U.S. patent application number 12/895327 was filed with the patent office on 2011-03-31 for methods, compositions, and kits for organ protection during systemic anticancer therapy.
Invention is credited to John P. FORD.
Application Number | 20110077260 12/895327 |
Document ID | / |
Family ID | 35449787 |
Filed Date | 2011-03-31 |
United States Patent
Application |
20110077260 |
Kind Code |
A1 |
FORD; John P. |
March 31, 2011 |
METHODS, COMPOSITIONS, AND KITS FOR ORGAN PROTECTION DURING
SYSTEMIC ANTICANCER THERAPY
Abstract
Methods, compositions, and kits are presented for local tissue
protection during systemic administration of anticancer therapeutic
agents.
Inventors: |
FORD; John P.; (Unadilla,
NY) |
Family ID: |
35449787 |
Appl. No.: |
12/895327 |
Filed: |
September 30, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12071648 |
Feb 25, 2008 |
7812030 |
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12895327 |
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11196921 |
Aug 3, 2005 |
7368456 |
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12071648 |
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10918199 |
Aug 13, 2004 |
6995165 |
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11196921 |
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10684203 |
Oct 10, 2003 |
6979688 |
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10918199 |
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10364383 |
Feb 12, 2003 |
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10684203 |
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60355764 |
Feb 12, 2002 |
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Current U.S.
Class: |
514/274 |
Current CPC
Class: |
A61K 31/337 20130101;
A61K 31/513 20130101; A61K 31/337 20130101; A61P 17/00 20180101;
A61K 31/704 20130101; A61K 31/7072 20130101; A61K 31/00 20130101;
A61K 31/555 20130101; A61K 31/513 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 31/555 20130101; A61P 43/00 20180101; A61K 31/7072
20130101; A61K 31/704 20130101; A61P 39/00 20180101; A61K 31/505
20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/274 |
International
Class: |
A61K 31/513 20060101
A61K031/513; A61P 39/00 20060101 A61P039/00 |
Claims
1-71. (canceled)
72. A formulation for topical administration to a body tissue
capable of establishing a local concentration of uracil in an
amount sufficient to protect the tissue from toxic effects of one
or more systemically distributed anticancer therapeutic agents or
metabolites thereof without abrogating the clinically efficacy of
said systemically distributed anticancer therapeutic agent or
metabolite, the composition comprising: uracil and a
pharmaceutically acceptable carrier suitable for local
application.
73. The formulation of claim 72, wherein uracil is present within
said formulation at a amount by weight of least about 0.01% and
less than about 60%.
74. The formulation of claim 72, wherein uracil is present within
said formulation at a amount by weight of least about 0.01% and
less than about 20%.
75. The formulation of claim 72, wherein uracil is present within
said formulation at a amount by weight of least about 0.01% and
less than about 10%.
76. The formulation of claim 72, wherein uracil is present within
said formulation at a amount by weight of least about 0.01% and
less than about 5%.
77. The formulation of claim 72, wherein uracil is present within
said composition at a amount by weight of least about 0.01%.
78. The formulation of claim 72, wherein uracil is present within
said composition at a amount by weight of at least about 0.1%.
79. The formulation of claim 72, wherein uracil is present within
said composition at a amount by weight of at least about 1.0%
80. The formulation of claim 72, wherein said formulation is an
ointment.
81. The formulation of claim 72, wherein said formulation is an
cream.
82. The formulation of claim 72, wherein said formulation is an
spray.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 10/684,203, filed Oct. 10, 2003, which is a
continuation-in-part of U.S. application Ser. No. 10/364,383, filed
Feb. 12, 2003, now abandoned, which claims the benefit of U.S.
provisional application No. 60/355,764, filed Feb. 12, 2002, now
expired, the disclosures of which are incorporated herein by
reference in their entireties.
BACKGROUND OF THE INVENTION
[0002] Systemic administration of antineoplastic chemical agents
has been a mainstay of cancer treatment for the past 50 years. But
despite success against an ever greater number of cancers, systemic
administration of these toxic agents is often attended by
deleterious side effects that limit their clinical usefulness.
[0003] For example, the antimetabolite fluorinated pyrimidines,
among the earliest-introduced of the chemotherapeutic agents,
remain front-line treatment for a variety of cancers 40 years after
their clinical introduction.
[0004] The prototype is 5-fluorouracil (5-FU), which is typically
administered parenterally, either by bolus or continuous
infusion.
[0005] Oral administration of 5-FU is disfavored due to the high
activity in the gut wall of dihydropyrimidine dehydrogenase (DPD),
the rate-limiting enzyme in 5-FU catabolism. To bypass this
problem, orally administrable fluoropyrimidine derivatives have
been developed, either in the form of 5-FU precursors, or
"prodrugs" (e.g., tegafur, Carmofur, capecitabine, and
doxifluridine), or as coadministered combinations of prodrugs with
DPD competitors or inhibitors (e.g. UFT, S-1, or Emitefur). Tegafur
(FTORAFUR.RTM.) (1-(2-tetrahydrofuryl)-5-fluorouracil), is a
congener of fluorouracil that introduces a tetrahydrofuran residue
in place of the deoxyribose residue in the 5'-deoxy-5-fluorouridine
(5'-FUDR) molecule. Carmofur, another orally administrable
fluoropyrimidine prodrug, is 1-hexylcarbamoyl-5-fluorouracil (also
known as HCFU). Capecitabine (XELODA.RTM., Roche Pharmaceuticals)
is a rationally designed fluoropyrimidine carbamate prodrug of
5'-FUDR that can be given orally.
[0006] Metabolism of 5-FU and of its prodrugs is complex.
[0007] With reference to FIG. 1, tegafur, administered orally, is
converted in the liver to 5-fluorouracil ("FU") by action of
cytochrome P450.
[0008] Capecitabine is converted to 5-FU in a multistep process. In
the liver, a 60 kDa carboxyesterase hydrolyzes much of the compound
to 5'-deoxy-5-fluorocytidine (5'-DFCR). Cytidine deaminase, an
enzyme found in most tissues, including tumors, subsequently
converts 5'-DFCR to 5'-deoxy-5-fluorouridine (5'-DFUR). The enzyme
thymidine phosphorylase (TP) then hydrolyzes 5'-DFUR to the active
drug 5-FU.
[0009] Within the cell, 5-FU can be converted to cytostatic (and/or
cytotoxic) metabolites by any one or more of three main "anabolic"
pathways, each catalyzed by a different enzyme. As labeled in FIG.
1, pathway 1 involves the action of orotate phosphoribosyl
transferase (OPRT), pathway 2 activates 5-FU via uridine
phosphorylase (UP), and pathway 3 requires the enzyme thymidine
phosphorylase (TP). These three pathways interconnect, converging
on two principal mechanisms of cell toxicity.
[0010] In the first, circled and labeled "a" at the right of FIG.
1, 5-FU is ultimately metabolized to 5-FUTP, which is incorporated
during transcription into RNA. Currently, it is thought that the
toxicity results from the accumulation of fluorouracil residues in
a wide variety of mRNAs coding for many different proteins, rather
than from alteration of any single cellular function.
[0011] The second principal mechanism of cell toxicity results from
anabolic activation of 5-FU to 5-FdUMP. As circled and labeled "b"
in FIG. 1, 5-FdUMP forms a ternary complex with thymidine synthase
(TS) and the cofactor 5,10-methylene tetrahydrofolate
(CH.sub.2THF). Tight complexation sequesters TS, preventing the
TS-mediated enzymatic formation of dTMP; this, in turn, decreases
the synthesis, and thus availability, of thymidine triphosphate
(dTTP), which is required for DNA replication and repair. Depletion
of dTTP acts as a cytostatic brake on cell growth and division;
more recently, it has been suggested that depletion of dTTP may
directly trigger programmed cell death (apoptotic) pathways.
[0012] Catabolic inactivation of 5-FU is conceptually simpler than
anabolic activation, with greater than 80% of an injected dose of
5-FU rapidly degraded by a single pathway, the first and
rate-limiting step of which is catalyzed by dihydropyrimidine
dehydrogenase (DPD) (also known, synonymously, as uracil reductase,
dihydrouracil dehydrogenase, and as dihydrothymine dehydrogenase).
The principal byproduct of catabolism, F-.beta.-alanine, is circled
and labeled "c" in FIG. 1.
[0013] Given the complex interrelatedness of the metabolic
pathways, the clinical efficacy of 5-FU and its
orally-administrable prodrugs depends, to a first, crude,
approximation on the relative activities of the DPD-mediated
catabolic pathway and each of the three principal anabolic
pathways. But despite intensive study, the extent to which any of
these pathways predominates in human tumors is unknown and is
likely to vary across tumor types and with different modes and
doses of drug administration. Malet-Martino et al., The Oncologist
7:288-323 (2002); Ichikawa et al., Brit. J. Cancer 89:1486-1492
(2003)
[0014] The situation becomes more complex when considering the
concurrent and interacting effects of multiple, competing,
substrates on the multiple and competing catabolic and anabolic
enzymes in the fluoropyrimidine pathway. Further complexity is
added by variation in the activity of these enzymes among a
genetically diverse human population, with plasma levels of 5-FU
varying by about three orders of magnitude among humans exposed to
the same dose of 5-FU.
[0015] UFT is a combination of uracil and ftorafur in a 4:1 molar
ratio. OFT is approved for clinical use in Europe and Japan; it has
been denied FDA approval for clinical marketing in the U.S.
[0016] After oral ingestion, the ftorafur component of UFT is
metabolized by P450 to 5-FU. The uracil component is intended to
compete with 5-FU for degradation by DPD; present at a several-fold
molar excess over ftorafur in the administered composition, and
thus intended to be present at a several-fold molar excess over
ftorafur (and thus 5-FU in tissues, uracil is intended to
outcompete 5-FU for reaction with DPD, inhibiting DPD catabolic
inactivation of 5-FU. The intended result is a higher circulating
level of 5-FU, leading to greater 5-FU-mediated cytotoxicity. Cao
et al., Clinical Cancer Res. 1:839-845 (1995).
[0017] But the actual in vivo concentrations of uracil and 5-FU
after UFT administration do not invariably follow the intended
ratio. Administration of UFT to rats results in a greater than
1000-fold variation in uracil level within various organs, and can
lead to up to a 100-fold excess of uracil over 5-FU in some
tissues. (Kawaguchi et al., Gann. 71(6):889-99. (1980)).
[0018] Furthermore, uracil can also compete with 5-FU for reaction
with the three principal anabolic activating enzymes. In order for
the UFT combination to show greater clinical efficacy than ftorafur
alone, uracil must not outcompete 5-FU for activation by at least
one of OPRT, TP, and UP in the tumor. The outcome thus depends upon
the relative amount of each of the four principal rate-limiting
enzymes in each of the cells and tissues taking up 5-FU, and on the
relative affinity of each of the enzymes for uracil and 5-FU. The
latter depends, in turn, at least in part on cellular pH: OPRT, for
example, favors 5-FU over uracil by about 50 times at neutral
pH.
[0019] Variation in the relative amounts of each of the four
principal rate-limiting enzymes among tissues and tumors makes a
priori prediction of UFT efficacy in any particular tumor
unreliable. And experiments in laboratory animals provide little
help: the relative affinities of these enzymes for 5-FU and for
uracil differ substantially among different animal species, and
particularly among different animal tumors.
[0020] Sludden et al. report, for example, that liver DPD activity
is highly variable within and among tested species. Sludden et al.,
Pharmacology 56:276-280 (1998). At least one study reports that
5-fluorouracil is a better substrate for human dihydrouracil
dehydrogenase (DPD) than is uracil, Naguib et al., Cancer Research
45:5405-5412 (1985).
[0021] And as complex as the physiology of fluoropyrimidine
metabolism may be with respect to desired antitumor effects, the
pathophysiology of fluoropyrimidine side-effects is even less well
understood.
[0022] Among these poorly understood side effects of
fluoropyrimidine administration, the physiology of hand-foot
syndrome ("HFS", "palmar-plantar erythrodysesthesia", "PPES") is
perhaps the most obscure.
[0023] HFS usually starts with numbness, tingling; redness, and
painless swelling of the hands and/or feet. Grade 1 HFS is
characterized by any of numbness, dysesthesia/parasthesia,
tingling, and/or painless swelling or erythema of the distal
extremities. Grade 2 is defined as painful erythema of the hands
and/or feet and/or discomfort affecting the patient's activities of
daily living. Grade 3 HFS is defined as moist desquamation,
ulceration, and blistering or severe pain of the hands and/or feet
and/or severe discomfort that causes the patient to be unable to
work or perform activities of daily living.
[0024] HFS is progressive with dose and duration of exposure to
fluoropyrimidines. The FDA-approved XELODA.RTM. product insert
reports a 54%-67% incidence of HFS irrespective of grade during
treatment with capecitabine at the FDA-approved dose, with a grade
3 incidence of 11-17%. HFS is also seen in treatment with other
chemotherapeutic agents, including antimetabolites such as
cytarabine, and agents of other classes, such as docetaxel and
doxorubicin, including pegylated liposomal forms of doxorubicin
(CAELYX.RTM.).
[0025] The pathophysiology of hand-foot syndrome is as yet unknown
and variously ascribed to metabolites of 5-FU, local drug
accumulation, increased levels of anabolic enzymes in the affected
tissues, and various other factors. See, for example, Childress and
Lokich, Amer. J. Clinical Oncology 26:435-436 (2003); Leo et al.,
J. Chemother. 6:423-426 (1994); Elasmar et al., Jpn J. Clin. Oncol.
31:172-174 (2001); and Fischel et al., "Experimental arguments for
a better understanding of hand-foot syndrome under capecitabine,"
Proc. Amer. Ass'n Cancer Res. 45:487 (abstract #2119) (March
2004).
[0026] In the face of such mechanistic uncertainty, the current
standard of practice is to cease or attenuate the dose of
fluoropyrimidine when hand-foot syndrome develops. Unfortunately,
the severity of syndrome appears to correlate with tumor response,
Chua et al., "Efficacy of capecitabine monotherapy in patients with
recurrent and metastatic nasopharyngeal carcinoma pretreated with
platinum-based chemotherapy," Proc. Am. Soc. Clin. Oncol. 22:511
(abstr. 2055) (2003); dose attenuation to reduce the symptoms of
hand-foot syndrome thus also reduces efficacy of tumor
treatment.
[0027] Topical treatment with DMSO, which has also been proposed,
see U.S. Pat. No. 6,060,083, is not typically practiced in the
clinic and is of uncertain efficacy.
[0028] While hand-foot syndrome is common during capecitabine
treatment, it is rarely seen with the ftorafur-containing prodrug
combinations UFT and S-1. S-1 lacks uracil yet, like UFT, causes
hand-foot syndrome only rarely. The reason for the disparate
prevalence is unknown, with the etiology of hand-foot syndrome with
S-1 administration suggested to differ from that seen with
capecitabine and/or 5-FU. Elasmar et al., Jpn J. Clin. Oncol.
31:172-174 (2001).
[0029] Systemically-administered chemotherapeutic agents other than
fluoropyrimidine antimetabolites also cause side effects in various
organs and tissues that are not involved in the disease being
treated. Many of these agents interact with, and are metabolized
by, complex metabolic pathways.
[0030] There is thus a need in the art for compositions and methods
for preventing and/or treating side effects of systemically
administered chemotherapeutic agents.
[0031] There is a further need in the art for methods and
compositions for preventing and/or treating side effects of
systemically administered chemotherapeutic agents that neither
abrogate nor attenuate the therapeutic effect of the systemically
administered agent, thus permitting such chemotherapeutic agents to
be used at therapeutic dosage levels.
[0032] There is a particular need for methods and compositions for
preventing and/or treating hand-foot syndrome, including methods
and compositions that would obviate the withdrawal or attenuation
of the dose of systemically administered chemotherapeutic agent,
thus permitting systemically administered chemotherapeutic agents,
such as fluoropyrimidines, to be administered at therapeutic dosage
levels.
SUMMARY OF THE INVENTION
[0033] The present invention solves these and other needs in the
art by providing methods, compositions, and kits for protecting
desired organs, tissues, and/or cells (collectively hereinafter,
"tissues") from the toxic effects of a systemically distributed
toxic agent, such as a systemically administered chemical,
biological, radiochemical, or radiobiological anticancer
chemotherapeutic agent.
[0034] The method is based on the asymmetric delivery of the
anticancer therapeutic agent and a tissue protectant to a subject,
with the anticancer therapeutic agent delivered throughout the
body, typically by systemic administration, and the protectant
vectored, or targeted, to the tissue to be protected.
[0035] In a first set of embodiments, the protectant is
administered so as to achieve high concentration at or within the
tissue to be protected, with low to negligible systemic
distribution. In a second set of embodiments, the protectant is
administered so as to reduce the concentration of the anticancer
therapeutic locally at or within the tissue to be protected. In
both cases, the protectant can serve to restore normal homeostasis
primarily, or exclusively, to the tissue to be protected.
[0036] In the first set of embodiments, the protectant is typically
administered locally, local administration being effective to
establish a concentration of the protectant agent at the desired
tissue that is sufficient to protect the tissue from toxicity by
the systemically distributed anticancer therapeutic agent. The
route of administration is chosen or adapted so as additionally to
constrain the circulating concentration of the protectant to levels
that are insufficient to abrogate the clinical efficacy of the
systemically distributed anticancer therapeutic agent or
metabolite.
[0037] The spatial differential in concentration achieved in the
methods of the present invention obviates the need to achieve a
pharmacological distinction between the agents, such as a
difference in affinity for one or more enzymes for which both
agents serve as substrates. The methods thus permit two agents
having near-identical pharmacokinetics and/or enzyme specificity or
affinity to serve, respectively, as the toxic therapeutic agent and
as the protectant.
[0038] The spatially directed administration of the protectant
allows concentrations of the protectant to be used that might be
deleterious or harmful if achieved systemically. The methods also
permit an agent to be used as a protectant that would, if
administered systemically, diminish or abrogate the clinical
efficacy of the systemically distributed anticancer therapeutic
agent.
[0039] In embodiments of the methods of the present invention in
which the protectant agent is, in current clinical practice,
coadministered with the toxic agent to achieve a systemic effect,
the method comprises dissociating the routes of administration of
the two agents, administering the toxic agent by means sufficient
to achieve systemic distribution--such as by enteral or parenteral
systemic administration--and administering the protectant agent in
a spatially directed fashion.
[0040] The protectant itself can usefully be a substrate, often
biologically active, for one or more enzymes involved in the
metabolic activation of the systemically distributed toxic agent.
The protectant, in other alternative embodiments, can physically
reduce, remove or inactive the anticancer therapeutic at the tissue
or organ to be protected.
[0041] Accordingly, in a first aspect, the invention provides a
method of protecting a desired body tissue from toxic effects of
one or more systemically distributed anticancer therapeutic agents
or metabolites thereof. The method comprises targeting one or more
protectant agents for nonsystemic delivery to the tissue desired to
be protected.
[0042] In a first series of embodiments, targeted nonsystemic
delivery comprises administering one or more protectant agents so
as to establish a local concentration of the protectant agents in
the tissue desired to be protected that is sufficient to protect
the tissue from the toxic effects of the systemic agent.
Administration is performed so as additionally to ensure that the
circulating concentration of the protectant agents is insufficient
to abrogate the clinical efficacy of the systemically distributed
anticancer therapeutic agent or metabolite at a tissue desired to
be treated.
[0043] In typical embodiments, the systemically distributed
anticancer therapeutic agent, or a metabolite or precursor thereof,
is systemically administered, for example by parenteral
administration, such as by intravenous administration, or enteral
administration, such as orally.
[0044] In these embodiments, typically the more protectant agents
is administered locally to the desired tissue, such as by topical
administration to an integumentary surface, such as skin.
[0045] The timing of administration of the protectant can vary.
[0046] In some embodiments, the one or more protectant agents is
administered before the at-risk tissue manifests toxic effects from
the systemically distributed anticancer therapeutic agent or
metabolite thereof, at times even before systemic administration of
the anticancer therapeutic agent (or metabolite or precursor
thereof). In various embodiments, the one or more protectant agents
is administered concurrently with systemic administration of the
anticancer therapeutic agent. In some embodiments, the protectant
is administered before, during, and after systemic administration
of the anticancer therapeutic agent.
[0047] In the first series of embodiments of the methods of the
present invention, the local concentration of each of the one or
more protectant agents is at least about 5-fold greater than the
circulating concentration of the protectant agent, often at least
about 10-fold greater than the circulating concentration of said
protectant agent, at times at least about 100-fold greater even at
least about 1000-fold greater than that in the circulation.
[0048] In some embodiments, at least one of the at least one
protectant agents inhibits in vivo activation of the systemically
administered anticancer therapeutic agent or metabolite or
precursor thereof, for example by inhibiting its anabolism. At
least one of the at least one protectant agents can, for example,
be a substrate for an enzyme involved in anabolic activation of the
systemically administered anticancer therapeutic agent, or a
metabolite or precursor thereof.
[0049] In other embodiments, at least one of the at least one
protectant agents facilitates in vivo catabolism of the
systemically administered anticancer therapeutic agent, or a
metabolite or precursor thereof.
[0050] The anticancer therapeutic agent, metabolite or precursor
thereof, can be an antimetabolite, such as a nucleotide, a
nucleoside, or a derivative, analogue, or precursor thereof. For
example, the systemically distributed (typically, systemically
administered) anticancer therapeutic agent can be ara-C
(cytarabine) or a fluoropyrimidine. The fluoropyrimidine can be
parenterally administrable fluoropyrimidines and/or orally
administrable.
[0051] In some embodiments, the fluoropyrimidine is 5-FU or a 5-FU
prodrug such as ftorafur, doxifluridine, and capecitabine. The
systemically administered fluoropyrimidine or fluoropyrimidine
prodrug can be composited with an inhibitor of dihydropyrimidine
dehydrogenase (DPD). Among such compositions is a composition
comprising ftorafur, 5-chloro-2,4-dihydroxypyridine, and oxonic
acid.
[0052] In other embodiments, the systemically distributed
(typically, systemically administered) anticancer therapeutic
agent, or metabolite or precursor thereof, can be an anthracycline,
or a topoisomerase I inhibitor, or an antagonist of EGF or VEGF.
For example, the systemically distributed agent can be an
anthracycline selected from the group consisting of doxorubicin,
nonpegylated liposomal doxorubicin, pegylated liposomal
doxorubicin, daunorubicin, liposomal daunorubicin, epirubicin, and
idarubicin.
[0053] The systemically distributed (typically, systemically
administered) anticancer therapeutic agent can be associated with
toxicity to an epithelium, such as an integumentary or mucosal
epithelium.
[0054] In certain embodiments, the toxicity is hand-foot syndrome.
In these embodiments, the protectant is usefully administered
topically to the palmar and/or plantar skin surface. In embodiments
in which hand-foot syndrome is caused by systemic administration of
a fluoropyrimidine, such as 5-FU or capecitabine, at least one of
said at least one protectant agents is usefully uracil, usefully
composited in a hydrophilic ointment for topical administration to
the skin of the hands and feet.
[0055] In a second series of embodiments of the methods of the
present invention, the targeted nonsystemic delivery of protectants
comprises administering the protectant agent so as to effect a
reduction, in the tissue desired to be protected, in the
concentration of the systemically distributed anticancer
therapeutic agent (or metabolite thereof) that is sufficient to
protect the tissue from the toxic effects of the systemic agent.
The circulating concentration of the protectant agents is
insufficient to abrogate the clinical efficacy of the systemically
distributed anticancer therapeutic agent or metabolite at a tissue
desired to be treated.
[0056] The methods of the present invention can sufficiently
protect, the at-risk tissue as to permit the full, unattenuated
dose of anticancer therapeutic agent to be administered, with
neither dose interruption, cessation, nor attenuation.
[0057] Thus, in a second aspect, the invention provides a method of
treating neoplasia.
[0058] The method comprises: systemically administering an
anticancer therapeutic agent, or a precursor or metabolite thereof,
to a subject in need thereof; and concurrently targeting one or
more protectant agents for nonsystemic delivery to the tissue
desired to be protected by any of the methods above-described.
[0059] For example, the method can comprise the concurrent
administration of one or more protectant agents so as to establish
a local concentration of the protectant agents in the tissue
desired to be protected that is sufficient to protect the tissue
from the toxic effects of the systemic agent. Administration is
performed so as additionally to ensure that the circulating
concentration of the protectant agents is insufficient to abrogate
the clinical efficacy of the systemically distributed anticancer
therapeutic agent or metabolite at a tissue desired to be
treated.
[0060] In other embodiments, the method can comprise the concurrent
administration of one or more protectant agents so as to effect a
reduction, in the tissue desired to be protected, in the
concentration of the systemically distributed anticancer
therapeutic agent for metabolite thereof) that is sufficient to
protect the tissue from the toxic effects of the systemic agent.
The circulating concentration of the protectant agents is
insufficient to abrogate the clinical efficacy of the systemically
distributed anticancer therapeutic agent or metabolite at a tissue
desired to be treated.
[0061] The systemically administered anticancer therapeutic agent,
precursor or metabolite thereof can be an antimetabolite, such a
fluoropyrimidine, including parenterally administrable and orally
administrable fluoropyrimidines, such as 5-FU, ftorafur, Carmofur,
capecitabine, doxifluridine, UFT, S-1, or Emitefur.
[0062] In such embodiments, at least one of the at least one
protectant agents concurrently administered with the
fluoropyrimidine can be uracil. The uracil can, for example, be
administered topically to the plantar and/or palmar skin
surfaces.
[0063] In another aspect, the invention provides pharmaceutical
compositions for local application to a body tissue, the
composition capable of establishing a local concentration of one or
more protectant agents sufficient to protect the tissue from toxic
effects of one or more systemically distributed anticancer
therapeutic agents or metabolites thereof without abrogating the
clinical efficacy of said systemically distributed anticancer
therapeutic agent or metabolite. The composition comprises at least
one protectant agent; and a pharmaceutically acceptable carrier
suitable for local application.
[0064] In some embodiments, at least one of the at least one
protectants in the composition is uracil. Uracil can be present
within the composition at a concentration by weight of at least
about 0.01%, often at least about 0.1%; even at least about 1.0%.
In various embodiments, uracil can be present within at a
concentration by weight of no more than about 60%, often at a
concentration of no more than about 5%.
[0065] In yet a further aspect, the invention provides kits for
oral delivery of an anticancer therapeutic agent or precursor
("prodrug") thereof with reduced toxicity to a desired tissue.
[0066] The kit comprises at least one dose of an orally
administrable anticancer therapeutic agent or precursor thereof;
and at least one dose of a locally administrable tissue protectant
composition. In some embodiments, the orally administrable
anticancer therapeutic agent or precursor is a fluoropyrimidine or
fluoropyrimidine composition, such as ftorafur, Carmofur,
capecitabine, doxifluridine, UFT, S-1, or Emitefur.
[0067] In presently preferred kits, the fluoropyrimidine is
capecitabine, the protectant composition is suitable for topical
delivery to the skin, and the protectant composition comprises
uracil. The uracil can usefully be present at a concentration by
weight of at least about 0.1%, even at least about 1.0%. The uracil
can be present within the composition at a concentration by weight
of no more than about 60%, even no more than about 10%, with uracil
usefully present in a weight percentage of about 0.11%-10%, even
1%-5%.
BRIEF DESCRIPTION OF THE DRAWINGS
[0068] The above and other objects and advantages of the present
invention will be apparent upon consideration of the following
detailed description taken in conjunction with the accompanying
drawings, in which like characters refer to like parts throughout,
and in which:
[0069] FIG. 1 shows the basic metabolic pathways for anabolic
activation and catabolic degradation of fluoropyrimidines, as known
in the art.
DETAILED DESCRIPTION
[0070] In a first aspect, the invention provides a method of
protecting a desired organ or body tissue from toxic effects of one
or more toxic agent, such as anticancer therapeutic agents, or
metabolites thereof, that are systemically distributed through the
body of a subject, typically a human patient undergoing
chemotherapy for cancer.
[0071] The body tissue desired to be protected may be any body
tissue that is not intended to be treated by the systemically
distributed anticancer therapeutic agent or anticancer therapeutic
agent metabolite.
[0072] For example, in embodiments in which the patient is being
treated for cancer, the body tissue desired to be protected would
typically be one that does not contain neoplastic cells.
Analogously, in embodiments in which the patient is being treated
with an anticancer therapeutic agent (or anticancer therapeutic
agent metabolite) to effect myeloablation, for example to condition
the patient prior to bone marrow transplantation, the tissue
desired to be protected may be any tissue other than the bone
marrow.
[0073] The method comprises administering one or more protectant
agents to the subject.
[0074] In a first series of embodiments, the one or more protectant
agents are so administered as to establish a local concentration of
protectant agent in the organ, tissue, or cells (hereinafter,
collectively "tissue") desired to be protected that is sufficient
to protect the tissue from the toxic effects of the systemically
distributed toxic agent, such as a systemically distributed
anticancer therapeutic agent or anticancer therapeutic agent
metabolite, yet also constrain the circulating concentration of
protectant to levels that are insufficient to abrogate the clinical
efficacy of the systemically distributed anticancer therapeutic
agent or metabolite.
[0075] In a second series of embodiments, the one or more
protectant agents are so administered as to lower the active
concentration of the systemically distributed toxic agent (such as
a systemically distributed anticancer therapeutic agent, or
metabolite thereof) at or within the tissue desired to be protected
to a level that protects the tissue from the toxic effects of the
systemically distributed toxic agent, without, however, lowering
the levels of the. systemically distributed toxic agent, at the
tissue desired to be treated, to levels that abrogate the clinical
efficacy of the systemically distributed anticancer therapeutic
agent or metabolite.
[0076] "Protection" intends a clinically observable decrease in one
or more toxic effects in the body tissue desired to be protected,
as compared to the toxic effects that would be seen absent the
protectant.
[0077] Protection can be total, preventing all symptoms of toxicity
in the desired tissue; protection can be partial, reducing and/or
delaying development of all or a subset of symptoms of toxicity in
the desired tissue. In some embodiments, protection is sufficient
to permit administration of the full dose and course of intended
therapy with anticancer therapeutic agent or metabolite or
precursor (prodrug) without dose cessation, dose attenuation,
and/or alteration in dosage schedule. In some embodiments,
protection is sufficient to allow an increase in dose of the
anticancer therapeutic agent or metabolite or precursor.
[0078] The circulating concentration of the one or more protectants
is constrained to levels that are insufficient to abrogate the
clinical efficacy of the systemically distributed anticancer
therapeutic agent or metabolite thereof.
[0079] "Abrogate" intends a diminution in efficacy of the
anticancer therapeutic agent (or metabolite thereof) at the tissue
desired to be treated that is sufficiently great as to render
therapy with the anticancer therapeutic agent or anticancer
therapeutic agent metabolite clinically ineffective or clinically
inadvisable. In some embodiments, the circulating concentration of
the one or more protectant agents is sufficiently low as to cause
no clinically observable diminution in potency or efficacy of the
systemically distributed anticancer therapeutic agent (or
metabolite thereof) at the tissue desired to be treated, such as a
tissue having neoplastic cells. In other embodiments, the
circulating concentration of the one or more protectant agents
causes a clinically observable diminution in potency or efficacy of
the systemically distributed anticancer therapeutic agent (or
metabolite) at the tissue desired to be treated, but is
insufficient to abrogate the clinical efficacy of the systemically
distributed anticancer therapeutic agent or metabolite thereof.
[0080] In typical embodiments, the local concentration of the one
or more protectants in the tissue desired to protected from toxic
effects will be greater than the concentration in the circulation.
In some embodiments, the circulating concentration of the one or
more protectants will be greater, in turn, than their concentration
in the tissues desired to be treated with the systemically
distributed anticancer therapeutic agent (such as a cancerous
tissue).
[0081] In some embodiments, the local concentration of each of the
one or more protectant agents in the tissue desired to be protected
is at least 5-fold greater than the circulating concentration of
the protectant agent. In other embodiments, the local concentration
is at least 10-fold, at least 20-fold, at least 30-fold, at least
40-fold, at least 50-fold or more greater than the concentration of
the protectant in the circulation. In various embodiments, the
local concentration can be as high as at least 60-fold, 70-fold,
80-fold, 90-fold, even as high as 100-fold or more greater than the
concentration of the protectant in the circulation. In some
embodiments, the local concentration of protectant can be as high
as 1000-fold higher than in the circulation, or even more.
[0082] In various embodiments, the local concentration of
protectant in the tissue desired to be protected is at least
10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at
least 50-fold or more greater than the concentration of the
protectant in the tissue desired to be treated. In various
embodiments, the local concentration in the tissue desired to be
protected can be as high as at least 60-fold, 70-fold, 80-fold,
90-fold, even as high as 100-fold or more greater than the
concentration of the protectant in the tissue desired to be
treated. In some embodiments, the local concentration of protectant
can be as high as 1000-fold higher than in the tissue desired to be
treated, or even more. The tissue desired to be treated can, e.g.,
be a tumor within a body tissue or the entirety of a body tissue
within which a portion of the cells are neoplastic.
[0083] Typically, the anticancer therapeutic agent or metabolite
becomes systemically distributed upon or following systemic
administration of the anticancer therapeutic agent, its metabolite,
or a precursor thereof to the patient.
[0084] The anticancer therapeutic agent (or metabolite) can be a
chemical agent, a biological agent, a radiochemical agent or a
radiobiological agent that has antineoplastic activity.
[0085] In some embodiments, the anticancer therapeutic agent,
metabolite thereof, or precursor thereof is administered
parenterally, such as by intravenous infusion, either continuous or
bolus infusion, by intramuscular injection, by subcutaneous
injection, or by intrathecal administration. In other embodiments,
the anticancer therapeutic agent, metabolite thereof, or precursor
thereof is administered orally. In yet other embodiments, the
anticancer therapeutic agent, metabolite, or precursor is
administered by transepithelial means, as by anal or vaginal
suppository. In yet other embodiments, the anticancer therapeutic
agent, metabolite, or precursor is implanted into the patient.
[0086] The systemically distributed anticancer therapeutic agent or
metabolite can be an antimetabolite, such as a nucleotide, a
nucleoside, or a derivative, analogue, or precursor thereof. For
example, in certain embodiments, the systemically distributed
anticancer therapeutic agent can be a purine antimetabolite such as
mercaptopurine, azathioprine, thioguanine, or fludarabine. In other
embodiments, the systemically distributed anticancer therapeutic
agent can be a pyrimidine antimetabolite such as ara-C
(cytarabine), gemcitabine, azacitidine, or a fluoropyrimidine, or a
metabolite thereof.
[0087] In some of these embodiments, the systemically distributed
anticancer therapeutic agent is a fluoropyrimidine.
[0088] In certain of these embodiments, the fluoropyrimidine is a
parenterally administrable fluoropyrimidine, such as 5-FU. In other
embodiments, the fluoropyrimidine is an orally administrable
fluoropyrimidine, such as capecitabine, doxifluridine, or tegafur,
alone or formulated in admixture with one or more inhibitors of
dihydropyrimidine dehydrogenase (DPD). In certain embodiments, for
example, the fluoropyrimidine (such as tegafur) can be administered
in a composition that further comprises uracil and/or
5-chloro-2,4-dihydroxypyridine, and optionally oxonic acid.
[0089] In other embodiments, the anticancer therapeutic agent is an
anthracycline, or precursor or metabolite thereof. In some of these
embodiments, the anticancer therapeutic agent can be selected from
the group consisting of doxorubicin, nonpegylated liposomal
doxorubicin, pegylated liposomal doxorubicin, daunorubicin,
liposomal daunorubicin, epirubicin, and idarubicin.
[0090] In other embodiments, the anticancer therapeutic agent can
be a taxane, such as docetaxel or paclitaxel.
[0091] In typical embodiments, the one or more protectant agents is
administered locally to the tissue desired to be protected. In some
such embodiments, the one or more protectant agents is administered
topically to the tissue desired to be protected. In other such
embodiments, the one or more protectant agents is administered by
local injection, such as by local injection of a depotized form of
the one or more protectant agents.
[0092] In some embodiments of the methods of the present invention,
the one or more protectant agents is administered before the tissue
desired to be protected manifests toxic effects of the systemically
distributed anticancer therapeutic agent or metabolite thereof.
[0093] Often, this prophylactic or preventative administration of
the one or more protectant agents is preferred. Such timing is
particularly preferred in embodiments in which the one or more
protectant agents is to be administered to the skin as the tissue
desired to be protected--e.g. to prevent, ameliorate, delay, or
treat hand-foot syndrome--because toxic side effects, once
manifested in the skin, can increase its permeability to, or
otherwise increase its absorption of, the protectant, potentially
increasing the circulating concentration of the protectant
agent.
[0094] In certain of these embodiments, the one or more protectant
agents is administered before systemic administration of the
anticancer therapeutic agent, metabolite thereof, or precursor
thereof. In certain embodiments, the one or more protectant agents
is administered concurrently with systemic administration of the
anticancer therapeutic agent, metabolite thereof, or precursor
thereof. In some embodiments, the one or more protectant agents is
administered before and during systemic administration of the
anticancer therapeutic agent, metabolite thereof, or precursor
thereof. In yet other embodiments, the one or more protectant
agents is optionally administered for a period following cessation
of systemic administration of the one or more anticancer
therapeutic agents, or precursors, or metabolites thereof.
[0095] The protectant agent can, in some embodiments, be one that
inhibits in vivo activation of the systemically administered
anticancer therapeutic agent, metabolite or precursor thereof.
[0096] For example, the protectant can in some embodiments inhibit
anabolic activation of a systemically administered anticancer
therapeutic agent, metabolite, or precursor thereof. In some
embodiments, the protectant agent can be a substrate, such as a
competitive substrate, of an enzyme involved in anabolic activation
of a systemically administered anticancer therapeutic agent or
metabolite or precursor thereof. In embodiments in which the
protectant acts as a substrate for an enzyme, the protectant agent
can be a naturally-occurring compound.
[0097] In embodiments in which the systemically distributed
anticancer therapeutic agent is a fluoropyrimidine, for example,
the protectant agent can be a substrate, such as a competitive
substrate, of an enzyme involved in anabolic activation of the
systemically administered fluoropyrimidine, such as a substrate for
thymidine phosphorylase (TP), and/or uridine phosphorylase (UP),
and/or orotate phosphoribosyl transferase (OPRT).
[0098] The protectant can, for example, be a naturally occurring
compound, such as a compound that serves as a substrate for any one
or more of TP, and OPT. The compound can be a naturally occurring
nitrogenous base, such as a pyrimidine, including uracil. In other
embodiments, the compound can be a non-naturally occurring
nitrogenous base, such as a nonnaturally occurring pyrimidine.
[0099] Typically, the protectant will not act as an irreversible
inhibitor of--or otherwise interfere with--an enzymatic activity or
pathway in the cell, and thus will not occasion an imbalance in the
absolute and relative nucleotide concentrations within the
cell.
[0100] In other embodiments, the protectant agent can be one that
facilitates in vivo catabolism of the systemically administered
anticancer therapeutic agent, metabolite, or precursor thereof.
[0101] In embodiments in which the systemically distributed
anticancer therapeutic agent is a fluoropyrimidine, for example,
the protectant agent can act to increase the amount or activity of
dihydropyrimidine dehydrogenase (DPD) in the tissue desired to be
protected.
[0102] For example, the protectant agent can include nucleic acids
capable of expressing a protein, such as DPD, and can be
administered, for example, by injection, as described, for example,
in U.S. Pat. Nos. 5,580,859 and 6,706,694, incorporated herein by
reference in its entirety.
[0103] The protectant agent may be administered using a variety of
dosage schedules designed to establish and maintain a local
concentration in the tissue desired to be protected that is
sufficient to protect the tissue from the toxic effects of the
systemically distributed anticancer therapeutic agent or anticancer
therapeutic agent metabolite, yet constrain the circulating
concentration of protectant to levels that are insufficient to
abrogate the clinical efficacy of the systemically distributed
anticancer therapeutic agent or metabolite.
[0104] The exact dosage schedule will depend, inter alia, on any
one or more of the identity of the systemically distributed
chemotherapeutic agent or metabolite, the circulating concentration
of chemotherapeutic agent or metabolite, the tissue desired to be
protected, the severity of side effects desired to be prevented or
treated, and the formulation of the protectant composition,
particularly its concentration in the protectant composition;
determination of the proper dosage schedule of protectant agent is
within the skill of the clinical artisan.
[0105] For example, in embodiments of the methods of the present
invention in which the protectant agent is administered topically
to skin in an ointment composition, the protectant can usefully be
administered once a day, twice a day, three times a day, four times
a day, or more times a day. As would be understood in the art, the
composition can be applied with different dosage schedules to
different tissues of a single patient. For example, the composition
may be applied twice a day to the plantar surface of the feet, but
applied more frequently to the hands, such as after each washing of
the hands. The exact schedule may vary by patient.
[0106] In some embodiments, the amount of protectant administered
per dose is at least 0.01 g, 0.02 g, 0.03 g, 0.04 g, 0.05 g, 0.06
g, 0.07 g, 0.08 g, 0.09 g, 0.1 g, 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6
g, 0.7 g, 0.8 g, 0.9 g, 1.0 g, 1.5 g, 2.0 g, 2.5 g, 3 g, 4 g, even
5 g or more, with intermediate values permissible. Typically, the
amount of protectant administered per dose is no more than about 10
g, 9 g, 8 g, 7 g, 6 g, even no more than about 5 g, 4.5 g, 4 g, 3.S
g, 3 g, 2 g, 1 g, and in certain embodiments even no more than
about 0.5 g, 0.4 g, 0.3 g, 0.2 g, even no more than about 0.1
g.
[0107] For example, in embodiments of the methods of the present
invention in which uracil as the protectant agent is administered
two to four times per day to the palmar and/or plantar surfaces of
a patient undergoing systemic administration of an anticancer
therapeutic agent, prodrug or metabolite thereof, such as systemic
administration of a fluoropyrimidine, such as 5-FU or capecitabine,
the amount of uracil administered per dose can usefully be at least
about 0.01 g, 0.02 g, 0.03 g, 0.04 g, 0.05 g, 0.06 g, 0.07 g, 0.08
g, 0.09 g, 0.1 g, 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g,
0.9 g, even at least 1.0 g, and typically no more than about 2.0 g,
1.5 g, 1.0 g, 0.9 g, 0.8 g, 0.7 g, 0.6 g, 0.5 g, 0.4 g, 0.3 g, 0.2
g, with a dose of 0.1 g currently preferred.
[0108] In another aspect, the invention provides protectant agents
formulated in compositions that permit local concentrations of
protectant to be established that are sufficient to protect the
tissue from the toxic effects of the systemically distributed
anticancer therapeutic agent or anticancer therapeutic agent
metabolite, yet constrain the circulating concentration of
protectant to levels that are insufficient to abrogate the clinical
efficacy of the systemically distributed anticancer therapeutic
agent or metabolite.
[0109] Compositions of the present invention comprise one or more
protectant agents and at least one pharmaceutically acceptable
carrier or excipient.
[0110] Each of the at least one protectant agents is typically
present in the protectant composition to a weight/weight percentage
of at least 0.01%, 0.05%, 1.0%, 1.5%, 2.0%, 2.5%, 3.5%, 4.0%, 4.5%,
5.0%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,
70%, 75%, even 80% or more, with intermediate values permissible,
and is typically present to a weight/weight percentage of no more
than about 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%,
25%, 20%, 15%, 10%, 5%, 4.5%, 4.0%, 3.5%, 3.0%, 2.5%, 2.0%, 1.5%,
1.0%, and even, at times, to a weight/weight percentage of no more
than about 0.05%, even as little as 0.01%.
[0111] In embodiments of the compositions of the present invention
comprising a plurality of protectant agents, typically the
plurality of protectants are cumulatively present to a
weight/weight percentage of at least 0.01%, 0.05%, 1.0%, 1.5%,
2.0%, 2.5%, 3.5%, 4.0%, 4.5%, 5.0%, 10%, 15%, 20%, 25%, 30%, 35%,
40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, even 80% or more, with
intermediate values permissible, and is typically present to a
weight/weight percentage of no more than about 80%, 75%, 70%, 65%,
60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 4.5%,
4.0%, 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1.0%, 0.05%, even as little, as
0.01%, with intermediate values permissible.
[0112] In embodiments that are presently preferred for protecting
the palmar and/or plantar skin surfaces from hand-foot syndrome,
such as during systemic administration of a fluoropyrimidine, an
anthracycline, or a taxane anticancer therapeutic agent, or
metabolite or precursor thereof, the compositions of the present
invention typically comprise uracil as the protectant agent, with
the composition comprising uracil to a weight/weight percentage of
at least 0.01%, 0.05%, 1.0%, 1.5%, 2.0%, 2.5%, 3.5%, 4.0%, 4.5%,
5.0%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,
70%, 75%, even 80% or more, with intermediate values permissible;
in such compositions, uracil is typically present to a
weight/weight percentage of no more than about 80%, 75%, 70%, 65%,
60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 4.5%,
4.0%, 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1.0%, and even, at times, to a
weight/weight percentage of no more than about 0.05%, even as
little as 0.01%, with intermediate values permissible.
[0113] In presently preferred compositions for protecting the
palmar and/or plantar skin surfaces, uracil is present to a
weight/weight percentage of at least about 0.1%, 0.2%, 0.3%, 0.4%,
0.5%, 0.6%, 0.7%, 0.8%, 0.9%, even to a weight/weight percentage of
at least about 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%,
1.8%, 1.9%, 2.0%, 2.5%, 3.0% or more, with intermediate values
permissible. In some embodiments, uracil is present to a
weight/weight percentage of at least about 3.5%, 4.0%, 4.5%, 5.0%,
10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, even at least
about 60%, typically no more than about 60%, 55%, 50%, 45%, 40%,
35%, 30%, 25%, 20%, 15%, 10%, 5%, 4.5%, 4.0%, 3.5%, 3.0%, 2.5%,
2.0%, 1.5%, 1.0%, 0.05%, with intermediate values permissible. In
certain useful embodiments, uracil is present to a weight/weight
percentage of about 1%.
[0114] The exact formulation of the protectant agent compositions
of the present invention will depend upon the identity of the
tissue desired to be protected. Pharmaceutical formulation is a
well-established art, and is further described in Gennaro (ed.),
Remington: The Science and Practice of Pharmacy, 20th ed.,
Lippincott, Williams & Wilkins (2000). (ISBN: 0683306472);
Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery
Systems, 7th ed., Lippincott Williams & Wilkins Publishers
(1999) (ISBN: 0683305727); and Kibbe (ed.), Handbook of
Pharmaceutical Excipients American Pharmaceutical Association, 3rd
ed. (2000) (ISBN: 091733096X), the disclosures of which are
incorporated herein by reference in their entireties.
[0115] In embodiments in which the tissue desired to be protected
is the skin, for example, the one or more protectant agents will
typically be formulated for localized, typically topical,
administration to the skin surface. In embodiments in which the
patient is being treated systemically with a fluoropyrimidine, an
anthracycline, or a taxane anticancer therapeutic agent, or
precursor or metabolite thereof, for example, the one or more
protectant agents will often be formulated for topical
administration to the palmar and plantar skin surfaces.
[0116] Compositions of the present invention intended for topical
administration to the skin may, for example, be anhydrous, aqueous,
or water-in-oil or oil-in-water emulsions. Emulsions are presently
preferred. Compositions of the present invention may further
include one or more pharmaceutically acceptable carriers or
excipients and various skin actives. Amounts of the carrier may
range from about 1 to about 99%, preferably from about 5 to about
70%, optimally from about 10 to about 40% by weight. Among useful
carriers are emollients, water, inorganic powders, foaming agents,
emulsifiers, fatty alcohols, fatty acids, and combinations
thereof.
[0117] Emollients can be selected from polyols, esters and
hydrocarbons.
[0118] Polyols suitable for the invention may include propylene
glycol, dipropylene glycol, polypropylene glycol, polyethylene
glycol, sorbitol, hydroxypropyl sorbitol, hexylene glycol,
1,3-butylene glycol, 1,2.6-hexanetriol, glycerin, ethoxylated
glycerin, propoxylated glycerin, xylitol and mixtures thereof
[0119] Esters useful as emollients include alkyl esters of fatty
acids having 10 to 20 carbon atoms. Methyl, isopropyl, and butyl
esters of fatty acids are useful herein. Examples include hexyl
laurate, isohexyl laurate, isohexyl palmitate, isopropyl palmitate,
decyl oleate, isodecyl oleate, hexadecyl stearate, decyl stearate,
isopropyl isostearate, diisopropyl adipate, diisohexyl adipate,
dihexyldecyl adipate, diisopropyl sebacate, lauryl lactate,
myristyl lactate, and cetyl lactate. Particularly preferred are
C12-C15 alcohol benzoate esters.
[0120] Esters useful as emollients also include alkenyl esters of
fatty acids having 10 to 20 carbon atoms. Examples thereof include
oleyl myristate, oleyl stearate and oleyl oleate.
[0121] Esters useful as emollients also include ether-esters such
as fatty acids esters of ethoxylated fatty alcohols.
[0122] Esters useful as emollients also include polyhydric alcohol
esters. Ethylene glycol mono and di-fatty acid esters, diethylene
glycol mono- and di-fatty acid esters, polyethylene glycol
(200-6000) mono- and di-fatty acid esters, polyglycerol poly-fatty
esters, ethoxylated glyceryl monostearate, 1,3-butylene glycol
monostearate, 1,3-butylene glycol distearate, polyoxyethylene
polyol fatty acid ester, sorbitan fatty acid esters, and
polyoxyethylene sorbitan fatty acid esters are satisfactory
polyhydric alcohol esters.
[0123] Esters useful as emollients additionally include wax esters
such as beeswax, spermaceti, myristyl myristate, stearyl
stearate.
[0124] Esters useful as emollients still further include sterol
esters, of which cholesterol fatty acid esters are examples
thereof.
[0125] Illustrative hydrocarbon carriers are mineral oil,
polyalphaolefins, petrolatum, isoparaffin, polybutenes and mixtures
thereof.
[0126] Inorganic powders are also useful as carriers in the
compositions of the present invention. Examples include clays (such
as Montmorillonite, Hectorite, Laponite and Bentonite), talc, mica,
silica, alumina, zeolites, sodium sulfate, sodium bicarbonate,
sodium carbonate, calcium sulfate and mixtures thereof.
[0127] The compositions of the present invention can also include
aerosol propellants, serving as, or in addition to, carriers or
excipients. Propellants can be based on volatile hydrocarbons such
as propane, butane, isobutene, pentane, isopropane and mixtures
thereof. Philips Petroleum Company is a source of such propellants
under trademarks including A31, A32, A51 and A70. Halocarbons
including fluorocarbons are further widely employed
propellants.
[0128] The compositions of the present invention, particularly
embodiments formulated for administration to the skin, can comprise
emulsifiers, either serving as, or in addition to, carriers or
excipients.
[0129] Emulsifiers may be selected from nonionic, anionic,
cationic, or amphoteric emulsifying agents. They may range in
amount anywhere from about 0.1 to about 20% by weight.
[0130] Illustrative nonionic emulsifiers are alkoxylated compounds
based on C10-C22 fatty alcohols and acids and sorbitan. These
materials are available, for instance, from the Shell Chemical
Company under the Neodol trademark. Copolymers of
polyoxypropylenepolyoxyethylene sold by the BASF Corporation under
the Pluronic trademark are sometimes also useful. Alkyl
polyglycosides available from the Henkel Corporation may also be
utilized for purposes of this invention.
[0131] Anionic type emulsifiers include fatty acid soaps, sodium
lauryl sulfate, sodium lauryl ether sulfate, alkyl benzene
sulphonate, mono- and di-alkyl acid phosphates, sarcosinates,
taurates and sodium fatty acyl isethionate.
[0132] Amphoteric emulsifiers useful in the compositions of the
present invention include such materials as dialkylamine oxide and
various types of betaines (such as cocamidopropyl betaine).
[0133] The compositions of the present invention can also include
preservatives, such as methyl paraben and propyl paraben are useful
to prevent microbial contamination.
[0134] In embodiments of the compositions of the present invention
formulated .for topical applidation to skin, the composition can
usefully be formulated as an ointment, a cream, a lotion, a paste,
an aerosol spray, a roll-on liquid, stick, or pad, or an aerosol
foam (mousse) composition.
[0135] For example, mousse compositions of the present invention
can be quick-breaking or slow-breaking foams, such as those
described in U.S. Pat. Nos. 6,730,288, 6,627,585, 6,589,518,
6,395,258, 6,383,472, 6,113,888, 6,113,881, 6,080,392, 5,783,202,
the disclosures of which are incorporated herein by reference in
their entireties.
[0136] In one embodiment, the composition is a hydrophilic ointment
comprising uracil as the protectant agent, and further comprising
methyl paraben, propyl paraben, sodium lauryl sulfate, propylene
glycol, sterol alcohol, white petrolatum, water and light mineral
oil.
[0137] In embodiments in which the tissue desired to be protected
is the mucosal epithelium of the mouth, as in chemotherapy-induced
stomatitis, the protectant agents can be applied to the oral cavity
in the form of a topical formulation. In methods of the present
invention for protecting mucosal epithelium from the toxic effects
of a systemically distributed anticancer therapeutic agent or
metabolite thereof, care is typically taken to prevent or to reduce
oral ingestion.
[0138] Formulations suitable for topical oral application include
oral emulsions, magmas, gels, swishes, lozenges, pastes, creams,
oral solutions, gums, etc., as are well known in the art. Any of
these topical oral vehicles can be used in conjunction with the
methods of the invention. Exact formulations, as well as methods of
their preparation, will be apparent to those of skill in the
art.
[0139] In one embodiment of a composition of the present invention
useful for topical delivery to the mucosal epithelium of the mouth,
the one or more protectant agents are administered in a topical
gel-like formulation comprising a gel-like vehicle. The gel-like
vehicle generally comprises a water-soluble gelling agent, a
humectant and water, and has a viscosity of about 500 to 100,000
cps, preferably about 10,000 to 50,000 cps, more preferably about
15,000 to 30,000 cps and most preferably about 20,000 to 25,000 cps
as measured with a Brookfield viscometer at about 25.degree. C. The
gelling agent provides the formulation with good mucoadhesion
properties; the humectant with good moisturizing and
moisture-barrier properties.
[0140] Gelling agents suitable for use with the vehicle of the
invention include, e.g., agar, bentonite, carbomer (e.g.,
carbopol), water soluble cellulosic polymers (e.g., carboxyalkyl
cellulose, hydroxyalkyl cellulose, alkyl cellulose, hydroxyalkyl
alkylcellulose), povidone, kaolin, tragacanth and veegum, with
hydroxylalkyl alkyl celluloses such as hydroxypropyl
methylcellulose being preferred.
[0141] Humectants suitable for use with the gel-like vehicle of the
invention include, e.g., glycerin, propylene glycol and sorbitol,
with sorbitol being preferred.
[0142] Generally, the vehicle comprises about 0.1% (w/w) to 10%
(w/w) water-soluble gelling agent, with about 0.25% (w/w) to 5%
(w/w) being preferred and about 0.5% (w/w) to 3% (w/w) being most
preferred and about 0.1% (w/w) to 20% (w/w) humectant. However, as
the viscosity of the gel-like vehicle is of considerable
importance, it will be understood that the above concentration
ranges are for guidance only. The actual concentration of gelling
agent will depend, in part, on the polymer selected, the supplier
and the specific lot number. The actual concentrations of other
ingredients will likewise affect the viscosity of the gel-like
formulation. Choosing appropriate concentrations to yield a
gel-like formulation with the desirable viscosity and other
properties described herein is within the capabilities of
ordinarily skilled artisans.
[0143] Additionally, the gel-like vehicle of the invention may
include antimicrobial preservatives. Antimicrobial preservatives
useful with the compositions of the invention include, but are not
limited to, antifungal preservatives such as benzoic acid,
alkylparabens, sodium benzoate and sodium propionate; and
antimicrobial preservatives such as benzalkonium chloride,
benzethonium chloride, benzyl alcohol, cetylpyridinium chloride,
chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate
and thimerosal, with alkylparabens such as methylparaben,
propylparaben and mixtures thereof being preferred.
[0144] An amount of antimicrobial preservative(s) effective for use
with the formulations of the invention will be apparent to those of
skill in the art and will depend, in part, on the antimicrobial
agent(s) used. Typical concentrations range from about 0.01% (w/w)
to about 2% (w/w).
[0145] The composition of the invention formulated for topical
administration to the oral mucosa may also contain from about 1%
(w/w) to 10% (w/w) of a sweetening agent such as aspartame,
dextrose, glycerin, malitol, mannitol, saccharin sodium, sorbitol,
sucrose and xylitol. Such sweetening agents are believed to aid
patient compliance.
[0146] The pH of the composition will depend on the tissue
protectant(s) contained in the composition. Determination of an
optimal pH for stability and efficacy is well within the skill of
the ordinary artisan.
[0147] Other optional ingredients that can be used without
deleteriously affecting, and in some cases even enhancing, the
efficacy of the formulations of the invention adapted for mucosal,
notably oral mucosal, delivery, include, but are not limited to,
acidifying agents such as acetic acid, citric acid, fumaric acid,
hydrochloric acid, lactic acid and nitric acid; alkalinizing agents
such as ammonia solution, ammonium carbonate, diethanolamine,
monoethanolamine, potassium hydroxide, sodium borate, sodium
carbonate, sodium hydroxide, triethanolamine and trolamine;
buffering agents such as potassium metaphosphate, potassium
phosphate, sodium acetate and sodium citrate; antioxidants such as
ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole,
butylated hydroxytoluene, hypophosphorous acid, monothioglyceride,
propyl gallate, sodium ascorbate, sodium bisulfite, sodium
formaldehyde sulfoxylate and sodium metabisulfite; chelating agents
such as edetate disodium and edetic acid; colorants such as
FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6,
FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5,
caramel and ferric oxide, red; and flavoring agents such as anise
oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil
vanillin. Suitable concentrations for use will be apparent to those
of skill in then art. Other optional ingredients, as well as
suitable concentrations for use, can be found, for example, in
Gennaro (ed.), Remington: The. Science and Practice of Pharmacy,
20th ed., Lippincott, Williams & Wilkins (2000) (ISBN:
0683306472).
[0148] In embodiments of the methods of the present invention in
which the tissue desired to be protected is rectal or colonic
mucosa--typically, embodiments in which the systemically
distributed anticancer therapeutic agent or precursor or metabolite
thereof is administered to treat a condition other than colorectal
carcinoma--the protectant compositions of the present invention can
be formulated for administration by enema.
[0149] The compositions of the present invention may be packaged
for single use or multiple use, with multiple use packaging
usefully designed to provide protectant composition sufficient for
the duration of a concurrent course of systemic therapy with
anticancer therapeutic agent.
[0150] For example, a uracil ointment useful in protecting palmar
and plantar surfaces from the toxic effects of systemically
distributed fluoropyrimidine or metabolite or prodrug thereof, may
usefully be packaged in an amount sufficient for at least a 14-day
or 21-day course.
[0151] The compositions of the present invention can also usefully
be packaged in kits.
[0152] The kits of the present invention can, for example, usefully
comprise a protectant composition and an orally administrable
anticancer therapeutic agent or precursor.
[0153] In some embodiments, the invention can comprise a protectant
composition formulated for application to a skin surface, such as
the palmar and/or plantar skin surface, and an orally administrable
fluoropyrimidine, such as tegafur, Carmofur, capecitabine,
doxifluridine, UFT, S-1, or Emitefur. In such embodiments, the kit
can comprise a plurality of doses of orally administrable
fluoropyrimidine, usefully a sufficient number of doses for a
standard course of therapy, and a sufficient amount of protectant
composition for administration during the course of oral
chemotherapy. The plurality of doses of orally administrable
fluoropyrimidine can be ganged together, for example in one or more
blister packs.
[0154] In some of these embodiments, the protectant composition of
the kit comprises uracil as the protectant; in certain of these
embodiments, uracil is present in a weight/weight percentage of
1.0%.
[0155] Embodiments of the kits of the present invention can
optionally, but usefully, comprise applicators, particularly in
embodiments in which the protectant composition is intended for
local administration to a tissue other than the skin surface.
[0156] Kits will typically also include instructions for
administration of the protectant composition and, if the kit
comprises an orally administrable anticancer therapeutic agent or
precursor, instructions for oral administration of the oral
agent.
[0157] In some embodiments, the kits can include dressings, such as
occlusive dressings, that facilitate the establishment of a
sufficient local concentration of the protectant composition.
[0158] The following examples are offered by way of illustration
only, and not by way of limitation.
EXAMPLE 1
[0159] The theoretical systemic exposure to uracil from the topical
application of a 1% w/w uracil ointment to the hands and feet can
be crudely estimated as follows.
[0160] Application of 0.1 gm of a 1% (w/w) uracil ointment to the
hands and feet four times a day represents an exposure of 4-8 mg of
uracil/day. The topical absorption of agents through intact skin
can be on the order of 1%, leading to a systemic absorption of
40-80 .mu.g/day. This contrasts with exposure of about 1200 mg/day
of uracil in OFT. Thus, the mean systemic uracil exposure with
uracil ointment averages about 0.00005 (0.005%) that of UFT.
[0161] At the skin surface, however, and in the underlying skin,
the concentration of uracil should be about 10 mg/ml. The average
plasma 5-FU concentration is usefully estimated at 0.5 .mu.g/ml.
Thus, topical administration of uracil ointment theoretically
establishes a local concentration of uracil that is approximately
2000-fold that of 5-FU at the skin, with a systemic dose only
0.005% that occasioned by oral administration of UFT.
EXAMPLE 2
[0162] A 48 year old female patient exhibited metastatic breast
cancer. She had refused mastectomy and had previously failed
adriamycin and cytoxan, weekly taxol, and weekly navelbine. She was
then placed on Xeloda.RTM. together with 1% uracil ointment applied
to the hands and feet. The 1% uracil ointment was used starting
with cycle 5 of treatment with Xeloda.RTM..
[0163] Table 1 below summarizes results on this patient.
TABLE-US-00001 TABLE 1 Course q3wk 1 2 3 4 5 6 7 8 Xeloda 1250
mg/m.sup.2 Same D/C 1000 mg/m.sup.2 1250 mg/m.sup.2 Same Same Same
dose bid .times. 14 after 4 bid .times. 14 bid .times. 14 14/21
days days Taxotere + + + + + + + + 75 mg/m.sup.2 Marker 12 .times.
8 .times. 8 7 .times. 7 7 .times. 7 9 .times. 9 8.5 .times. 8
.times. 8 8.5 .times. tumor 12 progression 8.5 8.5 size cm- on
lower prior to dose rx Xeloda .RTM. 1% 0 0 0 0 + + + + uracil
ointment Hand- ND* ND ++++ ++ 0 0 0 0 foot syndrome *ND: Not
described
[0164] The 1% uracil ointment allowed a re-escalation of the dose
of Xeloda.RTM. with anti-tumor activity at the higher dose of
Xeloda.RTM.. The 1% uracil ointment allowed a higher dose of
Xeloda.RTM. to be administered with improved anti-cancer efficacy
(compare columns 5 and 6). The 1% uracil ointment did not have any
discernible toxicity.
EXAMPLE 3
[0165] Another patient, a 68 year old white female diagnosed with
metastatic colon-cancer, was treated with Xeloda.RTM. and
thalidomide. Hand-Foot Syndrome developed. Complete reversal of the
syndrome occurred after topical treatment with a 1% uracil
ointment. The efficacy of the Xeloda.RTM. and thalidomide treatment
was unaffected by the concurrent use of 0.1 g 1% uracil ointment
four times a day. There were no dose reductions of chemotherapy or
treatment delays.
EXAMPLE 4
[0166] A 60 year old white female with metastatic colon cancer was
treated with 5-FU, Leucovorin.RTM., and Oxaliplatin, a common
regime of treatment for this form of cancer. The patient developed
hand-foot syndrome.
[0167] Topical application of 0.1 g of 1% uracil ointment four time
per day resulted in complete resolution of the syndrome. The
anti-cancer treatment remained efficacious. No side-effects were
noted as a result of the uracil ointment applications. There were
no dose reductions of chemotherapy or treatment delays.
[0168] In total, 7 patients have been treated with 1% uracil
ointment. In no case did hand-foot syndrome develop; there was no
observable toxic reaction to the 1% uracil ointment.
EXAMPLE 5
[0169] A patient with EGFR-expressing metastatic colorectal
carcinoma undergoing systemic treatment with cetuximab
(ERBITUX.RTM.) as single agent therapy develops dermatological
toxicity, including skin drying and fissuring and acneform
rash.
[0170] Cetuximab is a recombinant, human/mouse chimeric monoclonal
antibody that binds specifically to the extracellular domain of the
human epidermal growth factor receptor (EGFR), competitively
inhibiting the binding of epidermal growth factor (EGF) and other
ligands, such as transforming growth factor-.alpha..
[0171] The patient is treated topically at the site of skin
toxicity with 10% EGF (recombinant) in ointment formulation two to
four times a day, with reversal of skin toxicity manifestations,
permitting the full and unattenuated course of cetuximab to be
administered. Systemic absorption of EGF from the topical
application of ointment has negligible effect on clinical efficacy
of cetuximab therapy.
EXAMPLE 6
[0172] A patient being treated with 5-FU by infusion according to
the Roswell Park regimen develops diarrhea. The GI toxicity is
presumed to result from the local activation of 5-FU by OPRT in the
gut.
[0173] The patient is treated orally with a daily mixture of 10 mg
of orotate together with 10 mg adenine in a slow release capsule
formulation; diarrhea is reduced. Orotate, the natural substrate
for OPRT, has about a 50-fold lower Km for OPRT than 5-FU at
neutral pH. Adenine is included to balance purine (adenine) and
pyrimidine (orotate) administration and synthesis. The change in
systemic concentration of orotate and adenine is negligible.
EXAMPLE 7
[0174] A patient is being treated with bevacizumab (AVASTIN.TM.) in
combination with intravenous 5-fluorouracil-based for metastatic
carcinoma of the colon. Bevacizumab is a recombinant humanized
monoclonal IgG1 antibody that binds to and inhibits the biologic
activity of human vascular endothelial growth factor (VEGF).
[0175] The patient manifests skin toxicity.
[0176] A 1% w/v formulation of VEGF (recombinant) in an ointment
formulation is applied to the affected skin areas two to four times
per day, with resolution of the skin toxicity and negligible effect
on the systemic concentration of VEGF.
EXAMPLE 8
[0177] A patient being treated with CPT-11 (CAMPTOSAR.RTM.,
Irinotecan) for therapy of metastatic colorectal carcinoma
manifests serious diarrhea as a toxic side effect of chemotherapy.
Irinotecan and its active metabolite SN-38 bind to the
topoisomerase I-DNA complex and prevent religation of single-strand
breaks.
[0178] Aliquots of a mixture of plasmid DNA and topoisomerase I
protein are sealed in dialysis membranes having MW cutoff
sufficient to retain the protein/DNA complex and admit CPT-11. The
patient ingests (without chewing) one such dialysis tubing twice
per day, with significant reduction in diarrhea, due to partition
of CPT-11 and/or SN38, the active metabolite, into the sealed
dialysis membrane, reducing the level of CPT-11 to which the
gastrointestinal mucosa is exposed. The reaction between SN38 and
topoisomerase I and DNA requires only magnesium.
[0179] All patents, patent publications, and other published
references mentioned herein are hereby incorporated by reference in
their entireties as if each had been individually and specifically
incorporated by reference herein.
[0180] While specific examples have been provided, the above
description is illustrative and not restrictive. Any one or more of
the features of the previously described embodiments can be
combined in any manner with one or more features of any other
embodiments in the present invention. Furthermore, many variations
of the invention will become apparent to those skilled in the art
upon review of the specification. The scope of the invention
should, therefore, be determined by reference to the appended
claims, along with their full scope of equivalents.
* * * * *