U.S. patent application number 15/474217 was filed with the patent office on 2017-07-20 for formulations of vancomycin.
The applicant listed for this patent is SCIDOSE, LLC. Invention is credited to Nagesh PALEPU.
Application Number | 20170202906 15/474217 |
Document ID | / |
Family ID | 51989452 |
Filed Date | 2017-07-20 |
United States Patent
Application |
20170202906 |
Kind Code |
A1 |
PALEPU; Nagesh |
July 20, 2017 |
FORMULATIONS OF VANCOMYCIN
Abstract
Vancomycin-containing compositions substantially free of
precipitation after at least about 12 months of storage at
refrigerated or ambient conditions are disclosed. The compositions
include vancomycin or a pharmaceutically acceptable salt thereof; a
polar solvent including propylene glycol, polyethylene glycol and
mixtures thereof; lactic acid, a lactate salt, or mixtures thereof;
and optionally, a pH adjuster in an amount sufficient to maintain a
pH of the compositions at from about 3 to about 8.
Inventors: |
PALEPU; Nagesh;
(Southampton, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SCIDOSE, LLC |
Amherst |
MA |
US |
|
|
Family ID: |
51989452 |
Appl. No.: |
15/474217 |
Filed: |
March 30, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14894215 |
Nov 25, 2015 |
9616098 |
|
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PCT/US14/40396 |
May 30, 2014 |
|
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15474217 |
|
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61828739 |
May 30, 2013 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0019 20130101;
A61K 9/08 20130101; A61P 31/04 20180101; A61K 47/02 20130101; A61K
47/12 20130101; A61K 38/12 20130101; A61K 38/14 20130101; A61K
47/10 20130101 |
International
Class: |
A61K 38/14 20060101
A61K038/14; A61K 9/08 20060101 A61K009/08; A61K 47/02 20060101
A61K047/02; A61K 47/10 20060101 A61K047/10; A61K 47/12 20060101
A61K047/12 |
Claims
1. A vancomycin-containing composition, comprising: a) about 25
mg/mL to about 150 mg/mL vancomycin or a pharmaceutically
acceptable salt thereof; and b) a pharmaceutically acceptable fluid
having a pH of about 3 to about 8, comprising: i) about 25% (v/v)
to about 50% (v/v) of a polar solvent comprising propylene glycol,
polyethylene glycol or mixtures thereof; and ii) about 0.25 mmole
to about 0.94 mmole of lactic acid, lactate or mixtures thereof per
mL of pharmaceutically acceptable fluid; wherein the
vancomycin-containing composition has less than about 6%
degradation of vancomycin B, as determined by HPLC at a wavelength
of 280nm, after at least about 12 months of storage at a
temperature of from about 5.degree. C. to about 25.degree. C.
2. The vancomycin-containing composition of claim 1, wherein the pH
of said vancomycin-containing composition is from about 4 to about
6.
3. The vancomycin-containing composition of claim 1, wherein the pH
of said vancomycin-containing composition is about 5.5.
4. The vancomycin-containing composition of claim 1, further
comprising a pH adjustor.
5. The vancomycin-containing composition of claim 4, wherein the pH
adjustor is a base or conjugate of an acid.
6. The vancomycin-containing composition of claim 5, wherein the
base comprises either an amine buffer, sodium hydroxide, calcium
hydroxide, or mixtures thereof.
7. The vancomycin-containing composition of claim 5, wherein the
base is sodium hydroxide.
8. The vancomycin-containing composition of claim 4, wherein the pH
adjustor is an acid.
9. The vancomycin-containing composition of claim 8, wherein the
acid comprises either acetic acid, citric acid, hydrochloric acid,
phosphoric acid, malic acid, or mixtures thereof.
10. The vancomycin-containing composition of claim 9, wherein the
acid comprises hydrochloric acid.
11. The vancomycin-containing composition of claim 1, wherein the
pharmaceutically acceptable fluid comprises about 0.75 mmole to
about 1 mole of lactic acid, lactate or mixtures thereof per mL of
pharmaceutically acceptable fluid.
12. The vancomycin-containing composition of claim 1, wherein the
pharmaceutically acceptable fluid comprises about 0.75 mmole of
lactic acid, lactate or mixtures thereof per mL of pharmaceutically
acceptable fluid.
13. The vancomycin-containing composition of claim 1, wherein the
pharmaceutically acceptable fluid comprises about 1 mole of lactic
acid, lactate or mixtures thereof per mL of pharmaceutically
acceptable fluid.
14. The vancomycin-containing composition of claim 1, wherein the
polar solvent is propylene glycol.
15. The vancomycin-containing composition of claim 14, wherein the
pharmaceutically acceptable fluid comprises about 0.25 to about
0.625 mmole of lactic acid, lactate or mixtures thereof per mL of
pharmaceutically acceptable fluid and about 50% (v/v) propylene
glycol.
16. The vancomycin-containing composition of claim 14, wherein the
pharmaceutically acceptable fluid comprises about 0.3 mmole to
about 1.0 mole of lactic acid, lactate or mixtures thereof per mL
of pharmaceutically acceptable fluid and about 25% (v/v) propylene
glycol.
17. The vancomycin-containing composition of claim 1, wherein the
polar solvent is polyethylene glycol.
18. The vancomycin-containing composition of claim 17, wherein the
pharmaceutically acceptable fluid comprises about 0.25mmole to
about 0.62 mmole of lactic acid, lactate or mixtures thereof per mL
of pharmaceutically acceptable fluid and about 50% (v/v)
polyethylene glycol.
19. The vancomycin-containing composition of claim 1, wherein the
composition is substantially free of precipitation after at least
about 12 months of storage at a temperature of from about 5.degree.
C. to about 25.degree. C.
20. The vancomycin-containing composition of claim 1, wherein the
amount of vancomycin is from about 75 mg/mL to about 100 mg/mL.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser.
No. 14/894,215 filed Nov. 25, 2015, which in turn is a 371 U.S.
national stage of PCT International Application No.
PCT/US2014/040396, filed May 30, 2014, which claims the benefit of
U.S. Provisional Application Ser. No. 61/828,739 filed May 30,
2013, the disclosure of each of which is incorporated by reference
herein.
BACKGROUND OF THE INVENTION
[0002] Vancomycin is a glycopeptide antibiotic represented by the
following structural formula (I):
##STR00001##
[0003] Vancomycin is used in the prophylaxis and treatment of
infections caused by Gram-positive bacteria. Vancomycin is used in
the treatment of methicillin-resistant Staphylococcus aureus (MRSA)
and Methicillin-susceptible Staphylococcus aureus (MSSA), and to
treat patients who are penicillin-resistant. Vancomycin HCl is
commercially available inter alia, as a frozen premixed
formulation, which can be used for intravenous administration after
thawing.
[0004] Vancomycin exhibits premature degradation after
reconstitution of the lyophilized product. Vancomycin is stable in
water for approximately 24 hours after reconstitution, and is
therefore, not suitable for long-term storage in liquid form. There
is a need for vancomycin formulations with increased stability. The
present invention addresses this need.
SUMMARY OF THE INVENTION
[0005] In some aspects of the invention, the liquid
vancomycin-containing compositions include a) vancomycin or a
pharmaceutically acceptable salt thereof; b) a polar solvent
comprising propylene glycol, polyethylene glycol, or mixtures
thereof; c) lactic acid, a lactate salt or mixtures thereof; and
optionally d) a pH adjustor, in an amount sufficient to maintain a
pH of the vancomycin-containing composition at from about 3 to
about 8.
[0006] In some aspects of the invention, the amount of vancomycin
included in the compositions, as calculated on the basis of the HC1
salt, is from about 25 mg/mL to about 150 mg/mL. In other aspects
of the invention, the amount of vancomycin as calculated on the
basis of the HCl salt included in the compositions is from about
2.5 mg/mL to about 15 mg/mL.
[0007] In some aspects of the invention, the compositions include
from about 25% (v/v) to about 100% (v/v) of a polar solvent, more
preferably from about 25% (v/v) to about 50% (v/v). In other
aspects of the invention, the compositions include from about 1.20%
(v/v) to about 5% (v/v) of a polar solvent.
[0008] Still further aspects of the invention include methods of
treatment using vancomycin-containing compositions and kits
including the same.
[0009] One of the advantages of the liquid compositions prepared
according to the current invention is that they have substantially
improved long-term stability. The inventive vancomycin-containing
compositions are substantially free of precipitation after at least
about 24 months of storage at a temperature of from about 5.degree.
C. to about 25.degree. C. The inventive vancomycin-containing
compositions also exhibit less than about 6% degradation of
vancomycin B, as determined by high performance liquid
chromatography ("HPLC") at a wavelength of 280nm, after at least
about 18 months of storage at a temperature of from about 5.degree.
C. to about 25.degree. C. As used herein, the vancomycin
concentration is measured using the United States Pharmacopeia
(USP) official monograph for vancomycin for injection described in
USP 36, the contents of which are incorporated by reference
herein.
DETAILED DESCRIPTION OF THE INVENTION
[0010] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of ordinary skill in the art to which this invention belongs. In
the event that there is a plurality of definitions for a term
herein, those in this section prevail unless stated otherwise.
[0011] As used herein, "relative retention time" ("RRT") is
calculated by dividing the retention time of the peak of interest
by the retention time of the main peak. Any peak with an RRT <1
elutes before the main peak, and any peak with an RRT >1 elutes
after the main peak.
[0012] For purposes of the present invention, "substantially free
of precipitation" shall be understood to include
vancomycin-containing compositions in which precipitation is not
visually observed after a period of at least about 12 months at a
temperature of from about 5.degree. C. to about 25.degree. C.
"Substantially free of total impurities" shall be understood to
include vancomycin-containing compositions which exhibit less than
about 6% degradation of vancomycin B, as determined by HPLC at a
wavelength of 280nm, after at least about 12 months of storage at a
temperature of from about 5.degree. C. to about 25.degree. C. The
amount of impurities is further calculated as being based upon the
original amount vancomycin B (or salt thereof) being present in the
composition or formulation. In accordance with the USP official
monograph for vancomycin, the concentration of vancomycin is
determined by measuring the amount of vancomycin B by HPLC at a
wavelength of 280 nm. For the detailed procedure used to calculate
vancomycin B, refer to the USP monograph for vancomycin. In some
examples, a normalized loss of vancomycin B may be calculated by
dividing the concentration of vancomycin B at the testing point by
the initial concentration of vancomycin B, and then multiplying by
100.
[0013] For purposes of the present invention, a "pharmaceutically
acceptable fluid" is a fluid which is suitable for pharmaceutical
use, for example but not limited to solvents, vehicles, large
volume parenterals (LVPs) such as normal saline (i.e., 0.9% sodium
chloride) or 5% dextrose in water ("D5W"), and/or additional
diluents, if desired, etc.
[0014] In accordance with one aspect of the invention, there are
provided vancomycin-containing compositions including: [0015] a)
about 25 mg/mL to about 150 mg/mL vancomycin or a pharmaceutically
acceptable salt thereof; and [0016] b) a pharmaceutically
acceptable fluid having a pH of about 3 to about 8, comprising:
[0017] i) about 25% (v/v) to about 50% (v/v) of a polar solvent
comprising propylene glycol, polyethylene glycol, or mixtures
thereof; [0018] ii) about 0.25 mmole to about 0.94 mmole of lactic
acid, lactate or mixtures thereof per ml of pharmaceutically
acceptable fluid, which can be prepared, for example, by using
about 50% (v/v) to about 75% (v/v) of a solution comprising 0.5M to
1.25M lactate. In terms of mass amount, this may include, for
example, about 22% (w/v) to about 85% (w/v) lactic acid per se, or
a similar lactate concentration adjusted appropriately when using a
lactate salt or mixtures thereof); and [0019] iii) optionally, a pH
adjustor in an amount sufficient to maintain a pH of the
vancomycin-containing composition at from about 3 to about 8.
[0020] The inventive compositions are substantially free of visible
precipitation after at least about 12 months of storage at a
temperature of from about 5.degree. C. to about 25.degree. C.
Preferably, the vancomycin-containing compositions are
substantially free of precipitation for at least 24 months. The
total impurities in the inventive compositions resulting from the
degradation of vancomycin in the compositions is less than about 6%
degradation of vancomycin B, as determined by HPLC at a wavelength
of 280 nm, after at least about 12 months of storage at a
temperature of from about 5.degree. C. to about 25.degree. C.
Preferably, the vancomycin-containing compositions are stable for
at least 24 months of storage at a temperature of from about
5.degree. C. to about 25.degree. C. Without being bound by theory,
it is believed that the surprising long-term stability of solutions
prepared according to the present invention arises at least in part
from the interaction between lactic acid (or the lactate molecule
used in certain embodiments), the polar solvent (e.g., propylene
glycol) and vancomycin.
[0021] In some aspects of the invention, the vancomycin is
preferably present in the formulation as an HCl salt.
[0022] In some aspects of the invention, the vancomycin
concentration calculated on the basis of the HCl salt in the
inventive compositions is from about 25 mg/mL to about 150 mg/mL,
preferably about 75 mg/mL to about 100 mg/mL. Some preferred
concentrations of vancomycin include, for example, about 50 mg/mL
or 100 mg/mL. In alternative aspects, the amount of vancomycin is
outside these ranges but the amounts will be sufficient for single
or multiple administrations of dosages generally regarded as
effective amounts.
[0023] The compositions of the present invention can be maintained
at a pH of from about 3 to about 8. Preferably, the composition is
maintained at a pH of from about 4 to about 6. In at least one
embodiment, the pH is about 5.5.
[0024] In some embodiments of the invention, an optional pH
adjustor is included in the vancomycin-containing compositions. The
pH adjustor may take the form of one or more basic compounds or
conjugates of acids present in an amount sufficient to adjust or
maintain the pH of the composition to the range set forth above,
i.e., from about 3 to about 8, or to specific points in between
such as about 4 or about 6. One preferred base is sodium hydroxide.
Alternative bases are those commonly used in the art, including
TRIS or other amine buffers, sodium hydroxide and calcium
hydroxide. In some aspects the concentration of the base is about
1N or about 2N.
[0025] In some aspects of the invention, a lactate salt may be used
in conjunction with or in place of lactic acid. In these
embodiments, the optional pH adjustor may take the form of one or
more acids or conjugate bases present in sufficient quantity to
adjust the pH of the compositions to the ranges set forth above or
to maintain the pH within these ranges, i.e., from about 3 to about
8, or to specific points in between such as about 4 or about 6.
Alternative acids are those commonly used in the art, including but
not limited to acetic acid, citric acid, hydrochloric acid,
phosphoric acid and malic acid. In some aspects of the invention,
the concentration of lactic acid added either as the acid or as a
salt is set to an appropriate level to obtain a stabilizing effect.
For example, but not limited to, the compositions may comprise the
addition of pre-made lactic acid solution, which may be from about
0.25M to about 1.5M. Preferably, the concentration of lactic acid
solution used is from about 0.5M to about 1.25M or from about 0.75M
to about 1M. More preferably, the concentration of the solution of
lactic acid is about 1M.
[0026] Thus, the resulting final concentration of the lactic acid,
lactate or mixtures thereof in the vancomycin-containing
compositions of the present invention is preferably from about 0.25
mmole to about 0.94 mmole of lactic acid, lactate or mixtures
thereof per mL of total vancomycin concentrate solution. This can
be restated as about 22 to about 85 mg lactic acid per mL of total
vancomycin concentrate solution. More preferably, the final
concentration of the lactic acid or lactate in the
vancomycin-containing compositions of the present invention is
about 0.75 mmole per mL of total vancomycin concentrate,
alternatively stated as 0.75M, or about 67 mg lactic acid per mL of
total vancomycin concentrate solution.
[0027] In some aspects of the invention, the amount of lactic acid
solution of 0.25M to 1.5M is added at about 50% (v/v) or about 75%
(v/v). The lactic acid can be the DL form, the D form or the L
form. Preferably, the DL form of lactic acid is used. Salts of
lactic acid can also be added in conjunction with or in place of
lactic acid at equivalent molar amounts that can easily be
determined by one skilled in the art.
[0028] In several embodiments of the invention, the compositions
include a polar solvent comprising propylene glycol, polyethylene
glycol, or mixtures thereof. In some preferred aspects, the polar
solvent is propylene glycol (PG) or polyethylene glycol (PEG)
alone. For example, the compositions may include about 50% (v/v) of
a lactic acid solution and about 50% (v/v) propylene glycol.
Alternatively, the compositions may include about 75% (v/v) of a
lactic acid solution and about 25% (v/v) propylene glycol. In
another embodiment, the compositions may include about 50% (v/v) of
a lactic acid solution and about 50% (v/v) polyethylene glycol. The
amount of lactic acid solution and PG or PEG can also be varied
within these ranges, i.e., the ratio of the lactic acid solution:PG
or PEG in the compositions can range from about 50:50 to about
75:25. The molecular weight of the PEG will be within the range of
pharmaceutically acceptable weights although PEG 400 is preferred
in many aspects of the invention.
[0029] In some aspects of the invention, an antioxidant or free
radical scavenging agent, e.g., methionine, is further included in
the vancomycin-containing compositions. Other
pharmaceutically-suitable antioxidants or free radical scavengers
known in the art may be used, e.g., EDTA, citric acid, ascorbic
acid, butylated hydroxytoluene (BHT), butylated hydroxy anisole
(BHA), sodium sulfite, p-amino benzoic acid, glutathione, propyl
gallate, cysteine, methionine and N-acetyl cysteine.
[0030] In view of the foregoing, some preferred
vancomycin-containing compositions in accordance with the invention
include: [0031] I. a) vancomycin or a pharmaceutically acceptable
salt thereof, in an amount of about 50 mg/mL or 100 mg/mL; and
[0032] b) a pharmaceutically acceptable fluid having a pH of about
3 to about 8, comprising: [0033] i) about 25% (v/v) propylene
glycol; and [0034] ii) about 0.75 mmole of lactic acid, lactate or
mixtures thereof per mL of pharmaceutically acceptable fluid,
produced for example by adding about 75% (v/v) of 1M lactic acid or
lactate solution; and [0035] iii) sodium hydroxide in an amount
sufficient to maintain the pH of said vancomycin-containing
composition at about 5.5; [0036] II. a) vancomycin or a
pharmaceutically acceptable salt thereof, in an amount of about 50
mg/mL or 100 mg/mL; and [0037] b) a pharmaceutically acceptable
fluid having a pH of about 3 to about 8, comprising: [0038] i)
about 50% (v/v) propylene glycol; and [0039] ii) about 0.5 mmole of
lactic acid, lactate or mixtures thereof per mL of pharmaceutically
acceptable fluid, produced for example by adding about 50% (v/v) 1M
lactic acid or lactate solution; and [0040] iii) sodium hydroxide
in an amount sufficient to maintain the pH of said
vancomycin-containing composition at about 5.5; and [0041] III. a)
vancomycin or a pharmaceutically acceptable salt thereof, in an
amount of about 50 mg/mL or 100 mg/mL; and [0042] b) a
pharmaceutically acceptable fluid having a pH of about 3 to about
8, comprising: [0043] i) about 50% (v/v) polyethylene glycol;
[0044] ii) about 0.5 mmole of lactic acid, lactate or mixtures
thereof per mL of pharmaceutically acceptable fluid, produced for
example by adding about 50% (v/v) of a 1M lactic acid or lactate
solution; and [0045] iii) sodium hydroxide in an amount sufficient
to maintain a pH of said vancomycin-containing composition at about
5.5.
[0046] Each of these compositions have the same stability profiles
already described.
[0047] Another embodiment of the invention includes methods of
treating a vancomycin-sensitive disease in mammals, i.e., a
bacterial infection. The methods include administering, to a mammal
in need thereof, an effective amount of a vancomycin-containing
composition described herein.
[0048] Since the active ingredient portion of the inventive
compositions is an FDA-approved drug, those of ordinary skill will
recognize that the doses of vancomycin employed in this aspect of
the invention will be the similar to those employed in any
treatment regimens designed for vancomycin as marketed. The patient
package insert for vancomycin HCl containing dosing information is
incorporated herein by reference. The methods of treatment also
include administering the inventive formulations for any purpose or
physical condition for which vancomycin has been found to be
useful. In general, the daily intravenous dose may be typically
from about 1 g to about 2 g, administered as about 250 mg to about
500 mg every 3 to 6 hours or as about 1 g every 12 hours.
[0049] Another embodiment of the invention includes methods of
preparing vancomycin-containing compositions described herein. The
methods include reconstituting lyophilized vancomycin to a
concentration of about 25 mg/mL to about 150 mg/mL in a polar
solvent comprising PG, PEG or mixtures thereof, lactic acid or a
lactate salt, and an optional pH adjustor (i.e., an acid or base or
combination thereof), in an amount sufficient to maintain the pH of
the composition at from about 3 to about 8. The steps are carried
out under pharmaceutically acceptable conditions for sterility and
manufacturing.
[0050] The compositions of the present invention may be packaged in
any suitable sterile vial, infusion bag or container fit for the
sterile or non-sterile storage of a pharmaceutical such as
vancomycin. Suitable containers can be of a size sufficient to hold
one or more doses of vancomycin. Within this aspect from about 2 mL
to about 200 mL of the inventive compositions are packaged as a
single dose or a multi-dose. Preferably, from about 25 mL to about
100 mL, or from about 50 mL to about 100 mL are packaged in a
container. More preferably, about 100 mL is packaged in a
container. In some aspects of the invention, the concentration of
the vancomycin-containing compositions in the containers is from
about 25 mg/mL to about 150 mg/mL. Preferably, the concentration of
the vancomycin-containing compositions is from about 50 mg/mL to
about 100 mg/mL. In other aspects, the containers include from one
to about 25 doses. Preferably, the containers include from about
four to about 20 doses, or from about 10 to about 20 doses. In some
aspects, the vancomycin-containing compositions of the present
invention will be packaged in a vial. Typical Type 1 glass vials
are considered appropriate for injection or infusion vials.
[0051] A further aspect of the invention includes a kit containing
the vancomycin-containing compositions described herein. As will be
appreciated by those of ordinary skill, the kit will contain at
least one pharmaceutically acceptable vial or container containing
one or more doses of the vancomycin-containing compositions as well
as other pharmaceutically necessary materials for storing and/or
administering the drug, including instructions for storage and use,
infusion bag or container with normal saline (i.e., 0.9% sodium
chloride) or 5% dextrose in water (D.sub.5W), and/or additional
diluents, if desired, etc.
[0052] In some embodiments, other excipients can also be added to
adjust various properties of the formulation. For example, one or
more antioxidants or free radical scavenging agents can be added to
assist in improving the color changes that might occur. A preferred
antioxidant is methionine, which can be added in a range of from
about 0.25 mg to about 10 mg/mL, or more preferably in some
embodiments at a concentration of about 4 mg to about 6 mg/mL.
[0053] In accordance with another aspect of the invention, there
are provided vancomycin-containing compositions including: [0054]
a) vancomycin or a pharmaceutically acceptable salt thereof, in an
amount of about 2.5 mg/mL to about 10 mg/mL; and [0055] b) a
pharmaceutically acceptable fluid having a pH of about 3 to about
8, comprising: [0056] i) about 1.20% (v/v) to about 5% (v/v) of a
polar solvent comprising propylene glycol, polyethylene glycol, and
mixtures thereof; and [0057] ii) about 0.04 mmole to about 1 mmole
of lactic acid, lactate or mixtures thereof per mL of
pharmaceutically acceptable fluid, produced for example, by using a
0.04M to 1M lactic acid, lactate solution or mixtures thereof
(e.g., about 3 mg to about 90 mg lactic acid or lactate per
milliliter of the vancomycin-containing composition); and [0058]
iii) optionally, a pH adjustor, in an amount sufficient to maintain
a pH of the vancomycin-containing composition at from about 3 to
about 8.
[0059] These more dilute compositions are substantially free of
precipitation after at least about 12 months of storage at a
temperature of from about 5.degree. C. to about 15.degree. C.
Preferably, the vancomycin-containing compositions are
substantially free of precipitation for at least 24 months. The
total impurities in the inventive compositions resulting from the
degradation of vancomycin in the compositions is less than about 6%
degradation of vancomycin B as determined by HPLC at a wavelength
of 280nm, after at least about 12 months of storage at a
temperature of from about 5.degree. C. to about 15.degree. C.
Preferably, the vancomycin-containing compositions are stable for
at least about 24 months of storage at a temperature of from about
5.degree. C. to about 15.degree. C.
[0060] In some embodiments, the concentration of lactic acid,
lactate or mixtures thereof, added to the compositions is from
0.05M to 0.15M (e.g., about 0.05 mmole to about 0.15 mmole per per
mL of the final vancomycin-containing composition). In another
embodiment, the concentration of lactic acid or lactate is from
0.05M to 0.1M (e.g., about 0.05 mmole to about 0.1 mmole per mL of
the final vancomycin-containing composition).The lactate can be
selected from the DL form, the D form, the L form or mixtures
thereof. Preferably, the DL form of lactic acid is used.
[0061] In other embodiments, the compositions include a polar
solvent comprising propylene glycol, polyethylene glycol or
mixtures thereof. Preferably, the polar solvent is propylene glycol
(PG) or polyethylene glycol (PEG). For example, the compositions
may include from about 1.25% (v/v) to about 2.5% (v/v) PG.
Preferably, the compositions include 1.25% (v/v) or 2.5% PG (v/v).
Alternatively, the compositions may include from about 1.25% (v/v)
to about 2.5% (v/v) PEG. The molecular weight of the PEG will be
within the range of pharmaceutically acceptable weights although
PEG 400 is preferred in many aspects of the invention.
[0062] In some embodiments, the amount of vancomycin calculated on
the basis of the HCl salt in the inventive compositions is
generally at concentrations of from about 2.5 mg/mL to about 10
mg/mL. In another embodiment of the invention, the vancomycin
concentration is from about 5 mg/mL to about 7.5 mg/mL. Preferably,
the vancomycin concentration is about 5 mg/mL.
[0063] In some embodiments, the compositions include a pH modifier
which is present in an amount sufficient to adjust the pH of the
compositions to the ranges set forth above, i.e., from about 3 to
about 8, or to specific points in between such as about 4 or about
6. Preferably, the pH of the vancomycin-containing compositions is
about 4.5 or about 5.5. Either acids or bases, or mixtures thereof,
may be used, depending on the need. If lactic acid is used as the
source of lactate, one preferred base is sodium hydroxide.
Alternative bases are those commonly used in the art, including
TRIS or other amine buffers, and calcium hydroxide. Acids may also
be used to titrate the pH to a point within the ranges described
above, e.g., where a lactate salt is used.
[0064] In some embodiments, other excipients can also be added to
adjust various properties of the formulation. For example,
antioxidants or free radical scavenging agents may be added to
assist in improving the color changes that might occur during
storage.
[0065] In some aspects of the invention, the inventive compositions
are maintained during storage and/or prior to use at a temperature
of from about 5.degree. C. to about 10.degree. C. More preferably,
the compositions are maintained at a temperature of about 5.degree.
C., i.e., under refrigerated conditions.
[0066] Preferred embodiments of the invention include
vancomycin-containing compositions which include: [0067] I. A
vancomycin-containing composition, comprising: [0068] a) vancomycin
or a pharmaceutically acceptable salt thereof, in an amount of
about 5 mg/mL; and [0069] b) a pharmaceutically acceptable fluid
having a pH of about 3 to about 8, comprising: [0070] i) about
1.25% (v/v) propylene glycol; [0071] ii) about 0.05 mmole lactic
acid, lactate or mixtures thereof per mL of vancomycin-containing
composition (for example, about 4.5 mg lactic acid per mL of
vancomycin-containing composition); and [0072] iii) optionally, a
pH adjuster such as sodium hydroxide in an amount sufficient to
maintain the pH of the vancomycin-containing composition at about
5.5. [0073] II. A vancomycin-containing composition, comprising:
[0074] a) vancomycin or a pharmaceutically acceptable salt thereof,
in an amount of about 5 mg/mL; and [0075] b) a pharmaceutically
acceptable fluid having a pH of about 3 to about 8, comprising:
[0076] i) about 2.5% (v/v) propylene glycol; [0077] ii) 0.1 mmole
of lactic acid, lactate or mixtures thereof per milliliter of
vancomycin-containing composition (for example, about 9 mg of
lactic acid per ml of vancomycin-containing composition); and
[0078] iii) optionally, a pH adjuster such as sodium hydroxide in
an amount sufficient to maintain a pH of the vancomycin-containing
composition at about 5.5.
[0079] The stability profile of each of the above is the same as
previously mentioned, i.e., they are substantially free of
precipitation after at least about 12 months of storage at a
temperature of about 5.degree. C. to about 15.degree. C.
[0080] Another embodiment of the invention includes methods of
treating a vancomycin-sensitive disease in mammals, i.e., a
bacterial infection. The methods include administering, to a mammal
in need thereof, an effective amount of a vancomycin-containing
composition described herein.
[0081] Since the active ingredient portion of the inventive
compositions is an FDA-approved drug, those of ordinary skill will
recognize that the doses of vancomycin employed in this aspect of
the invention will be the similar to those employed in any
treatment regimens designed for vancomycin as marketed. The patient
package insert containing dosing information is incorporated herein
by reference. The methods of treatment also include administering
the inventive formulations for any purpose or physical condition
for which vancomycin has been indicated as being useful. The daily
intravenous dose is from about 1 g to about 2 g, administered as
about 250 mg to about 500 mg every 3 to 6 hours or as about 1 g
every 12 hours.
[0082] Another embodiment of the invention includes methods of
preparing vancomycin-containing compositions described herein. The
methods include reconstituting lyophilized vancomycin to a
concentration of about 2.5 mg/mL to about 10 mg/mL in a polar
solvent comprising PG, PEG or mixtures thereof, lactate, lactic
acid, or mixtures thereof, and an optional pH adjustor in an amount
sufficient to maintain the pH of the composition at from about 3 to
about 8. The steps are carried out under pharmaceutically
acceptable conditions for sterility and/or bioburden and
manufacturing.
[0083] The compositions of the present invention can be packaged in
any suitable sterile vial, infusion bag or container fit for the
appropriate storage of a pharmaceutical such as vancomycin.
Suitable containers can be of a size sufficient to hold one or more
doses of vancomycin. Within this aspect from about 25 mL to about
500 mL of the inventive compositions are packaged as a single dose
or a multi-dose. Preferably, from about 25 mL to about 400 mL, or
from about 50 mL to about 200 mL are packaged in a container. More
preferably, about 100 mL is packaged in a container. In some
aspects of the invention, the concentration of the
vancomycin-containing compositions in the containers is from about
2.5 mg/mL to about 15 mg/mL, or from about 5 mg/mL to about 10
mg/mL. Preferably, the concentration of the vancomycin-containing
compositions is about 5 mg/mL. In other aspects, the containers
include from one to about 5 doses. Preferably, the containers
include from about one to about four doses. In some aspects, the
vancomycin-containing compositions of the present invention may be
packaged in a vial. Typical Type 1 glass vials are a preferred
vial.
EXAMPLES
[0084] The following examples serve to provide further appreciation
of the invention but are not meant in any way to restrict the
effective scope of the invention.
Examples 1-4 (100mg/mL Vancomycin)
Example 1 (75% (v/v) 1M Lactic Acid Solution and 25% (v/v) PG):
[0085] A lactic acid solution was prepared by dissolving 7.68 g of
an 88% lactic acid solution in 40 mL water for injection. The pH
was then adjusted to 5.5 with a 2N sodium hydroxide solution. A
75:25 lactic acid:PG solution was prepared by adding 25 mL of PG to
the above lactic acid solution, and the volume was made up to 100
mL with water for injection. 10 g of vancomycin HCl was then added
to 75 ml of the 75:25 lactic acid:PG solution and the volume was
made up to 100 mL with the 75:25 lactic acid:PG solution to yield a
vancomycin concentration of 100 mg/mL. The sample was mixed well.
2N sodium hydroxide solution was added to the sample to bring the
pH to 5.5.
Example 2 (50% (v/v) 1M Lactic Acid Solution and 50% (v/v) PG):
[0086] A lactic acid solution was prepared by dissolving 5.12 g of
an 88% lactic acid solution in 40 mL water for injection. The pH
was then adjusted to 5.5 with a 2N sodium hydroxide solution. A
50:50 lactic acid:PG solution was prepared by adding 50 mL of PG to
the above lactic acid solution, and the volume was made up to 100
mL with water for injection. 10 g of vancomycin
[0087] HCl was then added to 75 mL of the 50:50 lactic acid:PG
solution and the volume was made up to 100 mL with the 50:50 lactic
acid:PG solution to yield a vancomycin concentration of 100 mg/mL.
The sample was mixed well. 2N sodium hydroxide solution was added
to the sample to bring the pH to 5.5.
Example 3
Comparative (95% (v/v) 1M Lactic Acid Solution and 5% (v/v)
PG):
[0088] A lactic acid solution was prepared by dissolving 9.728 g of
an 88% lactic acid solution in 40 mL water for injection. The pH
was then adjusted to 5.5 with a 2N sodium hydroxide solution. A
95:5 lactic acid:PG solution was prepared by adding 5 mL of PG to
the above lactic acid solution, and the volume was made up to 100
mL with water for injection. 10 g of vancomycin HCl was then added
to 75 mL of the 95:5 lactic acid:PG solution and the volume was
made up to 100 mL with the 95:5 lactic acid:PG solution to yield a
vancomycin concentration of 100 mg/mL. The sample was mixed well.
2N sodium hydroxide solution was added to the sample to bring the
pH to 5.5.
Example 4
Comparative (87.5% (v/v) 1M Lactic Acid Solution and 12.5% (v/v)
PG):
[0089] A lactic acid solution was prepared by dissolving 8.96 g of
an 88% lactic acid solution in 40 mL water for injection. The pH
was then adjusted to 5.5 with a 2N sodium hydroxide solution. A
87.5:12.5 lactic acid:PG solution was prepared by adding 12.5 mL of
PG to the above lactic acid solution, and the volume was made up to
100 mL with water for injection. 10 g of vancomycin
[0090] HCl was then added to 75 mL of the 87.5:12.5 lactic acid:PG
solution and the volume was made up to 100 mL with the 87.5:12.5
lactic acid:PG solution to yield a vancomycin concentration of 100
mg/mL. The sample was mixed well. 2N sodium hydroxide solution was
added to the sample to bring the pH to 5.5. [0091] Control:
[0092] A lactic acid solution was prepared by dissolving 10.24 g of
an 88% lactic acid solution in 40 mL water for injection. The pH
was then adjusted to 5.5 with a 2N sodium hydroxide solution. The
volume was made up to 100 mL with water for injection. 10 g of
vancomycin HCl was then added to the lactic acid solution to yield
a vancomycin concentration of 100 mg/mL. The sample was mixed well.
2N sodium hydroxide solution was added to the sample to bring the
pH to 5.5.
[0093] The samples were stored at 25.degree. C. and were analyzed
for visibly observable precipitation as reported in Table 1 below.
The test data is reported in Table 1 below.
TABLE-US-00001 TABLE 1 Stability of Vancomycin Solutions (100
mg/mL) at pH 5.5 Time to precipitation Example Formulation at
25.degree. C. Control 1M Lactic acid 6 days 1 75:25 (no
precipitation for at 1M Lactic acid least ~1 year) solution:PG 2
50:50 (no precipitation for at 1M Lactic acid least ~1 year)
solution:PG 3-Comparative 95:5 11 days 1M Lactic acid solution:PG
4-Comparative 87.5:12.5 16 days 1M Lactic acid solution:PG
[0094] As shown in Table 1, the samples including the ratio of 1M
lactic acid solution:PG within the range of from about 50:50 to
about 75:25 demonstrate excellent stability, as the solutions were
free of precipitation through at least one year at 25.degree.
C.
[0095] In contrast, the lactic acid solution control sample and the
samples including a ratio of lactic acid:PG outside the amounts
required herein, did not demonstrate physical stability. The
samples exhibited precipitation within16 days.
Example 5
(100 mg/mL Vancomycin)
[0096] A lactic acid solution was prepared by dissolving 7.68 g of
an 88% lactic acid solution in 40 mL water for injection. The pH
was then adjusted to 5.5 with a 2N sodium hydroxide solution. A
75:25 lactic acid:PG solution was prepared by adding 25 mL of PG to
the above lactic acid solution, and the volume was made up to 100
mL with water for injection. 10 g of vancomycin
[0097] HCl was then added to 75 mL of the 75:25 lactic acid:PG
solution and the volume was made up to 100 mL with the 75:25 lactic
acid:PG solution to yield a vancomycin concentration of 100 mg/mL.
The sample was mixed well. 2N sodium hydroxide solution was added
to the sample to bring the pH to 5.5.
[0098] The samples were stored at 25.degree. C. and were tested
after initial preparation, and again as indicated in Table 2 below.
The samples were tested to determine the amount of vancomycin B in
the samples after storage. The test data is reported in Table 2
below.
TABLE-US-00002 TABLE 2 Stability of Vancomycin (100 mg/mL) in
75:251M Lactic acid:PG at pH 5.5 at 25.degree. C. Storage Batch #
Period % Vancomycin B pH VCM-49 Initial 93.3 5.4 1 Month 92.9 5.14
2 Months 92.5 5.05 6 Months 92.3 5.02 12 Months 91.9 5.10 VCM-50
Initial 93.3 5.8 1 Month 92.9 5.21 2 Months 92.2 5.25 8.5 Months
91.9 5.15 12 Months 91.4 5.29 VCM-51 Initial 93.5 5.56 1 Month 92.6
5.05 2 Months 92.3 5.03 8 Months 92.3 5.10
[0099] As shown in Table 2, vancomycin in 75:25 1M lactic acid
solution:PG exhibited excellent stability at 25.degree. C. The
samples exhibited less than a 2% loss vancomycin B after more than
12 months of storage at 25.degree. C. The data presented in Table 2
translates into vancomycin-containing compositions having a shelf
life of at least 12 months at ambient or refrigerated
conditions.
Example 6
(50mg/mL Vancomycin)
[0100] A lactic acid solution was prepared by dissolving 3.84 g of
an 88% lactic acid solution in 40 mL water for injection. The pH
was then adjusted to 5.0 with a 2N sodium hydroxide solution. A
75:25 lactic acid solution:PG solution was prepared by adding 25 mL
of PG to the above lactic acid solution, and the volume was made up
to 100 mL with water for injection. 5g of vancomycin HCl and 0.25 g
of L-methionine were then added to 75 mL of the 75:25 lactic
acid:PG solution and the volume was made up to 100 mL with the
75:25 lactic acid:PG solution to yield a vancomycin concentration
of 50 mg/mL. The sample was mixed well. 2N sodium hydroxide
solution was added to the sample to bring the final pH to 5.0. In
previous studies, the vancomycin solutions turned pale yellow in
color when exposed to long term storage conditions. This color
change may be caused in part by the oxidative degradation of
vancomycin or impurities present in the vancomycin drug substance.
Therefore, methionine was included as a free radical scavenger and
vials were filled under a nitrogen atmosphere. The head space
oxygen in the following three batches ranged from 2% to 5%. Test
data are reported in Table 3 below.
TABLE-US-00003 TABLE 3 Stability of Vancomycin (50 mg/mL) in 75:25
0.5M Lactic acid solution:PG at pH 5.0 to 4.5 at 25.degree. C.
Storage Period Batch # (Months) % Vancomycin B pH VCM-83 Initial
92.4 5.02 1 92.0 4.98 3 91.0 4.95 6 88.4 4.85 12 87.3 4.82 VCM-84
Initial 92.2 4.64 1 91.9 4.76 3 91.0 4.42 6 86.9 4.58 12 86.2 4.49
VCM-87 Initial 91.7 4.40 1 91.6 4.55 3 89.3 4.88 6 88.8 4.42
[0101] As shown on the table above, a 4 to 6% loss of vancomycin
B-over a 12 month storage period at 25.degree. C. was observed.
Assuming an initial level of vancomycin B of 97-100%, one would
expect a shelf life of 24 months at 25.degree. C. storage assuming
a minimum of 80% level of vancomycin B as recited in the USP
monograph for vancomycin products.
Example 7
Vancomycin (100mg/mL): .about.8 L Batch Manufactured Under Aseptic
Conditions
[0102] Vancomycin batches (VCM49-51) in Example 5 display excellent
stability. A pilot scale batch was manufactured according to the
Example 5 protocol and filled into vials to assess the chemical
stability. The data are summarized in the Table 4 below
TABLE-US-00004 TABLE 4 Stability of Vancomycin (100 mg/mL) in 75%
1M lactic acid solution: 25% PG, methionine 5 mg/mL at pH 5.5 % of
Area % Area % initial of peak of peak Storage % of of at RRT at RRT
Batch # Temp. Time VCM B VCM B 0.66 1.81 pH VCM- Initial 94.9 100
0.30 0.96 5.56 118 30.degree. C. 3 M 92.5 97.5 1.00 1.88 5.54 6 M
90.4 95.3 1.27 2.43 5.52 25.degree. C. 3 M 93.0 98.0 0.67 1.25
5.54
[0103] As shown in the table above, vancomycin solutions prepared
according to this protocol possess outstanding stability. Only
about a 4% loss in vancomycin B was observed at 30.degree. C. after
six months. The increase in peak area % of two major degradation
products was observed to be less than 1.5%.
Example 8:
Vancomycin (5 mg/mL)
[0104] About 0.05M lactic acid solution was prepared by dissolving
0.772 g of an 88% lactic acid solution in 70 mL water for
injection. A 1.25% (v/v) PG solution was prepared by adding 1.881 g
of PG to the 0.05M lactic acid solution and mixed well. 1N sodium
hydroxide was added to adjust the pH to 5.0. The volume was brought
up to 150 mL with water for injection. 392.6 mg vancomycin was then
added to 60 mL of the 0.05M lactic acid solution:PG mixture and
mixed well. The volume of the solution was then made up to 75 mL
with 0.05M lactic acid solution:PG mixture.
[0105] The same procedure was followed for preparing the above
lactic acid solution with 1.25% (v/v) PG samples with pH 5.5 and
6.0. About 0.1M lactic acid solution was prepared by dissolving
1.549 g of an 88% lactic acid solution in 70 mL water for
injection. A 1.25% (v/v) PG solution was prepared by adding 1.889 g
of PG to the 0.1M lactic acid solution and mixed well. 1N sodium
hydroxide was added to adjust the pH to 5.0. The volume was brought
up to 150 mL with water for injection. 392.4 mg vancomycin was then
added to 60 mL of the 0.1M lactic acid solution:PG mixture and
mixed well. 1N sodium hydroxide was added to the solution, if
necessary, to adjust the pH to 5.0. The volume of the solution was
then made up to 75 mL with 0.1M lactic acid solution:PG
mixture.
[0106] The same procedure was followed for preparing the above
lactic acid solution with 1.25% (v/v) PG samples with pH 5.5 and
6.0. About 0.05M lactic acid solution was prepared by dissolving
0.775 g of an 88% lactic acid solution in 70 mL water for
injection. A 2.5% (v/v) PG solution was prepared by adding 3.754 g
of PG to the 0.05M lactic acid solution and mixed well. 1N sodium
hydroxide was added to adjust the pH to 5.0. The volume was brought
up to 150 mL with water for injection. 391.8 mg vancomycin was then
added to 60 mL of the 0.05M lactic acid solution:PG mixture and
mixed well. 1N sodium hydroxide was added to the solution, if
necessary, to adjust the pH to 5.0. The volume of the solution was
then made up to 75 mL with 0.05M lactic acid solution:PG
mixture.
[0107] The same procedure was followed for preparing the above
lactic acid solution with 2.5% (v/v) PG samples with pH 5.5 and
6.0. About 0.1M lactic acid solution was prepared by dissolving
1.554 g of an 88% lactic acid solution in 70 mL water for
injection. A 2.5% (v/v) PG solution was prepared by adding 3.76 g
of PG to the 0.1M lactic acid solution and mixed well. 1N sodium
hydroxide was added to adjust the pH to 5.0. The volume was brought
up to 150 mL with water for injection. 391.7 mg vancomycin was then
added to 60 mL of the 0.1M lactic acid solution:PG mixture and
mixed well. 1N sodium hydroxide was added to the solution, if
necessary, to adjust the pH to 5.0. The volume of the solution was
then made up to 75 mL with 0.1M lactic acid solution:PG
mixture.
[0108] The same procedure was followed for preparing the above
lactic acid solution with 2.5% (v/v) PG samples with pH 5.5 and
6.0. The samples were stored at 5.degree. C. and were analyzed for
visibly observable precipitation and were tested for impurities,
after initial preparation and again after 6 months. The samples
were also tested to determine the amount of vancomycin in the
samples after storage. The test data is reported in Table 5
below.
TABLE-US-00005 TABLE 5 Stability of Vancomycin Solutions (5 mg/mL)
in Lactic Acid and Propylene Glycol at 5.degree. C.at pH about 5.0,
5.5 and 6.0 % Lactic Propylene Assay % of Area % Area % Batch #
Acid (M) Glycol (Months) % VCM-B Initial RRT 0.66 RRT 1.81 pH
VCM-55 0.05 1.25 Initial 92.0 100.0 2.05 0.53 4.91 pH-5.0 6 91.1
99.0 2.02 1.29 4.79 12 90.8 98.7 2.74 3.01 4.60 VCM-56 0.05 1.25
Initial 94.0 100 1.50 0.38 5.39 pH-5.5 6 92.6 98.5 2.08 1.31 5.04
12 90.7 96.5 2.76 3.04 4.92 VCM-57 0.05 1.25 Initial 91.7 100 2.12
0.52 5.87 pH-6.0 6 90.5 98.7 2.09 1.39 5.29 12 90.4 98.6 2.68 3.13
5.11 VCM-58 0.1 1.25 Initial 93.4 100.0 1.69 0.45 4.97 pH-5.0 6
92.5 99.0 1.88 0.95 4.77 12 91.1 97.5 2.72 3.00 4.61 VCM-59 0.1
1.25 Initial 94.4 100.0 1.30 0.37 5.40 pH-5.5 6 93.6 99.2 1.91 0.96
4.89 12 90.4 95.8 2.85 3.12 4.80 VCM-60 0.1 1.25 Initial 94.4 100.0
1.31 0.36 5.92 pH-6.0 6 93.1 98.6 1.91 1.00 5.29 12 91.5 96.9 2.26
3.00 4.87 VCM-61 0.05 2.5 Initial 94.4 100.0 1.27 0.38 4.88 pH-5.0
6 92.8 98.3 2.05 1.23 4.5 12 91.1 96.5 2.55 2.81 4.66 VCM-62 0.05
2.5 Initial 94.2 100 1.35 0.37 5.45 pH-5.5 6 92.8 98.5 2.08 1.30
5.04 12 91.1 96.7 2.58 2.88 4.94 VCM-63 0.05 2.5 Initial 94.2 100.0
1.40 0.38 6.04 pH-6.0 6 92.6 98.3 2.19 1.43 5.26 12 91.1 96.7 2.64
2.95 5.11 VCM-64 0.1 2.5 Initial 94.8 100.0 1.32 0.37 4.94 pH-5.0 6
93.5 98.6 1.92 0.97 4.70 12 92.4 97.5 2.13 2.15 4.70 VCM-65 0.1 2.5
Initial 94.8 100.0 1.32 0.99 5.49 pH-5.5 6 93.5 98.6 1.93 1.02 5.01
12 92.4 97.5 2.28 2.16 5.00 VCM-66 0.1 2.5 Initial 94.8 100.0 1.33
0.37 5.95 pH-6.0 6 93.4 98.5 2.01 1.09 5.14 12 92.3 97.4 2.23 2.29
5.06
[0109] As can be seen in Table 5, the samples including the amount
of PG from about 1.25% (v/v) to about 2.5% (v/v), as claimed,
demonstrated excellent stability. The solutions were free of
precipitation after 12 months at 5.degree. C. The samples also
exhibited less than 2 to 4% loss of vancomycin B after 12 months of
storage at 5.degree. C. The data presented in Table 5 suggests
vancomycin-containing compositions according to the present
invention have a shelf life of at least two years under
refrigerated conditions.
* * * * *