Note: Descriptions are shown in the official language in which they were submitted.
CA 02683032 2009-10-20
DOCETAXEL FORMULATIONS WITH
LIPOIC ACID AND/OR DIHYDROLIPOIC ACID
CROSS-REFERENCE TO RELATED APPLICATIONS
100011 Not Applicable.
STATEMENT REGARDING
FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[00021 Not Applicable
FIELD OF THE INVENTION
[00031 The present invention relates to formulations of docetaxel, generally;
a solution of
docetaxel, in an initial concentrate strength, an intermediate concentrate
strength, and an infusion
strength, and diluent solutions for use in diluting the initial concentrate,
or diluent solutions for
diluting the intermediate concentrate to infusion strength, or diluent fluids
for diluting a solid
composition to the initial concentrate strength, the intermediate concentrate
strength or the
infusion strength. The invention further relates to the use of lipoic acid,
dihydrolipoic acid,
pharmaceutically acceptable salts of either and combinations thereof in
particular concentration
ranges..
BACKGROUND OF THE INVENTION
[00041 Docetaxel is an antineoplastic agent belonging to the taxoid family
being marketed by
Sanofi-Aventis under trade name Taxotere . It is prepared by semisynthesis
beginning with a
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=
precursor extracted from the renewable needle biomass of yew plants. The
chemical name for
docetaxel is (2R,3S)-N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester
with 5beta - 20 -
epoxy-1,2a,4,713, 10(3, 13a-hexahydroxytax-11-en-9 -one 4-acetate 2-benzoate,
trihydrate.
Docetaxel has the following structural formula:
HaC o off
H OH cab ...H
.~- O'er H3
CH, NH H H ~~' ,aH
HzC~ Q ,=_=,`
H,C O O H g H V=~ IO -3 H2O
O O 0
Docetaxel, as currently marketed by Sanofi-Aventis, is a white to almost-white
powder with an
empirical formula of C43H53N014. 3H20, and a molecular weight of 861.9. It is
highly
lipophilic and practically insoluble in water. Taxotere (docetaxel) Injection
Concentrate is a
clear yellow to brownish-yellow viscous solution. Taxotere is sterile, non-
pyrogenic, and is
available in single-dose vials containing 20 mg (0.5 ml) or 80 mg (2 ml)
docetaxel (on an
anhydrous basis). Each ml contains 40 mg docetaxel (on an anhydrous basis) and
1040 mg
polysorbate 80. For purposes of this specification, reference to an amount of
"docetaxel"
without reference to the specific form (i.e., hydrate, salt, etc.) will mean
the stated amount of the
free, anhydrous, non-solvated moiety of the drug in question unless the
context clearly requires
otherwise, notwithstanding the actual form of the compound then under
discussion. Thus, for
example, reference to 80.7 mg of docetaxel without reference to the form of
the drug, means that
amount of the actual drug form used which corresponds to the same number of
moles of the
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t
docetaxel moiety as 80.7 mg of free, unsolvated, anhydrous docetaxel. If free
docetaxel
trihydrate were to be used, this would mean 86.1 mg of free docetaxel
trihydrate. Similar
calculations for salts and solvates will be apparent to those of ordinary
skill in the art.
100051 Taxotere Injection Concentrate requires dilution prior to use. A
sterile, non-pyrogenic,
single-dose diluent is supplied for that purpose. The diluent for Taxotere
contains 13% ethanol
in water for injection, and is supplied in vials. The preparation of the
dilution is in two phases.
The concentrate (which is stored between 2-25 C (36 and 77 F)) is allowed to
come to room
temperature, if not already, along with any necessary diluent (13% ethanol in
water for injection
for the commercially available material) by letting them stand under room
temperature
conditions for about 5 minutes. Diluent is aseptically withdrawn from its vial
(approximately 1.8
ml for Taxotere 20 mg and approximately 7.1 ml for Taxotere 80 mg) into a
syringe by
partially inverting the vial, and transferring it to the appropriate vial of
Taxotere Injection
Concentrate. If the procedure is followed as described, an initial diluted
solution of 10mg
docetaxel/ml will result. This initial dilution is mixed by repeated
inversions for at least 45
seconds to assure full mixture of the concentrate and diluent. The vial should
not be shaken.
The resulting solution (10 mg docetaxel/ml) should be clear; however, there
may be some foam
on top of the solution due to the polysorbate 80. The initial diluted solution
may be used
immediately or stored either in the refrigerator or at room temperature for a
maximum of 8
hours.
[00061 The current Taxotere label indicates that the required amount of
docetaxel is then
aseptically withdrawn from the initial 10 mg docetaxel/ml solution with a
calibrated syringe and
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injected into a 250 ml infusion bag or bottle of either 0.9% Sodium Chloride
solution or 5%
Dextrose solution to produce a final concentration of 0.3 to 0.74 mg/ml. If a
dose greater than
200 mg of Taxotere is required, a larger volume of the infusion vehicle is
used so that a
concentration of 0.74 mg/ml docetaxel is not exceeded. (It has been found that
if this maximum
is exceeded in the final infusion concentration, the Taxotere precipitates
out of the formulation
having the polysorbate as the solubilizer.) The infusion is then thoroughly
mixed by manual
rotation. The final Taxotere dilution for infusion should be administered
intravenously as a 1-
hour infusion under ambient room temperature and lighting conditions.
[00071 Taxotere infusion solution, if stored between 2 and 25 C (36 and 77 F)
is stable for 4
hours. Fully prepared Taxotere infusion solution (in either 0.9% Sodium
Chloride solution or
5% Dextrose solution) should be used within 4 hours (including the 1 hour
intravenous
administration).
100081 The present marketed docetaxel (in Taxotere ) is dissolved in 100%
(w/v) polysorbate
80 (Tween-80) which results in severe side effects. Severe hypersensitivity
reactions
characterized by generalized rash/erythema, hypotension and/or bronchospasm,
or very rarely
fatal anaphylaxis, have been reported in patients in spite of receiving the
recommended 3-day
dexamethasone premedication. Hypersensitivity reactions require immediate
discontinuation of
the Taxotere infusion and administration of appropriate therapy. All the
hypersensitive
reactions mentioned above are primarily caused by and due to the presence of
polysorbate 80 in
the formulation. In order to reduce the side effects induced by polysorbate
80, all patients are
treated with dexamethasone for three days prior to therapy. Dexamethasone is a
steroid that
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suppresses the immune response in patients. Cancer patients under chemotherapy
generally have
a low level of immunity due to the destruction of healthy cells by the
chemotherapeutic agents.
Treatment with steroids will further compromise the patient's immunity and
patients will be
susceptible to bacterial and fungal attacks. Due to these side effects, most
of the patients drop
out of docetaxel therapy by the end of 2nd or 3rd cycle or skip a dose or
continue further therapy
at reduced dose. The recommended therapy is 6 cycles of docetaxel given once
every three
weeks. Thus, therapeutic activity and the maximum tolerated dose (MTD) of
docetaxel are
compromised due to the presence of polysorbate 80 in the formulation. Other
solubilizing
agents such as Cremophor EL (used in connection with the marketed paclitaxel
product Taxol )
having similar allergic reactions (requiring pre-medication with steroids and
antihistamines)
should also be avoided.
[00091 The inventor's prior efforts at formulations of this type are seen in
US 12/214,506, filed
June 19, 2008, published as US 2008/0319048 on 12/25/2008 and as
WO/2009/002425 on
12/31/2008. Those efforts included the use of a select number of solvents
inclusive of glycofurol
to prepae an initial concentrate, and a select number of diluent materials
inclusive of TPGS,
additional glycofurol, and optionally relatively large amounts of antioxidants
for diluting the
initial concentrate to an intermediate concentrate for use within a relatively
short time to prepare
the infusion for administration. Notwithstanding the advantages of those
formulations,
improvements thereover were still necessary and such improvements have
resulted in the present
invention.
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a
OBJECTS OF THE INVENTION
[00101 It is therefore an object of one embodiment of the invention to provide
a docetaxel
formulation having an improved chemical stability, which upon dilution to an
intermediate
concentration so that the window for use after such dilution is greater than 8
hours, greater than
12 hours, greater than 16 hours, up to 24 hours.
[00111 It is an object of another embodiment of the invention to provide a
docetaxel
formulation suitable for injection or dilution to injection concentrations
having greater than 8
hour, greater than 12 hours, greater than 16 hours, up to 24 hours stability
containing a member
selected from the group consisting of a-lipoic acid, dihydrolipoic acid,
pharmaceutically
acceptable salts of either and mixtures thereof.
[00121 It is an object of yet another embodiment of the invention to provide a
docetaxel
formulation containing a member selected from the group consisting of a-lipoic
acid,
dihydrolipoic acid, pharmaceutically acceptable salts of either and mixtures
thereof in amounts
of up to 2.5 parts by weight (based on free a-lipoic acid or dihydrolipoic
acid respectively) per
part relative to docetaxel (or pharmaceutically acceptable salt thereof based
on free docetaxel) in
such formulation.
[00131 Still another object of the invention is to provide a docetaxel/(a-
lipoic acid or
dihydrolipoic acid or pharmaceutically acceptable salts of either or mixtures
thereof) formulation
containing from greater than 0.025 parts to less than 2.5 parts of a member
selected from the
group consisting of a-lipoic acid, dihydrolipoic acid, pharmaceutically
acceptable salts of either
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=
and mixtures thereof based on free a-lipoic acid or free dihydrolipoic acid,
respectively) per part
of docetaxel (or pharmaceutically acceptable salt thereof based on free
docetaxel).
[00141 Still another object of the invention is to provide a diluent for a
docetaxel concentrate
which diluent contains a-lipoic acid or dihydrolipoic acid (or a
pharmaceutically acceptable salt
of either) in an amount sufficient that on dilution of (a) a docetaxel (or a
pharmaceutically
acceptable salt thereof) solid or liquid initial or intermediate concentrate
results in (b) (i)an
intermediate concentration to fully diluted concentration of docetaxel (or a
pharmaceutically
acceptable salt thereof) suitable for injection where the a-lipoic acid or
dihydrolipoic acid (or a
pharmaceutically acceptable salt thereof) is in a fixed ratio to docetaxel (or
a pharmaceutically
acceptable salt thereof) in the range of more than 0.2 parts to less than
2.5parts of a member
selected from the group consisting of a-lipoic acid, dihydrolipoic acid,
pharmaceutically
acceptable salts of either and mixtures thereof per part of docetaxel (or a
pharmaceutically
acceptable salt thereof based on free docetaxel).
[00151 Another object of the invention is to provide a docetaxel liquid
concentrate that further
includes glycofurol and a member selected from the group consisting of a-
lipoic acid,
dihydrolipoic acid, pharmaceutically acceptable salts of either and mixtures
thereof.
[00161 Still another object of the invention is to provide a docetaxel liquid
concentrate that
includes a member selected from the group consisting of a-lipoic acid,
dihydrolipoic acid,
pharmaceutically acceptable salts of either and mixtures thereof and is
substantially free of
polysorbate components and substantially free of Cremophor components.
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100171 An even further embodiment of the invention is to provide a docetaxel
liquid
concentrate that includes a member selected from the group consisting of a-
lipoic acid,
dihydrolipoic acid, pharmaceutically acceptable salts of either and mixtures
thereof and is
completely free of both polysorbate and Cremophor components.
[00181 It is yet another object of the invention to provide a docetaxel
formulation that includes
a member selected from the group consisting of a-lipoic acid, dihydrolipoic
acid,
pharmaceutically acceptable salts of either and mixtures thereof and has fewer
hypersensitivity
reactions than the currently commercially available formulations, which have a
polysorbate 80
surfactant component.
[00191 It is yet another object of the invention to provide a docetaxel
formulation that includes
a member selected from the group consisting of a-lipoic acid, dihydrolipoic
acid,
pharmaceutically acceptable salts of either and mixtures thereof and has fewer
hypersensitivity
reactions than the currently commercially available formulations, which have a
polysorbate
surfactant component.
100201 It is yet another object of the invention to provide a docetaxel
formulation that includes
a member selected from the group consisting of a-lipoic acid, dihydrolipoic
acid,
pharmaceutically acceptable salts of either and mixtures thereof and has fewer
hypersensitivity
reactions than the currently commercially available formulations, have a
polysorbate 80
surfactant component and an alcohol component.
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[00211 Still another object of the invention is to provide a substantially
polysorbate-free
docetaxel (or a pharmaceutically acceptable salt thereof) liquid concentrate
formulation that
includes a member selected from the group consisting of a-lipoic acid,
dihydrolipoic acid,
pharmaceutically acceptable salts of either and mixtures thereof and is also
substantially free of
hydroxyalkyl-substituted cellulosic polymers.
[00221 An even further object of the invention is to provide a substantially
polysorbate-free
and substantially Cremophor-free docetaxel (or a pharmaceutically acceptable
salt thereof) liquid
concentrate formulation that is free of hydroxyalkyl-substituted cellulosic
polymers.
[00231 Still another object of the invention is to provide a substantially
polysorbate-free
docetaxel (or a pharmaceutically acceptable salt thereof) liquid concentrate
formulation that
includes a member selected from the group consisting of a-lipoic acid,
dihydrolipoic acid,
pharmaceutically acceptable salts of either and mixtures thereof and is also
substantially free of
substituted cellulosic polymers.
[00241 An even further object of the invention is to provide a substantially
polysorbate-free
and substantially Cremophor-free docetaxel (or a pharmaceutically acceptable
salt thereof) liquid
concentrate formulation that includes a member selected from the group
consisting of a-lipoic
acid, dihydrolipoic acid, pharmaceutically acceptable salts of either and
mixtures thereof and is
free of substituted cellulosic polymers.
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[00251 Still another object of the invention is to provide a substantially
polysorbate-free
docetaxel (or a pharmaceutically acceptable salt thereof) liquid concentrate
formulation that
includes a member selected from the group consisting of a-lipoic acid,
dihydrolipoic acid,
pharmaceutically acceptable salts of either and mixtures thereof and is also
substantially free of
cellulosic polymers.
100261 An even further object of the invention is to provide a substantially
polysorbate-free
and substantially Cremophor-free docetaxel (or a pharmaceutically acceptable
salt thereof) liquid
concentrate formulation that includes a member selected from the group
consisting of a-lipoic
acid, dihydrolipoic acid, pharmaceutically acceptable salts of either and
mixtures thereof and is
free of cellulosic polymers.
[00271 Still another object of the invention is to provide a suitable primary
dilution formulation
for use in preparing the aforementioned docetaxel (or a pharmaceutically
acceptable salt thereof)
liquid concentrates which primary dilution formulation contains a member
selected from the
group consisting of a-lipoic acid, dihydrolipoic acid, pharmaceutically
acceptable salts of either
and mixtures thereof.
[00281 An even further object of the invention is to provide a final dilution
for injection of a
docetaxel (or a pharmaceutically acceptable salt thereof) containing product
that includes a
member selected from the group consisting of a-lipoic acid, dihydrolipoic
acid, pharmaceutically
acceptable salts of either and mixtures thereof and is in the substantial
absence or in the total
absence of polysorbate 80 surfactant.
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[00291 An even further object of the invention is to provide a final dilution
for injection of a
docetaxel (or a pharmaceutically acceptable salt thereof) containing product
further containing a
member selected from the group consisting of a-lipoic acid, dihydrolipoic
acid, pharmaceutically
acceptable salts of either and mixtures thereof in the substantial absence or
in the total absence of
polysorbate 80 and in the substantial absence of Cremophor.
[00301 An even further object of the invention is to provide a final dilution
for injection of a
docetaxel (or a pharmaceutically acceptable salt thereof) containing product
further containing a
member selected from the group consisting of a-lipoic acid, dihydrolipoic
acid, pharmaceutically
acceptable salts of either and mixtures thereof in the substantial absence or
in the total absence of
polysorbate 80 surfactant, in the substantial or total absence of Cremophor,
and in the substantial
or total absence of a hydroxyalkyl-substituted cellulosic polymer.
[00311 An even further object of the invention is to provide a final dilution
for injection of a
docetaxel (or a pharmaceutically acceptable salt thereof) containing product
further containing a
member selected from the group consisting of a-lipoic acid, dihydrolipoic
acid, pharmaceutically
acceptable salts of either and mixtures thereof in the substantial absence or
in the total absence of
polysorbate 80 surfactant, in the substantial or total absence of Cremophor,
in the substantial or
total absence of a hydroxyalkyl-substituted cellulosic polymer, and in the
substantial or total
absence of alcohol.
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[0032] An even further object of the invention is to provide a final dilution
for injection of a
docetaxel (or a pharmaceutically acceptable salt thereof) containing product
further containing a
member selected from the group consisting of a-lipoic acid, dihydrolipoic
acid, pharmaceutically
acceptable salts of either and mixtures thereof in the substantial absence or
in the total absence of
polysorbate surfactant.
[0033] An even further object of the invention is to provide a final dilution
for injection of a
docetaxel (or a pharmaceutically acceptable salt thereof) containing product
further containing a
member selected from the group consisting of a-lipoic acid, dihydrolipoic
acid, pharmaceutically
acceptable salts of either and mixtures thereof in the substantial absence or
in the total absence of
polysorbate and in the substantial absence of Cremophor.
[0034] An even further object of the invention is to provide a final dilution
for injection of a
docetaxel (or a pharmaceutically acceptable salt thereof) containing product
further containing a
member selected from the group consisting of a-lipoic acid, dihydrolipoic
acid, pharmaceutically
acceptable salts of either and mixtures thereof in the substantial absence or
in the total absence of
polysorbate surfactant, in the substantial or total absence of Cremophor, and
in the substantial or
total absence of a hydroxyalkyl-substituted cellulosic polymer.
[0035] An even further object of the invention is to provide a final dilution
for injection of a
docetaxel (or a pharmaceutically acceptable salt thereof) containing product
further containing a
member selected from the group consisting of a-lipoic acid, dihydrolipoic
acid, pharmaceutically
acceptable salts of either and mixtures thereof in the substantial absence or
in the total absence of
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polysorbate surfactant, in the substantial or total absence of Cremophor, in
the substantial or total
absence of a hydroxyalkyl-substituted cellulosic polymer, and in the
substantial or total absence
of alcohol.
100361 Still another object of the invention is to provide a suitable primary
dilution for use in
preparing the aforementioned final dilution for injection formulations of
docetaxel (or a
pharmaceutically acceptable salt thereof).
[00371 An even further object of the invention is to provide a docetaxel (or a
pharmaceutically
acceptable salt thereof) lyophilizate for reconstitution where the
lyophilizate further contains a
member selected from the group consisting of a-lipoic acid, pharmaceutically
acceptable salts of
either and mixtures thereof in an amount of less than 2.5 parts by weight
based on free a-lipoic
acid per part of docetaxel (or a pharmaceutically acceptable salt thereof) by
weight based on free
docetaxel.
[00381 Yet another object of the invention is to provide a docetaxel (or a
pharmaceutically
acceptable salt thereof) lyophilizate for reconstitution where the
lyophilizate further contains a
member selected from the group consisting of a-lipoic acid, dihydrolipoic
acid, pharmaceutically
acceptable salts of either and mixtures thereofand is substantially free or
totally free of
polysorbate 80 surfactant and substantially free or totally free of a
cremophor surfactant.
[00391 Yet another object of the invention is to provide a docetaxel (or a
pharmaceutically
acceptable salt thereof) lyophilizate for reconstitution where the
lyophilizate further contains a
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member selected from the group consisting of a-lipoic acid, dihydrolipoic
acid, pharmaceutically
acceptable salts of either and mixtures thereof and is substantially free or
totally free of
polysorbate 80 surfactant, substantially free or totally free of a cremophor
surfactant, and
substantially free or totally free of a hydroxyalkyl-substituted cellulosic
polymer.
[0040] Yet another object of the invention is to provide a docetaxel (or a
pharmaceutically
acceptable salt thereof) lyophilizate for reconstitution where the
lyophilizate is substantially free
or totally free of polysorbate 80 surfactant, substantially free or totally
free of a cremophor
surfactant, substantially free or totally free of a hydroxyalkyl-substituted
cellulosic polymer, and
substantially free of alcohol.
[0041] An even further object of the invention is to provide a docetaxel (or a
pharmaceutically
acceptable salt thereof) lyophilizate for reconstitution where the
lyophilizate further contains a
member selected from the group consisting of a-lipoic acid, dihydrolipoic
acid, pharmaceutically
acceptable salts of either and mixtures thereof and is substantially free or
totally free of a
polysorbate surfactant.
[0042] Yet another object of the invention is to provide a docetaxel (or a
pharmaceutically
acceptable salt thereof) lyophilizate for reconstitution where the
lyophilizate further contains a
member selected from the group consisting of a-lipoic acid, dihydrolipoic
acid, pharmaceutically
acceptable salts of either and mixtures thereof and is substantially free or
totally free of a
polysorbate surfactant and substantially free or totally free of a cremophor
surfactant.
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[00431 Yet another object of the invention is to provide a docetaxel (or a
pharmaceutically
acceptable salt thereof) lyophilizate for reconstitution where the
lyophilizate further contains a
member selected from the group consisting of a-lipoic acid, dihydrolipoic
acid, pharmaceutically
acceptable salts of either and mixtures thereof and is substantially free or
totally free of a
polysorbate surfactant, substantially free or totally free of a cremophor
surfactant, and
substantially free or totally free of a hydroxyalkyl-substituted cellulosic
polymer.
[00441 Yet another object of the invention is to provide a docetaxel (or a
pharmaceutically
acceptable salt thereof) lyophilizate for reconstitution where the
lyophilizate further contains a
member selected from the group consisting of a-lipoic acid, dihydrolipoic
acid, pharmaceutically
acceptable salts of either and mixtures thereof and is substantially free or
totally free of a
polysorbate 80 surfactant, substantially free or totally free of a cremophor
surfactant,
substantially free or totally free of a hydroxyalkyl-substituted cellulosic
polymer, and
substantially free of alcohol.
100451 Still another object of the invention is to provide a lyophilizate of
docetaxel (or a
pharmaceutically acceptable salt thereof) that can be reconstituted without
the use of polysorbate
80 surfactant in either the lyophilizate or in the diluents for reconstitution
and wherein a member
selected from the group consisting of a-lipoic acid, dihydrolipoic acid,
pharmaceutically
acceptable salts of either and mixtures thereof is present in at least one of
the lyophilizate and the
diluents formulation for reconstitution thereof.
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[0046] Yet another object of the invention is to provide a lyophilizate of
docetaxel (or a
pharmaceutically acceptable salt thereof) that can be reconstituted without
the use of polysorbate
80 surfactant and without the use of Cremophor surfactant in either the
lyophilizate or in the
reconstitution diluents and wherein a member selected from the group
consisting of a-lipoic acid,
dihydrolipoic acid, pharmaceutically acceptable salts of either and mixtures
thereof is present in
at least one of the lyophilizate and the diluents formulation for
reconstitution thereof.
[0047] Another object of the invention is to provide a lyophilizate of
docetaxel (or a
pharmaceutically acceptable salt thereof) that can be reconstituted without
the use of any of
polysorbate 80, Cremophor, and a hydroxyalkyl-substituted cellulosic polymer
in either the
lyophilizate or in the reconstitution diluents and wherein a member selected
from the group
consisting of a-lipoic acid, dihydrolipoic acid, pharmaceutically acceptable
salts of either and
mixtures thereof is present in at least one of the lyophilizate and the
diluents formulation for
reconstitution thereof.
[0048] Still another object of the invention is to provide a lyophilizate of
docetaxel (or a
pharmaceutically acceptable salt thereof) that can be reconstituted without
the use of any of
polysorbate 80, Cremophor, a hydroxyalkyl-substituted cellulosic polymer and
alcohol in either
the lyophilizate or in the reconstitution diluents and wherein a member
selected from the group
consisting of a-lipoic acid, dihydrolipoic acid, pharmaceutically acceptable
salts of either and
mixtures thereof is present in at least one of the lyophilizate and the
diluents formulation for
reconstitution thereof.
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100491 Still another object of the invention is to provide a lyophilizate of
docetaxel (or a
pharmaceutically acceptable salt thereof) that can be reconstituted without
the use of a
polysorbate surfactant in either the lyophilizate or in the diluents for
reconstitution and wherein a
member selected from the group consisting of a-lipoic acid, dihydrolipoic
acid, pharmaceutically
acceptable salts of either and mixtures thereof is present in at least one of
the lyophilizate and the
diluents formulation for reconstitution thereof.
[00501 Yet another object of the invention is to provide a lyophilizate of
docetaxel (or a
pharmaceutically acceptable salt thereof) that can be reconstituted without
the use of a
polysorbate surfactant and without the use of a Cremophor surfactant in either
the lyophilizate or
in the diluents for reconstitution and wherein a-lipoic acid (or a
pharmaceutically acceptable salt
thereof) is present in at least one of the lyophilizate and the diluents
formulation for
reconstitution thereof.
[00511 Another object of the invention is to provide a lyophilizate of
docetaxel (or a
pharmaceutically acceptable salt thereof) that can be reconstituted without
the use of any of a
polysorbate surfactant, a Cremophor, and a substituted cellulosic polymer in
either the
lyophilizate or in the diluents for reconstitution and wherein a member
selected from the group
consisting of a-lipoic acid, dihydrolipoic acid, pharmaceutically acceptable
salts of either and
mixtures thereof is present in at least one of the lyophilizate and the
diluents formulation for
reconstitution thereof.
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[00521 Still another object of the invention is to provide a lyophilizate of
docetaxel (or a
pharmaceutically acceptable salt thereof) that can be reconstituted without
the use of any of a
polysorbate surfactant, a Cremophor, a substituted cellulosic polymer and
alcohol in either the
lyophilizate or in the diluents for reconstitution and wherein a member
selected from the group
consisting of a-lipoic acid, dihydrolipoic acid, pharmaceutically acceptable
salts of either and
mixtures thereof is present in at least one of the lyophilizate and the
diluents formulation for
reconstitution thereof.
[00531 Yet another object of the invention is to provide formulations, liquid
concentrates,
lyophilizates, etc. containing docetaxel (or a pharmaceutically acceptable
salt thereof) that
contain a member selected from the group consisting of a-lipoic acid,
dihydrolipoic acid,
pharmaceutically acceptable salts of either and mixtures thereofand are
substantially free or
totally free of any cellulosic polymer and can be reconstituted or diluted
without the use a
substantial amount or without the use of any amount of a cellulosic polymer.
[00541 Another object of the invention is to provide a means to administer
docetaxel (or a
pharmaceutically acceptable salt thereof) to patients without the need for
administering
dexamethasone or any other steroid and/or without the need to administer an
antihistamine prior
to the initiation of the docetaxel administration.
100551 Yet another object of the invention is the avoidance of diarrheal side
effect
accompanying docetaxel administration primarily, if not totally, due to the
polysorbate present in
currently marketed docetaxel injection products.
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CA 02683032 2009-10-20
100561 An even further object of the invention is to provide a means to
administer docetaxel
(or a pharmaceutically acceptable salt thereof) to patients without the need
for administering
dexamethasone or any other steroid and/or without the need to administer an
antihistamine prior
to the initiation of the docetaxel administration and without the need for
administering
dexamethasone or any other steroid or antihistamine during or after the
docetaxel (or a
pharmaceutically acceptable salt thereof) administration for reasons related
to hypersensitivity to
the docetaxel or pharmaceutically acceptable salt thereof administration.
[00571 Still a further object of the invention is to provide formulations of
docetaxel (or a
pharmaceutically acceptable salt thereof) having an antioxidant amount of a
member selected
from the group consisting of a-lipoic acid, dihydrolipoic acid,
thioaminoacids,propyl gallate,
BHT, BHA and pharmaceutically acceptable salts of either and mixtures thereof
which is present
from about 500 parts by weight to 20,000 parts by weight per million parts by
weight of
docetaxel (or a pharmaceutically acceptable salt thereof based on free
docetaxel) except in the
case of lipoic acid or dihydrolipoic acid or their respective pharmaceutically
acceptable salts
which when present are present as discussed elsewhere in this specification.
100581 Yet another object of the invention is to provide a diluent solution
for a docetaxel (or a
pharmaceutically acceptable salt thereof) solution in a solvent for docetaxel
(or a
pharmaceutically acceptable salt thereof), which diluent solution contains a
member selected
from the group consisting of a-lipoic acid, dihydrolipoic acid,
pharmaceutically acceptable salts
of either and mixtures thereof in an amount of from >0.025 parts to 2.0 parts
by weight (based on
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CA 02683032 2009-10-20
free a-lipoic acid or dihydrolipoic acid respectively) relative to 1 part by
weight docetaxel (or a
pharmaceutically acceptable salt thereof based on free docetaxel).
[00591 Still another object of the invention is to provide a docetaxel (or a
pharmaceutically
acceptable salt thereof) formulation having a first amount of a-lipoic acid
(or a pharmaceutically
acceptable salt thereof) and a diluent solution therefor having a second
amount of a member
selected from the group consisting of a-lipoic acid, dihydrolipoic acid,
pharmaceutically
acceptable salts of either and mixtures thereof, such that on dilution of the
docetaxel (or a
pharmaceutically acceptable salt thereof) formulation with the diluent
solution therefor, the
resulting diluted formulation contains a member selected from the group
consisting of a-lipoic
acid, dihydrolipoic acid, pharmaceutically acceptable salts of either and
mixtures thereof in the
range of >0.025 parts by weight to 2.0 parts by weight (based on free a-lipoic
acid or free
dihydrolipoic acid respectively) relative to 1 part by weight of docetaxel (or
a pharmaceutically
acceptable salt thereof based on free docetaxel).
[00601 An even further object of the invention is to provide an infusion
solution having a
member selected from the group consisting of a-lipoic acid, dihydrolipoic
acid, pharmaceutically
acceptable salts of either and mixtures thereof present in an amount of >0.025
parts to 2.0 parts
by weight (based on free a-lipoic acid or dihydrolipoic acid respectively)
relative to 1 part by
weight docetaxel(or a pharmaceutically acceptable salt thereof based on free
docetaxel).
100611 Yet another object of the invention is to provide a solid formulation
of docetaxel (or a
pharmaceutically acceptable salt thereof) having a member selected from the
group consisting of
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CA 02683032 2009-10-20
a-lipoic acid, pharmaceutically acceptable salts of either and mixtures
thereof present, the a-
lipoic acid (or a pharmaceutically acceptable salt thereof) being present in
an amount of not more
than 1.5 parts by weight (based on free a-lipoic acid or relative to 1 part by
weight docetaxel (or
a pharmaceutically acceptable salt thereof based on free docetaxel).
[00621 Still a further object of the invention is to provide a solid
formulation of docetaxel (or a
pharmaceutically acceptable salt thereof) having a member selected from the
group consisting of
a-lipoic acid, pharmaceutically acceptable salts of either and mixtures
thereof present in an
amount of from >0.025 parts to 1.5 parts by weight (based on free a-lipoic
acid or respectively)
relative to 1 part by weight docetaxel (or a pharmaceutically acceptable salt
thereof based on free
docetaxel).
[00631 Still further objects of the invention will be appreciated by those of
ordinary skill in the
art.
BRIEF SUMMARY OF THE INVENTION
[00641 These and other objects of the invention can be achieved by a
composition comprising
docetaxel (or a pharmaceutically acceptable salt thereof) and (a) at least one
pharmaceutically
acceptable solubilizer excipient that can dissolve the docetaxel (or a
pharmaceutically acceptable
salt thereof) in amounts corresponding to at least 55 mg free docetaxel/ml or
(b) a mixture of
pharmaceutically acceptable hydrotropes that in concert (although not
individually) are capable
of dissolving docetaxel (or a pharmaceutically acceptable salt thereof) in
amounts corresponding
to at least 55 mg free docetaxel/ml or (c) mixtures thereof or (d) at least
one pharmaceutically
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CA 02683032 2009-10-20
acceptable solubilization excipient that can dissolve docetaxel (or a
pharmaceutically acceptable
salt thereof) in amounts corresponding to at least 55 mg free docetaxel/ml in
combination with at
least one pharmaceutically acceptable solubilization aid where the
solubilization aid does not
alone or in combination with other solubilization aids dissolve docetaxel or a
pharmaceutically
acceptable slat thereof in amounts corresponding to at least 55 mg free
docetaxel/ml and wherein
at least one of the solid docetaxel, the initial concentrate thereof in a
solubilizer or hydrotrope
blend or solubilizer or one or more of the individual hydrotropes, or a
diluent formulation for
diluting any of the foregoing to either an intermediate concentration or to an
infusion strength
formulation contains a member selected from the group consisting of a-lipoic
acid, dihydrolipoic
acid, pharmaceutically acceptable salts of either and mixtures thereofin an
mount such that by
the time the docetaxel (or a pharmaceutically acceptable salt thereof) is at
or below 10 mg (based
on free docetaxel/ml) of solution strength, the a member selected from the
group consisting of a-
lipoic acid, dihydrolipoic acid, pharmaceutically acceptable salts of either
and mixtures thereof is
present with the docetaxel (or a pharmaceutically acceptable salt thereof) and
in an amount of
from greater than 0.025 parts up to 2.5 parts by weight based on free a-lipoic
acid or
dihydrolipoic acid respectively relative to 1 part by weight docetaxel (or a
pharmaceutically
acceptable salt thereof based on free docetaxel). It is surprisingly found
that the lipoic acid
and/or dihydrolipoic aicd and/or pharmaceutically acceptable salts thereof in
these ranges impart
surprisingly valuable stability to the compositions of the invention. These
docetaxel (or
pharmaceutically acceptable salts thereof) solutions are either in the
pharmaceutically acceptable
solubilizer, hydrotropes , or mixtures thereof directly or in water solutions
thereof, generally
without further solubilization aids, but further such solubilization aids may
be included if
desired. Each of the solutions of the invention is preferably, but need not
be, in the substantial
-22-
CA 02683032 2009-10-20
absence of polysorbate 80, if not the total absence of polysorbate 80 and
optionally in the
substantial absence of or total absence of one or more of a polyethoxylated
vegetable oil, a
polyethoxylated castor oil, a polyethoxylated partially hydrogenated vegetable
oil, a
polyethoxylated partially hydrogenated castor oil, a polyethoxylated
hydrogenated vegetable oil,
a polyethoxylated hydrogenated castor oil, optionally in the substantial
absence of or in the total
absence of hydroxypropylmethylcellulose (preferably hydroxyalkyl
alkylcellulose, more
preferably substituted cellulosic polymers), and optionally in the substantial
absence of ethanol.
When ethanol is not substantially present, it may still be used in the
preparation of a lyophilizate,
but it is substantially, if not totally removed during the lyophilization
process. The avoidance of
the polysorbate 80 and Cremophor type solubilizers has the advantage that this
avoids the
hypersensitivity reactions that plague existing formulations of taxanes and
allows for the
reduction or elimination of steroid and/or antihistamine pre- and/or post
treatment necessitated
by concerns of hypersensitivity. Avoidance of the polysorbate 80 further
avoids the diarrheal
side effect caused thereby. Regardless of whether these materials are present
or absent, the
presence of the a member selected from the group consisting of a-lipoic acid,
dihydrolipoic acid,
pharmaceutically acceptable salts of either and mixtures thereofprovides
enhanced stability
during long term storage and/or enhanced storage stability time once diluted
to intermediate or
final administration conditions. Thus the inclusion of the a member selected
from the group
consisting of a-lipoic acid, dihydrolipoic acid, pharmaceutically acceptable
salts of either and
mixtures thereof component allows for an extension of the suitable time frame
in which one can
utilize diluted docetaxel solution, thereby improving efficiency in the
extemporaneous dilution of
docetaxel formulations for injection and the elimination of substantial waste
of materials. Where
the polysorbates and polyethoxylated oils are avoided, the formulations allow
for better, more
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CA 02683032 2009-10-20
effective dosing regimens and better patient compliance with recommended
dosings than with
the currently marketed taxane injectables.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING
100651 Not Applicable
DETAILED DESCRIPTION OF THE INVENTION
100661 The present invention is directed to (a) formulations of docetaxel, (b)
concentrates for
preparing injectable formulations of docetaxel, (c) docetaxel lyophilizates
for reconstituting into
such injectable compositions or into such concentrates for further dilution
into such
compositions; and further to (d) methods of manufacture of each. Methods of
treatment of
docetaxel treatable conditions with the docetaxel formulations, especially for
treatment without
the need for steroid pre-treatment or at least a reduction in the amount of
steroid pre-treatment as
compared to the present methods of administering docetaxel are also part of
the invention as is
the treatment without the need for antihistamine pre/post-treatment. The
formulations,
concentrates, lyophilizates, intermediate dilutions, and final administration
injectable
presentations are substantially free, preferably totally free of polysorbate
80, more preferably
substantially free, still more preferably totally free of any polysorbate
surfactant. Surprisingly
stable products of the invention are prepared by the inclusion of lipoic acid
or dihydrolipoic acid
or pharmaceutically acceptable salts thereof in amounts (based on the non-salt
forms thereof)
that are in the range of more than 0.025 parts to less than 0.25 parts by
weight relative to 1 part
of docetaxel or pharmaceutically acceptable salt thereof (based on free
docetaxel) that is present
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CA 02683032 2009-10-20
in the formulation or that upon dilution of a docetaxel formulation therewith,
will have these
components in the recited ranges.
[00671 If docetaxel is formulated with non-toxic pharmaceutically acceptable
excipients, it can
be administered to cancer patients at much higher doses (greater than the
current dosing range of
75 to 100mg/m2), or higher infusion rates (up to at least 1 mg/ml in 10 to 15
minutes infusion
time), for longer exposure to the drug (more than 6 cycles), and/or less than
3 weeks between
cycles; and without missing any dosing cycles or dose reduction due to side
effects. In other
words, if docetaxel is formulated with pharmaceutically acceptable innocuous
excipients, it will
be better tolerated in cancer patients and would be highly beneficial to them
as they can take the
medication for a longer period of time without dose interruption and reduction
(and therefore
potentially higher total and cumulative dose) compared to the current
formulation. Longer
exposure to the docetaxel maintains the dose density over a longer period in
the tumor and
thereby helps to better eradicate the cancer cells and minimizes the relapse
of the disease.
Furthermore, the reduction or elimination of the steroid pre-treatment phase
(in common use
with the existing marketed docetaxel product) means fewer concerns with immune
system
depression, drug-drug interactions with other drugs which the patient may be
taking, and the
avoidance of side effects of steroid administration. Still further, avoidance
of the Tween
component (polysorbate component) means removal of a substantial cause of the
diarrheal and
erythema side effects seen with current docetaxel infusions. Finally, with the
removal of the
polysorbate component (and optional removal of the alcohol component) and
enablement of
administration at higher dosages than currently suitable, docetaxel (or a
pharmaceutically
acceptable salt thereof) may now be used to treat conditions which it could
not previously be
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CA 02683032 2009-10-20
used to treat because of the dose limitations imposed by the polysorbate
and/or alcohol
components of the current TAXOTERE formulation.
[00681 For purposes of the present invention, the terms "solubilizer" and
"hydrotrope" will
have the following definitions: A "solubilizer" is a solvent that is capable
of dissolving
docetaxel (or a pharmaceutically acceptable salt thereof) to prepare liquid
concentrate in
concentrations of at least greater than 55 mg docetaxel (or a pharmaceutically
acceptable salt
thereof based on free docetaxel) per ml of solution in the solvent or in an
aqueous solution of the
solvent, while a "hydrotrope" is defined as a material that is present in
large quantities to
solubilize the lipophilic drug (and further prevents the precipitation of
docetaxel (or a
pharmaceutically acceptable salt thereof) (or other lipophilic agent in the
formulation) when the
liquid concentrate is further diluted to lower concentrations)). A hydrotrope
solubilizes
docetaxel or any such other lipophilic agent and requires large quantities to
dissolve the drug, but
still does not dissolve the drug to the extent as the solubilizer, but two or
more hydrotropes can
act synergistically on solubility such that the combination can be used as a
"solubilizer" in the
context of the present invention (again provided that the docetaxel (or a
pharmaceutically
acceptable salt thereof) has a solubility in that synergistic combination of
at least 55 mg (based
on free docetaxel)/ml). In some instances a solubilizer can provide sufficient
degree of
dissolution that a separate hydrotrope or other solubilization aid is not
needed, but this is
generally not the case (i.e. a separate hydrotrope is usually desirable). For
clarity, if a solvent
can be used to yield a solution in the solvent directly or in a water solution
thereof of docetaxel
(or a pharmaceutically acceptable salt thereof) at least 55 mg /ml, preferably
at least 60 mg/ml or
more (each based on free docertaxel), it is a "solubilizer" according to the
present invention. For
-26-
CA 02683032 2009-10-20
example, Tween 80, glycofurol, ethanol, etc. can be classified as solubilizers
while ethanol,
TPGS 1000, PEG 400 and propylene glycol are classified as hydrotropes. The
concentration of
drug in solubilizer varies depending on the lipophilicity of drug. The table
below shows a
number of solubility studies with docetaxel. Each of the solvents that are
reported to be able to
dissolve docetaxel (or a pharmaceutically acceptable salt thereof) to an
amount of at least about
55 mg/ml, preferably at least about 60 mg/ml each based on free docetaxel, is
a "solubilizer"
according to the present invention. Those of ordinary skill in the art will
know of other suitable
materials by either reference to literature or by conducting simple solubility
studies such as those
indicated in the Examples below. Some of the remaining materials where
docetaxel solubility is
greater than or equal to 10 mg/ml in the Table below can be seen to be
"hydrotropes" according
to the definitions of the present invention, with other materials being
neither solubilizers nor
hydrotropes but having some ability to dissolve docetaxel being
"solubilization aids". The
present invention generally, and preferably, does not use the polysorbates
(Tweens) even though
they are excellent solubilizers because of their tolerability problems as
injectable solution
components, and thus, the present invention is an attempt to obtain similar or
better results (than
the TAXOTERE formulation) without the use of polysorbate surfactants. However,
the use of a-
lipoic acid (or a pharmaceutically acceptable salt thereof) , even in the
Tween containing
formulations such as the currently marketed Taxotere offers benefits and are
within the scope of
a lesser preferred empbodiment of the invention. Some of the tested solvents,
such as N-Methyl
2-Pyrrolidone Labrofac, peceol and maisine 35-1 are not used in the parenteral
therapy, and are
not materials for use in the invention. Solubility studies conducted with
these excipients are to
understand how different excipients containing different functional groups are
contributing to the
solubility of docetaxel. A solubilizer can also act as a hydrotrope (on
dilution with infusion
-27-
CA 02683032 2009-10-20
fluid) if it is used in the sufficiently large quantities. For example,
docetaxel (or a
pharmaceutically acceptable salt thereof) solubility (based on free docetaxel)
in glycofurol is
about 200 mg/ml. When this liquid concentrate is diluted with water to
administration
concentrations, docetaxel precipitates out. Hence a special diluent is needed
to dilute the liquid
concentrate to prevent precipitation of docetaxel. If docetaxel is prepared as
about a 10 mg/ml
solution in glycofurol, it will not precipitate out when diluted with IV
fluids to administration
concentrations. Thus, by decreasing drug (based on free docetaxel) to
glycofurol ratio from
200:1w/w to about 10:1w/w (20-fold increase in glycofurol level), glycofurol
functions as a
solubilizer (in the concentrate) as well as a hydrotrope (in the diluted
infusion solution
concentration. In the table below and the rest of this specification, the
terms "solubilizer" and
"hydrotrope" will be used with reference to concentrates (both initial and
intermediate) unless
specifically indicated otherwise or the context so requires.
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CA 02683032 2009-10-20
PEG 400 10 mg/ ml Hydrotrope
Propylene Glycol 10 mg/ ml Hydrotrope
50%PEG 400/50% PG 15 mg/ ml Hydrotrope
2% Lutrol in PEG 400 15 mg/ ml Hydrotrope
Tween 80 60 mg/ ml Solubilizer
Tween 20 90 mg/ ml Solubilizer
Glycerol 1.65 mg/ ml Solubilization aid
Span 80 3.5 mg/ ml Solubilization aid
TPGS 1000 50 mg/ ml Hydrotrope
Labrofac (Capric triglyceride 35 mg/ ml Hydrotrope
PEG 4 ester. Macrogol 200)
Peceol (Glycerol mono Oleate 40) 7 mg/ ml Solubilization aid
Maisine 35-1 (Glycerol mono linoleate) 10 mg/ ml Hydrotrope
Ethanol 120 mg/ ml Solubilizer
N-Methyl 2-Pyrrolidone 17.6 mg/ ml Hydrotrope
Benzyl alcohol 90 mg/ ml Solubilizer
Benzyl benzoate 13 mg/ ml Hydrotrope
Acetic acid 60 mg/ ml Solubilizer
1-lactic acid 6 mg/ml Solubilization aid
Glycofurol 200 mg/ml Solubilizer
Dihydrolipoic acid > 120 mg/ml Solubilizer
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CA 02683032 2009-10-20
[00691 Even though some of the tested solvents showed very high solubility of
docetaxel
therein and would allow the manufacture of liquid concentrates, in a number of
instances, on
dilution with water and other common diluents (for the preparation of
injectable products, such
as normal saline or 5% dextrose solution), the docetaxel came out of solution.
Thus, the mere
suitability of a solvent as a solubilizer is not enough to complete the
present invention. Behavior
upon dilution with suitable injectable diluent solutions (water for injection,
saline solutions, or
dextrose solution for injection) needs to be explored as well in order to
obtain a suitable product.
Such further exploration will be within the ability of one of ordinary skill
in the art once aware of
the present disclosures.
100701 Notwithstanding the above, the solubilizers for the present invention
can be selected
(without limitation) from the group consisting of glycofurol, acetic acid, N-
(3-hydroxyethyl
lactamide, benzyl alcohol and ethanol. Ethanol, which may be present in
certain embodiments,
is preferably absent, more preferably totally absent. In the embodiments in
which it is present, it
may be present in an amount that upon dilution of the doxetaxel (or
pharmaceutically acceptable
salt thereof) containing portion to 10 mg (based on free docetaxel)/ml
solution, the ethanol
should not exceed 13% w/v of such solution. In most embodiments, ethanol is
not present in any
significant amount (typically less than about 2000 ppm, preferably less than
about 1000 ppm,
more preferably less than about 500 ppm, still more preferably less than about
250 ppm, and
most preferably not more than about 200 ppm), and in many embodiments is
completely absent.
Other solvents (those not acceptable for being present in the final
formulation for injection) for
docetaxel may be used in the preparation of the docetaxel (or pharmaceutically
acceptable salt
thereof) in the form to be used (such as in a crystallization or
lyophilization process provided
-30-
CA 02683032 2009-10-20
they are removed before utilization of the docetaxel in the preparation of the
solutions for use in
the present invention, but preferably they are not employed even in these
preparativeprocedures.
[00711 Glycofurol is also known as tetrahydrofurfuryl alcohol polyethylene
glycol ether and
has the following structure:
C 0
)-~ O
Jn OH
where n is on average 2 for glycofurol 75, but may be other integers for other
glycofurols.
Glycofurol, especially glycofurol 75, is one of the most preferred
solubilizers as docetaxel is
highly soluble therein (200 mg/ml in glycofurol 75). While glycofurol 75 is
the most preferred
of the glycofurols, those having an average n in the above formula of about 2
to about 8,
preferably 2 to about 6, more preferably 2 to about 4, more preferably about 2
or about 3 or
about 4 are also suitable. Larger values of n can be used, but the
appropriateness of the larger
glycofurols (average n in excess of about 8) falls off quickly.
100721 Hydrotropes for the present invention are generally selected (without
limitation) from
the group consisting of polyethylene glycol, especially PEG 400; propylene
glycol, Lutrol 2% in
PEG (especially in PEG 400); tocopherol compounds, particularly tocopherol-
polyethylene
glycols, more particularly tocopherol polyethylene glycol diacid (such as
succinates, maleates,
etc.) esters, especially tocopherol polyethyleneglycol succinates, most
preferably tocopherol
polyethylene glycol 1000 succinate (TPGS 1000); Labrofac; Peceol; Maisine 35-
I; N-methyl-2-
pyrrolidone; benzyl benzoate; ethyl carbonate, propylene carbonate, propylene
glycol; 1,3-
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CA 02683032 2009-10-20
butylene glycol; C1_4alkylesters of C12_18saturated, mono unsaturated or di-
unsaturated fatty
acids, especially ethyl oleate; dioxolanes; glycerol formal;
dimethylisosorbide, solketal; gentisic
acid; and mixtures thereof. Labrofac; Peceol; Maisine 35-I; and N-methyl-2-
pyrrolidone are
generally not suitable for injectable use and therefore, these materials are
least desired to be
used, and should be generally avoided. Some mixtures of the hydrotropes will
act
synergisitically on the solubility of docetaxel such that the combination can
be used as the
"solubilizer" of the present invention. Confirmation of which combinations of
hydrotropes that
will act synergistically on solubility so as to be so used as a solubilizer
can be done in routine
solubility experiments which are totally within the ordinary skill within the
art. When such
combinations are used in place of a material which is a solubilizer in its own
right, the
formulation may contain (a) additional amounts of one of the hydrotropes of
the synergistic
combination or (b) a different hydrotrope or (c) neither, or may further
contain a solubilization
aid if so desired.
100731 Docetaxel (or pharmaceutically acceptable salt thereof) active agent
can be dissolved in
the solubilizer (solubilizer includes mixtures of hydrotropes that have the
requisite solubility of
docetaxel therein to qualify the mixture as a solubilizer) alone or in a
mixture of the solubilizer
and hydrotrope to obtain a clear solution (i.e. initial high concentrate
formulation). This can be
in the presence or absence of water and preferably is in the absence of water.
When the
hydrotrope is to be present in the initial high concentrate solution, it is
preferably added to the
solubilizer first and the docetaxel (either alone or in solution with a
solubilizer) is added to the
solubilizer/hydrotrope solution, although other orders of addition are
suitable as well. These can
then be lyophilized and the lyophilizate reconstituted to form concentrates
using solvents,
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CA 02683032 2009-10-20
hydrotropes, solublization aids selected from the previously set forth group
of materials other
than those that are specifically indicated as being avoided and other than
those that are not
compatible with injectable formulations. The initial high concentrate solution
can be stored at
room temperature or under refrigeration conditions, preferably refrigerated
conditions
(preferably about 2 to about 8 C). The concentrate solution is then diluted
with a first diluent
that contains solubilizer and optionally hydrotrope (whether or not hydrotrope
is present in the
initial concentrate already) or may be diluted with just injectable diluent
fluid alone if the
solubilizer/hydrotrope are both already present, or with diluent having one or
both of the
solubilizer and/or hydrotrope regardless of whether the solubilizer/hydrotrope
are otherwise
present to obtain an intermediate concentrated solution generally in the
concentration range of 5-
20 mg docetaxel/ml or higher, preferably about 10 mg/ml (although other
intermediate
concentrations can be formed as well). This intermediate concentrate is
further diluted with an
injectable diluent solution (generally water for injection, normal saline
solution, or dextrose 5%
for injection) to concentrations of 0.3 to 0.74 mg (based on free
docetaxel)/ml, for administration
designed to be in the same concentration range as that recommended in the
currently marketed
Taxotere product; however, as discussed earlier, higher infusion
concentrations (at least up to 1
mg docetaxel (or pharmaceutically acceptable salt thereof based on free
docetaxel)/ml or higher)
as well as faster infusion rates are also suitable for the present invention
since there is no
polysorbate component present. If the hydrotrope is not present in the
concentrate formulation,
then the diluent solution to prepare the intermediate concentrate should
either have the
appropriate amount of hydrotrope present or the hydrotrope may be added
separately to the
concentrate at a point in time before dilution with the injectable diluent
solution. If desired, the
initial high concentrate solution may be diluted directly by the injectable
diluent (normal saline,
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CA 02683032 2009-10-20
water for injection, or D5W for example) to achieve the Taxotere recommended
administrable
concentration of not more than about 0.74 mg docetaxel per ml (or higher if
desired) if the initial
high concentration solution has sufficient amounts of both the solubilizer and
hydrotrope present,
although it is best to prepare the dilution in the two step process set out
above. In a highly
preferred embodiment, the docetaxel (or pharmaceutically acceptable salt
thereof) is dissolved in
a solubilizer (preferably glycofurol) to a concentration of about 40 mg/ml or
about 80 mg/ml
(each based on free docetaxel) or higher with or without an antioxidant
(preferably selected from
a-lipoic acid, dihydrolipoic aicd, and pharmaceutically acceptable salts
thereof) to form a first
(or initial) concentrate solution. Separately, a primary diluent formulation
is prepared
comprising at least one hydrotrope (preferably TPGS 1000 and/or PEG 400),
optionally
additional solubilizer (preferably selected from glycofurol and/or ethanol),
with water and
optionally suitable amounts of a tonicity adjuster and optionally suitable
amounts of a buffer or
other pH modifier. Where TPGS is one of the hydrotropes, it is present in the
primary diluent
preferably at a concentration of about 100 mg/ml to about 290 mg/ml (750 mg,
1000 mg, 1250
mg, 1500 mg, 1750 mg, and 2000 mg per 7 ml of primary diluents being
preferred). When PEG
400 is one of the hydrotropes used, it is preferably present in present in
amounts of 2.0-3.5 ml
per 7 ml of primary diluents.
[00741 The member selected from the group consisting of a-lipoic acid,
dihydrolipoic acid,
pharmaceutically acceptable salts of either and mixtures thereof component is
present in the
present invention in an amount (based on free a-lipoic acid or free
dihydrolipoic acid
respectively) in proportion to the docetaxel (or pharmaceutically acceptable
salt thereof based on
free docetaxel) when in the intermediate concentration formulation strength of
up to 2.5 parts,
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CA 02683032 2009-10-20
preferably not more than 2.0 parts, more preferably not more than 1.0 parts,
still more preferably
not more than 0.75 parts, even more preferably not more than 0.5 parts, still
even more
preferably not more than 0.25 parts (based on free a-lipoic acid or free
dihydrolipoic acid
respectively) per part of docetaxel (or pharmaceutically acceptable salt
thereof based on free
docetaxel); preferably from about 0.025 parts to about 0.2 parts, more
preferably about 0.03125
parts to about 0.1875 parts, still more preferably about 0.0375 parts to about
0.1275 parts, even
more preferably from about 0.05 parts to about 0.09375 parts, most preferably
about 0.0625 parts
(based on free a-lipoic aicd or dihydrolipoic acid respectively) per part of
docetaxel (or
pharmaceutically acceptable salt thereof based on free docetaxel). Prior to
formation of the
intermediate concentration formulation, the a-lipoic acid, dihydrolipoic acid,
pharmaceutically
acceptable salts of either and mixtures thereof component can be incorporated
in whole or in part
into the solid docetaxel (or pharmaceutically acceptable salt thereof), the
initial concentrate, or
the diluent formulation for dilution of the solid material or the diluent
formulation for dilution of
the initial concentration formulation into the intermediate concentration
formulation, or any
combination thereof so that once diluted to the intermediate concentration
formulation the
requisite total amounts of a member selected from the group consisting of a-
lipoic acid,
dihydrolipoic acid, pharmaceutically acceptable salts of either and mixtures
thereof is present as
set forth above.
[00751 Preferred formulations for the diluent for diluting an 80 mg docetaxel
(or
pharmaceutically acceptable salt thereof based on free docetaxel)/ml initial
concentrate into a 10
mg docetaxel (or pharmaceutically acceptable salt thereof based on free
docetaxel)/ml
intermediate concentrate contain (a) TPGS 1000, (b) PEG 400, (c) optionally a
member selected
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CA 02683032 2009-10-20
from the group consisting of a-lipoic acid, dihydrolipoic acid,
pharmaceutically acceptable salts
of either and mixtures thereof, preferably a-lipoic acid or a pharmaceutically
acceptable salt
thereof preferably present if the initial concentration docetaxel formulation
to be diluted has
insufficient amounts of this component to meet the requirements set forth for
this component
elsewhere), (d) water if needed to bring the primary diluent formulation
volume to 7 ml, (e)
optionally sodium or potassium chloride, and (f) optionally ethanol. 7 ml of
this primary diluent
is used to dilute every 1 ml of the 8Omg/ml solution described above to result
in a 10 mg
docetaxel (or pharmaceutically acceptable salt thereof)/ml intermediate
concentrate formulation
which is then ready to be added in an appropriate amount to an infusion
solution for infusion
administration in appropriate therapeutic infusion strengths. More preferably,
sample diluent
formulations are, without limitation set forth in the table below, but
formulations B and BG are
most highly preferred when all of the a-lipoic acid (or pharmaceutically
acceptable salt thereof)
is contained in the primary diluent formulation. Corresponding primary diluent
formulations are
also deemed set forth having lesser amounts of the a-lipoic acid or salt
thereof when a portion of
the a-lipoic acid, dihydrolipoic acid or salts thereof are contained in the
initial concentrate, and
corresponding primary primary diluent formulations having no a-lipoic acid or
salt thereof are
also contemplated for diluting initial concentrates where the initial
concentrate already has the
full requirement of the a-lipoic acid, dihydrolipoic acid or salts thereof.
For these corresponding
formulations, those corresponding to formulations B and BG below are, without
limitation also
preferred.
All amounts in the following table are in mg unless noted otherwise:
TPGS PEG a- a-lipoic acid NaCl Ethanol (in Water (q.s.
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CA 02683032 2009-10-20
1000 400 (in lipoic potassium salt ml) to stated ml)
ml) acid (basedon free
a-lipoic acid)
A 750 3.5 5.0 72 0.9 7.0
B 1000 3.5 5.0 72 0.9 7.0
C 1250 3.5 5.0 72 0.9 7.0
D 1500 3.5 5.0 72 0.9 7.0
E 1750 3.5 5.0 72 0.9 7.0
F 750 3.5 2.5 72 0.9 7.0
G 1000 3.5 2.5 72 0.9 7.0
H 1250 3.5 2.5 72 0.9 7.0
I 1500 3.5 2.5 72 0.9 7.0
J 1750 3.5 2.5 72 0.9 7.0
K 750 3.5 3.0 72 0.9 7.0
L 1000 3.5 3.0 72 0.9 7.0
M 1250 3.5 3.0 72 0.9 7.0
N 1500 3.5 3.0 72 0.9 7.0
0 1750 3.5 3.0 72 0.9 7.0
P 750 3.5 4.0 72 0.9 7.0
Q 1000 3.5 4.0 72 0.9 7.0
R 1250 3.5 4.0 72 0.9 7.0
S 1500 3.5 4.0 72 0.9 7.0
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CA 02683032 2009-10-20
T 1750 3.5 4.0 72 0.9 7.0
U 750 3.5 4.5 72 0.9 7.0
V 1000 3.5 4.5 72 0.9 7.0
W 1250 3.5 4.5 72 0.9 7.0
X 1500 3.5 4.5 72 0.9 7.0
Y 1750 3.5 4.5 72 0.9 7.0
Z 750 3.5 5.5 72 0.9 7.0
AA 1000 3.5 5.5 72 0.9 7.0
AB 1250 3.5 5.5 72 0.9 7.0
AC 1500 3.5 5.5 72 0.9 7.0
AD 1750 3.5 5.5 72 0.9 7.0
AE 750 3.5 6.0 72 0.9 7.0
AF 1000 3.5 6.0 72 0.9 7.0
AG 1250 3.5 6.0 72 0.9 7.0
AH 1500 3.5 6.0 72 0.9 7.0
Al 1750 3.5 6.0 72 0.9 7.0
AJ 750 3.5 10 72 0.9 7.0
AK 1000 3.5 10 72 0.9 7.0
AL 1250 3.5 10 72 0.9 7.0
AM 1500 3.5 10 72 0.9 7.0
AN 1750 3.5 10 72 0.9 7.0
AO 750 3.5 15 72 0.9 7.0
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CA 02683032 2009-10-20
AP 1000 3.5 15 72 0.9 7.0
AQ 1250 3.5 15 72 0.9 7.0
AR 1500 3.5 15 72 0.9 7.0
AS 1750 3.5 15 72 0.9 7.0
AT 750 3.5 20 72 0.9 7.0
AU 1000 3.5 20 72 0.9 7.0
AV 1250 3.5 20 72 0.9 7.0
AW 1500 3.5 20 72 0.9 7.0
AX 1750 3.5 20 72 0.9 7.0
AY 750 3.5 22.5 72 0.9 7.0
AZ 1000 3.5 22.5 72 0.9 7.0
BA 1250 3.5 22.5 72 0.9 7.0
BB 1500 3.5 22.5 72 0.9 7.0
BC 1750 3.5 22.5 72 0.9 7.0
BD 750 3.5 5.0 72 7.0
BE 1000 3.5 5.0 72 7.0
BF 1250 3.5 5.0 72 7.0
BG 1500 3.5 5.0 72 7.0
BH 1750 3.5 5.0 72 7.0
BI 750 3.5 2.5 72 7.0
BJ 1000 3.5 2.5 72 7.0
BK 1250 3.5 2.5 72 7.0
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CA 02683032 2009-10-20
BL 1500 3.5 2.5 72 7.0
BM 1750 3.5 2.5 72 7.0
BN 750 3.5 3.0 72 7.0
BO 1000 3.5 3.0 72 7.0
BP 1250 3.5 3.0 72 7.0
BQ 1500 3.5 3.0 72 7.0
BR 1750 3.5 3.0 72 7.0
BS 750 3.5 4.0 72 7.0
BT 1000 3.5 4.0 72 7.0
BU 1250 3.5 4.0 72 7.0
BV 1500 3.5 4.0 72 7.0
BW 1750 3.5 4.0 72 7.0
BX 750 3.5 4.5 72 7.0
BY 1000 3.5 4.5 72 7.0
BZ 1250 3.5 4.5 72 7.0
CA 1500 3.5 4.5 72 7.0
CB 1750 3.5 4.5 72 7.0
CC 750 3.5 5.5 72 7.0
CD 1000 3.5 5.5 72 7.0
CE 1250 3.5 5.5 72 7.0
CF 1500 3.5 5.5 72 7.0
CG 1750 3.5 5.5 72 7.0
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CA 02683032 2009-10-20
CH 750 3.5 6.0 72 7.0
CI 1000 3.5 6.0 72 7.0
CJ 1250 3.5 6.0 72 7.0
CK 1500 3.5 6.0 72 7.0
CL 1750 3.5 6.0 72 7.0
CM 750 3.5 10 72 7.0
CN 1000 3.5 10 72 7.0
CO 1250 3.5 10 72 7.0
CP 1500 3.5 10 72 7.0
CQ 1750 3.5 10 72 7.0
CR 750 3.5 15 72 7.0
CS 1000 3.5 15 72 7.0
CT 1250 3.5 15 72 7.0
CU 1500 3.5 15 72 7.0
CV 1750 3.5 15 72 7.0
CW 750 3.5 20 72 7.0
CX 1000 3.5 20 72 7.0
CY 1250 3.5 20 72 7.0
CZ 1500 3.5 20 72 7.0
DA 1750 3.5 20 72 7.0
DB 750 3.5 22.5 72 7.0
DC 1000 3.5 22.5 72 7.0
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CA 02683032 2009-10-20
DE 1250 3.5 22.5 72 7.0
DF 1500 3.5 22.5 72 7.0
DG 1750 3.5 22.5 72 7.0
DH 1000 3.5 5.0 0.9 7.0
DI 1000 3.5 5.0 36 0.9 7.0
DJ 1500 3.5 5.0 7.0
DK 1500 3.5 5.0 36 7.0
DL 1000 3.0 5.0 0.9 7.0
DM 1000 3.0 5.0 36 0.9 7.0
DN 1000 3.0 5.0 72 0.9 7.0
DO 1500 2.5 5.0 7.0
DP 1500 2.5 5.0 36 7.0
DQ 1500 2.5 5.0 72 7.0
DR 1000 3.0 5.0 0.9 7.0
DS 1000 3.0 5.0 36 0.9 7.0
DT 1000 3.0 5.0 72 0.9 7.0
DU 1500 2.5 5.0 7.0
DV 1500 2.5 5.0 36 7.0
DW 1500 2.5 5.0 72 7.0
DX 1000 3.0 2.5 2.5 0.9 7.0
DY 1000 3.0 2.5 2.5 36 0.9 7.0
DZ 1000 3.0 2.5 2.5 72 0.9 7.0
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CA 02683032 2009-10-20
EA 1500 2.5 2.5 2.5 7.0
EB 1500 2.5 2.5 2.5 36 7.0
EC 1500 2.5 2.5 2.5 72 7.0
Also preferred are the corresponding formulations wherein the a-lipoic acid is
replaced by the
same number of mg of dihydrolipoic acid or the a-lipoic acid potassium salt is
replaced by the
same number of mg of a-lipoic acid non-potassium pharmaceutically acceptable
alkaline salt
forms, or the same number of mg of dihdyrolipoic acid or its pharmaceutically
acceptable
alkaline salt forms.
[00761 This liquid concentrate and the diluent solution may then be packaged
and stored for
commercial distribution. The diluent solution is then used to dilute the
docetaxel concentrate to
an intermediate concentration of about 5 to about 20 mg docetaxel/ml,
preferably about 8 to
about 15 mg docetaxel/ml, more preferably about 10 mg docetaxel/ml. The
intermediate
concentration solution is then diluted to administration concentrations with
normal saline, 5%
dextrose, or other suitable injection diluents for administration to the
patient. In all preferred
cases, polysorbate 80 is limited to very minor amounts (substantially free of
polysorbate 80), or
is completely absent, preferably completely absent; more preferably any
polysorbate is
substantially absent and most preferably completely absent from the foregoing.
In some
embodiments, the lyophilizates, liquid concentrates, the intermediate
concentrates, and the
diluted for administration formulations are substantially free of, more
preferably totally free of
Cremophor, and preferably substantially free of, still more preferably totally
free of all
polyethoxylated vegetable oils (whether totally hydrogenated, partially
hydrogenated, or not
-43-
CA 02683032 2009-10-20
hydrogenated). In other embodiments, the lyophilizates, liquid concentrates,
the intermediate
concentrates, and the diluted for administration formulations are
substantially free of, still more
preferably totally free of ethanol. In yet further embodiments, the
lyophilizates, liquid
concentrates, the intermediate concentrates, and the diluted for
administration formulations are
substantially free of, preferably totally free of hydroxyalkyl substituted
cellulosic polymers
(preferably substituted cellulosic polymers, more preferably cellulosic
polymers). Still other
embodiments are substantially free, if not totally free of each of the
aforementioned
polysorbates, polyethoxylated vegetable oils (whether hydrogenated in whole or
in part or not
hydrogenated), and substituted cellulosic polymers, and in some preferred
embodiments ethanol.
[00771 In addition to merely dissolving the docetaxel, the docetaxel "as is"
or in the presence
of TPGS 1000 and/or the a-lipoic acid or salts thereof can be lyophilized and
presented as a
lyophilizate for reconstitution to a concentrate material (of either the
initial high concentrate
formulation concentrations or directly to the intermediate concentrate
formulations or even
directly to the administrable concentrations depending on whether the
lyophilizate contains the
member selected from the group consisting of a-lipoic acid, dihydrolipoic
acid, pharmaceutically
acceptable salts of either and mixtures thereof in the requisite amounts). The
lyophilization
procedure can be a routine lyophilization using an appropriate solvent for
lyophilization
purposes. Insofar as the lyophilization solvent is driven off in the course of
the lyophilization
procedure, lyophilization may use solvents that are not suitable for
parenteral administration, but
generally will use suitable materials for parenteral use. The docetaxel
solution for lyophilization
need not be a solution using a solubilizer or a hydrotrope of the present
invention as the
solubilizer and hydrotrope may then be added after the lyophile is formed, at
any of before, at, or
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CA 02683032 2009-10-20
upon reconstitution. However, if desired and the particular solubilizer and/or
hydrotrope and/or
solubilization aids and/or a member selected from the group consisting of a-
lipoic acid,
dihydrolipoic acid, pharmaceutically acceptable salts of either and mixtures
thereof that remain
in the lyophilizate during and through the lyophilization procedure, they may
be added to the
docetaxel solution before lyophilization so that the lyophilizate contains the
appropriate amounts
of docetaxel and optionally one or more solubilizers and/or hydrotropes and
optionally one or
more solubilization aids and optionally the member selected from the group
consisting of a-
lipoic acid, dihydrolipoic acid, pharmaceutically acceptable salts of either
and mixtures thereofof
the present invention. In such situations as the lyophilizate contains both
solubilizers and
hydrotrope and/or the a-lipoic acid (or pharmaceutically acceptable salt
thereof) in appropriate
amounts, reconstitution with the appropriate amount of injectable diluent
solution provides the
complete formulation of some embodiments of the present invention. In each
case, the
lyophilizate, the concentrates made therefrom, the intermediate concentrates
made therefrom,
and the formulation in the administration concentration are each subject to
the independent or
concurrent restrictions set forth above with respect to polysorbates,
Cremophors, polyethoxylated
vegetable oils, hydroxyalkyl substituted cellulosic polymers, substituted
cellulosic polymers,
cellulosic polymers, and ethanol as stated more fully concerning the
formulations made without
the use of lyophilization.
[00781 In addition, as a means to offset the acidic nature of some of the
components, a buffer
can be added such as phosphate buffer (or other suitable buffer, such as
without limitation,
carbonate/bicarbonate buffer), generally in an amount of about 0.5 to about 2
mg of phosphate
buffer for about each mg of a member selected from the group consisting of a-
lipoic acid,
-45-
CA 02683032 2009-10-20
dihydrolipoic acid, pharmaceutically acceptable salts of either and mixtures
thereof or other
acidic oxidative protectant in the formulation. The buffer may also be
included in the pre-
lyophilization solution, but is prefrerably added in the reconstitution or
dilution steps. The buffer
is selected so as to be capable to buffer the intermediate concentrate as well
as the final infusion
solution to a pH of about 5 to about 7.5, preferably about 5.5 to about 7.2,
more preferably about
6 to about 7, most preferably about 6.5 to about 7. Appropriate amounts of the
free acid or base
used and its conjugate salt to create the buffer will be within the ability of
those of ordinary skill
in the art. Alternate organic buffer materials include, without limitation,
the following materials
together with their conjugate salts (which free compound/salt conjugate may
form in situ from
either the free compound or the conjugate salt being added alone as known in
the art of buffer
materials) adipic acid, amino acids such as, without limitation, alanine,
arginine, asparagine,
aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine,
isoleucine, leucine, lysine,
methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine,
valine, etc.
Potassium hydroxide or sodium hydroxide, preferably potassium hydroxide, can
be used to make
final pH adjustments upward. The amount of potassium hydroxide or sodium
hydroxide used to
bring pH in the region of 5 to 7.5 is preferably 25 to 40 mg, but more or less
can be used as
appropriate. Hydrochloric acid or additional phosphoric acid can be used as
needed to make
final pH adjustments downward. Bicarbonate or carbonate salts, especially
sodium or potassium
salts thereof, most preferably potassium salts thereof, may be used to adjust
pH as well.
[00791 The initial concentration can be storeed for long periods of time of up
to about 2 years
(730 days), preferably from about one year (365 days) to about one and half
years (500) days, at
room temperature and longer still under refrigeration. The intermediate
concentrates can be
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CA 02683032 2009-10-20
stored at ambient temperatures for periods substantially in excess of 8 hours
such as at least up to
12, at least up to 16, and at least up to 24 hours, and still greater periods
when stored under
refrigeration conditions; however, it is preferably utilized (including
dilution to infusion strength
and infusion administration time within 48 hours after preparation of the
intermediate
concentrate, more preferably within 36 hours, still more preferably within 30
hours, yet more
preferably with 24 hours. Such preferred utilization times of the intermediate
concentrate
include within 23, 22, 21,20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10,9, 8, 7,
6, 5, 4, or fewer hours.
The longer periods allow for preparation of intermediate concentrates for use
once per day and
potentially less frequently allowing for substantial savings in pharmacy
preparation time,
especially over weekends and holidays, when staff may be at reduced levels,
whereas those that
must be used within 8 hours or less (as in the case of Taxotere) hospital
pharmacies may need to
prepare intermediate concentrates multiple times a day depending upon their
usage needs. Once
the intermediate concentrate is further diluted to the infusion concentration,
the invention
solutions can be used up to 8 (eight) hours or longer including the actual
infusion administration
time, but are preferably used in 5 hours or less. This allows for more
efficient preparation and
administration systems in hospitals and other care facilities, especially as
compared to Taxotere
which requires use of the infusion, including the infusion administration time
of no more than 4
hours.
100801 As the present invention is directed to delivery of docetaxel, once
diluted to appropriate
injection (especially infusion, most particularly IV infusion) concentrations,
it may be
administered in appropriate amounts for treating docetaxel responsive
conditions known in the
art. In addition, since the present invention permits higher doses and
concentrations than the
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CA 02683032 2009-10-20
currently marketed TAXOTERE, the concentrates and administrable dosage forms
thereof made
from the present invention are also useful for many of the indications known
in the art for
docetaxel based on non-clinical data for which the current marketed TAXOTERE
formulation is
not recommended because of an inability to administer docetaxel at a
sufficiently high dose,
either acutely or cumulatively. These include, without limitation, carcinomas
such as colorectal,
prostate, pancreatic and liquid tumors like lymphoma and leukemia.
100811 The following examples are presented to exemplify, not limit, the scope
of the present
invention, which is only limited by the claims appended hereto.
[00821 Initial concentrates containing a-lipoic acid or a salt thereof
(Examples 1-12)
100831 Example 1:
100841 a-lipoic acid is dissolved in glycofurol (glycofurol 75) in an amount
of 5 mg/ml and free
docetaxel active agent is dissolved therein to result in a final docetaxel
moiety concentration of 80
mg/ml of solution.
100851 Example 2
[00861 Example 1 is repeated except that the a-lipoic acid is added after the
docetaxel, rather than
before it.
100871 Examples 3 and 4
-48-
CA 02683032 2009-10-20
[00881 Examples 1 and 2 are repeated except that a-lipoic acid potassium salt
or sodium salt is
used in place of the free a-lipoic acid in an amount equivalent to the same
number of moles/ml as the
free a-lipoic acid.
100891 Examples 5-8
[00901 Examples 1-4 are repeated except that docetaxel hydrochloride is used
in place of free
docetaxel in an amount corresponding to the same number of moles/ml of 80
mg/ml of free
docetaxel.
100911 Examples 9-12
[00921 Examples 1-4 are repeated except that docetaxel trihydrate is used in
place of free
docetaxel in an amount corresponding to the same number of moles as 80 mg/ml
of the free
docetaxel.
100931 Initial concentrates using dihydrolipoic acid or a salt thereof
(Examples 13-24)
100941 Examples 13-24
[00951 Examples 1-12 are repeated except that 5 mg/ml dihydrolipoic acid or an
amount
equivalent to the same number of moles as 5 mg/ml of the free dihydrolipoic
acid of the
potassium or sodium salt thereof is used in place of the 5 mg/ml a-lipoic acid
or potassium salt
thereof of Examples 1-12.
100961 Diluents for Initial Concentrates
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CA 02683032 2009-10-20
100971 Example 25
[00981 The following formulation is prepared for use to dilute the initial
concentrates in
Examples 1-24 above to intermediate concentrate concentrations of 10 mg
docetaxel moiety/ml
of intermediate concentrate.
1.5 gm TPGS
2.5 ml PEG - 400
72 mg NaCl
Qs water to 7 ml.
100991 Example 26
101001 Example 25 is repeated except that the amount of TPGS, PEG, and NaCl
are adjusted in
accordance with the following table.
TPGS PEG-400 Osmotic Agent Optional
additional
A 1.0gm 2.5m1 72 mg NaCl ----------
B 1.25gm 2.5m1 72 mg NaCl ----------
C 1.75gm 2.5ml 72 mg NaCl ----------
D 2.0gm 2.5m1 72 mg NaCl ----------
E 1.0gm 2.5m1 72 mg KCl ----------
-50-
CA 02683032 2009-10-20
F 1.25gm 2.5m1 72 mg KC1 ----------
G 1.5gm 2.5m1 72 mg KC1 ----------
H 1.75gm 2.5m1 72 mg KCI ----------
I 2.0gm 2.5m1 72 mg KC1 ----------
J 1.0gm 2.Oml 72 mg NaCl ----------
K 1.259m 2.Oml 72 mg NaCl ----------
L 1.5gm 2.Oml 72 mg NaCl ----------
M 1.759m 2.Oml 72 mg NaCl ----------
N 2.0gm 2.Oml 72 mg NaCl ----------
0 1.0gm 3.Oml 72 mg NaCl ----------
P 1.25gm 3.Oml 72 mg NaCl ----------
Q 1.5gm 3.Oml 72 mg NaCl ----------
R 1.75gm 3.Oml 72 mg NaCl ----------
S 2.0gm 3.Oml 72 mg NaCl ----------
T 1.0gm 2.Oml 72 mg KC1 ----------
U 1.25gm 2.Oml 72 mg KCl ----------
V 1.5gm 2.Oml 72 mg KC1 ----------
W 1.75gm 2.Oml 72 mg KC1 ----------
X 2.0gm 2.Oml 72 mg KCI ----------
Y 1.0gm 3.Oml 72 mg KC1 ----------
Z 1.25gm 3.Oml 72 mg KCI ----------
AA 1.5gm 3.Oml 72 mg KC1 ----------
-51-
CA 02683032 2009-10-20
AB 1.75gm 3.0m1 72 mg KC1 ----------
AC 2.0gm 3.Oml 72 mg KC1 ----------
AD 1.0gm 2.5m1 36 mg NaCl ----------
AE 1.259m 2.5m1 36 mg NaCl ----------
AF 1.5gm 2.5m1 36 mg NaCl ----------
AG 1.759m 2.5ml 36 mg NaCl ----------
AH 2.0gm 2.5m1 36 mg NaCl ----------
Al 1.0gm 2.5m1 90 mg NaCl ----------
AJ 1.259m 2.5m1 90 mg NaCl ----------
AK 1.5gm 2.5m1 90 mg NaCl ----------
AL 1.759m 2.5m1 90 mg NaCl ----------
AM 2.0gm 2.5m1 90 mg NaCl ----------
AN 1.0gm 2.5ml ---------- ----------
AO 1.25gm 2.5ml ---------- ----------
AP 1.5gm 2.5ml ---------- ----------
AQ 1.75gm 2.5ml ---------- ----------
AR 2.0gm 2.5ml ---------- ----------
AS 1.0gm 2.5m1 36 mg KCl ----------
AT 1.25gm 2.5m1 36 mg KCl ----------
AU 1.5gm 2.5m1 36 mg KCl ----------
AV 1.75gm 2.5m1 36 mg KCl ----------
AW 2.0gm 2.5m1 36 mg KC1 ----------
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CA 02683032 2009-10-20
AX 1.0gm 2.5ml 36 mg KCl ----------
AY 1.25gm 2.5m1 36 mg KC1 ----------
AZ 1.5gm 2.5m1 36 mg KCl ----------
BA 1.75gm 2.5m1 36 mg KCl ----------
BB 2.0gm 2.5m1 36 mg KCI ----------
BC 1.0gm 2.5m1 72 mg NaCl 0.9m1 ethanol
BD 1.0gm 2.5m1 72 mg KC1 0.9m1 ethanol
BE 1.0gm 2.5m1 72 mg NaCl 0.9m1 ethanol
BF 1.0gm 2.5m1 72 mg NaCl 0.9m1 ethanol
BG 1.0gm 2.5m1 72 mg KC1 0.9m1 ethanol
BH 1.0gm 2.5ml 72 mg KC1 0.9m1 ethanol
BI 1.0gm 2.5m1 36 mg NaCl 0.9m1 ethanol
BJ 1.0gm 2.5ml 90 mg NaCl 0.9m1 ethanol
BK 1.0gm 2.5ml 90 mg NaCl 0.9ml ethanol
BL 1.0gm 2.5ml ---------- 0.9m1 ethanol
BM 1.0gm 2.5m1 36 mg KC1 0.9m1 ethanol
BN 1.0gm 2.5ml 36 mg KCI 0.9m1 ethanol
BO 1.25gm 2.5ml 72 mg NaCl 0.9m1 ethanol
BP 1.25gm 2.5m1 72 mg KCI 0.9m1 ethanol
BQ 1.25gm 2.5ml 72 mg NaCl 0.9m1 ethanol
BR 1.25gm 2.5m1 72 mg NaCl 0.9m1 ethanol
BS 1.25gm 2.5m1 72 mg KC1 0.9m1 ethanol
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CA 02683032 2009-10-20
BT 1.25gm 2.5m1 72 mg KC1 0.9m1 ethanol
BU 1.25gm 2.5m1 36 mg NaCl 0.9m1 ethanol
BV 1.25gm 2.5m1 90 mg NaCl 0.9m1 ethanol
BW 1.25gm 2.5m1 90 mg NaCl 0.9m1 ethanol
BX 1.25gm 2.5m1 ---------- 0.9m1 ethanol
BY 1.25gm 2.5m1 36 mg KCl 0.9m1 ethanol
BZ 1.25gm 2.5m1 36 mg KCI 0.9m1 ethanol
CA 1.25gm 2.5m1 72 mg NaCl 0.45m1 ethanol
CB 1.25gm 2.5ml 72 mg KC1 0.45m1 ethanol
CC 1.259m 2.Oml 72 mg NaCl 0.45m1 ethanol
CD 1.259m 3.Oml 72 mg NaCl 0.45m1 ethanol
CE 1.259m 2.Oml 72 mg KCl 0.45ml ethanol
CF 1.259m 3.Oml 72 mg KC1 0.45m1 ethanol
CG 1.259m 2.5ml 36 mg NaCI 0.45m1 ethanol
CH 1.25gm 2.5m1 90 mg NaCl 0.45m1 ethanol
CI 1.25gm 2.5ml 90 mg NaCl 0.45m1 ethanol
CJ 1.25gm 2.5ml ---------- 0.45m1 ethanol
CK 1.25gm 2.5m1 36 mg KC1 0.45m1 ethanol
CL 1.25gm 2.5m1 36 mg KC1 0.45m1 ethanol
[01011 Examples 27
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CA 02683032 2009-10-20
101021 The following formulation is prepared for use to dilute an initial
concentrate of
docetaxel that corresponds to the initial concentrates in Examples 1-24 except
that the initial
concentrates to be diluted with this example formulation are devoid of each a-
lipoic acid,
dihydrolipoic acid, and salts thereof.
5-25 mg a-lipoic acid
1.5 gm TPGS
2.5 ml PEG - 400
72 mg NaCl
Qs water to 7 ml.
101031 Example 28-32
[01041 Example 27 is repeated except that the 5-25 mg of a-lipoic acid is
replaced by the same
number of moles of one of a-lipoic acid sodium salt, a-lipoic acid potassium
salt, dihydrolipoic
acid, dihydrolipoic acid sodium salt, and dihydrolipoic acid potassium salt
respectively.
101051 Example 33
[01061 A concentrate of simply docetaxel 80 mg dissolved in glycofurol q.s to
1 ml is placed
on stability testing under the conditions set forth in the Table below with
the results set forth in
the Table EX-33A. This formulation lacks the lipoic acid or dihydrolipoic acid
or salts thereof
component required in formulations of the present invention.
Table EX-33A: Stability of docetaxel liquid concentrate (80 mg/ml), lot# DCT-
SOL-6
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CA 02683032 2009-10-20
Storage Time Content % of RRT of Degradant ID of Degradant
Temp. period mg/mL Initial Degradants Area %
Initial 77.7 100 1.42 0.07 Epi-DCT
0.21 0.11 Unknown
0.39 0.12 Unknown
30 0.48 0.05 Unknown
days 76.6 99 1.17 0.36 10-oxo-DCT
1.43 0.12 7-Epi-DCT
Total 0.76
0.19 0.11 Unknown
0.29 0.05 Unknown
0.38 0.22 Unknown
60 0.46 0.09 Unknown
days 76.4 98 0.87 0.05 Unknown
1.18 0.45 10-oxo-DCT
40 C 1.46 0.16 7-Epi-DCT
1.64 0.09 Unknown
Total 1.22
0.20 0.28 Unknown
0.35 0.12 Unknown
0.40 0.21 Unknown
0.46 0.05 Unknown
90 0.48 0.25 Unknown
days 75.4 97 0.52 0.05 Unknown
1.16 0.82 10-oxo-DCT
1.44 0.26 7-Epi-DCT
1.58 0.28 7-epi-l0-oxo
Total 2.32
0.88 0.05 Unknown
25 C 90days 76.9 99 1.17 0.28 10-oxo-DCT
1.45 0.09 7-Epi-DCT
Total 0.42
0.24 0.12 Unknown
0.40 0.18 Unknown
180 75.4 97 1.16 0.47 10-oxo-DCT
days 1.44 0.27
1.57 0.33 7-Epi-DCT
Total 1.37 7-epi-10-oxo
0.38 0.11 Unknown
0.46 0.12 Unknown
360 1.18 1.06 10-oxo-DCT
days 73.7 95 1.47 0.41 7- Epi-DCT
1.65 1.26 Unknown
Total 2.96
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We have also prepared the liquid concentrate in glycofurol at 40 mg/ml to
mimic the innovator
concentration. The stability data of this batch are summarized in Table EX-33B
below. This
formulation lacks the lipoic acid or dihydrolipoic acid or salts thereof
component required in
formulations of the present invention.
Table EX-33B: Stability of docetaxel liquid concentrate (40 mg/ml), lot# DCT-
SOL-7
Storage Time Content % of RRT of Degradant
Temp. period mg/mL Initial Degradants Area % ID of Degradant
Initial 38.0 100 1.43 0.07 Epi-DCT
0.21 0.12 Unknown
0.40 0.12 Unknown
30days 37.6 99 0.48 0.05 Unknown
1.17 0.42 10-oxo-DCT
1.43 0.13 7-Epi-DCT
Total 0.84
0.20 0.30 Unknown
0.31 0.09 Unknown
0.40 0.25 Unknown
60days 36.5 96 0.48 0.11 Unknown
1.16 0.48 10-oxo-DCT
40 C 1.44 0.15 7-Epi-DCT
1.58 0.05 7-epi-l0-oxo-dct
Total 1.38
0.20 0.36 Unknown
0.35 0.25 Unknown
0.40 0.19 Unknown
0.46 0.10 Unknown
90days 35.4 93 0.48 0.34 Unknown
0.51 0.07 Unknown
1.16 1.00 10-oxo-DCT
1.44 0.24 7-Epi-DCT
1.58 0.26 7-epi-10-oxo-dct
Total 2.81
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CA 02683032 2009-10-20
0.20 0.07 Unknown
0.87 0.05 Unknown
25 C 90days 37.5 99 1.16 0.24 10-oxo-DCT
1.44 0.09 7-Epi-DCT
Total 0.45
Table EX-33C: Stability of docetaxel liquid concentrate, Marketed Product:
Taxotere
Storage Time Content % of RRT of Degradant ID of Physical
Lot ID Temp. period mg/mL Initial Degradants Area % Degradant Observatio
ns
0.20 0.10 Unknown
0.35 0.05 Unknown
Initial 42.7 100.0 0.94 0.16 Unknown
1.18 0.11 10-oxo
1.45 0.04 7-Epi-DCT
Total 0.46
Mfg 0.20 0.13 Unknown
0.33 0.28 Unknown
By:
0.37 0.11 Unknown
Sanofi- 30 42.5 99.0 0.84 0.09 Unknown
Aventis days 0.95 0.14 Unknown
1.16 0.13 10-oxo DCT
1.43 0.08 7-Epi-DCT
Lot#: Total 0.96
D7A51 40 C 0.22 0.17 Unknown
7 0.33 0.24 Unknown Solution
0.36 0.09 Unknown color
0.59 0.04 Unknown
dy41.4 97.0 0.84 0.15 Unknown from changed
a e
days 0.95 0.15 Unknown yellow to
1.16 0.12 10-oxo DCT yellow
1.44 0.08 7-Epi-DCT
Total 1.04
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0.21 0.09 Unknown
0.33 0.14 Unknown Solution
0.60 0.06 Unknown color
0.84 0.51 Unknown changed
90 0.95 0.21 Unknown from
40.0 94.0 10-oxo
days 1.17 0.20 yellow to a
1.46 0.53 7-Epi-DCT darker
1.60 0.10 7-epi- 10- shade of
2.25 0.14 Unknown yellow
Total 1.98
Table EX-33D. Stability data for the following initial concentrate
formulation, having lipoic
acid (and/or dihydrolipoic acid and/or salts thereof) below the claim required
amounts
Docetaxel 80 mg
Lipoic acid 0.5 mg
Glycofurol 1.0 Ml
Table EX-33D:
Storage Time % of RRT of Degradant ID of
Temp. period Initial Degradants Area % Degradant
Initial 100 1.43 0.07 Epi-DCT
0.64 0.85 Unknown
0.76 0.23 Unknown
0.80 0.27 Unknown
40 C 30 96 0.88 0.06 Unknown
Days 10-oxo-
1.17 0.28 DCT
1.46 0.26 Epi-DCT
Total 1.95
60 Skipped due to technical reasons
days
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0.24 0.06 Unknown
0.47 0.13 Unknown
0.63 2.89 Unknown
0.70 0.05 Unknown
90 89 0.75 1.48 Unknown
Unknown
Days 0.78 0.56
0.89 0.18 Unknown
1.17 0.46 10-oxo-
1.46 0.35 DCT
Total 6.16 Epi-DCT
0.64 0.76 Unknown
0.76 0.12 Unknown
25 C 90 98 0.80 0.17 UUnknown
nknown
Days 0.87 0.05
1.18 0.26 10-oxo-
1.48 0.12 DCT
Epi-DCT
Table EX-33E: Stability data for the following initial concentrate
formulation, having lipoic
acid (and/or dihydrolipoic acid and/or salts thereof) below the claim required
amounts,
Docetaxel 80 mg
Lipoic acid 1.0 mg
Glycofurol qs 1.0 mL
Storage Time % of RRT of Degradant ID of
Temp. period Initial Degradants Area % Degradant
Initial 100 1.43 0.07 Epi-DCT
0.64 0.14 Unknown
0.87 0.05 Unknown
40 C 30 99 1.17 0.20 10-oxo-DCT
Days 1.46 0.27 Epi-DCT
1.62 0.05 Unknown
Total 0.71
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0.64 1.66 Unknown
97 0.75 0.44 Unknown
60 0.79 0.19 Unknown
days 1.17 0.30 10-oxo-DCT
1.46 0.20 Epi-DCT
Total 2.80
0.19 0.25 Unknown
0.23 0.05 Unknown
0.63 3.73 Unknown
90 0.75 2.44 Unknown
Days 91 0.78 0.84 Unknown
0.89 0.33 Unknown
1.18 0.48 10-oxo-DCT
1.47 0.29 Epi-DCT
Total 8.41
0.87 0.09 Unknown
25 C 90 1.19 0.18 10-oxo-DCT
Days 98 1.48 0.25 Epi-DCT
1.66 0.07 Unknown
Total 0.59
Table EX-33F: Stability data for the following formulation having lipoic acid
(and/or
dihydrolipoic acid and/or salts thereof) below the claim required amounts
Docetaxel 80 mg
Lipoic acid 2.0 mg
Glycofurol qs 1.0 mL
TABLE EX-33F
Storage Time % of RRT of Degradant ID of
Temp. period Initial Degradants Area % Degradant
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Initial 100 1.43 0.07 Epi-DCT
0.87 0.06 Unknown
30 1.17 0.17 1
99 DCT
Days 1.46 0.22 Epi-DCT
Total 0.45
0.63 1.07 Unknown
0.75 0.19 Unknown
60 97 0.79 0.06 1Unknown
0 xo-
Days 1.17 0.25 DCT
1.47 0.20 Epi-DCT
40C Total 1.76
0.19 0.14 Unknown
0.28 0.05 Unknown
0.63 2.76 Unknown
0.75 1.10 Unknown
90 0.78 0.39 Unknown
Days 93 0.88 0.11 Unknown
1.18 0.35 DCT
1.47 0.42 Epi-DCT
1.64 0.07
Total 5.39 Unknown
0.87 0.09 Unknown
1.19 0.18 1
90 DCT
25C Days 98 1.48 0.25 E i-DCT
1.66 0.07 Unknown
Total 0.25
Table EX-33G: Stability date for the following formulation, having lipoic acid
(and/or
dihydrolipoic acid and/or salts thereof) within the claim required amounts
DCT 80 mg/ml
Lipoic acid 5 mg/ml
Glycofurol qs to 1.0 ml
TABLE EX-33G
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CA 02683032 2009-10-20
Storage Time Content % of RRT of Degradant
Temp. period mg/ml Initial Degradants Area % ID of Degradant
Initial 70.6 100 1.43 0.06 7-Epi-DCT
0.87 0.06 Unknown
30 Days 70.0 99 1.18 0.11 10-oxo-DCT
1.46 0.21 7-Epi-DCT
Total 0.38
0.85 0.10 Unknown
1.17 0.16 10-oxo-DCT
40 C 60 Days 69.9 99 1.46 0.34 7-Epi-DCT
1.61 0.05 Unknown
Total 0.65
0.85 0.14 Unknown
1.18 0.29 10-oxo-DCT
90 Days 69.7 99 1.47 0.31 7-Epi-DCT
1.64 0.09 Unknown
Total 0.83
0.87 0.06 Unknown
25 C 90 Days 70.6 100 1.19 0.10 10-oxo-DCT
1.48 0.12 7-Epi-DCT
Total 0.28
101071 Example 34
101081 The concentrates (a) of Examples 1-24 are diluted with the diluents
formulation of
Examples 25-26 or (b) corresponding to Examples 1-24 except that they are
devoid of a-lipoic
acid, a salt thereof, dihydrolipoc acid, and a salt thereof are diluted with
the diluents of Examples
27-32 to result in intermediate concentrates having docetaxel concentrations
(based on the free
docetaxel moiety) of 10 mg/ml and containing a member selected from a-lipoic
acid, a salt
thereof, dihydrolipoc acid, a salt thereof, and mixtures thereof. These
intermediate concentrates
are added to standard infusion fluids suitable for administration as an
infusion of the docetaxel at
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CA 02683032 2009-10-20
an infusion administration concentration of 0.74 mg docetaxel moiety/ml of
infusion solution.
The diluted solution is clear for over a week.
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