Note: Descriptions are shown in the official language in which they were submitted.
CA 02683248 2009-10-20
SOLUBILIZED FORMULATION OF DOCETAXEL
CROSS-REFERENCE TO RELATED APPLICATIONS
[00011 Not applicable.
STATEMENT REGARDING
FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[00021 Not Applicable
FIELD OF THE INVENTION
[00031 The present invention relates liquid formulations of docetaxel, more
specifically to high
level concentrates of docetaxel in non-aqueous solvents, to diluents therefor
(hereinafter
"primary diluent") in the preparation of intermediate concentrates, to the
target concentration
range for infusions for animals (inclusive of without limitation, farm
animals, zoo animals, pet
animals, and humans, particularly mammals and most particularly humans) made
therefrom.
The invention further relates to the use of tocopherol polyethylene glycol
(1000) succinate
(TPGS) in appropriate concentrations to minimize infusion related reactions
along with ethanol
and PEG 400 in the preparation of such products, so that disadvantageous
materials such as
polysorbates and or cremophor type materials (polyethoxylated oils, whether
unhydrogenated,
hydrogenated, or partially hydrogenated) can be avoided in the preparations.
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BACKGROUND OF THE INVENTION
[0004] 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
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,4,7(3, 10(3, 13a-hexahydroxytax-l l-en-9 -one 4-acetate 2-benzoate,
trihydrate.
Docetaxel has the following structural formula:
Ho H O
HgC
OH CH3 ,..~1
01- CHI
CH3 NH H
HNC O ~.= i-.,. : =.
H
HNC O O =+ H O~0 {3HgO
O O H ` O
C~h
Docetaxel, as currently marketed by Sanofi-Aventis, is a white to almost-white
powder with an
empirical formula of C43H53NO14.3H2O, 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
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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
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.
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[0006] 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
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 (using the Taxotere
formulation), 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.
[0007] 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).
[0008] 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
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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 which
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 2d or 3'd 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 be avoided.
OBJECTS OF THE INVENTION
100091 It is therefore an object of the invention to provide a docetaxel
formulation suitable for
injection with little or no polysorbate 80 surfactant.
[00101 Yet another object of the invention is to provide a docetaxel liquid
concentrate
formulation that has little or no polysorbate 80 surfactant and further has
little or no Cremophor
surfactant.
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[00111 Still another object of the invention is to provide a docetaxel liquid
concentrate that has
little or no polysorbate.
100121 Another object of the invention is to provide a docetaxel liquid
concentrate that has
both little or no polysorbate and little or no Cremophor component.
100131 Still another object of the invention is to provide a docetaxel liquid
concentrate that is
completely free of polysorbate components.
100141 An even further embodiment of the invention is to provide a docetaxel
liquid
concentrate that is completely free of both polysorbate and Cremophor
components.
100151 It is a further object of the invention to provide a docetaxel (or
pharmaceutically
acceptable salt thereof) formulation containing TPGS at a substantially
reduced level as
compared to formulations specifically disclosed in US 2008/0319048.
[00161 It is yet another object of the invention to provide a docetaxel
formulation that has
fewer hypersensitivity reactions than the currently commercially available
formulations, which
currently available formulations have a polysorbate 80 surfactant component.
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100171 It is yet another object of the invention to provide a docetaxel
formulation that has
fewer hypersensitivity reactions than the currently commercially available
formulations, which
currently available formulations have a polysorbate surfactant component.
100181 Still another object of the invention is to provide a substantially
polysorbate-free
docetaxel liquid concentrate formulation that is also substantially free of
hydroxyalkyl-
substituted cellulosic polymers.
100191 An even further object of the invention is to provide a substantially
polysorbate-free
and substantially Cremophor-free docetaxel liquid concentrate formulation that
is free of
hydroxyalkyl-substituted cellulosic polymers.
[00201 Still another object of the invention is to provide a substantially
polysorbate-free
docetaxel liquid concentrate formulation that is also substantially free of
substituted cellulosic
polymers.
100211 An even further object of the invention is to provide a substantially
polysorbate-free
and substantially Cremophor-free docetaxel liquid concentrate formulation that
is free of
substituted cellulosic polymers.
100221 Still another object of the invention is to provide a substantially
polysorbate-free
docetaxel liquid concentrate formulation that is also substantially free of
cellulosic polymers.
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[0023] An even further object of the invention is to provide a substantially
polysorbate-free
and substantially Cremophor-free docetaxel liquid concentrate formulation that
is free of
cellulosic polymers.
[0024] Still another object of the invention is to provide a suitable primary
dilution formulation
for use in preparing the aforementioned docetaxel liquid concentrates.
[0025] An even further object of the invention is to provide a final dilution
for injection of a
docetaxel containing product in the substantial absence or in the total
absence of polysorbate 80
surfactant.
[0026] An even further object of the invention is to provide a final dilution
for injection of a
docetaxel containing product in the substantial absence or in the total
absence of polysorbate 80
and in the substantial absence of Cremophor.
[0027] An even further object of the invention is to provide a final dilution
for injection of a
docetaxel containing product 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.
[0028] An even further object of the invention is to provide a final dilution
for injection of a
docetaxel containing product in the substantial absence or in the total
absence of polysorbate
surfactant.
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[00291 An even further object of the invention is to provide a final dilution
for injection of a
docetaxel containing product in the substantial absence or in the total
absence of polysorbate and
in the substantial absence of Cremophor.
100301 An even further object of the invention is to provide a final dilution
for injection of a
docetaxel containing product 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.
[00311 It is a further object of the invention to provide a a final dilution
for injection docetaxel
(or pharmaceutically acceptable salt thereof) formulation containing TPGS at a
substantially
reduced level as compared to formulations specifically disclosed in US
2008/0319048.
[00321 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.
[00331 Yet another object of the invention is to provide formulations, liquid
concentrates, etc.
containing docetaxel that are substantially free or totally free of any
cellulosic polymer and can
be reconstituted or diluted without the use of a substantial amount of or
without the use of any
amount of a cellulosic polymer.
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[0034] Another object of the invention is to provide a means to administer
docetaxel 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.
[0035] 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.
[0036] An even further object of the invention is to provide a means to
administer docetaxel 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 administration.
[0037] Yet another object of the invention is to provide docetaxel formulation
containing
tocopherol polyethylene glycol (1000) succinate (TPGS) with reduced
hypersensitivity/infusion
reactions relative to other formulations with TPGS therein.
[0038] Still another object of the invention is to provide docetaxel
formulations that are
sufficiently stable, physically and chemically, that they can be used over a
longer time period
beginning at dilution from a high concentrate to an intermediate concentrate
through further
dilution to an infusion concentration and further through the infusion
administration time relative
to the currently marketed Taxotere product.
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100391 Still further objects of the invention will be appreciated by those of
ordinary skill in the
art.
BRIEF SUMMARY OF THE INVENTION
[00401 These and other objects of the invention can be achieved by a
composition comprising
docetaxel and (a) at least one pharmaceutically acceptable solubilizer
excipient that can dissolve
docetaxel in amounts of at least 55 mg/ml or (b) a mixture of pharmaceutically
acceptable
hydrotropes that in concert (although not individually) are capable of
dissolving docetaxel in
amounts of at least 55 mg/ml or (c) mixtures thereof or (d) at least one
pharmaceutically
acceptable solubilization excipient that can dissolve docetaxel in amounts of
at least 55 mg/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 in amounts of at least 55 mg/ml. These docetaxel 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. Two especially useful solvents for docetaxel
include, without
limitation, glycofurol and ethanol, as well as mixtures thereof. Each of the
solutions of the
invention is in the substantial absence of (a) polysorbate 80, if not the
total absence of
polysorbate 80, (b) 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, and (c)
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optionally in the substantial absence of or in the total absence of
hydroxypropylmethylcellulose
(preferably hydroxyalkyl alkylcellulose, more preferably substituted
cellulosic polymers). The
avoidance of the polysorbate 80 and Cremophor type solubilizers avoids the
hypersensitivity or
infusion reactions that plague existing formulations of taxanes and allows for
the optional
reduction or elimination of steroid and/or antihistamine pre- and/or post
treatment. Avoidance of
the polysorbate 80 further avoids the diarrheal side effect caused thereby.
Each of these allows
for better, more effective dosing regimens and better patient compliance with
recommended
dosings than with the currently marketed taxane injectables. The use of TPGS
in order to avoid
the polysorbates of the Taxotere formulation and the avoidance of the
Cremophor type
materials has been disclosed in US 200/0319048, and while those formulations
have been a
significant improvement over the marketed Taxotere formulation, further
improvements are still
required. Reducing the TPGS concentrations and glycofurol concentrations from
those
specifically set forth in US 2008/0319048 further lessens possible
hypersensitivity reactions but
results in precipitation of the docetaxel when the product is diluted with the
infusion fluids to
infusion administration concentrations. Surprisingly the inclusion of ethanol
avoids this
precipitation problem, allowing for both the reduction of these concentrations
while still
achieving a product that is of suitable stability, both chemically and
physically, even beyond that
of the Taxotere formulation and still avoiding many of the side effects of
the Taxotere
formulation.. These results are especially surprising in that these reductions
are reductions in
solubilizing materials for the docetaxel.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING
[00411 Not Applicable
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DETAILED DESCRIPTION OF THE INVENTION
[00421 The present invention is directed to (a) formulations of docetaxel, (b)
concentrates for
preparing injectable formulations of docetaxel, and further to (c) 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 optionally without the need
for antihistamine
pre/post-treatment. The formulations, concentrates, 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, optionally substantially free, preferably totally
free, of polyethoxylated
castor oil, polyethoxylated vegetable oil, their partial as well as their
fully hydrogenated
counterparts.
100431 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 I 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 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
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potentially higher total and cumulative dose) compared to the current TAXOTERE
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 enablement of administration at higher dosages than
currently
suitable, docetaxel may now be used to treat conditions which it could not
previously be used to
treat because of the dose limitations imposed by the polysorbate component of
the current
TAXOTERE formulation.
[00441 The present inventors have made efforts to develop formulations of
docetaxel without
the use of polysorbates and such efforts have been embodied within the
disclosure of US
12/214,506, filed June 19, 2008 and published as US 2008/0319048 on Dec. 25,
2008 (the `048
Publication), the entirety of which is incorporated herein by reference. The
present invention is
directed to improvements over the specific disclosures therein, which included
the substantial
absence of ethanol, and the presence of TPGS in combination with glycofurol
and docetaxel
where the TPGS was present in amounts of 1500 mg TPGS/80 mg docetaxel, where
the
docetaxel was provided from an initial concentrate having the 80 mg of the
docetaxel dissolved
in glycofurol at a concentration of 40mg docetaxel/ml. In addition, the
diluents used to dilute
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this concentrate to 10 mg docetaxel/ml contained additional glycofurol
(diluents formulations
typically containing 25% glycofurol), thereby resulting in a considerable
amount of
glycofurol/80 mg dose. The present invention reduces both the glycofurol
content of the various
compositions and reduces the amount of TPGS each relative to the amount of
docetaxel or
pharmaceutically acceptable salt thereof as compared to the ratios presented
in the `048
Publication. Surprisingly, a suitable formulation is achieved despite the
substantial reduction in
the primary solvent for the docetaxel (glycofurol) and the significant
reduction in the primary
hydrotrope in the diluent for the docetaxel concentrate. Such reductions in
the solubilizing
principles would have been expected to result in an unstable product, either
due to lack of
solubilization or the inability to maintain solubilization on dilution to
infusion strength.
[00451 Glycofurol is also known as tetrahydrofurfuryl alcohol polyethylene
glycol ether and
has the following structure:
O
JnOH
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.
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[0046] Hydrotropes for the present invention are generally selected (without
limitation) from
the group consisting of polyethylene glycol, especially PEG 400, polyethylene
glycol 600;
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).
[0047] Docetaxel active agent can be dissolved in the glycofurol alone or in a
mixture of the
glycofurol and ethanol or in a mixture of either with the polyethylene glycol
and/or the TPGS,
although for stability purposes for long term storage, it is preferable to
only add the TPGS and
polyethylene glycol close to the time when the final dilution to infusion
strength is desired, for
example within about 24 hours, preferably within about 18 hours, more
preferably within about
12 hours, still more preferably within about 6 hours, even more preferably
within about 4 hours
of when the product is to be utilized as an infusion (including the infusion
administration time).
The initial concentrate can be prepared in the presence or absence of water
and preferably is in
the absence of water. A preferred initial concentrate formulation is merely
docetaxel or a
pharmaceutically acceptable salt thereof in glycofurol at a concentration of
80 mg of active agent
(docetaxel) based on the docetaxel moiety/ml of solution without other
components. However, if
desired, ethanol can be present in this concentrate up to the maximum amount
of ethanol set
forth below for the diluted concentrate (such as when the initial concentrate
above is diluted to
about 10 mg docetaxel/ml, shortly before addition to infusion fluids). In
addition, if desired, the
initial concentrate can further have none of , or a portion of, or all of the
TPGS, polyethylene
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glycol, and optional tonicity agent, but preferably these latter three
materials are maintained
separately until dilution to the intermediate concentration amount (such as 10
mg docetaxel/ml).
When some amount of the components other than the glycolfurol and docetaxel
are included in
the initial concentrate (concentrations of docetaxel in excess of 10 mg/ml,
especially up to 40
g/ml or up to 80 mg/ml or even higher), the diluents used to dilute the
initial concentrate to the
intermediate concentrate (i.e., less than about 15 mg docetaxel/ ml)
compensates for that amount
by having a lesser amount of that same material in the diluents solution, so
that upon dilution of
the initial concentrate to the intermediate concentrate, and further to the
infusion concentration,
the ratios set forth herein between the TPGS and docetaxel and between the
ethanol and the
docetaxel are maintained within the stated ranges. In addition, the initial
concentrate or the
diluents solution further may contain an antioxidant, material, and in light
of the possibility that
the polyethylene glycol and the TPGS may have a slight peroxide presence
therewith, the
antioxidant is preferably present and preferably added to the docetaxel
concurrently with or
before the addition of the polyethylene glycol and the TPGS, although addition
of the antioxidant
slightly after these two materials is not precluded. In a very highly
preferred embodiment the
antioxidant material may be added to the glycofurol, most preferably at or
before the addition of
the docetaxel to the glycofurol. The initial high concentrate solution can be
stored at room
temperature or under refrigeration conditions (i.e., greater than 0 C to about
10 C, preferably
about 2-8 C for refrigeration conditions). The initial concentrate solution is
then diluted with a
diluent that contains TPGS, polyethylene glycol, ethanol, water, optional
antioxidant, and
optional tonicity adjuster, although one or more of these may be absent or
reduced in amount if
the initial concentrate already has them present so that upon dilution the
required levels are
present in the diluted concentrate before further dilution to infusion
strength. This intermediate
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diluted concentrate is further diluted with an injectable diluent solution or
IV infusion fluids
(generally water for injection, normal saline solution, or dextrose 5% for
injection, although
other fluids suitable for injection or infusion that are compatible with the
other components of
the formulation are acceptable as well) to concentrations of 0.3 to 0.74
mg/ml, for administration
designed to be in the same concentration range for infusion administration as
that recommended
in the currently marketed Taxotere product; however, as discussed earlier,
higher infusion
concentrations (at least up to 1 mg docetaxel/ml or higher) as well as faster
infusion rates are
also suitable for the present invention since there is no polysorbate
component present. In a
highly preferred embodiment, the docetaxel is dissolved in glycofurol to a
concentration of about
80 mg/ml or higher and optionally (but preferably present), a-lipoic acid (or
dihydrolipoic acid
or the alkaline pharmaceutically acceptable salts of either or mixtures
thereof, but preferably a-
lipoic acid or its sodium salt or potassium salt) is also included in this
initial formulation at an
amount of from more than 2 mg to less than 200 mg, preferably not more than
175 mg, more
preferably not more than 150 mg, still more preferably not more than 125 mg,
yet more
preferably not more than 100 mg, even more preferably not more than 75 mg,
still more
preferably not more than 50 mg, even yet more preferably not more than 25 mg,
and yet more
preferably not more than 20 mg, preferably from about 2.75 mg to about 15 mg ,
more preferably
from about 3 mg to about 10 mg , still more preferably from about 4 mg to
about 7.5 mg , even
more preferably from about 4.5 mg to about 6 mg, and most preferably about 5mg
to form a first
or initial concentrate solution. In a particularly preferred embodiment of the
present invention,
the foregoing amounts of a-lipoic acid (or dihydrolipoic acid or the alkaline
pharmaceutically
acceptable salts of either or mixtures thereof) are present per ml of the
initial concentrate. In
another particularly preferred embodiment of the present invention, the
foregoing mg amounts of
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a-lipoic acid (or dihydrolipoic acid or the alkaline pharmaceutically
acceptable salts of either or
mixtures thereof) are present per every 80 mg of docetaxel (or
pharmaceutically acceptable salt
thereof based on free docetaxel) that is in the initial concentrate.
Separately, TPGS 1000,
polyethylene glycol, ethanol, optionally (but preferably) tonicity adjuster
(preferably sodium
chloride) and optionally an antioxidant, (including, but not limited to, a-
lipoic acid,
dihydrolipoic acid, and their alkaline salts (preferably alkali metal salts,
more preferably sodium
or potassium salts, of either, and mixtures thereof) wherein the a-lipoic
acid, dihydrolipoic acid,
and their alkaline salts are included in this portion only to the extent that
they are not included in
the initial concentrates to the maximum amounts permitted in the initial
concentrates as set forth
in the preceding sentence) are dissolved in water to arrive at a diluent
formulation for the initial
concentrate. This liquid concentrate and the diluent solution are then
packaged and stored for
commercial distribution. The diluent solution is then used to dilute the
docetaxel initial
concentrate to intermediate diluted 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
diluted concentrate solution is then further diluted to administration
concentrations (0.3 mg
docetaxel/ml infusion to 0.74 mg docetaxel/ml infusion as currently
recommended in the
Taxotere product label, or higher, such as up to about 1 mg docetaxel/ml
infusion) with normal
saline, 5% dextrose, or other suitable injection diluents for administration
to the patient (i.e., the
diluted concentrate is added in an appropriate amount to an infusion bag for
infusion
administration to a patient). In all 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 liquid concentrates, the diluted
concentrates, and
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CA 02683248 2009-10-20
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
hydrogenated). In yet further embodiments, the liquid concentrates, the
diluted 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.
100481 In addition to merely dissolving the docetaxel, the docetaxel (as is or
in the presence of
TPGS and/or the lipoic acid (or its pharmaceutically acceptable salts) 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 other components required by the diluted concentrate and in the
appropriate
amounts). However, if these lyophilizates or solid blends of these
componentsare used, they are
preferably used to prepare an initial concentrate as described herein or used
to directly prepare
the intermediate concentrateas described herein. 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
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CA 02683248 2009-10-20
suitable materials for parenteral use, so as to avoid potential contamination
of the injection
product within even minor amounts of injection unsuitable solvents..
[00491 Additional components that may be incorporated into the invention
formulations
include auxiliary aids such protectants against oxidative degradation such as,
without limitation,
antioxidants and free radical scavengers, such as, without limitation, a-
lipoic acid (also known as
thioctic acid), its pharmaceutically acceptable salts, dihydrolipoic acid, its
pharmaceutically
acceptable salts, sulfa amino acids (such as, without limitation, methionine
and cysteine),
acetone bisulfite and its alkaline salts, ascorbic acid, among others known in
the art as suitable
for injection purposes. These optional materials are of value as the TPGS
component has the
potential of being contaminated with a small amount of peroxide molecules
formed during its
synthesis, which varies from batch to batch. Incorporation of the protectant
or free
radical/peroxide scavenger protects the docetaxel from oxidative and free
radical catalyzed
degradative processes that may be caused thereby. When included, the lipoic
acid or
dihydrolipoic acid (or the salts of either) generally included in the initial
concentrate (or even as
a blend with the raw docetaxel) but, when desired, may be included in the
diluent used to dilute
the initial concentrate to make the intermediate concentrate. Applicant has
also filed on even
date herewith an additional application that is specifically directed to
improved lipoic acid and/or
dihydrolipoic acid compositions of this nature, which is incorporated herein
in its entirety by
reference. Exemplary diluent compositions for diluting 1 ml of the initial
concentrate (about 80
mg docetaxel/ml and 5 mg/ml lipoic acid) to the diluted concentrate (10 mg
docetaxel/ml) are,
without limitation,
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CA 02683248 2009-10-20
TPGS 1000 1.Og 0.75g 0.5g
Polyethylene glycol 3.5m1 4.5 ml 5 ml
Ethanol 0.9m1 0.72 ml 1 ml
NaCl 72 mg 72 mg 72 mg
Water qs to 7 ml qs to 7 ml qs to 7 ml
A portion of the ethanol may be included in the initial concentrates, but if
so, the amount of the
ethanol in the diluent formulation is restricted so that upon dilution of the
initial concentrate with
the diluent formulation, to a concentration of docetaxel of 10 mg/ml, there is
preferably not more
than a total of 1 ml of ethanol present. When sulfa amino acids are used in
place of or in
addition to the lipoic acid, they can be used in amounts generally such that
the sum of the lipoic
acid and the sulfa amino acid amounts (on a molar basis) meet the limitations
for the lipoic acid
above (based on a molar basis). The remaining alternatives for lipoic acid as
set forth above can
be used in amounts such that once the formulation is diluted to administration
concentrations of
docetaxel, the alternative is present in an amount that is suitable for
infusions at the resultant
concentration AND total infusion dose. These amounts will be known to those of
ordinary skill
in the intravenous infusion administration art, such as by reference to
standard pharmaceutical
references as the United States Pharmacopoeia and Remington's Pharmaceutical
Sciences.
100501 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
currently marketed TAXOTERE, the concentrates and administrable dosage forms
thereof made
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CA 02683248 2009-10-20
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.
[00511 The following examples are presented to exemplify, not limit, the scope
of the present
invention, which is only limited by the claims appended hereto. In the
following examples LA =
Lipooic Acid; DCT = docetaxel; TPGS or Vitamin E TPGS = Tocopherol
PolyethyleneGlycol
Succinate; PEG = polyethyleneglycol.
100521 Example 1:
100531 The composition in the table below was diluted with Normal Saline to
the indicated
docetaxel concentration of either 0.75 mg/ml or 0.32 mg/ml and observed for
particulates over the
time indicated.
Composition Time 0.75mg/mL 0.32mg/mL
Liquid concentrate:
DCT - 80mg;
LA-5mg
Glycofurol -qs to Clear, no Clear, no
1mL Observed up particles particles
Diluent: to 8 hrs appeared appeared
TPGS 1000-750 mg
PEG 400-4.0 mL
Ethanol-0.9 mL
Water qs to 7 mL
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100541 Example 2:
[00551 The composition in the table below was diluted with Normal Saline to
the indicated
docetaxel concentration of either 0.75 mg/ml or 0.32 mg/ml and observed for
particulates over the
time indicated.
Composition Time 0.75mg/mL 0.32mg/mL
Liquid concentrate:
DCT - 80mg; LA- Initial Clear Clear
5mg!
Glycofurol -qs to 30 Min Clear Clear
1mL
Diluent:
TPGS 1000-750mg 60 Min Particles Clear
PEG 400-2.5mL
Ethanol-0.9mL
Water s to 7mL lhr 10min Particles Particles
100561 Examples 3-4:
[00571 The composition in the table below was diluted with Normal Saline to
the indicated
docetaxel concentration of either 0.75 mg/ml or 0.32 mg/ml and observed for
particulates over the
time indicated.
Label Time Content
Example Composition Claim period (mg/mL) Physical Observation
m mL at ART
DCT - 80mg Initial 0.34
Glycofurol - lmL 0.32 Particles appearance
Diluent 8 hr 0.31 started after 5.30 hr
Example Vit.E TPGS -750
3 mg Initial 0.74
PEG-400 - 6mL 0.74 Particles appearance
(No Ethanol &) 8 hr 0.73 started after 5.00 hr
Water s to 7mL
Example DCT - 80mg 0.32 Initial 0.33 Particles appearance
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CA 02683248 2009-10-20
4 Glycofurol - lmL g hr 0.31 started after 7.00 hr
Diluent
Vit.E TPGS -500
mg Initial 0.76
Ethanol - 1 mL
PEG-400 - 5 mL 0.74 Particles appearance
Water - qs to 7mL started after 7.00 hr
8hr 0.58
[00581 Example 5:
[00591 Compositions of docetaxel liquid concentrate containing a total amount
of 80mg of
docetaxel are prepared having the compositions shown in the following table.
In each case, the
antioxidant is chosen from (a) lipoic acid, (b) dihyrolipoic acid, (c) lipoic
acid sodium salt, (d) lipoic
acid potassium salt, (e) dihydrolipoic acid sodium salt, and (f) dihydrolipoic
acid potassium salt, and
each composition no. indicates a series of these six variants
Composition # Glycofurol Ethanol Antioxidant
I Iml 0 2.5mg
2 I ml 0 5.0mg
3 l ml 0 7.5mg
4 I ml 0 10.0mg
imi 0 12.5mg
6 lml 0 15.0mg
7 lml 0 17.5mg
8 I MI 0 20.0mg
9 0.5m1 0.5m1 2.5mg
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CA 02683248 2009-10-20
0.5m1 0.5m1 5.0mg
11 0.5m1 0.5m1 7.5mg
12 0.5m1 0.5m1 10.0mg
13 0.5m1 0.5m1 12.5mg
14 0.5m1 0.5m1 15.0mg
0.5m1 0.5m1 17.5mg
16 0.5m1 0.5m1 20.0mg
17 0.75m1 0.75m1 2.5mg
18 0.75m1 0.75m1 5.0mg
19 0.75m1 0.75m1 7.5mg
0.75m1 0.75m1 10.0mg
21 0.75m1 0.75m1 12.5mg
22 0.75m1 0.75m1 15.0mg
23 0.75m1 0.75m1 17.5mg
24 0.75m1 0.75m1 20.0mg
Iml 1ml 2.5mg
26 I ml I ml 5.0mg
27 I ml I ml 7.5mg
28 Iml lml 10.0mg
29 I ml I ml 12.5mg
I ml I ml 15.0mg
31 Iml Iml 17.5mg
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CA 02683248 2009-10-20
32 1 ml 1 ml 20.0mg
[0060] Example 6:
[0061] Compositions of the diluent for compositions 1-8 of Example 5
PEG 400 (ml) Ethanol (ml) TPGS-1000 (mg) NaC1(mg) Water QS
4 0.75 500 50 7
4 0.75 750 50 7
4 0.75 1000 50 7
0.75 500 50 7
5 0.75 750 50 7
5 0.75 1000 50 7
6 0.75 500 50 7
6 0.75 750 50 7
6 0.75 1000 50 7
4 1.00 500 50 7
4 1.00 750 50 7
4 1.00 1000 50 7
5 1.00 500 50 7
5 1.00 750 50 7
5 1.00 1000 50 7
6 1.00 500 50 7
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6 1.00 750 50 7
6 1.00 1000 50 7
4 0.75 500 65 7
4 0.75 750 65 7
4 0.75 1000 65 7
0.75 500 65 7
5 0.75 750 65 7
5 0.75 1000 65 7
6 0.75 500 65 7
6 0.75 750 65 7
6 0.75 1000 65 7
4 1.00 500 65 7
4 1.00 750 65 7
4 1.00 1000 65 7
5 1.00 500 65 7
5 1.00 750 65 7
5 1.00 1000 65 7
6 1.00 500 65 7
6 1.00 750 65 7
6 1.00 1000 65 7
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4 0.75 500 72 7
4 0.75 750 72 7
4 0.75 1000 72 7
0.75 500 72 7
5 0.75 750 72 7
5 0.75 1000 72 7
6 0.75 500 72 7
6 0.75 750 72 7
6 0.75 1000 72 7
4 1.00 500 72 7
4 1.00 750 72 7
4 1.00 1000 72 7
5 1.00 500 72 7
5 1.00 750 72 7
5 1.00 1000 72 7
6 1.00 500 72 7
6 1.00 750 72 7
6 1.00 1000 72 7
4 0.75 500 75 7
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CA 02683248 2009-10-20
4 0.75 750 75 7
4 0.75 1000 75 7
0.75 500 75 7
5 0.75 750 75 7
5 0.75 1000 75 7
6 0.75 500 75 7
6 0.75 750 75 7
6 0.75 1000 75 7
4 1.00 500 75 7
4 1.00 750 75 7
4 1.00 1000 75 7
5 1.00 500 75 7
5 1.00 750 75 7
5 1.00 1000 75 7
6 1.00 500 75 7
6 1.00 750 75 7
6 1.00 1000 75 7
100621 Example 7:
[00631 Compositions of the diluent for compositions 9-16 of Example 5
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CA 02683248 2009-10-20
PEG 400 (ml) Ethanol (ml) TPGS-1000 (mg) NaC1(mg) Water QS
4 0.25 500 50 7
4 0.25 750 50 7
4 0.25 1000 50 7
0.25 500 50 7
5 0.25 750 50 7
5 0.25 1000 50 7
6 0.25 500 50 7
6 0.25 750 50 7
6 0.25 1000 50 7
4 0.25 500 65 7
4 0.25 750 65 7
4 0.25 1000 65 7
5 0.25 500 65 7
5 0.25 750 65 7
5 0.25 1000 65 7
6 0.25 500 65 7
6 0.25 750 65 7
6 0.25 1000 65 7
4 0.25 500 72 7
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CA 02683248 2009-10-20
4 0.25 750 72 7
4 0.25 1000 72 7
0.25 500 72 7
5 0.25 750 72 7
5 0.25 1000 72 7
6 0.25 500 72 7
6 0.25 750 72 7
6 0.25 1000 72 7
4 0.25 500 75 7
4 0.25 750 75 7
4 0.25 1000 75 7
5 0.25 500 75 7
5 0.25 750 75 7
5 0.25 1000 75 7
6 0.25 500 75 7
6 0.25 750 75 7
6 0.25 1000 75 7
4 0.50 500 50 7
4 0.50 750 50 7
4 0.50 1000 50 7
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0.50 500 50 7
5 0.50 750 50 7
5 0.50 1000 50 7
6 0.50 500 50 7
6 0.50 750 50 7
6 0.50 1000 50 7
4 0.50 500 65 7
4 0.50 750 65 7
4 0.50 1000 65 7
5 0.50 500 65 7
5 0.50 750 65 7
5 0.50 1000 65 7
6 0.50 500 65 7
6 0.50 750 65 7
6 0.50 1000 65 7
4 0.50 500 72 7
4 0.50 750 72 7
4 0.50 1000 72 7
5 0.50 500 72 7
5 0.50 750 72 7
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CA 02683248 2009-10-20
0.50 1000 72 7
6 0.50 500 72 7
6 0.50 750 72 7
6 0.50 1000 72 7
4 0.50 500 75 7
4 0.50 750 75 7
4 0.50 1000 75 7
5 0.50 500 75 7
5 0.50 750 75 7
5 0.50 1000 75 7
6 0.50 500 75 7
6 0.50 750 75 7
6 0.50 1000 75 7
Example 8: Compositions of the diluent for compositions 17-24 of Example 5
PEG 400 (ml) Ethanol (ml) TPGS-1000 (mg) NaCI (mg) Water QS
4 0.1 500 50 6.5
4 0.1 750 50 6.5
4 0.1 1000 50 6.5
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CA 02683248 2009-10-20
0.1 500 50 6.5
5 0.1 750 50 6.5
5 0.1 1000 50 6.5
6 0.1 500 50 6.5
6 0.1 750 50 6.5
6 0.1 1000 50 6.5
4 0.1 500 65 6.5
4 0.1 750 65 6.5
4 0.1 1000 65 6.5
5 0.1 500 65 6.5
5 0.1 750 65 6.5
5 0.1 1000 65 6.5
6 0.1 500 65 6.5
6 0.1 750 65 6.5
6 0.1 1000 65 6.5
4 0.1 500 72 6.5
4 0.1 750 72 6.5
4 0.1 1000 72 6.5
5 0.1 500 72 6.5
5 0.1 750 72 6.5
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CA 02683248 2009-10-20
0.1 1000 72 6.5
6 0.1 500 72 6.5
6 0.1 750 72 6.5
6 0.1 1000 72 6.5
4 0.1 500 75 6.5
4 0.1 750 75 6.5
4 0.1 1000 75 6.5
5 0.1 500 75 6.5
5 0.1 750 75 6.5
5 0.1 1000 75 6.5
6 0.1 500 75 6.5
6 0.1 750 75 6.5
6 0.1 1000 75 6.5
4 0.25 500 50 6.5
4 0.25 750 50 6.5
4 0.25 1000 50 6.5
5 0.25 500 50 6.5
5 0.25 750 50 6.5
5 0.25 1000 50 6.5
6 0.25 500 50 6.5
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CA 02683248 2009-10-20
6 0.25 750 50 6.5
6 0.25 1000 50 6.5
4 0.25 500 65 6.5
4 0.25 750 65 6.5
4 0.25 1000 65 6.5
0.25 500 65 6.5
5 0.25 750 65 6.5
5 0.25 1000 65 6.5
6 0.25 500 65 6.5
6 0.25 750 65 6.5
6 0.25 1000 65 6.5
4 0.25 500 72 6.5
4 0.25 750 72 6.5
4 0.25 1000 72 6.5
5 0.25 500 72 6.5
5 0.25 750 72 6.5
5 0.25 1000 72 6.5
6 0.25 500 72 6.5
6 0.25 750 72 6.5
6 0.25 1000 72 6.5
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CA 02683248 2009-10-20
4 0.1-0.5 500 72 6.5
4 0.25 750 72 6.5
4 0.25 1000 72 6.5
0.25 500 72 6.5
5 0.25 750 72 6.5
5 0.25 1000 72 6.5
6 0.25 500 72 6.5
6 0.25 750 72 6.5
6 0.25 1000 72 6.5
4 0.25 500 75 6.5
4 0.25 750 75 6.5
4 0.25 1000 75 6.5
5 0.25 500 75 6.5
5 0.25 750 75 6.5
5 0.25 1000 75 6.5
6 0.25 500 75 6.5
6 0.25 750 75 6.5
6 0.25 1000 75 6.5
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Example 9: Compositions of the diluent for compositions 25-32 of Example 5
PEG 400 (ml) Ethanol (ml) TPGS-1000 (mg) NaCl (mg) Water QS
4 0.0 500 50 6.0
4 0.0 750 50 6.0
4 0.0 1000 50 6.0
0.0 500 50 6.0
5 0.0 750 50 6.0
5 0.0 1000 50 6.0
6 0.0 500 50 6.0
6 0.0 750 50 6.0
6 0.0 1000 50 6.0
4 0.0 500 65 6.0
4 0.0 750 65 6.0
4 0.0 1000 65 6.0
5 0.0 500 65 6.0
5 0.0 750 65 6.0
5 0.0 1000 65 6.0
6 0.0 500 65 6.0
6 0.0 750 65 6.0
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CA 02683248 2009-10-20
6 0.0 1000 65 6.0
4 0.0 500 72 6.0
4 0.0 750 72 6.0
4 0.0 1000 72 6.0
0.0 500 72 6.0
5 0.0 750 72 6.0
5 0.0 1000 72 6.0
6 0.0 500 72 6.0
6 0.0 750 72 6.0
6 0.0 1000 72 6.0
4 0.0 500 75 6.0
4 0.0 750 75 6.0
4 0.0 1000 75 6.0
5 0.0 500 75 6.0
5 0.0 750 75 6.0
5 0.0 1000 75 6.0
6 0.0 500 75 6.0
6 0.0 750 75 6.0
6 0.0 1000 75 6.0
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