Note: Descriptions are shown in the official language in which they were submitted.
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
TAXANE-BASED COMPOSITIONS AND METHODS OF USE
PRIORITY
This application claims priority under 35 U.S.C. ~ 119(e) from United States
Provisional
Application No. 60/191,802, filed March 24, 2000, the contents of which are
hereby incorporated
by reference.
TECHNICAL FIELD
The invention relates to novel compositions useful to administer aqueous
insoluble
medicaments, including medicaments known to be poorly absorbed when
administered orally.
The invention further relates to compositions and methods of using the same,
to achieve target
blood levels of a taxane in a mammal. Moreover, the invention relates to
methods of treatment
employing such compositions.
BACKGROUND ART
The scarcity of effective approaches to address poor solubility characteristic
of many
pharmacologically useful compounds (e.g., lipophilic, hydrophobic and
amphiphobic compounds)
is a critical shortcoming hindering drug development. Kagkadis et al., PDA J.
Pharm. Sci.
50(5):317-323 (1996) and Sweetana et al., PDA Pharm. Sci. 50(5):330-342 (1996)
teach that
poorly soluble compounds include for example cortisone, etoposide, cyclosporin
and proleukin.
Traditionally, because of poor or inconsistent systemic absorption from the
gastrointestinal tract,
poorly soluble drugs have been administered intravenously (involving
considerable physical and
2o psychological discomfort and potential local trauma, as well as additional
economic costs).
Poorly soluble chemotherapeutic and/or anticancer agents include taxanes, such
as
paclitaxel, which are not normally bioavailable when administered orally. Wani
et al., J. Am.
Chem. Soc., 93:2325 (1971) teaches that paclitaxel, a member of the taxane
family of terpenes, is
a natural diterpene product isolated from the Pacific yew tree (Taxus
brevifolia). Although the
exact mechanism responsible for paclitaxel's chemotherapeutic properties has
not been
elucidated, several studies, such as those of Schiff et al., Proc. Natl. Acad.
Sci. USA, 77:1561-
1565 (1980); Schiff et al., Nature, 277:665-667 (1979); and Kumar, J. Biol.
Chem., 256:10435-
10441 (1981), postulate that paclitaxel's ability to inhibit tumorigenic
growth stems from its
capacity to bind the N-terminal 31 amino acids of the beta-tubulin subunit in
the microtubule (see
Rao et al., J Biol Chem 269:3132-3134 (1994). Wood et al., New Eng. J. M.
332(15):1004-1014
(1995) attributes paclitaxel anticancer properties to the inhibition of
disassembly of microtubules
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
2
rendering them extraordinarily stable and dysfunctional, thereby causing cell
death by disrupting
normal dynamics required during cell division and vital interphase processes.
The scientific literature is replete of papers reporting the efficacy of
paclitaxel in the
treatment of a variety of unrelated conditions. See for example, Einzig et
al., Proc. Am. Soc.
Clin. Oncol., 20:46 (1996) for lung cancer and head and neck carcinomas;
Forastire et al., Sem.
Oncol., 20:56 (1990) for neoplasms in the skin; Chang et al., Cancer 77(1):14-
18 (1996) for
gastric cancer); Woo et al., Nature, 368:750 (1994) for polycystic kidney
disease; and Pouvelle et
al., J. Clin. Invest 44:413-417 (1994) for malaria.
Paclitaxel and docetaxel have been approved for clinical use in the treatment
of several,
l0 unrelated conditions. Markman et al., Yale J. of Bio. & Med., 64:583
(1991), and McGuire, et
al., Ann. Intern. Med. 111:273 (1989) disclose the use of paclitaxel for
refractory ovarian cancer
in the United States; Mavrodius et al., ASCO 18:254a (1999) describes the use
of docetaxel for
gastric cancer; Holmes et al., J. Nat. Cancer Inst., 83:1797 (1991) discloses
the use of paclitaxel
for chemotherapy for several types of neoplasms including breast cancer (see
also Taxol
(paclitaxel) Mead Johnson Oncology Products package insert); Fencel et al.,
ASCO 18:283a
(1999) teaches the use of paclitaxel and docetaxel for esophageal cancer;
Vanhoefer et al., ASCO
18:303a (1999) describes phase II studies using docetaxel in metastatic
gastric cancer; Kourossis
et al., ASCO 17:266(a) (1998) teaches the use of docetaxel as salvage
chemotherapy for advanced
gastric cancer; Xiao et al., ASCO 17:306(a) (1998) assessing new paclitaxel
treatment regimens
in patients with esophageal carcinoma who had been previously treated with
paclitaxel; Schultz et
al., reporting phase II trials of docetaxel in patients with hormone
refractory prostate cancer;
Ajani et al., J. Nat. Cancer Inst., 86:1086-1091 (1994), and Kelsen et al.
Seminars in Oncology
21:44-48 (1994) describe paclitaxel regimens for squamous cell carcinoma and
adenocarcinoma
as well as epidermoid cancer of the esophagus.
Thus far, efforts have been directed to the development of (i) suitable
injection and
infusion taxane formulations and (ii) to more water-soluble taxane analogs,
derivatives and
prodrugs. Thus, most paclitaxel formulations for IV infusion have been
developed utilizing
polyethoxylated castor oil, commercially available as CREMOPHOR ELTM, as the
drug carrier.
Polyethoxylated castor oil however, is itself toxic, produces vasodilation,
labored breathing,
lethargy, hypotension and death in dogs it is also suspected to cause allergic-
type reactions when
administered intravenously.
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
3
Alternative approaches have led to more water-soluble analogs, derivatives and
prodrugs
of taxanes. Hence, for example, "Modified Taxols IV; Synthesis and biological
activity of taxols
Modified in the side chain", Magri, N.F.; Kingston, DGI; J. Nat. Prod 1988,
51, 298, teaches
derivatized paclitaxel analogs in which the 2' and/or 7-position is
derivatized with groups that
would enhance water solubility. These efforts have yielded prodrug compounds
that are more
water-soluble than the parent compound and that display the cytotoxic
properties upon activation.
One important group of such prodrugs includes the 2'-onium salts of paclitaxel
and docetaxel (see
e.g. Nicolaou, et al., Angew. Chin. Int. Engl. 33:1583-1587 (1994)),
particularly the 2'-
methylpyridinium mesylate (2'-MPM) salts disclosed in PCT publication no. WO
98/58927.
l0 Suffness (ed.) in Taxol~ Science and Applications) CRC Press (1995) states
that to date none has
progressed to clinical evaluation because of marginal improvements in
solubility, stability
problems and low regeneration rates.
Preclinical studies have suggested that paclitaxel alone is not absorbed after
oral doses.
Walle et al., Drug Metabo. Disp. 26(4):343-346 (1998), reported that taxol is
not absorbed after
oral administration, and attributed low oral bioavailability to the action an
outwardly directed
efflux pump. Similarly, Eiseman, et al., Second NCI Workshop on Taxol and
Taxes (Sept. 1992),
and Suffness (ed.) in Taxol° Science and Applications) CRC Press (1995)
teach that paclitaxel is
very poorly absorbed when administered orally (less than 1 %). More
specifically, Eiseman et al.
indicates that paclitaxel has a bioavailability of 0% upon oral
administration, and Suffness et al.
reports that oral dosing with paclitaxel did not seem possible. For these
reasons, paclitaxel has
not been administered orally to human patients. Similarly, docetaxel (N-
debenzoyl-N-tert-
butoxycarbonyl-10-deacetyl paclitaxel), sold under the trademark
TAXOTERE° (Rhone-
Poulenc-Rorer S.A.) and administered in parenteral form for the treatment of
breast cancer.
The poor bioavailability of paclitaxel after oral administration may be
ascribed to a
membrane-bound P-glycoprotein which functions as an energy-dependent
transport, or efflux
pump, to decrease intracellular accumulation of drug by extruding xenobiotics
from the cell (see
e.g., Taxol ~ Science and Applications, supra). It is hypothesized that, by
preventing movement
through mucosal cells of the small intestine, the P-glycoprotein prevents
systemic absorption. A
number of known agents have been shown to inhibit P-glycoprotein (e.g.,
cyclosporin A,
verapamil, tamoxifen, quinidine and phenothiazines). Logically, efforts,
including clinical trials,
have been directed to study the effects of cyclosporine on anti-cancer agents
known to be subject
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
4
to multidrug resistance (MDR), such as paclitaxel (Fisher, et al., Proc. Am.
Soc. Clin. Oncol.
13:143 1994); doxorubicin (Bartlett, et al., J. Clin. Onc. 12:835-842 (1994);
and etoposide (Lum,
et al., J. Clin. Onc. 10:1635-1642 (1992)). The intravenous administration of
cyclosporine in
conjunction with anti-cancer drugs has been shown to result in higher blood
levels (presumably
through reduced body clearance) and exhibited the expected toxicity at
substantially lower dosage
levels. For a general discussion of the pharmacologic implications for the
clinical use of P-
glycoprotein inhibitors, see Lum, et al., Drug Resist. Clin. Onc. Hema~ 9:319-
336 (1995);
Schinkel, et al., Eur. J. Cancer 31A:1295-1298 (1995).
PCT publication WO 95/20980 (published August 10, 1995) (hereinafter "Genet")
l0 purports to teach a method for increasing the bioavailability of orally
administered hydrophobic
pharmaceutical compounds. This method comprises the concurrent oral
administration of a
bioenhancer including an inhibitor of a cytochrome P450 3A enzyme or an
inhibitor of P
glycoprotein-mediated membrane transport. Genet does not identify which
bioavailability
enhancing agents) improve the availability of specific target pharmaceutical
compounds, nor
does it teach specific dosage amounts, schedules or regimens for
administration of the enhancing
or target agents. The only combination disclosed is ketoconazole as the
enhancer, and
cyclosporin A as the target drug.
Genet merely provides that bioenhancers are hydrophobic compounds generally
comprising two co-planar aromatic rings, a positively charged nitrogen group
or a carbonyl group
-- a class that includes an unascertainable number of compounds, including
several inoperable
embodiments. Moreover, the classes of active agents disclosed by Genet include
the great
majority of pharmaceutical agents listed in the Physicians' Desk Reference and
thus, are of no
value to medical practitioners seeking safe, practical and effective methods
of orally
administering specific agents. Finally, Genet provides no teaching that could
be followed by one
of skill to identify suitable bioenhancer/active drug combinations or to
design therapeutically
effective oral modalities.
PCT publication no. WO 98/30205 (published July 16, 1998) (hereinafter "Quay")
allegedly discloses a method for increasing the bioavailability of poorly
soluble drugs. The
application discloses an emulsion of alpha-tocopherol including a surfactant.
Also included is
PEGylated Vitamin E. PEGylated alpha-tocopherol includes polyethylene glycol
subunits
attached by a succinic acid diester at the ring hydroxyl of Vitamin E. Alpha-
tocopherol allegedly
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
serves as a surfactant, stabilizer and a secondary solvent in emulsions of
alpha-tocopherol.
Notably, this reference is expressly limited to formulations that are (a)
emulsions and (b)
essentially ethanol-free.
Commonly-owned PCT publication no. WO 97/15269 discloses novel methods and
5 compositions to make bioavailable target agents including taxanes otherwise
displaying poor oral
bioavailability by oral co-administration of a bioavailability-enhancing agent
such as cyclosporin.
There remains a need to develop additional compositions and effective methods
suitable
for the oral administration of taxanes. Such compositions should be capable of
achieving target
therapeutic blood levels of taxane. For obvious practical reasons, such
compositions should be (i)
bioavailable, (ii) suitable to maintain the taxane in solution, (iii)
chemically stable over extended
periods of time and (iv) possess overall palatability while demonstrating long
term stability.
SUMMARY OF THE INVENTION
The present inventors have devised taxane-based compositions and methods of
using the
same useful to achieve target blood levels of the taxane, in a mammal. The
compositions exhibit
long-term stability and overall palatability. As exemplified herein, such
approaches provide the
means to achieve taxane blood levels comparable to the levels achieved by less
convenient
methodologies currently available such as, for example, therapeutically
effective infusion
modalities. The invention thus provides compositions and methods useful to
improve the
absorption of a taxane from the gastrointestinal tract into the bloodstream
and to provide target
blood levels, including therapeutically effective blood levels, of such taxane
in a mammal. In
some embodiments, the taxane blood levels achieved exceed those achieved by
compositions
disclosed in W097/15269. Moreover, the methods and compositions according to
the invention
are useful as analytical tools for biochemical studies as well as therapeutic
tools.
In a first aspect, the invention provides pharmaceutical compositions
demonstrating long-
term stability and overall palatability. Such compositions comprise a poorly
soluble medicament,
a carrier, a co-solubilizer, and a stabilizer. In a more preferred embodiment
of the invention, the
medicament is a taxane. Preferred embodiments of the invention may provide
more than one type
of taxane, carrier, co-solubilizer, or stabilizer. Some compositions of the
invention further include
additional components, such as for example surfactants, pharmaceutical
excipients, diluents,
sweeteners, flavoring agents or coloring agents, as described in more detail
herein. In particularly
preferred embodiments of the invention, the taxane is paclitaxel or docetaxel.
Upon oral
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
6
administration in conjunction with an oral bioavailability-enhancing agent,
some of the preferred
compositions of the invention provide taxane blood levels comparable to blood
levels achieved by
intravenous injection.
In a second aspect, the invention provides methods suitable to achieve
therapeutically
effective taxane blood levels in a mammal by the oral administration of the
pharmaceutical
compositions described. In particularly preferred embodiments, the methods of
the invention,
including the administration of a bioavailability enhancing agent, result in
taxane blood levels
which are comparable to those achieved by long term infusion such as 96-hours
infusion shown to
be therapeutically effective (e.g., for the treatment of advanced metastatic
breast cancer as
1o described in Wilson, et al., J. Clin. Oncol. 12:1621-1629 (1994), and
Seidman, et al., J. Clin.
Oncol. 16:3353-3361 (1998). Pharmaceutical compositions and bioavailability
enhancing agents
useful according to this aspect are as described for the first aspect of the
invention.
In a third aspect, the invention provides a method to investigate the
properties of
diterpenoids. More specifically, the invention provides tools to investigate
biochemical properties
of taxane moieties in novel formulations capable of mediating large increases
in solubility. Such
studies will lead to a more comprehensive pharmacokinetic and pharmaceutical
description of
taxanes essential to identify novel applications and possibly to further
optimize already existing
therapeutic outcomes.
A further aspect of the invention pertains to methods of treatment of a mammal
suffering
2o from a taxane-responsive disease by the oral administration of
pharmaceutical compositions as
described herein. In some embodiments, the pharmaceutical compositions of the
invention are
orally administered in conjunction with an oral bioavailability-enhancing
agent to provide blood
levels of the taxane which are comparable to the levels achieved by
intravenous injection of the
taxane. Pharmaceutical compositions and bioavailability enhancing agents
useful according to
this aspect are as described for the first aspect according to the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graphic representation showing the ability of compositions of
the invention
(PG/TPGS/ETOH and ascorbyl palmitate (40:40:20) with (~) 12 mg/ml, (O)
l5mg/ml, (~) 20
mg/ml, (o) 25 mg/ml, and (~ 50 mg/ml paclitaxel), to remain in solution for a
period of time
2hours in a reciprocal water-shaking bath.
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
7
Figure 2 is a graphic representation showing the average plasma concentrations
of
paclitaxel from (~) 9 patients orally administered a Cremophor EL based
formulation, and from
(o) 2 orally administered a composition of the present invention (PG/TPGS/ETOH
and ascorbyl
palmitate (40:40:20).
BEST MODE OF CARRYING OUT INVENTION
The present inventors have devised novel compositions and methods of using the
same to
orally administer aqueous insoluble medicaments, including medicaments known
to be poorly
absorbed when administered orally. The invention further relates to
compositions and methods of
using the same useful to achieve target blood levels, including therapeutic
blood levels, of a
taxane in a mammal. Moreover, the invention relates to treatment regimens
employing such
compositions. The U.S. patents and other publications identified herein are
within the knowledge
of those skilled in this field and are hereby incorporated by reference in
their entirety.
Technical and scientific terms used herein have the meaning commonly
understood by one
of skill in the art to which the present invention pertains, unless otherwise
defined. To ensure a
clear and complete understanding of the specification and claims, including
the scope to be given
such terms, the following definitions are provided. It is understood that
terms as defined may
appear in the noun, verb, singular as well as the plural counterpart forms.
Reference is made herein to various methodologies and materials known to those
of skill
in the art. Standard reference works setting forth the general principles of
pharmacology include
Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9'h Ed.,
McGraw Hill
Companies Inc., New York (1996). Standard reference works setting forth,the
general principles
of modern pharmaceutics (Remington's Pharmaceutical Sciences, 18'h Ed.,
Gennaro, Mack
Publishing Co., Easton, PA (1990) and Remington: The Science and Practice of
Pharmacy,
Lippincott, Williams & Wilkins (1995)).
Any suitable materials and/or methods known to those of skill can be utilized
in carrying
out the present invention. However, preferred materials and methods are
described. Materials,
reagents and the like to which reference is made in the following description
and examples are
obtainable from commercial sources, unless otherwise noted.
The present invention is intended for use with any mammal that may experience
the
benefits of the methods of the invention. Foremost among such mammals are
humans, although
the invention is not intended to be so limited, and is applicable to
veterinary uses.
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
8
In a first aspect, the invention provides pharmaceutical compositions
demonstrating long-
term stability and overall palatability. Such compositions comprise a taxane,
a carrier, a co-
solubilizer, and a stabilizer. For purposes of the invention, the term
"carrier" is used to denote a
moiety that maintains (and in preferred embodiments improves) the aqueous
solubility of the
taxane in the pharmaceutical composition of the invention. Carriers according
to the instant
invention include without limitation moieties that may also function as co-
solubilizers. The
carriers of the invention are characterized by a core structure that may be
either a straight chain
polyether or a branched glycol (e.g., glycol) coupled with at least one fatty
acid ester. Preferred
carriers for use in the invention are non-ionic surfactants or emulsifiers
having HLB values of at
l0 least about 10. It has been found that such non-ionic surfactants or
emulsifiers are not only
compatible carriers for the lipophilic taxanes (which are poorly soluble in
water) but also promote
absorption of the active ingredient from the gastrointestinal tract into the
bloodstream. Only those
members of these surfactant families that have HLB values of about 10 or
greater may be used as
Garners in the subject compositions.
Representative non-limiting examples of carriers according to the invention
include
Vitamin E TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate,
available from Eastman
Chemical Co., Kingsport, TN); saturated polyglycolyzed glycerides such as the
GELUCIRE'~' and
LABRASOL'T' products (Gattefosse Corp., Westwood, NJ) which include glycerides
of C8 - C,8
fatty acids; CREMOPHOR~' EL or other modified castor oils including
polyoxyethylated or
hydrogenated castor oils such as EL-P or RH40 modified castor oils (available
from BASF, Mt.
Olive, NJ); MYRJ'~'' polyoxyethylated stearate esters (sold by ICI Americas,
Charlotte, NC);
TWEEN"'' (ICI Americas) and CRILLET ~'' (available from Croda Inc.,
Parsippany, NJ)
polyoxyethylated sorbitan esters; BRIJ~M polyoxyethylated fatty ethers (ICI
Americas);
CROVOL'~" modified (polyethylene glycol) almond and corn oil glycerides,
including
polyethylene glycol almond or corn oil glycerides (Croda Inc., Edison, NJ);
EMSORB'~ sorbitan
diisostearate esters (Henkel Corp., Ambler, PA); SOLUTOL"'' polyoxyethylated
hydroxystearates
(BASF); and cyclodextrin.
Preferred pharmaceutical compositions of the invention comprise at least 30%
by weight
of carrier. In particularly preferred embodiments, the carrier is present in
an amount of from
about 30 to about 90% of the composition by weight. In a particularly
preferred embodiment, the
pharmaceutical composition of the invention comprises about 40% by weight of
Vitamin E TPGS.
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
9
The term "co-solubilizer" is used to designate a viscosity-reducing moiety
which increases
the fluidity of the compositions of the invention at body temperature, as
generally required for
oral bioavailability, and/or reduce the melting point of the compositions
below body temperature.
Preferred co-solubilizers according to the invention decrease the viscosity
and increase the
fluidity of the vehicle at body temperature, and also may increase the amount
of the active agent
that can be dissolved or dispersed in the vehicle in comparison with the use
of a carrier alone.
Co-solubilizers according to the invention include moieties capable of
functioning as carriers as
well. Co-solubilizers according to the instant invention include without
limitation moieties that
may also provide increased taxane solubility.
l0 Representative non-limiting examples of viscosity-reducing co-solubilizers
include
PHARMASOLVE~' (N-methyl-2-pyrrolidone, International Specialty Products,
Wayne, NJ);
MIGLYOL'T' glycerol or propylene glycol esters of caprylic and capric acids
(Hiils AG, Marl,
Germany); polyoxyethylated hydroxystearates, including stearyl or oleyl ethers
(e.g.,
SOLUTOL'~ HS 15) (BASF, Mt. Olive, NJ); TWEEN'M polyoxyethylated sorbitan
esters (ICI
Wilmington, DE); SOFTIGEN'~' polyethylene glycol esters of caprylic and capric
acids (Hiils
AG); modified castor oils including polyoxyethylated or hydrogenated castor
oils (such as
CREMOPHOR"~' EL, EP-P or RH 40) (BASF, Mt. Olive, NJ); vegetable oils such as
olive oil,
polyoxyethylated fatty ethers or modified castor oils; certain saturated
polyglycolyzed glycerides,
including glycerides of C8 - C18 fatty acids (such as a LABRASOLTM); citrate
esters such as
tributyl citrate, triethyl citrate and acetyl triethyl citrate, propylene
glycol, alone or in combination
with PHARMASOLVE'T", ethanol (preferably dehydrated ethanol), water, and lower
molecular
weight polyethylene glycols such as PEG 200, 300 and 400. In a particularly
preferred
embodiment, the co-solubilizer is ethanol. In a more particularly preferred
embodiment, the co-
solubilizer comprises propylene glycol and ethanol. Up to 90% of the
composition by weight
may be co-solubilizer. In some embodiments of the invention, from about 10 to
about 70% by
weight is co-solubilizer. In preferred embodiments of the invention, the co-
solubilizer is present
in an amount of from about 20 to about 60% by weight. Accordingly, preferred
pharmaceutical
compositions may comprise from about 10% to about 70% by weight of propylene
glycol, more
preferably from about 20 to about 60% by weight of propylene glycol. In a
particularly preferred
embodiment the pharmaceutical composition of the invention comprises about 40%
by weight of
propylene glycol.
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
In a particularly preferred embodiment, the pharmaceutical composition of the
invention
comprises from about 5 to about 50% by weight of ethanol, more preferably from
about 10 to
about 30% weight of ethanol. In most preferred embodiments, the pharmaceutical
composition of
the invention comprises about 20% by weight of ethanol.
5 Several materials identified as Garners have also been found to be effective
co-solubilizers,
either alone or in combination with other viscosity-reducing agents, or
certain other Garners. In
general, any solvent in which paclitaxel or other taxanes are at least
moderately soluble at body
temperature or with gentle heating can be used as a co-solubilizer in the
vehicle of the novel
compositions. Preferred co-solubilizers are those in which at least 25 mg/ml
of paclitaxel or other
to taxane can be dissolved at about 20-25°C. Some embodiments of the
invention comprise more
than one co-solubilizer. In some preferred embodiments, the compositions of
the invention
include at least two solubilizers.
The term "stabilizer" as used herein denotes a moiety that increases the
stability of a
taxane. Stabilizers according to the invention may stabilize taxanes by
decreasing the rates of
solvolysis (e.g., loss of the ester side chain at C-13 or deacetylation at C-
10) and/or epimerizarion
of the taxane molecule (e.g., at C-7) as compared to taxane. The stabilization
of a taxane by a
stabilizer according to the invention is detectable by a reduction of one or
more known
degradation products (e.g., 7-epi-taxol C, 10-deacetyltaxol, 7-epi-taxol, 7-
epi-10-deacetyl-taxol,
baccatin III, 10-deacetylbaccatin III, cephalomannine, nitine, 7-epi-
cephalomannine (see, for
2o example, Miller et al., J. Org. Chem. 46:1469-1474 (1981) and Volk, et al.,
J. Chromatography B
696: 99-115 (1997). In a particularly preferred embodiment of the invention,
the stabilizer is
ascorbic acid 6-palmitate (i.e., ascorbyl palmitate). Other stabilizers useful
in the present
invention include metal salts of acids such as alpha-hydroxy or beta-hydroxy
acids, metal sulfates
(e.g., FeS04, metal alpha-hydroxymethylsulfinates and metal sulfonates. The
metal salts are the
subject of Applicants' commonly owned U.S. patent application no , entitled
"Uses of
Metal Salts to Stabilize Taxane-based Compositions," filed of even date
herewith, and
incorporated herein by reference.
Without wishing to be bound by any particular theory limiting the invention,
Applicants
believe that some stabilizers reduce taxane degradation by inhibiting the
formation of radicals
and/or by the formation of a complex between neighboring polar oxygen
containing substituents
in the taxane skeleton. This new configuration creates a "lock" which holds
these chemical
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
11
groups in place. Minimizing the interaction of these substituents with the
surrounding medium
therefore decreases the rates of solvolysis and/or deprotonation of those
sites and thus decreases
the rate of degradation of the parent compound. Hence, in some embodiments of
the invention,
preferred stabilizers are radical inhibitors. Radical inhibitors are well
known in the art (see e.g.,
Remington's Pharmaceutical Sciences, supra)). Non-limiting representative
radical inhibitors
according to the invention include Fe2+ gluconate, Cuz+ gluconate, Zn2+
gluconate, Ca2+ascorbate,
HOCHZS02Na, ascorbyl palmitate, beta-carotene, zinc methionine and zinc
citrate.
Yet other preferred stabilizers contemplated by the inventors may additionally
aid in
preserving the color of the pharmaceutical compositions. An example of this
type of stabilizer is
to dl-alpha-tocopherol, commercially available from BASF (Mt. Olive, NJ).
The preferred range of the amount of stabilizer present in the compositions of
the
invention is from about 0.2% to about 1.0% by total weight of the composition.
In general, the
amount ranges from about 0.05% to about 2.0% by weight. Determinations are to
whether a
given substance functions as a stabilizer for purposes of the present
invention, and if so, the
optimal amount to add to the compostion, are made by routine experimentation.
For example,
taxane formulations containing varying amounts of the compound are subjected
to stress
conditions (e.g., 80 °C for 24 hours) and then analyzed by HPLC. The
formulations are compared
to a control (not containing the compound) and the percentage of unchanged
taxane is calculated
from the HPLC profile. Compounds that achieve taxane ratios of 97% are
generally considered
2o acceptable; compounds achieving ratios greater than 98.5% are preferred.
See also the Miller and
Volk publications, above.
Pharmaceutical compositions according to the invention may include more than
one type
of carrier, co-solubilizer, or stabilizer. In some embodiments, the
compositions of the invention
may optionally be formulated with additional components, such as for example
surfactants,
pharmaceutical excipients, diluents, sweeteners, flavoring agents or coloring
agents, as described
in more details herein. Conventional pharmaceutical excipients, diluents,
sweeteners, flavoring
agents, coloring agents and any other inert ingredients regularly included in
dosage forms
intended for oral administration are well known in the art (see Remington's
Pharmaceutical
Sciences, supra).
A "surfactant" according to the invention is an amphiphilic moiety having a
surface-active
group capable of maintaining and/or promoting the dispersion of an hydrophobic
compound
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
12
within an aqueous media. One of skill in the art will appreciate that
surfactants suitable in the
compositions of the invention are well known in the art. Non-limiting
representative surfactants
include Vitamin E (e.g. alpha-tocopherol) and beta-carotene.
The term "taxane" is used to identify a diterpene moiety that is only slightly
soluble in
water. Taxanes according to the invention include without limitation moieties
isolated from the
Pacific yew tree (Taxus brevifolia) as well as derivatives, analogs,
metabolites and prodrugs, and
other taxanes. Preferably, the taxane is selected from the group consisting of
paclitaxel,
docetaxel, derivatives, analogs, metabolites and prodrugs of paclitaxel or
docetaxel, and salts,
polymorphs and hydrates thereof. More preferably, the taxane comprises
paclitaxel. In some
l0 embodiments of the invention more than one taxane is included as active
ingredient.
The taxane concentration in the compositions of the invention may vary based
on the
carriers) co-solubilizer(s) and/or stabilizers selected and on the desired
total dose of taxane to be
administered orally to the mammal. The concentration of taxane in the
pharmaceutical
compositions according to the invention may range from about 2 to about 100
mg/ml, preferably
from about 6 to about 60 mg/ml or more, preferably from about 10 to about 50
mg/ml.
Applicants have discovered that the administration of an effective oral amount
of a
bioavailability-enhancing agent in conjunction with the administration of the
compositions
according to the invention furthers the achievement of a blood level of the
taxane that is
comparable to the blood level achieved by intravenous injection of the taxane.
As discussed infra,
a bioavailability-enhancing agent may be administered before, at the same
time, or immediately
after the administration of the compositions of the invention. Accordingly, in
some preferred
embodiments of the invention, the pharmaceutical compositions include a
bioavailability-
enhancing agent.
The term "bioavailability enhancing agent" also referred to as "enhancing
agent" or
"enabling agent", is used to refer to an agent capable of promoting the
absorption or
bioavailability of another agent. Preferred bioavailability enhancing agents
include cyclosporins
and related oligopeptides produced by species in the genus Topycladium,
ketoconazole,
dexverapamil, amiodarone, nifedipine, reserpine, quinidine, nicardipine,
ethacrynic acid,
propafenone, reserpine, amiloride, ergot alkaloids, cefoperazone,
tetracycline, chloroquine,
fosfomycin, ivermectin, tamoxifen VX-710, VX-853, genistein and related
isoflavonoids,
calphostin, ceramides, morphine, morphine congeners, other opioids and opioid
antagonists.
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
13
Cyclosporins are a group of nonpolar cyclic oligopeptides (some of which have
immunosuppressant activity) produced by the genus Topycladium, including,
e.g., Topycladium
inflatum gams (formerly designated as Trichoderma polysporum), Topycladium
terricola and
other fungi imperfecti. The major component, cyclosporin A (cyclosporine or
CsA), has been
identified along with several other analogs, for example, cyclosporins B
through Z, some of which
exhibit substantially less immunosuppressive activity than cyclosporin A. A
number of synthetic
and semi-synthetic analogs have also been prepared. See generally Jegorov et
al.,
Phytochemistry, 38:403-407 (1995). The present invention comprehends natural,
semi-synthetic,
synthetic analogs, and derivatives of cyclosporins. Cyclosporins, particularly
cyclosporine
(cyclosporin A), are known inhibitors of the P-glycoprotein efflux pump and
other transporter
pumps as well as of certain P450 degradative enzymes, but to date no effective
regimens for
applying this property clinically have been developed to the point of clinical
and commercial
feasibility or regulatory approval.
Cyclosporins which may be used in preferred embodiments of the invention
include, but
are not limited to: cyclosporins A through Z but particularly cyclosporin A
(cyclosporine), ,
cyclosporin F, cyclosporin D, dihydro cyclosporin A, dihydro cyclosporin C,
acetyl cyclosporin
A, PSC-833, SDZ-NIM 811 which is (Me-Ile-4)-cyclosporin, an antiviral, non-
immunosuppressive cyclosporin. Characteristic amino acid variations defining
cyclosporins A-Z
are described in Table 1 below.
Table l: Cyclosporins A-Z
y Amino acids
y- 1
yA ebmt bu ar eLeu al eLeu la -AlaeLeu elxu eVal
yB ebmt a ar eLeu al eIxu la -AlaeLeu elxu eVal
yC ebmt hr ar eLeu al eLeu la -AlaeLeu eLeu eVal
yD ebmt al ar eLeu al eLeu la -AlaeL.eu elxu eVal
yE ebmt bu ar eLeu al eL.eu la -AlaeL,eu elxu al
yF esoxy-Mebmtbu ar eLeu al eLeu la -AlaeLeu eLeu eVal
yG ebmt va ar eLeu al eLeu la -AlaeLeu eLeu eVal
yH ebmt bu ar eLeu al eLeu la -AlaeLeu eLeu -Mev
yI ebmt al ar elxu al eLeu la -AlaeLeu a eVal
yK esoxy-Mebmtal ar eLeu al eLeu la -AlaeLeu elxu eVal
yL mt bu ar eLeu al eLeu la -AlaeLeu eLeu eVal
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
14
y ebmt va ar eLeu al MeLeu la -Ala eLeu MeL.eueVal
yNebmt va ar eLeu al eLeu la -Ala eLeu a eVal
y0eLeu va ar eLeu al eLeu la -Ala eLeu eLeu eVal
yPmt ar eLeu al eL.eu la -Ala eLeu elxu eVal
yQebmt bu ar al al eLeu la -Ala eLeu eLeu eVal
yRebmt bu ar eLeu al a la -Ala eLeu a eVal
ySebmt ar al al eL.eu la -Ala eLeu eL,eu eVal
yTebmt bu ar eLeu al eLeu la -Ala eLeu a eVal
yUebmt bu ar eLeu al a la -Ala eLeu eLeu eVal
yVebmt bu ar eLeu al eL.eu la -Ala eLeu eLeu eVal
y ebmt ar eLeu al eL.eu la -Ala eLeu eLeu al
yXebmt va ar eLeu al eLeu la -Ala a eL.eu eVal
yYebmt va ar eLeu al a la -Ala eLeu eLeu eVal
yZeAmino bu ar eLeu al el,eu la -Ala eLeu eLeu eVal
octyl
cid
Gy= cyclorporin
In a more preferred embodiment, the invention provides a long term-stable
pharmaceutical
composition for oral administration to a mammal including a taxane, Vitamin E
TPGS, propylene
glycol, ethanol and ascorbyl palmitate.
A particularly preferred embodiment of the invention comprises the following
ingredients:
Ingredients % w/v U/mL
Paclitaxel 1.20 12.0 mg
Vitamin E TPGS(*) 40.00 400.00 mg
Propylene glycol USP 40.00 400.00 mg
to Ascorbyl Palmitate NF 0.50 5.0 mg
dl-alpha-tocopherol USP 0.50 5.0 mg
Dehydrated Alcohol q.s. to 100 mL q.s. to 1.0 mL
(*) d-alpha-tocopheryl polyethylene glycol 1000 succinate
The compositions of the invention may be prepared by any conventional method
known to
individuals of skill in the pharmaceutical arts for preparing liquid or other
fluid oral formulations
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
containing surfactant carriers and lipophilic active ingredients. Suitable non-
limiting
representative methods of preparing the compositions of the invention include
for example the
protocols described in examples herein. Since the majority of the preferred
carriers are very
viscous at room temperature, and in some cases retain a relatively high
viscosity even upon the
5 addition of a minor proportion of co-solubilizer, it is generally preferred
in preparing the
compositions to mix the carriers and co-solubilizers to be used, add the
taxane active ingredient,
and heat the resulting mixture while stirring, for example to about 40°
C. This method enables the
preparation of clear solutions. Certain co-solubilizers, however, particularly
PHARMASOLVE'T',
lower the carrier viscosity and enhance taxane solubility to such a degree
that the composition can
l0 be prepared by stirring at room temperature with no heating. It is
desirable that the viscosity of
the finished composition not be higher than 40,000 cps at body temperature
(approximately 37°
C).
The oral compositions of the invention may be in the form of true solutions,
emulsions or
suspensions, but solutions of the active taxane ingredient in the carrier or
carrier/co-solubilizer
15 system are preferred.
The invention also sets for the methods of using the compositions for a
variety of purposes
including, but not limited to therapeutic applications. Thus, in a second
aspect, the invention
provides methods to achieve target blood level of taxane in a mammal by the
oral administration
of an effective amount of a pharmaceutical composition as described herein.
Such methods are
suitable to provide a target blood level of the taxane which is comparable to
that achieved by
intravenous administration of the taxane. Although some of the oral
pharmaceutical compositions
of the invention may provide target blood levels, including therapeutic blood
levels of paclitaxel,
when administered alone, a preferred method of the invention is to administer
the oral
pharmaceutical compositions concomitantly with the administration of at least
one dose of an oral
bioavailability enhancing agent because the levels of taxane that are
subsequently achieved are in
fact associated with pharmacological activity of the taxane.
Pharmaceutical compositions and bioavailability enhancing agents useful
according to this
aspect are as described for the first aspect of the invention.
"Target blood levels" according to the invention are blood concentrations of a
taxane at or
3o above the threshold concentrations necessary to observe the particular
activities associated with
taxanes that are sought. Non-limiting representative examples include the
inhibition of tubulin
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
16
disassembly, which occurs at blood levels of about 0.1 l.tM or about 85 ng/ml
and the inhibition of
protein isoprenylation (which occurs at blood levels of about 0.03 ltM or
about 25 ng/ml).
Additionally, taxanes such as paclitaxel have been shown to inhibit
angiogenesis and to inhibit the
phosphorlation of intracellular Bcl-2. Some of these activities (such as the
direct inhibition of
oncogene functions or the inhibition of a transducing element) are directly
related to taxane
antitumorigenic properties. Hence, in some particularly preferred embodiments
of the invention
target blood levels are therapeutic blood levels at which a particular
pharmacological activity is
observed. Target blood levels may vary considerably due to a number of
variables such as for
example, use of concomitant medications, hepatitic status, albumin levels in
the mammal being
l0 treated and variations between different pharmaceutical formulations.
Target blood levels may be
easily ascertained by routine methodologies such as the administration of the
compositions of the
invention in step-wise increments while monitoring paclitaxel concentration in
the mammal.
In preferred embodiments of the invention wherein the mammal is a human in
need of a
regimen to inhibit of tubulin disassembly, target blood levels are at least
about 0.1 ~M or about 85
ng/ml for a period of time (e.g., several hours). In some embodiments of the
invention wherein
the mammal is a human in need of a regimen to inhibit protein isoprenylation,
target blood levels
are at least about 0.03 1.~M or about 25 ng/ml. Such target blood levels
include without limitation,
blood levels from about 25ng/ml to about 85ng/ml.
In a third aspect, the invention provides a method to investigate the physical
properties of
diterpenoids. More specifically, the invention provides tools useful to
investigate the biochemical
properties of taxane moieties in novel formulations capable of mediating
larger increases in tissue
distribution in vivo, without an increase in toxicity. Such tools, capable of
expanding taxane
volume of distribution, will allow investigators to elucidate a variety of
biochemical properties in
vivo, such as for example the effects of paclitaxel on the level of tubulin
and/or microtubule
associated proteins (MAPs) overexpression, cell cycle progression, and
nucleation of microtubule
assembly in various tissues. Such studies promise to lead to a more
comprehensive
pharmacokinetic and pharmacological description of taxanes essential to
identify novel
applications and possibly to further optimize already existing therapeutic
outcomes.
Finally, the methods and compositions according to the invention are useful in
therapeutic
approaches to taxane-responsive diseases. A "taxane-responsive disease" is
used to refer to any
condition including a disease condition, which is ameliorated by the oral
administration of
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
17
effective amounts of the pharmaceutical compositions described herein.
Generally, a taxane
responsive disease is characterized by uncontrolled cellular proliferation
including, but not limited
to the heterogeneous diseases of cancer, tumors, angiogenesis, psoriasis and
polycystic kidney
disease. As discussed supra, non-limiting representative examples of taxane-
responsive diseases
include cancers, tumors, Kaposi's sarcoma, malignancies, uncontrolled tissue
and cellular
proliferation secondary to tissue injury. Among the types of carcinoma that
may be treated
particularly effectively according to the methods of the invention, are
hepatocellular carcinoma
and liver metastases, cancers of the gastrointestinal tract, pancreas,
prostate and lung, and
Kaposi's sarcoma. Non-cancerous diseases that may be effectively treated in
accordance with the
l0 present invention are uncontrolled tissue or cellular proliferation
secondary to tissue injury,
polycystic kidney disease, inflammatory diseases (e.g., arthritis) and
malaria, including
chloroquine- and pyrimethamine-resistant malaria parasites (Pouvelle, et al.,
supra).
The terms "treatment" or "treating" as used herein with reference to a taxane
responsive
disease refer to prophylaxis and to the amelioration of symptoms already
present in an individual
by altering the taxane blood levels. It will be appreciated by a person of
skill that a treatment
need not be completely effective in preventing the onset of a disease or
eliminating the symptoms
associated with a disease, nor does a treatment need to cure a disease in
order to be effective. Any
reduction in the severity of the symptoms, delay in the onset of symptoms, or
delay in the rate of
progression of severity of symptoms is contemplated. Persons at risk of
developing a taxane-
responsive disease may be treated prophylactically based on any variety of
factors suggesting the
possible onset of the disease, e.g., family history, environmental exposure,
genetic markers, early
symptoms, and the like.
As discussed for other aspects, although some of the oral pharmaceutical
compositions of
the invention may provide target blood levels, including therapeutic blood
levels, of the taxane
when administered alone, the preferred method of the invention for treating a
mammal suffering
from taxane-responsive disease is to administer the oral compositions
containing a taxane such as
paclitaxel concomitantly with the administration of an oral bioavailability
enhancing agent.
Hence, a preferred embodiment of the method of the invention comprises the
oral administration
an enhancing agent simultaneously with, or prior to, or both simultaneously
with and prior to the
oral administration to increase the quantity of absorption of the taxane into
the bloodstream.
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
18
Pharmaceutical compositions and bioavailability enhancing agents useful
according to this aspect
of the invention are as described for the first aspect of the invention.
In general, the dosage range of the bioavailability enhancing agent to be co-
administered
with the taxane in accordance with the invention is from about 0.1 to about 20
mg/kg of patient
body weight, preferably from about 3 to about l5mg/kg of patient body weight,
and more
preferably from 5-10 mg/kg. "Co-administration" of the enhancing agent
comprehends
administration substantially simultaneously with the taxane (either less than
0.5 hr. before, less
than 0.5 hr. after or together), from about 0.5 to about 72 hr. before the
administration of the
taxane, or both, i.e., with one or more doses of the same or different
enhancing agents given at
l0 least 0.5 hr. before and one dose given substantially simultaneously with
(either together with or
immediately before of after) the target agent. Additionally, "co-
administration" comprehends
administering more than one dose of taxane within 72 hr. after a dose of
enhancing agent, in other
words, the enhancing agents) need not be administered again before or with
every administration
of taxane, but may be administered intermittently during the course of
treatment.
"Effective amounts" is used to denote known amounts of the taxane in the
pharmaceutical
compositions of the invention sufficient to achieve a particular taxane blood
level. The dosage
range of the orally administered taxane in the compositions of the invention
will vary in
accordance with a number of factors, including the particular taxane, on its
therapeutic index, the
requirements of the disease being treated, the age and condition of the
mammal, the nature of the
diseases) being treated the stage of the disease, other medications and being
taken by the
mammal, and the like. The pharmacology and pharmacokinetics of taxanes,
especially paclitaxel
and docetaxel, are well known. This pharmacological information can be used in
conjunction
with the exigencies of the mammal being treated to optimize dosing and
scheduling regimens.
One of skill in the art will appreciate that specific dosing and scheduling of
this composition may
be tailored to meet the requirements of each patient by trial and error while
monitoring the
patient's response (see Rowinsky, Oncology 11(3):7-19 (1997) for dosing and
scheduling
considerations).
Precise amounts of each of the taxane included in the oral dosage forms will
vary
depending on the age, weight, disease and condition of the patient. For
example, paclitaxel or
other taxane dosage forms may contain sufficient quantities of the target
agent to provide a daily
dosage of about 20-200 mg/m2 (based on the mammal/patient body surface area)
or about 0.5-30
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
19
mg/kg (based on mammal/patient body weight) as single or divided (2-3) daily
doses. Preferred
dosage amounts are about 50-200 mg/m2 or about 2-6 mg/kg to maintain blood
levels of taxane in
the range of SO-S00 ng/ml for extended periods of time (e.g., 8-12 hours)
after each oral dose.
These levels are at least comparable to those achieved with 96-hour IV
infusion paclitaxel therapy
(which unlike oral administration causes the patient great inconvenience,
discomfort, loss of
quality time, infection potential, etc.) (Wilson et al., J. Clin. Oncol.
12:1621-1629 (1994)).
Moreover, such blood levels of paclitaxel are more than sufficient to provide
the desired
pharmacological activities of the target drug, e.g., inhibition of tubulin
disassembly and inhibition
of protein isoprenylation which are directly related to its antitumor effects
by inhibiting oncogene
l0 functions and inhibition of signal-transducing proteins postulated to play
a pivotal role in cell
growth regulation.
Preferred dosing schedules for administration of oral paclitaxel are (a) the
daily
administration to a patient in need thereof of 1-3 equally divided doses
providing about 20-1000
mg/m2 (based on body surface area), and preferably about 50-200 mg/m2, with
daily
administration being continued for 1-4 consecutive days each 2-3 weeks, (b)
administration for
about one day each week, and (c) daily administration for two or three weeks,
followed by a one
week rest period. The former schedule is comparable to use of a 96-hour
paclitaxel infusion every
2-3 weeks, which is considered by some a preferred IV treatment regimen.
In a particularly preferred embodiment of the invention, the pharmaceutical
composition
2o administered comprises about 60mg/m2 paclitaxel by weight. In another
particularly preferred
embodiment, the pharmaceutical composition comprises about 180 mg/m2 by
weight.
Two or more different enhancing agents and/or two or more different taxane
target agents
may be administered together, alternately or intermittently in all of the
various aspects of the
method of the invention.
As discussed infra, oral paclitaxel administered alone (e.g., in a solid
dosage form or even
in a liquid vehicle not containing an oral absorption promoting carrier)
exhibits near zero
bioavailability. Upon oral administration of the compositions of the
inventions one hour after
administration of an effective oral dose of an oral bioavailability enhancing
agent, the amount of
the taxane absorbed into the bloodstream is at least about 15% of the amount
absorbed when the
same dose of paclitaxel is administered to intravenously in a standard
intravenous vehicle e.g.,
example a CREMOPHORTT' EL/ethanol vehicle. The relative percentage of
absorption is
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
determined by standard methodologies in the field such as by comparing the
respective AUC (is
the area under the plasma concentration-time curve, commonly used in
pharmacokinetics to
quantify the percentage of drug absorption and elimination determined after
oral/intravenous
administration of the drug. A high AUC is an indication that the drug tested
is more likely to be
5 available to reach the target tissue or organ. The novel pharmaceutical
compositions may be
administered in any known pharmaceutical dosage form. For example, the
compositions may be
encapsulated in a soft or hard gelatin capsule or may be administered in the
form of a liquid
preparation.
Oral administration of taxanes in accordance with the invention may actually
decrease
10 toxic side effects in many cases as compared with currently utilized IV
therapy. Rather than
producing a sudden and rapid high concentration in blood level as is usually
the case with an IV
infusion, absorption of the active agent through the gut wall (promoted by the
enhancing agents),
provides a more gradual appearance in the blood levels. A stable, steady-state
maintenance of
those levels at or close to the ideal range for a long period of time can be
more easily achieved
15 with oral administration than with the inconvenience and risk of infection
in an already immuno-
compromised host.
In a further embodiment of the present invention, the oral compositions of the
invention
may be administered in a two-part medicament system (e.g., to accommodate the
use of carriers
which are chemically or physically incompatible with desired adjunctive
ingredients such as
2o flavoring or coloring agents). In such cases, the taxane may be
administered to the patient as the
first part of the medicament in a solubilizing vehicle, which may be
sweetened, flavored or
colored as desired. The administration of the taxane may be followed by
administration of a
larger volume of fluid, for example 1 to 8 fluid ounces (30 - 240 ml),
containing at least one
carrier or a carrier/co-solubilizer system in accordance with the invention.
It has been discovered
that administration of the second, "chaser" formulation a short time after the
taxane can retard
precipitation of the taxane which might otherwise occur upon entry into the
gastric fluid and
promote oral absorption to a degree comparable to that observed when the
taxane is intermixed
with the carrier and administered simultaneously.
Illustrative examples of "chaser" formulations that may be used in a two-part
oral taxane
3o medicament include:
a) 2 - 20°Io (by weight) Vitamin E TPGS + water q.s.;
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
21
b) 2 - 25% Vitamin E TPGS + 2 - 25% PHARMASOLVE'~' + water q.s.; and
c) 2 - 20% Vitamin E TPGS + 2 - 25% propylene glycol + water q.s.
Pursuant to yet another aspect of the invention, the oral compositions of the
invention
contain not only one or more taxane but also one or more bioavailability
enhancing agents in a
combination dosage form. For example, such combination dosage form may contain
from about
0.1 to about 20 mg/kg (based on average patient body weight) of one or more of
cyclosporins A,
D, C, F and G, dihydro CsA, dihydro CsC and acetyl CsA together with about 20
to about 1000
mg/mz (based on average patient body surface area), and preferably about 50-
200 mg/m2 of
paclitaxel, docetaxel, other taxanes or paclitaxel or docetaxel derivatives.
l0 The compositions and methods of the present invention provide many
advantages in
comparison with prior art and intravenous regimens (e.g., added stability,
overall palatability,
decreased toxicity due to lower peak levels, patient convenience and comfort,
ease of
administration and lowered expense). In addition, the compositions and methods
of the invention
greatly reduce the likelihood of allergic hypersensitivity reactions common
with IV
administration, thereby reducing or overcoming the need for pre-medication
regimens (such as H-
1 and H-2 blockers plus steroids). The latter is of particular relevance in
the treatment of diabetic
cancer patients since it is known that steroids may cause diabetes mellitus.
The present invention provides for the administration of taxanes, e.g.,
paclitaxel, in
comparatively infrequent daily doses (e.g., about twice/day) and/or according
to schedules that
would otherwise not be possible or practical with the intravenous route. The
once-a-day
administration of a bioavailability enhancer (e.g., cyclosporin A) may suffice
even if more than
one dose of taxane is administered during the day. Hence, for example,
paclitaxel could be given
intermittently as single dose on a fixed schedule (weekly, biweekly, etc.) or
chronically, over a
period of consecutive days (e.g., 4 days) every 2-4 weeks with the goal of
keeping the levels
within a safe and effective "window".
The following examples are intended to further illustrate certain preferred
embodiments of
the invention and are not limiting in nature. These examples are not intended,
however, to limit
the invention in any way or to set forth specific active ingredients,
carriers, co-solubilizers,
enhancer agents, dosage ranges, testing procedures or other parameters that
must be used
exclusively to practice the invention. Hence, the use of paclitaxel to
illustrate aspects of taxanes
as a whole is purely for illustrative purposes and should not be construed as
limiting the invention.
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
22
Those skilled in the art will recognize, or be able to ascertain, using no
more than routine
experimentation, numerous equivalents to the specific substances and
procedures described
herein. Such equivalents are considered to be within the scope of this
invention, and are covered
by the following claims.
Example 1
Preparation of Representative Pharmaceutical Compositions
One of skill in the field will readily appreciate that a variety of protocols
may be used to
prepare representative compositions according to the invention. The following
is included merely
to illustrate the ease with which representative compositions according to the
invention may be
l0 prepared. Representative formulations according to the invention having the
following
ingredients were prepared (hereinafter referred to by the designation "Formula
One"):
Ingredients lo w/v U/ml
Paclitaxel 1.20 12.0 mg
Vitamin E TPGS(*) 40.00 400.00
mg
Propylene glycol USP 40.00 400.00
mg
Ascorbyl Palmitate NF 0.50 5.0 mg
dl-alpha-tocopherol USP 0.50 5.0 mg
2o Dehydrated Alcohol q.s. to 100 q.s. to
ml 1.0 ml
(*) d-alpha-tocopheryl polyethylene glycol 1000 succinate
Paclitaxel (NaPro BioTherapeutics, Inc., Boulder, CO), Ascorbyl Palmitate NF
(Aldrich
Chemical Co., Milwaukee WI), and dl-alpha-tocopherol USP (Roche Vitamins,
Nutley, NJ) in the
amounts specified above were placed in a suitable volumetric container and
dispersed in at least
two-thirds of the total amount of dehydrated ethanol (Florida Distillers Co.,
Lake Alfred, FL) to
be included (either 1.0 or 100 ml). Upon complete dispersion, the appropriate
amount of
propylene glycol was added and mixed for at least 30 minutes. Liquefied
Vitamin E TPGS (d-
alpha-tocopheryl polyethylene glycol 1000 succinate (Eastman Chemical Co.,
Kingsport, TN) (by
heating it separately to approximately 50-60° C or until it liquefies)
was added. The remainder of
the dehydrated alcohol was then added and the final formulation was cooled
slowly to
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
23
approximately 25-30° C (room temperature). Once the solution reached
room temperature, the
solution was adjusted to the final volume with ethanol while stirring
constantly until a light
yellow transparent solution was formed.
Example 2
Stability Analysis
As discussed supra, one of the advantages of the compositions of the invention
is their
stability. The following experiment illustrates the stability of the
compositions according to the
invention. The representative compositions prepared as described in Example 1
were assayed in
compliance with ICH guidelines. Using a suitable size Eppendorf Pipette, 10.2 -
10.5 ml of
l0 solution was delivered into individual l5cc amber glass bottles using a
28/400 Black Phenolic
Cap with Poly Seal Liner. Gross, tare and net weight of each bottle were
recorded. The bottles
were then placed upright at 40° C and 75% humidity. Subsets of bottles
were removed and tested
according to methodology well known in the field (i.e., presence of known
degradation products
by HPLC after each time point as shown below (2 weeks, and 1-6 months). As
shown in Table 2
below, the compositions were found to be stable showing minimal levels
(expressed as a % of
total impurities) of compounds considered hallmarks of paclitaxel degradation
such as 7-epi-
Taxol C, 10-deacetyltaxol, or baccatin III as compared to negative control
formulations based on
CREMOPHORE ELTM (data not shown). In addition, impurities were less than 3.5%
after as long
as six months of incubation (data not shown).
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
24
Table 2: Stability Analysis
DEGRADATION INITIAL2 1 MONTH 2 3 6 MONTHS
PRODUCTS WEEKS MONTHS MONTHS
7-Epi-Taxol ND ND ND ND ND 0.11
C
10-DeacetyltaxolND 0.04 0.04 0.11 0.12 0.04
7-Epi-taxol 0.06 0.07 0.06 0.06 0.06 0.16
7-Epi-10-deacetyl-0.14 0.15 0.17 0.15 0.14 0.21
taxol
Baccatin III ND 0.07 0.09 0.13 0.14 0.18
10-deacetylbaccatinND 0.02 0.02 0.04 0.02 0.02
III
7-Epi- ND ND ND ND ND 0.05
Cephalomannine
Example 3
Solubility Analysis
To assess paclitaxel solubility in representative compositions of the
invention,
formulations prepared as in Example 1 and having final paclitaxel
concentrations of 12, 15, 25,
and 50 mg/ml were diluted with water to a 1 to 11 ratio (1 ml paclitaxel
formulation and 10 ml
water). The solutions were then assayed by HPLC analytical method. As shown in
Figure 1,
paclitaxel remained in solution for at least two hours (thus showing
solubility for an adequate
l0 period of time) in all preparations with the exception of the 50 mg/ml
preparation. Notably,
preparations containing between 12 to 20 mg/ml remained in solution for the
entire duration of the
study.
Example 4
Pharmacokinetic Analysis
I5 The compositions and methods of the invention are used to achieve target
blood levels,
including therapeutic blood levels, of taxane in a mammal. To exemplify this
aspect of the
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
invention, two groups of patients (total of five patients) were first
administered an enhancing
agent preparation such as Neoral~ 5 mg/kg (Cyclosporin A, Novartis
Pharmaceuticals, Inc.,
Summit, New Jersey) and 30 minutes later were administered compositions
prepared as described
in Example 1 at single doses of 60 mg/m2 (n=2) and 180 mg/m2 (n=3) of
paclitaxel. Serial blood
5 samples were taken frequently over 30-48 hours and assayed for paclitaxel.
Individual and mean
pharmacokinetic parameters of paclitaxel are shown in Table 3. These results
show slightly
higher values for C~ and AUC following formula one than for the CREMOPHOR ELTM
formulation. With both doses therapeutic blood levels were achieved and there
was an
approximate 2-fold increase in systemic exposure of paclitaxel when one
compares the area under
l0 the plasma concentration vs. time curve for the 2 doses. The latter
suggests that the compositions
of the invention may provide sufficient levels of paclitaxel in plasma with
ingestion of less
ethanol than the CREMOPHOR ELTM based formulations.
Table 3. Comparison of Pharmacokinetic Parameters
PATIENT C~ AUC last (ng~hr/ml)AUC ;~f
(ng/ml) (ng~hr/ml)
1 189.3 929 1025
2 226.6 1126 1208
Mean 207.9 1029 1159.5
SD 26.3 137.2 146.4
CV 19.6 22.3 21.2
15 Table 4 shows a comparison of the pharmacokinetic parameters for a
CREMOPHOR
ELTM (a polyethoxylated castor oil )BtOH based formulation (n=9) versus those
for Formula One
(n=4) according to the invention.
Table 4. Comparison of Pharmacokinetic Parameters (C/E vs. Formula One)
C/E FORMULA ONE (AUCIV=50%
of CE value)
APPARENT BIOAVAILABILITY @ 42% 69.1%
60MG/ m'
AUC~- 60mg/m' 1409 1159.5
(56)
AUC~- 180 mg /m2 2844(70)2474
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
26
AUC RATIO 2.0 2.1
Example 5
Palatability Test
Another property of the compositions of the invention is their palatability as
compared
with their counterpart CREMOPHORTM EL (a polyethoxylated castor oil)/EtOH
based
formulations. Formulations prepared with traditional stabilizers have an
unpleasant bitter taste
probably due to the castor oil. For this purpose 5 ml aliquots of Formula One
(40% Vitamin E.
TPGS + 40% propylene glycol + 20% ethanol, see Example 1) and 75% CREMOPHORTM
EL +
25% Ethanol were placed in 17 glass vials (an additional vial without
formulations was used as a
l0 negative control). Various flavors commercially available from
international flavor & Fragrances,
Inc., Dayton, NJ; Crompton & Knowles, Charlotte, N.C. and Virginia Dave,
Brooklyn, NY) as
shown in Table 5 were added to 16 of these vials as follows: banana (0.5%),
cherry (0.2 and
0.5%), grape (0.5%), grape maskant (0.5%), mint (0.2 and 0.5%), pepper mint
(0.2 and 0.5%),
herbal mint (0.2 and 0.5%), pharmasweet (0.1%), prosweet (1%), rainbow sorbet
(0.5%),
watermelon (0.5%), and wintergreen (0.5%). Preparations were administered
blindly to test
individuals to taste and score as either (-) no good; (+) acceptable/ok; (++)
good; or (+++)
excellent. The numbers were marked on the cap of two groups of sample vials
that contained
placebo (formula one or 75% Cremophor EL/25% Ethanol with different flavor).
Random
solutions were taken from these vials by dropper. They were tasted by two
chemists. The results
versus number were recorded.
As shown in Table 5, Formula One in various preparations was found to be more
palatable
than counterpart formulations. Moreover, the banana-flavored preparation was
found to be
excellent.
Table 5. Flavor Testing
FORMULA One (75% Cremophor EL +
25% Ethanol
Blank* +** -
Banana (0.5%) +++ +
Cherry (0.2%) ++ +
Cherry (.5%) ++ +
Grape (0.5%)
++ +
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
27
Grape Maskant ++ +
Flavor (0.5%)
Mint (0.2%) ++ +
Mint (0.5%) ++ +
Peppermint (0.2%)++ +
Peppermint (0.5%)++ +
Herbal Mint Flavor++ +
(0.2%)
Herbal Mint Flavor++ +
(0.5%)
Pharmasweet Flavor++ +
(0.1 %)
Prosweet (1%) ++ +
Rainbow Sherbet ++ +
(0.5%)
Watermelon (0.5%)++ +
Wintergreen Flavor++ +
(0.5%)
*No flavor was added; Next column: **,-, no good, +, acceptable%k, ++, good,
+++, excellent.
Example 6
Comparative Absorption Assays
The purpose of the following experiment was to illustrate the ability of
representative
compositions and methods of the invention to yield absorption values greater
than those observed
with prior art IV methodologies. For this purpose groups of three male rats
each were fasted for
16 - 18 hours prior to dosing with 3H-radiolabeled paclitaxel. Each group of
animals received one
oral dose of cyclosporin A (5 mg/kg) prior to dosing with a representative
pharmaceutical
composition according to the invention including paclitaxel. One hour
subsequent to cyclosporin
l0 dosing, each group received approximately 9 mg/kg of paclitaxel orally in a
composition
according to the invention. Each group received a different oral formulation.
Blood samples
were collected from each animal at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post-
dose of paclitaxel.
The blood samples were combusted and assayed for total radioactivity. The
total blood
radioactivity levels (corresponding to concentration in the blood of 3H-
paclitaxel) were plotted on
a graph vs. time post-dose. Data for each group of rats were compiled in the
form of mean AUC,
C~ and T,I,aX. The percentage of absorption of 3H-paclitaxel for each group of
animals was
calculated by comparing the mean AUC value for the group to the corresponding
mean AUC of a
reference group of rats administered 3H-paclitaxel (9 mg/kg) intravenously in
the form of
PAXENE'~' (Baker Norton Pharmaceuticals, Miami FL) which includes CREMOPHOR~'
EL,
ethanol and citric acid. As shown in Table 6 several Garners and carrier/co-
solubilizer
combinations formulated into oral compositions containing paclitaxel in
accordance with the
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
28
invention were found to yield percentage absorption values in the experimental
animals of 15% or
greater in comparison with IV paclitaxel (data not shown).
Table 6. Garners and carner/co-solubilizer combinations which achieved greater
than 15 %
paclitaxel absorption
CARRIERSCO-SOLUBILIZERS
TPGS Pharma-PropyleneMygliols SoftigenPEG PropylenePEG 200
200 &
solve glycol & 400 glycol 400/
/Pharma-Pharmasolve
solve
GelucirePharma-Mygliols Olive Olive Olive CremophorCremophor
oil/ oil/ oil
44/14 solve Brij 97 Cremophor/'TPGSEL RH 40
RH 40
GelucireLabrasolTPGS/ Tween PEG 400
80
44/14 Solutol
HS 15
GelucireTween PEG 400 Cremophor
80
50/13 EL
CremophorPharma-Citrate EtOH / EtOH
esters H20
EL solve
CremophorEtOH
RH 40 /H20
Myrj Pharma-
49
solve
Myrj Pharma-Propylene
52
solve glycol
Myrj Pharma-
53
solve
Tween
40*
Tween
60*
Tween EtOH Citrate Olive PEG 400 H20
80* esters oil
Crillet
6*
Emsorb Pharma-
2726 solve
Solutol
HS
15*
Brij Pharma-
76
solve
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
29
Brij Pharma-
78
solve
Brij Pharma-
98
solve
Crovol
A-
40
Crovol
M-
40
-Cyclo-H20
dextrin
* Have been demonstrated to work as both solubilizer and carrier
Note : All carriers listed above can solubilize paclitaxel greater than 25
mg/ml at 37° C.
Example 7
Evaluation of Carriers
The experiments described hereinafter illustrate the ability of representative
oral
compositions formulated with different moieties as carriers to yield higher
absorption rates than
their respective IV counterparts when administered orally.
Polyoxyethylated (POE) Sorbitan Fatty Acid Esters as Carriers
l0 Table 7 lists formulations including certain POE sorbitan fatty acid esters
as carriers for
oral paclitaxel, alone or in combination with a co-solubilizer. In
formulations where more than
one component is present, the respective weight ratios of the components are
given. Each of
these formulations was tested in the animal model described supra and found to
yield a
percentage absorption of paclitaxel upon oral administration greater than 15%
paclitaxel
absorption. The table sets forth the total dose of paclitaxel incorporated
into each vehicle as
actually administered to the experimental animals, the concentration of
paclitaxel in the
composition, the HLB value of the carrier, the mean AUC value for the group of
rats receiving the
formulation and the percentage of paclitaxel absorption in comparison with
rats receiving IV
administration.
Table 7. Absorption Results of Polyoxyethylated (POE) Sorbitan
Fatty Acid Esters Surfactants as Carriers
Dose Conc. AUC %
FORMULATIONS [mg/kg] [ mg/ml] HLB pg.eqxh ABS*
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
r/ml
POE 20 sorbitan monolaurate 10.2 18 16.7 17.2 54.6
(Tween 20)
POE 20 sorbitan monopalmitate10.2 18 15.6 17.6 55.9
(Tween 40)
POE 20 sorbitan monostearate 8.9 25 14.9 17.1 62.3
(Tween 60)
POE 20 sorbitan tristearate 9.4 25 10.5 6.15 21.1
(Tween 65)
POE 20 sorbitan monooleate 9.0 18 15.0 11.4 40.9
(Tween 80)
POE 20 sorbitan monoisostearate9.3 20 14.9 13.6 47.5
(Crillet 6)
POE 40 sorbitan diisostearate/Pharmasolve10.2 25 15.0*7.76 24.6
(3:1)
(Em.rorb 2726)
* Percent absorption versus paclitaxel N AUC (same for Tables 4-11)
POE Alkyl Ethers as Carriers
Table 8 summarizes data for formulations containing POE alkyl ethers as
Garners. The
5 data correspond to the data described in the preceding table.
Table 8. Absorption Results of Polyoxyethylated (POE)
Alkyl Ethers Surfactants as Carriers
FORMULATIONS Dose Conc. AUC
[mg/kg][ mg/ml]HL.B pg.eqxhr/ml% ABS
POE 20 stearate ester/ Pharmasolve9.2 25 15.0* 10.3 36.4
(3:1) (Myrj
49J
POE 40 stearate ester/ Pharmasolve9.4 18 16.9* 16.2 57.3
(3:1) (Myrj
52J
POE 50 stearate ester/ Pharmasolve10.0 25 17.9* 7.01 22.3
(3:1) (Myrj
53J
* Not an actual HI.,B value of mixture. Numbers represent HL,B values of pure
surfactants
POE Stearates as Garners
l0 Table 9 summarizes data for formulations containing POE stearates as
Garners. The data
set forth correspond to the data described in Example 7.
Table 9. Absorption Results of Polyoxyethylated (POE)
Stearates as Carriers
FORMULATIONS Dose Conc. AUC
(mg/kg][ mg/ml]HLB pg.eqxhr/ml% ABS
POE 20 stearate ester/ Pharmasolve9.2 25 15.0* 10.3 36.4
(3:1) (Myrj
49J
POE 40 stearate ester/ Pharmasolve9.4 18 ~ 16.9* 16.2 57.3
(3:1) (Myrj ~ ~ ~ ~
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
31
52J
POE 50 stearate ester/ Pharmasolve10.0 25 17.9* 7.01 22.3
(3:1) (Myrj
53J
* Not an actual t11,13 value of mixture. lVUmbers represent tiLri values of
pure sttrtactants
Ethoxylated Modified Triglycerides as Carriers
Table 10 summarizes data for formulations containing ethoxylated-modified
triglycerides
as carriers. The data set forth correspond to the data described in Example 7.
Table 10. Absorption Results of Ethoxylated Modified Triglycerides as Carriers
FORMULATIONS Dose Conc. AUC % ABS
[mg/kg] [ mg/ml] HLB pg.eqxhr/ml
PEG-20 Almond Glycerides 9.5 20 10 8.06 27.6
(Crovol A-40)
PEG-20 Corn Glycerides 9.6 20 10 7.46 25.3
(Crovol M-40)
POE 660 Hydroxystearates as Carriers
Table 11 summarizes data for formulations containing POE 660 hydroxystearates
as
carriers. The data set forth correspond to the data described in Example 7.
Table 11. Absorption Results of Polyoxyethylated (POE) 660
Hydroxystearate as Garners
FORMULATIONS Dose Conc. AUC
[mg/kg] [ mg/ml]HLB ltg.eqxhr/ml% ABS
POE 660 hydroxystearate9.1 25 - 14 10.8 38.4
(Solutol NS IS)
Gelucire 44/14 + Solutol9.3 25 -- 14 6.54 22.8
HS + TPGS
(2:1:1)
Saturated Polyglycolized Glycerides as Carriers
Table 12 summarizes data for formulations containing saturated polyglycolized
glycerides
as carriers. The data set forth correspond to the data described in Example 7.
Table 12
Absorption Results of Saturated Polyglycolized Glycerides as Garners
FORMULATIONS Dose Conc. AUC % ABS
[mg/kg] [mg/ml] pg.eqxhr/ml
Gelucire 44/14 + PEG 10.3 25 11.9 37.4
400 (6 : 1)
Gelucire 44/14 + Labrasol9.3 ~ 25 ~ 12.1 ~ 42.1
(6 : 1) ~
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
32
Gelucire 44/14 + Mygliol8.7 25 4.75 17.6
810 (6 : 1)
Gelucire 44/14 + Mygliol10.3 25 8.45 26.6
818 (6 : 1)
Gelucire 44/14 + Mygliol9.5 25 6.48 22.0
840 (6 : 1)
Gelucire 44/14 + Cremophore9.5 25 10.7 36.6
RH 40 (6 :
1)
Gelucire 44/14 + Cremophor9.8 25 11.5 38.1
EL (6 : 1)
Gelucire 44/14 + Solutol9.3 25 6.54 22.8
HS + TPGS (2 : 1
1)
Gelucire 44/14 + Olive 9.6 20 11.9 39.9
Oil + Tween 80 (2
:1:1)
Gelucire 44/14 + Olive 9.6 20 9.83 33.2
Oil + TPGS (2 : 1
1)
Gelucire 44/14 + Olive 9.6 20 9.07 30.6
Oil + POE 10
Oleyl (2 : 1: 1)
Gelucire 44/14 + Olive 9.1 20 7.73 27.5
Oil + Cremophor
RH 40 (2 : 1 : 1)
Gelucire 44/14 + Tween 9.7 25 10.05 33.5
80 (6 : 1)
Gelucire 50/13 + Tween 9.4 25 8.21 28.4
80 (5 : 2)
Gelucire 50/13 + PEG 9.3 25 6.46 22.5
400 (6 : 1)
Gelucire 50/13 + Cremophor9.1 25 8.11 28.9
EL (6 : 1)
Labrasol : Saturated polyglycolyzed C8 -C10 glycerides (HLB=14)
Mygliols : Neutral oils (saturated coconut and palm kernel fatty acids) mainly
C8 - n
C10 fatty acids
Cremophor EL : Polyoxyl 35 castor oil (HI_B 12 - 14)
Cremophor RH 40 : Polyoxyl 40 Hydrogenated castor oil (HLB 14 - 16)
Vitamin E TPGS Systems as Carriers
Table 13 summarizes data for formulations containing Vitamin E TPGS systems as
Garners. The data set forth correspond to the data described in Example 7.
Table 13.
l0 Absorption Results of TPGS Systems as Carriers
FORMULATIONS Dose Conc. AUC % ABS*
[mg/kg] [mg/ml] ltg.eqxhr/ml
TPGS + Pharmasolve 8.2 25 8.93 35.2
( 1.5 : 1 )
TPGS +Pharmasolve 9.5 25 8.72 . 29.8
(1 : 1)
TPGS + Pharmasolve 9.1 ~ 25 ~ 8.83 ~ 31.4
(2 : 1) ~
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
33
TPGS + Propylene glycol8.5 20 9.65 36.9
(1 : 1)
TPGS + Pharmasolve 9.0 25 8.31 29.8
+ PEG
200 (2:1:1)
TPGS + Pharmasolve 8.2 25 6.62 26.3
+ PEG
400 (2:1:1)
TPGS + Pharmasolve 8.9 25 8.07 29.3
+ PG (2 :
1:1)
TPGS + Mygliol 810 9.1 25 5.65 20.0
(1 : 1)
TPGS + Softigen 767 10.2 25 8.66 27.5
(1 : 1)
TPGS + PEG 200 ( 1 8.3 25 7.75 30.4
: 1 )
TPGS + PEG 400 ( 1 9.6 25 7.32 24.6
: 1 )
Softigen 767 : PEG-6-Caprylic/Capric Glycerides
POE and Hydrogenated Castor Oil Derivatives as Carriers
Table 14 summarizes data for formulations containing POE and hydrogenated
castor oil
derivatives as carriers. The data set forth correspond to the data described
in Example 7.
Table 14.
Absorption Results of Polyoxyethylated Castor Oil (Cremophor) Derivative
Systems as Carriers
FORMULATIONS Dose Conc. AUC % ABS
[mg/kg] (mg/ml]pg.eqxhr/ml
N Paxene 10.0 6 11.15 37.2
Cremophor EL + Ethanol + Water 9.2 1.3 6.07 21.5
(1 : 1 : 8)
Iv Paxene + Water (1 : 1) 8.9 3 8.70 31.8
N Paxene + Water (1 : S) 9.1 1 10.76 38.5
Cremophor EL + Pharmasolve (1 : 8.6 20 6.74 25.3
1)
Cremophor EL + TBC (1 : 1) 9.0 20 9.35 31.9
Cremophor EL + Gelucire 44/14 (1 9.8 25 11.5 38.1
: 6)
Cremophor EL + Gelucire 50/13 (1 9.1 25 8.11 28.9
: 6)
Cremophor RH 40 + Ethanol + Water 9.0 3 7.14 25.7
(1 : 1 : 2)
Cremophor RH 40 + Gelucire 44/14 9.5 25 10.7 36.6
(1 : 6)
Cremophor RH 40 + Gelucire 44/14 9.1 20 7.73 27.5
+ Olive Oil (1 : 2 : 1)
Polysorbate 80 Carriers
CA 02404370 2002-09-24
WO 01/72299 PCT/USO1/09382
34
Table 15 summarizes data for formulations containing polysorbate 80 as at
least
one of the carriers. The data set forth correspond to the data described in
Example 7.
Table 15.
Absorption Results of Polysorbate 80 (Tween 80) Systems as Carriers
FORMULATIONS Dose Conc. AUC % ABS
[mg/kg][mg/ml]~g.eqxhr/ml
Polysorbate 80 9.0 18 11.4 40.9
Polysorbate 80 + Ethanol + Water8.0 1.2 7.92 31.2
(1 : 1 : 8)
Polysorbate 80 + Ethanol (3 : 8.9 18 9.97 36.3
1)
Polysorbate 80+ Water (3 : 1) 8.2 18 7.15 28.3
Polysorbate 80 + TBC (1 : 1) 9.5 20 9.12 31.2
Polysorbate 80 + ATEC ( 1 : 1 9.1 20 8.50 30.3
)
Polysorbate 80 + Olive oil (3 9.0 20 13.3 43.7
: 1)
Polysorbate 80 + PEG 400 (1 : 9.7 20 9.41 31.5
1)
Polysorbate 80 + Gelucire 44/14 9.6 20 11.9 39.9
+ Olive Oil (1 : 2 :1)
Polysorbate 80 + Gelucire 44/14 9.7 25 10.05 33.5
(1 : 6)
TBC = Tributyl citrate (citrate ester)
ATEC = Acetyl triethyl citrate (citrate ester)
It has thus been shown that there are provided compositions and methods which
achieve
the various objects of the invention and which are well adapted to meet the
conditions of practical
use. As various possible embodiments might be made of the above invention, and
as various
l0 changes might be made in the embodiments set forth above, it is to be
understood that all matters
herein described are to be interpreted as illustrative and not in a limiting
sense.
As used herein, the term "about" is intended to convey that the numbers and
ranges
disclosed herein are flexible and that practice of the present invention using
temperatures,
concentrations, amounts, etc. outside of the range or different from a single
value will achieve the
desired result. The term typically includes a deviation of ~ 10% of any value
it modifies.
Industrial Applicability
The present invention is useful in clinical medicine, and particularly in the
treatment of
malignant and non-malignant diseases.
