U.S. patent application number 15/165389 was filed with the patent office on 2016-10-27 for caspofungin acetate formulations.
The applicant listed for this patent is Fresenius Kabi USA LLC. Invention is credited to David Bowman, John Jiang, Keith Kwok, Joel Peterson, Arunya Usayapant.
Application Number | 20160310597 15/165389 |
Document ID | / |
Family ID | 47505366 |
Filed Date | 2016-10-27 |
United States Patent
Application |
20160310597 |
Kind Code |
A1 |
Jiang; John ; et
al. |
October 27, 2016 |
Caspofungin Acetate Formulations
Abstract
A caspofungin composition includes caspofungin acetate and at
least one amino acid, where the composition is a solid. The solid
composition may be made by forming a liquid mixture including a
solvent, caspofungin acetate and the amino acid(s), and
lyophilizing the liquid mixture.
Inventors: |
Jiang; John; (Chicago,
IL) ; Usayapant; Arunya; (Mundelein, IL) ;
Bowman; David; (Mattawan, MI) ; Kwok; Keith;
(Long Grove, IL) ; Peterson; Joel; (New Lenox,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Fresenius Kabi USA LLC |
Lake Zurich |
IL |
US |
|
|
Family ID: |
47505366 |
Appl. No.: |
15/165389 |
Filed: |
May 26, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13724266 |
Dec 21, 2012 |
|
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15165389 |
|
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61728406 |
Nov 20, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0019 20130101;
A61K 31/198 20130101; A61K 47/183 20130101; A61K 47/20 20130101;
A61K 9/19 20130101; A61K 38/12 20130101; A61K 31/198 20130101; A61K
2300/00 20130101 |
International
Class: |
A61K 47/18 20060101
A61K047/18; A61K 9/19 20060101 A61K009/19; A61K 38/12 20060101
A61K038/12 |
Claims
1. A composition, comprising: caspofungin acetate, and at least one
an amino acid; where the composition is a solid.
2. The composition of claim 1, where the at least one amino acid
comprises an amino acid having at least two primary or secondary
amine groups.
3. The composition of claim 2, where the at least one amino acid is
an amino acid selected from the group consisting of arginine,
asparagine, lysine, methyl lysine, and ornithine.
4. The composition of claim 1, where the at least one amino acid is
selected from the group consisting of alanine, 4-aminobutanoic
acid, 3-aminopentanoic acid, 5-aminopentanoic acid, 6-aminohexanoic
acid, 8-aminooctanoic acid, arginine, aspartic acid, asparagine,
cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine,
leucine, lysine, methionine, methyl lysine, ornithine,
phenylalanine, proline, serine, threonine, tryptophan, tyrosine and
valine.
5. The composition of claim 1, where the at least one amino acid is
selected from the group consisting of 6-aminohexanoic acid,
arginine, asparagine, glycine, lysine, methyl lysine, and
ornithine.
6. The composition of claim 1, where the at least one amino acid
comprises at least two amino acids.
7. The composition of claim 1, comprising from 10 to 150 mg
caspofungin acetate.
8. The composition of claim 1, comprising from 25 to 100 mg
caspofungin acetate.
9. The composition of claim 1, comprising from 50 to 70 mg
caspofungin acetate.
10. The composition of claim 1, where the mass ratio of the at
least one amino acid to caspofungin acetate is at least 3:5.
11. The composition of claim 1, where the mass ratio of the at
least one amino acid to caspofungin acetate is at least 1:1.
12. The composition of claim 1, where the mass ratio of the at
least one amino acid to caspofungin acetate is at least 2:1.
13. The composition of claim 1, where the mass ratio of the at
least one amino acid to caspofungin acetate is at most 3:1.
14. The composition of claim 1, where the mass ratio of the at
least one amino acid to caspofungin acetate is at most 2:1.
15. The composition of claim 1, where the mass ratio of the at
least one amino acid to caspofungin acetate is from 2:5 to 3:1.
16. The composition of claim 1, where the mass ratio of the at
least one amino acid to caspofungin acetate is from 3:5 to 2:1.
17. The composition of claim 1, where the mass ratio of the at
least one amino acid to caspofungin acetate is from 1:1 to 3:1.
18. A composition, formed by a method comprising: forming a liquid
mixture comprising a solvent, caspofungin acetate, and at least one
an amino acid; and lyophilizing the liquid mixture to form a solid
composition.
19. The composition of claim 18, where the at least one amino acid
is an amino acid having at least two primary or secondary amine
groups.
20. The composition of claim 19, where the at least one amino acid
is an amino acid selected from the group consisting of arginine,
asparagine, lysine, methyl lysine, and ornithine.
21. The composition of claim 18, where the at least one amino acid
is selected from the group consisting of alanine, 4-aminobutanoic
acid, 3-aminopentanoic acid, 5-aminopentanoic acid, 6-aminohexanoic
acid, 8-aminooctanoic acid, arginine, aspartic acid, asparagine,
cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine,
leucine, lysine, methionine, methyl lysine, ornithine,
phenylalanine, proline, serine, threonine, tryptophan, tyrosine and
valine.
22. The composition of claim 18, where the at least one amino acid
is selected from the group consisting of 6-aminohexanoic acid,
arginine, asparagine, glycine, lysine, methyl lysine, and
ornithine.
23. The composition of claim 18, where the at least one amino acid
comprises at least two amino acids.
24. The composition of claim 18, comprising from 10 to 150 mg
caspofungin acetate.
25. The composition of claim 18, comprising from 25 to 100 mg
caspofungin acetate.
26. The composition of claim 18, comprising from 50 to 70 mg
caspofungin acetate.
27. The composition of claim 18, where the mass ratio of the at
least one amino acid to caspofungin acetate is at least 3:5.
28. The composition of claim 18, where the mass ratio of the at
least one amino acid to caspofungin acetate is at least 1:1.
29. The composition of claim 18, where the mass ratio of the at
least one amino acid to caspofungin acetate is at least 2:1.
30. The composition of claim 18, where the mass ratio of the at
least one amino acid to caspofungin acetate is at most 3:1.
31. The composition of claim 18, where the mass ratio of the at
least one amino acid to caspofungin acetate is at most 2:1.
32. The composition of claim 18, where the mass ratio of the at
least one amino acid to caspofungin acetate is from 2:5 to 3:1.
33. The composition of claim 18, where the mass ratio of the at
least one amino acid to caspofungin acetate is from 3:5 to 2:1.
34. The composition of claim 18, where the mass ratio of the at
least one amino acid to caspofungin acetate is from 1:1 to 3:1.
35. The composition of claim 18, where the mass ratio of the at
least one amino acid to caspofungin acetate in the liquid mixture
is at least 2:5.
36. The composition of claim 18, where the mass ratio of the at
least one amino acid to caspofungin acetate in the liquid mixture
is at least 3:5.
37. The composition of claim 18, where the mass ratio of the at
least one amino acid to caspofungin acetate in the liquid mixture
is at least 1:1.
38. A composition, comprising: from 50 to 70 mg caspofungin
acetate, and arginine; where the mass ratio of arginine to
caspofungin acetate is from 2:5 to 3:1, and the composition is
solid.
39. The composition of claim 38, where the mass ratio of arginine
to caspofungin acetate is from 3:5 to 2:1.
40. The composition of claim 38, where the mass ratio of arginine
to caspofungin acetate is from 1:1 to 3:1.
Description
REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Nonprovisional
application Ser. No. 13/724,266, filed Dec. 21, 2012, entitled
"CASPOFUNGIN ACETATE FORMULATIONS", which claims the benefit of
U.S. Provisional Application No. 61/728,406 entitled "Caspofungin
Acetate Formulations" filed Nov. 20, 2012, both of which are
incorporated by reference in the entirety.
BACKGROUND
[0002] A variety of fungal infections can occur in patients due to
pathogenic Candida or Aspergillus fungus species. Examples of such
fungal infections include candidemia, candidiasis (including
esophageal infections, abdominal infections, pleural space
infections and peritoneal infections), and invasive aspergillosis.
Early antifungal agents typically attacked the inner cell membrane
of the invasive fungus. These early agents had a variety of
drawbacks, however, including toxic side effects, drug-drug
interactions, variations in efficacy between patients, and fungal
resistance.
[0003] A more recent family of antifungal agents is the
echniocandins, which treat fungal infections through a different
mechanism--inhibition of the enzyme that forms
.beta.-(1,3)-D-glucan, an essential component of the fungal outer
cell wall. Since .beta.-(1,3)-D-glucan does not occur naturally in
the cell walls of mammals, the action of echinocandins is unlikely
to be harmful to the cells of an infected patient. Due to the
difference in their mechanism of action relative to earlier agents,
echinocandins have not experienced wide resistance by target
fungi.
[0004] Caspofungin acetate was the first of the echinocandins to be
approved in the U.S. for use as an antifungal agent. The full name
for caspofungin acetate is reported as
1-[(4R,5S)-5-[(2-aminoethyl)amino]-N.sup.2-(10,12-dimethyl-1-oxotetradecy-
l)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine]
pneumocandin B.sub.0 diacetate (salt), and a representative
chemical structure of caspofungin acetate is shown in FIG. 1. An
approved treatment regimen for adults includes an initial
administration of 70 milligrams (mg) caspofungin acetate, followed
by daily administration of 50 mg caspofungin acetate, where each
administration is performed through intravenous infusion over 1
hour.
[0005] As caspofungin acetate has poor oral bioavailability, it
typically has been provided to medical personnel as a lyophilized
solid, which is then reconstituted before intravenous
administration to a patient. In one example, a formulation of
caspofungin acetate that is commercially available at present is
sold under the CANCIDAS.RTM. trademark. CANCIDAS.RTM. for Injection
(Merck & Co, Inc.; Whitehouse Station, N.J., USA) is currently
available as a lyophilized powder. CANCIDAS.RTM. is available in
vials containing either 54.6 mg or 75.6 mg of caspofungin acetate,
in combination with sucrose and mannitol, and including acetic acid
and sodium hydroxide as pH modifiers. CANCIDAS.RTM. is
reconstituted for administration by combining the lyophilized
powder with 10.8 milliliters (mL) of a reconstitution liquid (such
as 0.9% sodium chloride), to provide a solution having a
caspofungin acetate concentration of either 7 milligrams per
milliliter (mg/mL) or 5 mg/mL. This reconstituted liquid typically
is diluted with an infusion liquid prior to administration.
[0006] One challenge associated with the commercially available
formulation of caspofungin acetate is its instability, including
its instability at ambient temperatures. Degradation products of
caspofungin acetate at room temperature (.about.25.degree. C.)
include various dimers of caspofungin, as well as other substances.
Current protocols require caspofungin acetate to be stored at
-70.degree. C. (.+-.10.degree. C.), and require the lyophilized
CANCIDAS.RTM. formulation to be stored at temperatures of
2-8.degree. C. A reconstituted liquid formed from the CANCIDAS.RTM.
formulation must be diluted within one hour, and then either
administered within 24 hours or stored at 2-8.degree. C. for up to
48 hours. These temperature and time constraints present potential
difficulties for effective administration of caspofungin acetate,
both in medical professional settings and in outpatient settings.
See, for example, Tsiouris, Maria et al. "Stability and
compatibility of reconstituted caspofungin in select elastomeric
infusion devices", International Journal of Pharmaceutical
Compounding (2010), 14(5), 436-439.
[0007] Various reformulations have been reported to improve the
stability of caspofungin. The use of the acetate salt form of
caspofungin was an initial effort at improving the stability of
caspofungin, as earlier versions of caspofungin formulations used
the tartrate salt instead. Thus, the CANCIDAS.RTM. formulation,
which includes caspofungin in its acetate salt form, has improved
stability relative to formulations of caspofungin tartrate. See
U.S. Pat. No. 5,952,300, column 2, lines 22-56 and column 8,
lines
11-67.
[0008] In another example, the pH modifiers acetic acid and sodium
hydroxide were eliminated from the CANCIDAS.RTM. formulation, and
the resulting formulations had improved stability at ambient
temperatures. Lyophilized formulations were more stable with
respect to caspofungin at 25.degree. C. for 12 weeks, and
reconstituted solutions of the formulations were more stable with
respect to the caspofungin at 25.degree. C. for 2 days. See US
2009/0170753, paragraphs [0080], [0204]-[0207] and
[0214]-[0217].
[0009] In another example, the sucrose and mannitol in the
CANCIDAS.RTM. formulation were replaced with a non-reducing sugar
such as trehalose, and the resulting formulations had improved
stability at ambient temperatures. Lyophilized formulations
containing trehalose more were stable with respect to caspofungin
at 30.degree. C. for up to 72 weeks, and at 40.degree. C. for up to
24 weeks. See US 2010/0137197, paragraphs [0114]-[0119].
[0010] It is desirable to have caspofungin acetate formulations
that can be stored as lyophilized solids without the need for
control of the surrounding temperature. For example, it is
desirable for a lyophilized formulation of caspofungin acetate to
be stable at temperatures of 25.degree. C. or higher for a period
of from 6 months to 2 years. Preferably such stabilized
formulations would be convenient to prepare, store, reconstitute
and administer.
SUMMARY
[0011] In one aspect, the invention provides a composition
including caspofungin acetate and at least one amino acid, where
the composition is a solid.
[0012] In another aspect of the invention, there is a composition
including from 50 to 70 mg caspofungin acetate, and arginine. The
mass ratio of arginine to caspofungin acetate is from 2:5 to 3:1,
and the composition is a solid.
[0013] In another aspect of the invention, there is a composition,
formed by a method including forming a liquid mixture that includes
a solvent, caspofungin acetate and at least one amino acid, and
lyophilizing the liquid mixture to form a solid composition.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] The invention can be better understood with reference to the
following drawings and description. The components in the figures
are not necessarily to scale and are not intended to accurately
represent molecules or their interactions, emphasis instead being
placed upon illustrating the principles of the invention.
[0015] FIG. 1 depicts a chemical structure of caspofungin
acetate.
[0016] FIGS. 2A and 2B depict chemical structures of examples of
amino acids.
DETAILED DESCRIPTION
[0017] Lyophilized formulations that include caspofungin acetate
and an amino acid can protect caspofungin acetate from degradation.
These formulations may be stored at room temperature for up to two
years, and thus may not require storage in a refrigerator or
freezer prior to use. Reconstitution of the lyophilized
formulations with a carrier liquid can yield an injectable liquid
that may be used to administer caspofungin acetate.
[0018] A composition may include caspofungin acetate, at least one
amino acid and optionally one or more other substances, where the
composition is a solid. The solid composition may be prepared by
forming a liquid mixture including a solvent, caspofungin acetate
and at least one amino acid, and then lyophilizing the mixture. The
resulting solid composition may be used in administering
caspofungin acetate to a patient by combining the composition with
an aqueous carrier to form a solution or emulsion, which, for
example, can be injected into a patient.
[0019] Caspofungin acetate is a salt of one equivalent of
caspofungin and two equivalents of acetic acid, providing an
empirical formula of
C.sub.52H.sub.88N.sub.10O.sub.15.2C.sub.2H.sub.4O.sub.2, and a
formula weight of 1,213.42 grams per mole. The chemical structure
shown in FIG. 1 represents caspofungin acetate in its associated
form. Caspofungin acetate may dissociate from one or both of its
equivalents of acetic acid in the presence of a solvent; however,
the salt still includes both the cyclic caspofungin and the acetic
acid species. Thus, the term "caspofungin acetate" includes both an
associated combination of caspofungin and acetic acid, as well as
caspofungin and acetic acid in a dissociated state, such as may
occur when the salt is combined with a solvent.
[0020] Caspofungin acetate does not include salts of caspofungin
with substances other than acetic acid. For example, it has been
reported that caspofungin can form pharmaceutically acceptable
salts with substances including cations such as sodium, potassium,
aluminum, calcium, lithium, magnesium and zinc; acids such as
hydrochloric, hydrobromic, phosphoric, sulfuric, maleic, citric,
tartaric, succinic, oxalic, malic, glutamic, lactic, propionic and
pamoic acids; and bases such as ammonia, ethylenediamine,
N-methyl-glutamine, lysine, arginine, ornithine, choline,
N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine,
procaine, N-benzylphenethylamine, diethylamine, piperazine,
tris(hydroxymethyl)aminomethane and tetramethyl-ammonium hydroxide.
See U.S. Pat. No. 5,378,804 at column 1, line 67--column 2, line 5;
U.S. Pat. No. 5,936,062 at column 2, lines 47-67; and
US 2009/0170753 at paragraphs 35-36. These alternative salts,
however, do not include acetic acid species, and thus are not
included in the term "caspofungin acetate".
[0021] A solid composition that includes caspofungin acetate and an
amino acid may include an amount of caspofungin acetate that is
sufficient for a single initial dose of caspofungin acetate, or an
amount sufficient for a daily maintenance dose of caspofungin
acetate. A solid composition that includes caspofungin acetate and
an amino acid may include an amount of caspofungin acetate that is
sufficient for two or more initial doses of caspofungin acetate, or
an amount sufficient for two or more daily maintenance doses of
caspofungin acetate. The amount of caspofungin acetate in the
composition may be a different therapeutic amount. For example, the
amount of caspofungin acetate in the composition may be an amount
sufficient for half of a single initial dose, or for half of a
daily maintenance dose.
[0022] In one example, a solid composition that includes
caspofungin acetate and an amino acid may include from 10 to 150
milligrams (mg) caspofungin acetate. Preferably the composition
includes from 25 to 100 mg caspofungin acetate, or from 50 to 70 mg
caspofungin acetate. Presently preferred amounts of caspofungin
acetate in the composition include about 50 mg and about 70 mg.
[0023] A solid composition that includes caspofungin acetate and an
amino acid includes one or more amino acids, which are compounds
containing at least one carboxylic acid group [--C(.dbd.O)OH] and
at least one primary or secondary amine group [--NH.sub.2 or --RNH,
where --R is a molecular entity other than --H], but lacking a
secondary amide group [--C(.dbd.O)--NH--]. FIG. 2 depicts chemical
structures of examples of amino acids, including alanine 202,
4-aminobutanoic acid 204, 3-aminopentanoic acid 206,
5-aminopentanoic acid 208, 6-aminohexanoic acid 210,
8-aminooctanoic acid 212, arginine 214, aspartic acid 216,
asparagine 218, cysteine 220, glutamic acid 222, glutamine 224,
glycine 226, histidine 228, isoleucine 230, leucine 232, lysine
234, methionine 236, methyl lysine 238, ornithine 240,
phenylalanine 242, proline 244, serine 246, threonine 248,
tryptophan 250, tyrosine 252 and valine 254. Other amino acids,
including isomers and substituted derivatives of the amino acids
depicted in
FIG. 2, may be present in the composition.
[0024] Presently preferred amino acids for use in the solid
compositions that include caspofungin acetate and at least one
amino acid include 6-aminohexanoic acid 210, arginine 214,
asparagine 218, glycine 226, lysine 234, methyl lysine 238, and
ornithine 240. A solid composition that includes caspofungin
acetate and an amino acid may include one or more amino acids that
contain at least two primary or secondary amine groups. Examples of
amino acids containing at least two primary or secondary amine
groups include arginine 214, asparagine 218, lysine 234, methyl
lysine 238, and ornithine 240.
[0025] Surprisingly, it has been discovered that a solid
composition including caspofungin acetate and an amino acid may be
more stable than a solid composition including caspofungin acetate,
mannitol and sucrose, such as the CANCIDAS.RTM. formulation (Merck
& Co, Inc.). It is presently believed that solid compositions
that include caspofungin acetate and an amino acid may be able to
protect caspofungin acetate from degradation for a year or longer
at room temperature (.about.25.degree. C.), and for 6 months or
longer at elevated temperatures.
[0026] The amino acids arginine, asparagine and glycine can
stabilize caspofungin acetate in solid compositions. Table 1 lists
the results of stability analyses of lyophilized compositions of
caspofungin acetate with arginine 214, asparagine 218 and glycine
226, and for a conventional lyophilized composition of caspofungin
acetate with mannitol and sucrose. For each solid composition
listed in Table 1 that included an amino acid, 50 mg caspofungin
acetate was combined with the listed amino acid and with water for
injection (USP), and the pH was adjusted to about 6.0. The aqueous
mixtures were then lyophilized to provide solid powders. Samples of
each solid composition were sealed in vials at temperatures of
5.degree. C., 25.degree. C. or 40.degree. C. The stability of the
caspofungin acetate in the compositions over time at each
temperature was determined by analyzing samples by High Pressure
Liquid Chromatography (HPLC) and then calculating the total amount
of relevant impurities of caspofungin detected in each HPLC
analysis by peak area percent. The HPLC analysis was performed
using a reversed phase HPLC having a variable wavelength UV/VIS
detector and a C-18 column (2.7 micron, 150.times.4.6 mm ID). The
liquid sample was passed through the HPLC using gradient elution at
a flow rate of 1.0 mL/min and a temperature of 25.degree. C. The
impurities were detected using UV-detection at 225 nm, where the
limit of quantification was <0.05%. Table 1 lists the percent
total impurities measured for the lyophilized compositions.
TABLE-US-00001 TABLE 1 Stability of Caspofungin Acetate
Compositions FRESENIUS KABI USA LLC CONT - CASPOFUNGIN ACETATE
FORMULATIONS JONATHAN M. BLANCHARD DRAFT INTERNAL Gly- Argi- Aspar-
Mannitol + cine nine agine Sucrose* Mass Ratio 1:1 1:1 2:1 2:5 3:5
-- Amino Acid:Caspo- fungin Acetate: Moisture content (%): 0.50
0.54 1.24 0.87 1.45 -- Time Temperature (days) (.degree. C.) Total
Impurities (%) 4 5 1.61 0.60 -- -- 1.05 -- 7 1.57 0.65 0.62 0.80
1.05 -- 14 1.62 0.67 0.58 1.02 1.09 -- 29 1.98 -- 0.61 1.28 1.48 --
7 25 4.78 0.69 0.65 1.85 2.64 2.06 14 6.19 0.67 0.62 1.87 4.48 --
29 7.44 0.73 0.65 3.41 4.75 2.09 7 40 13.77 1.10 0.76 5.77 7.36
6.34 14 17.98 1.32 0.82 7.87 11.91 -- 29 21.30 1.62 0.91 13.66
13.14 23.65 56 -- 2.23 1.37 -- -- -- *Conventional formulation;
1.93% total impurities at time = 0 days
[0027] The solid composition having a mass ratio of arginine 214 to
caspofungin acetate of 2:1 had the lowest level of impurities of
the compositions listed in Table 1, from the initial days of the
analysis and up to 56 days at 40.degree. C. When stored at
5.degree. C., 25.degree. C. (.about.room temperature), and
40.degree. C. for 29 days, the impurity levels for this composition
were only 0.61%, 0.65% and 0.91% respectively.
[0028] This 2:1 arginine composition was more stable than the
conventional mannitol and sucrose composition at each time and
temperature for which comparative results are listed. When stored
at 25.degree. C. for 7 days, the level of impurities in the solid
composition having a mass ratio of arginine to caspofungin acetate
of 2:1 was 68% less than the level of impurities in the
conventional mannitol and sucrose composition
[68%=100%.times.(2.06%-0.65%)/2.06%]. When stored at 25.degree. C.
for 29 days, the level of impurities in the solid composition
having a mass ratio of arginine to caspofungin acetate of 2:1 was
69% less than the level of impurities in the conventional mannitol
and sucrose composition [69%=100%.times.(2.09%-0.65%)/2.09%]. When
stored at 40.degree. C. for 7 days, the level of impurities in the
solid composition having a mass ratio of arginine to caspofungin
acetate of 2:1 was 88% less than the level of impurities in the
conventional mannitol and sucrose composition
[88%=100%.times.(6.34%-0.76%)/6.34%]. When stored at 40.degree. C.
for 29 days, the level of impurities in the solid composition
having a mass ratio of arginine to caspofungin acetate of 2:1 was
96% less than the level of impurities in the conventional mannitol
and sucrose composition [96%=100%.times.(23.65%-0.91%)/23.65%].
[0029] When subjected to extended storage for 8 weeks (56 days) at
an elevated temperature of 40.degree. C., this 2:1 arginine
composition maintained a total impurity level of 1.37%, which is
acceptable under the International Conference on Harmonization of
Technical Requirements for Registration of Pharmaceuticals for
Human Use (ICH). Based on this acceptable stability under these
accelerated aging conditions, it is presently believed that a solid
composition including caspofungin acetate and arginine in a 2:1
mass ratio of amino acid to caspofungin acetate will be stable for
up to 2 years at room temperature, and will be stable for 6 months
or longer at 40.degree. C.
[0030] The effect of arginine 214 on the stability of caspofungin
acetate in a solid composition appeared to be related to the
relative amount of amino acid in the composition. The solid
composition having a mass ratio of arginine to caspofungin acetate
of 1:1 had a higher level of impurities than did the solid
composition having a mass ratio of arginine to caspofungin acetate
of 2:1, at each time and temperature for which comparative results
are listed.
[0031] Despite this decrease in stability, the composition having
the lower mass ratio of arginine to caspofungin acetate of 1:1 was
still more stable than the conventional mannitol and sucrose
composition at each temperature for which comparative results are
listed. When stored at 25.degree. C. for 7 days, the level of
impurities in the solid composition having a mass ratio of arginine
to caspofungin acetate of 1:1 was 67% less than the level of
impurities in the conventional mannitol and sucrose composition
[67%=100%.times.(2.06%-0.69%)/2.06%]. When stored at 25.degree. C.
for
29 days, the level of impurities in the solid composition having a
mass ratio of arginine to caspofungin acetate of 1:1 was 65% less
than the level of impurities in the conventional mannitol and
sucrose composition [65%=100%.times.(2.09%-0.73%)/2.09%]. When
stored at 40.degree. C. for 7 days, the level of impurities in the
solid composition having a mass ratio of arginine to caspofungin
acetate of 1:1 was 83% less than the level of impurities in the
conventional mannitol and sucrose composition
[83%=100%.times.(6.34%-1.10%)/6.34%]. When stored at 40.degree. C.
for 29 days, the level of impurities in the solid composition
having a mass ratio of arginine to caspofungin acetate of 1:1 was
93% less than the level of impurities in the conventional mannitol
and sucrose composition [93%=100%.times.(23.65%-1.62%)/23.65%].
[0032] The stabilizing effect of asparagine 218 with regard to
caspofungin acetate in a solid composition was less than the
stabilizing effect of arginine. The solid compositions having mass
ratios of asparagine to caspofungin acetate of 2:5 or 3:5 had
higher levels of impurities than did the solid compositions having
a mass ratio of arginine to caspofungin acetate of 2:1 or 1:1, at
each time and temperature for which comparative results are listed.
Compositions having a mass ratio of arginine to caspofungin acetate
greater than 3:5 were not analyzed due to the lower aqueous
solubility of asparagine in comparison to arginine. Despite this
decrease in stability relative to compositions containing arginine,
the stability of caspofungin acetate in compositions containing
asparagine was comparable to that of the conventional mannitol and
sucrose composition. Moreover, when stored at 40.degree. C. for 29
days, the level of impurities in the solid compositions having mass
ratios of asparagine to caspofungin acetate of 2:5 or 3:5 were
42-44% less than the level of impurities in the conventional
mannitol and sucrose composition
[(42%=100%.times.(23.65%-13.66%)/23.65%);
(44%=100%.times.(23.65%-13.14%)/23.65%)].
[0033] The stabilizing effect of glycine 226 with regard to
caspofungin acetate in a solid composition was less than the
stabilizing effects of either arginine or asparagine. The solid
composition having a mass ratio of glycine to caspofungin acetate
of 1:1 had higher levels of impurities than did the solid
compositions containing arginine or asparagine, at each time and
temperature for which comparative results are listed. As noted in
Tables 2 and 4 below, the mass ratio of glycine to caspofungin
acetate could be higher than 1:1, such as 2:1 or 3:1.
[0034] Despite this decrease in stability relative to compositions
containing arginine, the compositions of caspofungin acetate with
glycine were still more stable overall than the conventional
mannitol and sucrose composition when stored for 29 days at
40.degree. C. When stored at 40.degree. C. for 29 days, the level
of impurities in the solid composition having a mass ratio of
glycine to caspofungin acetate of 1:1 was 10% less than the level
of impurities in the conventional mannitol and sucrose
composition
[10%=100%.times.(23.65%-21.30%)/23.65%].
[0035] A variety of amino acids other than arginine, asparagine and
glycine also can stabilize caspofungin acetate in solid
compositions. Table 2 lists the results of stability analyses of
lyophilized compositions of caspofungin acetate with the amino
acids 6-aminohexanoic acid 210, arginine 214, glycine 226, lysine
234, methyl lysine 238 and ornithine 240. For each solid
composition listed in Table 2, 50 mg caspofungin acetate was
combined with the listed amino acid and with water for injection
(USP), and the pH was adjusted. The aqueous mixtures were then
lyophilized to provide solid powders. Samples of each solid
composition were sealed in vials at temperatures of 25.degree. C.,
40.degree. C. or 55.degree. C. The stability of the caspofungin
acetate in the compositions over time at each temperature was
determined by analyzing samples by HPLC and then calculating the
total amount of relevant impurities detected in each HPLC analysis
by peak area percent, as described above with regard to the results
of Table 1. Table 2 lists the percent total impurities measured for
the lyophilized compositions.
TABLE-US-00002 TABLE 2 Caspofungin Acetate (CA) Compositions
Containing Amino Acids (AA) Amino acid (AA): 6-amino- methyl
Arginine Glycine Ornithine Lysine hexanoic acid lysine Mass Ratio
(AA:CA): 1:1 3:1 2:1 2:1 2:1 2:1 pH*: 6.55 7.21 6.46 6.66 6.65 6.36
Moisture content (%): 0.67 1.36 0.56 0.64 0.64 0.46 Time
Temperature (weeks) (.degree. C.) Total Impurities (%) 0 -- 0.78
1.53 1.14 0.84 0.86 0.68 2 25 -- 9.70 5.01 2.72 2.66 0.92 4 --
10.55 4.01 3.13 3.97 0.94 8 -- -- -- -- -- 1.28 2 40 1.53 20.15
8.14 6.07 9.13 4.18 4 2.23 28.88 12.80 8.09 13.80 5.87 8 2.61 -- --
-- -- -- 12 2.56 -- -- -- -- -- 2 55 2.87 44.70 18.51 16.65 29.82
33.38 4 4.42 -- -- -- -- -- *pH of liquid when reconstituted in
water for injection.
[0036] Of the solid compositions listed in Table 2, the composition
having a mass ratio of arginine 214 to caspofungin acetate of 1:1
had the lowest level of impurities at elevated temperatures of
40.degree. C. and 55.degree. C., maintaining total impurity levels
below 5% for the times and temperatures listed. The compositions
containing 6-aminohexanoic acid 210, lysine 234, methyl lysine 238
or ornithine 240 were less stable than the arginine composition,
having total impurity levels of 5.87%-13.80% at an elevated
temperature of 40.degree. C. for 4 weeks, and total impurity levels
of 16.65%-33.38% at an elevated temperature of 55.degree. C. for 2
weeks. The composition containing glycine 226 was the least stable
of the amino acid compositions, having a total impurity level of
28.88% at an elevated temperature of 40.degree. C. for 4 weeks, and
a total impurity level of 44.70% at an elevated temperature of
55.degree. C. for 2 weeks.
[0037] Arginine can be used in different amounts relative to the
amount of caspofungin acetate in solid compositions. Table 3 lists
the results of stability analyses of lyophilized compositions of
caspofungin acetate having mass ratios of arginine 214 to
caspofungin acetate of 1:1 or 2:1. For each solid composition
listed in Table 3,
50 mg caspofungin acetate was combined with the listed amino acid
and with water for injection (USP), and the pH was adjusted. The
aqueous mixtures were then lyophilized to provide solid powders.
Samples of each solid composition were sealed in vials at
temperatures of 25.degree. C., 40.degree. C. or 55.degree. C. The
stability of the caspofungin acetate in the compositions over time
at each temperature was determined by analyzing samples by HPLC and
then calculating the total amount of relevant impurities detected
in each HPLC analysis by peak area percent, as described above with
regard to the results of Table 1. Table 3 lists the percent total
impurities measured for the lyophilized compositions.
TABLE-US-00003 TABLE 3 Caspofungin Acetate (CA) Compositions
Containing Amino Acids (AA) Amino acid (AA): Arginine Mass Ratio
(AA:CA): 1:1 2:1 2:1 2:1 pH*: 6.55 5.77 6.74 7.46 Moisture content
(%): 0.67 -- -- -- Time Temperature (weeks) (.degree. C.) Total
Impurities (%) 0 -- 0.78 1.25 1.28 1.50 12 25 -- 1.53 1.63 1.68 2
40 1.53 -- -- -- 4 2.23 1.91 2.03 2.12 8 2.61 2.73 2.42 2.52 12
2.56 2.84 2.69 2.77 2 55 2.87 3.82 3.96 4.08 4 4.42 4.81 4.91 5.39
*pH of liquid when reconstituted in water for injection.
[0038] The solid compositions having mass ratios of arginine 214 to
caspofungin acetate of 1:1 or 2:1 listed in Table 3 had good
stability of the caspofungin acetate. When stored at 40.degree. C.
for up to 12 weeks, each of the listed compositions maintained
total impurity levels below 3%. When stored at 55.degree. C., the
composition having an alkaline pH upon reconstitution had slightly
less stability of the caspofungin acetate than did the compositions
having acidic pH's. Each of the listed compositions, however,
maintained total impurity levels below 5.5% when stored at
55.degree. C. for up to
4 weeks.
[0039] The stabilization of caspofungin acetate by amino acids is
surprising and unexpected, as shown by comparing the stabilities of
solid compositions of caspofungin acetate in combination with a
typical lyophilization stabilizing agent and/or glycine. Solid
compositions of caspofungin acetate containing hydroxyethyl starch
(HES) were less stable than were solid compositions of caspofungin
acetate containing glycine. As HES is a typical lyophilization
stabilizing agent, the improvement in caspofungin acetate
stabilization that occurs when HES is replaced with glycine is not
due to a simple replacement of one known stabilizing agent with
another stabilizing agent. Moreover, since glycine was the least
effective stabilizer of the amino acids listed in Tables 1 and 2
above, the improvement in stabilization achieved by replacing the
HES with an amino acid is not a result of optimization of the amino
acid composition.
[0040] Table 4 lists the results of stability analyses of
lyophilized compositions of caspofungin acetate with HES and/or
glycine. For each formulation listed in Table 4,
50 mg caspofungin acetate was combined with the listed excipient(s)
and with water for injection (USP), and the pH was adjusted to
about 6.0. The aqueous mixtures were then lyophilized to provide
solid powders. Samples of each formulation were sealed in vials at
temperatures of 5.degree. C., 25.degree. C. or 40.degree. C. The
stability of the caspofungin acetate in the formulations over time
at each temperature was determined by analyzing samples by HPLC and
then calculating the total amount of relevant impurities detected
in each HPLC analysis by peak area percent, as described above with
regard to the results of Table 1. Table 4 lists the percent total
impurities for lyophilized formulations of caspofungin acetate with
the excipients HES and/or glycine.
TABLE-US-00004 TABLE 4 Stability of Caspofungin Acetate
Compositions Containing HES and/or Glycine Excipient HES + HES
Glycine (1:1) Glycine Mass Ratio 2:1 2:1 2:1 1:1 1:1
(Excipient:Caspo- fungin Acetate): Moisture content 0.62 0.39 0.49
0.53 1.29 (%): Time Temperature (days) (.degree. C.) Total
Impurities (%) 0 -- 2.10 1.25 0.81 0.90 1.02 7 5 2.90 1.57 0.90
1.08 1.12 14 2.85 1.61 0.85 1.09 -- 28 3.40 1.75 0.84 1.09 1.31 7
25 6.48 3.39 1.48 2.09 2.58 14 8.79 4.30 1.90 2.67 3.59 28 10.15
5.89 2.68 3.76 5.31 7 40 18.04 12.21 5.10 7.87 8.08 14 24.71 16.98
7.59 12.52 13.17 28 -- -- 9.40 13.76 --
[0041] The HES formulation (mass ratio of HES to caspofungin
acetate of 2:1) had a high level of impurities even at the
beginning of the analysis. The 2.10% impurity level at the
beginning of the analysis rose to 3.40%, 10.15% and 24.71% after
storage for 28 days at 5.degree. C., for 28 days at 25.degree. C.
(room temperature), and for 14 days at 40.degree. C.,
respectively.
[0042] Substituting half of the HES excipient with glycine reduced
the amount of impurities in the formulation relative to the amounts
in the 2:1 HES formulation. Substituting half of the HES excipient
with glycine reduced the amount of impurities at the beginning of
the analysis by 41% [40.5%=100%.times.(2.10%-1.25%)/2.10%], reduced
the amount of impurities after storage for 28 days at 5.degree. C.
by 49% [48.5%=100%.times.(3.40%-1.75%)/3.40%], reduced the amount
of impurities after storage for 28 days at 25.degree. C. by 42%
[42.0%=100%.times.(10.15%-5.89%)/10.15%], and reduced the amount of
impurities after storage for 14 days at 40.degree. C. by 31%
[31.3%=100%.times.(24.71%-16.98%)/24.71%].
[0043] Substituting the remaining HES excipient with glycine
further reduced the amount of impurities in the formulation. The
formulations with glycine but without HES as an excipient (mass
ratio of glycine to caspofungin acetate of 1:1 or 2:1), had
impurity levels of approximately 1% or lower at the beginning of
the analysis. Substituting the remaining HES excipient with glycine
(mass ratio glycine to caspofungin acetate of 2:1) further reduced
the amount of impurities at the beginning of the analysis by 35%
[35.2%=100%.times.(1.25%-0.81%)/1.25%], further reduced the amount
of impurities after storage for 28 days at 5.degree. C. by 52%
[52.0%=100%.times.(1.75%-0.84%)/1.75%], further reduced the amount
of impurities after storage for
28 days at 25.degree. C. by 55%
[54.5%=100%.times.(5.89%-2.68%)/5.89%], and further reduced the
amount of impurities after storage for 14 days at 40.degree. C. by
55% [55.3%=100%.times.(16.98%-7.59%)/16.98%]. Overall, substituting
the entire HES excipient with glycine reduced the amount of
impurities at the beginning of the analysis by 61%
[61.4%=100%.times.(2.10%-0.81%)/2.10%], reduced the amount of
impurities after storage for 28 days at 5.degree. C. by 75%
[75.3%=100%.times.(3.40%-0.84%)/3.40%], reduced the amount of
impurities after storage for 28 days at 25.degree. C. by 74%
[73.6%=100%.times.(10.15%-2.68%)/10.15%], and reduced the amount of
impurities after storage for 14 days at 40.degree. C. by 69%
[69.3%=100%.times.(24.71%-7.59%)/24.71%].
[0044] The stabilization of caspofungin acetate due to removal of
HES was observed even when the concentration of the amino acid was
lower than the concentration of the HES. The formulation having a
mass ratio glycine to caspofungin acetate of 1:1 and a moisture
content of 0.53% corresponded to removing the HES excipient from
the formulation having a mass ratio of HES to glycine to
caspofungin acetate of 1:1:1. Thus, removal of the HES reduced the
amount of impurities at the beginning of the analysis by 28%
[28.0%=100%.times.(1.25%-0.90%)/1.25%], reduced the amount of
impurities after storage for 28 days at 5.degree. C. by 38%
[37.7%=100%.times.(1.75%-1.09%)/1.75%], reduced the amount of
impurities after storage for 28 days at 25.degree. C. by 36%
[36.2%=100%.times.(5.89%-3.76%)/5.89%], and reduced the amount of
impurities after storage for 14 days at 40.degree. C. by 26%
[26.3%=100%.times.(16.98%-12.52%)/16.98%].
[0045] Overall, switching the formulation from a mass ratio of HES
to caspofungin acetate of 2:1 to a mass ratio of glycine to
caspofungin acetate of 1:1 (moisture content of 0.53%) reduced the
amount of impurities at the beginning of the analysis by 57%
[57.1%=100%.times.(2.10%-0.90%)/2.10%], reduced the amount of
impurities after storage for 28 days at 5.degree. C. by 68%
[67.9%=100%.times.(3.40%-1.09%)/3.40%], reduced the amount of
impurities after storage for 28 days at 25.degree. C. by 63%
[63.0%=100%.times.(10.15%-3.76%)/10.15%], and reduced the amount of
impurities after storage for 14 days at 40.degree. C. by 49%
[49.3%=100%.times.(24.71%-12.52%)/24.71%]. Thus, although the
caspofungin acetate was less stable in a formulation having a
glycine to caspofungin acetate mass ratio of 1:1 than in a
formulation having a glycine to caspofungin acetate mass ratio of
2:1, the caspofungin acetate was still more stable when combined
with glycine as the only excipient than when HES was the only
excipient.
[0046] The stabilization of lyophilized caspofungin acetate in
combination with an amino acid may be affected by the water content
of the lyophilized solid. Referring to Table 3, an approximately
2-fold increase in water content (from 0.53% to 1.29%) of the
lyophilized formulation containing a 1:1 mass ratio of glycine to
caspofungin acetate resulted in a decrease in caspofungin acetate
stability. Even this decreased stability, however, was an
improvement over the formulations that included HES as an excipient
but that had a lower moisture content. Thus, even when combined
with a moisture increase of 231%
[230.8%=100%.times.(1.29%-0.39%)/0.39%], removing the HES excipient
from the formulation having a mass ratio of HES to glycine to
caspofungin acetate of 1:1:1 reduced the amount of impurities at
the beginning of the analysis by 18%
[18.4%=100%.times.(1.25%-1.02%)/1.25%], reduced the amount of
impurities after storage for 28 days at 5.degree. C. by 25%
[25.1%=100%.times.(1.75%-1.31%)/1.75%], reduced the amount of
impurities after storage for 28 days at 25.degree. C. by 10%
[9.8%=100%.times.(5.89%-5.31%)/5.89%], and reduced the amount of
impurities after storage for 14 days at 40.degree. C. by 22%
[22.4%=100%.times.(16.98%-13.17%)/16.98%]. Overall, switching the
formulation from a mass ratio of HES to caspofungin acetate of 2:1
to a mass ratio of glycine to caspofungin acetate of 1:1, even when
combined with a moisture increase of 108%
[108.1%=100%.times.(1.29%-0.62%)/0.62%], reduced the amount of
impurities at the beginning of the analysis by 51%
[51.4%=100%.times.(2.10%-1.02%)/2.10%], reduced the amount of
impurities after storage for 28 days at 5.degree. C. by 62%
[61.5%=100%.times.(3.40%-1.31%)/3.40%], reduced the amount of
impurities after storage for 28 days at 25.degree. C. by 48%
[47.7%=100%.times.(10.15%-5.31%)/10.15%], and reduced the amount of
impurities after storage for 14 days at 40.degree. C. by 47%
[46.7%=100%.times.(24.71%-13.17%)/24.71%].
[0047] The surprising and unexpected stabilization of caspofungin
by amino acids may be used to prepare solid compositions including
caspofungin acetate that are more stable than a conventional solid
composition including caspofungin acetate, mannitol and sucrose.
The surprising and unexpected stabilization of caspofungin by amino
acids may be used to prepare solid compositions including
caspofungin acetate that are able to protect caspofungin acetate
from degradation for a year or longer at room temperature
(.about.25.degree. C.), and for 6 months or longer at elevated
temperatures.
[0048] A solid composition that includes caspofungin acetate and an
amino acid may include an amount of the amino acid sufficient to
stabilize the caspofungin acetate. Preferably the amount of the
amino acid in the composition is at most an amount that will
dissolve in a sample of aqueous liquid, such as a volume of aqueous
liquid used for reconstitution of the solid composition.
[0049] In one example, a solid composition that includes
caspofungin acetate and an amino acid may include from 20 to 350 mg
of the amino acid. For a solid composition that includes
approximately 50 mg caspofungin acetate, the amount of amino acid
in the composition preferably is from 20 to 250 mg, from 20 to 150
mg, from 20 to 100 mg, from 30 to 250 mg, from 30 to 150 mg, or
from 30 to 100 mg. For a solid composition that includes
approximately 70 mg caspofungin acetate, the amount of amino acid
in the composition preferably is from 28 to 350 mg, from 28 to 210
mg, from 28 to 140 mg, from 42 to 350 mg, from 42 to 210 mg, or
from 42 to 140 mg.
[0050] A solid composition that includes caspofungin acetate and an
amino acid may have a mass ratio of amino acid to caspofungin of at
least 2:5, where the mass of amino acid in the ratio accounts for
all amino acid species present in the solid composition. Preferably
the mass ratio of amino acid to caspofungin acetate is at least
3:5, at least 1:1 or at least 2:1. Preferably the mass ratio of
amino acid to caspofungin acetate is at most 3:1 or at most 2:1.
Preferably the mass ratio of amino acid to caspofungin acetate is
from 2:5 to 3:1, from 3:5 to 2:1, or from 1:1 to 3:1.
[0051] A solid composition that includes caspofungin acetate and an
amino acid may further include an acid and/or a base. The pH of a
saturated solution of caspofungin acetate in water is about 6.6
(CANCIDAS.RTM. prescribing information, Merck Sharp & Dohme
Corp., June, 2010, p. 14). The amount of the acid and/or base may
be an amount sufficient to provide a pH in the range of 5 to 7 or
of 6 to 7 when the composition is reconstituted in 10.8 mL of an
aqueous liquid. Preferably the amount of the acid and/or base may
be an amount sufficient to provide a pH in the range of 5 to 7 or
of 6 to 7 when the composition is reconstituted in 10.8 mL of 0.9%
aqueous sodium chloride (USP), sterile water for injection, or
bacteriostatic water for injection containing either 0.9% benzyl
alcohol or a combination of methylparaben and propylparaben.
Presently preferred acids include hydrochloric acid. Presently
preferred bases include sodium hydroxide.
[0052] A solid composition that includes caspofungin acetate and an
amino acid may further include one or more other substances.
Non-limiting examples of other substances include bulking agents,
carriers, diluents, fillers, salts, buffers, stabilizers,
solubilizers, preservatives, antioxidants, and tonicity
contributors. Substances that may be useful in formulating
pharmaceutically acceptable compositions, and methods of forming
such compositions, are described for example in Remington: The
Science and Practice of Pharmacy, 20th Ed., ed. A. Gennaro,
Lippincott Williams & Wilkins, 2000, and in Kibbe, "Handbook of
Pharmaceutical Excipients," 3.sup.rd Edition, 2000. Preferably the
solid composition does not include dextrose, as caspofungin acetate
is reportedly unstable when reconstituted in a liquid containing
dextrose. See CANCIDAS.RTM. prescribing information, Merck Sharp
& Dohme Corp., June, 2010, p. 3.
[0053] A solid composition including caspofungin acetate, at least
one amino acid and optionally one or more other substances may be
prepared by forming a liquid mixture that includes a solvent,
caspofungin acetate, amino acid(s) and optionally one or more other
substances, and lyophilizing the liquid mixture. The lyophilizing
may include freeze-drying the liquid mixture to provide a solid
composition. The liquid mixture may include caspofungin acetate and
an amino acid in the amounts described above. The liquid mixture
may further include an acid, a base and/or one or more other
substances, as described above.
[0054] The liquid mixture may include from 0.1 to 5 mL solvent,
from 10 to 150 mg caspofungin acetate, and from 20 to 350 mg amino
acid. The liquid mixture may include from 0.5 to 2 mL solvent, from
25 to 100 mg caspofungin acetate, and from 20 to 350 mg amino acid.
The liquid mixture may include from 0.75 to 1.5 mL solvent, from 50
to 70 mg caspofungin acetate, and from 20 to 350 mg amino acid. The
mass ratio of amino acid to caspofungin acetate in the liquid
mixture may be from 2:5 to 3:1, from 3:5 to 2:1, or from 1:1 to
3:1.
[0055] The solvent, caspofungin acetate, amino acid, optional acid,
optional base and one or more other optional substances may be
combined in any order when forming the liquid mixture. For example,
a liquid mixture may be formed by adding the caspofungin acetate
and the amino acid(s) to a container including the solvent, and
then adding the acid and/or base to achieve the desired pH in the
liquid mixture. The liquid mixture preferably has a pH of from 6 to
7. A presently preferred pH of the liquid mixture is 6.+-.1.
[0056] The liquid mixture including the solvent, caspofungin
acetate, amino acid, and any other optional ingredients may be
lyophilized to form a solid composition, such as by subjecting the
liquid mixture to freeze-drying. Freeze-drying of the liquid
mixture may include maintaining the liquid mixture in an inert
atmosphere, such as nitrogen or argon. Preferably the liquid
mixture is placed in glass vials prior to lyophilization, and the
amount of the liquid mixture in each vial is based on the amount of
caspofungin acetate intended to be present in the final solid
composition in the vial.
[0057] In a typical lyophilization process, the temperature of the
liquid mixture is lowered to a temperature at or below the
solidification point of the liquid mixture. If the liquid mixture
forms a glass when cooled, the solidification point is the glass
transition temperature. If the liquid mixture forms crystals when
cooled, the solidification point is the eutectic point. The
solidified mixture is then dried under vacuum. Typically, the
drying process includes a primary drying step in which the
temperature of the solidified mixture is raised gradually while
most of the water is removed from the mixture by the vacuum, and a
secondary drying step in which the temperature of the solidified
mixture is raised further while residual moisture is removed from
the mixture by the vacuum. The temperature is kept at or below the
desired storage temperature for the final solid composition.
Lyophilization typically is complete within 48 hours, but may
require additional time. The solid composition resulting from the
lyophilization typically is sealed for later use. Details regarding
the lyophilization process may be found, for example, in Remington:
The Science and Practice of Pharmacy, 20th Ed., ed. A. Gennaro,
Lippincott Williams & Wilkins, 2000.
[0058] The lyophilized solid composition may be stored for later
reconstitution and administration. Preferably the solid composition
is stored at a temperature of from 10.degree. C. to 40.degree. C.,
from 15.degree. C. to 35.degree. C., from 20.degree. C. to
30.degree. C., or about 25.degree. C. Preferably the solid
composition is sealed in a glass vial to protect the composition
from moisture in the surrounding environment.
[0059] A solid composition including caspofungin acetate, at least
one amino acid and optionally one or more other substances may be
administered to a patient by combining the composition with an
aqueous carrier liquid to form an aqueous mixture, and
administering the aqueous mixture into the patient by, for example,
injection. Preferably, the aqueous carrier liquid is a
pharmaceutically acceptable carrier liquid. Non-limiting examples
of pharmaceutically acceptable carrier liquids include water and
saline, such as sodium chloride injection, phosphate buffered
saline (PBS), Ringers solution or lactated Ringers injection. The
aqueous carrier liquid also may include fixed oils, fatty esters or
polyols, particularly if the aqueous mixture for injection is a
suspension. The aqueous carrier liquid also may include one or more
other substances such as buffers, stabilizers, solubilizers,
preservatives and antioxidants. Preferably the solid composition
dissolves in the aqueous carrier liquid to form a solution.
[0060] Presently preferred aqueous carrier liquids include sodium
chloride injection, such as solutions containing 0.9%, 0.45% or
0.225% sodium chloride. Presently preferred aqueous carrier liquids
include sterile water for injection. Presently preferred aqueous
carrier liquids include bacteriostatic water for injection, which
may include, for example, either 0.9% benzyl alcohol or a
combination of methylparaben and propylparaben. Presently preferred
aqueous carrier liquids include lactated Ringers injection.
Preferably the aqueous carrier liquid does not include
dextrose.
[0061] The amount of aqueous carrier liquid may be sufficient to
provide an initial aqueous mixture containing caspofungin acetate
at a concentration of 5 milligrams per milliliter (mg/mL) or 7
mg/mL. At these concentrations, it is convenient to provide a 50 mg
or 70 mg dose of caspofungin acetate to a patient, such as by
dispensing 10 milliliters (mL) of the aqueous mixture into another
aqueous liquid to form a final aqueous mixture. While an initial
aqueous mixture containing caspofungin acetate at a concentration
of 5 or 7 mg/mL may be injected into a patient, the presently
recommended procedure includes combining the initial aqueous
mixture with another aqueous liquid to form a final aqueous
mixture, which is then administered to a patient.
[0062] The amount of aqueous carrier liquid may be sufficient to
provide a final aqueous mixture containing caspofungin acetate at a
concentration of at most 0.5 mg/mL. For example, 10 mL of an
initial aqueous mixture containing 5 or 7 mg/mL caspofungin acetate
may be combined with 250 mL of an aqueous carrier liquid to provide
a final aqueous mixture containing 0.19 mg/mL or 0.27 mg/mL
caspofungin acetate (0.192 mg/mL=50 mg/(250 mL+10 mL); 0.269
mg/mL=70 mg/(250 mL+10 mL)). Presently preferred concentrations of
caspofungin acetate in a final aqueous mixture for administration
to a patient are from 0.05 to 0.5 mg/mL, from 0.1 to
0.4 mg/mL, and from 0.15 to 0.3 mg/mL. Presently preferred
concentrations of caspofungin acetate in a final aqueous mixture
for administration to a patient include 0.19 mg/mL and 0.27
mg/mL.
[0063] An aqueous mixture formed from the solid composition may be
administered to provide an initial dose of 50-70 mg of caspofungin
acetate to a patient. An aqueous mixture formed from the solid
composition may be administered to provide a daily dose of 35-70 mg
of caspofungin acetate to a patient. Doses outside of these ranges
also may be administered. Typically, an initial dose includes
70 mg caspofungin acetate, and subsequent daily doses include 50
mg/mL caspofungin acetate. Daily doses of 70 mg/mL caspofungin
acetate may be advisable under certain conditions, such as an
insufficient response by the fungal infection and co-administration
with other drugs that induce drug clearance (such as rifampin,
nevirapine, efavirenz, carbamazepine, dexamethasone and phenytoin).
Daily doses below 50 mg/mL of caspofungin acetate may be advisable
under certain conditions, such as for pediatric patients or
patients having moderate hepatic impairment.
[0064] To provide a clear and more consistent understanding of the
specification and claims of this application, the following
definitions are provided.
[0065] The term "group" means a linked collection of atoms or a
single atom within a molecular entity, where a molecular entity is
any constitutionally or isotopically distinct atom, molecule, ion,
ion pair, radical, radical ion, complex, conformer etc.,
identifiable as a separately distinguishable entity.
[0066] The term "amino acid" means a molecular entity that includes
at least one carboxylic acid group [--C(.dbd.O)OH] and at least one
primary or secondary amine group [--NH.sub.2 or --RNH, where --R is
a molecular entity other than --H], but lacking a secondary amide
group [--C(.dbd.O)--NH--].
[0067] The term "mass ratio" of two substances means the mass of
one substance (S1) relative to the mass of the other substance
(S2), where both masses have identical units, expressed as
S1:S2.
[0068] The term "lyophilizing" means removing from a solution or an
emulsion one or more substances having the lowest boiling points by
freezing the solution or emulsion and applying a vacuum to the
frozen mixture.
[0069] The term "solid" means a substance that is not a liquid or a
gas. A solid substance may have one of a variety of forms,
including a monolithic solid, a powder, a gel or a paste.
[0070] While various embodiments of the invention have been
described, it will be apparent to those of ordinary skill in the
art that other embodiments and implementations are possible within
the scope of the invention. Accordingly, the invention is not to be
restricted except in light of the attached claims and their
equivalents.
* * * * *