U.S. patent application number 13/237193 was filed with the patent office on 2012-04-26 for caspofungin composition.
This patent application is currently assigned to XELLIA PHARMACEUTICALS APS. Invention is credited to Suresh Gidwani, Anita Bevetek Mocnik, Neil Parikh, Piyush Patel, Atul Patil, Swapnil Shirode.
Application Number | 20120101030 13/237193 |
Document ID | / |
Family ID | 44677877 |
Filed Date | 2012-04-26 |
United States Patent
Application |
20120101030 |
Kind Code |
A1 |
Shirode; Swapnil ; et
al. |
April 26, 2012 |
Caspofungin Composition
Abstract
The present invention relates to a composition comprising
caspofungin or a pharmaceutical acceptable salt thereof and
succinate or lactate as a buffering agent.
Inventors: |
Shirode; Swapnil; (Nasik,
IN) ; Patel; Piyush; (Mumbai, IN) ; Gidwani;
Suresh; (Mumbai, IN) ; Parikh; Neil; (Irvine,
CA) ; Patil; Atul; (Maharashtra, IN) ; Mocnik;
Anita Bevetek; (Kraljevec, HR) |
Assignee: |
XELLIA PHARMACEUTICALS APS
Copenhagen S.
DK
|
Family ID: |
44677877 |
Appl. No.: |
13/237193 |
Filed: |
September 20, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61384333 |
Sep 20, 2010 |
|
|
|
Current U.S.
Class: |
514/3.4 ;
514/3.6 |
Current CPC
Class: |
A61P 3/10 20180101; A61K
38/12 20130101; A61P 31/10 20180101; A61K 47/12 20130101; A61K
47/10 20130101; A61K 47/26 20130101; A61K 9/19 20130101; A61K
9/0019 20130101 |
Class at
Publication: |
514/3.4 ;
514/3.6 |
International
Class: |
A61K 38/12 20060101
A61K038/12; A61P 3/10 20060101 A61P003/10 |
Claims
1. A composition comprising: a) a pharmaceutically effective amount
of caspofungin or a pharmaceutically acceptable salt thereof; b) a
pharmaceutically acceptable amount of one or more pharmaceutically
acceptable excipients effective to form a lyophilized cake; and c)
a pharmaceutically effective amount of a buffering agent selected
from the group consisting of lactate and succinate.
2. A composition according to claim 1, wherein the pharmaceutically
acceptable salt of caspofungin is an acetate salt.
3. A composition according to claim 1, wherein the buffering agent
is succinate.
4. A composition according to claim 1, wherein the buffering agent
is lactate.
5. A composition according to claim 1, wherein the one or more
excipients is selected from the group consisting of diluents,
antioxidants, and preservatives.
6. A composition according to claim 1, wherein the excipients is
selected from the group consisting of sucrose, mannitol; and a
combination thereof.
7. A compositing according to claim 1, wherein the composition
comprises: a) a pharmaceutically acceptable amount of caspofungin
or a pharmaceutically acceptable salt thereof; b) about 10-200
mg/ml of one or more pharmaceutically acceptable excipients
effective to form a lyophilized cake; c) a pharmaceutically
effective amount of lactate or succinate effective to provide a
pharmaceutically acceptable pH.
8. A composition according to claim 7, wherein the composition
comprises an amount of caspofungin or a salt thereof corresponding
to about 42 mg/ml caspofungin.
9. A composition according to claims 8, wherein the composition
comprises: a) about 46 mg/ml diacetate salt of caspofungin; b)
about 30 mg/ml sucrose and about 20 mg/ml mannitol; and c) about
1.5 mg/ml succinate or about 1.15 mg/ml lactate.
10. A process for making a caspofungin composition according to
claim 1 comprising the steps of: a) mixing an aqueous solution
comprising a pharmaceutically acceptable amount of one or more
excipients with a pharmaceutically effective amount of a buffering
agent selected from the group consisting of lactate and succinate;
b) optional adjusting the pH by adding a base to obtain a
pharmaceutically acceptable pH; c) adding to the mixture of a) a
pharmaceutically acceptable amount of caspofungin or a
pharmaceutically acceptable salt thereof; d) optional adjusting the
pH by adding a base to obtain a pharmaceutically acceptable pH; e)
filtering the solution obtained in d).
11. A process for making a caspofungin composition according to
claim 9, wherein step a) is performed by firstly preparing an
aqueous solution comprising a pharmaceutically effective amount of
a buffering agent selected from the group consisting of lactate and
succinate; and then adding to said solution of buffering agent a
pharmaceutically acceptable amount of one or more excipients
dissolved in water.
12. A process for making a caspofungin composition according to
claim 9, wherein step a) is performed by firstly dissolving a
pharmaceutically acceptable amount of one or more excipients in
water; then adding to said solution of exipient(s) a
pharmaceutically effective amount of a buffering agent selected
from the group consisting of lactate and succinate.
13. A process according to claim 9, wherein the pH is adjusted to
5.0-5.7 in step b).
14. A process according to claim 9, wherein the pH is adjusted to
about 6 in step d).
15. A process according to claim 9, wherein caspofungin diacetate
is added in step c).
16. A lyophilized formulation consisting of a composition which
prior to lyophilization corresponds to a composition according to
claim 9.
17. A formulation for parenteral administration consisting of a
lyophilized formulation according to claim 16, wherein said
lyophilized formulation is dissolved in a pharmaceutically
acceptable reconstitution solution suitable for parenteral
administration to a patient in need thereof.
18. A formulation for parenteral administration according to claim
17, wherein the pharmaceutically acceptable reconstitution solution
is selected from the group consisting of distilled water, sterile
water, physiologic saline, and bacteriostatic water.
19. A kit comprising a first container comprising the lyophilized
formulation according to claim 15 and a second container comprising
a parenterally acceptable solvent for reconstitution thereof, and
optionally a container comprising means for administrating the
reconstituted solution to a patient in need thereof.
20. A method of treating or preventing a fungal infection,
comprising parenterally administering to an individual in need
thereof a composition according to claim 8.
21. The method according to claim 20, wherein the infections is
caused by a fungus belonging to the species Candida or
Aspergillus.
22. The method according to claim 21, wherein the infections is
caused by a fungus belonging to the species infection is caused by
C. albicans, C. tropicalis, C. krusei, C. glabrata, A. fumigatus,
A. flavus and A. nigerc.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Patent Application Ser. No. 61/384,333, filed Sep. 20, 2010, which
is incorporated by reference herein in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to a composition comprising
caspofungin or a pharmaceutical acceptable salt thereof and
succinate or lactate as a buffering agent.
BACKGROUND
[0003] Caspofungin (CAS 162808-62-0) is the first of a new class of
semi-synthetic antifungal agents belonging to the class of
echinocandins. It may be represented by the formula I
##STR00001##
[0004] Caspofungin is commonly prepared by synthetic derivatisation
of pneumocandin B.sub.0 which is obtained by fermentation of the
fungus Glarea lozoyensis. The antifungal activity of caspofungin is
due to its inhibition of the biosynthesis of .beta.-(1,3)-D-glucan,
an integral component of the fungal cell wall. It is used for the
treatment of invasive aspergillosis in patients who are refractory
to or intolerant of other therapies, as well as empirical therapy
for presumed fungal infections in febrile, neutropenic
patients.
[0005] Caspofungin as a compound is claimed in the U.S. Pat. No.
5,378,804 issued to Merck & Co.
[0006] U.S. Pat. No. 5,952,300 discloses a composition for treating
and/or preventing fungal infections comprising caspofungin and the
pharmaceutically active salt thereof, a pharmaceutically active
amount of an acetate buffer and a pharmaceutically acceptable
amount of excipients such as a sucrose/mannitol mixture to form a
lyophilized cake.
[0007] A lyophilized caspofungin product is available on the
marketed as its diacetate salt by Merck & Co., under the trade
name Cancidas.RTM. (RLD product). Cancidas.RTM. contains in
addition to the active ingredient caspofungin diacetate, acetic
acid, sodium hydroxide, sucrose and mannitol. Before administration
to a patient, the lyophilized product is reconstituted by adding a
diluent and the desired amount of the diluted mixture is
transferred to infusion bag to be administered to the patient in
need thereof.
[0008] A well known problem with caspofungin compositions prepared
for reconstitution prior to administration to the patient, is that
the compound is highly unstable resulting in the formation of
various degradation products such as e.g. hydrolysis products
(impurity B) and dimerization products (impurity C). There will
also be impurities present in the composition being formed during
the fermentation of the starting material and which have passed
along through the synthesis of caspofungin. The main impurity
originating from the fermentation is the serine analogue of
caspofungin having the formula as shown in WO 2009/158034
[0009] In addition to the above mentioned degradation impurities
and impurities formed during preparation of known caspofungin
compositions, further non-characterised impurities are also
present. The mechanisms behind the formation of the impurities are
not fully understood. However, it is known that the buffer system
used when preparing the composition may increase the degradation
product formation during preparation and storage. In U.S. Pat. No.
5,952,300 it is, for example, stated that the use of tartrate
buffer resulted in undesired degradation products. The solution to
the degradation problem according to the teaching of U.S. Pat. No.
5,952,300 is the use of an acetate buffer.
[0010] Various other strategies are also known to avoid degradation
and improve the stability of caspofungin compositions. For example,
in WO 2009/002481, a lyophilized caspofungin composition comprising
in addition to caspofungin diacetate and an acetate buffer, one or
more non-reducing sugars such as trehalose, sucrose, raffinose, or
sorbitol or combinations thereof is disclosed.
[0011] In WO 2008/012310, a caspofungin composition is disclosed
comprising, in addition to a pharmaceutically acceptable salt of
caspofungin and excipients, only very low levels of a buffering
agent, or which is free of a buffering agent.
[0012] Although various solutions to the impurity problem are
suggested in the prior art, there is still a need for a caspofungin
composition with improved stability in respect of the formation of
impurities during storage.
SUMMARY OF THE INVENTION
[0013] The present inventors have surprisingly found that an
antifungal composition according to the present invention
comprising caspofungin or a pharmaceutically acceptable salt
thereof, one or more pharmaceutically acceptable excipients and
including succinat or lactate as a buffering agent, is stable
resulting in reduced formation of degradation products during
storage.
[0014] The present invention therefore provides a composition
comprising a) a pharmaceutically effective amount of caspofungin or
a pharmaceutically acceptable salt thereof; b) a pharmaceutically
acceptable amount of one or more pharmaceutically acceptable
excipients effective to form a lyophilized cake; and c) a
pharmaceutically effective amount of a buffering agent selected
from the group consisting of lactate and succinate.
[0015] According to one aspect of the invention, the
pharmaceutically acceptable salt of caspofungin is an acetate salt.
According to another aspect, the composition according to the
invention comprises a diacetate salt of caspofungin.
[0016] According to yet another aspect of the invention, the
buffering agent of the composition is succinate. According to yet
another aspect of the invention, the buffering agent of the
composition is lactate.
[0017] Furthermore, a composition is provided wherein the
excipients is selected from the group consisting of stabilisers,
diluents, antioxidants, or preservatives. According to one aspect,
the stabilisators are selected from the group consisting of sucrose
and mannitol; or a combination thereof.
[0018] According to a further aspect of the present invention, a
compositing is provided comprising a) pharmaceutically acceptable
amount of caspofungin or a pharmaceutically acceptable salt
thereof; b) about 10-200 mg/ml of one or more pharmaceutically
acceptable excipients effective to form a lyophilized cake; and c)
a pharmaceutically effective amount of lactate or succinate
providing a pharmaceutically acceptable pH.
[0019] According to one embodiment, the composition of the
invention comprises an amount of caspofungin or a salt thereof
corresponding to about 42 mg/ml caspofungin. According to yet
another embodiment, the composition of the invention comprises
about 46 mg/ml diacetate salt of caspofungin; about 30 mg/ml
sucrose and about 20 mg/ml mannitol; and about 1.5 mg/ml succinate
or about 1.15 mg/ml lactate.
[0020] The present invention furthermore provides a process for
making a caspofungin composition according the invention comprising
the steps of a) mixing an aqueous solution comprising a
pharmaceutically acceptable amount of one or more excipients with a
pharmaceutically effective amount of a buffering agent selected
from the group consisting of lactate and succinate; b) optionally
adjusting the pH by adding a base to obtain a pharmaceutically
acceptable pH; c) adding to the mixture of a) a pharmaceutically
acceptable amount of caspofungin or a pharmaceutically acceptable
salt thereof; d) optionally adjusting the pH by adding a base to
obtain a pharmaceutically acceptable pH; and e) filtering the
solution obtained in d).
[0021] The mixing of the solutions of step a) of the above process
may be performed in any order. Thus, according to one embodiment, a
process is provided wherein step a) is performed by firstly
preparing an aqueous solution comprising a pharmaceutically
effective amount of a buffering agent selected from the group
consisting of lactate and succinate; then adding to the said
solution of buffering agent a pharmaceutically acceptable amount of
one or more excipients dissolved in water. According to another
embodiment, a process is provided wherein step a) is performed by
firstly dissolving a pharmaceutically acceptable amount of one or
more excipients in water; then adding to said solution of
excipient(s) a pharmaceutically effective amount of a buffering
agent selected from the group consisting of lactate and
succinate.
[0022] According to one embodiment, the pH of step b) of the
present invention is adjusted to 5.0-5.7. According to another
embodiment, the pH of step d) of the present invention is adjusted
to about 6.
[0023] According to one embodiment, a caspofungin salt, preferably
caspofungin diacetate, is added in step c) of the process.
[0024] The present invention also provides a lyophilized
formulation which consists of a composition which prior to
lyophilization corresponds to a composition according to present
invention.
[0025] The present invention furthermore provides a formulation for
parenteral administration consisting of a lyophilized formulation
according to the invention, wherein said lyophilized formulation is
dissolved in a pharmaceutically acceptable reconstitution solution
suitable for parenteral administration to a patient in need
thereof. The pharmaceutically acceptable reconstitution solution
may e.g. be selected from the group consisting of distilled or
sterile water commonly used for injections, physiologic saline, and
bacteriostatic water.
[0026] According to yet another aspect of the invention, a kit is
provided comprising a first container comprising the lyophilized
formulation according to the invention and a second container
comprising a parenterally acceptable solvent for reconstitution
thereof, and optionally a container comprising means for
administrating the reconstituted solution to a patient in need
thereof.
[0027] The reconstituted formulation according to the present
invention may preferably be used in a method for treating or
preventing a fungal infection comprising parenterally administering
to a patient in need thereof, e.g. wherein the administration is
performed by infusion or injection.
[0028] The present invention finally provides a use of a
composition according to the invention for the preparation of a
formulation for parenteral administration for the treatment or
prevention of fungal infection, such as infections caused by a
fungus belonging to the species Candida or Aspergillus, such as
e.g. infections is caused by a fungus belonging to the species
infection is caused by C. albicans, C. tropicalis, C. krusei, C.
glabrata, A. fumigatus, A. flavus and A. nigerc. A method according
to any of the claims 15-16, for the treatment or prevention of
fungal infection, wherein the infections is caused by a fungus
belonging to the species Candida or Aspergillus.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] FIG. 1 shows the change in the amount of the total
impurities in the lyophilized formulations prepared according to
example 1 after storage in 1 month (1M) and 2 months (2M),
respectively, i.e., caspofungin composition comprising caspofungin
diacetate, sucrose, mannitol and as buffering agent either lactate,
succinate, tartrate or acetate, and as control, a composition as
above not comprising a buffering agent.
[0030] FIG. 2 shows the changes in impurity B (hydrolysis
degradation product), Impurity C (dimerization product) and the
total amounts of impurities in the lyophilized formulation prepared
according to example 2 after storage in 1 month (1M), 2 months (2M)
and 3 months (3M).
[0031] FIG. 3 shows the changes in impurity B (hydrolysis
degradation product), Impurity C (dimerization product) and the
total amounts of impurities in the lyophilized formulation prepared
according to example 3 after storage in 1 month (1M), 2 months (2M)
and 3 months (3M).
DETAILED DESCRIPTION OF THE INVENTION
[0032] The present invention will now be described in more detail
with reference to figures and examples. The following description
and examples intend to illustrate the present invention, and should
in no way be considered limiting. Furthermore, the skilled person
will acknowledge that various modifications may be introduced
without departing from the scope of the invention. Accordingly,
other embodiments of the present invention which are within the
abilities of the skilled person are to be understood to be within
the scope of the claims.
[0033] The term "caspofungin" as used herein means caspofungin free
base known under the CAS number 162808-62-0. The composition of the
present invention may comprise caspofungin or a pharmaceutical
acceptable salt thereof. The term "pharmaceutically acceptable
salts of caspofungin" as used herein means any non-toxic salts of
caspofungin. The skilled person is well known with suitable organic
or inorganic acids that may be used to form salts of caspofungin,
including mono-, di- and tri acid forms. For example,
pharmaceutically acceptable acid addition salts may be formed using
acids such as hydrochloric, hydrobromic, sulphonic, phosphoric,
maleic, malic, lactic, citric, acetic, tartaric, propionic,
succinic, oxalic, glutamic, pamoic acid etc. Also other acids well
known to the skilled person in respect of forming pharmaceutically
active salts may be used. Reference is inter alia made to Berge et
al., 1977, "Pharmaceutical salts", J. Pharm. Sci., 66(1), page
1-19. Several pharmaceutical acceptable salts of caspofungin are
furthermore known from e.g. U.S. Pat. No. 5,952,300, and WO
2008/12310.
[0034] According to one aspect of the invention, a lyophilized
formulation is provided comprising the acetate salt of caspofungin.
According to yet another aspect of the invention, a lyophilized
formulation is provided comprising the diacetate salt of
caspofungin. An acetate salt of caspofungin, such as a diacetate
salt of caspofungin may be prepared as disclosed in U.S. Pat. No.
5,952,300.
[0035] The term "lyophilized formulation" as used herein means a
formulation being prepared by lyophilization/freeze drying of a
mixture comprising a pharmaceutically effective amount of
caspofungin or a pharmaceutically acceptable salt thereof; a
pharmaceutically acceptable amount of one or more pharmaceutically
acceptable excipients; and a pharmaceutically acceptable amount of
a buffering agent selected from the group consisting of lactate and
succinate. The lyophilized formulation may be comprised in
lyophilization vials suitable for transport and handling, and for
the providing of a reconstituted formulation ready to be
administered to a patient in need thereof.
[0036] The one or more pharmaceutically acceptable excipients of
the composition of the invention may be any pharmaceutically
acceptable excipients suitable for formation of a lyophilized cake.
The one or more pharmaceutically acceptable excipients may further
be well known diluent(s) or carrier(s) suitable for parenteral
administration and which are well known to the skilled person.
Suitable excipients that may be comprised in a composition
according to the present invention may be selected from the
non-limiting list of the group consisting of stabilizers, diluents,
antioxidants, preservatives and the like. For example, a
non-limiting list of stabilizers useful in the composition of the
present invention comprises sucrose, trehalose, raffinose, sorbitol
and/or mannitol.
[0037] According to one aspect of the invention, the composition of
the present invention comprises sucrose or mannitol, or a
combination thereof. Based on the teaching of the present
invention, the skilled person will be able to select the
appropriate excipients and amounts thereof for the manufacturing of
a composition according to the present invention.
[0038] According to the present invention, the composition of the
invention comprises as a buffering agent lactate or succinate. The
buffering agent can be obtained by either dissolving the salt or
the acid form of the buffering agent into water e.g. lactate-salt
or lactic acid or succinate-salt or succinic acid. When preparing
the composition of the present invention, the buffer agent may also
be used in solid form, such as by adding succinic acid or lactic
acid into a solution of excipients. Said buffering agent is used in
a pharmaceutically effective amount ensuring the providing and
maintenance of a pharmaceutically acceptable pH value. More
specifically, a pharmaceutically acceptable pH value within the
meaning of the present invention is in the range of about 5 to
about 8, such as e.g. about 5.5-7.5, such as about 5.5-7.0, such as
about 5.5-6.5, such as e.g. about 6.0.
[0039] The composition of the present invention results in reduced
formation of total impurities during storage of a lyophilized
formulation prepared therefrom compared with lyophilized
formulations based on an acetate buffer system or lyophilized
formulations known in the art prepared from a composition not
comprising a buffering agent. The term "total impurities" as used
herein means the total amount of impurities commonly present in a
pharmaceutically acceptable caspofungin product or a
pharmaceutically active caspofungin salt prepared according to
method for preparing caspofungin or a salt thereof well known to
the skilled person in the art. The total amount of impurities
present may be measured by HPLC-analysis. The change in the total
amount of impurities during storage may be presented as the sum of
the area percentage of the total amount of impurities in a
formulation to be analysed. The persons skilled in the art are
familiar with various applicable HPLC devices and methods for
measuring the formation of impurities during storage.
[0040] The composition according to the present invention is
prepared by dissolving and mixing the ingredients, filtering the
obtained mixture, and after transferring the solution to suitable
vials. The so obtained solution is lyophilized to obtain a
lyophilized cake. Lyophilization, or freeze-drying, is a
dehydration process typically used to preserve unstable materials
or make a material more convenient for transport. It is commonly
used within the pharmaceutical industry and involves freezing of
the material in question and reduction of the surrounding pressure,
adding enough heat to allow the frozen water in the material to
sublime and thus be removed from the resulting lyophilized product.
The skilled person is well known with the various means and devices
available for lyophilization within the pharmaceutical area. The
composition according to the present invention is preferably
lyophilized in pharmaceutically acceptable vials according to the
method of the present invention to obtain a lyophilized cake of the
composition of the present invention.
[0041] The so obtained lyophilized formulation contained in a
lyophilization vial may later be reconstituted to its original form
prior to administration of the reconstituted solution to a patient
in need thereof. The term "formulation for parenteral
administration" as used herein means liquid formulation comprising
a pharmaceutically effective amount of the caspofungin composition
according to the present invention, and wherein said composition
have been dissolved in or mixed with one or more pharmaceutically
acceptable reconstitution solutions.
[0042] The reconstitution may be performed by dissolving the
lyophilized product in a pharmaceutically acceptable reconstitution
solution. The skilled persons in the art are familar with various
solutions useful for the reconstitution of a lyophilized
caspofungin formulation. A pharmaceutically acceptable
reconstitution solution is e.g. distilled or sterile water commonly
used for injections, physiologic saline, or bacteriostatic water
for injection. Bacteriostatic water commonly comprises
bacteriostatic compounds as preservatives, such as e.g. benzyl
alcohol.
[0043] A pharmaceutically acceptable amount of the reconstituted
formulation may then be transferred to means suitable for
parenteral administration, such as e.g. intramuscular,
subcutaneous, intravenous, intra-peritoneal administration.
[0044] The reconstituted formulation according to the present
invention may be used to treat or prevent infections in a patient.
The formulation may inter alia be used to prevent or fight an
infections caused by fungus belonging to the Candida species and
Aspergillus species. More specifically, said formulation may be
used to treat or prevent infections caused by e.g. C. albicans, C.
tropicalis, C. krusei, C. glabrata, A. fumigatus, A. flavus and A.
niger. The present invention therefore also provides a method for
the treatment or prevention of fungal infection, such as the
infections cause by the above mentioned species.
EXAMPLES
[0045] Preparation of Caspofungin Diacetate Formulations
[0046] A caspofungin composition was prepared by firstly dissolving
mannitol in water, then adding sucrose and succinic acid. After the
addition of succinic acid, pH was determined and 0.1 M NaOH was
then added to adjust the pH to 4.0. To the so-obtained solution,
caspofungin diacetate corresponding to 42 mg/ml caspofungin was
added. The pH of the so obtained solution was then again adjusted
to pH 6.1 with 0.1 M NaOH, and the solution was mixed by
stirring.
[0047] The volume of the solution was adjusted to 400 ml by adding
water acceptable for injection, and filtered through a 0.22 .mu.m
filter. The solution was thereafter transferred to 10 ml
lyophilization vials and stopped with sterile rubber stoppers. The
solution was then subjected to lyophilization. The preparation of
the composition, except during freeze drying, was performed at a
temperature of 2-8.degree. C.
[0048] The amount of the various ingredients of the composition was
as listed in the below table 1.
TABLE-US-00001 TABLE 1 Caspofungin diacetate 46.58 mg/ml Sucrose
30.00 mg/ml Mannitol 20.00 mg/ml Succinic Acid 1.50 mg/ml
[0049] Similar formulations with the difference that lactic acid,
tartaric acid, citric acid or acetic acid was used in stead of
succinic acid were prepared according to the above method. In
addition, a formulation not comprising any buffering agent was
prepared as a control.
[0050] The lyophilized cakes obtained were further subjected to
analysing to determine the stability in respect of formation of
impurities during storage (example 4). However, due to unexpected
and undesirable precipitation of caspofungin when using citric acid
as a buffering agent, said composition was abandoned for further
analysing
Preparation of Caspofungin Diacetate Formulation with Succinic
Acid
[0051] A caspofungin composition was prepared by firstly dissolving
succinic acid in water, then the pH of the solution was adjusted to
about 5.5-5.7 by adding NaOH solution. Then secondly sucrose and
mannitol were added to the above solution. If needed the pH was
again adjusted to about 5.5-5.7 by addition of NaOH. To the so
obtained solution, caspofungin diacetate was added. After complete
dissolution the pH was again adjusted with NaOH to reach about
5.9-6.1. The solution volume was then adjusted to final value to
reach the concentrations given in Table 1.
[0052] The so obtained composition was filtered through a 0.22
.mu.m filter and thereafter transferred to 10 ml lyophilization
vials and stopped with sterile rubber stoppers. The solution was
then subjected to lyophilization. The preparation of the
composition, except during freeze drying, was performed at a
temperature of 2-8.degree. C.
Preparation of Caspofungin Diacetate Formulation with Lactic
Acid
[0053] A caspofungin composition was prepared by firstly dissolving
lactic acid in water, then the pH of the solution was adjusted to
about 5.0 by adding NaOH solution. Then secondly sucrose and
mannitol were added to the above solution. If needed the pH was
again adjusted to about 5.0 by addition of NaOH. To the so obtained
solution, caspofungin diacetate was added. After complete
dissolution the pH was, if needed, adjusted with NaOH to reach
about 6.3. The solution volume was then adjusted to final value to
reach the concentrations given in Table 2 below.
[0054] The so obtained composition was filtered through a 0.22
.mu.m filter and thereafter transferred to 10 ml lyophilization
vials and stopped with sterile rubber stoppers. The solution was
then subjected to lyophilization. The preparation of the
composition, except during freeze drying, was performed at a
temperature of 2-8.degree. C.
[0055] The amount of the various ingredients of the final
composition was as listed in the below table 2.
TABLE-US-00002 TABLE 2 Caspofungin diacetate 46.58 mg/ml Sucrose
30.00 mg/ml Mannitol 20.00 mg/ml Lactic Acid 1.14 mg/ml
Analysis of Stability of Caspofungin Compositions
[0056] The formulations prepared according to example 1, example 2
and example 3 were stored in the lyophilized state at 2-8.degree.
C. for 1, 2 and 3 months, respectively, before stability testing.
Prior to testing, the lyophilized material was dissolved in a
pharmaceutically acceptable reconstitution solution. The so
obtained solutions where then analysed by HPLC according to
standard methods well known to the skilled person in the art.
[0057] The results of the stability testing, including 1 and 2
months data, of the composition prepared according to example 1 are
shown in FIG. 1.
[0058] The results of the stability testing of the composition
prepared according to example 2 are shown in FIG. 2.
[0059] The results of the stability testing of the composition
prepared according to example 3 are shown in FIG. 3.
[0060] Surprisingly, the stability testing according to FIG. 1
revealed that a lyophilized formulation based on a composition
prepared using succinate or lactate as a buffering agent showed
lower formation of total impurities compared with the compositions
comprising acetate or tartrate. The fact that acetate seems not to
be superior in respect of formation of the impurities determined is
surprising taking into account the teaching of the prior art. As
mentioned above, U.S. Pat. No. 5,952,300 teach that the use of
tartrate buffer results in the formation of undesired degradation
product in contrast to acetate buffer. It is furthermore
surprisingly observed that the amount of impurities increase during
storage when no buffering agent is added, contrary to the teaching
of WO2008/12310.
[0061] When we compare the composition prepared according to
example 2 and example 3 above with the product sold in the market
by Merck (RLD) we get the following data regarding levels of
impurities, see table 3.
TABLE-US-00003 TABLE 3 Composition Composition example 2 example 3
RLD Impurity B (%) 0.39 0.44 0.38 Impurity C (%) 0.09 0.13 0.17
Total impurities 1.8 1.9 2.1
[0062] The results in table 3 again shows that the use of acetate
buffer in the composition is not superior compared with for
instance succinate buffer or lactate buffer which is surprising
taking into account the teaching of the prior art.
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