TECHNICAL FIELD
[0001] This disclosure relates to pharmaceutical formulations of taxane compounds for
parenteral administration, methods of making the pharmaceutical formulations and methods of
treating cancer patients using the pharmaceutical formulations.
BACKGROUND
[0002] Taxanes are diterpenes that are widely used in chemotherapy. They were
originally discovered in plants of the genus Taxus (yews) and were first derived from these
natural sources. Several are now chemically synthesized. Among the taxanes, the best known
are paclitaxel (TAXOL) and docetaxel (TAXOTERE), which is a semisynthetic analog of
paclitaxel. Taxanes exert their anti-cancer activity by inhibiting tubulin depolymerization in
cells, thus inhibiting mitosis.
[0003] Parenteral administration by injection is the typical route of administration of
taxanes. However, taxanes are substantially insoluble in water and in other commonly used
medicinal parenteral organic solvents, which has presented a challenge to formulation for
pharmaceutical use. Docetaxel is typically formulated with POLYSORBATE 80 (Tween 80, a
nonionic surfactant and emulsifier) to improve solubility. Paclitaxel is typically formulated
with the nonionic surfactant CREMOPHOR EL (polyoxyethylated castor oil). Increased
toxicity, including hypersensitivity reactions, anaphylaxis and other serious side effects are
associated with these excipients. Pre-medication and additional treatment to prevent
hypersensitivity is therefore often necessary. Such additional treatment includes hormone
treatment, steroid medications, dexamethasone, diphenhydramine and cimetidine. In addition,
the patient must be monitored closely for severe allergic reactions, such as observation of
blood pressure, breathing rate, and heart rate. Increased toxicity and side effects sometimes
restrict the continuation and completion of taxane treatments thus limiting its effectiveness.
[0004] The currently available pharmaceutical formulations of taxanes also suffer from
unsatisfactory stability. For example, the docetaxel formulation has low stability, and must be
stored at or below room temperature protected from light. Alternatively, they need to be stored
as a lyophilized solid prior to re-constitution to a liquid for patient administration. In the IV
solution docetaxel has a tendency to precipitate, and requires careful handling procedures such
as to avoid shaking.
[0005] Efforts to improve the safety and efficacy of taxane pharmaceutical
formulations, particularly with paclitaxel and docetaxel, have generally focused on liposomal
formulations, nano-granules, cross-linking with albumin, and formulation with cyclodextrin
based complexes. It has been shown that complexes with cyclodextrin enhance docetaxel
stability, enhance its solubility, and can also enhance drug activity and reduce toxic side
effects. However, the solubility of docetaxel after complexing with cyclodextrin is still
relatively low, and is inconvenient for clinical use due to a requirement for a substantial
amount of solvent to solubilize the complex. Further, because cyclodextrin can degrade ester
compounds such as docetaxel, stability can be compromised.
[0006] Formulations of docetaxel and paclitaxel requiring reduced amounts organic
solvent and cyclodextrin have been reported. See U.S. Patent No. 8,481,511 and U.S. Patent
No. 8,426,385. These formulations of either docetaxel or paclitaxel in complexes with
hydroxypropyl-B-cyclodextrin (HP-B-CD) and/or sulfobutylether-B-cyclodextrin (SBE-B-CD)
provide improved water-solubility and stability, as demonstrated by the Ka. To prepare the
compositions, paclitaxel or docetaxel is dissolved in ethanol and added to an aqueous solution
of cyclodextrin derivatives, stirring until the taxane is dissolved. Ethanol is then removed via
reduced pressure to obtain the complex in liquid form. However, the liquid form is physicochemically
unstable and must be lyophilized to obtain a stable solid (i.e., a lyophilized powder)
composition. Chemical and physical stability in liquid form, after reconstitution, is limited to
2-3 hours. Because the powder must be reconstituted before use, the risk of exposure of
medical personnel to these cytotoxic compounds is increased. In addition, the present
inventors have observed that the lyophilized powder cannot be reconstituted in normal saline,
as the API has limited physical stability in saline and quickly precipitates. It can however, be
reconstituted in dextrose.
[0007] Although there has been some success in improving biocompatibility, in vivo
tolerance, solubilization and formulation stability, there is still a need for further improvements
in these parameters for pharmaceutical taxane compositions, particularly in parenteral
formulations. The present invention addresses these needs. In contrast to the prior art
cyclodextrin/taxane powders, the stable liquid pharmaceutical compositions comprising
taxane/B-cyclodextrin complexes disclosed herein, based on accelerated aging studies, are
expected to remain chemically and physically stable at temperatures from 0 °C to ambient
temperature for at least one year, and may be diluted for use in either normal saline or
dextrose. The present liquid pharmaceutical compositions also represent significant
improvements over the prior art in that they do not contain toxic solubilizers such as
CREMOPHOR EL and POLYSORBATE 80 (aka TWEEN 80).
SUMMARY
[0008] In a first aspect the invention is directed to liquid pharmaceutical compositions
comprising complexes of a taxane with a B-cyclodextrin or a B-cyclodextrin derivative (a
"taxane/B-cyclodextrin complex"), polyethylene glycol (PEG), an alcohol suitable for
parenteral administration, and water. In certain embodiments, the liquid pharmaceutical
compositions may comprise a selected amount by weight of the taxane, 5 to 100 parts by
weight (p.b.w.) of the B-cyclodextrin or B-cyclodextrin derivative relative to the taxane, 10 to
50 p.b.w. of the PEG relative to the taxane, and 5 to 60 p.b.w. of the alcohol relative to the
taxane. The remainder of the composition is water, such as pyrogen-free water suitable for
injection. Stated on the basis of the weight ratios of the components of the liquid
pharmaceutical compositions, the ratio of taxane to B-cyclodextrin or B-cyclodextrin derivative
to PEG may be in the range of 1:5:50 to 1:100:10, with alcohol suitable for parenteral
administration present in a weight ratio of 5 to 60 relative to taxane and water in a weight ratio
of 10 to 50 relative to taxane. In further specific embodiments of the foregoing liquid
pharmaceutical compositions, the B-cyclodextrin may be present at 40-100 p.b.w., the
polyethylene glycol may be present at 10-30 p.b.w., the alcohol may be present at 5-40 p.b.w.,
and/or water may be present at 10-50 p.b.w. relative to the weight of taxane. Specific examples
include liquid pharmaceutical compositions comprising a weight ratio of taxane to Bcyclodextrin
or B-cyclodextrin derivative to PEG of 1:50:30, 1:40:30, or 1:60:20. Further
specific examples include liquid pharmaceutical compositions comprising a weight ratio of
taxane to B-cyclodextrin or B-cyclodextrin derivative to PEG to alcohol to water of
1:50:30:20:10, 1:40:30:30:20, or 1:60:20:5:30.
[0009] In a further embodiment, the liquid pharmaceutical compositions may further
comprise one or more of a weak organic acid, an antioxidant, and a chelator. In a specific
embodiment, the alcohol suitable for parenteral administration may be selected from the group
consisting of ethanol, benzyl alcohol, and combinations thereof; the weak organic acid may be
citric acid, acetic acid, or phosphoric acid; the antioxidant may be selected from the group
consisting of sodium bisulfite, sodium metabisulfite and combinations thereof, and; the
chelator may be disodium edetate. In a further specific embodiment, the liquid pharmaceutical
composition may comprise 2-5 p.b.w. of the weak organic acid (to adjust the final pH as
desired), 0.01-0.1 p.b.w. of the antioxidant, and 0.01-0.5 p.b.w. of the chelator.
[0010] In any of the foregoing embodiments of the liquid pharmaceutical compositions,
the taxane may be paclitaxel, docetaxel, cabazitaxel, ortataxel, tesetaxel or a combination
thereof. In any of the foregoing embodiments of the liquid pharmaceutical formulation, the Bcyclodextrin
may be selected from the group consisting of sulfobutylether-B-cyclodextrin,
hydroxypropyl-B-cyclodextrin, hydroxypropyl-sulfobutylether-B-cyclodextrin, acet-Bcyclodextrin,
methyl-B-cyclodextrin, 2,6-dimethyl-B-cyclodextrin, B-cyclodextrin and
combinations thereof. In any of the foregoing embodiments, the alcohol suitable for parenteral
administration may be selected from the group consisting of ethanol, benzyl alcohol, and
combinations thereof. In any of the foregoing embodiments, the polyethylene glycol may be a
low molecular weight PEG, and in specific embodiments may be selected from the group
consisting of PEG 200, PEG 300, PEG 400, PEG 600, and combinations thereof.
[0011] Another embodiment of any of the foregoing liquid pharmaceutical
compositions provides a liquid pharmaceutical compositions comprising complexes of a taxane
with a B-cyclodextrin or a B-cyclodextrin derivative (a "taxane/B-cyclodextrin complex"),
polyethylene glycol (PEG), an alcohol suitable for parenteral administration, a
polyvinylpyrrolidone (aka povidone or PVP) and water. In some embodiments the povidone
has an average molecular weight of 2000-3000 g/mol. In some embodiments the liquid
pharmaceutical compositions comprise a weight ratio of taxane to povidone of 1:1 to 1:10. In
a specific embodiment the weight ratio of taxane to povidone is 1:5. Specific examples include
liquid pharmaceutical compositions comprising a weight ratio of taxane to B-cyclodextrin or Bcyclodextrin
derivative to PEG to povidone of 1:50:30:5, 1:40:30:5, or 1:60:20:5. Further
specific examples include liquid pharmaceutical compositions comprising a weight ratio of
taxane to B-cyclodextrin or B-cyclodextrin derivative to PEG to povidone of 1:50:20:5 and
1:60:15:5. Still other specific examples include liquid pharmaceutical compositions
comprising a weight ratio of taxane to B-cyclodextrin or B-cyclodextrin derivative to PEG to
povidone of 1:40:20:5 and 1:30:30:5.
[0012] In a second aspect, the invention provides methods of making the liquid
pharmaceutical compositions described above. The methods may comprise the steps of:
a) dissolving a taxane in an alcohol suitable for parenteral administration to form a
taxane solution;
b) dispersing a low molecular weight polyethylene glycol in water to form a
dispersion, and dissolving the b-cyclodextrin or b-cyclodextrin derivative in the
dispersion;
c) optionally, dispersing povidone into the dispersion obtained in step (b);
d) combining the taxane solution obtained in step (a) and the dispersion obtained in
step (b) or (c);
e) adjusting the combination obtained in step (d) to a final volume with the alcohol or
water; and
f) optionally, adjusting pH of the final volume by addition of a weak organic acid.
[0013] In a specific embodiment, the method of making the liquid pharmaceutical
compositions described above comprises:
a) combining the taxane with a portion of the alcohol suitable for parenteral
administration and mixing until the taxane is dissolved;
b) dispersing the polyethylene glycol in the water;
c) adding the b-cyclodextrin, the b-cyclodextrin derivative, or mixture thereof, to
the polyethylene glycol/water dispersion obtained in step (b), and mixing until the b-
cyclodextrin or the b-cyclodextrin derivative is dissolved;
d) optionally, dispersing povidone into the mixture obtained in step (c);
e) adding a remaining portion of the ethanol to the mixture obtained in step (c) or
(d) and mixing to form a homogenous solution; and
f) adding the taxane/alcohol mixture obtained in step (a) to the solution obtained
in step (e) while mixing under an inert atmosphere to obtain a homogeneous solution of the
liquid pharmaceutical composition.
[0014] Certain embodiments of the methods of making the pharmaceutical
compositions may include a further step of sterilizing the homogeneous solution obtained. The
sterilization may be filter sterilization. In further embodiments, in step (a), the taxane may be
combined with ¼ to ½ of the total amount of alcohol suitable for parenteral administration in
the final formulation. In other embodiments, the method may further comprise the step of
mixing one or more of a weak organic acid, an antioxidant and a chelator in the water in step
(b). In some embodiments, the steps (c), (d), (e) and (f of the process may be carried out
under an inert atmosphere such as nitrogen. In a modification of such embodiments, all steps
of the process are carried out under an inert atmosphere such as nitrogen. In certain
embodiments, the compounds and their amounts used in the methods of making the liquid
pharmaceutical compositions may be those discussed above with respect to the liquid
pharmaceutical composition, per se.
[0015] In a third aspect, the invention provides methods of treating cancer in a patient
by parenteral administration to the cancer patient of any of the foregoing embodiments of the
liquid pharmaceutical compositions, in an amount sufficient to treat the cancer. Accordingly,
the invention also provides use of the liquid pharmaceutical formulation of any of the
foregoing embodiments of the liquid pharmaceutical compositions for the treatment of cancer
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] The Figure shows the results of accelerated aging stability studies for an
exemplary liquid pharmaceutical composition as described herein.
DETAILED DESCRIPTION
[0017] Before describing several exemplary embodiments of the invention, it is to be
understood that the invention is not limited to the details of construction or process steps set
forth in the following description. The invention is capable of other embodiments and of being
practiced or being carried out in various ways.
[0018] Reference throughout this specification to "one embodiment," "certain
embodiments," "one or more embodiments" or "an embodiment" means that a particular
feature, structure, material, or characteristic described in connection with the embodiment is
included in at least one embodiment of the invention. Thus, the appearances of the phrases
such as "in one or more embodiments," "in certain embodiments," "in one embodiment" or "in
an embodiment" in various places throughout this specification are not necessarily referring to
the same embodiment of the invention. Furthermore, the particular features, structures,
materials, or characteristics may be combined in any suitable manner in one or more
embodiments.
[0019] As used herein the term "taxane" refers, individually and collectively, to
diterpene compounds of the taxane family. Included are naturally occurring taxanes,
derivatives of such naturally occurring taxanes, semi-synthetic taxanes and synthetic taxanes.
[0020] As used herein the term "taxane/B-cyclodextrin complex" refers to the complex
formed by the interaction of a B-cyclodextrin or a derivative of a B-cyclodextrin molecule
having a 7-membered sugar ring (B-cyclodextrin ring) with a hydrophobic diterpene which is a
member of the taxane drug family (including naturally occurring compounds and their
derivatives, semi-synthetic compounds, and synthetic compounds) in a manner which improves
the solubility of the taxane in aqueous media.
[0021] As used herein, the term "physical stability" refers to an absence of: precipitate
formation, turbidity, opaqueness, or coagulation/gelatinous formation in the liquid
pharmaceutical taxane/B-cyclodextrin complex compositions over time.
[0022] As used herein, the term "chemical stability" refers to an absence of chemical
impurity formation and/or an absence of taxane degradation in the liquid pharmaceutical
taxane/B-cyclodextrin complex compositions over time.
[0023] As used herein the term "parenteral administration" refers to administration of a
composition to a patient via injection or infusion. Included are intravenous injection,
subcutaneous injection and intramuscular injection. Also included is infusion, which is
typically administration via the intravenous route over a period of time. "Suitable for
parenteral administration" refers to acceptable safety of a component when parenterally
administered, which is typically established by regulatory approval of the component for such
use.
[0024] As used herein the term "treatment" of cancer and its equivalents refers to
reducing the symptoms or extent of cancer in a patient by administration of a drug or drug
formulation. Treatment may also include curing the cancer or reducing the cancer burden to
levels below detection limits, or preventing its recurrence.
[0025] In certain embodiments, the liquid pharmaceutical compositions described
herein comprise taxane complexes with a B-cyclodextrin or B-cyclodextrin derivative,
polyethylene glycol (PEG), an alcohol suitable for parenteral administration, and water. The
taxane portion of the taxane/B-cyclodextrin complex may be any naturally-occurring, semisynthetic
or synthetic hydrophobic taxane known in the art, including those that have
regulatory approval for clinical use (e.g., paclitaxel, docetaxel, and cabazitaxel, ) as well as
those that are in development or otherwise known in the art. Examples of suitable taxanes that
are of scientific interest but are not currently approved for commercial use include DJ-927
(tesetaxel), ortataxel, XRP9881, DHA-paclitaxel, and BMS-184476). In specific
embodiments, the liquid pharmaceutical compositions described herein comprise paclitaxel,
docetaxel, or a combination thereof, in the taxane/B-cyclodextrin-derivative complex.
[0026] The B-cyclodextrin portion of the taxane/B-cyclodextrin complex may be any
suitable B-cyclodextrin or derivative of B-cyclodextrin. Specific examples include
sulfobutylether-B-cyclodextrin (SBE-B-CD) (which may or may not be as its sodium salt),
hydroxypropyl-B-cyclodextrin (HP-B-CD), hydroxypropyl-sulfobutylether-B-cyclodextrin (HPSBE-
B-CD), acet-B-cyclodextrin, methyl-B-cyclodextrin, 2,6-dimethyl-B-cyclodextrin, Bcyclodextrin
and combinations thereof. In specific embodiments, the liquid pharmaceutical
compositions described herein comprise sulfobutylether-B-cyclodextrin sodium,
hydroxypropyl-B-cyclodextrin, hydroxypropyl- sulfobutylether-B-cyclodextrin or a combination
thereof, in the taxane/B-cyclodextrin complex.
[0027] The polyethylene glycol component of the liquid pharmaceutical compositions
described herein may be any pharmaceutically acceptable PEGs known in the art that are
suitable for pharmaceutical applications and that are suitable to provide improved physical and
chemical stability to the composition. In certain embodiments, the PEG component of the
compositions is a low molecular weight PEG which has a molecular weight of 2000 daltons or
less. In a particular embodiment, the PEG component of the composition has a molecular
weight of from about 200 daltons to about 800 daltons. In a specific embodiment, the PEG
component of the composition has a molecular weight of 300 daltons, 400 daltons, or 600
daltons.
[0028] The alcohol suitable for parenteral administration used in the liquid
pharmaceutical compositions described herein may be any alcohol that is suitably safe for
parenteral administration (whether diluted with water or undiluted). Typically, the alcohol will
be approved by regulatory authorities for parenteral use. Examples of suitable
pharmaceutically acceptable alcohols include ethanol, benzyl alcohol, and combinations
thereof. In a specific embodiment, the alcohol component of the liquid pharmaceutical
compositions described herein is ethanol.
[0029] The taxane/B-cyclodextrin complex, low molecular weight PEG, and alcohol
suitable for parenteral administration are the basic components of the liquid pharmaceutical
compositions. Typically, the remainder of the composition is water, for example water for
injection.
[0030] In certain embodiments, the pH of the liquid pharmaceutical composition may
optionally be adjusted by inclusion of a weak organic acid in an amount sufficient to further
improve the stability of the taxane. Taxanes typically show improved stability in the acidic pH
range. If necessary or desired, the pH may be adjusted into the range of 3-8, or 4-7, or 3.5-4 by
addition of the weak organic acid. The weak organic acid added to adjust the pH may be, for
example, citric acid, acetic acid, ascorbic acid, aspartic acid, formic acid, lactic acid, glutamic
acid, phosphoric acid or succinic acid. However, suitable compositions in the range of pH 3.5-
4 can often be obtained without adjustment of the pH with weak organic acid. The liquid
pharmaceutical compositions described herein may also optionally contain one or more
antioxidants, as is known in the art. Any natural or synthetic antioxidant that is suitable for
parenteral administration may be included in the compositions. Examples of suitable
antioxidants include sodium bisulfite, sodium metabisulfite, and combinations thereof. The
liquid pharmaceutical compositions described herein may also optionally contain one or more
chelator compounds as is known in the art that are suitable for parenteral administration.
Examples of suitable chelators include ethylenediaminetetraacetic acid salts (EDTA, aka:
disodium edetate; calcium edetate). In a specific example, the chelator used in the liquid
pharmaceutical compositions described herein is disodium EDTA. As discussed above, the
remainder of the composition after selection of the base component amounts and the amounts
of optional components (if any) is water, for example water for injection.
[0031] A specific embodiment of the liquid pharmaceutical compositions described
above is a composition which comprises the base components (i.e., taxane/B-cyclodextrin
complex, low molecular weight polyethylene glycol, alcohol suitable for parenteral
administration, and water) as follows: a selected amount of the taxane by weight, 5 to 200
p.b.w. of the B-cyclodextrin or B-cyclodextrin derivative with respect to the taxane, 50 to 20
p.b.w. of the polyethylene glycol relative to the taxane, 5 to 60 p.b.w. of the alcohol suitable
for parenteral administration relative to the taxane, and 10 to 50 p.b.w. of the water relative to
the taxane. Any or all of the optional components of the compositions may be added to this
base formulation in the amounts disclosed herein. A further specific embodiment of the liquid
pharmaceutical compositions comprise a selected amount of the taxane by weight, 5 to 100
p.b.w. of the B-cyclodextrin or B-cyclodextrin derivative with respect to the taxane, 50 to 10
p.b.w. of the polyethylene glycol relative to the taxane, 5 to 60 p.b.w. of the alcohol suitable
for parenteral administration relative to the taxane, and 10 to 50 p.b.w. of the water relative to
the taxane. As a specific example, the liquid pharmaceutical compositions may comprise 1
p.b.w. taxane, 40 to 60 p.b.w. of the b-cyclodextrin or B-cyclodextrin derivative relative to the
taxane, 20 to 30 p.b.w. of the polyethylene glycol relative to the taxane, 5 to 30 p.b.w. of the
alcohol suitable for parenteral administration relative to the taxane, and 10 to 30 p.b.w. water
relative to the taxane.
[0032] Weight ratios of the components of certain specific embodiments of the liquid
pharmaceutical compositions include 1:40:30, 1:50:30 or 1:60:20 (taxane: B-cyclodextrin or Bcyclodextrin
derivative:PEG). Such embodiments include; for example, weight ratios of
1:40:30:30:20 (taxane: B-cyclodextrin or B-cyclodextrin derivative:PEG:alcohol:water),
1:50:30:20:10 (taxane: B-cyclodextrin or B-cyclodextrin derivative:PEG:alcohol:water), and
1:60:20:5:30 (taxane: B-cyclodextrin or B-cyclodextrin derivative:PEG:alcohol:water).
[0033] A further specific embodiment of any of the foregoing liquid pharmaceutical
compositions is a composition which further comprises optional components as follows: 2-5
p.b.w. of a weak organic acid relative to the taxane (to adjust the final pH), 0.01-0.1 p.b.w. of
an antioxidant relative to the taxane, and/or 0.01-0.5 p.b.w. of a chelator relative to the taxane.
[0034] In a further embodiment, any of the foregoing liquid pharmaceutical
compositions may optionally further comprise a soluble polyvinylpyrrolidone (aka povidone or
PVP, for example povidone PF12 or PF17). The inclusion of povidone in the composition
further improves its chemical and physical stability. The selected soluble povidone is
preferably suitable for parenteral use, i.e., with low endotoxin levels. Examples include
Kollidon® soluble povidones from BASF, such as Kollidon® PF12 (Mw 2,000-3,000),
Kollidon® PF17 (Mw 7,000-11,000), and mixtures thereof. Other suitable low-endotoxin
soluble povidones are also available commercially, including Plasdone™ C-12 (nominal Mw
4,000) and Plasdone™ C-17 (nominal Mw 10,000) from Ashland. Because it is difficult to
determine the molecular weight of povidone polymers directly, the K-value has been adopted
to classify the various molecular weights of povidones. The K-value is a function of the
average degree of polymerization and the intrinsic viscosity of the polymer, and is calculated
from the kinematic viscosity of an aqueous polymer solution. Examples of povidones for use
in the invention, characterized by their K-value, include povidones having K-values of 10.2-
13.8, povidones having K-values of 15.5-17.5, and mixtures thereof. Specific examples
include povidones having K-values of about 12, povidones having K-values of about 17, and
mixtures thereof.
[0035] In some embodiments the liquid pharmaceutical compositions comprise a
weight ratio of taxane to povidone of 1:1 to 1:10. In a specific embodiment the weight ratio of
taxane to povidone is 1:5. Specific examples include liquid pharmaceutical compositions
comprising a weight ratio of taxane to b-cyclodextrin or b-cyclodextrin derivative to PEG to
povidone of 1:50:30:5, 1:40:30:5, or 1:60:20:5. Further specific examples include liquid
pharmaceutical compositions comprising a weight ratio of taxane to b-cyclodextrin or b-
cyclodextrin derivative to PEG to povidone of 1:50:20:5 and 1:60:15:5. Other specific
examples include liquid pharmaceutical compositions comprising a weight ratio of taxane to b-
cyclodextrin or b-cyclodextrin derivative to PEG to povidone of 1:40:20:5 and 1:30:30:5.
[0036] The liquid pharmaceutical compositions described herein are physically and
chemically stable as liquid solutions for an extended period of time. That is, under conditions
of accelerated aging the impurities remain low (i.e., below allowable limits set by the United
States Pharmacopeia USP35 standards for taxanes) and the taxane shows no decomposition,
precipitation or turbidity formation. The compositions therefore provide the advantage of
long-term stable storage in a liquid form that reduces risk to medical personnel handling the
compositions. To use the liquid pharmaceutical taxane/B-cyclodextrin compositions for
treatment of a cancer patient, the concentrated composition as described above is diluted to the
appropriate dose in a pharmaceutically acceptable aqueous medium (for example, in an IV or
infusion bag at the patient bed-side) and delivered parenterally to the patient for treatment of
the cancer. The reconstitution and mixing step that increases exposure of medical personnel
when using lyophilized powder formulations is therefore eliminated. Also eliminated are
problems associated with incomplete dissolution, precipitation after dissolution and frothing
during dissolution, with the avoidance of very sensitive shaking/mixing restrictions required
for prior art taxane compositions). Persons skilled in the art can determine the effective dose
and administration protocol to achieve treatment of specific cancers using the liquid
pharmaceutical compositions described herein. Accordingly, use of the liquid pharmaceutical
compositions described herein for treatment of cancer is an embodiment of the invention.
Generally, the route of delivery of the diluted composition will be by intravenous injection or
intravenous infusion.
[0037] The present liquid pharmaceutical compositions also have the advantage that
they can be diluted in either saline or dextrose. This is in contrast to the lyophilized powders
disclosed in U.S. Patent No. 8,481,511 and U.S. Patent No. 8,426,385, which form stable
solutions only when reconstituted in dextrose, i.e., reconstitution in saline results in
precipitation of the taxane. Because the liquid pharmaceutical compositions described herein
can be diluted directly into an infusion bag and do not contain toxic solubilizers and
emulsifiers, treatment of patients using the liquid pharmaceutical compositions substantially
reduces the risk of toxicity to both medical personnel (who must handle the compositions) and
to patients (who are at risk for potentially life-threatening hypersensitivity reactions to
solubilizers used in the prior art).
[0038] In one aspect, the liquid pharmaceutical compositions disclosed herein may be
used in methods for treating cancer patients by administering any of the foregoing liquid
pharmaceutical formulations to a cancer patient in an amount sufficient for cancer treatment.
Accordingly, it is also to be understood that embodiment of such methods or treatment include
use of any of the foregoing liquid pharmaceutical formulations for treatment of cancer. In
general, the amount of taxane administered and the duration of treatment are within the skill
and knowledge of the medical practitioner. However, it is to be understood that the present
taxane formulations do not need to be reconstituted prior to administration. That is, the present
liquid pharmaceutical taxane formulations can simply be diluted using saline or dextrose to
obtain the desired taxane concentration for administration to the patient, including dilution by
direct injection of the concentrate into the patient's IV bag.
[0039] The liquid pharmaceutical compositions described herein may be prepared by
the following general method:
a) dissolving a taxane in an alcohol suitable for parenteral administration to form a
taxane solution;
b) dispersing a low molecular weight polyethylene glycol in water to form a
dispersion, and dissolving a b-cyclodextrin or b-cyclodextrin derivative in the
dispersion;
c) optionally, dispersing povidone into the dispersion obtained in step (b);
d) combining the taxane solution obtained in step (a) and the dispersion obtained in
step (b) or (c) to form a homogeneous solution; and
e) if needed, adjusting the homogeneous solution obtained in step (d) to a final volume
with the alcohol or water.
[0040] The liquid pharmaceutical compositions described herein may also be prepared
by the following specific method:
a) combining the taxane with a portion of the alcohol and mixing until the taxane
is dissolved;
b) dispersing the polyethylene glycol in the water;
c) adding the b-cyclodextrin, or mixture thereof, to the polyethylene glycol/water
dispersion obtained in step (b), and mixing until the b-cyclodextrin is dissolved;
d) optionally, dispersing povidone into the mixture obtained in step (c);
e) adding a remaining portion of the alcohol to the mixture obtained in step (c) or
(d) and mixing to form a solution; and
f adding the taxane/alcohol mixture obtained in step (a) to the solution obtained
in step (e) while mixing to obtain a homogeneous solution of the liquid pharmaceutical
composition.
[0041] In certain embodiments, steps (c), (d), (e) and (f of the above method may be
conducted under an inert atmosphere, for example nitrogen or argon. In alternative
embodiments all of the steps of the preparations methods may be conducted under an inert
atmosphere, for example nitrogen or argon.
[0042] The portion of the alcohol suitable for parenteral administration that is added in
step (a) in some embodiments may be ¼ to ½ of the total amount in the final composition. The
remaining amount of alcohol may then be added in step (e). The ratio of each component used
in the method is calculated based on the desired composition of the final product, as discussed
above and the amount of each component used in the method is calculated based on the desired
final amount of the final product, as discussed above. Any or all of the steps of the process
may be carried out under an inert atmosphere such as nitrogen or argon. In contrast to the prior
art lyophilized powder formulations discussed above, the alcohol suitable for parenteral
administration is not removed in the manufacturing process and is a component of the final
liquid pharmaceutical compositions described herein.
[0043] If any or all of the optional components of the composition (weak organic acid,
antioxidant and/or chelator) are to be included in the liquid pharmaceutical composition, they
may be added to the water in step (b) prior to addition of the polyethylene glycol, and mixed to
dissolve. The PEG may then be dispersed in the solution of water and optional component(s).
The weak organic acid may also be added at to the homogeneous solution at the end of the
process to adjust the final pH to the desired value.
[0044] In certain embodiments, the water used for preparation of the liquid
pharmaceutical compositions may be water for injection (WFI), which is pyrogen-free. It may
still be desirable, however, to sterilize the final product before dispensing it into individual
vials and sealing. Sterilization may be accomplished by filter sterilization, for example by
filtration through a 0.22 mhi membrane filter.
Examples
Accelerated Aging Stability Studies
[0045] A liquid pharmaceutical composition as described above, comprising -10
mg/mL docetaxel was diluted and subjected to accelerated aging at 40 °C for eleven days. The
levels of impurities as specified by USP35 (United States Pharmacopeia 35) for taxane
compositions were analyzed by HPLC at regular intervals. Stability was tested at 6 hours on
day 0. Impurity levels in the liquid pharmaceutical compositions were compared to the
allowable level according to the USP35 standard. The results are shown in Fig. 1. It can be
seen that all impurities (Substances A-F) are substantially below the USP35 limits for the
entire 1-day period of accelerated aging. In addition, the impurities that are present do not
increase over the 1 1 days of testing, and no new impurities or degradation products were
formed, indicating that the composition is chemically stable. The composition was also
physically stable, as no precipitate or turbidity was formed.
[0046] In addition, the concentration of docetaxel remained constant at 9.52 mg/mL
throughout the 1 1 days of accelerated aging. This confirms that the taxane does not
decompose even at 40 °C for 11 days.
Stability of Exemplary Formulations
[0047] Various liquid pharmaceutical compositions were prepared as described above,
comprising weight ratios of docetaxel to cyclodextrin to PEG from 1:5:50 to 1:100:10. pH of
the formulations was about 3.5-4.0 without adjustment. Stability at 40°C with respect to the
level of impurities was analyzed by HPLC at regular intervals as specified by USP35 (United
States Pharmacopeia 35) for taxane compositions. Impurity levels in the liquid pharmaceutical
compositions were compared to the allowable level according to the USP35 standard. The
time point at which the levels of impurities exceeded the allowable level for each of the
compositions is shown in Table 1:
Table 1. Weight Ratios of Drug to Excipients
[0048] Physical stability of the samples was confirmed visually and no turbidity,
cloudiness or precipitation was observed during the time periods in which the samples were
chemically stable. Formulations comprising at least 1:5:50 parts by weight of
docetaxel:cyclodextrin:PEG300 exhibited extended chemical stability on accelerated aging (2
months). Chemical stability could be increased to at least six months by increasing the
proportion of cyclodextrin and reducing the proportion of PEG300 (formulations having
weight ratios from 1:40:30 to 1:100:10). Intermediate duration of chemical stability was
obtained with ratios from 1:10:50 to 1:30:40. Table 2 shows the formulations tested in Table 1
normalized to a single vial containing 20 mg. of docetaxel:
Table 2. Normalized to single vial (20
Pharmaceutical Compositions Containing Povidone
[0049] Pharmaceutical compositions were prepared as above with the addition of
povidone PF12. Compositions comprised docetaxel:ethanol:PEG300:cyclodextrin:povidone in
weight ratios as shown in Table 3.
[0050] Table 3
Example Docetaxel Povidone cyclodextrin PEG 300 ethanol Stability
PF12
M API solidified
1 5 45 0 18 during
stirring.
N Completely
dissolved
1 5 60 15 30 after 30 min.
Reconstitution
stability > 6
hr.
O Completely
1 5 50 20 24 dissolved
after 30 min.
Reconstitution
stability > 3.5
hr. Impurity
level
acceptable at
25 °C after 6
months.
[0051] Although the invention herein has been described with reference to particular
embodiments, it is to be understood that these embodiments are merely illustrative of the
principles and applications of the present invention. It will be apparent to those skilled in the
art that various modifications and variations can be made to the method and apparatus of the
present invention without departing from the spirit and scope of the invention. Thus, it is
intended that the present invention include modifications and variations that are within the
scope of the appended claims and their equivalents.

What is claimed is:
1. A liquid pharmaceutical composition comprising:
a taxane complexed with a B-cyclodextrin or B-cyclodextrin derivative;
a low molecular weight polyethylene glycol;
an alcohol suitable for parenteral administration; and
water.
2. The liquid pharmaceutical composition of claim 1 which comprises a selected amount
of the taxane by weight, 5 to 100 parts by weight (p.b.w.) of the B-cyclodextrin or BAA
BB CC DD EE FF GG HH II JJ KK LL MM NN 0 0 PP QQ RR
cyclodextrin derivative relative to the taxane, 10 to 50 p.b.w. of the PEG relative to the taxane,
5 to 60 p.b.w. of the alcohol relative to the taxane, and 10 to 50 p.b.w. of the water relative to
the taxane.
3. The liquid pharmaceutical composition of claim 1 or 2 which comprises a weight ratio
of taxane to B-cyclodextrin or B-cyclodextrin derivative to PEG of 1:50:30, 1:40:30, 1:60:20,
1:80:20, or 1:100:10.
4. The liquid pharmaceutical composition of any of claims 1 to 3 which comprises a
weight ratio of taxane to B-cyclodextrin or B-cyclodextrin derivative to PEG to alcohol to water
of 1:50:30:20:10, 1:40:30:30:20, 1:60:20:5:30, 1:80:20:40:40, or 1:100:10:10:50.
5. The liquid pharmaceutical composition of any of claims 1-4 further comprising a
soluble povidone suitable for parenteral use.
6. The liquid pharmaceutical composition of claim 5, wherein the povidone is selected
from the group consisting of povidones having a K-value of 10.2-13.8, povidones having a ¬
value of 15.5-17.5, and mixtures thereof.
7. The liquid pharmaceutical composition of claim 6, wherein the povidone has a K-value
of about 12 or a K-value of about 17.
8. The liquid pharmaceutical composition of any of claims 5-7, wherein the weight ratio
of taxane to povidone is 1:5.
9. The liquid pharmaceutical composition of any of claims 1-8, further comprising one or
more of a weak organic acid, an antioxidant, and a chelator.
10. The liquid pharmaceutical composition of claim 9, wherein the chelator is disodium
edentate (EDTA).
11. The liquid pharmaceutical composition of claim 9, wherein the antioxidant is selected
from the group consisting of sodium bisulfite, sodium metabisulfite, and combinations thereof.
12. The liquid pharmaceutical composition of claim 9, wherein the weak organic acid is
citric acid.
13. The liquid pharmaceutical composition of any of claims 9-12 which comprises 2-5
p.b.w. of the weak organic acid, 0.01-0.1 p.b.w. of the antioxidant, and/or 0.01-0.5 p.b.w.of the
chelator.
14. The liquid pharmaceutical composition of any of claims 1-13, wherein the taxane is
selected from the group consisting of paclitaxel, docetaxel, and combinations thereof.
15. The liquid pharmaceutical composition of any of claims 1-14, wherein the Bcyclodextrin
or b-cyclodextrin derivative is selected from the group consisting of
sulfobutylether-B-cyclodextrin sodium, hydroxypropyl-B-cyclodextrin, hydroxypropylsulfobutylether-
B-cyclodextrin, acet-B-cyclodextrin, methyl-B-cyclodextrin, 2,6-dimethyl-Bcyclodextrin,
and combinations thereof.
16. The liquid pharmaceutical composition of any of claims 1-15, wherein the polyethylene
glycol is selected from the group consisting of PEG 200, PEG 300, PEG 400, PEG 600, and
combinations thereof.
17. The liquid pharmaceutical composition of any of claims 1-16, wherein the alcohol
suitable for parenteral administration is selected from the group consisting of ethanol, npropanol,
isopropanol, benzyl alcohol, and combinations thereof.
18. The liquid pharmaceutical composition of any of claims 1-5, which comprises 40 to
100 p.b.w. of the B-cyclodextrin or B-cyclodextrin derivative relative to the taxane and 10 to 30
p.b.w. of the PEG relative to the taxane.
19. A method of making the liquid pharmaceutical composition of claim 1 comprising:
a) dissolving a taxane in an alcohol suitable for parenteral administration to form a
taxane solution;
b) dispersing a low molecular weight polyethylene glycol in water to form a
dispersion, and dissolving a B-cyclodextrin or B-cyclodextrin derivative in the
dispersion;
c) optionally, dispersing povidone into the dispersion obtained in step (b);
d) combining the taxane solution obtained in step (a) and the dispersion obtained in
step (b) or (c) to obtain a homogeneous solution; and
e) as needed, adjusting the homogeneous solution obtained in step (d) to a final
volume with the alcohol or water.
20. The method of claim 19, which comprises the steps of:
a) combining the taxane with a portion of the alcohol and mixing until the taxane
is dissolved;
b) dispersing the polyethylene glycol in the water;
c) adding the B-cyclodextrin, B-cyclodextrin derivative, or combination thereof, to
the polyethylene glycol/water dispersion obtained in step (b), and mixing until the Bcyclodextrin
is dissolved;
d) optionally, dispersing povidone into the mixture obtained in step (c);
e) adding a remaining portion of the alcohol to the mixture obtained in step (c) or
(d) and mixing to form a solution; and
f adding the taxane/alcohol mixture obtained in step (a) to the solution obtained
in step (e) while mixing to obtain a homogeneous solution of the liquid pharmaceutical
composition.
21. The method of claim 19 or 20, further comprising sterilizing the homogeneous solution
obtained in step (f).
22. The method of claim 21, wherein the homogeneous solution is filter-sterilized.
23. The method of any of claims 19-22, wherein pH of the homogeneous solution is
adjusted with a weak organic acid.
24. The method of any of claims 19-22, wherein step (b) further comprises mixing one or
more of a weak organic acid, an antioxidant and a chelator in the water.
25. The method of claim 24, wherein the alcohol is ethanol, the weak organic acid is citric
acid, the antioxidant is selected from the group consisting of sodium bisulfite, sodium
metabisulfite and combinations thereof, and the chelator is disodium edetate.
26. The method of any of claims 19-25, wherein the B-cyclodextrin or B-cyclodextrin
derivative is selected from the group consisting of sulfobutylether-B-cyclodextrin,
hydroxypropyl-B-cyclodextrin, hydroxypropyl- sulfobutylether-B-cyclodextrin, acet-Bcyclodextrin,
methyl-B-cyclodextrin, 2,6-dimethyl-B-cyclodextrin, and combinations thereof.
27. The method of any of claims 19-26, wherein the taxane is paclitaxel, docetaxel, or a
combination thereof.
28. The method of any of claims 19-27, wherein one or more steps of the process are
carried out under an inert atmosphere.
29. The method of any of claims 19-28, comprising dispersing povidone having a K-value
of 10.2-13.8, a K-value of 15.5-17.5, or a mixture thereof.
30. A method of treating a cancer in a patient comprising parenterally administering the
liquid pharmaceutical formulation of any of claims 1-18 to the cancer patient in an amount
sufficient to treat the cancer.
31. The liquid pharmaceutical formulation of any of claims 1-18 for use in the treatment of
cancer.