0.005% (w/v) to about
0.05% (w/v), about 0.005% (w/v) to about 0.1% (w/v), about 0.02%
(w/v) to about 0.1% (w/v), and/or about 0.05% (w/v) to about 0.2%
(w/v)), and Polysorbate 80 at a concentration of about 0.001% (w/v)
to about 2% (w/v) (e.g., about 0.002% (w/v) to about 0.01% (w/v),
about 0.005% (w/v) to about 0.1% (w/v), about 0.005% (w/v) to about
0.05% (w/v), about 0.02% (w/v) to about 0.1% (w/v), about 0.03%
(w/v) to about 0.1% (w/v), 0.04% (w/v) to about 0.1% (w/v), about
0.05% (w/v) to about 0.2% (w/v), about 0.03% (w/v), about 0.04%
(w/v), and/or about 0.1% (w/v)). Optionally, the acetate-containing
stable aqueous adalimumab formulation has a pH of about 4.8 to
about 5.7, for example, about 4.9 to about 5.6, about 5.0 to about
5.5, about 5.1 to about 5.4, about 5.1 to about 5.3, about 5.1 to
about 5.2, about 5.2 to about 5.3, and/or about 5.2. Optionally,
the pH of the stable aqueous adalimumab formulation is adjusted
using a strong acid and/or a strong base including, but not limited
to, hydrochloric acid, sodium hydroxide, calcium hydroxide, MSA,
and/or MEA.
[0383] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Polysorbate 20 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3.
[0384] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Polysorbate 80 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3.
[0385] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3.
[0386] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Docusate sodium at a concentration of about 0.005% (w/v) to about
0.05% (w/v), and has a pH of about 5.1 to 5.3.
[0387] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
benzalkonium chloride at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3.
[0388] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Span 40 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3.
[0389] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Triton X-100 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3.
[0390] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM, and
arginine-HCl at a concentration of about 80 to about 120 mM, and
has a pH of about 5.1 to 5.3.
[0391] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Polysorbate 80 at a concentration of about 0.0025% (w/v) to about
0.025% (w/v), and has a pH of about 5.1 to 5.3.
[0392] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Polysorbate 80 at a concentration of about 0.005% (w/v) to about
0.05% (w/v), and has a pH of about 5.1 to 5.3.
[0393] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Polysorbate 80 at a concentration of about 0.025% (w/v) to about
0.25% (w/v), and has a pH of about 5.1 to 5.3.
[0394] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Polysorbate 20 at a concentration of about 0.0025% (w/v) to about
0.025% (w/v), and has a pH of about 5.1 to 5.3.
[0395] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Polysorbate 20 at a concentration of about 0.005% (w/v) to about
0.05% (w/v), and has a pH of about 5.1 to 5.3.
[0396] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Polysorbate 20 at a concentration of about 0.025% (w/v) to about
0.25% (w/v), and has a pH of about 5.1 to 5.3.
[0397] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Triton X-100 at a concentration of about 0.0025% (w/v) to about
0.025% (w/v), and has a pH of about 5.1 to 5.3.
[0398] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Triton X-100 at a concentration of about 0.005% (w/v) to about
0.05% (w/v), and has a pH of about 5.1 to 5.3.
[0399] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Triton X-100 at a concentration of about 0.025% (w/v) to about
0.25% (w/v), and has a pH of about 5.1 to 5.3.
[0400] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Pluronic F68 at a concentration of about 0.025% (w/v) to about
0.25% (w/v), and has a pH of about 5.1 to 5.3.
[0401] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3.
[0402] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 120 to about 160
mg/mL, acetate at a concentration of about 15 mM to about 25 mM,
calcium chloride at a concentration of about 30 to about 60 mM,
arginine-HCl at a concentration of about 80 to about 120 mM, and
Pluronic F68 at a concentration of about 0.2% (w/v) to about 0.6%
(w/v), and has a pH of about 5.1 to 5.3.
[0403] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 150 to about 180
mg/mL, acetate at a concentration of about 5 mM to about 10 mM,
sucrose at a concentration of about 7% (w/v) to about 10% (w/v),
and Polysorbate 80 at a concentration of about 0.05% (w/v) to about
0.2% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with MSA and/or
MEA.
[0404] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 50
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.5% (w/v) to about 7.1% (w/v),
calcium chloride at a concentration of about 15 to about 35 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3.
[0405] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 50
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.0% (w/v) to about 6.5% (w/v),
calcium chloride at a concentration of about 15 to about 35 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3.
[0406] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 50
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.6% (w/v) to about 7.2% (w/v),
MEA-HCl at a concentration of about 20 to about 40 mM, and Pluronic
F68 at a concentration of about 0.05% (w/v) to about 0.5% (w/v),
and has a pH of about 5.1 to 5.3.
[0407] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 50
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.7% (w/v) to about 7.3% (w/v),
calcium chloride at a concentration of about 5 to about 15 mM,
guanidine hydrochloride (GnHCl) at a concentration of about 10 to
about 30 mM, and Pluronic F68 at a concentration of about 0.05%
(w/v) to about 0.5% (w/v), and has a pH of about 5.1 to 5.3.
[0408] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 50
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.7% (w/v) to about 7.3% (w/v),
calcium chloride at a concentration of about 5 to about 15 mM,
NaCMC at a concentration of about 0.2% (w/v) to about 1% (w/v), and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3.
[0409] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL, acetate at a concentration of about 5 mM to about 15 mM, and
sucrose at a concentration of about 8% (w/v) to about 10% (w/v),
and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with HCl and/or NaOH.
[0410] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 8% (w/v) to about 10% (w/v),
and Polysorbate 80 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0411] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 8.5% (w/v) to about 9.5% (w/v),
and Polysorbate 80 at a concentration of about 0.05% (w/v) to about
0.2% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0412] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 8% (w/v) to about 10% (w/v),
and Pluronic F68 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0413] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 110
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 8.5% (w/v) to about 9.5% (w/v),
and Pluronic F68 at a concentration of about 0.05% (w/v) to about
0.2% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0414] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.4% (w/v) to about 7.2% (w/v),
calcium chloride at a concentration of about 15 to about 35 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0415] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
proline at a concentration of about 190 to about 250 mM, calcium
chloride at a concentration of about 15 to about 35 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0416] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.5% (w/v) to about 7.3% (w/v),
MEA-HCl at a concentration of about 20 to about 40 mM, and Pluronic
F68 at a concentration of about 0.05% (w/v) to about 0.5% (w/v),
and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0417] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.9% (w/v) to about 7.7% (w/v),
MSA at a concentration of about 20 to about 40 mM, and Pluronic F68
at a concentration of about 0.05% (w/v) to about 0.5% (w/v), and
has a pH of about 5.1 to 5.3. Optionally, the pH of the formulation
is adjusted within this range with NaOH, Ca(OH).sub.2, or MEA.
[0418] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.5% (w/v) to about 7.3% (w/v),
sodium chloride at a concentration of about 20 to about 45 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0419] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 8% (w/v) to about 10% (w/v),
and Pluronic F68 at a concentration of about 0.01% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0420] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 110
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 8.5% (w/v) to about 9.5% (w/v),
and Pluronic F68 at a concentration of about 0.03% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0421] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.4% (w/v) to about 7.2% (w/v),
calcium chloride at a concentration of about 15 to about 35 mM, and
Pluronic F68 at a concentration of about 0.01% (w/v) to about 0.1%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0422] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
proline at a concentration of about 190 to about 250 mM, calcium
chloride at a concentration of about 15 to about 35 mM, and
Pluronic F68 at a concentration of about 0.01% (w/v) to about 0.1%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0423] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.5% (w/v) to about 7.3% (w/v),
MEA-HCl at a concentration of about 20 to about 40 mM, and Pluronic
F68 at a concentration of about 0.01% (w/v) to about 0.1% (w/v),
and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0424] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.9% (w/v) to about 7.7% (w/v),
MSA at a concentration of about 20 to about 40 mM, and Pluronic F68
at a concentration of about 0.01% (w/v) to about 0.1% (w/v), and
has a pH of about 5.1 to 5.3. Optionally, the pH of the formulation
is adjusted within this range with NaOH, Ca(OH).sub.2, or MEA.
[0425] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.5% (w/v) to about 7.3% (w/v),
sodium chloride at a concentration of about 20 to about 45 mM, and
Pluronic F68 at a concentration of about 0.01% (w/v) to about 0.1%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0426] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 8% (w/v) to about 10% (w/v),
and Polysorbate 80 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0427] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.4% (w/v) to about 7.2% (w/v),
calcium chloride at a concentration of about 15 to about 35 mM, and
Polysorbate 80 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0428] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
proline at a concentration of about 190 to about 250 mM, calcium
chloride at a concentration of about 15 to about 35 mM, and
Polysorbate 80 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0429] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.5% (w/v) to about 7.3% (w/v),
MEA-HCl at a concentration of about 20 to about 40 mM, and
Polysorbate 80 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0430] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.9% (w/v) to about 7.7% (w/v),
MSA at a concentration of about 20 to about 40 mM, and Polysorbate
80 at a concentration of about 0.05% (w/v) to about 0.5% (w/v), and
has a pH of about 5.1 to 5.3. Optionally, the pH of the formulation
is adjusted within this range with NaOH, Ca(OH).sub.2, or MEA.
[0431] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.5% (w/v) to about 7.3% (w/v),
sodium chloride at a concentration of about 20 to about 45 mM, and
Polysorbate 80 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0432] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 8% (w/v) to about 10% (w/v),
and Polysorbate 80 at a concentration of about 0.01% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0433] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 110
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 8.5% (w/v) to about 9.5% (w/v),
and Polysorbate 80 at a concentration of about 0.03% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0434] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.4% (w/v) to about 7.2% (w/v),
calcium chloride at a concentration of about 15 to about 35 mM, and
Polysorbate 80 at a concentration of about 0.01% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0435] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 110
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.6% (w/v) to about 7% (w/v),
calcium chloride at a concentration of about 20 to about 30 mM, and
Polysorbate 80 at a concentration of about 0.03% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0436] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
proline at a concentration of about 190 to about 250 mM, calcium
chloride at a concentration of about 15 to about 35 mM, and
Polysorbate 80 at a concentration of about 0.01% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0437] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.5% (w/v) to about 7.3% (w/v),
MEA-HCl at a concentration of about 20 to about 40 mM, and
Polysorbate 80 at a concentration of about 0.01% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0438] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.9% (w/v) to about 7.7% (w/v),
MSA at a concentration of about 20 to about 40 mM, and Polysorbate
80 at a concentration of about 0.01% (w/v) to about 0.1% (w/v), and
has a pH of about 5.1 to 5.3. Optionally, the pH of the formulation
is adjusted within this range with NaOH, Ca(OH).sub.2, or MEA.
[0439] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.5% (w/v) to about 7.3% (w/v),
sodium chloride at a concentration of about 20 to about 45 mM, and
Polysorbate 80 at a concentration of about 0.01% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0440] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 110
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.7% (w/v) to about 7.1% (w/v),
sodium chloride at a concentration of about 25 to about 40 mM, and
Polysorbate 80 at a concentration of about 0.03% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0441] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 8% (w/v) to about 10% (w/v),
and Polysorbate 20 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0442] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.4% (w/v) to about 7.2% (w/v),
calcium chloride at a concentration of about 15 to about 35 mM, and
Polysorbate 20 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0443] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
proline at a concentration of about 190 to about 250 mM, calcium
chloride at a concentration of about 15 to about 35 mM, and
Polysorbate 20 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0444] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.5% (w/v) to about 7.3% (w/v),
MEA-HCl at a concentration of about 20 to about 40 mM, and
Polysorbate 20 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0445] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.9% (w/v) to about 7.7% (w/v),
MSA at a concentration of about 20 to about 40 mM, and Polysorbate
20 at a concentration of about 0.05% (w/v) to about 0.5% (w/v), and
has a pH of about 5.1 to 5.3. Optionally, the pH of the formulation
is adjusted within this range with NaOH, Ca(OH).sub.2, or MEA.
[0446] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.5% (w/v) to about 7.3% (w/v),
sodium chloride at a concentration of about 20 to about 45 mM, and
Polysorbate 20 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0447] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 8% (w/v) to about 10% (w/v),
and Polysorbate 20 at a concentration of about 0.01% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0448] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.4% (w/v) to about 7.2% (w/v),
calcium chloride at a concentration of about 15 to about 35 mM, and
Polysorbate 20 at a concentration of about 0.01% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0449] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
proline at a concentration of about 190 to about 250 mM, calcium
chloride at a concentration of about 15 to about 35 mM, and
Polysorbate 20 at a concentration of about 0.01% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0450] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.5% (w/v) to about 7.3% (w/v),
MEA-HCl at a concentration of about 20 to about 40 mM, and
Polysorbate 20 at a concentration of about 0.01% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0451] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.9% (w/v) to about 7.7% (w/v),
MSA at a concentration of about 20 to about 40 mM, and Polysorbate
20 at a concentration of about 0.01% (w/v) to about 0.1% (w/v), and
has a pH of about 5.1 to 5.3. Optionally, the pH of the formulation
is adjusted within this range with NaOH, Ca(OH).sub.2, or MEA.
[0452] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, acetate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 6.5% (w/v) to about 7.3% (w/v),
sodium chloride at a concentration of about 20 to about 45 mM, and
Polysorbate 20 at a concentration of about 0.01% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0453] Exemplary aqueous adalimumab formulations are provided in
Table D. Each formulation in Table D may optionally include
Pluronic F68 at a concentration of about 0.001% (w/v) to about 10%
(w/v) (e.g., about 0.005% (w/v) to about 1% (w/v), about 0.01%
(w/v) to about 0.1% (w/v), about 0.01% (w/v) to about 1% (w/v),
about 0.05% (w/v) to about 0.1% (w/v), about 0.05% (w/v) to about
0.4% (w/v), about 0.05% (w/v) to about 0.5% (w/v), about 0.1% (w/v)
to about 2% (w/v), about 0.2% (w/v) to about 1% (w/v), about 0.01%
(w/v), about 0.05% (w/v), about 0.1% (w/v), and/or about 0.4%
(w/v)), Polysorbate 20 at a concentration of about 0.001% (w/v) to
about 2% (w/v) (e.g., about 0.002% (w/v) to about 0.01% (w/v),
about 0.005% (w/v) to about 0.05% (w/v), about 0.005% (w/v) to
about 0.1% (w/v), about 0.02% (w/v) to about 0.1% (w/v), and/or
about 0.05% (w/v) to about 0.2% (w/v)), or Polysorbate 80 at a
concentration of about 0.001% (w/v) to about 2% (w/v) (e.g., about
0.002% (w/v) to about 0.01% (w/v), about 0.005% (w/v) to about 0.1%
(w/v), about 0.005% (w/v) to about 0.05% (w/v), about 0.02% (w/v)
to about 0.1% (w/v), about 0.03% (w/v) to about 0.1% (w/v), 0.04%
(w/v) to about 0.1% (w/v), about 0.05% (w/v) to about 0.2% (w/v),
about 0.03% (w/v), about 0.04% (w/v), and/or about 0.1% (w/v)).
Each formulation in Table D has a pH of about 5.0 to about 5.5,
e.g., about 5.1 to about 5.3 and/or about 5.2. Optionally, the pH
of each formulation in Table D is adjusted using a strong acid
and/or strong base including, but not limited to, hydrochloric
acid, sodium hydroxide, calcium hydroxide, MSA, and/or MEA.
TABLE-US-00004 TABLE D Protein conc. Buffer Excipient(s) 50 mg/mL
10 mM sodium acetate 6.8% (w/v) sucrose 25 mM CaCl.sub.2 50 mg/mL
10 mM calcium acetate 6.2% (w/v) sucrose 25 mM CaCl.sub.2 50 mg/mL
10 mM sodium acetate 6.9% (w/v) sucrose 30 mM MEA-HCl 50 mg/mL 10
mM sodium acetate 7% (w/v) sucrose 10 mM CaCl.sub.2 20 mM GnHCl 50
mg/mL 10 mM sodium acetate 7% (w/v) sucrose 10 mM CaCl.sub.2 0.5%
NaCMC 50 mg/mL 10 mM acetate 9% (w/v) sucrose 100 mg/mL 10 mM
acetate 9% (w/v) sucrose 100 mg/mL 10 mM acetate 6.8% (w/v) sucrose
25 mM CaCl.sub.2 100 mg/mL 10 mM acetate 220 mM proline 25 mM
CaCl.sub.2 100 mg/mL 10 mM acetate 6.9% (w/v) sucrose 30 mM MEA-HCl
100 mg/mL 10 mM acetate 7.3% (w/v) sucrose 30 mM MSA 100 mg/mL 10
mM acetate 6.9% (w/v) sucrose 35 mM NaCl
[0454] Exemplary aqueous adalimumab formulations are provided in
Table E. Each formulation in Table E has a pH of about 5.0 to about
5.5, e.g., about 5.1 to about 5.3 and/or about 5.2. Optionally, the
pH of each formulation in Table E is adjusted using a strong acid
and/or strong base including, but not limited to, hydrochloric
acid, sodium hydroxide, calcium hydroxide, MSA, and/or MEA.
TABLE-US-00005 TABLE E Protein conc. Buffer Excipient(s) Surfactant
50 mg/mL 10 mM sodium 6.8% (w/v) sucrose 0.1% (w/v) acetate 25 mM
CaCl.sub.2 Pluronic F68 50 mg/mL 10 mM calcium 6.2% (w/v) sucrose
0.1% (w/v) acetate 25 mM CaCl.sub.2 Pluronic F68 50 mg/mL 10 mM
sodium 6.9% (w/v) sucrose 0.1% (w/v) acetate 30 mM MEA-HCl Pluronic
F68 50 mg/mL 10 mM sodium 7% (w/v) sucrose 0.1% (w/v) acetate 10 mM
CaCl.sub.2 Pluronic F68 20 mM GnHCl 50 mg/mL 10 mM sodium 7% (w/v)
sucrose 0.1% (w/v) acetate 10 mM CaCl.sub.2 Pluronic F68 0.5% NaCMC
50 mg/mL 10 mM acetate 9% (w/v) sucrose 0.1% (w/v) Polysorbate 80
100 mg/mL 10 mM acetate 9% (w/v) sucrose 0.1% (w/v) Pluronic F68
100 mg/mL 10 mM acetate 6.8% (w/v) sucrose 0.1% (w/v) 25 mM
CaCl.sub.2 Pluronic F68 100 mg/mL 10 mM acetate 220 mM proline 0.1%
(w/v) 25 mM CaCl.sub.2 Pluronic F68 100 mg/mL 10 mM acetate 6.9%
(w/v) sucrose 0.1% (w/v) 30 mM MEA-HCl Pluronic F68 100 mg/mL 10 mM
acetate 7.3% (w/v) sucrose 0.1% (w/v) 30 mM MSA Pluronic F68 100
mg/mL 10 mM acetate 6.9% (w/v) sucrose 0.1% (w/v) 35 mM NaCl
Pluronic F68 100 mg/mL 10 mM acetate 9% (w/v) sucrose 0.05% (w/v)
Pluronic F68 100 mg/mL 10 mM acetate 6.8% (w/v) sucrose 0.05% (w/v)
25 mM CaCl.sub.2 Pluronic F68 100 mg/mL 10 mM acetate 220 mM
proline 0.05% (w/v) 25 mM CaCl.sub.2 Pluronic F68 100 mg/mL 10 mM
acetate 6.9% (w/v) sucrose 0.05% (w/v) 30 mM MEA-HCl Pluronic F68
100 mg/mL 10 mM acetate 7.3% (w/v) sucrose 0.05% (w/v) 30 mM MSA
Pluronic F68 100 mg/mL 10 mM acetate 6.9% (w/v) sucrose 0.05% (w/v)
35 mM NaCl Pluronic F68 100 mg/mL 10 mM acetate 9% (w/v) sucrose
0.1% (w/v) Polysorbate 80 100 mg/mL 10 mM acetate 6.8% (w/v)
sucrose 0.1% (w/v) 25 mM CaCl.sub.2 Polysorbate 80 100 mg/mL 10 mM
acetate 220 mM proline 0.1% (w/v) 25 mM CaCl.sub.2 Polysorbate 80
100 mg/mL 10 mM acetate 6.9% (w/v) sucrose 0.1% (w/v) 30 mM MEA-HCl
Polysorbate 80 100 mg/mL 10 mM acetate 7.3% (w/v) sucrose 0.1%
(w/v) 30 mM MSA Polysorbate 80 100 mg/mL 10 mM acetate 6.9% (w/v)
sucrose 0.1% (w/v) 35 mM NaCl Polysorbate 80 100 mg/mL 10 mM
acetate 9% (w/v) sucrose 0.05% (w/v) Polysorbate 80 100 mg/mL 10 mM
acetate 6.8% (w/v) sucrose 0.05% (w/v) 25 mM CaCl.sub.2 Polysorbate
80 100 mg/mL 10 mM acetate 220 mM proline 0.05% (w/v) 25 mM
CaCl.sub.2 Polysorbate 80 100 mg/mL 10 mM acetate 6.9% (w/v)
sucrose 0.05% (w/v) 30 mM MEA-HCl Polysorbate 80 100 mg/mL 10 mM
acetate 7.3% (w/v) sucrose 0.05% (w/v) 30 mM MSA Polysorbate 80 100
mg/mL 10 mM acetate 6.9% (w/v) sucrose 0.05% (w/v) 35 mM NaCl
Polysorbate 80 100 mg/mL 10 mM acetate 9% (w/v) sucrose 0.1% (w/v)
Polysorbate 20 100 mg/mL 10 mM acetate 6.8% (w/v) sucrose 0.1%
(w/v) 25 mM CaCl.sub.2 Polysorbate 20 100 mg/mL 10 mM acetate 220
mM proline 0.1% (w/v) 25 mM CaCl.sub.2 Polysorbate 20 100 mg/mL 10
mM acetate 6.9% (w/v) sucrose 0.1% (w/v) 30 mM MEA-HCl Polysorbate
20 100 mg/mL 10 mM acetate 7.3% (w/v) sucrose 0.1% (w/v) 30 mM MSA
Polysorbate 20 100 mg/mL 10 mM acetate 6.9% (w/v) sucrose 0.1%
(w/v) 35 mM NaCl Polysorbate 20 100 mg/mL 10 mM acetate 9% (w/v)
sucrose 0.05% (w/v) Polysorbate 20 100 mg/mL 10 mM acetate 6.8%
(w/v) sucrose 0.05% (w/v) 25 mM CaCl.sub.2 Polysorbate 20 100 mg/mL
10 mM acetate 220 mM proline 0.05% (w/v) 25 mM CaCl.sub.2
Polysorbate 20 100 mg/mL 10 mM acetate 6.9% (w/v) sucrose 0.05%
(w/v) 30 mM MEA-HCl Polysorbate 20 100 mg/mL 10 mM acetate 7.3%
(w/v) sucrose 0.05% (w/v) 30 mM MSA Polysorbate 20 100 mg/mL 10 mM
acetate 6.9% (w/v) sucrose 0.05% (w/v) 35 mM NaCl Polysorbate
20
[0455] Exemplary aqueous adalimumab formulations are provided in
Table F.
TABLE-US-00006 TABLE F Protein pH Adjusting conc. Buffer
Excipient(s) Agent Surfactant pH 50 mg/mL 10 mM sodium 6.8% (w/v)
sucrose HCl/NaOH, 0.1% (w/v) 5.2 acetate 25 mM CaCl.sub.2
HCl/Ca(OH).sub.2, Pluronic F68 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 50 mg/mL 10 mM calcium 6.2% (w/v) sucrose HCl/NaOH, 0.1%
(w/v) 5.2 acetate 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2, Pluronic F68
HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 50 mg/mL 10 mM sodium 6.9%
(w/v) sucrose HCl/NaOH, 0.1% (w/v) 5.2 acetate 30 mM MEA-HCl
HCl/Ca(OH).sub.2, Pluronic F68 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 50 mg/mL 10 mM sodium 7% (w/v) sucrose HCl/NaOH, 0.1% (w/v)
5.2 acetate 10 mM CaCl.sub.2 HCl/Ca(OH).sub.2, Pluronic F68 20 mM
GnHCl HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 50 mg/mL 10 mM sodium
7% (w/v) sucrose HCl/NaOH, 0.1% (w/v) 5.2 acetate 10 mM CaCl.sub.2
HCl/Ca(OH).sub.2, Pluronic F68 0.5% NaCMC HCl/MEA,
MSA/Ca(OH).sub.2, or MSA/MEA 50 mg/mL 10 mM acetate 9% (w/v)
sucrose HCl/NaOH, 0.1% (w/v) 5.2 HCl/Ca(OH).sub.2, Polysorbate 80
HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM acetate 9%
(w/v) sucrose HCl/NaOH, 0.1% (w/v) 5.2 HCl/Ca(OH).sub.2, Pluronic
F68 HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM acetate
6.8% (w/v) sucrose HCl/NaOH, 0.1% (w/v) 5.2 25 mM CaCl.sub.2
HCl/Ca(OH).sub.2, Pluronic F68 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM acetate 220 mM proline HCl/NaOH, 0.1% (w/v)
5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2, Pluronic F68 HCl/MEA,
MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM acetate 6.9% (w/v)
sucrose HCl/NaOH, 0.1% (w/v) 5.2 30 mM MEA-HCl HCl/Ca(OH).sub.2,
Pluronic F68 HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM
acetate 7.3% (w/v) sucrose NaOH, 0.1% (w/v) 5.2 30 mM MSA
Ca(OH).sub.2, or Pluronic F68 MEA 100 mg/mL 10 mM acetate 6.9%
(w/v) sucrose HCl/NaOH, 0.1% (w/v) 5.2 35 mM NaCl HCl/Ca(OH).sub.2,
Pluronic F68 HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM
acetate 9% (w/v) sucrose HCl/NaOH, 0.05% (w/v) 5.2
HCl/Ca(OH).sub.2, Pluronic F68 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM acetate 6.8% (w/v) sucrose HCl/NaOH, 0.05%
(w/v) 5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2, Pluronic F68 HCl/MEA,
MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM acetate 220 mM proline
HCl/NaOH, 0.05% (w/v) 5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2,
Pluronic F68 HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM
acetate 6.9% (w/v) sucrose HCl/NaOH, 0.05% (w/v) 5.2 30 mM MEA-HCl
HCl/Ca(OH).sub.2, Pluronic F68 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM acetate 7.3% (w/v) sucrose NaOH, 0.05%
(w/v) 5.2 30 mM MSA Ca(OH).sub.2, or Pluronic F68 MEA 100 mg/mL 10
mM acetate 6.9% (w/v) sucrose HCl/NaOH, 0.05% (w/v) 5.2 35 mM NaCl
HCl/Ca(OH).sub.2, Pluronic F68 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM acetate 9% (w/v) sucrose HCl/NaOH, 0.1%
(w/v) 5.2 HCl/Ca(OH).sub.2, Polysorbate 80 HCl/MEA,
MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM acetate 6.8% (w/v)
sucrose HCl/NaOH, 0.1% (w/v) 5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2,
Polysorbate 80 HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10
mM acetate 220 mM proline HCl/NaOH, 0.1% (w/v) 5.2 25 mM CaCl.sub.2
HCl/Ca(OH).sub.2, Polysorbate 80 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM acetate 6.9% (w/v) sucrose HCl/NaOH, 0.1%
(w/v) 5.2 30 mM MEA-HCl HCl/Ca(OH).sub.2, Polysorbate 80 HCl/MEA,
MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM acetate 7.3% (w/v)
sucrose NaOH, 0.1% (w/v) 5.2 30 mM MSA Ca(OH).sub.2, or Polysorbate
80 MEA 100 mg/mL 10 mM acetate 6.9% (w/v) sucrose HCl/NaOH, 0.1%
(w/v) 5.2 35 mM NaCl HCl/Ca(OH).sub.2, Polysorbate 80 HCl/MEA,
MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM acetate 9% (w/v)
sucrose HCl/NaOH, 0.05% (w/v) 5.2 HCl/Ca(OH).sub.2, Polysorbate 80
HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM acetate 6.8%
(w/v) sucrose HCl/NaOH, 0.05% (w/v) 5.2 25 mM CaCl.sub.2
HCl/Ca(OH).sub.2, Polysorbate 80 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM acetate 220 mM proline HCl/NaOH, 0.05%
(w/v) 5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2, Polysorbate 80
HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM acetate 6.9%
(w/v) sucrose HCl/NaOH, 0.05% (w/v) 5.2 30 mM MEA-HCl
HCl/Ca(OH).sub.2, Polysorbate 80 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM acetate 7.3% (w/v) sucrose NaOH, 0.05%
(w/v) 5.2 30 mM MSA Ca(OH).sub.2, or Polysorbate 80 MEA 100 mg/mL
10 mM acetate 6.9% (w/v) sucrose HCl/NaOH, 0.05% (w/v) 5.2 35 mM
NaCl HCl/Ca(OH).sub.2, Polysorbate 80 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM acetate 9% (w/v) sucrose HCl/NaOH, 0.04%
(w/v) 5.2 HCl/Ca(OH).sub.2, Polysorbate 80 HCl/MEA,
MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM acetate 6.8% (w/v)
sucrose HCl/NaOH, 0.04% (w/v) 5.2 25 mM CaCl.sub.2
HCl/Ca(OH).sub.2, Polysorbate 80 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM acetate 220 mM proline HCl/NaOH, 0.04%
(w/v) 5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2, Polysorbate 80
HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM acetate 6.9%
(w/v) sucrose HCl/NaOH, 0.04% (w/v) 5.2 30 mM MEA-HCl
HCl/Ca(OH).sub.2, Polysorbate 80 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM acetate 7.3% (w/v) sucrose NaOH, 0.04%
(w/v) 5.2 30 mM MSA Ca(OH).sub.2, or Polysorbate 80 MEA 100 mg/mL
10 mM acetate 6.9% (w/v) sucrose HCl/NaOH, 0.04% (w/v) 5.2 35 mM
NaCl HCl/Ca(OH).sub.2, Polysorbate 80 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM acetate 9% (w/v) sucrose HCl/NaOH, 0.03%
(w/v) 5.2 HCl/Ca(OH).sub.2, Polysorbate 80 HCl/MEA,
MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM acetate 6.8% (w/v)
sucrose HCl/NaOH, 0.03% (w/v) 5.2 25 mM CaCl.sub.2
HCl/Ca(OH).sub.2, Polysorbate 80 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM acetate 220 mM proline HCl/NaOH, 0.03%
(w/v) 5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2, Polysorbate 80
HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM acetate 6.9%
(w/v) sucrose HCl/NaOH, 0.03% (w/v) 5.2 30 mM MEA-HCl
HCl/Ca(OH).sub.2, Polysorbate 80 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM acetate 7.3% (w/v) sucrose NaOH, 0.03%
(w/v) 5.2 30 mM MSA Ca(OH).sub.2, or Polysorbate 80 MEA 100 mg/mL
10 mM acetate 6.9% (w/v) sucrose HCl/NaOH, 0.03% (w/v) 5.2 35 mM
NaCl HCl/Ca(OH).sub.2, Polysorbate 80 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM acetate 9% (w/v) sucrose HCl/NaOH, 0.1%
(w/v) 5.2 HCl/Ca(OH).sub.2, Polysorbate 20 HCl/MEA,
MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM acetate 6.8% (w/v)
sucrose HCl/NaOH, 0.1% (w/v) 5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2,
Polysorbate 20 HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10
mM acetate 220 mM proline HCl/NaOH, 0.1% (w/v) 5.2 25 mM CaCl.sub.2
HCl/Ca(OH).sub.2, Polysorbate 20 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM acetate 6.9% (w/v) sucrose HCl/NaOH, 0.1%
(w/v) 5.2 30 mM MEA-HCl HCl/Ca(OH).sub.2, Polysorbate 20 HCl/MEA,
MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM acetate 7.3% (w/v)
sucrose NaOH, 0.1% (w/v) 5.2 30 mM MSA Ca(OH).sub.2, or Polysorbate
20 MEA 100 mg/mL 10 mM acetate 6.9% (w/v) sucrose HCl/NaOH, 0.1%
(w/v) 5.2 35 mM NaCl HCl/Ca(OH).sub.2, Polysorbate 20 HCl/MEA,
MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM acetate 9% (w/v)
sucrose HCl/NaOH, 0.05% (w/v) 5.2 HCl/Ca(OH).sub.2, Polysorbate 20
HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM acetate 6.8%
(w/v) sucrose HCl/NaOH, 0.05% (w/v) 5.2 25 mM CaCl.sub.2
HCl/Ca(OH).sub.2, Polysorbate 20 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM acetate 220 mM proline HCl/NaOH, 0.05%
(w/v) 5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2, Polysorbate 20
HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM acetate 6.9%
(w/v) sucrose HCl/NaOH, 0.05% (w/v) 5.2 30 mM MEA-HCl
HCl/Ca(OH).sub.2, Polysorbate 20 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM acetate 7.3% (w/v) sucrose NaOH, 0.05%
(w/v) 5.2 30 mM MSA Ca(OH).sub.2, or Polysorbate 20 MEA 100 mg/mL
10 mM acetate 6.9% (w/v) sucrose HCl/NaOH, 0.05% (w/v) 5.2 35 mM
NaCl HCl/Ca(OH).sub.2, Polysorbate 20 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA
[0456] Exemplary aqueous adalimumab formulations are also provided
in Tables 8, 9, 12, 14 and 15. In an embodiment, the stable aqueous
adalimumab formulation is one of the acetate formulations described
in Tables D, E, F, 8, 9, 12, 14 or 15 provided herein.
[0457] In an embodiment, a lyophilized form of any one of the
foregoing acetate-containing adalimumab formulations is
provided.
Formulations of Adalimumab with Benzoate Buffer
[0458] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 200
mg/mL, such as about 90 to about 120 mg/mL, about 170 to about 190,
about 160 to about 190 mg/mL, about 60 to about 90 mg/mL, about 40
to about 60 mg/mL, about 50 mg/mL, about 100 mg/mL, or about 170
mg/mL, benzoate at a concentration of about 5 mM to about 50 mM
(e.g., about 10 mM to about 30 mM, about 10 mM, about 15 mM, about
20 mM, and/or about 25 mM), and one or more excipients. Suitable
excipients include certain stabilizers such as certain amino acids
and amino acid derivatives, certain polyols, certain acids, certain
amines, certain salts, and certain surfactants. Examples of
suitable amino acids and amino acid derivatives include proline
(e.g., at a concentration of about 0.1 to about 450 mM, about 50 to
about 300 mM, or about 250 mM to about 350 mM). Examples of
suitable polyols include sucrose (e.g., at a concentration of about
0.1% (w/v) to about 15% (w/v), about 4% (w/v) to about 10% (w/v),
about 4% (w/v) to about 9% (w/v), about 6.5% (w/v), about 6.8%
(w/v), about 6.9% (w/v), about 9% (w/v)) and sorbitol (e.g., at a
concentration of about 0.1% (w/v) to about 10% (w/v), about 3%
(w/v) to about 5% (w/v), and/or about 4% (w/v)). Examples of
suitable acids include methane sulfonic acid (MSA) (e.g., at a
concentration of about 0.1 to about 150 mM or about 0.1 to about 50
mM). Examples of suitable amines include MEA-HCl (e.g., at a
concentration of about 0.1 to about 150 mM or about 0.1 to about 40
mM) and MEA (e.g., at a concentration of about 0.1 to about 300 mM
or about 0.1 to about 50 mM). Examples of suitable salts include
sodium chloride (e.g., at a concentration of about 10 to about 100
mM, about 60 to about 90 mM, about 15 to about 50 mM, and/or about
35 mM) and calcium chloride (e.g., at a concentration of about 1 to
about 150 mM, about 5 to about 50 mM, about 10 to about 30 mM,
about 20 to about 40 mM, about 30 to about 50 mM, about 40 to about
80 mM, about 50 to about 100 mM, or about 25 mM). Examples of
suitable surfactants include Pluronic F68 (e.g., at a concentration
of about 0.001% (w/v) to about 10% (w/v), about 0.005% (w/v) to
about 1% (w/v), about 0.05% (w/v) to about 0.4% (w/v), about 0.05%
(w/v) to about 0.1% (w/v), about 0.01% (w/v), about 0.05% (w/v),
and/or about 0.1% (w/v)), Polysorbate 20 (e.g., at a concentration
of about 0.001% (w/v) to about 2% (w/v) or about 0.005% (w/v) to
about 0.1% (w/v)), and Polysorbate 80 (e.g., at a concentration of
about 0.001% (w/v) to about 2% (w/v), about 0.005% (w/v) to about
0.1% (w/v), about 0.005% (w/v) to about 0.05% (w/v), about 0.03%
(w/v) to about 0.1% (w/v), about 0.04% (w/v) to about 0.1% (w/v),
about 0.03% (w/v), about 0.04% (w/v), and/or about 0.1% (w/v)).
Optionally, the benzoate-containing stable aqueous adalimumab
formulation has a pH of about 4.8 to about 5.7, for example, about
4.9 to about 5.6, about 5.0 to about 5.5, about 5.1 to about 5.4,
about 5.1 to about 5.3, about 5.1 to about 5.2, about 5.2 to about
5.3, and/or about 5.2. Optionally, the pH of the stable aqueous
adalimumab formulation is adjusted using a strong acid and/or a
strong base including, but not limited to, hydrochloric acid,
sodium hydroxide, calcium hydroxide, MSA, and/or MEA.
[0459] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 200
mg/mL, such as about 90 to about 120 mg/mL, about 170 to about 190,
about 160 to about 190 mg/mL, about 60 to about 90 mg/mL, about 40
to about 60 mg/mL, about 50 mg/mL, about 100 mg/mL, or about 170
mg/mL, benzoate at a concentration of about 5 mM to about 50 mM
(e.g., about 10 mM to about 30 mM, about 10 mM, about 15 mM, about
20 mM, and/or about 25 mM), and one or more excipients selected
from the group consisting of proline at a concentration of about
0.1 to about 450 mM (e.g., about 50 to about 300 mM or about 250 mM
to about 350 mM), sodium chloride at a concentration of about 10 to
about 100 mM (e.g., about 60 to about 90 mM, about 15 to about 50
mM, and/or about 35 mM), calcium chloride at a concentration of
about 1 to about 150 mM (e.g., about 5 to about 50 mM, about 10 to
about 30 mM, about 20 to about 40 mM, about 30 to about 50 mM,
about 40 to about 80 mM, about 50 to about 100 mM, or about 25 mM),
sucrose at a concentration of about 0.1% (w/v) to about 15% (w/v)
(e.g., about 4% (w/v) to about 10% (w/v), about 4% (w/v) to about
9% (w/v), about 6.5% (w/v), about 6.8% (w/v), about 6.9% (w/v),
about 9% (w/v)), sorbitol at a concentration of about 0.1% (w/v) to
about 10% (w/v) (e.g., about 3% (w/v) to about 5% (w/v) and/or
about 4% (w/v)), methane sulfonic acid (MSA) at a concentration of
about 0.1 to about 150 mM (e.g., about 0.1 to about 50 mM), MEA-HCl
at a concentration of about 0.1 to about 150 mM (e.g., about 0.1 to
about 40 mM), MEA at a concentration of about 0.1 to about 300 mM
(e.g., about 0.1 to about 50 mM), Pluronic F68 at a concentration
of about 0.001% (w/v) to about 10% (w/v) (e.g., about 0.005% (w/v)
to about 1% (w/v), about 0.05% (w/v) to about 0.4% (w/v), about
0.01% (w/v), about 0.05% (w/v) to about 0.1% (w/v), about 0.05%
(w/v), and/or about 0.1% (w/v)), Polysorbate 20 at a concentration
of about 0.001% (w/v) to about 2% (w/v) (e.g., about 0.005% (w/v)
to about 0.1% (w/v)), and Polysorbate 80 at a concentration of
about 0.001% (w/v) to about 2% (w/v) (e.g., about 0.005% (w/v) to
about 0.1% (w/v), about 0.005% (w/v) to about 0.05% (w/v), about
0.03% (w/v) to about 0.1% (w/v), about 0.04% (w/v) to about 0.1%
(w/v), about 0.03% (w/v), about 0.04% (w/v), and/or about 0.1%
(w/v)). Optionally, the benzoate-containing stable aqueous
adalimumab formulation has a pH of about 4.8 to about 5.7, for
example, about 4.9 to about 5.6, about 5.0 to about 5.5, about 5.1
to about 5.4, about 5.1 to about 5.3, about 5.1 to about 5.2, about
5.2 to about 5.3, and/or about 5.2. Optionally, the pH of the
stable aqueous adalimumab formulation is adjusted using a strong
acid and/or a strong base including, but not limited to,
hydrochloric acid, sodium hydroxide, calcium hydroxide, MSA, and/or
MEA.
[0460] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 60 to about 90
mg/mL, benzoate at a concentration of about 10 mM to about 30 mM,
and proline at a concentration of about 250 to about 350 mM, and
has a pH of about 5.1 to 5.3. Optionally, the pH of the formulation
is adjusted within this range with MEA.
[0461] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, benzoate at a concentration of about 10 mM to about 30 mM,
and proline at a concentration of about 250 to about 350 mM, and
has a pH of about 5.1 to 5.3. Optionally, the pH of the formulation
is adjusted within this range with NaOH.
[0462] In an embodiment, a lyophilized form of any one of the
foregoing benzoate-containing adalimumab formulations is
provided.
Formulations of Adalimumab with Glycolate Buffer
[0463] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 200
mg/mL, such as about 90 to about 120 mg/mL, about 170 to about 190,
about 160 to about 190 mg/mL, about 60 to about 90 mg/mL, about 40
to about 60 mg/mL, about 50 mg/mL, about 100 mg/mL, or about 170
mg/mL, glycolate at a concentration of about 5 mM to about 50 mM
(e.g., about 10 mM to about 30 mM, about 10 mM, about 15 mM, about
20 mM, and/or about 25 mM), and one or more excipients. Suitable
excipients include certain stabilizers such as certain amino acids
and amino acid derivatives, certain polyols, certain acids, certain
amines, certain salts, and certain surfactants. Examples of
suitable amino acids and amino acid derivatives include proline
(e.g., at a concentration of about 0.1 to about 450 mM, about 250
mM to about 350 mM, or about 50 to about 300 mM). Examples of
suitable polyols include sucrose (e.g., at a concentration of about
0.1% (w/v) to about 15% (w/v), about 4% (w/v) to about 10% (w/v),
about 4% (w/v) to about 9% (w/v), about 6.5% (w/v), about 6.8%
(w/v), about 6.9% (w/v), about 9% (w/v)) and sorbitol (e.g., at a
concentration of about 0.1% (w/v) to about 10% (w/v), about 3%
(w/v) to about 5% (w/v), and/or about 4% (w/v)). Examples of
suitable acids include methane sulfonic acid (MSA) (e.g., at a
concentration of about 0.1 to about 150 mM or about 0.1 to about 50
mM). Examples of suitable amines include MEA-HCl (e.g., at a
concentration of about 0.1 to about 150 mM or about 0.1 to about 40
mM) and MEA (e.g., at a concentration of about 0.1 to about 300 mM
or about 0.1 to about 50 mM). Examples of suitable salts include
sodium chloride (e.g., at a concentration of about 10 to about 100
mM, about 60 to about 90 mM, about 15 to about 50 mM, and/or about
35 mM) and calcium chloride (e.g., at a concentration of about 1 to
about 150 mM, about 5 to about 50 mM, about 10 to about 30 mM,
about 20 to about 40 mM, about 30 to about 50 mM, about 40 to about
80 mM, about 50 to about 100 mM, or about 25 mM). Examples of
suitable surfactants include Pluronic F68 (e.g., at a concentration
of about 0.001% (w/v) to about 10% (w/v), about 0.005% (w/v) to
about 1% (w/v), about 0.05% (w/v) to about 0.4% (w/v), about 0.05%
(w/v) to about 0.1% (w/v), about 0.01% (w/v), about 0.05% (w/v),
and/or about 0.1% (w/v)), Polysorbate 20 (e.g., at a concentration
of about 0.001% (w/v) to about 2% (w/v) or about 0.005% (w/v) to
about 0.1% (w/v)), and Polysorbate 80 (e.g., at a concentration of
about 0.001% (w/v) to about 2% (w/v), about 0.005% (w/v) to about
0.1% (w/v), about 0.005% (w/v) to about 0.05% (w/v), about 0.03%
(w/v) to about 0.1% (w/v), about 0.04% (w/v) to about 0.1% (w/v),
about 0.03% (w/v), about 0.04% (w/v), and/or about 0.1% (w/v)).
Optionally, the glycolate-containing stable aqueous adalimumab
formulation has a pH of about 4.8 to about 5.7, for example, about
4.9 to about 5.6, about 5.0 to about 5.5, about 5.1 to about 5.4,
about 5.1 to about 5.3, about 5.1 to about 5.2, about 5.2 to about
5.3, and/or about 5.2. Optionally, the pH of the stable aqueous
adalimumab formulation is adjusted using a strong acid and/or a
strong base including, but not limited to, hydrochloric acid,
sodium hydroxide, calcium hydroxide, MSA, and/or MEA.
[0464] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 200
mg/mL, such as about 90 to about 120 mg/mL, about 170 to about 190,
about 160 to about 190 mg/mL, about 60 to about 90 mg/mL, about 40
to about 60 mg/mL, about 50 mg/mL, about 100 mg/mL, or about 170
mg/mL, glycolate at a concentration of about 5 mM to about 50 mM
(e.g., about 10 mM to about 30 mM, about 10 mM, about 15 mM, about
20 mM, and/or about 25 mM), and one or more excipients selected
from the group consisting of proline at a concentration of about
0.1 to about 450 mM (e.g., about 250 mM to about 350 mM or about 50
to about 300 mM), sodium chloride at a concentration of about 10 to
about 100 mM (e.g., about 60 to about 90 mM, about 15 to about 50
mM, and/or about 35 mM), calcium chloride at a concentration of
about 1 to about 150 mM (e.g., about 5 to about 50 mM, about 10 to
about 30 mM, about 20 to about 40 mM, about 30 to about 50 mM,
about 40 to about 80 mM, about 50 to about 100 mM, or about 25 mM),
sucrose at a concentration of about 0.1% (w/v) to about 15% (w/v)
(e.g., about 4% (w/v) to about 10% (w/v), about 4% (w/v) to about
9% (w/v), about 6.5% (w/v), about 6.8% (w/v), about 6.9% (w/v),
about 9% (w/v)), sorbitol at a concentration of about 0.1% (w/v) to
about 10% (w/v) (e.g., about 3% (w/v) to about 5% (w/v) and/or
about 4% (w/v)), methane sulfonic acid (MSA) at a concentration of
about 0.1 to about 150 mM (e.g., about 0.1 to about 50 mM), MEA-HCl
at a concentration of about 0.1 to about 150 mM (e.g., about 0.1 to
about 40 mM), MEA at a concentration of about 0.1 to about 300 mM
(e.g., about 0.1 to about 50 mM), Pluronic F68 at a concentration
of about 0.001% (w/v) to about 10% (w/v) (e.g., about 0.005% (w/v)
to about 1% (w/v), about 0.05% (w/v) to about 0.4% (w/v), about
0.05% (w/v) to about 0.1% (w/v), about 0.01% (w/v), about 0.05%
(w/v), and/or about 0.1% (w/v)), Polysorbate 20 at a concentration
of about 0.001% (w/v) to about 2% (w/v) (e.g., about 0.005% (w/v)
to about 0.1% (w/v)), and Polysorbate 80 at a concentration of
about 0.001% (w/v) to about 2% (w/v) (e.g., about 0.005% (w/v) to
about 0.1% (w/v), about 0.005% (w/v) to about 0.05% (w/v), about
0.03% (w/v) to about 0.1% (w/v), about 0.04% (w/v) to about 0.1%
(w/v), about 0.03% (w/v), about 0.04% (w/v), and/or about 0.1%
(w/v)). Optionally, the glycolate-containing stable aqueous
adalimumab formulation has a pH of about 4.8 to about 5.7, for
example, about 4.9 to about 5.6, about 5.0 to about 5.5, about 5.1
to about 5.4, about 5.1 to about 5.3, about 5.1 to about 5.2, about
5.2 to about 5.3, and/or about 5.2. Optionally, the pH of the
stable aqueous adalimumab formulation is adjusted using a strong
acid and/or a strong base including, but not limited to,
hydrochloric acid, sodium hydroxide, calcium hydroxide, MSA, and/or
MEA.
[0465] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, glycolate at a concentration of about 10 mM to about 30 mM,
and proline at a concentration of about 250 to about 350 mM, and
has a pH of about 5.1 to 5.3. Optionally, the pH of the formulation
is adjusted within this range with MEA or NaOH.
[0466] In an embodiment, a lyophilized form of any one of the
foregoing glycolate-containing adalimumab formulations is
provided.
Formulations of Adalimumab with Lactate Buffer
[0467] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 200
mg/mL, such as about 90 to about 120 mg/mL, about 160 to 190 mg/mL,
about 40 to about 60 mg/mL, about 50 mg/mL, about 100 mg/mL, or
about 170 mg/mL, lactic acid and/or lactate at a concentration of
about 0.1 mM to about 300 mM (e.g., about 2 mM to about 30 mM,
about 10 mM to about 30 mM, about 5 mM to about 15 mM, about 10 mM,
about 15 mM, about 20 mM, and/or about 25 mM), and one or more
excipients. Suitable excipients include certain stabilizers such as
certain amino acids and amino acid derivatives, certain
polyethylene glycols and polyethylene glycol derivatives, certain
salts, certain polyols, certain acids, certain amines, and certain
surfactants. Examples of suitable amino acids include proline
(e.g., at a concentration of about 0.1 to about 450 mM, about 50 to
about 300 mM, about 110 to about 300 mM, about 250 to about 350 mM,
about 190 to about 250 mM, and/or about 220 mM). Examples of
suitable polyethylene glycols include PEG 600 (e.g., at a
concentration of about 0.1% (w/v) to about 30% (w/v) or about 4%
(w/v) to about 13% (w/v)), PEG 400 (e.g., at a concentration of
about 0.1% (w/v) to about 20% (w/v) or about 0.5% (w/v) to about 2%
(w/v)), and PEG 200 (e.g., at a concentration of about 0.1% (w/v)
to about 10% (w/v) or about 1.6% (w/v) to about 3.8% (w/v)).
Examples of suitable salts include calcium chloride (e.g., at a
concentration of about 1 to about 150 mM, about 5 to about 50 mM,
about 10 to about 30 mM, about 20 to about 30 mM, about 20 to about
40 mM, about 30 to about 50 mM, about 40 to about 80 mM, about 50
to about 100 mM, or about 25 mM) and sodium chloride (e.g., at a
concentration of about 10 to about 100 mM, about 60 to about 90 mM,
about 15 to about 50 mM, or about 35 mM). Examples of suitable
polyols include sucrose (e.g., at a concentration of about 0.1%
(w/v) to about 15% (w/v), about 4% (w/v) to about 10% (w/v), about
4% (w/v) to about 9% (w/v), about 6.5% (w/v), about 6.8% (w/v),
about 6.9% (w/v), about 9% (w/v)) and sorbitol (e.g., at a
concentration of about 0.1% (w/v) to about 10% (w/v), about 3%
(w/v) to about 5% (w/v), and/or about 4% (w/v)). Examples of
suitable acids include methane sulfonic acid (MSA) (e.g., at a
concentration of about 0.1 to about 150 mM or about 0.1 to about 50
mM). Examples of suitable amines include monoethanolamide
hydrochloride (MEA-HCl) (e.g., at a concentration of about 0.1 to
about 150 mM or about 0.1 to about 40 mM) and monoethanolamide
(MEA) (e.g., at a concentration of about 0.1 to about 300 mM or
about 0.1 to about 50 mM). Examples of suitable surfactants include
Pluronic F68 (e.g., at a concentration of about 0.001% (w/v) to
about 10% (w/v), about 0.005% (w/v) to about 1% (w/v), about 0.05%
(w/v) to about 0.5% (w/v), about 0.05% (w/v) to about 0.4% (w/v),
about 0.05% (w/v) to about 0.1% (w/v), about 0.01% (w/v), about
0.05% (w/v), and/or about 0.1% (w/v)), Polysorbate 20 (e.g., at a
concentration of about 0.001% (w/v) to about 2% (w/v) or about
0.005% (w/v) to about 0.1% (w/v)), and Polysorbate 80 (e.g., at a
concentration of about 0.001% (w/v) to about 2% (w/v), about 0.005%
(w/v) to about 0.1% (w/v), about 0.005% (w/v) to about 0.05% (w/v),
about 0.03% (w/v) to about 0.1% (w/v), 0.04% (w/v) to about 0.1%
(w/v), about 0.05% (w/v) to about 0.1% (w/v), about 0.03% (w/v),
about 0.04% (w/v), and/or about 0.1% (w/v)). Optionally, the
lactate-containing stable aqueous adalimumab formulation has a pH
of about 4.8 to about 5.7, for example, about 4.9 to about 5.6,
about 5.0 to about 5.5, about 5.1 to about 5.4, about 5.1 to about
5.3, about 5.1 to about 5.2, about 5.2 to about 5.3, and/or about
5.2. Optionally, the pH of the stable aqueous adalimumab
formulation is adjusted using a strong acid and/or a strong base
including, but not limited to, hydrochloric acid, sodium hydroxide,
calcium hydroxide, MSA, and/or MEA.
[0468] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 200
mg/mL, such as about 90 to about 120 mg/mL, about 160 to 190 mg/mL,
or about 40 to about 60 mg/mL, about 50 mg/mL, about 100 mg/mL, or
about 170 mg/mL, lactic acid and/or lactate at a concentration of
about 0.1 mM to about 300 mM (e.g., about 2 mM to about 30 mM,
about 10 mM to about 30 mM, about 5 mM to about 15 mM, about 10 mM,
about 15 mM, about 20 mM, and/or about 25 mM), and one or more
excipients selected from the group consisting of proline at a
concentration of about 0.1 to about 450 mM (e.g., about 50 to about
300 mM, about 110 to about 300 mM, about 250 to about 350 mM, about
190 to about 250 mM, and/or about 220 mM), PEG 600 at a
concentration of about 0.1% (w/v) to about 30% (w/v) (e.g., about
4% (w/v) to about 13% (w/v)), PEG 400 at a concentration of about
0.1% (w/v) to about 20% (w/v) (e.g., about 0.5% (w/v) to about 2%
(w/v)), PEG 200 at a concentration of about 0.1% (w/v) to about 10%
(w/v) (e.g., about 1.6% (w/v) to about 3.8% (w/v)), calcium
chloride at a concentration of about 1 to about 150 mM (e.g., about
5 to about 50 mM, about 10 to about 30 mM, about 20 to about 30 mM,
about 20 to about 40 mM, about 30 to about 50 mM, about 40 to about
80 mM, about 50 to about 100 mM, or about 25 mM), sodium chloride
at a concentration of about 10 to about 100 mM (e.g., about 60 to
about 90 mM, about 15 to about 50 mM, and/or about 35 mM), sucrose
at a concentration of about 0.1% (w/v) to about 15% (w/v) (e.g.,
about 4% (w/v) to about 10% (w/v), about 4% (w/v) to about 9%
(w/v), about 6.5% (w/v), about 6.8% (w/v), about 6.9% (w/v), about
9% (w/v)), sorbitol at a concentration of about 0.1% (w/v) to about
10% (w/v) (e.g., about 3% (w/v) to about 5% (w/v) and/or about 4%
(w/v)), methane sulfonic acid (MSA) at a concentration of about 0.1
to about 150 mM (e.g., about 0.1 to about 50 mM), monoethanolamide
hydrochloride (MEA-HCl) at a concentration of about 0.1 to about
150 mM (e.g., about 0.1 to about 40 mM), monoethanolamide (MEA) at
a concentration of about 0.1 to about 300 mM (e.g., about 0.1 to
about 50 mM), Pluronic F68 at a concentration of about 0.001% (w/v)
to about 10% (w/v) (e.g., about 0.005% (w/v) to about 1% (w/v),
about 0.05% (w/v) to about 0.5% (w/v), about 0.05% (w/v) to about
0.4% (w/v), about 0.05% (w/v) to about 0.1% (w/v), about 0.01%
(w/v), about 0.05% (w/v), and/or about 0.1% (w/v)), Polysorbate 20
at a concentration of about 0.001% (w/v) to about 2% (w/v) (e.g.,
about 0.005% (w/v) to about 0.1% (w/v)), and Polysorbate 80 at a
concentration of about 0.001% (w/v) to about 2% (w/v) (e.g., about
0.005% (w/v) to about 0.1% (w/v), about 0.005% (w/v) to about 0.05%
(w/v), about 0.03% (w/v) to about 0.1% (w/v), 0.04% (w/v) to about
0.1% (w/v), about 0.05% (w/v) to about 0.1% (w/v), about 0.03%
(w/v), about 0.04% (w/v), and/or about 0.1% (w/v)). Optionally, the
lactate-containing stable aqueous adalimumab formulation has a pH
of about 4.8 to about 5.7, for example, about 4.9 to about 5.6,
about 5.0 to about 5.5, about 5.1 to about 5.4, about 5.1 to about
5.3, about 5.1 to about 5.2, about 5.2 to about 5.3, and/or about
5.2. Optionally, the pH of the stable aqueous adalimumab
formulation is adjusted using a strong acid and/or a strong base
including, but not limited to, hydrochloric acid, sodium hydroxide,
calcium hydroxide, MSA, and/or MEA.
[0469] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, lactate at a concentration of about 10 mM to about 30 mM,
and proline at a concentration of about 250 to about 350 mM, and
has a pH of about 5.1 to 5.3. Optionally, the pH of the formulation
is adjusted within this range with MEA or NaOH.
[0470] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, lactate at a concentration of about 5 mM to about 15 mM, PEG
600 at a concentration of about 8% (w/v) to about 9% (w/v), and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3.
[0471] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, lactate at a concentration of about 5 mM to about 15 mM, PEG
600 at a concentration of about 3% (w/v) to about 5% (w/v), PEG 200
at a concentration of about 1.2% (w/v) to about 2% (w/v), and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3.
[0472] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, lactate at a concentration of about 5 mM to about 15 mM, PEG
600 at a concentration of about 8% (w/v) to about 9% (w/v), and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3.
[0473] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, lactate at a concentration of about 5 mM to about 15 mM, PEG
600 at a concentration of about 3% (w/v) to about 5% (w/v), PEG 200
at a concentration of about 1.2% (w/v) to about 2% (w/v), and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3.
[0474] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, lactate at a concentration of about 5 mM to about 15 mM, PEG
200 at a concentration of about 3.5% (w/v) to about 4.2% (w/v), and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3.
[0475] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
proline at a concentration of about 190 to about 250 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3.
[0476] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
proline at a concentration of about 190 to about 240 mM, calcium
chloride at a concentration of about 15 to about 35 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MSA and/or MEA.
[0477] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
proline at a concentration of about 200 to about 250 mM, calcium
chloride at a concentration of about 10 to about 30 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MSA and/or MEA.
[0478] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, lactate at a concentration of about 5 mM to about 15 mM, PEG
600 at a concentration of about 11% (w/v) to about 15% (w/v),
calcium chloride at a concentration of about 20 to about 40 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MSA and/or MEA.
[0479] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, lactate at a concentration of about 5 mM to about 15 mM, PEG
600 at a concentration of about 11% (w/v) to about 15% (w/v),
calcium chloride at a concentration of about 10 to about 30 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MSA and/or MEA.
[0480] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, lactate at a concentration of about 5 mM to about 15 mM, PEG
600 at a concentration of about 8% (w/v) to about 9% (w/v), calcium
chloride at a concentration of about 10 to about 30 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MSA and/or MEA.
[0481] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, lactate at a concentration of about 5 mM to about 15 mM, PEG
600 at a concentration of about 3% (w/v) to about 5% (w/v), PEG 200
at a concentration of about 1.2% (w/v) to about 2% (w/v), calcium
chloride at a concentration of about 10 to about 30 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MSA and/or MEA.
[0482] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, lactate at a concentration of about 5 mM to about 15 mM, PEG
200 at a concentration of about 3.5% (w/v) to about 4.2% (w/v),
calcium chloride at a concentration of about 10 to about 30 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MSA and/or MEA.
[0483] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, lactate at a concentration of about 5 mM to about 15 mM, PEG
600 at a concentration of about 5% (w/v) to about 5.7% (w/v),
calcium chloride at a concentration of about 10 to about 30 mM,
proline at a concentration of about 90 to about 130 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MSA and/or MEA.
[0484] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
calcium chloride at a concentration of about 10 to about 30 mM,
proline at a concentration of about 190 to about 250 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MSA and/or MEA.
[0485] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
calcium chloride at a concentration of about 15 to about 35 mM,
proline at a concentration of about 190 to about 250 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0486] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
calcium chloride at a concentration of about 15 to about 35 mM,
proline at a concentration of about 190 to about 250 mM, and
Pluronic F68 at a concentration of about 0.01% (w/v) to about 0.1%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0487] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 8% (w/v) to about 10% (w/v),
and Pluronic F68 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0488] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 8% (w/v) to about 10% (w/v),
and Pluronic F68 at a concentration of about 0.01% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0489] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 110
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 8.5% (w/v) to about 9.5% (w/v),
and Pluronic F68 at a concentration of about 0.03% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0490] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 8% (w/v) to about 10% (w/v),
calcium chloride at a concentration of about 15 mM to about 35 mM,
and Pluronic F68 at a concentration of about 0.005% (w/v) to about
0.05% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH
of the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0491] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 8% (w/v) to about 10% (w/v),
calcium chloride at a concentration of about 15 mM to about 35 mM,
and Pluronic F68 at a concentration of about 0.01% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0492] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
calcium chloride at a concentration of about 15 to about 35 mM,
proline at a concentration of about 190 to about 250 mM, and
Polysorbate 80 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0493] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
calcium chloride at a concentration of about 15 to about 35 mM,
proline at a concentration of about 190 to about 250 mM, and
Polysorbate 80 at a concentration of about 0.01% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0494] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 8% (w/v) to about 10% (w/v),
and Polysorbate 80 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0495] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 8% (w/v) to about 10% (w/v),
and Polysorbate 80 at a concentration of about 0.01% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0496] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
calcium chloride at a concentration of about 15 to about 35 mM,
proline at a concentration of about 190 to about 250 mM, and
Polysorbate 20 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0497] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
calcium chloride at a concentration of about 15 to about 35 mM,
proline at a concentration of about 190 to about 250 mM, and
Polysorbate 20 at a concentration of about 0.01% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0498] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 8% (w/v) to about 10% (w/v),
and Polysorbate 20 at a concentration of about 0.05% (w/v) to about
0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0499] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, lactate at a concentration of about 5 mM to about 15 mM,
sucrose at a concentration of about 8% (w/v) to about 10% (w/v),
and Polysorbate 20 at a concentration of about 0.01% (w/v) to about
0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with HCl, NaOH,
Ca(OH).sub.2, MEA, and/or MSA.
[0500] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 mg/ml to about
200 mg/ml, or about 160 mg/ml to about 190 mg/mL, or about 80 mg/ml
to about 120 mg/ml, or about 90 mg/ml to about 110 mg/ml, or about
95 mg/ml to about 105 mg/ml, or about 40 mg/ml, or about 45 mg/ml,
or about 50 mg/ml, or about 55 mg/ml, or about 60 mg/ml, or about
65 mg/ml, or about 70 mg/ml, or about 75 mg/ml, or about 80 mg/ml,
or about 85 mg/ml, or about 90 mg/ml, or about 95 mg/ml, or about
100 mg/ml, or about 105 mg/ml, or about 110 mg/ml, or about 115
mg/ml, or about 120 mg/ml, or about 125 mg/ml, or about 130 mg/ml,
or about 135 mg/ml, or about 140 mg/ml, or about 145 mg/ml, or
about 150 mg/ml, or about 155 mg/ml, or about 160 mg/ml, or about
165 mg/ml, or about 170 mg/ml, or about 175 mg/ml, or about 180
mg/ml, or about 185 mg/ml, or about 190 mg/mL, with the following
excipients:
(a) lactate buffer at a concentration of about 5 mM to about 15 mM,
or about 7 mM to about 12 mM, or about 9 mM to about 11 mM, or
about 5 mM, or about 6 mM, or about 7 mM, or about 8 mM, or about 8
mM, or about 9 mM, or about 10 mM, or about 11 mM, or about 12 mM,
or about 13 mM, or about 14 mM, or about 15 mM; (b) calcium
chloride at a concentration of about 5 to about 30 mM, about 10 to
about 20 mM, or about 12.5 mM to about 17.5 mM, or about 14 mM to
about 16 mM, or about 10 mM, or about 10.5 mM, or about 11 mM, or
about 11.5 mM, or about 12 mM, or about 12.5 mM, or about 13 mM, or
about 13.5 mM, or about 14 mM, or about 14.5 mM, or about 15 mM, or
about 15.5 mM, or about 16 mM, or about 16.5 mM, or about 17 mM, or
about 17.5 mM, or about 18 mM, or about 18.5 mM, or about 19 mM, or
about 19.5 mM, or about 20 mM; (c) sucrose at a concentration of
about 4% (w/v) to about 10% (w/v), or about 6% (w/v) to about 8.5%
(w/v), or about 4% (w/v), or about 4.5% (w/v), or about 5% (w/v),
or about 5.5% (w/v), or about 6% (w/v), or about 6.5% (w/v), or
about 7% (w/v), or about 7.1% (w/v), or about 7.2% (w/v), or about
7.3% (w/v), or about 7.4% (w/v), or about 7.5% (w/v), or about 7.6%
(w/v), or about 7.7% (w/v), or about 7.8% (w/v), or about 8% (w/v),
or about 8.5% (w/v); (d) Pluronic F68 at a concentration of about
0.03% (w/v) to about 0.09% (w/v), or about 0.03% (w/v) to about
0.06% (w/v), about 0.01% (w/v) to about 0.2% (w/v), about 0.01%
(w/v) to about 0.1% (w/v), about 0.03% (w/v) to about 0.1% (w/v),
or about 0.05% (w/v) to about 0.07% (w/v), or about 0.03% (w/v), or
about 0.04% (w/v), or about 0.05% (w/v), or about 0.06% (w/v), or
about 0.07% (w/v), or about 0.08% (w/v), about 0.09% (w/v), or
about 0.1% (w/v); and (e) has a pH of about 3.5 to about 8, or
about 4 to about 7, or about 4.5 to about 6, or about 5 to about
5.5, or about 3.5, or about 4, or about 4.5, or about 4.6, or about
4.7, or about 4.8, or about 4.9, or about 5.0, or about 5.1, or
about 5.2, or about 5.3, or about 5.4, or about 5.5, or about 5.6,
or about 5.7, or about 5.8, or about 5.9, or about 6.0, or about
6.5, or about 7.0, or about 7.5, or about 8.0.
[0501] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration or about 40 mg/ml to 200
mg/ml, lactate buffer at a concentration of about 5 mM to about 15
mM, sucrose at a concentration of about 4% (w/v) to about 10%
(w/v), calcium chloride at a concentration of about 5 to about 30
mM, and Pluronic F68 at a concentration of about 0.03% (w/v) to
about 0.1% (w/v), and has a pH of about 3.5 to 8.
[0502] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration or about 40 mg/ml to 200
mg/ml, lactate buffer at a concentration of about 1 mM to about 15
mM, sucrose at a concentration of about 4% (w/v) to about 10%
(w/v), calcium chloride at a concentration of about 10 to about 20
mM, and Pluronic F68 at a concentration of about 0.03% (w/v) to
about 0.1% (w/v), and has a pH of about 3.5 to 8.
[0503] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 80 mg/ml to about
120 mg/mL, lactate buffer at a concentration of about 7 mM to about
12 mM, sucrose at a concentration of about 4% (w/v) to about 10%
(w/v), calcium chloride at a concentration of about 12.5 to about
17.5 mM, and Pluronic F68 at a concentration of about 0.03% (w/v)
to about 0.07% (w/v), and a pH of about 4 to about 7.
[0504] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 mg/ml to about
110 mg/mL, lactate buffer at a concentration of about 9 mM to about
11 mM, sucrose at a concentration of about 6% (w/v) to about 8.5%
(w/v), calcium chloride at a concentration of about 14 to about 16
mM, and Pluronic F68 at a concentration of about 0.03% (w/v) to
about 0.07% (w/v), and a pH of about 5.0 to about 5.5.
[0505] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 100 mg/mL, lactate
buffer at a concentration of about 10 mM, sucrose at a
concentration of about 7.4% (w/v), calcium chloride at a
concentration of about 15 mM, and Pluronic F68 at a concentration
of about 0.06% (w/v), and a pH of about 5.2.
[0506] Exemplary aqueous adalimumab formulations are provided in
Table G. Each formulation in Table G may optionally include
Pluronic F68 at a concentration of about 0.001% (w/v) to about 10%
(w/v) (e.g., about 0.005% (w/v) to about 1% (w/v), about 0.01%
(w/v) to about 0.1% (w/v), about 0.01% (w/v) to about 1% (w/v),
about 0.05% (w/v) to about 0.1% (w/v), about 0.05% (w/v) to about
0.4% (w/v), about 0.01% (w/v), about 0.05% (w/v) to about 0.5%
(w/v), about 0.1% (w/v) to about 2% (w/v), about 0.2% (w/v) to
about 1% (w/v), about 0.05% (w/v), about 0.1% (w/v), and/or about
0.4% (w/v)), Polysorbate 20 at a concentration of about 0.001%
(w/v) to about 2% (w/v) (e.g., about 0.002% (w/v) to about 0.01%
(w/v), about 0.005% (w/v) to about 0.05% (w/v), about 0.005% (w/v)
to about 0.1% (w/v), about 0.02% (w/v) to about 0.1% (w/v), and/or
about 0.05% (w/v) to about 0.2% (w/v)), or Polysorbate 80 at a
concentration of about 0.001% (w/v) to about 2% (w/v) (e.g., about
0.002% (w/v) to about 0.01% (w/v), about 0.005% (w/v) to about 0.1%
(w/v), about 0.005% (w/v) to about 0.05% (w/v), about 0.02% (w/v)
to about 0.1% (w/v), about 0.03% (w/v) to about 0.1% (w/v), 0.04%
(w/v) to about 0.1% (w/v), about 0.05% (w/v) to about 0.2% (w/v),
about 0.03% (w/v), about 0.04% (w/v), and/or about 0.1% (w/v)).
Each formulation in Table G has a pH of about 5.0 to about 5.5,
e.g., about 5.1 to about 5.3 and/or about 5.2. Optionally, the pH
of each formulation in Table G is adjusted using a strong acid
and/or strong base including, but not limited to, hydrochloric
acid, sodium hydroxide, calcium hydroxide, MSA, and/or MEA.
TABLE-US-00007 TABLE G Protein conc. Buffer Excipient(s) 100 mg/mL
10 mM lactate 220 mM proline 25 mM CaCl.sub.2 100 mg/mL 10 mM
lactate 9% (w/v) sucrose 100 mg/mL 10 mM lactate 9% (w/v) sucrose
25 mM CaCl.sub.2
[0507] Exemplary aqueous adalimumab formulations are provided in
Table H. Each formulation in Table H has a pH of about 5.0 to about
5.5, e.g., about 5.1 to about 5.3 and/or about 5.2. Optionally, the
pH of each formulation in Table H is adjusted using a strong acid
and/or strong base including, but not limited to, hydrochloric
acid, sodium hydroxide, calcium hydroxide, MSA, and/or MEA.
TABLE-US-00008 TABLE H Protein conc. Buffer Excipient(s) Surfactant
100 mg/mL 10 mM lactate 220 mM proline 0.1% (w/v) 25 mM CaCl.sub.2
Pluronic F68 100 mg/mL 10 mM lactate 9% (w/v) sucrose 0.1% (w/v)
Pluronic F68 100 mg/mL 10 mM lactate 9% (w/v) sucrose 0.1% (w/v) 25
mM CaCl.sub.2 Pluronic F68 100 mg/mL 10 mM lactate 220 mM proline
0.05% (w/v) 25 mM CaCl.sub.2 Pluronic F68 100 mg/mL 10 mM lactate
9% (w/v) sucrose 0.05% (w/v) Pluronic F68 100 mg/mL 10 mM lactate
9% (w/v) sucrose 0.05% (w/v) 25 mM CaCl.sub.2 Pluronic F68 100
mg/mL 10 mM lactate 220 mM proline 0.01% (w/v) 25 mM CaCl.sub.2
Pluronic F68 100 mg/mL 10 mM lactate 9% (w/v) sucrose 0.01% (w/v)
Pluronic F68 100 mg/mL 10 mM lactate 9% (w/v) sucrose 0.01% (w/v)
25 mM CaCl.sub.2 Pluronic F68 100 mg/mL 10 mM lactate 220 mM
proline 0.1% (w/v) 25 mM CaCl.sub.2 Polysorbate 80 100 mg/mL 10 mM
lactate 9% (w/v) sucrose 0.1% (w/v) Polysorbate 80 100 mg/mL 10 mM
lactate 220 mM proline 0.05% (w/v) 25 mM CaCl.sub.2 Polysorbate 80
100 mg/mL 10 mM lactate 9% (w/v) sucrose 0.05% (w/v) Polysorbate 80
100 mg/mL 10 mM lactate 220 mM proline 0.1% (w/v) 25 mM CaCl.sub.2
Polysorbate 20 100 mg/mL 10 mM lactate 9% (w/v) sucrose 0.1% (w/v)
Polysorbate 20 100 mg/mL 10 mM lactate 220 mM proline 0.05% (w/v)
25 mM CaCl.sub.2 Polysorbate 20 100 mg/mL 10 mM lactate 9% (w/v)
sucrose 0.05% (w/v) Polysorbate 20
[0508] Exemplary aqueous adalimumab formulations are provided in
Table I.
TABLE-US-00009 TABLE I Protein pH Adjusting conc. Buffer
Excipient(s) Agent Surfactant pH 100 mg/mL 10 mM lactate 220 mM
proline HCl/NaOH, 0.1% (w/v) 5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2,
Pluronic F68 HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM
lactate 9% (w/v) sucrose HCl/NaOH, 0.1% (w/v) 5.2 HCl/Ca(OH).sub.2,
Pluronic F68 HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM
lactate 9% (w/v) sucrose HCl/NaOH, 0.1% (w/v) 5.2 25 mM CaCl.sub.2
HCl/Ca(OH).sub.2, Pluronic F68 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM lactate 220 mM proline HCl/NaOH, 0.05%
(w/v) 5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2, Pluronic F68 HCl/MEA,
MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM lactate 9% (w/v)
sucrose HCl/NaOH, 0.05% (w/v) 5.2 HCl/Ca(OH).sub.2, Pluronic F68
HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM lactate 9%
(w/v) sucrose HCl/NaOH, 0.05% (w/v) 5.2 25 mM CaCl.sub.2
HCl/Ca(OH).sub.2, Pluronic F68 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM lactate 220 mM proline HCl/NaOH, 0.01%
(w/v) 5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2, Pluronic F68 HCl/MEA,
MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM lactate 9% (w/v)
sucrose HCl/NaOH, 0.01% (w/v) 5.2 HCl/Ca(OH).sub.2, Pluronic F68
HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM lactate 9%
(w/v) sucrose HCl/NaOH, 0.01% (w/v) 5.2 25 mM CaCl.sub.2
HCl/Ca(OH).sub.2, Pluronic F68 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM lactate 220 mM proline HCl/NaOH, 0.1% (w/v)
5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2, Polysorbate 80 HCl/MEA,
MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM lactate 9% (w/v)
sucrose HCl/NaOH, 0.1% (w/v) 5.2 HCl/Ca(OH).sub.2, Polysorbate 80
HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM lactate 220
mM proline HCl/NaOH, 0.05% (w/v) 5.2 25 mM CaCl.sub.2
HCl/Ca(OH).sub.2, Polysorbate 80 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM lactate 9% (w/v) sucrose HCl/NaOH, 0.05%
(w/v) 5.2 HCl/Ca(OH).sub.2, Polysorbate 80 HCl/MEA,
MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM lactate 220 mM proline
HCl/NaOH, 0.1% (w/v) 5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2,
Polysorbate 20 HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10
mM lactate 9% (w/v) sucrose HCl/NaOH, 0.1% (w/v) 5.2
HCl/Ca(OH).sub.2, Polysorbate 20 HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 10 mM lactate 220 mM proline HCl/NaOH, 0.05%
(w/v) 5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2, Polysorbate 20
HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 10 mM lactate 9%
(w/v) sucrose HCl/NaOH, 0.05% (w/v) 5.2 HCl/Ca(OH).sub.2,
Polysorbate 20 HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA
[0509] Exemplary aqueous adalimumab lactate formulations are also
provided in Tables 1, 11, 12, 13, 15, 16 and 17. In an embodiment,
the stable aqueous adalimumab formulation is one of the lactate
buffer formulations described in Tables G, H, I, 1, 11, 12, 13, 15,
16 or 17 provided herein.
[0510] In an embodiment, a lyophilized form of any one of the
foregoing lactate-containing adalimumab formulations is
provided.
Formulations of Adalimumab with Histidine Buffer
[0511] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 200
mg/mL, such as about 90 to about 120 mg/mL, about 160 to 190 mg/mL,
about 40 to about 60 mg/mL, about 50 mg/mL, about 100 mg/mL, or
about 170 mg/mL, histidine at a concentration of about 5 mM to
about 50 mM (e.g., about 5 mM to about 15 mM, about 10 mM, about 15
mM, about 20 mM, and/or about 25 mM), and one or more excipients.
Suitable excipients include certain stabilizers such as certain
amino acids and amino acid derivatives, certain salts, certain
polyols, certain acids, certain amines, and certain surfactants.
Examples of suitable amino acids and amino acid derivatives include
proline (e.g., at a concentration of about 0.1 to about 450 mM,
about 50 to about 300 mM, or about 270 to about 370 mM). Examples
of suitable salts include calcium chloride (e.g., at a
concentration of about 1 to about 150 mM, about 5 to about 50 mM,
about 10 to about 30 mM, about 20 to about 40 mM, about 30 to about
50 mM, about 40 to about 80 mM, about 50 to about 100 mM, or about
25 mM) and sodium chloride (e.g., at a concentration of about 10 to
about 100 mM, about 60 to about 90 mM, about 15 to about 50 mM,
and/or about 35 mM). Examples of suitable polyols include sucrose
(e.g., at a concentration of about 0.1% (w/v) to about 15% (w/v),
about 4% (w/v) to about 10% (w/v), about 4% (w/v) to about 9%
(w/v), about 6.5% (w/v), about 6.8% (w/v), about 6.9% (w/v), about
9% (w/v)) and sorbitol (e.g., at a concentration of about 0.1%
(w/v) to about 10% (w/v), about 3% (w/v) to about 5% (w/v), and/or
about 4% (w/v)). Examples of suitable acids include methane
sulfonic acid (MSA) (e.g., at a concentration of about 0.1 to about
150 mM or about 0.1 to about 50 mM). Examples of suitable amines
include MEA-HCl (e.g., at a concentration of about 0.1 to about 150
mM or about 0.1 to about 40 mM) and MEA (e.g., at a concentration
of about 0.1 to about 300 mM or about 0.1 to about 50 mM). Examples
of suitable surfactants include Pluronic F68 (e.g., at a
concentration of about 0.001% (w/v) to about 10% (w/v), about
0.005% (w/v) to about 1% (w/v), about 0.05% (w/v) to about 0.4%
(w/v), about 0.05% (w/v) to about 0.1% (w/v), about 0.01% (w/v),
about 0.05% (w/v), and/or about 0.1% (w/v)), Polysorbate 20 (e.g.,
at a concentration of about 0.001% (w/v) to about 2% (w/v) or about
0.005% (w/v) to about 0.1% (w/v)), and Polysorbate 80 (e.g., at a
concentration of about 0.001% (w/v) to about 2% (w/v), about 0.005%
(w/v) to about 0.1% (w/v), about 0.005% (w/v) to about 0.05% (w/v),
about 0.03% (w/v) to about 0.1% (w/v), about 0.04% (w/v) to about
0.1% (w/v), about 0.03% (w/v), about 0.04% (w/v), and/or about 0.1%
(w/v)). Optionally, the histidine-containing stable aqueous
adalimumab formulation has a pH of about 4.8 to about 5.7, for
example, about 4.9 to about 5.6, about 5.0 to about 5.5, about 5.1
to about 5.4, about 5.1 to about 5.3, about 5.1 to about 5.2, about
5.2 to about 5.3, about 6.4 to about 7.2, about 6.5 to about 7.1,
about 6.6 to about 7.0, about 6.7 to about 6.9, about 6.7 to about
6.8, about 6.8 to about 6.9, about 5.2, and/or about 6.8.
Optionally, the pH of the stable aqueous adalimumab formulation is
adjusted using a strong acid and/or a strong base including, but
not limited to, hydrochloric acid, sodium hydroxide, calcium
hydroxide, MSA, and/or MEA.
[0512] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 200
mg/mL, such as about 90 to about 120 mg/mL, about 160 to 190 mg/mL,
about 40 to about 60 mg/mL, about 50 mg/mL, about 100 mg/mL, or
about 170 mg/mL, histidine at a concentration of about 5 mM to
about 50 mM (e.g., about 5 mM to about 15 mM, about 10 mM, about 15
mM, about 20 mM, and/or about 25 mM), and one or more excipients
selected from the group consisting of proline at a concentration of
about 0.1 to about 450 mM (e.g., about 50 to about 300 mM or about
270 to about 370 mM), calcium chloride at a concentration of about
1 to about 150 mM (e.g., about 5 to about 50 mM, about 10 to about
30 mM, about 20 to about 40 mM, about 30 to about 50 mM, about 40
to about 80 mM, about 50 to about 100 mM, or about 25 mM), sodium
chloride at a concentration of about 10 to about 100 mM (e.g.,
about 60 to about 90 mM, about 15 to about 50 mM, and/or about 35
mM), sucrose at a concentration of about 0.1% (w/v) to about 15%
(w/v) (e.g., about 4% (w/v) to about 10% (w/v), about 4% (w/v) to
about 9% (w/v), about 6.5% (w/v), about 6.8% (w/v), about 6.9%
(w/v), about 9% (w/v)), sorbitol at a concentration of about 0.1%
(w/v) to about 10% (w/v) (e.g., about 3% (w/v) to about 5% (w/v)
and/or about 4% (w/v)), methane sulfonic acid (MSA) at a
concentration of about 0.1 to about 150 mM (e.g., about 0.1 to
about 50 mM), MEA-HCl at a concentration of about 0.1 to about 150
mM (e.g., about 0.1 to about 40 mM), MEA at a concentration of
about 0.1 to about 300 mM (e.g., about 0.1 to about 50 mM),
Pluronic F68 at a concentration of about 0.001% (w/v) to about 10%
(w/v) (e.g., about 0.005% (w/v) to about 1% (w/v), about 0.05%
(w/v) to about 0.4% (w/v), about 0.05% (w/v) to about 0.1% (w/v),
about 0.01% (w/v), about 0.05% (w/v), and/or about 0.1% (w/v)),
Polysorbate 20 at a concentration of about 0.001% (w/v) to about 2%
(w/v) (e.g., about 0.005% (w/v) to about 0.1% (w/v)), and
Polysorbate 80 at a concentration of about 0.001% (w/v) to about 2%
(w/v) (e.g., about 0.005% (w/v) to about 0.1% (w/v), about 0.005%
(w/v) to about 0.05% (w/v), about 0.03% (w/v) to about 0.1% (w/v),
about 0.04% (w/v) to about 0.1% (w/v), about 0.03% (w/v), about
0.04% (w/v), and/or about 0.1% (w/v)). Optionally, the
histidine-containing stable aqueous adalimumab formulation has a pH
of about 4.8 to about 5.7, for example, about 4.9 to about 5.6,
about 5.0 to about 5.5, about 5.1 to about 5.4, about 5.1 to about
5.3, about 5.1 to about 5.2, about 5.2 to about 5.3, about 6.4 to
about 7.2, about 6.5 to about 7.1, about 6.6 to about 7.0, about
6.7 to about 6.9, about 6.7 to about 6.8, about 6.8 to about 6.9,
about 5.2, and/or about 6.8. Optionally, the pH of the stable
aqueous adalimumab formulation is adjusted using a strong acid
and/or a strong base including, but not limited to, hydrochloric
acid, sodium hydroxide, calcium hydroxide, MSA, and/or MEA.
[0513] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, histidine at a concentration of about 5 mM to about 15 mM,
proline at a concentration of about 270 to about 370 mM, and
calcium chloride at a concentration of about 10 to about 30 mM, and
has a pH of about 6.7 to 6.9. Optionally, the pH of the formulation
is adjusted within this range with MEA and/or MSA.
[0514] Exemplary aqueous adalimumab formulations are provided in
Table J.
TABLE-US-00010 TABLE J Protein pH Adjusting conc. Buffer
Excipient(s) Agent pH 100 mg/mL 10 mM histidine 320 mM proline
HCl/NaOH, 5.2 20 mM CaCl.sub.2 HCl/Ca(OH).sub.2, HCl/MEA,
MSA/Ca(OH).sub.2, or MSA/MEA
[0515] In an embodiment, a lyophilized form of any one of the
foregoing histidine-containing adalimumab formulations is
provided.
Formulations of Adalimumab without Buffer
[0516] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 200
mg/mL, such as about 90 to about 120 mg/mL, about 160 to 190 mg/mL,
about 40 to about 60 mg/mL, about 50 mg/mL, about 100 mg/mL, or
about 170 mg/mL, and one or more excipients. Suitable excipients
include certain stabilizers such as certain amino acids and amino
acid derivatives, certain polyethylene glycols and polyethylene
glycol derivatives, certain salts, certain polyols, certain acids,
certain amines, and certain surfactants. Examples of suitable amino
acids and amino acid derivatives include proline (e.g., at a
concentration of about 0.1 to about 450 mM, about 50 to about 300
mM, or about 60 to about 300 mM). Examples of suitable polyethylene
glycols and polyethylene glycol derivatives include PEG 600 (e.g.,
at a concentration of about 0.1% (w/v) to about 30% (w/v) or about
1.2% (w/v) to about 14.5% (w/v)) and PEG 200 (e.g., at a
concentration of about 0.1% (w/v) to about 10% (w/v) or about 0.6%
(w/v) to about 4.8% (w/v)). Examples of suitable salts include
calcium chloride (e.g., at a concentration of about 1 to about 150
mM, about 5 to about 50 mM, about 10 to about 30 mM, about 20 to
about 40 mM, about 30 to about 50 mM, about 40 to about 80 mM,
about 20 to about 100 mM, about 50 to about 100 mM, or about 25 mM)
and sodium chloride (e.g., at a concentration of about 10 to about
100 mM, about 60 to about 90 mM, about 15 to about 50 mM, and/or
about 35 mM). Examples of suitable polyols include sorbitol (e.g.,
at a concentration of about 0.1% (w/v) to about 10% (w/v), about 3%
(w/v) to about 5% (w/v), and/or about 4% (w/v)) and sucrose (e.g.,
at a concentration of about 0.1% (w/v) to about 15% (w/v), about 4%
(w/v) to about 10% (w/v), about 4% (w/v) to about 9% (w/v), about
6.5% (w/v) to about 7.3% (w/v), about 6.5% (w/v), about 6.8% (w/v),
about 6.9% (w/v), about 9% (w/v)). Examples of suitable acids
include MSA (e.g., at a concentration of about 0.1 to about 150 mM,
about 0.1 to about 50 mM, or about 20 to about 90 mM). Examples of
suitable amines include MEA-HCl (e.g., at a concentration of about
0.1 to about 150 mM, about 0.1 to about 40 mM, or about 60 to about
90 mM) and MEA (e.g., at a concentration of about 0.1 to about 300
mM, about 0.1 to about 50 mM, or about 60 to about 90 mM). Examples
of suitable surfactants include Pluronic F68 (e.g., at a
concentration of about 0.001% (w/v) to about 10% (w/v), about
0.005% (w/v) to about 1% (w/v), about 0.05% (w/v) to about 0.5%
(w/v), about 0.05% (w/v) to about 0.4% (w/v), about 0.05% (w/v) to
about 0.1% (w/v), about 0.01% (w/v), about 0.05% (w/v), and/or
about 0.1% (w/v)), Polysorbate 20 (e.g., at a concentration of
about 0.001% (w/v) to about 2% (w/v) or about 0.005% (w/v) to about
0.1% (w/v)), and Polysorbate 80 (e.g., at a concentration of about
0.001% (w/v) to about 2% (w/v), about 0.005% (w/v) to about 0.1%
(w/v), about 0.005% (w/v) to about 0.05% (w/v), about 0.03% (w/v)
to about 0.1% (w/v), 0.04% (w/v) to about 0.1% (w/v), about 0.05%
(w/v) to about 0.1% (w/v), about 0.03% (w/v), about 0.04% (w/v),
and/or about 0.1% (w/v)). Optionally, the stable aqueous adalimumab
formulation without buffer has a pH of about 4.8 to about 5.7, for
example, about 4.9 to about 5.6, about 5.0 to about 5.5, about 5.1
to about 5.4, about 5.1 to about 5.3, about 5.1 to about 5.2, about
5.2 to about 5.3, and/or about 5.2. Optionally, the pH of the
stable aqueous adalimumab formulation is adjusted using a strong
acid and/or a strong base including, but not limited to,
hydrochloric acid, sodium hydroxide, calcium hydroxide, MSA, and/or
MEA.
[0517] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 200
mg/mL, such as about 90 to about 120 mg/mL, about 160 to 190 mg/mL,
about 40 to about 60 mg/mL, about 50 mg/mL, about 100 mg/mL, or
about 170 mg/mL, and one or more excipients selected from the group
consisting of proline at a concentration of about 0.1 to about 450
mM (e.g., about 50 to about 300 mM or about 60 to about 300 mM),
PEG 600 at a concentration of about 0.1% (w/v) to about 30% (w/v)
(e.g., about 1.2% (w/v) to about 14.5% (w/v)), PEG 200 at a
concentration of about 0.1% (w/v) to about 10% (w/v) (e.g., about
0.6% (w/v) to about 4.8% (w/v)), calcium chloride at a
concentration of about 1 to about 150 mM (e.g., about 5 to about 50
mM, about 10 to about 30 mM, about 20 to about 40 mM, about 30 to
about 50 mM, about 40 to about 80 mM, about 20 to about 100 mM,
about 50 to about 100 mM, or about 25 mM), sodium chloride at a
concentration of about 10 to about 100 mM (e.g., about 60 to about
90 mM, about 15 to about 50 mM, and/or about 35 mM), MSA at a
concentration of about 0.1 to about 150 mM (e.g., about 0.1 to
about 50 mM or about 20 to about 90 mM), MEA-HCl at a concentration
of about 0.1 to about 150 mM (e.g., about 0.1 to about 40 mM or
about 60 to about 90 mM), MEA at a concentration of about 0.1 to
about 300 mM (e.g., about 0.1 to about 50 mM or about 60 to about
90 mM), sorbitol at a concentration of about 0.1% (w/v) to about
10% (w/v) (e.g., about 3% (w/v) to about 5% (w/v), and/or about 4%
(w/v)), sucrose at a concentration of about 0.1% (w/v) to about 15%
(w/v) (e.g., about 4% (w/v) to about 10% (w/v), about 4% (w/v) to
about 9% (w/v), about 6.5% (w/v) to about 7.3% (w/v), about 6.5%
(w/v), about 6.8% (w/v), about 6.9% (w/v), about 9% (w/v)),
Pluronic F68 at a concentration of about 0.001% (w/v) to about 10%
(w/v) (e.g., about 0.005% (w/v) to about 1% (w/v), about 0.05%
(w/v) to about 0.5% (w/v), about 0.05% (w/v) to about 0.4% (w/v),
about 0.05% (w/v) to about 0.1% (w/v), about 0.01% (w/v), about
0.05% (w/v), and/or about 0.1% (w/v)), Polysorbate 20 at a
concentration of about 0.001% (w/v) to about 2% (w/v) (e.g., about
0.005% (w/v) to about 0.1% (w/v)), and Polysorbate 80 at a
concentration of about 0.001% (w/v) to about 2% (w/v) (e.g., about
0.005% (w/v) to about 0.1% (w/v), about 0.005% (w/v) to about 0.05%
(w/v), about 0.03% (w/v) to about 0.1% (w/v), 0.04% (w/v) to about
0.1% (w/v), about 0.05% (w/v) to about 0.1% (w/v), about 0.03%
(w/v), about 0.04% (w/v), and/or about 0.1% (w/v)). Optionally, the
stable aqueous adalimumab formulation without buffer has a pH of
about 4.8 to about 5.7, for example, about 4.9 to about 5.6, about
5.0 to about 5.5, about 5.1 to about 5.4, about 5.1 to about 5.3,
about 5.1 to about 5.2, about 5.2 to about 5.3, and/or about 5.2.
Optionally, the pH of the stable aqueous adalimumab formulation is
adjusted using a strong acid and/or a strong base including, but
not limited to, hydrochloric acid, sodium hydroxide, calcium
hydroxide, MSA, and/or MEA.
[0518] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, MSA at a concentration of about 10 to about 30 mM, and
proline at a concentration of about 250 to about 350 mM, and has a
pH of about 5.1 to 5.3. Optionally, the pH of the formulation is
adjusted within this range with MEA or NaOH.
[0519] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 600 at a concentration of about 8% (w/v) to about 10%
(w/v), calcium chloride at a concentration of about 10 to about 30
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0520] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 600 at a concentration of about 6.5% (w/v) to about 7.3%
(w/v), PEG 200 at a concentration of about 0.3% (w/v) to about 1%
(w/v), calcium chloride at a concentration of about 10 to about 30
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0521] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 600 at a concentration of about 4% (w/v) to about 5%
(w/v), PEG 200 at a concentration of about 1.5% (w/v) to about 2.1%
(w/v), calcium chloride at a concentration of about 10 to about 30
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0522] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 600 at a concentration of about 0.9% (w/v) to about 1.5%
(w/v), PEG 200 at a concentration of about 2.5% (w/v) to about 3.5%
(w/v), calcium chloride at a concentration of about 10 to about 30
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0523] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 200 at a concentration of about 3% (w/v) to about 5%
(w/v), calcium chloride at a concentration of about 10 to about 30
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0524] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 600 at a concentration of about 6.9% (w/v) to about 7.7%
(w/v), proline at a concentration of about 40 to about 80 mM,
calcium chloride at a concentration of about 10 to about 30 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MEA and/or MSA.
[0525] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 600 at a concentration of about 5% (w/v) to about 6%
(w/v), proline at a concentration of about 90 to about 150 mM,
calcium chloride at a concentration of about 10 to about 30 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MEA and/or MSA.
[0526] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 600 at a concentration of about 2% (w/v) to about 3%
(w/v), proline at a concentration of about 150 to about 210 mM,
calcium chloride at a concentration of about 10 to about 30 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MEA and/or MSA.
[0527] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, proline at a concentration of about 200 to about 300 mM,
calcium chloride at a concentration of about 10 to about 30 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MEA and/or MSA.
[0528] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, sorbitol at a concentration of about 3% (w/v) to about 5%
(w/v), calcium chloride at a concentration of about 15 to about 35
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with HCl, NaOH,
CaCl.sub.2), MEA, and/or MSA.
[0529] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 110
mg/mL, sorbitol at a concentration of about 3.5% (w/v) to about
4.5% (w/v), calcium chloride at a concentration of about 20 to
about 30 mM, and Pluronic F68 at a concentration of about 0.05%
(w/v) to about 0.2% (w/v), and has a pH of about 5.1 to 5.3.
Optionally, the pH of the formulation is adjusted within this range
with HCl, NaOH, CaCl.sub.2), MEA, and/or MSA.
[0530] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, sorbitol at a concentration of about 3% (w/v) to about 5%
(w/v), calcium chloride at a concentration of about 15 to about 35
mM, and Pluronic F68 at a concentration of about 0.01% (w/v) to
about 0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with HCl, NaOH,
CaCl.sub.2), MEA, and/or MSA.
[0531] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 110
mg/mL, sorbitol at a concentration of about 3.5% (w/v) to about
4.5% (w/v), calcium chloride at a concentration of about 20 to
about 30 mM, and Pluronic F68 at a concentration of about 0.03%
(w/v) to about 0.1% (w/v), and has a pH of about 5.1 to 5.3.
Optionally, the pH of the formulation is adjusted within this range
with HCl, NaOH, CaCl.sub.2), MEA, and/or MSA.
[0532] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, sorbitol at a concentration of about 3% (w/v) to about 5%
(w/v), calcium chloride at a concentration of about 15 to about 35
mM, and Polysorbate 80 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with HCl, NaOH,
CaCl.sub.2), MEA, and/or MSA.
[0533] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, sorbitol at a concentration of about 3% (w/v) to about 5%
(w/v), calcium chloride at a concentration of about 15 to about 35
mM, and Polysorbate 80 at a concentration of about 0.01% (w/v) to
about 0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with HCl, NaOH,
CaCl.sub.2), MEA, and/or MSA.
[0534] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, sorbitol at a concentration of about 3% (w/v) to about 5%
(w/v), calcium chloride at a concentration of about 15 to about 35
mM, and Polysorbate 20 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with HCl, NaOH,
CaCl.sub.2), MEA, and/or MSA.
[0535] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, sorbitol at a concentration of about 3% (w/v) to about 5%
(w/v), calcium chloride at a concentration of about 15 to about 35
mM, and Polysorbate 20 at a concentration of about 0.01% (w/v) to
about 0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with HCl, NaOH,
CaCl.sub.2), MEA, and/or MSA.
[0536] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, sucrose at a concentration of about 5% (w/v) to about 8%
(w/v), calcium chloride at a concentration of about 15 to about 35
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0537] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, sucrose at a concentration of about 6.1% (w/v) to about 6.9%
(w/v), calcium chloride at a concentration of about 15 to about 35
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with HCl, NaOH,
CaCl.sub.2), MEA, and/or MSA.
[0538] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 110
mg/mL, sucrose at a concentration of about 6.3% (w/v) to about 6.7%
(w/v), calcium chloride at a concentration of about 20 to about 30
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.2% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with HCl, NaOH,
CaCl.sub.2), MEA, and/or MSA.
[0539] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, sucrose at a concentration of about 6.1% (w/v) to about 6.9%
(w/v), calcium chloride at a concentration of about 15 to about 35
mM, and Pluronic F68 at a concentration of about 0.01% (w/v) to
about 0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with HCl, NaOH,
CaCl.sub.2), MEA, and/or MSA.
[0540] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 110
mg/mL, sucrose at a concentration of about 6.3% (w/v) to about 6.7%
(w/v), calcium chloride at a concentration of about 20 to about 30
mM, and Pluronic F68 at a concentration of about 0.03% (w/v) to
about 0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with HCl, NaOH,
CaCl.sub.2), MEA, and/or MSA.
[0541] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, sucrose at a concentration of about 6.1% (w/v) to about 6.9%
(w/v), calcium chloride at a concentration of about 15 to about 35
mM, and Polysorbate 80 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with HCl, NaOH,
CaCl.sub.2), MEA, and/or MSA.
[0542] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, sucrose at a concentration of about 6.1% (w/v) to about 6.9%
(w/v), calcium chloride at a concentration of about 15 to about 35
mM, and Polysorbate 80 at a concentration of about 0.01% (w/v) to
about 0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with HCl, NaOH,
CaCl.sub.2), MEA, and/or MSA.
[0543] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, sucrose at a concentration of about 6.1% (w/v) to about 6.9%
(w/v), calcium chloride at a concentration of about 15 to about 35
mM, and Polysorbate 20 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with HCl, NaOH,
CaCl.sub.2), MEA, and/or MSA.
[0544] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, sucrose at a concentration of about 6.1% (w/v) to about 6.9%
(w/v), calcium chloride at a concentration of about 15 to about 35
mM, and Polysorbate 20 at a concentration of about 0.01% (w/v) to
about 0.1% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with HCl, NaOH,
CaCl.sub.2), MEA, and/or MSA.
[0545] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, proline at a concentration of about 200 to about 250 mM,
calcium chloride at a concentration of about 15 to about 35 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MEA and/or MSA.
[0546] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 600 at a concentration of about 11% (w/v) to about 15%
(w/v), calcium chloride at a concentration of about 20 to about 40
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0547] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 160 to about 190
mg/mL, sucrose at a concentration of about 5% (w/v) to about 8%
(w/v), calcium chloride at a concentration of about 15 to about 35
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0548] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, sucrose at a concentration of about 6.9% (w/v) to about 7.7%
(w/v), calcium chloride at a concentration of about 10 to about 30
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0549] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 200 at a concentration of about 4.5% (w/v) to about 5.1%
(w/v), calcium chloride at a concentration of about 10 to about 30
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0550] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, sorbitol at a concentration of about 3% (w/v) to about 5%
(w/v), calcium chloride at a concentration of about 15 to about 35
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with HCl.
[0551] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 600 at a concentration of about 13% (w/v) to about 16%
(w/v), calcium chloride at a concentration of about 10 to about 30
mM, and Pluronic F68 at a concentration of about 0.05% (w/v) to
about 0.5% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the
pH of the formulation is adjusted within this range with MEA and/or
MSA.
[0552] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 90 to about 120
mg/mL, PEG 600 at a concentration of about 3% (w/v) to about 3.6%
(w/v), calcium chloride at a concentration of about 10 to about 30
mM, proline at a concentration of about 150 to about 210 mM, and
Pluronic F68 at a concentration of about 0.05% (w/v) to about 0.5%
(w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MEA and/or MSA.
[0553] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL and PEG 600 at a concentration of about 10% (w/v) to about
11% (w/v), and has a pH of about 5.1 to 5.3. Optionally, the pH of
the formulation is adjusted within this range with MEA and/or
MSA.
[0554] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL, PEG 600 at a concentration of about 8% (w/v) to about 9%
(w/v), and calcium chloride at a concentration of about 15 to about
35 mM, and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MEA and/or MSA.
[0555] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL, PEG 600 at a concentration of about 6% (w/v) to about 7%
(w/v), and calcium chloride at a concentration of about 40 to about
60 mM, and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MEA and/or MSA.
[0556] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL, PEG 600 at a concentration of about 3.4% (w/v) to about 4%
(w/v), and calcium chloride at a concentration of about 65 to about
85 mM, and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MEA and/or MSA.
[0557] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL and calcium chloride at a concentration of about 80 to about
120 mM, and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MEA and/or MSA.
[0558] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL and proline at a concentration of about 250 to about 350 mM,
and has a pH of about 5.1 to 5.3. Optionally, the pH of the
formulation is adjusted within this range with MEA and/or MSA.
[0559] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL, proline at a concentration of about 200 to about 250 mM, and
calcium chloride at a concentration of about 15 to about 35 mM, and
has a pH of about 5.1 to 5.3. Optionally, the pH of the formulation
is adjusted within this range with MEA and/or MSA.
[0560] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL, proline at a concentration of about 120 to about 180 mM, and
calcium chloride at a concentration of about 40 to about 60 mM, and
has a pH of about 5.1 to 5.3. Optionally, the pH of the formulation
is adjusted within this range with MEA and/or MSA.
[0561] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL, proline at a concentration of about 60 to about 90 mM, and
calcium chloride at a concentration of about 65 to about 85 mM, and
has a pH of about 5.1 to 5.3. Optionally, the pH of the formulation
is adjusted within this range with MEA and/or MSA.
[0562] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL, proline at a concentration of about 200 to about 300 mM, MEA
at a concentration of about 40 to about 80 mM, and MSA at a
concentration of about 40 to about 80 mM, and has a pH of about 5.1
to 5.3. Optionally, the pH of the formulation is adjusted within
this range with MEA and/or MSA.
[0563] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL, proline at a concentration of about 150 to about 210 mM, MEA
at a concentration of about 40 to about 80 mM, and MSA at a
concentration of about 40 to about 80 mM, and has a pH of about 5.1
to 5.3. Optionally, the pH of the formulation is adjusted within
this range with MEA and/or MSA.
[0564] In an embodiment, the stable aqueous adalimumab formulation
includes adalimumab at a concentration of about 40 to about 60
mg/mL, proline at a concentration of about 90 to about 150 mM, MEA
at a concentration of about 70 to about 110 mM, and MSA at a
concentration of about 70 to about 110 mM, and has a pH of about
5.1 to 5.3. Optionally, the pH of the formulation is adjusted
within this range with MEA and/or MSA.
[0565] Exemplary aqueous adalimumab formulations are provided in
Table J. Each formulation in Table J may optionally include
Pluronic F68 at a concentration of about 0.001% (w/v) to about 10%
(w/v) (e.g., about 0.005% (w/v) to about 1% (w/v), about 0.01%
(w/v) to about 0.1% (w/v), about 0.01% (w/v) to about 1% (w/v),
about 0.05% (w/v) to about 0.1% (w/v), about 0.05% (w/v) to about
0.4% (w/v), about 0.01% (w/v), about 0.05% (w/v) to about 0.5%
(w/v), about 0.1% (w/v) to about 2% (w/v), about 0.2% (w/v) to
about 1% (w/v), about 0.05% (w/v), about 0.1% (w/v), and/or about
0.4% (w/v)), Polysorbate 20 at a concentration of about 0.001%
(w/v) to about 2% (w/v) (e.g., about 0.002% (w/v) to about 0.01%
(w/v), about 0.005% (w/v) to about 0.05% (w/v), about 0.005% (w/v)
to about 0.1% (w/v), about 0.02% (w/v) to about 0.1% (w/v), and/or
about 0.05% (w/v) to about 0.2% (w/v)), or Polysorbate 80 at a
concentration of about 0.001% (w/v) to about 2% (w/v) (e.g., about
0.002% (w/v) to about 0.01% (w/v), about 0.005% (w/v) to about 0.1%
(w/v), about 0.005% (w/v) to about 0.05% (w/v), about 0.02% (w/v)
to about 0.1% (w/v), about 0.03% (w/v) to about 0.1% (w/v), 0.04%
(w/v) to about 0.1% (w/v), about 0.05% (w/v) to about 0.2% (w/v),
about 0.03% (w/v), about 0.04% (w/v), and/or about 0.1% (w/v)).
Each formulation in Table J has a pH of about 5.0 to about 5.5,
e.g., about 5.1 to about 5.3 and/or about 5.2. Optionally, the pH
of each formulation in Table J is adjusted using a strong acid
and/or strong base including, but not limited to, hydrochloric
acid, sodium hydroxide, calcium hydroxide, MSA, and/or MEA.
TABLE-US-00011 TABLE J Protein conc. Excipient(s) 100 mg/mL 4%
(w/v) sorbitol 25 mM CaCl.sub.2 100 mg/mL 6.5% (w/v) sucrose 25 mM
CaCl.sub.2
[0566] Exemplary aqueous adalimumab formulations are provided in
Table K. Each formulation in Table K has a pH of about 5.0 to about
5.5, e.g., about 5.1 to about 5.3 and/or about 5.2. Optionally, the
pH of each formulation in Table K is adjusted using a strong acid
and/or strong base including, but not limited to, hydrochloric
acid, sodium hydroxide, calcium hydroxide, MSA, and/or MEA.
TABLE-US-00012 TABLE K Protein conc. Excipient(s) Surfactant 100
mg/mL 4% (w/v) sorbitol 0.1% (w/v) Pluronic F68 25 mM CaCl.sub.2
100 mg/mL 6.5% (w/v) sucrose 0.1% (w/v) Pluronic F68 25 mM
CaCl.sub.2 100 mg/mL 4% (w/v) sorbitol 0.05% (w/v) Pluronic F68 25
mM CaCl.sub.2 100 mg/mL 6.5% (w/v) sucrose 0.05% (w/v) Pluronic F68
25 mM CaCl.sub.2 100 mg/mL 4% (w/v) sorbitol 0.1% (w/v) Polysorbate
80 25 mM CaCl.sub.2 100 mg/mL 6.5% (w/v) sucrose 0.1% (w/v)
Polysorbate 80 25 mM CaCl.sub.2 100 mg/mL 4% (w/v) sorbitol 0.05%
(w/v) Polysorbate 80 25 mM CaCl.sub.2 100 mg/mL 6.5% (w/v) sucrose
0.05% (w/v) Polysorbate 80 25 mM CaCl.sub.2 100 mg/mL 4% (w/v)
sorbitol 0.1% (w/v) Polysorbate 20 25 mM CaCl.sub.2 100 mg/mL 6.5%
(w/v) sucrose 0.1% (w/v) Polysorbate 20 25 mM CaCl.sub.2 100 mg/mL
4% (w/v) sorbitol 0.05% (w/v) Polysorbate 20 25 mM CaCl.sub.2 100
mg/mL 6.5% (w/v) sucrose 0.05% (w/v) Polysorbate 20 25 mM
CaCl.sub.2
[0567] Exemplary aqueous adalimumab formulations are provided in
Table L.
TABLE-US-00013 TABLE L Protein pH Adjusting conc. Excipient(s)
Agent Surfactant pH 100 mg/mL 4% (w/v) sorbitol HCl/NaOH, 0.1%
(w/v) Pluronic F68 5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2, HCl/MEA,
MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 6.5% (w/v) sucrose HCl/NaOH,
0.1% (w/v) Pluronic F68 5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2,
HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 4% (w/v) sorbitol
HCl/NaOH, 0.05% (w/v) Pluronic F68 5.2 25 mM CaCl.sub.2
HCl/Ca(OH).sub.2, HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL
6.5% (w/v) sucrose HCl/NaOH, 0.05% (w/v) Pluronic F68 5.2 25 mM
CaCl.sub.2 HCl/Ca(OH).sub.2, HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA
100 mg/mL 4% (w/v) sorbitol HCl/NaOH, 0.1% (w/v) Polysorbate 80 5.2
25 mM CaCl.sub.2 HCl/Ca(OH).sub.2, HCl/MEA, MSA/Ca(OH).sub.2, or
MSA/MEA 100 mg/mL 6.5% (w/v) sucrose HCl/NaOH, 0.1% (w/v)
Polysorbate 80 5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2, HCl/MEA,
MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 4% (w/v) sorbitol HCl/NaOH,
0.05% (w/v) Polysorbate 80 5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2,
HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 6.5% (w/v) sucrose
HCl/NaOH, 0.05% (w/v) Polysorbate 80 5.2 25 mM CaCl.sub.2
HCl/Ca(OH).sub.2, HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL
4% (w/v) sorbitol HCl/NaOH, 0.1% (w/v) Polysorbate 20 5.2 25 mM
CaCl.sub.2 HCl/Ca(OH).sub.2, HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA
100 mg/mL 6.5% (w/v) sucrose HCl/NaOH, 0.1% (w/v) Polysorbate 20
5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2, HCl/MEA, MSA/Ca(OH).sub.2,
or MSA/MEA 100 mg/mL 4% (w/v) sorbitol HCl/NaOH, 0.05% (w/v)
Polysorbate 20 5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2, HCl/MEA,
MSA/Ca(OH).sub.2, or MSA/MEA 100 mg/mL 6.5% (w/v) sucrose HCl/NaOH,
0.05% (w/v) Polysorbate 20 5.2 25 mM CaCl.sub.2 HCl/Ca(OH).sub.2,
HCl/MEA, MSA/Ca(OH).sub.2, or MSA/MEA
[0568] In an embodiment, a lyophilized form of any one of the
foregoing adalimumab formulations without buffer is provided.
Methods of Treatment
[0569] The invention provides for methods of treating a patient
suffering from a TNF-.alpha. associated disease or disorder
comprising administering to the patient any of the stable aqueous
adalimumab formulations of the invention (or lyophilized
formulations thereof once reconstituted, e.g., with sterile water
for injection). The TNF-.alpha. diseases and disorders include, but
are not limited to, inflammatory diseases and disorders, intestinal
diseases and disorders, autoimmune diseases and disorders, eye
diseases and disorders, pulmonary diseases and disorders, and
infectious diseases and disorders. The term "patient" includes
humans and non-human animal subjects.
[0570] The invention also provides for compositions comprising any
of the stable aqueous or lyophilized adalimumab formulations of the
invention for the treatment of a TNF-.alpha. associated disease or
disorder, such as inflammatory diseases and disorders, intestinal
diseases and disorders, autoimmune diseases and disorders, eye
diseases and disorders, pulmonary diseases and disorders, and
infectious diseases and disorders.
[0571] The invention further provides for use of the stable aqueous
or lyophilized adalimumab formulations of the invention for the
preparation of a medicament for the treatment of TNF-.alpha.
associated diseases or disorders, such as inflammatory diseases and
disorders, intestinal diseases and disorders, autoimmune diseases
and disorders, eye diseases and disorders, pulmonary diseases and
disorders, and infectious diseases and disorders.
[0572] Inflammatory diseases and disorders include, but are not
limited to, arthritis, adult and juvenile rheumatoid arthritis,
juvenile idiopathic arthritis, polyarticular juvenile idiopathic
arthritis, psoriatic arthritis, osteoarthritis including erosive
osteoarthritis and hund osteoarthritis, plaque psoriasis, general
pustular psoriasis, nail and scalp psoriasis, hidradenitis
suppurativa, ankylosing spondylitis, interstitial cystitis,
spondyloarthritis including peripheral spondyloarthritis and axial
spondyloarthritis, spondylarthropathy, pulmonary inflammation
disorder, allergy, uveitis, chronic pulmonary inflammation disease,
vascular inflammation, enthesitis related arthritis, enthesopathy,
coronary atherosclerosis, inflammatory bone disorders, bone
resorption disease, hepatitis including alcoholic hepatitis,
chronic pouchitis, inflammatory bowel disease, adult and pediatric
Crohn's disease, ulcerative colitis, schleritis, sarcoidosis,
cutaneous sarcoidosis, Netherton syndrome, and giant cell
arteritis.
[0573] Intestinal diseases and disorders include, but are not
limited to, chronic pouchitis, inflammatory bowel disease, adult
and pediatric Crohn's disease, ulcerative colitis, small bowel
lesions, anal squamous intraepithelial lesions, anal fissures, and
intestinal Behcet's disease.
[0574] Autoimmune diseases and disorders include, but are not
limited to, adult and juvenile rheumatoid arthritis, juvenile
idiopathic arthritis, psoriasis, plaque psoriasis, general pustular
psoriasis, nail and scalp psoriasis, psoriasis vulgaris, psoriasis
arthropica, psoriatic arthritis, pyoderma gangrenosum, gouty
arthritis, allergy, multiple sclerosis, autoimmune diabetes,
autoimmune uveitis, nephrotic syndrome, diabetic ulcers, and graft
vs. host disease
[0575] Eye diseases and disorders include, but are not limited to,
uveitis, anterior uveitis, intermediate uveitis and posterior
uveitis, refractory diabetic retinopathy, choroid diseases,
choroidal neovascularization, macular degeneration including
age-related macular degeneration, albinism, Behcet's syndrome,
Hermanski-Pudluk syndrome, panuveitis, pars planitis, retinal
degeneration, uveal diseases, retinal vascular disorders, and
schleritis.
[0576] Infectious diseases and disorders include, but are not
limited to, malaria, acquired immune deficiency (AIDS),
cytomegalovirus infection and influenza.
[0577] Pulmonary disease and disorders include, but are not limited
to, adult respiratory distress syndrome, asthma, refractory asthma,
pulmonary inflammation disorder, shock lung, chronic pulmonary
inflammatory disease, pulmonary sarcoidosis, pulmonary fibrosis and
silicosis.
[0578] Other TNF-.alpha. associated diseases and disorders include,
but are not limited to, mucopolysaccharidosis including
mucopolysaccharidosis type I, mucopolysaccharidosis type II,
mucopolysaccharidosis type IV, cancers, cachexia, ischemia of the
heart, coagulation disturbances, acute disc prolapse, sleep apnea,
anaplastic thyroid cancer and focal segmental
glomeruloschelorisis.
[0579] Stable aqueous adalimumab formulations of the invention (or
lyophilized formulations thereof once reconstituted, e.g., with
sterile water for injection) may be administered subcutaneously,
intravenously, parenterally, intradermally, intramuscularly, and/or
intraperitoneally using standard techniques. For example, the
stable aqueous adalimumab formulations of the invention may be
prepared to be subcutaneously administered using a pre-filled
syringe. Specifically, any of the formulations of the invention may
be administered once every week or 6 to 8 days or 7 to 10 days, or
every other week or every two weeks or 12 to 16 days or 7 to 14
days or 13 to 15 days, or every three weeks or 19 to 23 days, or
every month or 26 to 30 days or 29 to 31 days, or every five weeks
or 33 to 34 days, or every six weeks or 40 to 44 days, or every
seven weeks or 47 to 51 days, or every two months or 54 to 58 days
subcutaneously, intravenously, parenterally, intradermally,
intramuscularly, and/or intraperitoneally at a therapeutically
effective dosage and in the formulations described herein for an
indefinite period of time for the treatment of the diseases and
conditions described above.
[0580] Administration and dosage regimens of stable aqueous
adalimumab formulations of the invention (or lyophilized
formulations thereof once reconstituted, e.g., with sterile water
for injection) can be adjusted to provide an effective amount for
an optimum therapeutic response. For example, a single bolus can be
administered, two or more divided doses can be administered over
time or the dose can be proportionally reduced or increased as
indicated by the exigencies of the therapeutic situation. For
example, a unit dose can be administered over two consecutive days
every two weeks. Unit dosing refers to a physically discrete amount
of adalimumab or a biosimilar thereof suited as unitary dosages for
the patients to be treated; each unit contains a predetermined
quantity of active biopharmaceutical calculated to produce a
desired therapeutic effect.
[0581] The dosing regimen of stable aqueous adalimumab formulations
of the invention (or lyophilized formulations thereof once
reconstituted, e.g., with sterile water for injection) may comprise
administering a dose given on Day one, followed by the
administration of the same dose every other week. For example, a
dose of 40 mg adalimumab or biosimilar thereof is administered
every other week in patients suffering from rheumatoid arthritis,
psoriatic arthritis or ankylosing spondylitis. For patients
suffering from juvenile idiopathic arthritis that are 10 kg (22
lbs) to less than 15 kg (33 lbs), a dose of 10 mg adalimumab or
biosimilar thereof is administered every other week, for example.
For patients suffering from juvenile idiopathic arthritis that are
15 kg (33 lbs) to less than 30 kg (66 lbs), a dose of 20 mg
adalimumab or biosimilar thereof is administered every other week,
for example. For patients suffering from juvenile idiopathic
arthritis that are greater or equal to 30 kg (66 lbs), a dose of 40
mg adalimumab or biosimilar thereof is administered every other
week, for example. This dosing regimen may also include
administering methotrexate (MTX), other non-biologic DMARDS,
glucocorticoid, nonsteroidal anti-inflammatory drugs (NSAIDS)
and/or analgesics throughout the administration or for a portion of
the time of administration of any of the stable aqueous adalimumab
formulations of the invention.
[0582] The dosing regimen of stable aqueous adalimumab formulations
of the invention may (or lyophilized formulations thereof once
reconstituted, e.g., with sterile water for injection) comprise
administering an initial dose given on day one or split over two
consecutive days, followed by the administration of the same or a
reduced dose two weeks later (Day 15), e.g. the initial dose
reduced by half. The dosing regimen may further comprise
administration of the same or further reduced dose two weeks later
(Day 29); e.g. a dose that is a fourth of the initial dose which
will be continued as a maintenance dose every two weeks. For
example, for patients suffering from adult Crohn's disease or
ulcerative colitis, an initial dose of 160 mg adalimumab or
biosimilar thereof is administered on Day 1, a second dose of 80 mg
adalimumab or biosimilar thereof is administered two weeks later
(Day 15), followed by a maintenance dose of 40 mg adalimumab or
biosimilar thereof administered two weeks later (Day 29) that is
continued every other week. For patients suffering from pediatric
Crohn's disease that are 17 kb (37 lbs) to less than 40 kg (88
lbs), an initial dose of 80 mg adalimumab or biosimilar thereof is
administered on Day 1, a second dose of 40 mg adalimumab or
biosimilar thereof is administered two weeks later (Day 15),
followed by a maintenance dose of 20 mg adalimumab or biosimilar
thereof administered two weeks later (Day 29) that is continued
every other week, for example. For patients suffering from
pediatric Crohn's disease that are greater than 40 kg (88 lbs), an
initial dose of 160 mg adalimumab or biosimilar thereof is
administered on Day 1, a second dose of 80 mg adalimumab or
biosimilar thereof is administered two weeks later (Day 15),
followed by a maintenance dose of 40 mg adalimumab or biosimilar
thereof administered two weeks later (Day 29) that is continued
every other week, for example. This dosing regimen may also include
administering aminosalicylates and/or corticosteroids,
azathioprine, 6-mercaptopurine (6-MP) or MTX throughout the
administration or for a portion of the time of administration of
any of the stable aqueous adalimumab formulations of the
invention.
[0583] The dosing regimen of stable aqueous adalimumab formulations
of the invention (or lyophilized formulations thereof once
reconstituted, e.g., with sterile water for injection) may comprise
administering an initial dose given on Day one or split over two
consecutive days, followed by the administration of the same or a
reduced dose two weeks later (Day 15), e.g. an initial dose reduced
by half. The dosing regimen may further comprise administration of
the same or further reduced dose two weeks later (Day 29), e.g. a
dose that is a fourth of the initial dose. For example, an initial
dose of 160 mg adalimumab or biosimilar thereof is administered on
Day 1, a second dose of 80 mg adalimumab or biosimilar thereof is
administered two weeks later (Day 15), and a third dose of 40 mg
adalimumab or biosimilar thereof is administered on Day 29 followed
by administration of 40 mg adalimumab or biosimilar thereof every
week. This dosing regimen may be administered to patients suffering
from hidradenitis suppurativa.
[0584] The dosing regimen of stable aqueous adalimumab formulations
of the invention (or lyophilized formulations thereof once
reconstituted, e.g., with sterile water for injection) may comprise
administering an initial dose given on Day one or split over two
consecutive days, followed by the administration of the same or a
reduced dose one week after the initial dose e.g. an initial dose
reduced by half and continued administration every other week. For
example, an initial dose of 80 mg adalimumab or biosimilar thereof,
followed by administration of 40 mg adalimumab or biosimilar
thereof every other week starting one week after the initial dose.
This dosing regimen may be administered to patients suffering from
plaque psoriasis or uveitis.
[0585] The invention provides for a method of preparing a stable
aqueous adalimumab formulations of the invention, comprising
combining an aqueous solution comprising one or more excipients and
an therapeutically effective amount of adalimumab using techniques
standard in the art. The invention further provides for a method of
preparing the stable lyophilized adalimumab formulations of the
invention, comprising lyophilizing an aqueous adalimumab
formulation comprising one or more excipients and a therapeutically
effective amount of adalimumab using techniques standard in the
art.
[0586] The foregoing detailed description is not intended to define
every aspect of the invention, and other features and advantages of
the present disclosure will be apparent to those skilled in the
art. The present disclosure is intended to be related as a unified
document, and it should be understood that all combinations of
features described herein are contemplated, even if the combination
of features are not found together in the same sentence, paragraph,
or section of this disclosure. In addition, the disclosure
includes, as an additional aspect, all embodiments of the invention
narrower in scope in any way than the variations specifically
mentioned above. With respect to aspects of the disclosure
described or claimed with "a" or "an," it should be understood that
these terms mean "one or more" unless context unambiguously
requires a more restricted meaning. With respect to elements
described as one or more within a set, it should be understood that
all combinations within the set are contemplated. If aspects of the
disclosure are described as "comprising" a feature, embodiments
also are contemplated "consisting of" or "consisting essentially
of" the feature. Additional features and variations of the
disclosure will be apparent to those skilled in the art from the
entirety of this application, and all such features are intended as
aspects of the disclosure.
[0587] The present disclosure will be more readily understood by
reference to the following examples, which are provided by way of
illustration and are not intended to be limiting.
EXAMPLES
[0588] The following Examples describe formulations of the present
disclosure.
[0589] General Materials: In the following examples, an adalimumab
biosimilar as described in Velayudhan et al., BioDrugs 30:339-351
(2016) (i.e., ABP 501) was used.
[0590] General Analytical Methods: Cation-exchange high-performance
liquid chromatography (CEX-HPLC) and size-exclusion
high-performance liquid chromatography (SE-HPLC) were used to
assess stability. CEX-HPLC examines changes in charge, mainly due
to deamidation, which is measured as pre-peak or acidic growth, and
SE-HPLC is used to resolve and measure soluble aggregation, also
known as high molecular weight species (HMWS), which is determined
as a growth in pre-peak area. To be considered significant, changes
in degradation should be greater than the intermediate precision of
the assays: the standard deviation is +/-0.16 for the CEX-HPLC
method and +/-0.032 for the SE-HPLC method. CEX-HPLC was performed
using, a Pro Pac WCX-10 analytical column, 4.0 mm.times.250 mm
(Dionex, 054993) for the charge separation of protein in a gradient
mobile phase. Mobile Phase A was 20 mM sodium phosphate, pH 6.8 and
Mobile Phase B was 20 mM sodium phosphate, 0.5 M NaCl, pH 6.8.
Samples were injected onto the column at a 50 .mu.g mass load and
detected at a wavelength of 230 nm. SE-HPLC was performed using an
Agilent 1200 system. A TSK-GEL G3000SWXL column, 5 .mu.M particle
size, 7.8.times.300 nm (Tosoh Bioscience, 08541) to separate
protein by size. A UV detector with a wavelength of 220 nm was used
to detect samples injected at a mass load of 35 .mu.g. The mobile
phase which allows for separation on the column was 100 mM sodium
phosphate, 250 mM sodium chloride, pH 6.8.
[0591] Opalescence measurement was also used to assess stability.
Opalescence examines physical instability of a formulation due to
the presence of aggregates. Opalescence was measured in a 2100 AN
Turbidimeter, using 13 cm.times.100 mm glass tubes and a 13 mm
sample tube adapter. Samples of at least 2.5 mL were used for each
measurement. A standard curve was generated using Stablcal.RTM.
turbidity standard (Hach Company) prepared to expected turbidimetry
readings of 3, 6, 18 and 30 nephelometric turbidity units (NTUs) by
diluting a stock standard in water.
[0592] Transport stress studies were also used to assess stability.
Frozen formulations were thawed statically at room temperature
protected from light using a TempTale.RTM. temperature monitor to
monitor temperature conditions in the cold room during the thaw.
After fully thawing, the cap on the bottle was tightened to avoid
leakage. The bottle was placed on its side and rolled gently for
4-6 minutes to ensure thorough mixing. The bottle was then placed
at -30.degree. C. for 8 hours to re-freeze. Freezing was confirmed
visually. The freeze-thaw process was repeated for a total of 3
cycles. Next, the formulation was mixed with an overhead mixer for
15 minutes to simulate shear from a mixing operation, and then
filtered at 2-8.degree. C. under pressure using a 0.2 .mu.m PVDF
filter. The formulation was sterile-filtered a second time prior to
filling into syringes followed by stoppering. The formulations were
pressure-filtered through a 0.2 .mu.m PVDF filter, then hand-filled
into syringes or vials. The hand-filled syringes were stoppered
using an ASPU (autoclavable stopper placement unit) system. The
filled and stoppered syringes were placed in a laminar air flow
hood at room temperature for 3 days to mimic room temperature and
light exposure stresses expected during manufacturing. Temperature
was recorded using a TempTale.RTM. temperature monitor, and UV and
visible light levels were recorded using a photometer. A portion of
the filled syringes were subjected to simulated air and ground
transportation stresses. Air and ground simulated transport stress
studies were carried out. for a total duration of 91.5 hours, with
air transportation vibration of 48 hours and truck transportation
vibration for 43.5 hours. Samples were also subjected to the
International Safe Transit Association (ISTA 3A) drop test sequence
six times which included drops 1 thru 9 prior to the 91.5 hour air
and ground vibrational simulation and drops 10 thru 17 after the
air and ground vibrational transport simulation. The syringes were
stored for 2 weeks at 40.degree. C. Stability was assessed by
SE-HPLC, CEX-HPLC, and micro-flow imaging (MFI). MFI measures the
presence of sub-visible particles by passing a sample through a
visual flow cell, counting particles as they pass through the cell,
and categorizing into different bins based on size. An aspect ratio
is applied to resolve silicone oil, if present, from proteinaceous
particles. MFI (Micro-Flow Imaging) was performed on MFI 5200
systems. The size range of particles measured was from 1 to 70
.mu.m. The sample volume measured was 1 mL, with pre filled
syringes pooled into a clean glass vial to allow for adequate
volume of at least 1 mL for measurement. Between each measurement,
the system was flushed and a baseline established before
proceeding. For each sample measurement, a digital camera is used
to magnify, record the size, shape and morphology of visible
particles.
[0593] Conductivity is the ability of an aqueous solution to
conduct an electric current between two electrodes. Because a
current flows via ion transport, the more ions in a particular
solution, the higher the conductivity. Conductivity of the
formulations described herein was assessed on a Model CDM83, Thermo
Orion 4 or Model 5230 Seven Compact, Mettler Toledo instrument,
using a conductivity cell. At minimum of at least 20 mL sample
(Thermo Orion) or 3 mL sample (Mettler Toledo) was used for each
measurement. The cell was rinsed with water and dried between
sample measurements. Conductivity measurements were performed at
ambient room temperature, and is reported using the standard SI
unit of siemens per meter (S/m).
[0594] Osmolality is the concentration of a solution in terms of
amount of solute quantity of solvent. For example, serum has an
osmolality ranging from about 270-300 mOsM. Osmolality of the
formulations described herein can be determined using, for example,
Freezing Point Depression Osmometry.
Example 1
Effect of Buffer Composition on Formulation Stability
[0595] Adalimumab biosimilar was prepared in a target formulation
buffer by centrifuge concentration using a 30 kD MW cutoff filter
tube. 2 mL of adalimumab biosimilar was diluted with the target
formulation buffer to a volume of 15 mL, followed by a centrifuge
concentration step to a final volume of around 2 mL before
repeating the dilution and centrifuge concentration step three
times. Around 3 mL were collected after the last centrifuge
concentration step, which was diluted with the desired formulation
buffer to 100 mg/mL, sterile filtered and aliquoted into 5 cc glass
vials. Following the filling step, samples were placed at
40.degree. C. and examined for stability at approximately 1 week, 2
weeks and 4 weeks.
[0596] The formulation buffers used for the centrifuge
concentration step contained various buffers, with the pH of the
buffer adjusted to 5.2.+-.0.1 using either NaOH or monoethanolamine
(MEA). Each buffer contained isotonic proline as an additional
excipient. Formulations without buffer were prepared by adjusting
the pH of methane sulfonic acid (MSA) to pH 5.2.+-.0.1 with MEA or
NaOH. The composition of the formulation buffer, and the pH and
antibody (Ab) concentration of the formulations are provided in
Table 1.
TABLE-US-00014 TABLE 1 pH adjusting Ab conc. Ref. Buffer Excipient
agent pH (mg/mL) 1A 20 mM benzoate 300 mM proline MEA 5.2 73 1B 20
mM benzoate 300 mM proline NaOH 5.2 109 1C 20 mM glutamate 300 mM
proline MEA 5.2 105 1D 20 mM glutamate 300 mM proline NaOH 5.1 111
1E 20 mM glycolate 300 mM proline MEA 5.2 110 1F 20 mM glycolate
300 mM proline NaOH 5.2 108 1G 20 mM lactate 300 mM proline MEA 5.1
109 1H 20 mM lactate 300 mM proline NaOH 5.1 104 1I -- 20 mM MSA
MEA 5.3 100 300 mM proline 1J -- 20 mM MSA NaOH 5.3 107 300 mM
proline
[0597] To assess stability, the % acidic peak was measured by
CEX-HPLC after 0, 6, 13, and 28 days at 40.degree. C. As shown in
FIG. 1, the formulations containing lactate or glycolate buffers
demonstrated less acidic peak growth over time compared to the
formulations containing benzoate or glutamate buffers. The
formulations without buffer, but including MSA, demonstrated
stability comparable to the buffered formulations and improved
compared to the benzoate and glutamate-buffered formulations at the
28 day time point.
[0598] Stability also was assessed by measuring high molecular
weight species (HMWS) by SE-HPLC after 0, 6, 13, and 28 days at
40.degree. C. As shown in FIG. 2, the formulations containing
lactate demonstrated significantly less HMWS growth over time
compared to the other formulations. Compared to glycolic acid,
lactic acid has a structure that differs only by including an
additional methyl group. As shown in FIG. 2, HMWS were surprisingly
lower for the formulations containing lactate compared to the
formulations containing glycolate. The formulations without buffer,
but including MSA, demonstrated stability comparable to the
buffered formulations.
Example 2
Effect of PEG, Dextran, and Calcium Chloride on Formulation
Stability
[0599] Adalimumab biosimilar solution at a concentration of 220
mg/mL ("UF DF stock") was prepared by ultrafiltration/diafiltration
(UF DF) into a buffer of 20 mM glutamate, pH 5.1 using a Cogent
.mu.Scale tangential flow filtration (TFF) system with a delta
pressure set to about 23 psi. A Millipore Pellicon 3 Ultracell 30
kD 0.11 m.sup.2 cassette was used as the exchange filter. The
resulting material was then further concentrated to 220 mg/mL to
obtain the UF DF stock.
[0600] Stock 2.times. excipient solutions were prepared, and were
then diluted into UF DF stock adalimumab biosimilar solution. Upon
final dilution and mixing in of the 2.times. excipients, the
adalimumab biosimilar concentration was adjusted to about 100
mg/mL. If needed, the pH was adjusted to 5.2.+-.0.2 using NaOH or
HCl. The composition of the formulation buffer, and the pH and
antibody concentration of the formulations are provided in Table 2.
Following sterile filtration, aliquots were filled into 5 cc glass
vials and stored at -30.degree. C., 4.degree. C., and 40.degree.
C.
TABLE-US-00015 TABLE 2 Ab conc. Ref. Buffer Excipient(s) pH (mg/mL)
2A 20 mM glutamate 7% PEG 3350 5.4 114 2B 20 mM glutamate 7% PEG
3350 5.3 114 45 mM calcium chloride 2C 20 mM glutamate 10% dextran
5.1 128 2D 20 mM glutamate 10% dextran 5.2 119 45 mM calcium
chloride 2E 20 mM glutamate 1% PEG 200 5.1 110 2F 20 mM glutamate
1% PEG 200 5.1 115 40 mM calcium chloride 2G 20 mM glutamate 2% PEG
600 5.1 110 2H 20 mM glutamate 2% PEG 600 5.1 109 40 mM calcium
chloride
[0601] To assess stability, the % acidic peak was measured by
CEX-HPLC after 0, 7, 14, and 28 days at 40.degree. C. As shown in
FIG. 3, the formulations containing calcium chloride and one of PEG
200, PEG 600, PEG 3350, or dextran demonstrated less acidic peak
growth over time compared to otherwise similar formulations without
calcium chloride. In addition, the formulations containing PEG 200
or PEG 600 demonstrated less acidic peak growth over time compared
to the formulations containing PEG 3350 or dextran.
[0602] Stability also was assessed by measuring HMWS by SE-HPLC
after 0, 7, 14, and 28 days at 40.degree. C. As shown in FIG. 4,
the formulations containing PEG 200, PEG 600, or PEG 3350 (alone or
in combination with calcium chloride) demonstrated less HMWS growth
over time compared to the formulations containing dextran.
Example 3
Effect of Proline, PEG, MSA, TEA, and Calcium Chloride on Frozen
Stability
[0603] Stock 2.times. excipient solutions in 20 mM glutamate
buffer, pH 5.2 were added to the UF DF stock adalimumab biosimilar
solution described in Example 2 to a final protein concentration of
100 mg/mL. If needed, the pH was adjusted to 5.2.+-.0.2 using NaOH
or HCl. The final formulations were sterile filtered and placed
into 5 cc glass vials for subsequent tests.
[0604] Three free thaw (F/T) cycles were executed, with room
temperature thaws of samples stored at -30.degree. C. at each
cycle. After the freeze thaw cycles, each formulation was then
analyzed for stability and the remainder of the material stored at
-30.degree. C. for long term storage stability. The composition of
the formulation buffer, and the pH and antibody concentration of
the formulations are provided in Table 3.
TABLE-US-00016 TABLE 3 Ab conc. Ref. Buffer Excipient(s) pH (mg/mL)
3A 20 mM glutamate 250 mM proline 5.1 119 3B 20 mM glutamate 1% PEG
3350 5.4 114 2A 20 mM glutamate 7% PEG 3350 5.4 114 2B 20 mM
glutamate 7% PEG 3350 5.3 114 45 mM calcium chloride 2E 20 mM
glutamate 1% PEG 200 5.1 110 2F 20 mM glutamate 1% PEG 200 5.1 115
40 mM calcium chloride 2G 20 mM glutamate 2% PEG 600 5.1 109 2H 20
mM glutamate 2% PEG 600 5.1 109 40 mM calcium chloride 3C 20 mM
glutamate 100 mM MSA 5.2 109 50 mM TEA
[0605] Stability was assessed by measuring HMWS by SE-HPLC after 0
days, after 3 F/T cycles, and after 83 days at -30.degree. C. As
shown in FIG. 5, the formulations containing proline demonstrated
almost no HMWS growth over time.
[0606] Stability was also assessed by measuring HMWS by SE-HPLC
after 0 days, after 3 F/T cycles, after 35 days at -30.degree. C.,
and after 56 days at -30.degree. C. As shown in FIG. 6, the
formulations containing PEG 600 and a formulation with MSA and
triethanolamine (TEA) demonstrated a small decrease in HMWS growth
upon F/T stress and storage at -30.degree. C. compared to the
formulations containing PEG 200.
Example 4
Effect of Salts on Formulation Stability
[0607] The OF DF stock adalimumab biosimilar solution described in
Example 2 was diluted to 170 mg/mL with 20 mM glutamate, pH 5.2
buffer and various salts were added directly by weight until
dissolved at a final concentration of 75 mM. A stock concentrated
solution of proline in the 20 mM glutamate, pH 5.2 buffer was also
added to achieve a final concentration of 100 mM. After preparing
the protein solutions, the pH was adjusted if needed with either
HCl or NaOH to 5.2.+-.0.4. The composition of the formulation
buffer, and the pH and antibody concentration of the formulations
are provided in Table 4. Following sterile filtration, aliquots
were filled into 5 cc glass vials and stored at -30.degree. C.,
4.degree. C., and 40.degree. C.
TABLE-US-00017 TABLE 4 Ab conc. Ref. Buffer Excipient(s) pH (mg/mL)
4A 20 mM glutamate 75 mM sodium borate 5.6 175 100 mM proline 4B 20
mM glutamate 75 mM sodium bicarbonate 5.2 180 100 mM proline 4C 20
mM glutamate 75 mM sodium sulfate 5.2 183 100 mM proline 4D 20 mM
glutamate 15 mM calcium sulfate 5.1 178 100 mM proline 4E 20 mM
glutamate 75 mM ammonium sulfate 5.2 175 100 mM proline 4F 20 mM
glutamate 75 mM calcium chloride 5.1 172 100 mM proline 4G 20 mM
glutamate 75 mM sodium chloride 5.2 167 100 mM proline 4H 20 mM
glutamate 75 mM magnesium chloride 5.1 193 100 mM proline
[0608] To assess stability, the % acidic peak was measured by
CEX-HPLC after 0, 7, 14, and 28 days at 40.degree. C. As shown in
FIG. 7, the formulations containing calcium chloride or magnesium
chloride demonstrated less acidic peak growth over time compared to
the formulations containing sodium borate, sodium bicarbonate,
sodium sulfate, calcium sulfate, ammonium sulfate, or sodium
chloride.
[0609] Stability also was assessed by measuring HMWS by SE-HPLC
after 0, 7, 14, and 28 days at 40.degree. C. As shown in FIG. 8,
the formulations containing calcium sulfate, ammonium sulfate,
calcium chloride, sodium chloride, or magnesium chloride
demonstrated less HMWS growth over time compared to the
formulations containing sodium borate, sodium bicarbonate, or
sodium sulfate.
Example 5
Effect of MEA on Formulation Stability
[0610] The OF DF stock adalimumab biosimilar solution described in
Example 2 was diluted with 20 mM glutamate buffer, pH 5.0 and 2M
MEA in volumes needed to generate the final MEA concentrations
shown in Table 5. After preparing the protein solutions, the pH was
adjusted if needed with either HCl or NaOH to 5.2. The composition
of the formulation buffer, and the pH and antibody concentration of
the formulations are provided in Table 5. Following sterile
filtration, aliquots were filled into 5 cc glass vials and stored
at 4.degree. C. or 40.degree. C.
TABLE-US-00018 TABLE 5 Ab conc. Ref. Buffer Excipient(s) pH (mg/mL)
5A 20 mM glutamate 30 mM MEA 5.2 182 5B 20 mM glutamate 80 mM MEA
5.2 182 5C 20 mM glutamate 115 mM MEA 5.2 185 5D 20 mM glutamate
160 mM MEA 5.2 177
[0611] To assess stability, the % acidic peak was measured by
CEX-HPLC after 0, 7, 14, and 28 days at 40.degree. C. As shown in
FIG. 9, the formulations containing higher concentrations of MEA
(e.g., 160 mM MEA) demonstrated less acidic peak growth over time
compared to the formulations containing lower concentrations of MEA
(e.g., 30 mM MEA). The ratio of % acidic peak after 28 days to the
% acidic peak at 0 days was 2.23 for formulation 5A, 2.17 for
formulation 5B, 2.11 for formulation 5C, and 2.09 for formulation
5D.
[0612] Stability also was assessed by measuring HMWS by SE-HPLC
after 0, 7, 14, and 28 days at 40.degree. C. As shown in FIG. 10,
the formulations containing higher concentrations of MEA (e.g., 160
mM MEA) demonstrated slightly less HMWS growth over time compared
to the formulations containing lower concentrations of MEA (e.g.,
30 mM MEA).
Example 6
Effect of Excipients on Formulation Stability
[0613] The OF DF stock adalimumab biosimilar solution described in
Example 2 was diluted to around 105 mg/mL once excipients were
added. In each formulation, 2.times. stock excipient solutions in
20 mM glutamate buffer, pH 5.2 were added to a final protein
concentration of around 105 mg/mL. The pH was adjusted to
5.2.+-.0.1 with HCl or NaOH if needed. The final formulations were
sterile filtered and placed into 5 cc glass vials for subsequent
tests. The composition of the formulation buffer, and the pH and
antibody concentration of the formulations are provided in Table
6.
TABLE-US-00019 TABLE 6 Ab conc. Ref. Buffer Excipient(s) pH (mg/mL)
6A 20 mM glutamate 1.4% ethanol 5.1 102 6B 20 mM glutamate 0.5%
ethanol 5.2 106 40 mM calcium chloride 6C 20 mM glutamate 0.5%
ethanol 5.2 108 1% PEG 3350 40 mM calcium chloride 6D 20 mM
glutamate 150 mM TEA 5.2 107 40 mM calcium chloride 6E 20 mM
glutamate 30 mM TEA 5.2 105 75 mM calcium chloride 6F 20 mM
glutamate 0.5% ethanol 5.2 106 6G 20 mM glutamate 0.5% ethanol 5.2
106 2% PEG 200 6H 20 mM glutamate 0.25% ethanol 5.2 102 2% PEG 200
6I 20 mM glutamate 0.5% ethanol 5.1 105 100 mM MSA 6J 20 mM
glutamate 0.5% ethanol 5.2 105 0.5% poly(vinylpyrrolidone) (PVP)
10K 100 mM MSA 6K 20 mM glutamate 0.5% ethanol 5.2 101 100 mM
MEA
[0614] To assess stability, the % acidic peak was measured by
CEX-HPLC after 0, 7, 14, and 28 days at 40.degree. C. As shown in
FIG. 11, the formulations containing ethanol with calcium chloride,
ethanol with calcium chloride and PEG 3350, TEA with calcium
chloride, and ethanol with MEA demonstrated less than 30% of acidic
peak after 4 weeks at 40.degree. C. The formulations containing
1.4% ethanol with no additional excipients demonstrated stability
comparable to the formulations containing 0.5% ethanol with no
additional excipients at the 4 week time point.
[0615] Stability also was assessed by measuring HMWS by SE-HPLC
after 0, 7, 14, and 28 days at 40.degree. C. As shown in FIG. 12,
the formulation containing 1.4% ethanol with no additional
excipients demonstrated less than 1% of HMWS after 4 weeks at
40.degree. C. The formulations containing 0.5% ethanol, ethanol in
combination with calcium chloride, ethanol in combination with
calcium chloride and PEG 3350, ethanol in combination with PEG 200,
and ethanol in combination with MEA demonstrated less than 1.5% of
HMWS at the 4 week time point.
Example 7
Effect of Amino Acids on Formulation Stability
[0616] Adalimumab biosimilar was prepared in a buffer containing 15
mM glutamate, pH 5.2 using a Cogent .mu.Scale TFF system with a 30
kD Millipore cassette and a pressure difference of about 23 psi.
The protein was concentrated to 114 mg/mL, and the resulting
material in 15 mM glutamic acid, pH 5.2 buffer was then
concentrated by centrifugation concentration to 186 mg/mL. In each
formulation, 2.times. stock excipient solutions in 15 mM glutamate
buffer, pH 5.2 were added to the starting material, resulting in a
final protein concentration of around 90-100 mg/mL. The pH was
adjusted to 5.2 with HCl or NaOH if needed. The final formulations
were sterile filtered and placed into 5 cc glass vials for
subsequent tests. The composition of the formulation buffer, and
the pH and antibody concentration of the formulations are provided
in Table 7.
TABLE-US-00020 TABLE 7 Ab conc. Ref. Buffer Excipient(s) pH (mg/mL)
7A 15 mM glutamate 100 mM alanine 5.2 92 45 mM calcium chloride 7B
15 mM glutamate 100 mM asparagine 5.2 95 45 mM calcium chloride 7C
15 mM glutamate 100 mM isoleucine 5.2 96 45 mM calcium chloride 7D
15 mM glutamate 100 mM serine 5.2 98 45 mM calcium chloride 7E 15
mM glutamate 20 mM aspartic acid 5.2 96 80 mM proline 45 mM calcium
chloride 7F 15 mM glutamate 25 mM creatine 5.2 96 75 mM proline 45
mM calcium chloride 7G 15 mM glutamate 50 mM glutamine 5.2 97 50 mM
proline 45 mM calcium chloride 7H 15 mM glutamate 50 mM leucine 5.2
97 50 mM proline 45 mM calcium chloride 7I 15 mM glutamate 50 mM
phenylalanine 5.2 97 50 mM proline 45 mM calcium chloride 7J 15 mM
glutamate 25 mM tryptophan 5.2 90 75 mM proline 45 mM calcium
chloride
[0617] To assess stability, the % acidic peak was measured by
CEX-HPLC after 0 and 7 days at 40.degree. C. As shown in FIG. 13,
the formulations containing alanine, serine, proline in combination
with glutamine, or proline in combination with creatine, for
example, demonstrated 18-19% of acidic peak after 7 days incubation
at 40.degree. C., in comparison to the formulation containing
proline in combination with phenylalanine, which demonstrated
almost 20% of acidic peak after 7 days.
[0618] Stability also was assessed by measuring HMWS by SE-HPLC
after 0 and 7 days at 40.degree. C. As shown in FIG. 14, the
formulations containing alanine, asparagine, isoleucine, serine,
proline in combination with aspartic acid, proline in combination
with creatine, proline in combination with glutamine, and proline
in combination with tryptophan demonstrated about 0.5% or less of
HMWS after 7 days at 40.degree. C.
Example 8
Effect of Nonionic, Anionic, or Cationic Surfactants on Formulation
Stability
[0619] Adalimumab biosimilar was prepared using a Cogent .mu.Scale
TFF system with a 30 kD Millipore cassette and a pressure
difference of about 23 psi in a buffer containing 20 mM acetate, 45
mM calcium chloride, and 100 mM arginine, with a final pH of 5.2.
The resulting protein was concentrated to greater than 143 mg/mL.
The material was then used for the addition of stock surfactant
solutions to the final concentrations of surfactant and protein
listed in Table 8. Final pH adjustment to 5.2 was accomplished with
NaOH or HCl. For accelerated stability tests, aliquots were filled
into 5 cc glass vials and examined for stability at 40.degree. C.
For shaking stress studies, 36 mL of each formulation in 50 cc
containers was subjected to continued shaking stress at room
temperature. The composition of the formulation buffer, and the pH
and antibody concentration of the formulations are provided in
Table 8.
TABLE-US-00021 TABLE 8 Ab conc. Ref. Buffer Surfactant Excipient(s)
pH (mg/mL) 8A 20 mM acetate 0.1% Polysorbate 20 45 mM calcium 5.2
140 chloride 100 mM arginine-HCl 8B 20 mM acetate 0.1% Polysorbate
80 45 mM calcium 5.2 140 chloride 100 mM arginine-HCl 8C 20 mM
acetate 0.1% Pluronic F68 45 mM calcium 5.2 140 chloride 100 mM
arginine-HCl 8D 20 mM acetate 0.01% Docusate 45 mM calcium 5.2 140
sodium chloride 100 mM arginine-HCl 8E 20 mM acetate 0.1%
benzalkonium 45 mM calcium 5.2 140 chloride chloride 100 mM
arginine-HCl 8F 20 mM acetate 0.1% Span 40 45 mM calcium 5.2 140
chloride 100 mM arginine-HCl 8G 20 mM acetate 0.1% Triton X-100 45
mM calcium 5.2 140 chloride 100 mM arginine-HCl 8H 20 mM acetate --
45 mM calcium 5.2 140 chloride 100 mM arginine-HCl
[0620] To assess stability, the % acidic peak was measured by
CEX-HPLC after 0, 3, and 7 days at 40.degree. C. As shown in FIG.
15, the formulations containing nonionic, anionic, or cationic
surfactants demonstrated similar amounts of acidic peak after 7
days at 40.degree. C., in comparison to a formulation without
surfactant.
[0621] Stability also was assessed by measuring HMWS by SE-HPLC
after 0, 3, 7, and 14 days at 40.degree. C. As shown in FIG. 16,
the formulations containing nonionic, anionic, or cationic
surfactants demonstrated similar amounts of HMWS after 14 days at
40.degree. C., in comparison to a formulation without
surfactant.
[0622] Stability was further assessed after subjecting the
formulations to shaking stress. The % acidic peak was measured by
CEX-HPLC after continuous shaking at room temperature for 0 and 158
hours. As shown in FIG. 17, the formulations containing surfactants
demonstrated around 0.3% or less of acidic peak after continuous
shaking at room temperature for 158 hours, in comparison to a
formulation without surfactant. HMWS were measured by SE-HPLC after
continuous shaking at room temperature for 0 and 158 hours. As
shown in FIG. 18, the formulation containing benzalkonium chloride
demonstrated about twice the percentage of HMWS, in comparison to
the formulations containing other surfactants and a formulation
without surfactant.
Example 9
Effect of Nonionic, Anionic, or Cationic Surfactants on Formulation
Stability
[0623] Adalimumab biosimilar in a buffer consisting of 20 mM
acetate, with 45 mM calcium chloride and 100 mM arginine, with a
final pH set at 5.2 was used to assess stability upon stirring
stress. The final formulation pH was adjusted to 5.2 using NaOH or
HCl. Surfactants were chosen and selected at low, medium and high
levels to assess stirring stability with adalimumab biosimilar at a
final concentration of approximately 140 mg/mL. Stock surfactant
solutions were made and diluted with the starting material to
achieve the final surfactant concentrations as shown in Table 9.
For each formulation condition, 30 mL were prepared, transferred to
50 cc containers and stirred continuously for 5 days at room
temperature.
TABLE-US-00022 TABLE 9 Ab conc. Ref. Buffer Surfactant Excipient(s)
pH (mg/mL) 9A 20 mM acetate 0.005% Polysorbate 80 45 mM calcium 5.2
137 chloride 100 mM arginine-HCl 9B 20 mM acetate 0.01% Polysorbate
80 45 mM calcium 5.2 135 chloride 100 mM arginine-HCl 9C 20 mM
acetate 0.05% Polysorbate 80 45 mM calcium 5.2 138 chloride 100 mM
arginine-HCl 9D 20 mM acetate 0.005% Polysorbate 20 45 mM calcium
5.2 138 chloride 100 mM arginine-HCl 9E 20 mM acetate 0.01%
Polysorbate 20 45 mM calcium 5.2 136 chloride 100 mM arginine-HCl
9F 20 mM acetate 0.05% Polysorbate 20 45 mM calcium 5.2 136
chloride 100 mM arginine-HCl 9G 20 mM acetate 0.005% Triton X-100
45 mM calcium 5.2 134 chloride 100 mM arginine-HCl 9H 20 mM acetate
0.01% Triton X-100 45 mM calcium 5.2 139 chloride 100 mM
arginine-HCl 9I 20 mM acetate 0.05% Triton X-100 45 mM calcium 5.2
138 chloride 100 mM arginine-HCl 9J 20 mM acetate 0.05% Pluronic
F68 45 mM calcium 5.2 139 chloride 100 mM arginine-HCl 9K 20 mM
acetate 0.1% Pluronic F68 45 mM calcium 5.2 139 chloride 100 mM
arginine-HCl 9L 20 mM acetate 0.4% Pluronic F68 45 mM calcium 5.2
134 chloride 100 mM arginine-HCl
[0624] To assess stability, the % acidic peak was measured by
CEX-HPLC after stirring at room temperature for 0, 1, 2, and 5
days. The results are shown in FIG. 19. With the exception of the
0.005% Polysorbate 80 formulation (9A), which had a slightly higher
level of % acidic peak, there was no meaningful difference due to
the level of surfactant in the range tested on stability as
measured by CEX-HPLC.
[0625] Stability also was assessed by measuring HMWS by SE-HPLC
after stirring at room temperature for 0, 1, 2, and 5 days. The
results are shown in FIG. 20. No meaningful differences in the
amount of HMWS were observed in the concentration range of
surfactants examined.
[0626] Stability additionally was assessed by measuring opalescence
after stirring at room temperature for 0, 1, 2, and 5 days. As
shown in FIG. 21, the formulations containing low levels of
Polysorbate 20 or Polysorbate 80 demonstrated the highest
opalescence of the formulations tested after stirring at room
temperature for 5 days. In comparison, the formulations containing
Pluronic F68 demonstrated the lowest opalescence of the
formulations tested after stirring at room temperature for 5
days.
Example 10
Effect of Nontraditional Surfactants on Formulation Stability
[0627] Adalimumab biosimilar was prepared in a buffer containing 15
mM glutamate, 300 mM proline, pH 5.2 using the Cogent .mu.Scale TFF
system described in Example 2. Surfactant stock solutions were then
added to obtain a final protein concentration close to 110 mg/mL.
The pH was adjusted to 5.2 using NaOH or HCl if needed. Aliquots
were then filled into 5 cc glass vials for evaluation of stability
at accelerated temperature. The composition of the formulation
buffer, and the pH and antibody concentration of the formulations
are provided in Table 10.
TABLE-US-00023 TABLE 10 Ab conc. Ref. Buffer Surfactant
Excipient(s) pH (mg/mL) 10A 15 mM glutamate 0.01% benzalkonium 300
mM proline 5.2 109 chloride 10B 15 mM glutamate 0.01% guanidine HCl
300 mM proline 5.2 109 10C 15 mM glutamate 0.01% lecithin 300 mM
proline 5.2 109 10D 15 mM glutamate 0.01% oleic acid 300 mM proline
5.2 109 10E 15 mM glutamate 0.01% Polysorbate 80 300 mM proline 5.2
109 10F 15 mM glutamate 0.1% polyvinyl alcohol 300 mM proline 5.2
100 205K 10G 15 mM glutamate 0.1% polyvinyl alcohol 300 mM proline
5.2 100 31K 10H 15 mMglutamate 0.01% PVP 300 mM proline 5.2 109 10I
15 mM glutamate 0.01% protamine 300 mM proline 5.2 109 sulfate
[0628] To assess stability, the % acidic peak was measured by
CEX-HPLC after 0, 7, 14, and 28 days at 40.degree. C. The results
are shown in FIG. 22. The amount of acidic peak formed after
storage at 40.degree. C. for 28 days was found to be similar.
Meaningful differences were not observed.
[0629] Stability also was assessed by measuring HMWS by SE-HPLC
after 0, 7, 14, and 28 days at 40.degree. C. The results are shown
in FIG. 23. The formulations containing benzalkonium chloride and
protamine sulfate (10A and 10I) appeared to have the lowest amount
of HMWS after 28 days at 40.degree. C.
Example 11
Effect of PEG, Proline, and Calcium Chloride on Formulation
Stability
[0630] Adalimumab biosimilar frozen in a buffer with 20 mM glutamic
acid, pH 5.2 was thawed and subjected to dialysis using dialysis
tubing into one of the following buffers: 20 mM calcium chloride;
10 mM lactate; 4.2% mannitol; and 14.4 mM sodium phosphate with 7.7
mM citrate, 105 mM sodium chloride and 1.2% mannitol. Stock
excipient solutions were then added to achieve the final
concentrations as shown in Table 11. If needed, the pH was adjusted
to 5.2.+-.0.1 with MEA or MSA. Comparative formulations were also
prepared and adjusted to pH 5.2.+-.0.1 with NaOH or HCl as needed.
The final formulation compositions, pH, and antibody concentration
are listed in Table 11.
TABLE-US-00024 TABLE 11 Buffer/pH Adjusting Ab conc. Osmolality
Ref. Agent Excipient(s) Surfactant pH (mg/mL) (mOsm/kg) Comp.
---/HCl, NaOH 4.2% mannitol 0.1% 5.2 102 271 1A polysorbate 80
Comp. 7.7 mM citrate, 105 mM NaCl 0.1% 5.1 110 309 2A 14.1 mM 1.2%
mannitol polysorbate 80 sodium phosphate 11A ---/MEA, 9% PEG 600
0.1% Pluronic 5.1 105 383 MSA 20 mM calcium F68 chloride 11B
---/MEA, 6.9% PEG 600 0.1% Pluronic 5.1 97 367 MSA 0.6% PEG 200 F68
20 mM calcium chloride 11C ---/MEA, 4.5% PEG 600 0.1% Pluronic 5.1
104 321 MSA 1.8% PEG 200 F68 20 mM calcium chloride 11D ---/MEA,
1.2% PEG 600 0.1% Pluronic 5.1 112 349 MSA 3% PEG 200 F68 20 mM
calcium chloride 11E ---/MEA, 4% PEG 200 0.1% Pluronic 5.1 99 321
MSA 20 mM calcium F68 chloride 11F ---/MEA, 7.3% PEG 600 0.1%
Pluronic 5.2 114 439 MSA 60 mM proline F68 20 mM calcium chloride
11G ---/MEA, 5.5% PEG 600 0.1% Pluronic 5.1 107 404 MSA 120 mM F68
proline 20 mM calcium chloride 11H ---/MEA, 2.5% PEG 600 0.1%
Pluronic 5.2 105 410 MSA 180 mM F68 proline 20 mM calcium chloride
11I ---/MEA, 240 mM 0.1% Pluronic 5.1 109 367 MSA proline F68 20 mM
calcium chloride 11J 10 mM lactate 8.4% PEG 600 0.1% Pluronic 5.1
107 379 F68 11K 10 mM lactate 4% PEG 600 0.1% Pluronic 5.1 102 307
1.6% PEG 200 F68 Comp. ---/HCl, NaOH 4.2% mannitol 0.1% 5.2 173 301
1B polysorbate 80 Comp. 7.7 mM citrate 105 mM NaCl 0.1% 5.1 174 317
2B 14.1 mM 1.2% mannitol polysorbate 80 sodium phosphate 11L 10 mM
lactate 8.4% PEG 600 0.1% Pluronic 5.2 177 488 F68 11M 10 mM
lactate 4% PEG 600 0.1% Pluronic 5.2 178 413 1.6% PEG 200 F68 11N
10 mM lactate 3.8% PEG 200 0.1% Pluronic 5.2 182 310 F68 11O 10 mM
lactate 220 mM 0.1% Pluronic 5.2 170 389 proline F68
[0631] To assess stability, the % acidic peak was measured by
CEX-HPLC after 0, 2, and 4 weeks at 40.degree. C. and at 25.degree.
C. The results are shown in FIG. 24 and FIG. 25. At 25.degree. C.,
meaningful differences were not observed. After storage at
40.degree. C., the formulations labeled 2A and 2B appeared to have
higher growth of the % acidic peak, however the other formulations
tested did not show apparent differences that could be considered
meaningful.
[0632] Stability also was assessed by measuring HMWS by SE-HPLC
after 0, 2, and 4 weeks at 40.degree. C. and at 25.degree. C. The
results are shown in FIG. 26 and FIG. 27. In formulations at a
protein concentration of around 170 mg/mL, the formulation buffered
with lactate and containing proline had superior stability, both at
25.degree. C. and at 40.degree. C. In formulations containing PEG
200 or PEG 600, stability was worse than the other formulations at
170 mg/mL. Formulations at approximately 100 mg/mL also showed a
preference for proline in that the amount of HMWS was reduced as
the proline concentration increased, a trend which was most
apparent at 40.degree. C. and to a lesser extent at 25.degree.
C.
[0633] Stability was assessed after freeze/thaw cycling as
described in Example 3. The percentage of HMWS was measured by
SE-HPLC after 0 days and after 3 F/T cycles. The results are shown
in FIG. 28. In general, at around 100 mg/mL, the comp 1A and comp
2A formulations appeared to have the largest increase in HMWS
compared to the other formulations examined. At 170 mg/mL, the
formulation with PEG 600 and PEG 200 (11M) appeared to have the
largest increase in HMWS.
Example 12
Effect of Sorbitol, Sucrose, Proline, PEG, and Calcium Chloride on
Formulation Stability
[0634] Adalimumab biosimilar starting material was prepared using a
Cogent .mu.Scale TFF with a 30 kD Millipore cassette and a pressure
difference of about 23 psi in the following buffers: 4.2% mannitol;
14.4 mM sodium phosphate with 7.7 mM citrate, 105 mM sodium
chloride and 1.2% mannitol; 7.3% sucrose with 20 mM calcium
chloride; 20 mM calcium chloride; 4% sorbitol with 25 mM calcium
chloride; 320 mM proline with 20 mM calcium chloride; 10 mM lactate
with 225 mM proline and 20 mM calcium chloride; 10 mM lactate with
20 mM calcium chloride; 10 mM acetate with 9% sucrose. The pH was
adjusted as shown in Table 12. The resulting protein was
concentrated to achieve the concentration provided in Table 12,
with the exception of Comp 3A which was diluted to 100 mg/mL with
buffer from a bulk preparation at 170 mg/mL. The formulations are
provided in Table 12. The formulations were stored at -30.degree.
C.
TABLE-US-00025 TABLE 12 Buffer/pH Adjusting Ab conc. Ref. Agent
Excipient(s) Surfactant pH (mg/mL) Comp. 3A -- 4.2% mannitol 0.1%
5.2 100 Polysorbate 80 Comp. 3B -- 4.2% mannitol 0.1% 5.2 170
Polysorbate 80 Comp. 4 14.1 mM sodium 105 mM NaCl 0.1% 5.2 50
phosphate 1.2% mannitol Polysorbate 80 7.7 mM citrate 12A --/MSA,
MEA 7.3% sucrose 0.1% Pluronic 5.2 100 20 mM calcium F68 chloride
12B --/MSA, MEA 4.8% PEG 200 0.1% Pluronic 5.2 100 20 mM calcium
F68 chloride 12C --/HCl 4% sorbitol, 0.1% Pluronic 5.2 100 25 mM
calcium F68 chloride 12D --/MSA, MEA 14.5% PEG 600 0.1% Pluronic
5.2 100 20 mM calcium F68 chloride 12E 10 mM histidine/ 320 mM
proline -- 6.8 100 MSA, MEA 20 mM calcium chloride 12F 10 mM
lactate/ 225 mM proline 0.1% Pluronic 5.2 170 MSA, MEA 20 mM
calcium F68 chloride 12G 10 mM lactate/ 13% PEG 600 0.1% Pluronic
5.2 170 MSA, MEA 20 mM calcium F68 chloride 12H 10 mM acetate/ 9%
sucrose 0.1% 5.2 170 MSA, MEA Polysorbate 80
[0635] To assess stability, the % acidic peak was measured by
CEX-HPLC after 0 days, after transport, and after storing the
transported sample at 40.degree. C. for 2 weeks. The results are
shown in FIG. 29. After 2 weeks at 40.degree. C., the lowest amount
of % acidic peak was found in the formulation buffered with lactate
and containing calcium chloride (12F). Otherwise, formulations
buffered with histidine, containing PEG 600 at a high concentration
or the formulation buffered with sodium phosphate were less stable
(12E, 12D, Comp 4). The antibody concentration of each formulation,
i.e. whether at 50, 100 or 170 mg/mL did not appear to influence
the amount of % acidic peak.
[0636] Stability also was assessed by measuring HMWS by SE-HPLC
after 0 days, after transport, and after storing the transported
sample at 40.degree. C. for 2 weeks. The results are shown in FIG.
30. The lower the concentration, the lower the amount of HMWS. This
is shown in comparing Comp 3B, Comp 3A and Comp 4 in which as the
concentration changes from 170 mg/mL to 100 mg/mL to 50 mg/mL the
HMWS is correspondingly reduced. For the other formulations tested,
at 170 mg/mL, there are differences in the amount of HMWS after two
weeks at 40.degree. C. The lowest amount of HMWS was measured for
the acetate formulation with sucrose (12H), followed by the lactate
buffered formulation with proline (12F) and finally the formulation
with the high amount of PEG 600 (12G). In formulations at 100
mg/mL, the lowest HMWS was found in the self-buffering formulation
with sorbitol and calcium chloride (12C). The addition of PEG 200
resulted in more HMWS at 100 mg/mL (12B).
[0637] Stability was further assessed by MFI. The results are shown
in FIGS. 31-36. High particle counts at 5 .mu.M were measured in
the formulation containing proline and calcium chloride after
transport stress (12E). In general, particle counts were higher at
100 mg/mL than at 170 mg/mL at the 5 .mu.M particle size. At 100
mg/mL, formulation Comp 3A and the self-buffered formulation with
sorbitol had lower particle counts at 5 .mu.M post transport than
the other formulations tested at this concentration (compare 12C
and Comp 3A to 12A, 12B, 12D and 12E). The particle count trends
observed at 5 .mu.M were also observed at the 10 .mu.M particle
size. The lowest particle counts at 10 .mu.M were measured at 170
mg/mL. At 100 mg/mL, a low particle count increase post transport
was also observed in the self-buffered formulation with sorbitol
(12C) and in Comp 3A. Finally, the particle count trends reported
for the 5 .mu.M and 10 particle sizes were also observed at 25
.mu.M. The lowest particle counts were again at the 25 size. At 100
mg/mL, the lowest particle counts post transport were measured in
formulations Comp 3A, 12A and 12C.
Example 13
Effect of PEG, Proline, and Calcium Chloride on Formulation
Stability
[0638] Adalimumab biosimilar starting material at 200 mg/mL was
diluted to 180 mg/mL and then subjected to dialysis using 3 kD
cutoff dialysis tubing in the following buffers: 20 mM calcium
chloride, pH adjusted with MSA or MEA; 14.4 mM sodium phosphate
with 7.7 mM citrate, 105 mM sodium chloride and 1.2% mannitol, pH
adjusted with HCl or NaOH to a final pH of 4.8; 10 mM lactate with
20 mM calcium chloride, pH adjusted with MSA or MEA; and 4.2%
mannitol, pH adjusted with MSA or MEA. Stock excipient solutions
were then added to achieve the final concentrations as shown in
Table 13 and the pH was adjusted to 5.2 if needed. The formulations
are provided in Table 13.
TABLE-US-00026 TABLE 13 Buffer/pH Adjusting Ab conc. Ref. Agent
Excipient(s) Surfactant pH (mg/mL) Comp. 5A --/HCl, NaOH 4.2%
mannitol 0.1% 5.2 100 Polysorbate 80 Comp. 6A 14.1 mM sodium 105 mM
NaCl 0.1% 5.2 100 phosphate 1.2% mannitol Polysorbate 80 7.7 mM
citrate/ HCl, NaOH 13A --/MSA, MEA 9% PEG600 0.1% Pluronic 5.2 100
20 mM calcium F68 chloride 13B --/MSA, MEA 6.9% PEG600 0.1%
Pluronic 5.2 100 0.6% PEG200 F68 20 mM calcium chloride 13C --/MSA,
MEA 4.5% PEG600 0.1% Pluronic 5.2 100 1.8% PEG200 F68 20 mM calcium
chloride 13D --/MSA, MEA 1.2% PEG600 0.1% Pluronic 5.2 100 3%
PEG200 F68 20 mM calcium chloride 13E --/MSA, MEA 4% PEG200 0.1%
Pluronic 5.2 100 20 mM calcium F68 chloride 13F --/MSA, MEA 7.3%
PEG600 0.1% Pluronic 5.2 100 20 mM calcium F68 chloride 60 mM
proline 13G --/MSA, MEA 5.5% PEG600 0.1% Pluronic 5.2 100 20 mM
calcium F68 chloride 120 mM proline 13H --/MSA, MEA 2.5% PEG600
0.1% Pluronic 5.2 100 20 mM calcium F68 chloride 180 mM proline 131
--/MSA, MEA 20 mM calcium 0.1% Pluronic 5.2 100 chloride F68 240 mM
proline 13J 10 mM lactate/ 20 mM calcium 0.1% Pluronic 5.2 100 MSA,
MEA chloride F68 8.4% PEG 600 13K 10 mM lactate/ 20 mM calcium 0.1%
Pluronic 5.2 100 MSA, MEA chloride F68 4% PEG 600, 1.6% PEG 200
Comp. 5B --/HCl, NaOH 4.2% mannitol 0.1% 5.2 170 Polysorbate 80
Comp. 6B 14.1 mM sodium 105 mM NaCl 0.1% 5.2 170 phosphate 1.2%
mannitol Polysorbate 80 7.7 mM citrate/ HCl, NaOH 13L 10 mM
lactate/ 8.4% PEG600 0.1% Pluronic 5.2 170 MSA, MEA 20 mM calcium
F68 chloride 13M 10 mM lactate/ 4% PEG600 0.1% Pluronic 5.2 170
MSA, MEA 1.6% PEG200 F68 20 mM calcium chloride 13N 10 mM lactate/
3.8% PEG200 0.1% Pluronic 5.2 170 MSA, MEA 20 mM calcium F68
chloride 13O 10 mM lactate/ 20 mM calcium 0.1% Pluronic 5.2 170
MSA, MEA chloride F68 220 mM proline
[0639] To assess stability, the % acidic peak was measured by
CEX-HPLC after 0, 2, and 4 weeks at 40.degree. C. and at 25.degree.
C. The results are shown in FIG. 37 and FIG. 38. At 25.degree. C.,
after 4 weeks, the lowest % acidic peak was found in the
formulation containing proline and calcium chloride (13I) and the
formulation with PEG 200 and PEG 600 and calcium chloride (13D).
Lower growth was also observed in formulations with a mixture of
PEG 600, proline and calcium chloride (13H) and in the formulation
buffered with sodium phosphate (Comp 6A). In formulations at a
concentration of 170 mg/mL, the lowest % acidic peak after storage
for 4 weeks at 25.degree. C. was found in the lactate buffer
formulation with proline (13O) and in the sodium phosphate buffered
formulation (Comp 6B). After 4 weeks at 40.degree. C., meaningful
differences between formulations were not as apparent. The highest
amount of % acidic peak found after 4 weeks at 40.degree. C. were
in the formulations buffered with sodium phosphate at both 100 and
170 mg/mL (Comp 6A, Comp 6B respectively.)
[0640] Stability was assessed by measuring HMWS by SE-HPLC after 0,
2, and 4 weeks at 40.degree. C. and at 25.degree. C. The results
are shown in FIG. 39 and FIG. 40. At 25.degree. C., after 4 weeks,
the formulation with proline and calcium chloride had the lowest
HMWS (13I). Otherwise, increasing concentrations of PEG 600 and
lower proline levels in formulations resulted in higher amounts of
HMWS (compare 13I, 13H, 13G and 13F). In formulations at 170 mg/mL
stored for 4 weeks at 25.degree. C., the proline formulation with
calcium chloride was again superior in having the lowest HMWS
(13O). At 40.degree. C., similar trends to those observed at
25.degree. C. were noted. The proline formulations had the lowest
amount of HMWS at both 100 mg/mL and 170 mg/mL (13I, 13O). At
4.degree. C., stability was assessed by measuring HMWS by SE-HPLC
after 0, 4, and 8 weeks. The results are shown in FIG. 41. Minimal
growth of HMWS is observed at 4.degree. C. in most formulations. At
time zero, the lowest HMWS in the 100 mg/mL formulation is found in
the proline formulation with calcium chloride (13I). Likewise, at
170 mg/mL, HMWS is minimized in the lactate buffer formulation with
proline at time zero (13O). Finally, stability was assessed by
measuring HMWS by SE-HPLC after 0 weeks, after 3 F/T cycles, and
after 8 weeks at -30.degree. C. The results are shown in FIG. 42.
In agreement with the results obtained at 4.degree. C., the proline
formulation at 100 and 170 mg/mL (13I, 13O) had the lowest amount
of HMWS and no meaningful change in HMWS after the freeze thaw
cycles. Most formulations did not show meaningful change upon
repeated freezing and thawing at -30.degree. C. The lone exception
appears to be the Comp 5A formulation, in which HMWS increased upon
repeated freezing and thawing and after 8 weeks at -30.degree.
C.
Example 14
Effect of PEG, Proline, MEA, MSA and Calcium Chloride on
Formulation Stability
[0641] Adalimumab biosimilar starting material at 50 mg/mL was
prepared using 3.5 kD cutoff dialysis tubing in the following
buffers: 5 mM MEA with 5 mM MSA, pH adjusted using MSA or MEA to a
final pH of 4.8; 14.4 mM sodium phosphate with 7.7 mM citrate, 105
mM sodium chloride and 1.2% mannitol, pH adjusted with HCl or NaOH
to a final pH of 4.8; 4.2% mannitol, pH adjusted with HCl or NaOH
to a final pH of 4.8; 10 mM acetate with 9% sucrose, pH adjusted
with HCl or NaOH to a final pH of 4.8. Stock excipient solutions
were then added to achieve the final concentrations as shown in
Table 14 and the pH was adjusted to 5.2 if needed. The formulations
are provided in Table 14.
TABLE-US-00027 TABLE 14 pH Adjusting Ab conc. Ref. Buffer
Excipient(s) Agent pH (mg/mL) Comp. 7 14.1 mM sodium 105 mM NaCl
HCl, NaOH 5.2 50 phosphate 1.2% mannitol 7.7 mM citrate Comp. 8 --
4.2% mannitol HCl, NaOH 5.2 50 14A 10 mM acetate 9% sucrose HCl,
NaOH 5.2 50 14B -- 10.4% PEG600 MSA, MEA 5.2 50 14C -- 8.5% PEG600
MSA, MEA 5.2 50 25 mM calcium chloride 14D -- 6.4% PEG600 MSA, MEA
5.2 50 50 mM calcium chloride 14E -- 3.7% PEG600 MSA, MEA 5.2 50 75
mM calcium chloride 14F -- 100 mM calcium MSA, MEA 5.2 50 chloride
14G -- 300 mM proline MSA, MEA 5.2 50 14H -- 225 mM proline MSA,
MEA 5.2 50 25 mM calcium chloride 14I -- 150 mM proline MSA, MEA
5.2 50 50 mM calcium chloride 14J -- 75 mM proline MSA, MEA 5.2 50
75 mM calcium chloride 14K -- 240 mM proline MSA, MEA 5.2 50 60 mM
MEA 60 mM MSA 14L -- 180 mM proline MSA, MEA 5.2 50 60 mM MEA 60 mM
MSA 14M -- 120 mM proline MSA, MEA 5.2 50 90 mM MEA 90 mM MSA
[0642] To assess stability, the % acidic peak was measured by
CEX-HPLC after 0, 2, and 4 weeks at 40.degree. C. and after 0, 2,
4, and 8 weeks at 25.degree. C. The results are shown in FIG. 43
and FIG. 44. At 25.degree. C., after 8 weeks, lower amounts of HMWS
were measured in the formulation with proline and high MEA and MSA
(14M) and in the formulations with the higher concentrations of
calcium chloride (14E, 14F and 14J). As is shown by comparing
formulations 14B, 14C, 14D, 14E and 14F, the level of HMWS
increased as the concentration of PEG 600 increased after 8 weeks
at 25.degree. C. Similar trends were observed at 40.degree. C. that
had been apparent at 25.degree. C. Increasing levels of calcium
chloride were beneficial in minimizing the formation of HMWS. PEG
600 was not preferred for stability at 40.degree. C. Low HMWS was
observed in the formulation containing proline and high MEA and MSA
after 4 weeks at 40.degree. C. Stability was assessed by measuring
acidic peak by CEX-HPLC after 0, 4 and 8 weeks at 4.degree. C. The
results are shown in FIG. 45. Minor differences were measured in
the % acidic peak at time zero and after storage for 8 weeks at
4.degree. C. These differences were not considered meaningful.
Stability was assessed by measuring acidic peak by CEX-HPLC after 0
days, after 3 F/T cycles, and after 4 weeks at -30.degree. C. The
results are shown in FIG. 46. Consistent with the results obtained
at 4.degree. C., differences between formulations were minor and
apparent growth of the % acidic peak was not observed after
multiple freeze thaws and 8 weeks storage at -30.degree. C.
[0643] Stability also was assessed by measuring HMWS by SE-HPLC
after 0 days and after 3 F/T cycles. The results are shown in FIG.
47. For most formulations, multiple freezing and thawing did not
result in growth of HMWS, with the exception of formulation Comp 8.
Several formulations, although not showing an increase in HMWS
after multiple freeze thaw steps, did grow in HMWS after storage at
-30.degree. C. following the freeze thaw steps (formulations Comp.
8, self-buffered, and 14M, containing high amounts of MEA and MSA).
Stability was assessed by measuring HMWS by SE-HPLC after 0 and 2
weeks at 40.degree. C. and at 25.degree. C. The results are shown
in FIG. 48 and FIG. 49. After storage at 40.degree. C. for 4 weeks,
HMWS growth appeared to be higher in formulations containing PEG
600 or higher amounts of calcium chloride and in the formulation
buffered with sodium phosphate (Comp 7, 14B, 14C, 14D, 14E, 14F).
Overall, the highest amount of HMWS at >3% was measured in the
formulation with higher MEA and MSA (14M). Low amounts of HMWS were
observed in the formulation buffered with acetate and the proline
formulation (14A, 14G). Similar trends were observed at 25.degree.
C. as were found at 40.degree. C. Low HMWS were apparent in
formulations 14A and 14G, with PEG 600 not preferred for stability,
along with high levels of MEA and MSA. Finally, stability was also
assessed at 4.degree. C. by SE-HPLC after 0, 4 and 8 weeks. The
results are shown in FIG. 50. Meaningful growth of HMWS at
4.degree. C. was not observed in most formulations, with the
exception of the formulations containing higher amounts of PEG 600
(14B, 14C). As discussed previously, at time zero the highest HMWS
was observed in the formulation containing high levels of MEA and
MSA.
Example 15
Stability of Self-Buffered, Lactate Buffered, and Acetate Buffered
Formulations
[0644] Three adalimumab formulations were prepared, as shown in
Table 15.
TABLE-US-00028 TABLE 15 Buffer/pH Adjusting Ab conc. Ref. Agent
Excipients Surfactant pH (mg/mL) Conductivity 15A --/HCl, 4% 0.05%
Pluronic 5.2 100 4.7 mS/cm Ca(OH).sub.2 sorbitol, 30 mM F68 calcium
chloride 15B 10 mM 6% 0.006% 5.1 100 4.78 mS/cm Lactate/HCl,
sucrose, Pluronic F68 Ca(OH).sub.2 30 mM calcium chloride 15C 10 mM
6% 0.1% 5.2 100 4.05 mS/cm Acetate/HCl, sucrose, 45 mM Polysorbate
80 NaOH NaCl
[0645] To assess stability, the % acidic peak was measured by
CEX-HPLC at 0 days, 1 week, 2 weeks, 1 month, and 2 months, at
2-8.degree. C., and at 0 days, 1 week, 2 weeks, 1 month, and 2
months at 25.degree. C. The results are shown in FIG. 51
(2-8.degree. C.) and FIG. 52 (25.degree. C.). All three formulation
(formulations 15A-C) exhibited similar stability with respect to
acidic species at 2-8.degree. C. At 25.degree. C., formulation 15C
(acetate buffer with sodium chloride) had the highest amount of %
acidic peak.
[0646] Stability also was assessed by measuring HMWS by SE-HPLC
after 0 days, 1 week, 2 weeks, 1 month, and 2 months at 2-8.degree.
C., and after 0 days, 1 week, 2 weeks, 1 month, and 2 months at
25.degree. C. The results are shown in FIGS. 53 (2-8.degree. C.)
and 54 (25.degree. C.). At time zero, the highest HMWS was measured
in the self-buffered formulation, followed by the acetate buffer
formulation with sodium chloride and the lactate buffer formulation
with calcium chloride, respectively. This trend was maintained at
4.degree. C. over time, with the lactate buffer formulation having
the least amount of HMWS. Likewise, at 25.degree. C., the lactate
buffer formulation exhibited the least growth of HMWS. At the 1 and
2 month time point, the rate of degradation also slowed down
compared to the earlier time points at 25.degree. C. This trend was
observed for all formulations at 25.degree. C. At 4.degree. C., the
rate of growth of HMWS were similar for each formulation, with a
minor increase observed in all formulations after time zero and up
to two weeks, followed by a leveling off of the rate after the two
week time point. The lactate buffer formulation also had the lowest
amount of HMWS at time zero.
[0647] Stability also was assessed by measuring the count of 5
.mu.M, 10 .mu.M, and 25 .mu.M sub-visible particles by MFI in
non-transported and transported samples at 2-8.degree. C. for 1, 2,
and 4 weeks. The particles exhibited an equivalent circular
diameter of at least 5.000 and an aspect ratio of less than 0.700.
The results are shown in FIGS. 55-57. All formulations at
.ltoreq.25 .mu.M had low particle counts. For the 10 .mu.M
sub-visible counts, the acetate formulation (formulation 15B)
showed the lowest amount of sub-visible particles. For the
non-spherical .ltoreq.5 .mu.M particle counts, the self-buffered
and lactate buffer formulations (formulations 15A and 15C) showed
higher particle counts at t=0 (pre-transport) and at later time
points compared to the acetate formulation with sodium chloride. In
general, for .ltoreq.5 .mu.M particle counts, each formulation
showed an increase in particles post-transport, followed by a trend
of lower particle counts at the 1 week, 2 week and 4 week time
points.
Example 16
Effect of Surfactant and Salt on Formulation Stability
[0648] Several adalimumab formulations (formulations 16A-16L) were
prepared, as shown in Table 16.
TABLE-US-00029 TABLE 16 Buffer/pH Conductivity Adjusting CaCl.sub.2
Ab conc. Osmolality Ref. Agent (mM) Excipient Surfactant pH (mg/mL)
Viscosity 16A --/-- 0 4% 0.09% 5.21 97.89 0.76 mS/cm sorbitol
Polysorbate 20 241 mOsm 2.54 mPa s 16B --/60 .mu.L 15 4% 0.09% 5.09
99.37 3.01 mS/cm Ca(OH).sub.2 sorbitol Polysorbate 20 283 mOsm 2.59
mPa s 16C --/40 .mu.L 30 4% 0.03% 5.06 103.47 4.98 mS/cm
Ca(OH).sub.2 sorbitol Polysorbate 20 317 mOsm 2.62 mPa s 16D --/40
.mu.L 15 4% 0.03% 5.1 99.99 3.07 mS/cm Ca(OH) sorbitol Polysorbate
20 283 mOsm 2.46 mPa s 16E --/60 .mu.L 30 4% 0.09% 5.03 103.77 4.97
mS/cm Ca(OH).sub.2 sorbitol Polysorbate 20 316 mOsm 2.54 mPa s 16F
10 mM 0 6% sucrose 0.10% Pluronic 5.25 97.68 0.744 mS/cm Lactate/--
F68 219 mOsm 2.82 mPa s 16G 10 mM 15 6% sucrose -- 5.09 111.79 2.99
mS/cm Lactate/-- 268 mOsm 3.03 mPa s 16H 10 mM 15 6% sucrose 0.08%
Pluronic 5.09 106.72 2.97 mS/cm Lactate/-- F68 266 mOsm 3.00 mPa s
16I 10 mM 15 6% sucrose 0.02% Pluronic 5.06 109.35 2.99 mS/cm
Lactate/-- F68 268 mOsm 2.93 mPa s 16J 10 mM 30 6% sucrose 0.2%
Pluronic 5.04 101.79 4.99 mS/cm Lactate/-- F68 305 mOsm 2.75 mPa s
16K 10 mM 30 6% sucrose 0.08% Pluronic 5.05 102.27 5.03 mS/cm
Lactate/-- F68 309 mOsm 2.70 mPa s 16L 10 mM 30 6% sucrose 0.03%
Pluronic 5.04 104.89 5.06 mS/cm Lactate/-- F68 308 mOsm 2.68 mPa
s
[0649] To assess stability, the % acidic peak was measured by
CEX-HPLC in non-transported samples and transported samples at 0,
1, and 2 weeks at 4.degree. C., 25.degree. C., and 40.degree. C.
The results are shown in FIGS. 58-63. No meaningful differences in
the % acidic peak were exhibited at time 0 for all twelve
formulations. The lack of meaningful differences between
formulations was also apparent after 1 month at 4.degree. C. for
both transport stressed and non-transport stressed conditions. At
25.degree. C., and 40.degree. C., as a general trend, formulations
without calcium chloride (16A and 16F) had the highest amount of %
acidic peak after 1 month. In addition, differences between
transported stressed and non-transported stressed formulations were
not apparent at 25.degree. C. At 40.degree. C., the non-transported
formulations that were self-buffered and containing calcium
chloride (16B-16E) had lower rates of growth of % acidic peak
compared to the identical formulations that were transport
stressed. Otherwise, the presence of calcium chloride appears to
reduce the formation of the acidic peak at both 25.degree. C. and
at 40.degree. C.
[0650] Stability also was assessed by measuring HMWS by SE-HPLC
after 0 days, after transport, and after storing the
non-transported and transported samples at 4.degree. C., 25.degree.
C., or 40.degree. C. for 1, 2, and 4 weeks. The results are shown
in FIGS. 64-69. The formulations having the combination of lactate
buffer and calcium chloride (e.g., formulations 16G-16L), versus
self-buffered and formulations with sorbitol (formulations 16A-E),
exhibited the lowest amount of HMWS at time 0. Formulations having
lactate buffer exhibited better stability than formulations without
lactate buffer at 25.degree. C. Formulations having 15 mM of
calcium chloride (formulations 16G-16I) exhibited better stability
than formulations having 0 mM or 30 mM of calcium chloride. This
trend was more apparent in the self-buffered formulations (16A-16E)
in which 15 mM calcium chloride was superior for stability at
25.degree. C. compared to self-buffered formulations with 30 mM
calcium chloride. Overall, formulations having the combination of
lactate buffer and calcium chloride exhibited surprisingly superior
stability at 25.degree. C. After storage for 1 month at 40.degree.
C., the growth of HMWS appeared to increase faster in the lactate
buffer formulations compared to the self-buffered formulations,
however the amount of HMWS formed did not exceed that of the HMWS
measured in the self-buffered formulations at this same temperature
and time point. In general, formulations having the combination of
lactate buffer and 15 mM calcium chloride exhibited the lowest
amount of HMWS, in part, because they initially had the lowest
amount of HMWS.
[0651] Stability also was assessed by measuring the count of 5
.mu.M, 10 .mu.M, and 25 .mu.M sub-visible particles by MFI in
non-transported and transported samples at 4.degree. C., 25.degree.
C., or 40.degree. C. for 1, 2, and 4 weeks. The particles exhibited
an equivalent circular diameter of at least 5.000 and an aspect
ratio of less than 0.700. The results are shown in FIGS. 70-72. For
the 5 .mu.M size particles, the lactate buffered formulation with
0.25% Pluronic F68 had the highest number of particles following
transport and at later time points. In the self-buffered
formulations, the absence of calcium chloride resulted likewise in
a high 5 .mu.M particle count initially and over time. These
results were not expected, especially with the higher level of
Pluronic F68 in the lactate buffer formulation associated with high
particle counts. In the lactate buffer formulations in general at 5
.mu.M, 0.13% Pluronic F68 appeared best at minimizing particles in
formulations with either 15 mM or 30 mM calcium chloride. FIGS.
70A-B. At the 10 .mu.M particle level, a similar trend to that
observed for the 5 .mu.M results was observed. The lactate buffer
formulation with 0.13% Pluronic F68 was effective in reducing the
number of particles compared to higher Pluronic F68 at 0.25%. FIGS.
71A-B. Finally, at 25 Pluronic F68 at 0.13% minimized particle
growth in lactate buffer formulations. Calcium chloride at
concentrations of either 15 or 30 mM minimized particle growth in
self-buffered formulations in the presence of PS 20. FIGS.
72A-B.
Example 17
Effect of Calcium Chloride Concentration on the Stability of
Lactate Buffer Formulations
[0652] Several adalimumab formulations (formulations 17A-17E) were
prepared, as shown in Table 17.
TABLE-US-00030 TABLE 17 Buffer/pH Adjusting CaCl.sub.2 Ab conc.
Conductivity Ref. Agent (mM) Excipient Surfactant pH (mg/mL)
Osmolality 17A 10 mM 5 8.3% 0.03% Pluronic 5.11 100 1.339 mS/cm
Lactate/HCl, sucrose F68 292 mOsm Ca(OH).sub.2 17B 10 mM 10 7.8%
0.03% Pluronic 5.12 100 2.125 mS/cm Lactate/HCl, sucrose F68 304
mOsm Ca(OH).sub.2 17C 10 mM 15 7.4% 0.03% Pluronic 5.10 100 2.792
mS/cm Lactate/HCl, sucrose F68 304 mOsM Ca(OH).sub.2 17D 10 mM 20
6.9% 0.03% Pluronic 5.13 100 3.527 mS/cm Lactate/HCl, sucrose F68
302 mOsM Ca(OH).sub.2 17E 10 mM -- mM 8.8% 0.03% Pluronic 5.23 100
0.534 mS/cm Lactate/HCl, sucrose F68 314 mOsM Ca(OH).sub.2
[0653] To assess stability, the % acidic peak was measured by
CEX-HPLC after 0 days, after transport, and after 1 week, 2 weeks
and 4 weeks at 4.degree. C., 25.degree. C. and 40.degree. C. The
results are shown in FIGS. 73-78. At time zero, the % acidic peak
was similar either with or without transport stress, with only
minor variability observed. After 1 month at 25.degree. C., the
rate of growth was similar in all formulations, with the level of
calcium chloride in the range evaluated in this study having minor
to no impact, tested in both transport stressed and non-transport
stressed samples. In formulations stored at 40.degree. C., a
smaller amount of % acidic peak was observed as the level of
calcium chloride increased after 1 month's storage. This trend was
observed for both the transport and non-transport stressed
formulations. Otherwise, transport stress did not appear to result
in higher rates of degradation.
[0654] Stability also was assessed by measuring HMWS by SE-HPLC
after 0 days, after transport, and after storing the
non-transported and transported samples at 4.degree. C., 25.degree.
C., or 40.degree. C. for 1, 2, and 4 weeks. The results are shown
in FIGS. 79-84. At time zero, a very minor increase in HMWS was
observed as the calcium chloride level increased. This is most
likely not meaningful, considering assay variability. Formulations
that were transport stressed did not appear to have higher HMWS
than non-transport stressed formulations. After one month at
25.degree. C. and at 40.degree. C., it is difficult to detect a
correlation in formulations with a higher amount of HMWS and
increasing amounts of calcium chloride. These results suggest that
levels of calcium chloride in the range tested do not adversely
affect stability with respect to the formation of HMWS.
[0655] Stability also was assessed by measuring the count of 5
.mu.M, 10 .mu.M, and 25 .mu.M sub-visible particles by MFI in
non-transported and transported samples. The particles exhibited an
equivalent circular diameter of at least 5.000 and an aspect ratio
of less than 0.700. The results are shown in FIGS. 85-87. In
formulations tested for particle counts at .ltoreq.5 .mu.m, counts
appeared to spike after transport stress, however the particle
counts dropped at all time points and temperature conditions
thereafter. High temperature exposure (25.degree. C., 40.degree.
C.) resulted in only a modest increase in particles. There was a
less apparent spike in particles .ltoreq.10 .mu.m in most
formulations that had been transport stressed, but the counts were
also reduced at the 1 month time point at all temperatures tested.
A modest particle count increase was also observed in samples
stored after 1 month at 25.degree. C. and 40.degree. C. MFI results
measured for particles in the range .ltoreq.25 .mu.m did not show
an apparent trend, as the number of particles was low or not
detected.
[0656] All publications, patents and patent applications cited in
this specification are herein incorporated by reference as if each
individual publication or patent application were specifically and
individually indicated to be incorporated by reference. Although
the foregoing invention has been described in some detail by way of
illustration and example for purposes of clarity of understanding,
it will be readily apparent to those of ordinary skill in the art
in light of the teachings of this disclosure that certain changes
and modifications may be made thereto without departing from the
spirit or scope of the disclosed embodiments.
Sequence CWU 1
1
101107PRTArtificial SequenceLight chain variable region 1Asp Ile
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr 20 25
30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser
Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
Gln Pro65 70 75 80Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn
Arg Ala Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 1052121PRTArtificial SequenceHeavy chain variable region 2Glu
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
Val 35 40 45Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp
Ser Val 50 55 60Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
Ala Val Tyr Tyr Cys 85 90 95Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser
Ser Leu Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser
Ser 115 1203214PRTArtificial SequenceFull length light chain 3Asp
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10
15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr
20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
Ile 35 40 45Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe
Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
Leu Gln Pro65 70 75 80Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr
Asn Arg Ala Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro
Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp
Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170
175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr
Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 2104224PRTArtificial
SequenceFull length heavy chain 4Glu Val Gln Leu Val Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala
Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Thr Trp
Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val 50 55 60Glu Gly Arg Phe
Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala
Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly 100 105
110Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
Thr Ala 130 135 140Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
Pro Val Thr Val145 150 155 160Ser Trp Asn Ser Gly Ala Leu Thr Ser
Gly Val His Thr Phe Pro Ala 165 170 175Val Leu Gln Ser Ser Gly Leu
Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190Pro Ser Ser Ser Leu
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205Lys Pro Ser
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215
220511PRTArtificial SequenceL-CDR1 5Arg Ala Ser Gln Gly Ile Arg Asn
Tyr Leu Ala1 5 1067PRTArtificial SequenceL-CDR2 6Ala Ala Ser Thr
Leu Gln Ser1 579PRTArtificial SequenceL-CDR3MISC_FEATURE(9)..(9)Xaa
is Thr or Ala 7Gln Arg Tyr Asn Arg Ala Pro Tyr Xaa1
585PRTArtificial SequenceH-CDR1 8Asp Tyr Ala Met His1
5917PRTArtificial SequenceH-CDR2 9Ala Ile Thr Trp Asn Ser Gly His
Ile Asp Tyr Ala Asp Ser Val Glu1 5 10 15Gly1012PRTArtificial
SequenceH-CDR3MISC_FEATURE(12)..(12)Xaa is Tyr or Asn 10Val Ser Tyr
Leu Ser Thr Ala Ser Ser Leu Asp Xaa1 5 10
* * * * *