U.S. patent application number 17/139420 was filed with the patent office on 2021-05-13 for cysteine composition and injection.
The applicant listed for this patent is Exela Sterile Medicines LLC. Invention is credited to Alain Constancis, Pierre Danner, Gauthier Pouliquen, Jill Simpson, Angela Sutterer.
Application Number | 20210137869 17/139420 |
Document ID | / |
Family ID | 1000005345868 |
Filed Date | 2021-05-13 |
![](/patent/app/20210137869/US20210137869A1-20210513\US20210137869A1-2021051)
United States Patent
Application |
20210137869 |
Kind Code |
A1 |
Sutterer; Angela ; et
al. |
May 13, 2021 |
CYSTEINE COMPOSITION AND INJECTION
Abstract
Cysteine compositions comprising less than about 400 .mu.g/L of
aluminum. For example, solutions of cysteine comprising a
pharmaceutically acceptable solvent, cysteine, and less than about
145 .mu.g/L of aluminum, wherein the solution is devoid of visible
particulate matter. Cysteine compositions described herein may be
suitable for injection. For example, disclosed cysteine solutions
may be provided intravenously to meet amino acid nutritional
requirement in individuals receiving total parenteral nutrition.
Also provided are processes for preparing cysteine compositions,
and methods for providing cysteine to individuals in need
thereof.
Inventors: |
Sutterer; Angela;
(Chesterfield, MO) ; Simpson; Jill; (Chesterfield,
MO) ; Pouliquen; Gauthier; (Ternay, FR) ;
Constancis; Alain; (Lyon, FR) ; Danner; Pierre;
(Francheville, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Exela Sterile Medicines LLC |
Lenoir |
NC |
US |
|
|
Family ID: |
1000005345868 |
Appl. No.: |
17/139420 |
Filed: |
December 31, 2020 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
16658893 |
Oct 21, 2019 |
|
|
|
17139420 |
|
|
|
|
16373255 |
Apr 2, 2019 |
10543186 |
|
|
16658893 |
|
|
|
|
16355028 |
Mar 15, 2019 |
10493051 |
|
|
16373255 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0019 20130101;
A61P 3/02 20180101; A61K 9/08 20130101; A61K 31/198 20130101 |
International
Class: |
A61K 31/198 20060101
A61K031/198; A61K 9/08 20060101 A61K009/08; A61K 9/00 20060101
A61K009/00; A61P 3/02 20060101 A61P003/02 |
Claims
1. A process for preparing a solution of cysteine hydrochloride,
the process comprising: acidifying water to a pH from about 1.0 to
about 1.5 to form acidified water; dissolving cysteine
hydrochloride in the acidified water to form a solution; and
filling and sealing a container with the solution, wherein the
solution is disposed under flow of an inert gas during the filling
and sealing.
2. The process of claim 1, wherein the acidifying is performed
under flow of an inert gas.
3. The process of claim 1, wherein the acidifying comprises adding
hydrochloric acid.
4. The process of claim 1, wherein the pH of the acidified water is
from about 1.0 to about 1.3.
5. The process of claim 1, further comprising sparging the water
with an inert gas to achieve a dissolved oxygen content of less
than about 2 mg/L in the water prior to the acidifying.
6. The process of claim 1, wherein the dissolving comprises adding
about 40 mg to about 60 mg of cysteine hydrochloride per 1 mL of
acidified water.
7. The process of claim 1, wherein the dissolving comprises adding
about 50 mg of cysteine hydrochloride per 1 mL of acidified
water.
8. The process of claim 1, wherein the dissolving comprises
stirring the cysteine hydrochloride and the acidified water under
flow of an inert gas.
9. The process of claim 1, further comprising checking and
adjusting, if necessary, the pH of the solution to a value from
about 1.0 to about 1.5 prior to the filling and sealing.
10. The process of claim 1, further comprising sterile filtering
the solution prior to the filling and sealing.
11. The process of claim 10, wherein the sterile filtering
comprises passing the solution through at least one 0.22 .mu.m
filter.
12. The process of claim 1, wherein the acidifying, the dissolving,
and the filling and sealing are performed at ambient
temperature.
13. The process of claim 1, wherein the acidifying occurs prior to
the dissolving.
14. The process of claim 1, wherein the container is a silica-lined
glass vial.
15. The process of claim 1, wherein the solution of cysteine
hydrochloride has a pH from about 1.0 to about 1.5.
16. The process of claim 1, wherein the solution of cysteine
hydrochloride comprises about 50 mg/mL of cysteine
hydrochloride.
17. The process of claim 1, wherein the solution of cysteine
hydrochloride is free of visible particulate matter.
18. The process of claim 1, wherein the solution of cysteine
hydrochloride has a cystine content of less than about 1% by weight
of the total cysteine present in the solution of cysteine
hydrochloride.
19. The process of claim 1, wherein the solution of cysteine
hydrochloride has a cystine content of less than about 0.5% by
weight of the total cysteine present in the solution of cysteine
hydrochloride.
20. The process of claim 1, wherein the solution of cysteine
hydrochloride has a dissolved oxygen content of less than about 2
mg/L.
21. The process of claim 1, wherein the solution of cysteine
hydrochloride has an aluminum content of less than about 145
.mu.g/L.
22. The process of claim 1, wherein the solution of cysteine
hydrochloride is stable when stored for at least six months at
25.degree. C. and 60% relative humidity.
23. The process of claim 1, wherein the solution of cysteine
hydrochloride is stable when stored for at least 12 months at
25.degree. C. and 60% relative humidity.
24. The process of claim 1, wherein the solution of cysteine
hydrochloride is stable when stored for at least 18 months at
25.degree. C. and 60% relative humidity.
25. The process of claim 1, wherein the solution of cysteine
hydrochloride is stable when stored for at least 24 months at
25.degree. C. and 60% relative humidity.
26. The process of claim 1, wherein the solution of cysteine
hydrochloride is free of visible particulate matter when stored for
at least six months at 25.degree. C. and 60% relative humidity.
27. The process of claim 1, wherein the solution of cysteine
hydrochloride is free of visible particulate matter when stored for
at least 12 months at 25.degree. C. and 60% relative humidity.
28. The process of claim 1, wherein the solution of cysteine
hydrochloride is free of visible particulate matter when stored for
at least 18 months at 25.degree. C. and 60% relative humidity.
29. The process of claim 1, wherein the solution of cysteine
hydrochloride is free of visible particulate matter when stored for
at least 24 months at 25.degree. C. and 60% relative humidity.
30. The process of claim 1, wherein the solution of cysteine
hydrochloride has an aluminum content of less than about 145
.mu.g/L when stored for at least six months at 25.degree. C. and
60% relative humidity.
31. The process of claim 1, wherein the solution of cysteine
hydrochloride has an aluminum content of less than about 145
.mu.g/L when stored for at least 12 months at 25.degree. C. and 60%
relative humidity.
32. The process of claim 1, wherein the solution of cysteine
hydrochloride has an aluminum content of less than about 145
.mu.g/L when stored for at least 18 months at 25.degree. C. and 60%
relative humidity.
33. The process of claim 1, wherein the solution of cysteine
hydrochloride has an aluminum content of less than about 145
.mu.g/L when stored for at least 24 months at 25.degree. C. and 60%
relative humidity.
34.-65. (canceled)
66. A solution of cysteine hydrochloride comprising about 40 mg/mL
to about 60 mg/mL of cysteine hydrochloride and a pH from about 1.0
to about 1.5, wherein the cysteine hydrochloride solution is
prepared by a process comprising: acidifying water to a pH from
about 1.0 to about 1.5 to form acidified water; dissolving about 40
mg to about 60 mg of cysteine hydrochloride per 1 mL of acidified
water to form the solution; and filling and sealing a container in
which the solution is disposed under flow of an inert gas.
67. A cysteine hydrochloride solution comprising about 50 mg/mL of
cysteine hydrochloride and having a pH from about 1.0 to about 1.5,
wherein the cysteine hydrochloride solution is prepared by a
process comprising: acidifying water to a pH from about 1.0 to
about 1.5 to form acidified water; and dissolving about 50 mg of
cysteine hydrochloride per 1 mL of acidified water to form the
cysteine hydrochloride solution.
68. The process of claim 1, further comprising checking that the
solution of cysteine hydrochloride has a dissolved oxygen content
of less than about 2 mg/L and, if necessary, adjusting the
dissolved oxygen content prior to the filling and sealing.
69. The process of claim 68, wherein the adjusting comprises
sparging the solution of cysteine hydrochloride with an inert gas
to achieve the dissolved oxygen content of less than about 2
mg/L.
70. A solution of cysteine comprising about 10 mg/mL to about 100
mg/mL of cysteine prepared by acidifying water to a pH from about
1.0 to about 1.5 to form acidified water and dissolving about 10
mg/mL to about 100 mg/mL of cysteine per 1 mL of acidified water to
form the solution, wherein the solution of cysteine has a pH from
about 1.0 to about 1.5.
71. A solution of cysteine comprising about 10 mg/mL to about 100
mg/mL of cysteine and less than about 1% of cystine by weight of
the total cysteine present in the solution, wherein the solution
has a pH from about 1.0 to about 1.5 and the solution is devoid of
visible particulate matter.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/658,893, filed Oct. 21, 2019, which is a
continuation of U.S. patent application Ser. No. 16/373,255, filed
Apr. 2, 2019, now U.S. Pat. No. 10,543,186, which is a continuation
of and claims priority to U.S. patent application Ser. No.
16/355,028, filed Mar. 15, 2019, now U.S. Pat. No. 10,493,051.
FIELD
[0002] The present disclosure relates to cysteine compositions
having less than about 400 .mu.g/L of aluminum and/or exhibiting
extended stability.
BACKGROUND
[0003] Cysteine is considered a semi-essential amino acid for
newborn infants and is routinely added to neonatal total parenteral
nutrition (TPN) formulations. However, the stability of cysteine is
low in solution, e.g., it can oxidize to form cystine, a disulfide
dimer, which has a lower solubility than cysteine. Most crystalline
amino acid solutions have pH levels of about 5-7, which would favor
the conversion of cysteine to cystine. For these reasons, cysteine
has typically been formulated as a separate parenteral nutrition
additive and tends to be mixed with other TPN components just prior
to use. Thus, preparations of cysteine with improved stability
would be beneficial.
[0004] Aluminum is a contaminant commonly found in parenteral
nutrition additive solutions. Research indicates that patients with
impaired kidney function, including neonates, who receive
parenteral levels of aluminum at greater than 4 to 5 .mu.g per kg
per day accumulate aluminum at levels associated with central
nervous system and bone toxicity. In an attempt to limit the risk
of aluminum toxicity, the U.S. Food and Drug Administration (FDA)
has rules limiting the total aluminum content in TPN formulations.
Since some preparations of cysteine can contain up to 5000 .mu.g/L
of aluminum, the total daily aluminum limit may be exceeded. Thus,
preparations of cysteine with reduced levels of aluminum would also
be beneficial.
SUMMARY
[0005] Among the various aspects of the present disclosure is the
provision of solutions of cysteine, each of which includes a
pharmaceutically acceptable solvent (e.g., water), cysteine (e.g.,
cysteine hydrochloride), and less than about 400 .mu.g/L of
aluminum. In some embodiments, the aluminum content may be
substantially lower than 400 .mu.g/L; for instance, the aluminum
content of some embodiments may be less than about 145 .mu.g/L,
less than about 100 .mu.g/L, less than about 30 .mu.g/L, or even
less than about 10 .mu.g/L. In some embodiments, the aluminum
content may range from about 0 .mu.g/L to about 400 .mu.g/L or from
about 3 .mu.g/L to about 145 .mu.g/L. The aluminum content of some
solutions described herein may be characterized with respect to
specific storage conditions. For instance, the aluminum content of
some embodiments may be less than about 400 .mu.g/L when the
solution is stored in a silica-lined vial i) for 6 months at
40.degree. C. and 75% relative humidity or ii) for 18 months at
25.degree. C. and 60% relative humidity.
[0006] Some of the above-described solutions exhibit relatively low
pHs and/or include low levels of dissolved oxygen content. For
instance, some solutions may have a pH from about 1.0 to about 2.5,
a pH from about 1.0 to about 1.5, or a pH from about 1.0 to about
1.3. As another example, some solutions may have a dissolved oxygen
content of less than 2 mg/L.
[0007] The solutions of cysteine set forth above may be devoid of
visible particulate matter and/or precipitated particles of
cystine. For instance, a solution may be devoid of visible
particulate matter when stored for 18 months at 25.degree. C. and
60% relative humidity. As another example, a solution may be devoid
of visible particulate matter when stored for 6 months at
40.degree. C. and 75% relative humidity.
[0008] Some embodiments of the solutions set forth above may be
characterized as being sterile and/or formulated for injection
(e.g., intravenous injection).
[0009] All of the features described above may exist individually
or in any combination. For instance, in some embodiments, the
solution may be characterized as having 50 mg/mL of cysteine
hydrochloride monohydrate, less than 145 .mu.g/L of aluminum, and a
pH from about 1.0 to about 2.5, as well as being devoid of visible
particulate matter.
[0010] Another aspect of the present disclosure provides a
silica-lined vial having a solution of cysteine (such as any of
those described above) disposed therein. The solution in the vial
may be overlaid with a layer of nitrogen. The vial may be sealed in
any appropriate manner (e.g., with a cap) and may include a
pierceable septum or the like to enable the solution to be drawn
therefrom for administration (e.g., intravenous administration) to
individuals. In certain iterations, the solution in the vial
comprises 50 mg of cysteine hydrochloride monohydrate per mL of
water for injection adjusted to pH 1.0 to 2.5. In some iterations,
the vial comprises 10 mL of the solution, which may or may not be
required to be diluted prior to administration to an individual in
need thereof.
[0011] Yet another aspect of the present disclosure encompasses a
total parenteral nutrition formulation that includes a solution of
cysteine described herein.
[0012] Still another aspect of the present disclosure provides a
solution of cysteine having a cysteine monomer content of at least
99% by weight and a cystine dimer content of less than 1% by
weight. The dissolved oxygen content of the solution may be less
than about 2 mg/L, and the pH of the solution may be from about 1.0
to about 1.5. In some embodiments, the cystine dimer content of the
solution may be less than about 0.5% by weight. The solution of
this aspect is preferably devoid of precipitated particles of
cystine dimer. In some embodiments of this aspect, the solution may
have an aluminum content of less than about 400 .mu.g/L or less
than about 145 .mu.g/L.
[0013] Still another aspect of the present disclosure provides
processes for preparing cysteine having i) an aluminum content of
less than about 400 .mu.g/L (e.g., the aluminum content of any of
the solutions of cysteine described above) and/or ii) a cystine
dimer content of less than about 1% (or even less than about 0.05%)
by weight. In this process, cysteine powder is added to a volume of
a pharmaceutically acceptable solvent (e.g., water) to form a
mixture. That mixture is mixed (e.g., stirred, agitated, or the
like) to form a solution. The solution is then filtered to form a
filtered solution, which can be dispensed into an appropriate
container (e.g., a vial, such as a glass vial that may have an
interior lining of silica). This process is preferably (but not
necessarily) conducted under a nitrogen atmosphere.
[0014] In some embodiments of the above-described processes for
preparing cysteine, the pharmaceutically acceptable solvent may be
acidified (e.g., by addition of 1/8th molar equivalent of
hydrochloric acid). This acidification typically (but not
necessarily) would occur prior to adding the cysteine powder to the
pharmaceutically acceptable solvent. As a result of this
acidification, the pharmaceutically acceptable solvent preferably
exhibits a pH well below 5. For instance, in some embodiments, the
resulting pH of the pharmaceutically acceptable solvent may be
between about 1.0 and about 2.5 (e.g., a pH of from about 1.0 to
about 1.3).
[0015] Still with respect to the above-described processes for
preparing cysteine, the pharmaceutically acceptable solvent may be
degassed (e.g., by sparging same with nitrogen). In certain
iterations, the dissolved oxygen content of the pharmaceutically
acceptable solvent may be less than about 2 mg/L.
[0016] In some embodiments of the above-described processes for
preparing cysteine, the filtered solution in the container may be
overlaid with a layer of nitrogen, and the container may be sealed.
In such embodiments, the filtered solution in the sealed container
is preferably devoid of visible particulate matter. In some
embodiments, the filtered solution in the sealed container may be
characterized as being devoid of visible particulate matter i)
after storage for 6 months at 40.degree. C. and 75% relative
humidity or ii) after storage for 18 months at 25.degree. C. and
60% relative humidity.
[0017] Another aspect of the present disclosure encompasses a
method for providing cysteine to a patient (e.g., neonate) in need
of receiving total parenteral nutrition. In this method, the
patient is administered a solution of cysteine described herein.
The solution may be administered in any appropriate manner but is
preferably administered intravenously. Further, the cysteine
solution may be diluted (e.g., with saline, water for injection,
and/or an amino acid solution) prior to administration to the
patient.
[0018] Other aspects and features of the present disclosure are
described in more detail below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 presents an image of vials kept open to air for 25
days. Cysteine was dissolved at a concentration of 58 mg/m L. The
pH of the solution was not adjusted (pH 1.3), was adjusted to pH
1.1 with hydrochloric acid, or was adjusted to pH 1.5 with sodium
hydroxide.
[0020] FIG. 2A shows an image of vials after being open in the lab
for 14 days. Cysteine was dissolved in water (with no pH
adjustment) or in acidified water (addition of HCl) at a
concentration of 50 mg/ml with stirring for 15 or 90 minutes.
[0021] FIG. 2B shows an image of vials after being open in the lab
for 14 days. Cysteine was dissolved in water (with no pH
adjustment) or in acidified water (addition of HCl) at a
concentration of 58 mg/ml with stirring for 15 or 90 minutes.
DETAILED DESCRIPTION
[0022] The present disclosure provides cysteine compositions having
low levels of aluminum. In general, cysteine compositions disclosed
herein are solutions comprising a pharmaceutically acceptable
solvent, cysteine, and less than about 400 .mu.g/L of aluminum. In
some instances, cysteine solutions disclosed herein comprise less
than about 145 .mu.g/L of aluminum. Cysteine solutions described
herein may be used as additives to amino acid solutions to meet
nutritional requirements of individuals requiring total parenteral
nutrition. Some cysteine solutions disclosed herein may be stable
over time (i.e., the level of aluminum is essentially constant and
the compositions remain free of visible particulate matter). Also
provided herein are methods for preparing cysteine compositions,
and methods of using cysteine compositions to provide cysteine to
individuals in need thereof.
(I) Cysteine Compositions
[0023] One aspect of the present disclosure provides compositions
comprising cysteine. The term "cysteine" as used herein refers to
"L-cysteine." The "L" refers to the orientation of the chiral
center of cysteine. All amino acids in the body are in the "L"
configuration. Thus, L-cysteine and cysteine refer to the same
moiety and the terms are often used interchangeably in clinical and
nonclinical literature.
[0024] In general, the cysteine compositions disclosed herein are
liquid compositions (e.g., solutions comprising cysteine dissolved
in a pharmaceutically acceptable solvent). Suitable
pharmaceutically acceptable solvents include water, acidified
water, low concentration salt solutions, or saline solutions, which
are of sufficient purity to be included in pharmaceutical
formulations. The cysteine solution may further include
hydrochloric acid and/or sodium hydroxide (e.g., to adjust the
pH).
[0025] In general, the cysteine composition or solution has an
aluminum content of less than about 400 .mu.g/L. In certain
embodiments, the aluminum content may be less than about 350
.mu.g/L, less than about 300 .mu.g/L, less than about 200 .mu.g/L,
or less than about 150 .mu.g/L. In specific embodiments, the
cysteine composition or solution may contain less than about 145
.mu.g/L of aluminum. In various embodiments, the aluminum content
may be less than about 140 .mu.g/L, less than about 135 .mu.g/L,
less than about 130 .mu.g/L, less than about 125 .mu.g/L, less than
about 120 .mu.g/L, less than about 115 .mu.g/L, less than about 110
.mu.g/L, less than about 105 .mu.g/L, less than about 100 .mu.g/L,
less than 95 .mu.g/L, less than about 90 .mu.g/L, less than about
85 .mu.g/L, less than about 80 .mu.g/L, less than about 75 .mu.g/L,
less than about 70 .mu.g/L, less than about 65 .mu.g/L, less than
about 60 .mu.g/L, less than about 55 .mu.g/L, less than about 50
.mu.g/L, less than about 45 .mu.g/L, less than about 40 .mu.g/L,
less than about 35 .mu.g/L, less than about 30 .mu.g/L, less than
about 25 .mu.g/L, less than about 20 .mu.g/L, less than about 15
.mu.g/L, less than about 10 .mu.g/L, or less than about 5 .mu.g/L.
In still other embodiments, the aluminum content may range from
about 0 .mu.g/L to about 400 .mu.g/L, from about 0 .mu.g/L to about
145 .mu.g/L, from about 0 .mu.g/L to about 100 .mu.g/L, from about
0 .mu.g/L to about 30 .mu.g/L, or from about 0 .mu.g/L to about 10
.mu.g/L.
[0026] In general, the cysteine composition or solution is
essentially free of visible particulate matter. In specific
embodiments, the cysteine composition or solution is devoid of
visible particulate matter. "Visible particulate matter," as used
herein, is defined as precipitated particles or crystals,
irregularly shaped visible particles or crystals, or
crystalline-like visible particles or crystals, but may also
include fiber, dust, or other visible particle contaminants. In
general, the visible particulate matter refers to particles or
crystals of cystine, a disulfide dimer of cysteine (see Example 2),
which forms in the presence of oxygen (air) and has reduced
solubility at higher pH levels. The cysteine composition or
solution may comprise a low percentage of cystine in solution but
be devoid of particles of precipitated cystine. For example, in
some embodiments, the cysteine composition or solution may comprise
less than about 1 by weight of soluble cystine. In certain
embodiments, the cysteine composition or solution may comprise less
than about 0.9 wt %, less than about 0.8 wt %, less than about 0.7
wt %, less than about 0.6 wt %, less than about 0.5 wt %, less than
about 0.4 wt %, less than about 0.3 wt %, less than about 0.2 wt %,
or less than about 0.1 wt % of cystine in solution (and be devoid
of particles of precipitated cystine).
[0027] The pH of the cysteine composition or solution may range
from about 1.0 to about 2.5. In various embodiments, the pH of the
cysteine composition or solution may range from about 1.0 to about
1.25, from about 1.25 to about 1.5, from about 1.5 to about 1.75,
from about 1.75 to about 2.0, from about 2.0 to about 2.25, or from
about 2.25 to about 2.5. In some embodiments, the pH of the
cysteine composition or solution may be about 1.5 or less (e.g.,
may range from about 1.0 to about 1.5). In other embodiments, the
pH of the cysteine composition or solution may be about 1.3 or less
(e.g., may range from about 1.0 to about 1.3). In further
embodiments, the pH of the cysteine composition or solution may be
about 1.2 or less (e.g., may range from about 1.0 to about 1.2). In
additional embodiments, the pH of the cysteine composition or
solution may be about 1.1 or less (e.g., may range from about 1.0
to about 1.1). In specific embodiments, the pH of the cysteine
composition or solution may be about 1.1, about 1.2, or about
1.3.
[0028] In general, the cysteine composition or solution may have a
dissolved oxygen content of less than about 8 mg/L. In various
embodiments, the dissolved oxygen content of the cysteine
composition or solution may be less than about 7 mg/L, less than
about 6 mg/L, less than about 5 mg/L, less than about 4 mg/L, less
than about 3 mg/L, less than about 2 mg/L, less than about 1 mg/L,
less than about 0.8 mg/L, less than about 0.6 mg/L, less than about
0.4 mg/L, or less than about 0.2 mg/L. In specific embodiments, the
dissolved oxygen content of the cysteine composition or solution
may be less than about 2 mg/L (or 2 ppm).
[0029] The cysteine composition or solution may contain a variety
of forms of cysteine. For example, the cysteine composition or
solution may contain cysteine free base or a pharmaceutically
acceptable salt of cysteine. Pharmaceutically acceptable salts of
cysteine include, without limitation, acetate, aspartate, benzoate,
bitartrate, citrate, formate, gluconate, glucuronate, glutamate,
fumarate, hydrochloride, hydrobromide, hydroiodide, hypophosphite,
isobutyrate, isocitrate, lactate, malate, maleate, meconate,
methylbromide, methanesulfonate, monohydrate, mucate, nitrate,
oxalate, phenylpriopionate, phosphate, phthalate, propionate,
pyruvate, salicylate, stearate, succinate, sulfate, tannate,
tartrate, terephthalate, valerate, and the like. In exemplary
embodiments, the cysteine composition or solution contains cysteine
hydrochloride, the hydrochloride salt of cysteine. In specific
embodiments, the cysteine composition or solution comprises
cysteine hydrochloride monohydrate, which is the most soluble form
of solid cysteine.
[0030] The concentration of cysteine in the cysteine composition or
solution may vary. For example, the concentration of cysteine may
range from about 10 mg/mL to about 100 mg/mL. In some embodiments,
the concentration of cysteine in the cysteine composition or
solution may be range from about 10-20 mg/mL, from about 20-40
mg/mL, from about 40-60 mg/mL, from about 60-80 mg/mL, or from
about 80-100 mg/mL. In certain embodiments, the concentration of
cysteine may range from about 40 mg/mL to about 60 mg/mL, from
about 45 mg/mL to about 55 mg/mL, or from about 49 mg/mL to about
51 mg/m L. In specific embodiments, the cysteine composition or
solution comprises cysteine hydrochloride and the concentration of
cysteine hydrochloride in the composition or solution may be about
50 mg/m L.
[0031] In general, more than 99% by weight of the total amount of
cysteine present in the composition or solution is monomeric (and
less than 1% by weight of the total amount of cysteine in the
composition or solution is a disulfide dimer, i.e., cystine). In
various embodiments, more than 99.1 wt %, more than 99.2 wt %, more
than 99.3 wt %, more than 99.4 wt %, more than 99.5 wt %, more than
99.6 wt %, more than 99.7 wt %, more than 99.8 wt %, or more than
99.9 wt % of the cysteine is monomeric.
[0032] The cysteine compositions or solutions disclosed herein may
be dispensed into glass vials having a thin layer of silica on the
interior surface (e.g., silica-lined vials), and wherein the
composition or solution is overlaid with nitrogen prior to sealing
of the glass vial. The glass vial may contain 4 mL, 6 mL, 10 mL, 15
mL, 20 mL, 30 mL, 40 mL, or 50 mL of the cysteine composition or
solution. In specific embodiments, the vial contains 10 mL of
cysteine composition or solution. For example, a vial may contain
10 mL of a 50 mg/mL solution of cysteine hydrochloride monohydrate
in water adjusted to pH 1.0 to 2.5. In certain embodiments, more
than one vial comprising the cysteine composition or solution is
packaged together for distribution. For example, a package may
comprise five 10-mL vials of cysteine composition or solution as
disclosed herein.
[0033] The cysteine compositions or solutions, when dispensed into
vials as described above, are substantially stable for at least one
month, at least three months, at least six months, at least nine
months, at least 12 months, at least 18 months, or at least 24
months when stored at 25.degree. C. and 60% relative humidity or
40.degree. C. and 75% relative humidity. Substantially stable means
that the level of aluminum does not substantially change (e.g.,
does not increase) from the initial level present when the
composition or solution was dispensed into the vial, and the
composition or solution remains free of visible particulate matter.
In particular embodiments, the composition or solution is
substantially stable i) for at least 18 months when stored at
25.degree. C. and 60% relative humidity or ii) for at least 6
months when stored at 40.degree. C. and 75% relative humidity.
[0034] The cysteine compositions or solutions provided herein may
be formulated in a variety of dosage forms. Suitable dosage forms
include injectable formulations, or oral formulations. In some
embodiments, the injectable formulation may be for parenteral
administration, e.g., intravenous, intramuscular, intrathecal, and
the like. In specific embodiments, the injectable formulation may
be for intravenous administration.
[0035] In exemplary embodiments, the cysteine composition is a
solution comprising 50 mg of cysteine hydrochloride monohydrate
dissolved in one mL of water for injection that is adjusted to pH
1.0 to 2.5, and the solution of cysteine hydrochloride contains
less than 145 .mu.g/L of aluminum. US Pharmacopeia (USP) calls for
not less than 85% and no more than 115% of the labeled amount of
cysteine hydrochloride monohydrate. Thus, cysteine compositions
labeled with a concentration of 50 mg/mL may contain from 42.5
mg/mL to 57.5 mg/mL of cysteine hydrochloride monohydrate.
[0036] The 50 mg/mL solution of cysteine hydrochloride monohydrate
may have a dissolved oxygen content of less than 2 mg/L. The 50
mg/mL solution of cysteine hydrochloride monohydrate is devoid of
visible particulate matter. In some embodiments, 10 mL of the 50
mg/mL cysteine hydrochloride monohydrate is packaged in a
silica-lined glass vial. The 50 mg/mL solution of cysteine
hydrochloride monohydrate is diluted prior to use (e.g., for use as
an additive in total parenteral nutrition formulations). In
general, the vial comprising the 50 mg/mL solution of cysteine
hydrochloride monohydrate is stored at 20.degree. C. to 25.degree.
C. (68.degree. F. to 77.degree. F.). In some embodiments,
excursions to 15.degree. C. to 30.degree. C. (59.degree. F. to
86.degree. F.) are permitted [see USP Controlled Room Temperature].
In one embodiment, the vial is not frozen.
(II) Processes for Preparing Cysteine Compositions
[0037] Another aspect of the present disclosure encompasses
processes for preparing the cysteine compositions disclosed herein.
In general, the processes comprise (a) adding cysteine powder to
water to form a mixture, (b) mixing the mixture until dissolution
is complete, thereby forming a clear solution, (c) filtering the
solution to form a filtered solution, and (d) dispensing the
filtered solution into containers or vials, which are then sealed.
To minimize oxygen exposure, all media (water, hydrochloric acid
(HCl), sodium hydroxide) may be degassed by sparging with nitrogen,
and the steps of the process may be conducted under nitrogen
atmosphere (e.g., via use of a mixing bag or atmosbag under
constant flow of nitrogen). All steps of the process generally are
performed at ambient (e.g., room) temperature.
[0038] The water used in step (a) may be degassed to the desired
level of dissolved oxygen by sparging with nitrogen. The degassed
water may be acidified by adding HCl, wherein the HCl may have been
degassed by sparging with nitrogen. The amount of HCl added to the
water may vary. In some embodiments, the water may be acidified by
adding 1/8th molar equivalent of HCl. In other embodiments, the
acidified water may be adjusted to have a concentration of 0.01N
HCl. In additional embodiments, the acidified water may have a pH
of about 1.1. The level of dissolved oxygen and the pH of the
acidified water may be monitored during this step of the process.
The appropriate mass of cysteine powder is added a volume of
acidified water that is close to the final volume needed to provide
the desired concentration (thus, the concentration of cysteine at
dissolution is nearly the same as the final desired concentration
of cysteine).
[0039] The duration of mixing at step (b) may vary depending upon,
for example, the concentration of cysteine, the volume of the
mixture, and the like. The duration of mixing is generally just
long enough to ensure complete dissolution of the cysteine,
resulting in formation of a clear solution. Extended mixing times
may lead to increased levels of dissolved oxygen in the resulting
solution. The mixture may be mixed by stirring with a mixing blade
or paddle. The rate of stirring can and will vary depending upon,
for example, the concentration of cysteine, the volume of the
mixture, and so forth. Upon complete dissolution, the pH of the
clear solution may be monitored, and the pH may be adjusted by the
addition of degassed HCl or degassed NaOH. The volume (or weight)
of the clear solution may be adjusted such that the final
concentration of cysteine is at the desired level. For example,
additional degassed water may be added to the clear solution. As
mentioned above, the mixing/dissolution step may be performed under
nitrogen flow.
[0040] Step (c) comprises filtering the cysteine solution through
at least one 0.22 .mu.m filter. The filtration step may reduce the
bioburden level in the cysteine solution and sterilize the
solution. The filter may comprise polyvinylidene difluoride (PVDF),
polyethersulfone (PES), cellulose nitrate, cellulose acetate or
nylon. In specific embodiments, step (c) comprises serial
filtration through two PVDF 0.22 .mu.m filters. The filtration step
may be performed under nitrogen flow.
[0041] The final step comprises dispensing the filtered cysteine
solution into containers and sealing the containers. In general,
the filtered cysteine solution is dispensed into silica-lined glass
vials. The size or capacity of the vials may vary, and the volume
of filtered cysteine solution dispensed into a vial may vary. In
various embodiments, the volume of solution dispensed in a vial may
be 4 mL, 6 mL, 10 mL, 15 mL, 20 mL, 30 mL, 40 mL, or 50 mL. In
specific embodiments, vials are filled with 10 mL of the filtered
cysteine solution. The filling may be performed under nitrogen
flow. Once filled with the appropriate volume, the cysteine
solution generally is overlaid with nitrogen, and then the vial is
sealed using conventional means. For example, the vial may be
sealed with a cap, e.g., a cap comprising a pierceable septum. The
filled vials generally are inspected to confirm the correct fill
volume, check integrity of the sealing system, and confirm absence
of particulates (e.g., visible cystine particles, fiber particles,
dust particles). Vials not meeting these criteria are rejected.
[0042] The final vials that pass inspection may be packaged in
multi-unit packages. For example, five 10 mL vials may be packaged
into one package. Different numbers of vials and different sized
vials can readily be packaged into multi-unit packages.
(III) Methods of Using Cysteine Compositions
[0043] Still another aspect of the present disclosure encompasses
methods of using cysteine compositions disclosed herein to provide
cysteine to individuals in need thereof. The disclosed cysteine
compositions may be used to meet amino acid nutritional
requirements in individuals receiving total parenteral nutrition.
Provided herein are methods for providing cysteine to individuals
in need thereof. In these methods, an injectable composition that
includes cysteine is prepared by admixing a cysteine composition
described herein with an amino acid injection composition. The
injectable composition is then administered to the individual.
[0044] In general, the cysteine compositions disclosed herein can
be used to meet amino acid nutritional requirements in individuals
receiving total parenteral nutrition. In general, total parenteral
nutrition tends to be administered intravenously (e.g., via central
venous infusion). A cysteine composition described herein can be
added to crystalline amino acid solution for administration as
total parenteral nutrition following appropriate dilution. The
crystalline amino acid solution generally includes the nine
essential amino acids and may further comprise nonessential amino
acids. Total parenteral nutrition can deliver a mixture of fluid,
electrolytes, sugars, amino acids, vitamins, minerals, and often
lipids to individual in need thereof.
[0045] Cysteine compositions disclosed herein may be provided to
individuals who are unable to receive feedings or fluids by mouth
or are unable to absorb nutrients through the gastrointestinal
tract. In specific embodiments, the individual may be a neonate,
which is an infant that is 28 days of less of age. In other
embodiments, the individual may be a preterm infant, who is less
than 28 days after term. In still other embodiments, the cysteine
compositions may be administered to individuals with severe liver
disease who may have impairment in the enzymatic conversion of
cysteine. In such embodiments, the individual may be an infant,
toddler or child less than 18 years of age.
[0046] The dose of cysteine can vary, depending (for example) on
the total amount of amino acids administered to the individual. In
general, the total amount of amino acids administered to a neonate
via a total parenteral formulation may not exceed 3.5 grams of
amino acids per kg per day. In general, the dose of cysteine may
range from about 10 mg to about 50 mg of cysteine per gram of amino
acid. In certain embodiments, the dose may be within the range of
15-20 mg of cysteine per gram of amino acid, the range of about
20-25 mg of cysteine per gram of amino acid, the range of about
25-30 mg of cysteine per gram of amino acid, or the range of about
30-40 mg of cysteine per gram of amino acid. In specific
embodiments, the dose may be about 15 mg, about 22 mg, about 30 mg,
or about 40 mg of cysteine per gram of amino acid.
[0047] In specific embodiments, cysteine compositions disclosed
herein may be diluted with a solution of crystalline amino acids
prior to administration to neonates receiving total parenteral
nutrition. For example, an amino acid admixture may be prepared by
adding the appropriate volume of a 50 mg/mL solution of cysteine
hydrochloride monohydrate to a crystalline amino acid solution to
provide cysteine at 2.2% of the total amino acids being supplied.
Thus, a neonate receiving amino acids at 2.5 g/kg/day would be
provided 55 mg/kg/day of cysteine or 1.1 mL/kg/day of 50 mg/mL
cysteine solution; and a neonate receiving 3.0 g/kg/day of amino
acids would be provided 1.3 mL/kg/day of 50 mg/mL cysteine
solution.
[0048] Generally, the injectable composition may be prepared by
aseptically diluting the amino acid admixture with appropriate
caloric substrates (e.g., to supply the patient with adequate
energy). The admixture may be inspected visually for particulate
matter and discoloration prior to administration. The admixture may
be refrigerated until ready for use and typically would be used
within 24 hours of mixing. The injectable composition comprising
cysteine may be administered intravenously. Those skilled in the
art are familiar with means for administration as well as means for
determining the rate of administration.
Definitions
[0049] When introducing elements of the embodiments described
herein, the articles "a", "an", "the" and "said" are intended to
mean that there are one or more of the elements. The terms
"comprising", "including" and "having" are intended to be inclusive
and mean that there may be additional elements other than the
listed elements.
[0050] The term "about," generally is meant to encompass deviations
of plus or minus five percent. However, when used in reference to a
labeled pharmaceutical composition, it encompasses deviations of
plus or minus fifteen percent (per USP guidelines). For example, a
cysteine composition labeled with a concentration of 50 mg/mL may
contain from 42.5 mg/mL to 57.5 mg/mL of cysteine hydrochloride
monohydrate.
EXAMPLES
[0051] The following examples illustrate various embodiments of the
present disclosure.
Example 1: Reduction in Aluminum Levels
[0052] Solutions of cysteine hydrochloride tend to be acidic (e.g.,
have a pH from .about.1.0 to 2.5), suggesting that they could leach
aluminum from standard borosilicate glass vials. To address this
issue, several vial types were surveyed in a study (summarized in
Table 1). In this study, aluminum content in 50 mg/mL solution of
cysteine HCl was compared across various vials that were or were
not subjected to terminal sterilization via heating. The study also
evaluated aluminum content in the unapproved reference drug. The
study showed that the use of Type I+ vials, which have an interior
silica lining, greatly limited the aluminum content. In the study,
aluminum contents in Type I+ vials were observed to be <10
.mu.g/L for all samples and conditions tested, which is 2-3 orders
of magnitude lower than observed for the reference drug product and
for other unlined vial types.
TABLE-US-00001 TABLE 1 Summary of aluminum content results in
different vial types subjected to different terminal sterilization
conditions Time Aluminum Vial Treated at Content, Sample size Vial
Type 121.degree. C. .mu.g/L Bulk AV- NA NA None 6.2 FFP-17-0006
AV-FFP-17- 10-mL Type 1+, lined None 4.2 0006 10-mL Type 1,
unlined, None 33.9 molded 50-mL Type 1, unlined, None 17.4 molded A
50-mL Type 1, unlined, None 26.3 molded B 10-mL Type 1+, lined 20
min 7.3 10-mL Type 1, unlined, 20 min 60.9 molded 50-mL Type 1,
unlined, 20 min 52.5 molded A 50-mL Type 1, unlined, 20 min 91.3
molded B Reference 10-mL Unknown None 427 drug 10-mL Unknown 20 min
560
Example 2: Identification of Particulate Matter as Cystine
[0053] During scale-up production of cysteine hydrochloride, about
40-60% the API-filled vials were rejected during visual inspection
because solid particles appeared after the vials were stored for
several days at room temperature. The colorless, flat, irregularly
shaped, crystalline-appearing particles were identified as cystine
by a combination of Fourier Transform Infrared Spectroscopy (FTIR)
and stereomicroscopy techniques.
Example 3: Solubility of Cysteine and Cystine
[0054] Cystine, a sulfur-sulfur dimer of cysteine, can form in the
presence of oxygen (air) in cysteine solutions. Cystine, especially
the free base, is several orders of magnitude less soluble in
aqueous solutions than cysteine, and the solubility of cystine
decreases as the pH increases. Thus, if enough cystine dimer is
formed in the cysteine hydrochloride Injection drug product, the
cystine may precipitate, or form undesirable particulates, in the
solution. A summary of the solubility of the cystine and cysteine
species is shown in Table 2.
TABLE-US-00002 TABLE 2 Summary of solubility results for cysteine
and cystine species Solubility (mg/mL) at Species Media 22.degree.
C. Cystine free base Water 0.14 Cysteine HCl Injection, 0.59 50
mg/mL Cystine dihydrochloride Water 1.04 Cysteine HCl Injection,
9.93 50 mg/mL Cysteine free base Water 18.74 Cysteine hydrochloride
Water 493.99
[0055] Furthermore, the solubility of cystine increases as the pH
decreases. For example, at pH 1.4, the solubility of cystine is
approximately 1 mg/ml, whereas at pH 1.0, its solubility increases
to approximately 4 mg/mL (Carta et al., J Chem Eng Data, 1996,
41(3):414-417).
Example 4: Solubilization at 50 mg/mL at pH 1.1 or pH 1.3
[0056] To determine whether the formation of cystine particulates
could be reduced, the process for preparing cysteine hydrochloride
injection was modified by degassing solutions to reduce the levels
of oxygen and adjusting the pH to a lower level. In particular,
water was degassed by nitrogen sparging to reach various levels of
dissolved oxygen (DO): 0.2 mg/L, 2.6 mg/L, and 7.0 mg/L. The pH of
the final solution was 1.3-1.4. One part of the solution was
adjusted to pH 1.1 by addition of 5N HCl (which had been degassed
by nitrogen sparging). The water (at the different pH levels) was
added to cysteine hydrochloride monohydrate powder at 50 mg/mL
(under N.sub.2 flow). The solution was stirred until dissolution
was complete and the solution was clear. The solution was filtered,
dispensed into (type 1+silica lined) vials, and sealed under
nitrogen. In order to have a reference at a saturated oxygen value,
one vial of each series was exposed to air for several seconds
before sealing. The protocol is outlined below in Table 3.
TABLE-US-00003 TABLE 3 Solubilization at 50 mg/mL Opened in the lab
before pH adjustment % DO/DO mg/L sealing No pH adjustment
2.6%/0.22 mg/L No (~1.3) No Yes Kept open in the lab 29.4%/2.55
mg/L No No Yes Aerated water No 81.0%/7.02 mg/L No pH adjustment
2.6%/0.22 mg/L No to ~1.1 No Yes 29.4%/2.55 mg/L No No Yes
[0057] No particles were visible after 40 days in the vials sealed
under nitrogen whatever the level of dissolved oxygen (DO) and
whatever the pH. Particle formation was only observed for the vial
left open in the lab. In increase in the level of dissolved oxygen
is expected when vials are exposed to air.
Example 5: Solubilization at 58 mg/mL at pH 1.1, pH 1.3, or pH
1.5
[0058] Generally, cysteine HCl is prepared at an intermediate
concentration (.about.58 mg/mL) and then adjusted to 50 mg/mL prior
to filtration and bottling. Cysteine hydrochloride monohydrate
powder was added under nitrogen flow to water degassed by nitrogen
sparging (to reach 0.2 mg/L or 2.4 mg/L of dissolved oxygen). The
pH was about 1.3 in the final solution. In one fraction, the pH of
the solution was adjusted to pH 1.1 by addition of 5N HCl
(previously degassed by nitrogen sparging). In another fraction,
the pH was adjusted to 1.5 with 0.1N NOH (previously degassed). The
solutions were stirred until dissolution was complete, diluted to
50 mg/ml with water (previously degassed), filtered, and filled
into (lined) vials, which were then sealed under nitrogen. In order
to have a reference at a saturated oxygen value, one vial of each
series was exposed to air, and one vial of each series was kept
open in the lab.
TABLE-US-00004 TABLE 4 Solubilization at 58 mg/mL Opened in the lab
before pH adjustment % DO/DO mg/L sealing No pH adjustment (~1.3)
2.4%/0.22 mg/L Yes No No Kept open in the lab 27.3%/2.43 mg/L Yes
No No Kept open in the lab pH adjusted to ~1.1 2.4%/0.22 mg/L Yes
No No Kept open in the lab 27.3%/2.43 mg/L Yes No No Kept open in
the lab pH adjusted to ~1.3 2.4%/0.22 mg/L Yes No No Kept open in
the lab 27.3%/2.43 mg/L Yes No No Kept open in the lab
[0059] No particles were visible (observation over 80 days) in the
vials sealed under nitrogen whatever the level of dissolved oxygen
(DO) and whatever the pH. In contrast, many particles appeared in
samples exposed or kept open in air at pH 1.3 or 1.5 after 5 to 13
days (FIG. 1). A few particles were also observed after 25 days at
pH 1.1. HCl (5M) was added to the pH 1.3 samples exposed to air
(many particles) to decrease the pH to 1.1. A complete dissolution
of the particles was observed after 8 hr without stirring,
presumably due to re-solubilization of cystine at the lower pH.
[0060] The following conclusion can be drawn from the data of
Examples 4 and 5: (i) air exposure and oxidation foster particle
formation, (ii) acidic pH appears to slow down oxidation and
cystine precipitation, and (iii) an intermediate concentration of
58 mg/mL appears to promote particle formation.
Example 6: Comparative Study
[0061] A study was undertaken to directly compare (i) 50 mg/mL vs.
58 mg/mL dissolution concentration of cysteine HCl, (ii)
dissolution in water vs. dissolution in acidic water (addition of
5N HCl to obtain a final concentration of 0.01N HCl), and (iii) 15
min vs. 90 min duration of stirring during dissolution. All
experiments were carried out in parallel and launched the same day
using Type 1+silica-lined vials. All steps were performed under
nitrogen with low dissolved oxygen levels (less than 0.5 mg/L). For
each series, 3 vials were sealed under nitrogen and one vial was
exposed to air to assess accelerated oxidizing conditions.
[0062] No particles were observed after 66 days under any condition
for the vials sealed under nitrogen. In vials left open, particles
were observed after 7 days in those with no pH adjust and high
dissolution concentration (58 mg/mL). FIGS. 2A and 2B presents
images at 14 days in vials kept open in the lab. For these samples,
the duration of stirring increased the abundance of particles in
vials with higher pH (i.e., those without pH adjustment) (FIG. 2B).
On the contrary, decreasing the pH to about 1.1 helped prevent
formation of particles whatever the stirring duration (FIG.
2A).
[0063] In samples without pH adjustment and exposed to air for
longer than 14 days, particles were observed after 37 days in those
dissolved at 50 mg/mL and stirred for 90 min. Particles were
observed after 66 days in those dissolved at 50 mg/mL and stirred
for 15 min. In contrast, no particles were observed after 66 days
in samples with a more acidic pH (pH 1.1), regardless of
dissolution concentration and stirring duration.
[0064] From the studies described above, the manufacturing process
was modified to ensure that all steps were conducted in low oxygen
environment, all liquids were degassed to reduce dissolved oxygen
levels, and the initial water used to dissolve the cysteine was
acidified. Adopting these changes reduced the percentage of
rejected vials (e.g., containing particulates) per batch as high as
about 50% to less than about 0.05%.
Example 7: Stability Studies
[0065] Vials of 50 mg/mL of cysteine HCl from various batches were
stored at room temperature and assayed at selected time points. The
data are presented below in Table 5. (1 ppb=1 .mu.g/L)
TABLE-US-00005 TABLE 5 Stability at room temperature Sample Time
Cysteine Cystine Aluminum Lab Batch, lined vial 18 mo 100.8% 1.2%
<3 ppb Batch 1700141, unlined vial 12 mo 99.7% 1.05% 182 ppb 18
mo 97.5% 1.23% 370 ppb Batch 1700196, unlined vial 6 mo 98.4% 0.84%
189 ppb 12 mo 98.2% 1.17% 273 ppb Batch 1800029, lined vial 6 mo
98.5% 0.83% <3 ppb 9 mo 97.8% 0.91% <3 ppb Batch 1800030,
lined vial 6 mo 98.6% 0.91% <3 ppb 9 mo 96.7% 0.98% <3 ppb
Batch 1800031, lined vial 6 mo 98.2% 1.00% <3 ppb 9 mo 95.6%
1.10% <3 ppb Lab batch, low pH, lined vial 3 mo 101.2% 0.19%
<3 ppb Batch 1800172, lined vial 0 mo 99.2% 0.46% <3 ppb
Batch 1800229, lined vial 0 mo 98.1% 0.66% <3 ppb
* * * * *