Note: Descriptions are shown in the official language in which they were submitted.
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THERAPEUTIC FORMULATIONS
Cross Reference to Related Applications
~ooo~~ This application claims priority under 35 U.S.C. 119 to U.S. Patent
Application
Serial No. 10/683,952, filed 9 October 2003, and to PCT Application
PCT/LTS03/032055, filed 9 October 2003, each of which is incorporated herein
in its
entirety.
Field of the Invention
~0002~ The present invention relates to the formulation and delivery of
therapeutic
substances. More particularly, this invention relates to formulations and
methods for
the treatment of hyperproliferative diseases, especially cancer. The invention
has
relevance to the arts of pharmacology and medicinal chemistry.
BACKGROUND
~ooos~ The class of polyketides known as epothilones has emerged as a source
of potentially
therapeutic compounds having modes of action similar to paclitaxel (Bollag, et
al.
1995; Service 1996; Winkler and Axelsen 1996; Bollag 1997; Cowden and Paterson
1997). Interest in the epothilones and epothilone analogs has grown with the
observations that certain epothilones are active against tumors that have
developed
resistance to paclitaxel (Harris, et al. 1999a) as well as reduced potential
for
undesirable side-effects (Muhlradt and Sasse 1997). Among the epothilones and
epothilone analogs being investigated for therapeutic efficacy are epothilone
B 1
(Oza, et al. 2000) and the semi-synthetic epothilone B analogs, BMS-247550 2,
also
known as "azaepothilone B" (Colevas, et al. 2001; Lee, et al. 2001; McDaid, et
al.
2002; Yamaguchi, et al. 2002), and BMS-310705 3.
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~S ~ O., ~S ~ O.,
N I ~~, .,.OH N I ~~,. ,.OH
O, ~ ~ HN, ~
OH O O OH
1 2
H2N~--
N
>H
3
~oooa~ Desoxyepothilone B 4, also known as "epothilone D" is another
epothilone
derivative having promising anti-tumor properties viz. paclitaxel that is
being
investigated for therapeutic efficacy (Su, et al. 1997; Chou, et al. 1998a;
Chou, et al.
1998b; Harris, et al. 1999b; Chou, et al. 2001; Danishefsky, et al. 2001b;
Martin and
Thomas 2001; Danishefsky, et al. 2002). This compound has also demonstrated
less
toxicity than epothilones having 12, 13-epoxides, such as epothilone B or BMS-
247550, presumably due to the lack of the highly reactive epoxide moiety.
S
N
.. H
4
~ooos~ Generally, pharmacologists and physicians prefer therapeutic
formulations to have
good oral availability to enhance patient compliance and ease of
administration
(DeMario and Ratain 1998). Formulations showing oral activity in mice have
been
described for BMS-247550 and BMS-310705 (Lee 2002a; b); however, these
compounds lack the structural combination of a lactone oxygen and olefin found
with
epothilone D.
~ooos~ A single report of a polyethylene glycol-400:ethanol ( 10:1 )
formulation of
epothilone D delivered orally to one mouse (at a dose of 50 mg/kg) showed no
2
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discernable effect on tumor size (Chou, et al. 1998b). Unfortunately,
epothilone D
has poor aqueous solubility; and current epothilone I7 formulations include a
castor
oil derivative solubilizing agent sold under the trade name CREMOPHOR~ (BASF
Aktiengesellschaft) to enhance solubility. These formulations are suitable
only for
intravenous delivery. While current epothilone D formulations are acceptable
for
clinical and therapeutic use, CREMOPHOR~ has been associated with patient
discomfort and toxicity. CREMAPHOR~-free formulations of epothilone B for
intravenous delivery have been described (Van Hoogevest 1999). Therefore, it
would
be preferable to provide enhanced formulations of epothilone D that do not
require
CREMOPHOR~ and, still more preferably, that can be delivered orally.
SUMMARY OF THE INVENTION
~oooy In one aspect, the present invention provides pharmaceutical
compositions for
treating a hyperproliferative disease, typically, but not necessarily, in a
mammal,
preferably in a human. In one embodiment, the present invention provides a
pharmaceutical composition comprising an epothilone and a pharmaceutically
acceptable carrier, embodiments of which carrier will be described in greater
detail
hereinbelow. The epothilone is provided in a therapeutically effective
concentration,
and the pharmaceutical composition is effective to deliver a therapeutically
effective
amount of epothilone by oral administration.
~oooa~ In particular embodiments of the pharmaceutical compositions provided
by the
invention, the pharmaceutical composition of the invention includes at least
one
cyclodextrin, and, in more particular embodiments, the cyclodextrin is an
hydroxyalkyl-~3-cyclodextrin, and, in a still more particular embodiment, an
hydroxypropyl-~3-cyclodextrin. In other embodiments of the invention, the
cyclodextrin is a sulfoalkylcyclodextrin, and in more particular embodiments,
the
sulfoalkylcyclodextrin is a sulfopropyl-(3-cyclodextrin.
~ooos~ In other embodiments of the invention, the epothilone and cyclodextrin
are provided
in a lyophilized form, which, in some embodiments, is a lyophilate "cake".
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~oo~o~ In another embodiment, the compounds and compositions of the present
invention
are used in combination with other therapeutic agents or procedures. In
particular
embodiments, the other therapeutic agents include other antiproliferative
agents,
agents that enhance the antiproliferative activity of the antiproliferative
compound
(e.g., inhibitors of Hsp90), and agents that mitigate undesired side-effects
of the
antiproliferative agent.
[0011] In another aspect of the invention, the pharmaceutical compositions
provided are
used to treat cancers. In particular embodiments, the compositions comprising
an
epothilone are used to treat cancers sensitive to epothilones.
~00~2~ In other embodiments, the pharmaceutical compositions provided are used
to treat
non-cancer diseases characterized by cellular hyperproliferation (e.g.,
psoriasis,
restenosis, multiple sclerosis, rheumatoid arthritis, atherosclerosis, and the
like).
~oo~s~ In another aspect, the invention provides pharmaceutical compositions
effective to
provide therapeutically effective dosage levels of an epothilone to a patient
in need of
such treatment. In particular embodiments, the composition is effective at
providing
a dosage level between about 0.1 mg/m2 and about 200 mg/mZ.
DETAILED DESCRIPTION OF THE INVENTION
~oo~a~ In one aspect, the present invention provides pharmaceutical
compositions (also
referred to simply as "compositions") for treating a hyperproliferative
disease,
typically, but not necessarily, in a mammal, preferably in a human. In one
embodiment, the present invention provides a pharmaceutical composition
comprising an epothilone and a pharmaceutically acceptable carrier,
embodiments of
which carrier will be described in greater detail hereinbelow. The epothilone
is
provided in a therapeutically effective concentration, and the pharmaceutical
composition is effective to deliver a therapeutically effective amount of
epothilone
by oral administration. In certain embodiments, the pharmaceutical
compositions are
provided in a physical form suitable for oral administration, e.g., soft gel
caps.
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[0015] As used herein, the term "epothilone" is used to refer to any
epothilone, such as, but
are not limited to, epothilone A, epothilone B, epothilone C, epothilone D,
epothilone
E, epothilone F, 4-desmethylepothilone D, azaepothilone B, 21-aminoepothilone
B,
9, 10-dehydroepothilone D, 9, 10-dehydro-26-trifluoro-epothilone D,
11-hydroxyepothilone D, 19-oxazolylepothilone D, 10, 11-dehydro-epothilone D,
19-oxazolyl-10, 11-dehydro-epothilone D, 9,10-dehydroepothilone B, 9,10-
dehydroepothilone D, 26-trifluoro-9,10-dehydroepothilone B or D, and analogs
and
derivatives thereof. The epothilone used in the pharmaceutical compositions of
the
invention can thus be any epothilone, and, more particularly, any epothilone
having
useful therapeutic properties (Hoefle, et al. 1993; Nicolaou, et al. 1998;
Reichenbach,
et al. 1998; Danishefsky, et al. 1999a; Danishefsky, et al. 1999b; Hoefle, et
al. 1999;
Nicolaou, et al. 1999a; Nicolaou, et al. 1999b; Vite, et al. 1999a; Vite, et
al. 1999b;
Vite, et al. 1999d; c; Hoefle, et al. 2000a; Hoefle, et al. 2000b;
Danishefsky, et al.
2001a; Danishefsky, et al. 2001b; Santi, et al. 2001; Avery 2002; Danishefsky,
et al.
2002; Nicolaou, et al. 2002a; Nicolaou, et al. 2002b; Wessjohann and Scheid
2002;
White, et al. 2002). Such epothilones can be obtained using any combination of
total
chemical synthesis, partial chemical synthesis, or chemobiosynthesis methods
and
materials known to those of skill in organic chemistry, medicinal chemistry,
and
biotechnology arts (Hoefle, et al. 1993; Hoefle and Kiffe 1997; Hofle and
Kiffe
1997; Schinzer, et al. 1997; 1998; Hofle and Seflcow 1998; Mulzer and
Mantoulidis
1998; Nicolaou, et al. 1998; Reichenbach, et al. 1998; Schinzer, et al. 1998;
Wessjohann and Gabriel 1998; Wessjohann and Kalesse 1998; Altmann, et al.
1999;
Danishefsky, et al. 1999a; Danishefsky, et al. 1999b; Hoefle, et al. 1999;
Hofmann,
et al. 1999; Kim and Borzilleri 1999; Kim and Johnson 1999; Klar, et al.
1999a; b;
Mulzer and Mantoulidis 1999; Nicolaou, et al. 1999a; Nicolaou, et al. 1999b;
Schupp, et al. 1999; Vite, et al. 1999a; Vite, et al. 1999b; Vite, et al.
1999d; c; Beyer
and Mueller 2000; Borzilleri, et al. 2000; Buchmann, et al. 2000; Cabral 2000;
Georg, et al. 2000; Gustafsson and Betlach 2000; Hoefle, et al. 2000a; Hoefle,
et al.
2000b; Hofle, et al. 2000; Julien, et al. 2000; Kim and Johnson 2000; Li, et
al. 2000;
Mulzer, et al. 2000; Arslanian, et al. 2001; Danishefsky, et al. 2001a;
Danishefsky, et
al. 2001b; Kim and Johnson 2001; Klar, et al. 2001; Kumar, et al. 2001; Lee
2001;
Li, et al. 2001); (Mulzer and Martin 2001; Santi, et al. 2001; Strohhaecker
2001;
Vite, et al. 2001; Avery 2002; Danishefsky, et al. 2002; Dimarco, et al. 2002;
Hoefle
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ana ~riaser ~uu~; ~uuen, et al. 2002; Khosla and Pfeifer 2002; itocn ana
Loiseleur
2002; Kuesters and Unternaehrer 2002; Li, et al. 2002; Nicolaou, et al. 2002a;
Nicolaou, et al. 2002b; Santi, et al. 2002a; Santi, et al. 2002b; Santi, et
al. 2002c;
Smith, et al. 2002; Wessjohann and Scheid 2002; Wessjohann, et al. 2002;
White, et
al. 2002). Specific examples of epothilones having useful therapeutic
properties
include, but are not limited to, epothilone A, epothilone B, epothilone C,
epothilone D, 4-desmethylepothilone D, azaepothilone B, 21-aminoepothilone B,
9, 10-dehydroepothilone D, 9, 10-dehydro-26-trifluoro-epothilone D,
11-hydroxyepothilone D, 19-oxazolylepothilone D, 10, 11-dehydro-epothilone D,
19-oxazolyl-10, 11-dehydro-epothilone D, 9,10-dehydroepothilone B, 9,10-
dehydroepothilone D, and analogs and derivatives thereof.
~oo~s~ In more particular embodiments of the pharmaceutical compositions
provided by the
invention, the pharmaceutical composition of the invention includes at least
one
cyclodextrin. The term "cyclodextrin" as used herein is meant to encompass
both
native cyclodextrins (e.g., a, (3, 'y-cyclodextrins and the like) as well as
derivatized
forms of the native cyclodextrins, such as hydroxyalkylated cyclodextrins
(e.g.,
hydroxyethylated and hydroxypropylated cyclodextrins), sulfoalkylated
cyclodextrins
(e.g., sulfopropylated and sulfobutylated cyclodextrins), and other chemically
derivatized cyclodextrins. In particular embodiments, the cyclodextrin is an
hydroxyalkyl-(3-cyclodextrin, and, in a still more particular embodiment, an
hydroxypropyl-(3-cyclodextrin. Still more particular embodiments in which the
carrier includes a hydroxypropyl-(3-cyclodextrin include those for which the
hydroxypropyl-(3-cyclodextrin has a degree of substitution of at least about
4.6%,
and, more specifically a degree of substitution of at least about 6.5%. Still
more
specific embodiments of the pharmaceutical composition of the invention are
those
for which the carrier includes an hydroxypropyl-(3-cyclodextrin having a
degree of
substitution between about 4.6% and about 6.5%. In other embodiments of the
invention, the cyclodextrin is a sulfopropyl-~i-cyclodextrin.
~oo~y In one embodiment, the epothilone used in the pharmaceutical composition
is
epothilone D. In a more specific embodiment, the pharmaceutical composition of
the
invention comprises epothilone D and a hydroxyalkyl-~3-cyclodextrin, and, in a
still
more particular embodiment, a hydroxypropyl-(3-cyclodextrin. In sill more
specific
6
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embodiments of pharmaceutical compositions comprising epofhilone ~ and a
hydroxypropyl-(3-cyclodextrin, the hydroxypropyl-(3-cyclodextrin has a degree
of
substitution of at least about 4.6%, and, more specifically, a degree of
substitution of
at least about 6.5%. Still more specific embodiments of the pharmaceutical
composition of the invention are those for which the epothilone is epothilone
D and
the carrier includes a hydroxypropyl-(3-cyclodextrin having a degree of
substitution
between about 4.6% and about 6.5%. Among the pharmaceutical compositions of
the
invention including epothilone D and a hydroxypropyl-(3-cyclodextrin, more
specific
embodiments include those for which the epothilone D and the
hydroxypropyl-~3-cyclodextrin are combined in a weight ratio of about 10 mg
epothilone D to about 0.4 g of hydroxypropyl-(3-cyclodextrin.
~oo~s~ In other embodiments of the invention, the epothilone and cyclodextrin
are provided
in a lyophilized form, which, in some embodiments, is a lyophilate "cake".
Such
embodiments can be made using materials and techniques that will be familiar
to
those having skill in the pharmacy arts (Gennaro 2000). In one particular
embodiment, an epothilone and a hydroxyalkyl-~3-cyclodextrin are combined in
an
alcohol-water solution that is lyophilized. More specific embodiments include
those
in which epothilone D and a hydroxypropyl-(3-cyclodextrin are combined in a
alcohol-water solution that is then lyophilized. In still more particular
embodiments,
about 10 mg epothilone D and about 0.4 g of hydroxypropyl-~i-cyclodextrin are
combined in a 60% tent-butanol-water solution that is then lyophilized. In
still more
specific embodiments, about 10 mg epothilone D and about 0.4 g of
hydroxypropyl-(3-cyclodextrin are combined in a 60% tent-butanol-water
solution
and then lyophilized to form a "cake".
[0019] Surprisingly, the lyophilates provided by the invention, as described
above, have
been found to possess useful solubility in pharmaceutically useful carriers,
especially
pharmaceutically useful carriers that are expected to be better tolerated than
carriers
comprising CREMAPHOR~. Thus, in another aspect, the present invention provides
useful pharmaceutical compositions comprising an epothilone and a
hydroxyalkyl-~3-cyclodextrin as described above, in a pharmaceutically
acceptable
carrier that lacks any substantial amount of CREMAPHOR~. More particular
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embodiments of the present invention include pharmaceutical compositions
resulting
from the reconstitution of the lyophylate described above using a mixture
including
water, ethanol, and at least one glycol. As used herein, the term "glycol" is
meant to
include molecules such as propylene glycol, polyethylene glycol 400,
polyoxyethylene sorbitan monooleate (sold under the trade name TWEEN 80), and
related oxygenated hydrocarbons. It is understood that glycols of various
chain
lengths and molecular weights (e.g., polyethylene glycol 1000, other TWEEN
compounds) are encompassed within this definition. For therapeutic uses, the
water
used in the reconstitution mixture is water of a degree of purity that is
suitable for
injection.
~0020~ In some embodiments, the mixture used to reconstitute the lyophylate
includes water,
ethanol and polyoxyethylene sorbitan monooleate (TWEEN 80). In more specific
embodiments, the mixture includes at least about 10% water (% v/v), more
particularly at least about 40% water (% v/v), and, still more particularly,
at least
about 60% water (% v/v). In some embodiments, the mixture for reconstitution
the
lyophylate includes between about 60% water and about 70% water (% v/v), more
particularly between about 60% water and about 65% water (% v/v), and, in
particular embodiment, about 62.5% water (% v/v).
~002~~ In some embodiments of the reconstitution mixture having water in the
concentrations just described, the mixture further include TWEEN 80 in a
concentration between about 25% (% v/v) and about 10% (% v/v), more
particularly
between about 20% (% v/v) and about 15% (% v/v). In one particular embodiment,
TWEEN 80 is provided in a concentration of about 15% (% v/v).
~oozz~ In some embodiments, the reconstitution mixture just described includes
a
concentration of water and a concentration of TWEEN 80 as just described, with
the
balance of the mixture being ethanol. Examples of suitable reconstitution
mixtures
include water/ethanol/TWEEN 80 concentrations (% v/v) of: 10/65/25, 20/55/25,
40/35/25, 62.5/12.5/25, 60/20/20, and 60/25/15. In another embodiment, the
reconstitution mixture is propylene glycol/ethanol/water in the ration
40/10/50
(% v/v).
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[0023] The above-described reconstitution mixtures are suitable for use with
any lyophylate
formed using any of the combinations of epothilone(s) and a
hydroxyalkyl-(3-cyclodextrin or sulfoalkyl-(3-cyclodextrin described above.
More
particular embodiments include compositions resulting from the reconstitution
of a
lyophylate including epothilone D. Still more particular embodiments include
those
compositions resulting from the reconstitution of a lyophylate for which the
epothilone is epothilone D and the hydroxyalkyl-(3-cyclodextrin is
hydroxypropyl-~i-cyclodextrin. Still more particular embodiments include those
compositions resulting from the reconstitution of a lyophylate for which the
epothilone is epothilone D and the sulfoallcyl-~i-cyclodextrin is
sulfoypropyl-(3-cyclodextrin.
~ooza~ Some embodiments of the invention include compositions resulting from
the
reconstitution of a lyophylate formed from about 10 mg epothi:one D and about
0.4 g
of hydroxypropyl-~3-cyclodextrin that have been combined in a 60% tert-
butanol-water solution, and a reconstitution mixture that includes a
water/ethanol/TWEEN 80 combination (% v/v) of: 10/65/25, 20/55/25, 40/35/25,
62.5/12.5/25, 60/20/20, or 60/25/15. In a more specific embodiment, the
lyophylate
formed from about 10 mg epothilone D and about 0.4 g of
hydroxypropyl-(3-cyclodextrin that have been combined in a 60% tert-butanol-
water
solution, and the reconstitution mixture is a water/ethanol/TWEEN 80
combination
(% v/v) of: 62.5/12.5/25, 60/20/20, or 60/25/15. A still more specific
embodiment is
a composition resulting from the reconstitution of a lyophilate formed from
about 10
mg epothilone D and about 0.4 g of hydroxypropyl-(3-cyclodextrin that have
been
combined in a 60% tent-butanol-water solution, and a reconstitution mixture
that
includes a water/ethanol/TWEEN 80 combination (% v/v) of 62.5/12.5/25.
~oo2s~ In another embodiment of the invention, the epothilone used in the
pharmaceutical
composition is 9,10-dehydroepothilone D. In a more specific embodiment of the
invention, the pharmaceutical composition comprises 9,10-dehydroepothilone D
and
a hydroxyalkyl-(3-cyclodextrin, and, in a still more specific embodiment, a
hydroxypropyl-(3-cyclodextrin. In still more specific embodiments of
pharmaceutical
compositions comprising 9,10-dehydroepothilone D and an
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hydroxypropyl-(3-cyclodextrin, the hydroxypropyl-(3-cyclodextrin has a degree
of
substitution of at least about 4.6%, and, more specifically, a degree of
substitution of
at least about 6.5%. Still more specific embodiments of the pharmaceutical
composition of the invention are those for which the epothilone is 9,10-
dehydroepothilone D and the carrier includes an hydroxypropyl-(3-cyclodextrin
having a degree of substitution between about 4.6% and about 6.5%.
~oo2s~ In other embodiments of the invention, the epothilone is provided as an
injection
concentrate, comprising the epothilone dissolved in a pharmaceutically
acceptable
carrier, and the injection concentrate is diluted prior to administration. In
particular
embodiments of the invention, the pharmaceutically acceptable carrier used to
produce the injection concentrate comprises an alcohol, for example ethanol.
In
further particular embodiments of the invention, the pharmaceutically
acceptable
carrier used to produce the injection concentrate comprises ar alcohol alczng
with a
glycol, for example propylene glycol. In specific embodiments, the injection
concentrate comprises 9,10-dehydroepothilone D dissolved at a concentration of
between about 0.1 mg/mL and about SO mg/mL in a pharmaceutically acceptable
carrier comprising ethanol and propylene glycol. In more specific embodiments,
the
injection concentrate comprises 9,10-dehydroepothilone D dissolved at a
concentration of between about 0.1 mg/mL and about 50 mg/mL in a
pharmaceutically acceptable carrier comprising about 50-90% (v/v) of ethanol
and
about 10-50% (v/v) of propylene glycol. In more specific embodiments, the
injection
concentrate comprises 9,10-dehydroepothilone D dissolved at a concentration of
between about 0.1 mg/mL and about 50 mg/mL in a pharmaceutically acceptable
carrier comprising about 70% (v/v) of ethanol and about 30% (v/v) of propylene
glycol. In even more specific embodiments, the injection concentrate comprises
9,10-
dehydroepothilone D dissolved at a concentration of between about 1 mg/mL and
about 10 mg/mL in a pharmaceutically acceptable carrier comprising about 70%
(v/v) of ethanol and about 30% (v/v) of propylene glycol. In an even more
specific
embodiment, the injection concentrate consists of 9,10-dehydroepothilone D
dissolved at a concentration of about 5 mg/mL in a pharmaceutically acceptable
carrier consisting of about 7C1% (v/v) of ethanol and about 30% (v/v) of
propylene
glycol.
to
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~oo2y The above-described injection concentrates are diluted into suitable
diluents prior to
administration. In certain embodiments of the invention, these diluents
comprise one
or more cyclodextrins, chosen from the list described above, dissolved in
water for
injection. In specific embodiments, the diluent comprises hydroxyalkyl-
(3-cyclodextrin dissolved in water for injection. In more specific embodiments
of the
invention, the diluent comprises hydroxypropyl-~i-cyclodextrin dissolved in
water
for injection at a concentration of between about 10 mg/mL and about 1000
mg/mL.
In even more specific embodiments of the invention, the diluent comprises
hydroxypropyl-(3-cyclodextrin dissolved in water for injection at a
concentration of
between about 50 mg/mL and about 500 mg/mL. In even more specific embodiments
of the invention, the diluent comprises hydroxypropyl-(3-cyclodextrin
dissolved in
water for injection at a concentration of between about 50 mg/mL and about 250
mg/mL. In even more specific embodiments of the invention, the diluent
comprises
hydroxypropyl-(3-cyclodextrin dissolved in water for injection at a
concentration of
between about 133 mg/mL. In certain embodiments of the invention, the
injection
concentrate is diluted between about 2-fold (v/v) and about 20-fold (v/v) into
the
diluent. In specific embodiments of the invention, the injection concentrate
is diluted
between about 5-fold (v/v) and about 15-fold (v/v) into the diluent. In even
more
specific embodiments of the invention, the injection concentrate is diluted
about 10-
fold (v/v) into the diluent.
~oo2s~ Certain embodiments of the invention thus provide pharmaceutical
compositions
comprising an epothilone dissolved in a pharmaceutically acceptable carrier,
wherein
the carrier comprises an alcohol, a glycol, and a cyclodextrin. In specific
embodiments, the invention provides pharmaceutical compositions comprising
9,10-
dehydroepothilone dissolved in a pharmaceutically acceptable carrier, wherein
the
carrier comprises an alcohol, a glycol, and a cyclodextrin. In more specific
embodiments, the invention provides pharmaceutical compositions comprising
9,10-
dehydroepothilone dissolved in a pharmaceutically acceptable carrier, wherein
the
carrier comprises ethanol, propylene glycol, and hydroxypropyl-(3-
cyclodextrin. In
even more specific embodiments, the invention provides pharmaceutical
compositions consisting of 9,10-dehydroepothilone dissolved in a
pharmaceutically
acceptable carrier, wherein the carrier consists essentially of ethanol,
propylene
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glycol, and hydroxypropyl-(3-cyclodextrin. In even more specific embodiments,
the
invention provides pharmaceutical compositions consisting of 9,10-
dehydroepothilone at about 0.5 mg/mL dissolved in a pharmaceutically
acceptable
carrier, wherein the carrier consists essentially of about 7% (v/v) of
ethanol, about
3% (v/v) of propylene glycol, and about 12% (w/v) of hydroxypropyl-(3-
cyclodextrin
in water for injection.
Ioo2s1 Without wishing to be bound by any particular theory of action, the
effectiveness of
the combination of a hydroxyalkyl-(3-cyclodextrin lyophylate in one of the
aqueous
reconstitution mixtures described herein to form a therapeutically effective
composition is consistent with the formation of an complex between the
hydroxyalkyl-(3-cyclodextrin and the epothilone in the lyophylate, and, more
specifically, an inclusion complex between the hydroxyalkyl-(3-cyclodextrin
and the
epothilone in the lyophylate. Thus, in some embodiments, the present invention
includes epothilone D-hydroxypropyl-(3-cyclodextrin complexes, and, more
specifically, epothilone D-hydroxypropyl-(3-cyclodextrin inclusion complexes.
The
above-described complexes and inclusion complexes can be formed in either the
lyophylate and/or the reconstituted solution.
Therapeutic Applications of the Compositions of the Invention
looaol The compositions described herein are effective to deliver a
therapeutically effective
amount of an epothilone to treat an epothilone-mediated disease, i.e., a
disease that
responds favorably to the administration of an epothilone to a patient, such
as a
mammal, and, more particularly, a human, to epothilone administration. Thus,
the
present invention also includes methods for treating epothilone-mediated
diseases.
Examples of epothilone-mediated diseases include, but are not limited to,
hyperproliferative diseases, such as cancer, including: cancers of the head
and neck
which include tumors of the head, neck, nasal cavity, paranasal sinuses,
nasopharynx,
oral cavity, oropharynx, larynx, hypopharynx, salivary glands, and
paragangliomas;
cancers of the liver and biliary tree, particularly hepatocellular carcinoma;
intestinal
cancers, particularly colorectal cancer; treat ovarian cancer; small cell and
non-small
cell lung cancer; breast cancer sarcomas, such as fibrosarcoma, malignant
fibrous
histiocytoma, embryonal rhabdomysocarcoma, leiomysosarcoma, neurofibrosarcoma,
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osteosarcoma, synovial sarcoma, liposarcoma, and alveolar soft part sarcoma;
neoplasms of the central nervous systems, particularly brain cancer; lymphomas
such
as Hodgkin's lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma,
mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage
large cell lymphoma, Burkitt's lymphoma, and T-cell anaplastic large cell
lymphoma. Clinically, practice of the methods and use of compositions
described
herein will result in a reduction in the size or number of the cancerous
growth and/ or
a reduction in associated symptoms (where applicable). Pathologically,
practice of
the method and use of compositions described herein will produce a
pathologically
relevant response, such as: inhibition of cancer cell proliferation, reduction
in the size
of the cancer or tumor, prevention of further metastasis, and inhibition of
tumor
angiogenesis.
~oos~~ The methods and compositions of the present invention can be used in
combination
therapies. In other words, the inventive compounds and compositions can be
administered concurrently with, prior to, or subsequent to one or more other
desired
therapeutic or medical procedures. The particular combination of therapies and
procedures in the combination regimen will take into account compatibility of
the
therapies and/or procedures and the desired therapeutic effect to be achieved.
Thus,
the compositions described herein can be combined with other treatment
modalities,
such as surgery and/or radiation. The compositions described herein can also
be used
in combination with other oncolytic agents, such a 5-fluorouracil or 5'-deoxy-
S-fluoro-N-[(pentyloxy)carbonyl]-cytidine (sold under that trade name XELODA~
(Roche). Illustrative examples of other anti-cancer agents include but are not
limited
to: (i) alkylating drugs such as mechlorethamine, chlorambucil,
Cyclophosphamide,
Melphalan, Ifosfamide; (ii) antimetabolites such as methotrexate; (iii)
microtubule
stabilizing agents such as vinblastin, paclitaxel, docetaxel, and
discodermolide; (iv)
angiogenesis inhibitors; (v) and cytotoxic antibiotics such as doxorubicin
(adriamycin), bleomycin, and mitomycin. Illustrative examples of other anti-
cancer
procedures include: (i) surgery; (ii) radiotherapy; and (iii) photodynamic
therapy.
~oos2~ In another embodiment, the compounds and compositions of the present
invention
are used in combination with an agent or procedure to mitigate potential side
effects
from the inventive compound or composition such as diarrhea, nausea and
vomiting.
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Diarrhea may be treated with antidiarrheal agents such as opioids (e.g.
codeine,
diphenoxylate, difenoxin, and loeramide), bismuth subsalicylate, and
octreotide.
Nausea and vomiting may be treated with antiemetic agents such as
dexamethasone,
metoclopramide, diphenyhydramine, lorazepam, ondansetron, prochlorperazine,
thiethylperazine, and dronabinol.
~ooaa~ In another aspect of the present invention, the inventive compositions
are used to
treat non-cancer disorders that are characterized by cellular
hyperproliferation.
Illustrative examples of such disorders include but are not limited to:
atrophic
gastritis, inflammatory hemolytic anemia, graft rejection, inflammatory
neutropenia,
bullous pemphigoid, coeliac disease, demyelinating neuropathies,
dermatomyositis,
inflammatory bowel disease (ulcerative colitis and Crohn's disease), multiple
sclerosis, myocarditis, myositis, nasal polyps, chronic sinusitis, pemphigus
vulgaris,
primary glomerulonephrifis, psoriasis, surgical adhesions, stenosis or
restenosis,
scleritis, scleroderma, eczema (including atopic dermatitis. irritant
dermatitis, allergic
dermatitis), periodontal disease (i.e., periodontitis), polycystic kidney
disease, and
type I diabetes. Other examples include vasculitis (e.g., Giant cell arteritis
(temporal
arteritis, Takayasu's arteritis), polyarteritis nodosa, allergic angiitis and
granulomatosis (Churg-Strauss disease), polyangitis overlap syndrome,
hypersensitivity vasculitis (Henoch-Schonlein purpura), serum sickness, drug-
induced vasculitis, infectious vasculitis, neoplastic vasculitis, vasculitis
associated
with connective tissue disorders, vasculitis associated with congenital
deficiencies of
the complement system, Wegener's granulomatosis, Kawasaki's disease,
vasculitis of
the central nervous system, Buerger's disease and systemic sclerosis);
gastrointestinal
tract diseases (e.g., pancreatitis, Crohn's disease, ulcerative colitis,
ulcerative
proctitis, primary sclerosing cholangitis, benign strictures of any cause
including
ideopathic (e.g., strictures of bile ducts, esophagus, duodenum, small bowel
or
colon); respiratory tract diseases (e.g., asthma, hypersensitivity
pneumonitis,
asbestosis, silicosis and other forms of pneumoconiosis, chronic bronchitis
and
chronic obstructive airway disease); nasolacrimal duct diseases (e.g.,
strictures of all
causes including ideopathic); and eustachean tube diseases (e.g., strictures
of all
causes including ideopathic).
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[0034] The method of treating such diseases comprises administering a
therapeutically
effective amount of an inventive compound to a subject suffering therefrom.
The
method may be repeated as necessary. The inventive methods are described in
greater
detail below with reference to three illustrative non-cancer disorders.
loossl In one embodiment, the compounds of the present invention are used to
treat
psoriasis, a condition characterized by the cellular hyperproliferation of
keratinocytes
which builds up on the skin to form elevated, scaly lesions. The method
comprises
administering a therapeutically effective amount of an inventive compound to a
subject suffering from psoriasis. The method may be repeated as necessary
either to
decrease the number or severity of lesions or to eliminate the lesions.
Clinically,
practice of the method will result in a reduction in the size or number of
skin lesions,
diminution of cutaneous symptoms (pain, burning and bleeding of the affected
skin)
and/ or a reduction in associated symptoms (e.g., joint redness, heat,
swelling,
diarrhea. abdominal pain). Pathologically, practice of the method will result
in at
least one of the following: inhibition of keratinocyte proliferation,
reduction of skin
inflammation (for example, by impacting on: attraction and growth factors,
antigen
presentation, production of reactive oxygen species and matrix
metalloproteinases),
and inhibition of dermal angiogenesis.
loossl In another embodiment, the compounds of the present invention are used
to treat
multiple sclerosis, a condition characterized by progressive demyelination in
the
brain. Although the exact mechanisms involved in the loss of myelin are not
understood, there is an increase in astrocyte proliferation and accumulation
in the
areas of myelin destruction. At these sites, there is macrophage-like activity
and
increased protease activity which is at least partially responsible for
degradation of
the myelin sheath. The method comprises administering a therapeutically
effective
amount of an inventive compound to a subject suffering from multiple
sclerosis. The
method may be repeated as necessary to inhibit astrocyte proliferation and/or
lessen
the severity of the loss of motor function and/or prevent or attenuate chronic
progression of the disease. Clinically, practice of the method will result in
improvement in visual symptoms (visual loss, diplopia), gait disorders
(weakness,
axial instability, sensory loss, spasticity, hyperreflexia, loss of
dexterity), upper
extremity dysfunction (weakness, spasticity, sensory loss), bladder
dysfunction
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(urgency, incontinence, hesitancy, incomplete emptying), depression, emotional
lability, and cognitive impairment. Pathologically, practice of the method
will result
in the reduction of one or more of the following, such as myelin loss,
breakdown of
the blood-brain barrier, perivascular infiltration of mononuclear cells,
immunologic
abnormalities, gliotic scar formation and astrocyte proliferation,
metalloproteinase
production, and impaired conduction velocity.
~oos~~ In another embodiment, the compositions of the present invention are
used to treat
rheumatoid arthritis, a multisystem chronic, relapsing, inflammatory disease
that
sometimes leads to destruction and ankyiosis of affected joints. Rheumatoid
arthritis
is characterized by a marked thickening of the synovial membrane which forms
vinous projections that extend into the joint space, multilayering of the
synoviocyte
lining (synoviocyte proliferation), infiltration of the synovial membrane with
white
blood cells (macrophages, lymphocytes, plasma cells, and lymphoid follicles;
called
an "inflammatory synovitis"), and deposition of fibrin with cellular necrosis
within
the synovium. The tissue formed as a result of this process is called pannus
and,
eventually the parmus grows to fill the joint space. The pannus develops an
extensive
network of new blood vessels through the process of angiogenesis that is
essential to
the evolution of the synovitis. Release of digestive enzymes (matrix
metalloproteinases (e.g., collagenase, stromelysin)) and other mediators of
the
inflammatory process (e.g., hydrogen peroxide, superoxides, lysosomal enzymes,
and
products of arachadonic acid metabolism) from the cells of the parmus tissue
leads to
the progressive destruction of the cartilage tissue. The pannus invades the
articular
cartilage leading to erosions and fragmentation of the cartilage tissue.
Eventually
there is erosion of the subchondral bone with fibrous ankylosis and ultimately
bony
ankylosis, of the involved joint.
~ooss~ In another embodiment, the compositions of the present invention are
used to threat
atherosclerosis and/or restenosis, particularly in patients whose blockages
may be
treated with an endovascular stmt. Atherosclerosis is a chronic vascular
injury in
which some of the normal vascular smooth muscle cells ("VSMC") in the artery
wall,
which ordinarily control vascular tone regulating blood flow, change their
nature and
develop "cancer-like" behavior. These VSMC become abnormally proliferative,
secreting substances (growth factors, tissue-degradation enzymes and other
proteins)
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which enable them to invade and spread into the inner vessel lining, blocking
blood
flow and making that vessel abnormally susceptible to being completely blocked
by
local blood clotting. Restenosis, the recurrence of stenosis or artery
stricture after
corrective procedures, is an accelerated form of atherosclerosis.
Alternatively, the
compositions of the invention can be used to provide a coating comprising a
therapeutically effective amount of an epothilone on a stmt for and delivering
the
stmt to the diseased artery in a subject suffering from atherosclerosis.
Methods for
coating a stmt with a compound are described for example by U.S. Patent Nos.
6,156,373 and 6,120, 847. Clinically, practice of the present invention will
result in
one or more of the following: (i) increased arterial blood flow; (ii) decrease
in the
severity of clinical signs of the disease; (iii) decrease in the rate of
restenosis; or (iv)
prevention/attenuation of the chronic progression of atherosclerosis.
Pathologically,
practice of the present invention will produce at least one of the following
at the site
of stmt implantation: (i) decrease in the inflammatory response, (ii)
inhibition of
VSMC secretion of matrix metalloproteinases; (iii) inhibition of smooth muscle
cell
accumulation; and (iv) inhibition of VSMC phenotypic dedifferentiation.
Dosage Levels and Administration
[0039] In one embodiment, the compositions of the invention are effective to
provide dosage
levels of an epothilone, especially epothilone D, or an epothilone selected
from the
group consisting of: epothilone A, epothilone B, epothilone C,
4-desmethylepothilone D, azaepothilone B, 21-aminoepothilone B,
9, 10-dehydroepothilone D, 9, 10-dehydro-26-trifluoro-epothilone D,
11-hydroxyepothilone D, 19-oxazolylepothilone D, 10, 11-dehydro-epothilone D,
19-oxazolyl-10, 11-dehydro-epothilone D, 9,10-dehydroepothilone B, 9,10-
dehydroepothilone D, 26-trifluoro-9,10-dehydoepothilone D, and 26-trifluoro-
9,10-
dehydroepothilone B, which dosage is to be administered to a subject suffering
from
cancer or a non-cancer disorder characterized by cellular proliferation are of
the order
from about 0.1 mg/m2 to about 200 mg/m2 which may be administered as a bolus
(in
any suitable route of administration, including oral or intravenous
administration) or
a continuous infusion (e.g., one hour, three hours, six hours, 24 hours, 48
hours or 72
hours) every week, every two weeks, or every three weeks as needed. It will be
understood, however, that the specific dose level for any particular patient
depends
1~
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on a variety of factors. These factors include the activity of the specific
compound
employed; the age, body weight, general health, sex, and diet of the subject;
the time
and route of administration and the rate of excretion of the drug; whether a
drug
combination is employed in the treatment; and the severity of the condition
being
treated.
~ooao~ In another embodiment, the dosage levels are from about 10 mg/m2 to
about 150
mg/m2, preferably from about 10 mg/mz to about 75 mg/m2 and more preferably
from
about 15 mg/m2 to about 50 mg/m2 once every three weeks as needed and as
tolerated. In another embodiment, the dosage levels are from about 1 mg to
about 150
mg/m2, preferably from about 10 mg/m2 to about 75 mg/m2 and more preferably
from
about 25 mg/m2 to about 50 mg/mz once every two weeks as needed and as
tolerated.
In another embodiment, the dosage levels are from about 1 mg/m2 to about 100
mg/m2, preferably from about 5 mg/mz to about 50 mg/m2 and more preferably
from
about 10 mg/m2 to about 25 mg/m2 once every week as needed and as tolerated.
In
another embodiment, the dosage levels are from about 0.1 mg/m2 to about 25
mg/mz,
preferably from about 0.5 mg/m2 to about 15 mg/m2 and more preferably from
about
1 mg/m2 to about 10 mg/m2 once daily as needed and tolerated.
~ooa~~ In another embodiment, the dosage levels are from about 0.1 mg/m2 to
about 50
mg/m2, preferably from about 0.1 mg/m2 to about 25 mg/m2, and more preferably
from about 0.5 mg/m2 to about 25 mg/m2 once every three weeks as needed and as
tolerated.
~ooa2~ In order to ensure that toxic limits are not exceeded, side effects are
monitored,
including peripheral neuropathy, which may manifest itself as numbness in the
limbs,
dizziness, and the like. Monitoring should begin at some relevant time after
infusion;
in general, the lower the dosage, the longer the interval between treatment
and
monitoring. For example, at a dose level of 9 to 60 mg/m2 per infusion
monitoring
will typically start at day 5 and continue to day 15; however, at higher
dosages such
as 90 to 120 mg/mz, monitoring should begin the day after infusion is
terminated.
Other side effects may include nausea and vomiting, fatigue, rash, alopecia,
and
alteration in vital signs such as orthostatic hypotension. Myelosuppression
should
also be monitored although myelosuppression is generally not seen with this
drug.
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WO 2005/034964 PCT/US2004/033339
Myelosuppression may manifest itself as anemia, neutropenia, thrombocytopenia,
and the like.
[0043] In general, the pharmacokinetics are favorable. Pharmacokinetics are
not dose-
dependent and the dependence of AUC on dosage was linear from 9 to 150 mg/mz.
The half life of epothilone D has a mean value of 9.6 ~ 2.2 hours and a volume
of
distribution (VZ) is 172 t 741, indicating good drug penetration. This is
somewhat
higher on average than the values for paclitaxel, which are 140 ~ 701. These
pharmacokinetic parameters do not change for a second infusion as compared to
a
first infusion.
~ooaa~ The effectiveness of the drug may be monitored by measuring bundling of
microtubules in interphase cells. This is considered a reasonable indicator of
effectiveness of microtubule stabilizing agents such as paclitaxel or an
epothilone.
The bundle formation may readily be measured by immunofluorescence or Western
blotting. In a typical determination, whole blood is collected from patients
and
mononuclear cells (PBMC's) are isolaoed for evaluation of bundle formation.
Substantial amounts of bundle formation are obtained when the dosage is as low
as
18 mg/m2 and this increases with dosage. At 120 mg/m2 most of the
microtublules
are bundled.
Examples
~ooas~ The following Examples illustrate certain aspects of the present
invention to aid those
of skill in the art in the art in practicing the invention. The Examples in no
way limit
the scope of the invention in any manner.
EXAMPLE 1
Formation of Epothilone D-Hydroxypropyl-~-Cyclodextrin Lyophylate
~ooas~ A combination of ten milligrams ("mg") of epothilone D and 0.4 grams
("g") of
hydroxypropyl-~i-cyclodextrin ("HP(3CD") were dissolved in 60% tert-butanol-
water
to make 1 milliliter ("mL") of solution. A second solution having ten mg of
epothilone D and ten mg of mannitol dissolved in 60% tert-butanol-water was
prepared. A third solution of ten mg of epothilone D and ten mg of mannitol in
60%
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WO 2005/034964 PCT/US2004/033339
tent-butanol-water was also prepared. Formulation solutions containing ten
mg/mL
epothilone D were poured into 8 mL glass vials for lyophilization.
~ooay Each of the three solutions was freeze-dried using a commercially
available
lyophilization apparatus to form an excellent lyophilate cake. The cake
containing
hydroxypropyl-(3-cyclodextrin appeared harder and less smooth than the other
two
cakes.
EXAMPLE 2
Reconstitution of the Epothilone D-Hydroxypropyl-~-Cyclodextrin Lyophylate
and Solubility in Normal Saline
~ooas~ The solubilities of the lyophilates made as described in Section 0 were
determined
for a variety of reconstitution solvents at ambient temperature (i.e., at a
temperature
between about 20 °C and about 25 °C). Approximately one mg of
epothilone D was
placed in a glass test tube. Serial additions of reconstitution solvent to
make
100 microliters ("~L")-, 900 ~L-, and 9.0 mL-volume solutions were made to the
test
tube. After each addition of reconstitution composition, the solution was
shaken
vigorously for thirty seconds. Upon dissolution of the lyophilate, the
solubility upon
dilution with normal saline was determined.
[0049] Only lyophilates made using hydroxypropyl-(3-cyclodextrin showed
desirable
solubilities (i.e., a solubility greater than about one mg/mL). The results
for various
reconstitution solvents are shown in Table 1. ("WfI" is water, "PG" is
propylene
glycol, "EtOH" is ethanol, and "PEG400" is polyethylene glycol 400. The symbol
"D" indicates dissolution; the letter "P" indicates precipitation.)
Table 1
Reconstitution Solubility S Solubility After Dilution
Solvent(% v/v) (mg/mL) with
Normal Saline
1:10/1:20/1:100
WfI/EtOH/Tween 80
10/65/25 1 < S < 10 D/ /
20/55/25 1 < S < 10 D/ /
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WO 2005/034964 PCT/US2004/033339
Reconstitution Solubility Solubility After Dilution
Solvent(% v/v) S with
(mg/mL) Normal Saline
1:10/1:20/1:100
40/35/25 1 < S < 10 D/ /
62.5/12.5/25 1 < S < 10 D/ /
60/20/20 2 < S < 10 D/D/
60/25/15 S > 10 D/D/D
60/35/5 S > 10 P/ /
PG/EtOH/WfI
40/10/50 0.1 < S < 1.0 D/ /
~ooso~ The results indicate the best results are achieved with the three-
component solvent
system: WfI/EtOH/Tween 80 = 60/25/15 (% v/v), which could be diluted in normal
saline as much as 100-fold without precipitation. Compositions for which the
amount
of Tween 80 was more than about 20% by volume, or less than about 10% by
volume, showed less favorable dilution performance.
EXAMPLE 3
Oral Activity of Epothilone D
[0051] Three test groups, each of five rats, received either an i.v. dose of
epothilone D (10
mg/kg), an oral dose of epothilone D at 20 mg/kg, or an oral dose of
epothilone D at
40 mg/kg. Blood samples were collected from the rats over a 24-hour period
following dosing. The absolute bioavailability at the 20 mg/kg and 40 mg/kg
oral
doses ranged from 7-10% and 10-20%, respectively. The half life was 8 hours
for
the i.v. group snf 5.6-6 hours for the oral groups. As expected, Cmax was
significantly higher and clearance was faster with i.v. dosing.
~oos2~ In a similar study, three beagle dogs received a single 2 mg/kg i.v.
dose of epothilone
D followed at one week intervals by a 2 mg/kg and 4 mg/kg oral dose of
epothilone
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WO 2005/034964 PCT/US2004/033339
D administered by gavage in the same vehicle as i.v. dosing (30% propylene
glycol,
20% Chremophor~, and 50% ethanol) diluted 1:10. Blood samples were collected
pre-dose, at the end of infusion, or immediately post-dose following oral
administration through 48 hours post-dose. Hetamology and blood chemistries
were
monitored to ensure animals had recovered prior to each dose. Dogs receiving
i.v.
epothilone D experienced significant hypersensitivity reactions, but oral
dosing was
well-tolerated.
~ooss~ Plasma samples from the dogs were analyzed using an LC/MS/MS assay
validated
over a range of 2 ng/mL - 500 ng/mL, and the data was analyzed using Kinetica
version 4.1.1 (InnaPhase Corporation, Philadelphia, PA). Pharmacokinetic
parameters were calculated using non-compartmental analysis and modeled using
a
two-compartment extravascular model. The calculated AUC for the 2 mg/kg and 4
mg/kg oral doses were 9,856 ~ 3,879 ng*h/mL and 15,486 ~ 8,060 ng*h/mL
respectively, and the oral bioavailability was > 50%. The average half life
with oral
dosing was 9.13 hours with the half life somewhat longer with the 4 mg/kg dose
(10.9 hours versus 6.4 hours for the 2 mg/kg dose). The average clearance with
oral
dosing was 0.27 L/h/kg, VSS = 2.57 L/kg, and MRT = 9.81 hours. Clearance, VSS,
MRT, and half life were essentially the same as observed with i.v. dosing.
[0054] These data demonstrate that epothilone D has good oral bioavailability,
suggesting
that oral administration to cancer patients or patients suffereing from other
hyperproliferative conditions or diseases is feasible.
EXAMPLE 4
Formulation of 9,10-dehydroepothilone D
[0055] An injection concentrate was prepared by dissolving traps-9,10-
dehydropeothilone D
at a concentration of 5 mg/mL in 70% (v/v) ethanol and 30% (v/v) propylene
glycol.
The injection concentrate (2 mL + 0.2 mL overfill) was filled aseptically into
5-mL
Type I glass serum vials (22-mm neck), closed with a 20-mm Teflon-coated
stopper,
and sealed with white laquered flip-off crimp seals. Sterile, dry nitrogen was
used to
displace the air during the filling of the injection concentrate into each
vial.
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WO 2005/034964 PCT/US2004/033339
[0056) The diluent was prepared by dissolving hydroxypropyl-(3-cyclodextrin at
a
concentration of 133 mg/mL in water for injection. The diluent (18 mL) was
filled
aseptically into 20-mL Type 1 glass serum vials (22-mm neck), closed with a 20-
mm
Teflon-coated stopper, and sealed with white laquered flip-off crimp seals.
[0057] The parenteral dosage form of traps-9,10-dehydroepothilone D was
prepared by
removing 2 mL of the injection concentrate and adding it to the vial
containing 18
mL of diluent. The resulting solution comprising 0.5 mg/mL of traps-9,10-
dehydroepothilone D was gently mixed. The parenteral dosage form may be
further
diluted into saline (0.9% w/v NaCI) to provide injection solutions of lower of
trans-
9,10-dehydroepothilone D concentrations. Typically, these dilutions range from
about 0.05 mg/mL to about 0.1 mg/mL, but may vary depending upon therapeutic
needs.
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