U.S. patent application number 15/543104 was filed with the patent office on 2018-11-01 for liquid formulation of cabazitaxel.
The applicant listed for this patent is EMCURE PHARMACEUTICALS LIMITED. Invention is credited to Arpan Suresh CHUDASAMA, Deepak Pragjibhai GONDALIYA, Mukund Keshav GURJAR, Samit Satish MEHTA, Haresh Ishwarbhai PATEL, Hiren Pravinbhai PATEL, Neha Manubhai PATEL.
Application Number | 20180311203 15/543104 |
Document ID | / |
Family ID | 55795018 |
Filed Date | 2018-11-01 |
United States Patent
Application |
20180311203 |
Kind Code |
A1 |
PATEL; Hiren Pravinbhai ; et
al. |
November 1, 2018 |
LIQUID FORMULATION OF CABAZITAXEL
Abstract
The present invention relates to a stable liquid formulation of
cabazitaxel. The formulation comprises cabazitaxel, and at least
one solubilizer. Typically, formulations are in the form of
ready-to-use solutions or concentrates.
Inventors: |
PATEL; Hiren Pravinbhai;
(Pune, IN) ; PATEL; Haresh Ishwarbhai; (Pune,
IN) ; CHUDASAMA; Arpan Suresh; (Pune, IN) ;
PATEL; Neha Manubhai; (Pune, IN) ; GONDALIYA; Deepak
Pragjibhai; (Pune, IN) ; GURJAR; Mukund Keshav;
(Pune, IN) ; MEHTA; Samit Satish; (Pune,
IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
EMCURE PHARMACEUTICALS LIMITED |
Pune |
|
IN |
|
|
Family ID: |
55795018 |
Appl. No.: |
15/543104 |
Filed: |
January 7, 2016 |
PCT Filed: |
January 7, 2016 |
PCT NO: |
PCT/IN2016/000009 |
371 Date: |
July 12, 2017 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/08 20130101; B82Y
5/00 20130101; A61K 47/14 20130101; A61P 35/00 20180101; A61K
9/0019 20130101; A61K 47/10 20130101; A61K 47/12 20130101; A61K
9/5123 20130101; A61K 9/1075 20130101; A61K 9/10 20130101; A61K
31/337 20130101; A61K 47/44 20130101; A61K 9/5146 20130101 |
International
Class: |
A61K 31/337 20060101
A61K031/337; A61K 9/00 20060101 A61K009/00; A61K 9/10 20060101
A61K009/10; A61K 9/51 20060101 A61K009/51; A61K 47/10 20060101
A61K047/10 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 12, 2015 |
IN |
102/MUM/2015 |
Jul 3, 2015 |
IN |
2555/MUM/2015 |
Claims
1. A stable, liquid pharmaceutical composition, comprising
cabazitaxel or a pharmaceutically acceptable salt thereof, at least
one solubilizer and a solvent.
2. The stable, liquid pharmaceutical composition of claim 1,
wherein the composition is in the form of a nanodispersion
comprising nanoparticles having a mean size less than 500 nm,
preferably less than 300 nm.
3. The stable, liquid pharmaceutical composition of claim 1,
wherein the composition is a ready to use formulation.
4. The stable, liquid pharmaceutical composition of claim 1,
wherein the solubilizer is selected from the group comprising of
benzyl alcohol, tertiary-butyl alcohol, isopropyl alcohol, acetic
acid, glycols, polysorbates, polyoxyethylene glycol esters,
polyoxyethylene castor oil derivatives and suitable mixtures
thereof.
5. The stable, liquid pharmaceutical composition of claim 4,
wherein the solubilizer is Polyethylene glycol.
6. The stable, liquid pharmaceutical composition of claim 1,
wherein the solvent is ethanol.
7. The stable, liquid pharmaceutical composition of claim 1,
wherein the composition further comprises at least one stabilizer
selected from the group comprising of chelating agents,
phospholipids and sterols.
8. The stable, liquid pharmaceutical composition of claim 1,
wherein the composition further comprises one or more
pharmaceutically acceptable excipients selected from the group
comprising co-solvents, buffers, tonicity adjusting agents,
emulsifying agents, pH adjusters, antioxidants, preservatives, and
mixtures thereof.
9. The stable, liquid pharmaceutical composition of claim 1,
wherein the composition is suitable for parenteral
administration.
10. A method of preparation of the stable, liquid pharmaceutical
composition of claim 1, comprising the steps of: i. dissolving or
mixing solubilizer, stabilizer, co-solvent, antioxidant, tonicity
adjusting agents, buffers and preservatives in a solvent or mixture
of solvents; ii. dissolving cabazitaxel in the solution obtained in
step (i), and adjusting the pH if required; iii. filtering the
solution obtained in step (ii) through suitable sterile grade
membrane filter iv. purging pure nitrogen into the filtered final
solution; and v. filling measured volume of the solution in vials
and purging pure nitrogen in the headspace of vials before closing
with rubber stopper.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a stable liquid cabazitaxel
formulation. The formulation comprises cabazitaxel and at least one
solubilizer. Typically, the present formulations are in the form of
ready-to-use solutions or concentrates. Further, the present
invention also relates to manufacturing processes of stable liquid
cabazitaxel formulation.
BACKGROUND OF THE INVENTION
[0002] The Chemical Compound, (2.alpha.,5.beta.,7.beta.,
10.beta.,13a)-4-acetoxy-13-({(2R,3S)-3 [(tertbutoxycarbonyl)
amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,-
20-epoxytax-11-en-2-yl benzoate, which is generically known as
"cabazitaxel" is a member of the taxane family. Cabazitaxel is the
7, 10-dimethoxy analogue of docetaxel and like other members of
taxane family, it is also a microtubule inhibitor, which is
presently approved worldwide, in combination with prednisone, for
treatment of patients with hormone-refractory metastatic prostate
cancer previously treated with a docetaxel-containing treatment
regimen.
[0003] Cabazitaxel is marketed worldwide under the brand name of
JEVTANA.RTM. by Sanofi Aventis. JEVTANA.RTM. is supplied as a kit
consisting of (a) a JEVTANA.RTM. injection, which contains 60 mg
cabazitaxel in 1.5 mL polysorbate 80; and (b) a diluent, containing
approximately 5.7 mL 13% (w/w) ethanol. Prior to administration,
the JEVTANA.RTM. injection must first be mixed with the diluent,
which dilutes the amount of cabazitaxel to 10 mg/mL, and then
further diluted into a 250 mL PVC-free container of either 0.9%
sodium chloride solution or 5% dextrose solution for infusion. The
concentration of cabazitaxel in the resulting final infusion
solution should be between 0.10 mg/mL and 0.26 mg/mL.
[0004] JEVTANA.RTM. Injection is a micellar formulation. The
pre-mix solution prepared by the first dilution is supersaturated
by about 400% and is inherently physically unstable. It requires
repeated inversions for at least 45 seconds to assure complete
mixing of the concentrated drug solution and the diluent. The
pre-mix solution, having a concentration of 10 mg of cabazitaxel
per mL should be used immediately, preferably within 30 minutes and
requires further dilution before administration. Even after second
dilution, the concentration of cabazitaxel in the solution remains
supersaturated and therefore should be used for intravenous
administration immediately, with 8 hours, if stored at room
temperature or with 24 hours, if stored under refrigeration
conditions. Further, these supersaturated solutions are prone to
crystallization and hence the prescribing information for
JEVTANA.RTM. instructs that if crystals and/or particulates appear
in the diluted infusion solution, it must not be used and should be
discarded.
[0005] Therefore, various attempts have been made to prepare the
cabazitaxel formulations with improved properties, however, the
lipophilic property and it's practically insolubility in water,
having solubility about 8 pg per mL, has vexed researches in this
field.
[0006] International Application Publication No. WO 2013/024495
discloses cabazitaxel or a pharmaceutically acceptable salt thereof
and at least one solubilizer dissolved in alcoholic solvents.
[0007] U.S. Patent Application Publication No. 2012/0065255
discloses a sterile pharmaceutical formulation comprising
cabazitaxel which is substantially free of polysorbates and
polyethoxylated castor oil. The composition comprises of
cabazitaxel or a pharmaceutically acceptable salt thereof; a
solubilizer, tocopherol polyethylene glycol succinate, one or more
hydrotropes and optionally one or more agents having a pKa of about
3 to about 6 and optionally one or more antioxidizing agent.
[0008] U.S. Patent Application Publication No. 2014/0171495
discloses an enclosed liquid pharmaceutical composition container,
comprising a liquid phase and a gaseous phase, wherein the liquid
phase comprises cabazitaxel, polysorbate 80, ethanol, and one or
more pH adjusters to maintain pH about 2.8-6.0, and the gaseous
phase is saturated with CO.sub.2.
[0009] U.S. Pat. No. 7,241,907 discloses a process for preparing an
acetone solvate of cabazitaxel by crystallization from an aqueous
acetone solution and use of the same for preparing pharmaceutical
composition.
[0010] Thus, there remains a need for a stable, single-vial
formulation for cabazitaxel, which needs to be diluted only once
for intravenous infusion. Ideally, such formulations would be
conveniently prepared for use and would exhibit enhanced storage
stability at ambient conditions.
OBJECT OF THE INVENTION
[0011] It is therefore an object of the present invention to
provide a stable pharmaceutical composition comprising
cabazitaxel.
[0012] Another object of the present invention is to provide a
stable, single-vial formulation, suitable for parenteral
administration comprising cabazitaxel, which is ready for direct
dilution with an infusion solution or for direct introduction into
an infusion bag.
[0013] Yet another object of the present invention is to provide a
stable injectable pharmaceutical formulation comprising cabazitaxel
or a pharmaceutically acceptable salt thereof, at least one
solubilizer and a solvent.
[0014] Further another object of the present invention is to
provide a simple, commercially viable process for preparation of an
injectable formulation of cabazitaxel.
SUMMARY OF THE INVENTION
[0015] Applicant has developed stable formulations of cabazitaxel.
These cabazitaxel formulations are single-vial injection
concentrates, which are sterile liquids in a single vial ready to
be diluted with an infusion solution.
[0016] Thus, in one embodiment, the present invention provides a
stable, liquid pharmaceutical composition, comprising cabazitaxel
or a pharmaceutically acceptable salt thereof, at least one
solubilizer and a solvent.
[0017] In another embodiment, the stable, liquid pharmaceutical
composition of the present invention is in the form of a
nanodispersion comprising nanoparticles having a mean size less
than 500 nm, preferably less than 300 nm.
[0018] In yet another embodiment, the stable, liquid pharmaceutical
composition of the present invention is a ready to use formulation,
suitable for parenteral administration.
[0019] In another embodiment, the present invention provides
processes for manufacturing cabazitaxel compositions, wherein
embodiments of such processes involve dissolving cabazitaxel in a
suitable solvent comprising a solubilizer and other
pharmaceutically acceptable excipients, adjusting the pH and
filtering.
[0020] These and other advantages of the compositions disclosed
herein, as well as additional inventive features, will be apparent
from the description of the invention provided herein.
DETAILED DESCRIPTION OF THE INVENTION
[0021] The present invention is directed to a stable, liquid
pharmaceutical composition, comprising cabazitaxel or a
pharmaceutically acceptable salt thereof, at least one solubilizer
and a solvent.
[0022] The present invention is also directed to a stable, liquid,
composition of cabazitaxel, presented as a single-vial injectable
solution, ready for direct dilution with an infusion solution,
without need for preparation of a premix solution.
[0023] "Single-vial injection solution" refers to a sterile liquid
in a single vial that can be administered by intravenous route to a
patient upon dilution with only an infusion solution, i.e., no
other dilution may be necessary before dilution with the infusion
solution.
[0024] "Infusion solution" refers to a sterile isotonic solution,
typically stored in a bag or bottle that is employed to dilute the
single-vial injection concentrate or the diluted injection
concentrate for administration to a patient.
[0025] As used herein, the term "cabazitaxel" includes the compound
cabazitaxel, pharmaceutically acceptable salts of cabazitaxel,
isomers, solvates, complexes and hydrates, anhydrous forms thereof,
and any polymorphic or amorphous form or combinations thereof.
[0026] As used herein, the term "stable compositions" refers to any
preparation of cabazitaxel having sufficient stability to allow
storage at a convenient temperature, such as between about
0.degree. C. and about 60.degree. C., for a pharmaceutically
acceptable duration of time. Preferably, the composition are stable
for a period of time, such as at least about one week, at least
about one month, at least about three months, at least about six
months, at least about one year, or at least about 2 years.
[0027] As used herein, the term "solubilizer" refers to a solvent
that is capable of dissolving cabazitaxel, or a pharmaceutically
acceptable salt thereof.
[0028] As used herein, the term "stabilizer" refers to a substance
that allows stable storing of the pharmaceutical composition of the
present invention. The term "stabilization" refers to that the loss
of an active ingredient is less than a certain amount, typically
less than 10% during certain period and under specific storage
condition. The term stabilizer as used herein refers to one or more
agents that increase the stability of cabazitaxel formulation, such
as by increasing the amount of time before the cabazitaxel degrades
to an unusable form. In specific embodiments, the agent prolongs
the efficacy of cabazitaxel over time and/or upon subjection to
conditions that degrade cabazitaxel to a form having reduced
efficacy, such exemplary conditions being air, heat, and/or
light.
[0029] The present invention is also directed to a stable, liquid
pharmaceutical composition in the form of a nanodispersion
comprising nanoparticles having a mean size less than 500 nm,
preferably less than 300 nm.
[0030] As used herein the term "nanoparticles" means any particle
having controlled dimensions of the order of nanometers. The
nanoparticles as used in the present invention mean a polymeric
nanoparticle (matrix of polymer entrapping the drug) and/or a
polymeric nanovesicle (polymer stabilized nano sized vesicle
encapsulating the drug) and/or a polymeric. nanocapsule (polymeric
membrane surrounding drug in core) and/or nano sized particles of
the drug stabilized by surfactants, and the like having mean size
less than 500 nm, preferably, less than 300 nm.
[0031] The formulations of the present invention are particularly
suited for use in parenteral administration, and are typically
employed in combination with prednisone for treatment of patients
with hormone-refractory metastatic prostate cancer previously
treated with a docetaxel-containing treatment regimen.
[0032] According to a preferred embodiment of the present
invention, the formulations of the present invention comprise
nanoparticles having a mean size less than 300 nm dispersed in a
vehicle comprising a water miscible solvent; said nanoparticles
comprising a taxane derivative, a polymer and very low amount of
surfactants.
[0033] Nanoparticles or nanosized particles in themselves afford
many advantages in terms of efficient drug delivery. It has been
realized that either incorporation of a drug into a delivery
vehicle or attachment of the drug to the vehicle can afford many
advantages in comparison to the administration of the drug in its
free form. Incorporation of drug in vehicle can affect tissue
specific distribution, in particular preferential accumulation in a
certain tissue of interest or at a disease site, targeting of drug
to a particular cell type, decrease of interaction with blood
components, enhanced protection of the drug from premature
degradation and increase in circulation time. Nanoparticles have
engineered specificity, allowing them to deliver a higher
concentration of pharmaceutical agent to a desired location or
target site of action. Upon intravenous administration, particles
are recognized by liver and spleen macrophages and preferentially
they are taken up by the liver macrophages.
[0034] The particle size of the nanoparticles is determined using
conventional methods of measuring and expressing particle size like
Malvern particle size analysis, sieving, light scattering optical
microscopy, image analysis, sedimentation and such other methods
known to one skilled in the art. Particle size distribution
information can be obtained from the values D10, D50, and D90, such
as can be generated from a Malvern particle size determination.
Without wishing to be bound by any theory, the applicants believe
that the delivery of drug through nanodispersion comprising
nanoparticles having mean size less than 500 nm, preferably, less
than 300 n, leads to enhanced internalization and accumulation of
the drug in the target tumor tissues and cells. Such increased
internalization levels provides a potent treatment strategy for
curing tumors associated with cancer.
[0035] According to one embodiment of the present invention, the
particle size of the nanoparticles is in the range of 10 nm to 475
nm. In preferred embodiments of the present invention, the particle
size is less than 200 nm. In most preferred embodiments of the
present invention, the particle size is in the range of 10 nm to
200 nm. The present invention typically provides a nanodispersion
comprising nanoparticles having a mean size less than 300 nm
dispersed in a vehicle comprising a water miscible solvent; said
nanoparticles comprising one or more taxane derivative, a polymer
and a surfactant.
[0036] In another preferred embodiment, the present invention
provides pharmaceutical composition comprising cabazitaxel at
concentrations about 5 mg/mL to about 200 mg/mL. Typically the
concentrations of cabazitaxel are in the range of about 10 mg/mL to
about 100 mg/mL.
[0037] The solubilizers used in the present invention include, but
are not limited to, benzyl alcohol, tertiary-butyl alcohol,
isopropyl alcohol, acetic acid, glycols, polysorbates,
polyoxyethylene glycol esters, polyoxyethylene castor oil
derivatives and suitable mixtures thereof.
[0038] The glycol is preferably selected from the group consisting
of polyethylene glycols, propylene glycol, tetra glycol and
mixtures thereof. Polyethylene glycol (e.g. PEG 300 and PEG 400) is
an excipient which is widely used in pharmaceutical formulations.
Preferably, the polyethylene glycol has a molecular weight in the
range from 200 to 600. More preferably, the polyethylene glycol has
a molecular weight of about 400 (PEG 400). A person skilled in the
art will know that a polyethylene glycol having a molecular weight
above 600 is likely to be solid and can be used in non-aqueous
systems.
[0039] The persons skilled in the art will understand that when the
solvent system is described as nonaqueous, this merely indicates
that water is not specifically added to the formulation. There can
be some water present in the formulation due to its presence in
some of the commercial components used, and water may also be
absorbed from the environment into the formulation. Formulations
containing these incidental amounts of water are included within
the scope of the application. Because of good solubility of
cabazitaxel in ethanol, it is commonly used as a non-aqueous
solvent.
[0040] Various substances can be used as stabilizer in injectable
formulations. In particular embodiments, the stabilizer or
stability-enhancing agent may be considered a preservative and/or
antioxidant, chelating agents, yet, itself does not destabilize the
formulation. Useful but exemplary antioxidants include one or more
of cysteine, acetylcysteine, thioglycerol, citric acid, alpha
tocopherol or a combination thereof. In another embodiment, the
stability-enhancing agent includes, for example, chelating agents
(e.g., citrate, malic acid, edetate, or pentetate), sodium
pyrophosphate, and sodium gluconate.
[0041] In another embodiment of the present invention, the
cabazitaxel formulation can from nano-particulate formulation on
final dilution. Therefore, to increase stability by increasing the
negative zeta potential of nanoparticles, certain negatively
charged components may be added as stability enhancing agents. Such
negatively charged components include, but are not limited to bile
salts, bile acids, glycocholic acid, cholic acid, chenodeoxycholic
acid, taurocholic acid, glycochenodeoxycholic acid,
taurochenodeoxycholic acid, litocholic acid, ursodeoxycholic acid,
dehydrocholic acid, and others; phospholipids including lecithin
(egg yolk) based phospholipids which include the following
phosphatidylcholines: palmitoyloleoylphosphatidylcholine,
palmitoyllinoleoylphosphatidylcholine,
stearoyllinoleoylphosphatidyl-choline,
stearoyloleoylphosphatidylcholine,
stearoylarachidoylphosphatidylcholine, and
dipalmitoylphosphatidylcholine. Other phospholipids including
L-.alpha.-dimyristoyl-phosphatidylcholine (DMPC),
dioleoylphosphatidylcholine (DOPC), distearoylphosphatidylcholine
(DSPC), hydrogenated soy phosphatidylcholine (HSPC), and other
related compounds. Negatively charged surfactants or emulsifiers
are also suitable as stability enhancing agents, e.g., sodium
cholesteryl sulfate and the like.
[0042] In another embodiment, the present formulations can contain
buffers, tonicity adjusting agents, emulsifying agents, pH
adjusters, antioxidants and preservatives that render the
formulation compatible with the blood of the intended recipient.
The present invention may also include suitable co-solvents such
as, for example, polyvinylpyrrolidone, polyvinyl alcohol,
glycerine, or combinations thereof.
[0043] The formulations can be presented in unit-dose or multi-dose
sealed containers, such as ampules and vials, and can be stored in
a freeze-dried (lyophilized) condition requiring only the addition
of the sterile liquid excipient e.g., water for injection,
immediately prior to use.
[0044] In another embodiment, the present invention provides a
method for preparing a single-container, liquid cabazitaxel
formulation in an enclosed container. The liquid cabazitaxel
formulation in the single vial is stable and is ready to be diluted
once and administered to a patient. The typical method comprises
the steps of: [0045] i. dissolving or mixing solubilizer,
stabilizer, co-solvent, antioxidant, tonicity adjusting agents,
buffers and preservatives in a solvent or mixture of solvents;
[0046] ii. dissolving cabazitaxel in the solution obtained in step
(i), and adjusting the pH if required; [0047] iii. filtering the
solution obtained in step (ii) through suitable sterile grade
membrane filter [0048] iv. purging pure nitrogen into the filtered
final solution; and [0049] v. filling measured volume of the
solution in vials and purging pure nitrogen in the headspace of
vials before closing with rubber stopper.
[0050] The following examples further illustrate the invention but
should not be construed as in any way limiting its scope. In
particular, the processing conditions are merely exemplary and can
be readily varied by one of ordinary skill in the art.
TABLE-US-00001 TABLE 1 Liquid Formulations of Cabazitaxel An
injectable solution of cabazitaxel was prepared by using the
excipients as shown in following table. All the excipients are
dissolved in ethanol and then the required quantity of cabazitaxel
was added to this solution. The obtained solution was filtered
through sterile filteration and filled into vials. % w/w Sr. No
Ingredients Example-1 Example-2 Example-3 Example-4 Example-5
Example-6 1 Cabazitaxel 1.00 1.00 10.00 10.00 2.72 2.15 2
Polyethylene Glycol 400 42.70 54.90 43.88 70.00 -- -- 3 Ethanol
39.50 41.00 39.98 10.00 26.53 42.24 4 Citric acid Anhydrous 0.10
1.42 0.40 -- -- -- 5 Macrogol 15 hydroxy stearate 16.70 -- -- -- --
-- 6 Alpha tocopherol -- 0.08 -- -- -- -- 7 Sodium Cholesteryl
sulfate -- 1.56 0.70 0.67 -- -- 8 Polysorbate 80 -- -- -- -- 70.74
55.61 9 Soy Phosphatidyl Choline -- -- 5.00 -- -- -- 10 Caprylic
acid polymer -- -- -- 0.83 -- -- 11 Povidone -- -- -- 8.33 --
--
Example 7: Stability Study
[0051] The formulations prepared according to Table 1 are subjected
to stability studies. The results are summarised in the below Table
2 & 3.
TABLE-US-00002 TABLE 2 Stability study results at 40.degree. C./75%
RH Impurity content (in %) w.r.t time (in days): Formulation No.
Initial 30 days 60 days 90 days 180 days Example-1 0.21 0.31 0.31
0.36 0.66 Example-2 0.17 0.20 0.36 0.40 0.60 Example-3 0.25 ND*
0.40 0.48 0.57 Example-4 0.13 0.23 0.17 0.19 0.24 Example-5 0.20
0.35 0.61 0.54 0.87 Example-6 0.10 0.48 0.66 0.86 1.48 *ND--Not
detected
TABLE-US-00003 TABLE 3 Stability study results at 25.degree. C./60%
RH Formulation Impurity content (in %) w.r.t time (in days): No.
Initial 30 days 60 days 90 days 180 days 270 days Example-1 0.21
0.23 0.29 0.18 0.25 0.33 Example-2 0.17 0.20 0.17 0.18 0.25 0.41
Example-3 0.25 ND* ND* 0.20 0.75 0.38 Example-4 0.13 0.12 0.13 0.18
0.12 0.19 Example-5 0.20 0.17 0.39 0.18 0.32 -- Example-6 0.10 0.30
0.28 0.35 0.76 0.66 *ND--Not detected
* * * * *