U.S. patent application number 14/937689 was filed with the patent office on 2016-09-08 for injectable pharmaceutical compositions of an anthracenedione derivative with anti-tumoral activity.
The applicant listed for this patent is CTI BioPharma Corp.. Invention is credited to Alberto Bernareggi, Valeria Livi.
Application Number | 20160256557 14/937689 |
Document ID | / |
Family ID | 11449903 |
Filed Date | 2016-09-08 |
United States Patent
Application |
20160256557 |
Kind Code |
A1 |
Bernareggi; Alberto ; et
al. |
September 8, 2016 |
INJECTABLE PHARMACEUTICAL COMPOSITIONS OF AN ANTHRACENEDIONE
DERIVATIVE WITH ANTI-TUMORAL ACTIVITY
Abstract
Injectable pharmaceutical compositions containing
6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione
dimaleate as active ingredient in the form of a lyophilised powder
with a carrier selected from lactose and dextran, mixed with sodium
chloride.
Inventors: |
Bernareggi; Alberto;
(Concorezzo, IT) ; Livi; Valeria; (Monza,
IT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CTI BioPharma Corp. |
Seattle |
WA |
US |
|
|
Family ID: |
11449903 |
Appl. No.: |
14/937689 |
Filed: |
November 10, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12964861 |
Dec 10, 2010 |
9211262 |
|
|
14937689 |
|
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|
10514301 |
Jul 18, 2005 |
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PCT/EP2003/004871 |
May 9, 2003 |
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12964861 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/02 20130101;
A61P 43/00 20180101; A61K 47/36 20130101; A61P 35/00 20180101; A61K
9/0019 20130101; A61K 9/19 20130101; A61K 31/473 20130101; A61P
35/02 20180101; A61K 47/26 20130101 |
International
Class: |
A61K 47/36 20060101
A61K047/36; A61K 47/02 20060101 A61K047/02; A61K 47/26 20060101
A61K047/26; A61K 31/473 20060101 A61K031/473 |
Foreign Application Data
Date |
Code |
Application Number |
May 16, 2002 |
IT |
MI2002A001040 |
Claims
1. A pharmaceutical composition comprising
6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione
dimaleate and: i) a lactose carrier mixed with sodium chloride; or
ii) a dextran carrier mixed with sodium chloride, wherein the
composition is in the form of a lyophilized powder.
2. The pharmaceutical composition of claim 1, wherein the carrier
is lactose.
3. The pharmaceutical composition of claim 1, further comprising an
antioxidant.
4. The pharmaceutical composition of claim 1, wherein the weight
ratio of the carrier to the sodium chloride is between 1:1 and
3:1.
5. The pharmaceutical composition of claim 1, wherein the weight
ratio of the
6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione
dimaleate to the carrier is between 1:2 and 1:6.
6. An aqueous composition comprising
6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione
dimaleate and: i) a lactose carrier mixed with sodium chloride; or
ii) a dextran carrier mixed with sodium chloride, wherein the
concentration of the
6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione
dimaleate in the composition ranges from 7-15 mg/ml.
7. The aqueous composition of claim 6, comprising from 10 to 40
mg/ml sodium choloride and from 20 to 60 mg/ml lactose.
8. The pharmaceutical composition of claim 1, wherein the
pharmaceutical composition comprises a unit dose of between 25 and
200 mg of
6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione
dimaleate.
9. The pharmaceutical compositions of claim 8, wherein the unit
dose comprises 50 mg of
6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione
dimaleate.
10. A kit comprising the pharmaceutical composition of claim 1, and
an ampoule containing a sterile solvent suitable to reconstitute
the lyophilized powder, such that the lyophilized powder is
suitable for parenteral administration.
11. A process for preparing the pharmaceutical composition of claim
1, the process comprising: lyophilizing an aqueous solution of
6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione
dimaleate in the presence of: i) lactose and sodium chloride; or
ii) dextran and sodium chloride, wherein the step of lyophilizing
comprises: freezing the solution at a temperature below at least
-45.degree. C. for at least 3 hours; drying the frozen solution to
form a product, by increasing the temperature of the frozen
solution to -35.degree. C..+-.5.degree. C. in approximately 3 hours
and maintaining said temperature for at least 40 hours; and then
drying the product by increasing the temperature of the product to
+30.degree. C..+-.5.degree. C. in 10 hours and maintaining said
temperature for at least 8 hours.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of the filing date of
U.S. patent application Ser. No. 10/514,301, filed Jul. 18, 2005,
which claims priority from international Patent Application No.
PCT/EP03/04871, filed May 9, 2003, which claims priority from
Italian Patent Application No. MI2002A001040, filed May 16, 2002,
the disclosures of which are incorporated by reference herein
[0002] The present invention relates to injectable pharmaceutical
compositions containing
6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione
dimaleate (from now on also referred to as "BBR 2778") as active
ingredient in the form of a lyophilised powder with a carrier
selected from lactose and dextran, mixed with sodium chloride.
PRIOR ART
[0003] BBR 2778 is a novel anthracenedione derivative with
anti-tumoral activity which acts as a DNA intercalating agent and
topoisomerase II inhibitor. Pre-clinical studies demonstrate that
its cardiotoxicity is lower than that of other known drugs
belonging to the same class. BBR 2778 has proved more active than
mitoxantrone against haematological tumours, especially ascitic
L1210 leukaemia and YC-8 lymphoma, in a wide range of doses.
[0004] Clinical trials on the use of BBR 2778 in the treatment of
non-Hodgkin's lymphoma are at an advanced stage.
[0005] The formulation of BBR2778 in injectable liquid
pharmaceutical compositions has proved problematic in terms of
stability in solution using common solvents suitable for parenteral
administration, especially intravenous administration.
[0006] A lyophilised formulation to be reconstituted with a
suitable solvent such as saline immediately before use has
therefore been considered.
[0007] Here again, however, unforeseeable problems arose, partly
due to the low solubility of BBR 2778 in water and the need to use
sodium chloride solutions in concentrations ranging from 0.9 to 4%,
in which the drug is progressively more soluble. However, the
presence of sodium chloride requires the use of long lyophilisation
cycles due to the low glass transition temperature observed.
[0008] The choice of lyophilisation carrier has also proved
critical in terms of the stability of the final formulation and in
operational terms.
[0009] For example, if mannitol is used as lyophilisation carrier,
stable formulations are only obtained if they are stored at
temperatures of approx. 5.degree. C. or lower; stability studies
conducted at 25.degree. C. with 60% relative humidity (RH) showed
unacceptable levels of degradation products after only one month.
The characterisation of the finished product in the solid state
demonstrates that BBR 2778 is transformed from a crystalline raw
material to an amorphous powder in the lyophilisate, with a
consequent reduction in stability. The choice of carriers with
greater protective properties consequently focused on polymeric
substances like polyvinylpyrrolidone (PVP, Povidone).
[0010] Replacing mannitol with Povidone K 17 produced a stable
lyophilisate even at 25.degree. C., 60% RH, but Povidone has been
removed from the list of excipients approved for parenteral
administration in the USA (Fed. Reg. 8 Mar. 1999, Vol. 64, Num. 64)
and requires a long lyophilisation cycle due to the low glass
transition temperature observed (-37.degree. C.), which requires
primary drying to be conducted at a temperature below -37.degree.
C.
[0011] Unsatisfactory results were also obtained with the use of
other conventional lyophilisation carriers such as urea, glycine,
ammonium chloride and TRIS in the presence and absence of sodium
chloride, and by lyophilisation of BBR 2778 in the absence of
excipients.
DESCRIPTION OF THE INVENTION
[0012] It has now been found that it is possible to obtain stable
lyophilised formulations of BBR 2778 in the presence of sodium
chloride by using lactose or dextran as lyophilisation carrier.
[0013] A first aspect of the invention therefore provides
injectable pharmaceutical compositions containing
6,9-bis[(2-aminoethyl)amino]benzo[q]isoquinoline-5,10-dione
dimaleate (BBR 2778) as active ingredient in the form of a
lyophilised powder with a carrier selected from lactose and
dextran, mixed with sodium chloride, to be reconstituted with a
solvent suitable for reconstituting the lyophilisate and suitable
for parenteral administration, which solvent is preferably
contained in a separate ampoule.
[0014] A further aspect of the invention relates to a process for
the preparation of said compositions.
DETAILED DESCRIPTION OF THE INVENTION
[0015] In the compositions of the invention, the weight ratio
between the carrier and sodium chloride is critical, and is
typically between 1:1 and 3:1.
[0016] The weight ratio between BBR 2778 and the carrier is
preferably between 1:2 and 1:6. The particularly preferred carrier
is lactose.
[0017] The unit dose of BBR 2778 will usually be between 25 and 200
mg, and preferably between 50 and 100 mg. The unit dose currently
being tested in clinical trials is 50 mg. For this latter quantity
of active ingredient, the preferred compositions according to the
invention will contain 100 to 200 mg of sodium chloride and 100 to
300 mg of lactose.
[0018] If required, the compositions of the invention can also
contain other excipients commonly used for parenteral formulations,
such as antioxidants, buffers, local anaesthetics, salts, amino
acids and the like.
[0019] The vials or ampoules of sterile lyophilised powder will
then be reconstituted at the time of use with sterile solvents
constituted by sterile pyrogen-free water or sterile saline, in
volumes of approx. 5 ml to 20 ml, depending on the active
ingredient content.
[0020] The compositions of the invention are prepared by a process
which comprises lyophilisation of an aqueous solution of BBR 2778,
lactose or dextran and sodium chloride by means of [0021] a
freezing stage at a temperature below at least -45.degree. C. for
at least 3 hours; [0022] a primary drying stage consisting of
increasing the temperature of the product to -35.degree.
C..+-.5.degree. C. in approx. 3 hours and maintaining said
temperature for at least 40 hours; [0023] a secondary drying stage
consisting of increasing the temperature of the product to
+30.degree. C..+-.5.degree. C. in 10 hours and maintaining said
temperature for at least 8 hours.
[0024] The compositions according to the invention are stable at
room temperature for at least 24 months. The lyophilised product is
not subject to deliquescence, and maintains its appearance
unchanged over time.
[0025] A further advantage of the invention is the reduction in
lyophilisation times and the consequent reduction in the cost of
the process.
[0026] The following examples illustrate the invention in greater
detail.
EXAMPLE 1
[0027] Preparation of vials containing lyophilised BBR 2778 in the
presence of lactose and sodium chloride.
[0028] A solution containing 10 mg/ml of BBR 2778, 20 mg/ml of NaCl
and 60 mg/ml of lactose, prepared by dissolving the various
components in water for injection at 20-25.degree. C., is
distributed between type I glass vials under sterile conditions at
the rate of 5 ml per vial, after sterile filtration. A
lyophilisation stopper is placed on the mouth of the vials.
[0029] The pre-stoppered vials are then loaded directly onto
lyophilisation shelves and frozen at -45.degree. C..+-.5.degree. C.
for at least 3 hours.
[0030] Primary drying is conducted by increasing the temperature of
the shelves in the vacuum freeze-dryer from -45.degree. C. to
-30.degree. C..+-.3.degree. C. in 3 hours, and maintaining the
temperature at -30.degree. C. for 40 hours.
[0031] Secondary drying is performed by increasing the temperature
of the shelves from -30.degree. C. to +30.degree. C..+-.3.degree.
C. in 10 hours and then maintaining said temperature of +30.degree.
C. for a further 8 hours. The freeze-dryer is returned to
atmospheric pressure with nitrogen filtered under sterile
conditions, and the vials are stoppered by activating the
stoppering device. The vials are unloaded in a sterile environment
and crimped.
[0032] When reconstituted with 5 ml of water for injection, the
solution has a pH of between 3.0 and 4.5.
[0033] Accelerated stability tests conducted on the lyophilisate at
40.degree. C. for 12 months have demonstrated a reduction in BBR
2778 titre within the limits of the specifications approved for the
product, and a purity exceeding 95%. The stability is also
confirmed at 25.degree. C. even after the 12-month observation
period.
EXAMPLE 2
[0034] Preparation of vials containing lyophilised BBR 2778 in the
presence of dextran and sodium chloride.
[0035] A solution containing 10 mg/ml of BBR 2778, 20 mg/ml of NaCl
and 60 mg/ml of dextran 40000, prepared by dissolving the various
components in water for injection at 20-25.degree. C., is
distributed between type I glass vials under sterile conditions, at
the rate of 5 ml per vial, after sterile filtration. A
lyophilisation stopper is placed on the mouth of the vials.
[0036] The pre-stoppered vials are then loaded onto trays, which
are placed on the shelves of the freeze-dryer. The vials are then
frozen in the lyophilisation chamber at -45.degree. C..+-.5.degree.
C. for at least 3 hours.
[0037] Primary drying is conducted by increasing the temperature of
the shelves in the vacuum freeze dryer from -45.degree. C. to
0.degree. C..+-.2.degree. C. in 6 hours and maintaining the
temperature at 0.degree. C. for 30 hours. The temperature of the
product during primary drying is maintained at around -30.degree.
C.
[0038] Secondary drying is performed by increasing the temperature
of the shelves from 0.degree. C. to +30.degree. C..+-.2.degree. C.
in 3 hours and then maintaining said temperature of +30.degree. C.
for a further hours. The freeze-dryer is returned to atmospheric
pressure with nitrogen filtered under sterile conditions, and the
vials are stoppered by activating the stoppering device. The vials
are unloaded in a sterile environment and crimped.
[0039] When reconstituted with 5 ml of water for injection. the
solution has a pH of between 3.0 and 4.5.
[0040] Accelerated stability tests conducted on the lyophilisate at
40.degree. C. for 4 months have demonstrated a reduction in BBR
2778 titre within the limits of the specifications approved for the
product, and a purity exceeding 96%.
* * * * *