U.S. patent application number 14/739339 was filed with the patent office on 2015-11-05 for compositions and methods for treating and preventing dermatoses.
The applicant listed for this patent is Asymmetric Therapeutics, LLC. Invention is credited to John P. Ford.
Application Number | 20150313901 14/739339 |
Document ID | / |
Family ID | 46331882 |
Filed Date | 2015-11-05 |
United States Patent
Application |
20150313901 |
Kind Code |
A1 |
Ford; John P. |
November 5, 2015 |
COMPOSITIONS AND METHODS FOR TREATING AND PREVENTING DERMATOSES
Abstract
The invention encompasses protectant agents including uracil or
a metabolite thereof that effectively treat the cutaneous
toxicities and dermatological side-effects associated with
chemotherapeutic agents. Specifically, and surprisingly, the
compositions of the invention including uracil or a metabolite
thereof are effective for treating various dermatoses including
atopic dermatitis, irritant contact dermatitis, radiation-induced
dermatitis, dry skin dermatitis, papulopustular rashes, xerosis,
pruritus, actinic keratosis, and genital warts.
Inventors: |
Ford; John P.; (Unadilla,
NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Asymmetric Therapeutics, LLC |
Unadilla |
NY |
US |
|
|
Family ID: |
46331882 |
Appl. No.: |
14/739339 |
Filed: |
June 15, 2015 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13566632 |
Aug 3, 2012 |
9084788 |
|
|
14739339 |
|
|
|
|
12893692 |
Sep 29, 2010 |
8258147 |
|
|
13566632 |
|
|
|
|
12114602 |
May 2, 2008 |
7816366 |
|
|
12893692 |
|
|
|
|
12073424 |
Mar 5, 2008 |
7662829 |
|
|
12114602 |
|
|
|
|
11196921 |
Aug 3, 2005 |
7368456 |
|
|
12073424 |
|
|
|
|
10918199 |
Aug 13, 2004 |
6995165 |
|
|
11196921 |
|
|
|
|
10684203 |
Oct 10, 2003 |
6979688 |
|
|
10918199 |
|
|
|
|
10364383 |
Feb 12, 2003 |
|
|
|
10684203 |
|
|
|
|
60355764 |
Feb 12, 2002 |
|
|
|
Current U.S.
Class: |
514/274 |
Current CPC
Class: |
A61K 31/555 20130101;
A61K 9/006 20130101; A61K 31/00 20130101; A61P 35/00 20180101; A61K
31/704 20130101; A61K 31/7072 20130101; A61K 31/337 20130101; A61P
17/04 20180101; A61K 31/513 20130101; A61K 31/513 20130101; A61K
31/505 20130101; A61K 31/337 20130101; A61K 31/7072 20130101; A61K
31/555 20130101; A61K 31/704 20130101; A61P 17/00 20180101; A61P
17/12 20180101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 9/06 20130101; A61K
2300/00 20130101 |
International
Class: |
A61K 31/513 20060101
A61K031/513; A61K 9/06 20060101 A61K009/06; A61K 9/00 20060101
A61K009/00 |
Claims
1-42. (canceled)
43. A method of protecting a mucosal epithelium of a mouth of a
patient from undesirable side-effects of an anticancer composition
comprising 5-fluorouracil or a prodrug thereof, the method
comprising: administering a pharmaceutical composition comprising
uracil to the mucosal epithelium of the mouth of the patient so as
to establish a local concentration of uracil in the mucosal
epithelium sufficient to protect the mucosal epithelium from the
undesirable side-effects, with a circulating concentration of
uracil induced by administration of the pharmaceutical composition
being insufficient to abrogate a clinical efficacy of the
anticancer composition.
44. The method of claim 43, wherein the anticancer composition
comprises 5-fluorouracil.
45. The method of claim 43, wherein the anticancer composition
comprises the prodrug, wherein the prodrug is selected from the
group consisting of ftorafur, doxifluridine, and capecitabine.
46. The method of claim 43, wherein uracil is present in the
pharmaceutical composition at a pharmaceutical concentration by
weight of at least about 0.01%.
47. The method of claim 43, wherein uracil is present in the
pharmaceutical composition at a pharmaceutical concentration by
weight of no more than about 60%.
48. The method of claim 43, wherein the pharmaceutical composition
further comprises at least one carrier generating a delivery
vehicle selected from the group consisting of an oral emulsion, a
magma, a gel, a swish, a lozenge, a paste, a cream, an oral
solution, and a gum.
49. The method of claim 43, wherein the undesirable side-effects
comprise chemotherapy-induced stomatitis.
50. The method of claim 43, wherein the pharmaceutical composition
further comprises a gel-like vehicle such that the pharmaceutical
composition is a topical gel-like formulation.
51. The method of claim 50, wherein the gel-like vehicle comprises
a water-soluble gelling agent, a humectant, and water, and wherein
the gel-like vehicle has a viscosity of about 10,000 to 50,000 cps
at 25.degree. C. as measured with a Brookfield viscometer.
52. The method of claim 51, wherein the water-soluble gelling agent
is selected from the group consisting of agar, bentonite, carbomer,
carbopol, a water-soluble cellulosic polymer, carboxyalkyl
cellulose, hydroxyalkyl cellulose, alkyl cellulose, hydroxyalkyl
alkylcellulose, povidone, kaolin, tragacanth, veegum, and
hydroxypropyl methylcellulose.
53. The method of claim 51, wherein the humectant is selected from
the group consisting of glycerin, propylene glycol, and
sorbitol.
54. The method of claim 51, wherein the gel-like vehicle comprises
0.1% (w/w) to 10% (w/w) water-soluble gelling agent and 0.1% (w/w)
to 20% (w/w) humectant.
55. The method of claim 50, wherein the gel-like vehicle further
comprises at least one antimicrobial preservative.
56. The method of claim 43, wherein the pharmaceutical composition
further comprises 1% (w/w) to 10% (w/w) of at least one sweetening
agent.
57. The method of claim 43 further comprising the step of
systemically administering the anticancer composition to the
patient.
58. A kit for oral delivery of an anticancer composition with
protection of a mucosal epithelium of a mouth of a patient from
undesirable side-effects, the kit comprising: at least one dose of
the anticancer composition, wherein the anticancer composition
comprises 5-fluorouracil or a prodrug thereof; and at least one
dose of a pharmaceutical composition comprising uracil for topical
administration to the mucosal epithelium to establish a local
concentration of uracil in the mucosal epithelium sufficient to
protect the mucosal epithelium from the undesirable side-effects of
the anticancer composition, with a circulating concentration of
uracil from the pharmaceutical composition being insufficient to
abrogate a clinical efficacy of the anticancer composition.
59. The kit of claim 58, wherein the pharmaceutical composition
further comprises at least one carrier generating a delivery
vehicle selected from the group consisting of an oral emulsion, a
magma, a gel, a swish, a lozenge, a paste, a cream, an oral
solution, and a gum.
60. The kit of claim 58, wherein the undesirable side-effects
comprise chemotherapy-induced stomatitis.
61. The kit of claim 58, wherein the pharmaceutical composition
further comprises a gel-like vehicle such that the pharmaceutical
composition is a topical gel-like formulation.
62. The kit of claim 58, wherein the gel-like vehicle comprises a
water-soluble gelling agent, a humectant, and water, and wherein
the gel-like vehicle has a viscosity of about 10,000 to 50,000 cps
at 25.degree. C. as measured with a Brookfield viscometer.
63. The kit of claim 62, wherein the water-soluble gelling agent is
selected from the group consisting of agar, bentonite, carbomer,
carbopol, a water-soluble cellulosic polymer, carboxyalkyl
cellulose, hydroxyalkyl cellulose, alkyl cellulose, hydroxyalkyl
alkylcellulose, povidone, kaolin, tragacanth, veegum, and
hydroxypropyl methylcellulose.
64. The kit of claim 62, wherein the humectant is selected from the
group consisting of glycerin, propylene glycol, and sorbitol.
65. The kit of claim 62, wherein the gel-like vehicle comprises
0.1% (w/w) to 10% (w/w) water-soluble gelling agent and 0.1% (w/w)
to 20% (w/w) humectant.
66. The kit of claim 61, wherein the gel-like vehicle further
comprises at least one antimicrobial preservative.
Description
1. CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/566,632, filed Aug. 3, 2012, which is a continuation of U.S.
application Ser. No. 12/893,692, filed Sep. 29, 2010, which issued
as U.S. Pat. No. 8,258,147, which is a continuation of U.S.
application Ser. No. 12/114,602, filed May 2, 2008, which issued as
U.S. Pat. No. 7,816,366, which application is a continuation of
U.S. application Ser. No. 12/073,424, filed Mar. 5, 2008, which
issued as U.S. Pat. No. 7,662,829, which is a continuation of U.S.
application Ser. No. 11/196,921, filed Aug. 3, 2005, which issued
as U.S. Pat. No. 7,368,456, which is a continuation of U.S. patent
application Ser. No. 10/918,199, filed on Aug. 13, 2004, which
issued as U.S. Pat. No. 6,995,165, which is a continuation-in-part
of U.S. application Ser. No. 10/684,203, filed Oct. 10, 2003, which
issued as U.S. Pat. No. 6,979,688, 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, the disclosures of which are
incorporated herein by reference in their entireties.
2. FIELD OF THE INVENTION
[0002] The invention encompasses compositions and methods of
treating or preventing various dermatoses using compositions or
formulations including uracil or a metabolite thereof.
3. BACKGROUND OF THE INVENTION
3.1 Dermatoses Related to Cancer Treatment
[0003] 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. The
anti-metabolite 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.
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
fluoruracil 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.
[0005] With reference to FIG. 1, tegafur, administered orally, is
converted in the liver to 5-fluorouracil ("FU") by action of
cytochrome P450.
[0006] 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-fluorocyidine (5'-DFCR). Cytidine deaminase, an
enzyme found in most tissues, including tumors, subsequently
converts 5'-DFCR to 5'-deoxy-5-fluorourdine (5'-DFUR). The enzyme
thymidine phosphorylase (TP) then hydrolyzes 5'-DFUR to the active
drug 5-FU.
[0007] Within the cell, -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 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.
[0008] 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.
[0009] 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.
[0010] 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.
[0011] 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).
[0012] 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.
[0013] UFT is a combination of uracil and ftorafur in a 4:1 molar
ratio. UFT is approved for clinical use in Europe and Japan; it has
been denied FDA approval for clinical marketing in the United
States.
[0014] 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).
[0015] 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)).
[0016] 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.
[0017] 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.
[0018] 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).
[0019] And a 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.
[0020] 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.
[0021] 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 patients 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.
[0022] 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.).
[0023] 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 26:4356 (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).
[0024] 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 hand-foot 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 rumor
treatment.
[0025] 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.
[0026] 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-I administration suggested to differ from that seen with
capecitabine and/or 5-FU. Elasmar et al., Jpn J. Clin. Oncol.
31:172 174 (2001).
[0027] 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.
[0028] There is thus a need in the art for compositions and methods
for preventing and/or treating side effects of systemically
administered chemotherapeutic agents.
[0029] 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.
[0030] 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.
3.2. Dermatoses
[0031] While the skin is widely regarded as an ideal barrier to
protect an organism, it is also an organ in its own right and
susceptible to disease and infection. Skin cancers, skin disease
and skin inflammation, aside from being affected by the side
effects of chemotherapy, are disruptive, if not deadly, to the
organism. Furthermore, disease or inflammation of the skin can
further exacerbate the dermatological side effects caused by
chemotherapeutics.
[0032] Dermatoses are diseases of the skin, including cancers,
viruses, bacteria, and inflammatory diseases. Dermatoses may be
hereditary or brought about by contact with allergens, molds, or
pollen. Dermatoses may further be caused or exacerbated by stress
and fatigue. Dermatoses may be the result of deficiencies in
vitamin A or result from other diseases such as diabetes.
Dermatoses may include, but are not limited to, atopic dermatitis,
irritant contact dermatitis, radiation-induced dermatitis, dry skin
dermatitis, papulopustular rashes, xerosis, pruritis, actinic
keratosis, phototoxic dermatitis, genital warts, herpes,
superficial basal cell carcinoma, eczema, psoriasis, acne, tinea
and ulcers.
[0033] Given the scope of underlying causes of dermatoses, most
current treatments are directed to the underlying cause, such as
the particular virus or bacterium. Most current treatments for
dermatoses, therefore, rely on systemic administration of an agent,
such as an anti-biotic or anti-viral, to treat the condition.
Accordingly, current therapies rely on an accurate diagnosis in
order to effectively treat the dermatosis. Furthermore, as is known
in the art, disease can adapt to a treatment to resist the efficacy
of the agent. For example bacteria and viruses can mutate to
develop resistance to a drug. Cancers also can adapt and become
inert to the effects of chemotherapeutic agents.
[0034] The use of topical agents to treat dermatoses is desirable
as it places an agent at the site it is most needed without being
overly invasive or suffering from systemic limitations, such as the
first-pass effect with the liver. However, most topical treatments
are aimed at alleviating certain symptoms and not at treating or
preventing the cause of the dermatosis. Moreover, some treatments,
especially ones available generally may exacerbate a particular
dermatosis, especially if the dermatosis is caused by or
exacerbated by a substance or allergen the subject has been exposed
to.
[0035] Thus a need is felt for an effective topical agent capable
of treating or preventing dermatoses that does not require an acute
diagnosis. Accordingly, a single agent capable of alleviating and
treating various dermatoses, regardless of the underlying cause,
would be of great benefit.
[0036] The present invention provides protectant agents including
uracil or a metabolite thereof that effectively prevent and/or
treat the cutaneous toxicities and dermatological side-effects
associated with chemotherapeutic agents. Additionally, and
surprisingly, the protectant agents including uracil or a
metabolite thereof provide compositions and methods for treating or
preventing various dermatoses.
4. SUMMARY OF THE INVENTION
[0037] The present invention solves these and other needs in the
art by providing methods, compositions, and kits for treating,
preventing, or managing dermatoses including administering a
therapeutically or prophylactically effective amount of uracil or a
metabolite thereof.
[0038] In certain embodiments, the invention encompasses protecting
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.
[0039] The invention also encompasses methods based on the
asymmetric delivery of the anticancer therapeutic agent and a
tissue protectant including uracil or a metabolite thereof 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.
[0040] The invention further encompasses methods of treating or
preventing side-effects caused of systemic anticancer agents by
administering a composition including one or more protectant agents
including uracil or a metabolite thereof to a subject in need
thereof, preferably a mammal, more preferably a human. In certain
embodiments, the protectant may alleviate or prevent certain
side-effects from manifesting. In other embodiments, the protectant
may be of use in local or topical application prior to, during, or
post treatment or combinations thereof.
[0041] In another embodiment, the invention encompasses methods of
treating or alleviating or preventing the onset or progression of
dermatoses, including, for example, eczema, pruritis; psoriasis;
acne; impetigo; warts; tinea; blisters caused by herpes simplex-
and/or herpes simplex-2; atopic dermatitis; irritant contact
dermatitis; radiation-induced dermatitis; dry skin dermatitis;
papulopustular rashes; xerosis; actinic keratosis; genital warts;
superficial basal cell carcinoma; and combinations thereof by
administering a composition including uracil or a metabolite
thereof to a subject in need thereof, preferably a mammal, more
preferably a human.
[0042] In another embodiment, the protectant agent such as, for
example, uracil or a metabolite thereof is administered so as to
achieve high concentration at or within the tissue to be protected,
with low to negligible systemic distribution. In another
embodiment, the protectant agent such as, for example, uracil or a
metabolite, thereof 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.
[0043] In another embodiment, the protectant agent such as, for
example, uracil or a metabolite thereof is 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 agent to levels that are
insufficient to abrogate the clinical efficacy of the systemically
distributed anticancer therapeutic agent or metabolite.
[0044] The spatial differential in concentration achieved in the
methods of the 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 agent such as, for example, uracil or a
metabolite thereof.
[0045] The spatially directed administration of the protectant
agent such as, for example, uracil or a metabolite thereof 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.
[0046] In embodiments of the methods of the invention in which the
protectant agent is, in current clinical practice, coadministered
with the anti-cancer agent to achieve a systemic effect, the method
comprises dissociating the routes of administration of the two
agents, administering the anti-cancer agent by means sufficient to
achieve systemic distribution--such as by enteral or parenteral
systemic administration--and administering the protectant agent
such as, for example, uracil or a metabolite thereof in a spatially
directed fashion.
[0047] The protectant agent such as, for example, uracil or a
metabolite thereof 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.
[0048] Accordingly, in another embodiment, the invention
encompasses methods of protecting a desired body tissue from toxic
effects of one or more systemically distributed anti-cancer
therapeutic agents or metabolites thereof. The method comprises
targeting one or more protectant agents for nonsystemic delivery to
the tissue desired to be protected.
[0049] in other embodiments, targeted nonsystemic delivery includes
administering one or more protectant agents so as to establish a
local concentration of the protectant agent such as, for example,
uracil or a metabolite thereof 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.
[0050] 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.
[0051] In these embodiments, typically the protectant agent is
administered locally to the desired tissue, such as by topical
administration to an integumentary surface, such as skin.
[0052] The timing of administration of the protectant can vary.
[0053] In other embodiments, the one or more protectant agents such
as, for example, uracil or a metabolite thereof 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.
[0054] In other embodiments of the methods of the invention, the
local concentration of each of the one or more protectant agents
such as, for example, uracil or a metabolite thereof 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.
[0055] In some embodiments, at least one of the at protectant
agents such as, for example, uracil or a metabolite thereof
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.
[0056] In other embodiments, at least one of the protectant agents
such as, for example, uracil or a metabolite thereof facilitates in
vivo catabolism of the systemically administered anticancer
therapeutic agent, or a metabolite or precursor thereof.
[0057] The anticancer therapeutic agent, metabolite or precursor
thereof, can be an anti-metabolite, 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.
[0058] 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.
[0059] 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.
[0060] The systemically distributed (typically, systemically
administered) anticancer therapeutic agent can be associated with
toxicity to an epithelium, such as an integumentary or mucosal
epithelium.
[0061] In certain embodiments, the toxicity is hand-foot syndrome.
In these embodiments, the protectant agent such as, for example,
uracil or a metabolite thereof 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.
[0062] In other embodiments, the protectant is useful for treatment
of cutaneous toxicities arising from epidermal growth factor
inhibition (eg, Erbitux.RTM.) including papulopustular rashes,
xerosis and pruritus, and combinations thereof.
[0063] In other embodiments of the methods of the invention, the
targeted nonsystemic delivery of protectant agents such as, for
example, uracil or a metabolite thereof includes 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.
[0064] 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.
[0065] Thus, in another embodiment the invention provides a method
of treating neoplasia.
[0066] 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.
[0067] For example, the method can include the concurrent
administration of one or more protectant agents such as, for
example, uracil or a metabolite thereof 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.
[0068] In other embodiments, the method can comprise the concurrent
administration of one or more protectant agents such as, for
example, uracil or a metabolite thereof 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.
[0069] 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.
[0070] In such embodiments, at least one of the at least one
protectant agents such as, for example, uracil or a metabolite
thereof concurrently administered with the fluompyimidine can be
uracil. The uracil can, for example, be administered topically to
the plantar and/or palmar skin surfaces.
[0071] In another aspect, the invention encompasses pharmaceutical
compositions for local application to a body tissue, the
composition capable of establishing a local concentration of one or
more protectant agents such as, for example, uracil or a metabolite
thereof 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 includes at least one protectant agent
such as, for example, uracil or a metabolite thereof; and a
pharmaceutically acceptable carrier suitable for local
application.
[0072] 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 wt. %, often at least about 0.1 wt. %, even at least
about 1.0 wt. %. In various embodiments, uracil can be present
within at a concentration by weight of no more than about 60 wt. %,
often at a concentration of no more than about wt. 5%.
[0073] In yet a further embodiment, the invention encompasses kits
for oral delivery of an anticancer therapeutic agent or precursor
("prodrug") thereof with reduced toxicity to a desired tissue.
[0074] The kit includes 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.
[0075] In kits, the fluoropyrimidine is capecitabine, the
protectant agent is uracil or a metabolite thereof composition and
the protectant is suitable for topical delivery to the skin. 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%.
5. BRIEF DESCRIPTION OF THE DRAWINGS
[0076] 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:
[0077] FIG. 1 shows the basic metabolic pathways for anabolic
activation and catabolic degradation of fluoropyrimidines.
[0078] FIG. 2 shows a summary of the clinical effects seen in the
various grades of sand and Foot Syndrome.
[0079] FIG. 3A shows a first set of examples of the incidence Hand
and Foot syndrome occurs when treating various cancers with varying
doses of Xeloda.RTM..
[0080] FIG. 3B shows a second set of examples of the incidence Hand
and Foot syndrome occurs when treating various cancers with varying
doses of Xeloda.RTM..
[0081] FIG. 3C shows a third set of examples of the incidence Hand
and Foot syndrome occurs when treating various cancers with varying
doses of Xeloda.RTM..
[0082] FIG. 3D shows the prevalence of Hand and Foot syndrome and
other side effects when treating various cancers with varying doses
of Xeloda.RTM..
[0083] FIG. 4A shows the incidence of Hand and Foot syndrome in
clinical trials for capecitabine.
[0084] FIG. 4B shows the incidence of Hand and Foot syndrome in
clinical trials for drugs in combination.
[0085] FIG. 5 shows the approach to modifying capecitabine dosing
based on the grade of Hand and Foot syndrome.
[0086] FIG. 6 illustrates the reductive and oxidative metabolic
pathway of uracil (or thymine) metabolism to beta-alanine (or
beta-aminobutyric acid) and malonic acid (methyl malonic acid).
6. DETAILED DESCRIPTION OF THE INVENTION
6.1 Compositions of the Invention
[0087] The invention encompasses compositions and formulations that
are useful in treating, preventing or managing various dermatoses.
In certain embodiments, the compositions include at least one
protectant agent including, for example, uracil. Uracil can be
included 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% 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%.
[0088] As used herein, "Compositions" or "Compositions" of the
invention refers to a composition including a therapeutically or
prophylactically effective amount of uracil or a metabolite
thereof.
[0089] Uracil (or thymine) is a pyrmidine and metabolizes according
to the metabolic pathways in FIG. 1. Accordingly, in certain
embodiments the compositions and formulations of the invention
include a metabolite of uracil.
[0090] Accordingly, a metabolite of uracil or a uracil analog may
act as a protectant. The oxidative pathway resulting urea or
derivative thereof and malonic acid or derivatives thereof may
provide beneficial effects to the local area. The topical presence
or production of urea may, for example, rehydrate the epithelium.
This is of use, for example, in relieving radiation-induced
dermatitis. The presence or production of malonic acid or malonate
and derivatives thereof may inhibit cell adhesion and inhibit
inflammation. Such effects are of use in disorders or side effects
including arthritis, asthma, and psoriasis.
[0091] In other embodiments, the compositions can include, for
example, a naturally occurring compound, such as a compound that
serves as a substrate for any one or more of TP, UP, and OPT. The
compound can be a naturally occurring nitrogenous base, such as a
pyrimidine, including uracil or metabolites thereof. In other
embodiments, the compound can be a non-naturally occurring
nitrogenous base, such as a non-naturally occurring pyrimidine.
[0092] Typically, the agents in the compositions 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.
[0093] In other embodiments, the compositions can be one that
facilitates in vivo catabolism of the systemically administered
anticancer therapeutic agent, metabolite, or precursor thereof.
[0094] In other embodiments, the compositions are suitable for
administration locally to the tissue desired to be protected. In
some such embodiments, the compositions are administered topically
to the tissue desired to be protected. In ether such embodiments,
the compositions are administered by local injection, such as by
local injection of a depotized form of the one or more protectant
agents, including for example, uracil or a metabolite thereof.
[0095] The compositions 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.
[0096] 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
treated, the severity of side effects desired to be prevented or
treated, and the formulation of the active agent in the
composition, particularly its concentration in the composition;
determination of the proper dosage schedule of active agent is
within the skill of the clinical artisan.
[0097] For example, in embodiments of the methods of the invention
in which the composition is administered topically to skin in an
ointment, the uracil or a metabolite thereof 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 area in need, for example 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.
[0098] In some embodiments, the amount of uracil or metabolite
thereof administered per dose is at least 0.01 g, 0.02 g, 0.03 g,
0.04 g, 0.0 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 uracil or metabolite thereof
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, 3.5 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.
[0099] For example, in embodiments of the compositions 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.
[0100] In another aspect, the invention provides protectant agents,
including for example uracil or metabolite thereof 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.
[0101] Compositions of the present invention comprise one or more
protectant agents such as uracil or metabolite thereof and at least
one pharmaceutically acceptable carrier or excipient.
[0102] Each of the at least one protectant agents such as uracil or
metabolite thereof 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% 30%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 45%,
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%.
[0103] In certain embodiments, the compositions comprise 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%, 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%, 10%, 0.05%, even as little as 0.01%, with intermediate
values permissible.
[0104] In certain embodiments, the compositions are useful for
treating skin surfaces for example protecting the palmar and/or
plantar from hand-foot syndrome, from side-effect associated with
systemic administration of a fluoropyrimidine, an anthracycline, or
a taxane anticancer therapeutic agent, or metabolite or precursor
thereof, the compositions of the invention typically include uracil
or a metabolite thereof 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.
[0105] In preferred compositions for treating, preventing or
managing 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%, 40%, 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%, 40%, 35%, 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%.
[0106] The exact formulation of the uracil compositions of the
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 at al., Pharmaceutical
Dosage Forms and Drug Delivery Systems, 7th ed., Lippiacott
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.
[0107] Compositions of the 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 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.
[0108] Emollients can be selected from polyols, esters and
hydrocarbons. 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.
[0109] 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 palmirate,
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.
[0110] 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.
[0111] Esters useful as emollients also include ether-esters such
as fatty acids esters of ethoxylated fatty alcohols.
[0112] 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.
[0113] Esters useful as emollients additionally include wax esters
such as beeswax, spermaceti, myristyl myristate, stearyl
stearate.
[0114] Esters useful as emollients still further include sterol
esters, of which cholesterol fatty acid esters are examples
thereof.
[0115] Illustrative hydrocarbon carriers are mineral oil,
polyalphaolefins, petrolatum, isoparaffin, polybutenes and mixtures
thereof.
[0116] 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.
[0117] The compositions of she 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 A3, A32, A51 and A70. Halocarbons including
fluorocarbons are further widely employed propellants.
[0118] 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.
[0119] 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.
[0120] 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.
[0121] 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.
[0122] 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).
[0123] The compositions of the present invention can also include
preservatives, such as methyl paraben and propyl paraben are useful
to prevent microbial contamination.
[0124] In embodiments of the compositions of the present invention
formulated for topical application 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.
[0125] 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.
[0126] 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.
[0127] 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.
[0128] 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.
[0129] In one embodiment of a composition of the 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.
[0130] 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, hydrosyalkyl cellulose, alkyl cellulose, hydroxyalkyl
alkylcellulose), povidone, kaolin, tragacanth and veegum, with
hydroxyalkyl alkyl celluloses such as hydroxypropyl methylcelluose
being preferred.
[0131] Humectants suitable for use with the gel-like vehicle of the
invention include, e.g., glycerin, propylene glycol and sorbitol,
with sorbitol being preferred.
[0132] 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.
[0133] 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.
[0134] 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.
[0135] 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).
[0136] 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.
[0137] 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.
[0138] 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, tactic 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).
6.2. Methods of Treating, Preventing, or Managing Dermatoses
[0139] In certain embodiments, the inventions encompass methods of
treating, preventing, or managing dermatoses. During the course of
testing the compositions of the invention in side-effects
associated with patients undergoing chemotherapy, the inventors
surprisingly and unexpectedly determined that the compositions of
the invention could be useful in treating, preventing, or managing
various dermatoses, in general.
6.2.1. Dermatoses Associated with Chemotherapy
[0140] Accordingly, in certain embodiments, the invention
encompasses methods 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. The toxic agent may be
a chemical, biological, radiochemical, or radiobiological
agent.
[0141] In certain embodiments, 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.
[0142] In certain 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.
[0143] For example, in embodiments in which the patient is being
treated for cancer, the body issue 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.
[0144] In certain embodiments, the protectant, for example, uracil
or a metabolite thereof, is of use for treating the side-effects
caused by systemic anticancer agents. The protectant, for example,
uracil or a metabolite thereof may alleviate or prevent certain
side effects from manifesting. The protectant, for example, uracil
or a metabolite thereof may be of use in local or topical
application prior to, during, or post treatment or combinations
thereof.
[0145] The method may comprise administering one or more protectant
agents for example, uracil or a metabolite thereof to the
subject.
[0146] The protectant for example, uracil or a metabolite thereof
itself may further usefully be a substrate, often biologically
active, for on one or more enzymes involved in the metabolic
activation of the systemically distributed toxic agent. The
protectant, for example, uracil or a metabolite thereof in other
alternative embodiments, can physically reduce, remove or inactive
the anticancer therapeutic at the tissue or organ to be
protected.
[0147] In a first series of embodiments, the one or more protectant
agents, for example, uracil or a metabolite thereof 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. The route of administration is chosen or adapted so as
additionally to constrain the circulating concentration to levels
that are insufficient to abrogate the clinical efficiency of the
systemically distributed anticancer therapeutic agent or
metabolite. By way of example, local concentration may be achieved
by direct administration to a local area or by targeting delivery
to the desired local area. Direct administration may be by
injection or by topical application.
[0148] A spatial differential in concentration may be achieved in
the methods of the present invention to obviate 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 for example, uracil or a metabolite thereof.
[0149] The spatially directed administration of the protectant, for
example, uracil or a metabolite thereof 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, for example, uracil or a metabolite thereof that
would, if administered systemically, diminish or abrogate the
clinical efficacy of the systemically distributed anticancer
therapeutic agent.
[0150] In a second series of embodiments, the one or more
protectant agents, for example, uracil or a metabolite thereof, 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.
[0151] "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.
[0152] 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.
[0153] The circulating concentration of the one or more
protectants, for example, uracil or a metabolite thereof is
constrained to levels that are insufficient to abrogate the
clinical efficacy of the systemically distributed anticancer
therapeutic agent or metabolite thereof.
[0154] "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 be desired to be treated, but is
insufficient to abrogate the clinical efficacy of the systemically
distributed anticancer therapeutic agent or metabolite thereof.
[0155] In typical embodiments, the local concentration of the one
or more protectants in the tissue desired to protect 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).
[0156] In some embodiments, the local concentration of each of the
one or more protectant agents, for example, uracil or a metabolite
thereof 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 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.
[0157] In some embodiments, at least one of the at least one
protectant agents, for example, uracil or a metabolite thereof
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 for example, uracil or a metabolite
thereof 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.
[0158] In various embodiments, the local concentration of
protectant, for example, uracil or a metabolite thereof 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,
for example, uracil or a metabolite thereof in the tissue desired
to be treated. In some embodiments, the local concentration of
protectant, for example, uracil or a metabolite thereof 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, for example, be
a tumor within a body tissue or the entirety of a body tissue
within which a portion of the cells are neoplastic.
[0159] Treatment with the protectant, for example, uracil or a
metabolite thereof is useful for cutaneous toxicities. Cutaneous
toxicities may include papulopustular rashes, xerosis and pruritus,
which have a significant impact on health and quality of life. A
majority of patients treated with agents targeting the epidermal
growth factor receptor (EGFR) experience cutaneous toxicities.
Biologic agents targeting EGFR are as a robust treatment option for
various solid tumors, yet the cutaneous side-effects can severely
affect the ability to provide a sufficient dose. Treatment with the
protectant is useful for cutaneous toxicities arising from
epidermal growth factor inhibition (e.g., Erbitux.RTM.), including
papulopustular rashes, xerosis and pruritus.
[0160] In certain 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
flueropyrimidine, an anthiracycline, 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 planter skin surfaces.
[0161] In other embodiments, the compositions are administered
before the tissue desired to be protected manifests toxic effects
of the systemically distributed anticancer therapeutic agent or
metabolite thereof.
[0162] Often, this prophylactic or preventative administration of
the one or more protectant agents, for example, uracil or a
metabolite thereof is preferred. Such timing is particularly
preferred in embodiments in which the one or more protectant
agents, for example, uracil or a metabolite thereof 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, for example,
uracil or a metabolite thereof.
[0163] The protectant agents may be used to also treat or counter
side-effects from systemic anticancer therapeutic agents.
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.
[0164] The anticancer therapeutic agent (or metabolite thereof) can
be a chemical agent, a biological agent, a radiochemical agent or a
radiobiological agent that has antineoplastic activity.
[0165] 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.
[0166] 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.
[0167] In some of these embodiments, the systemically distributed
anticancer therapeutic agent is a fluoropyrimidine.
[0168] The systemically distributed (typically, systemically
administered) anticancer therapeutic agent can be associated with
toxicity to an epithelium, such as an integumentary or mucosal
epithelium. 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.
[0169] In certain embodiments, the fluoropyrimidine is a
parenterally administrable fluoropyrimidine, such as 5-FU,
ftorafur, Carmofur, capecitabine, doxifluridine, UFT, S-1, or
Emitefur. 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. 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 the systemically distributed anticancer
therapeutic agent or metabolite. The composition comprises at least
one protectant agent; and a pharmaceutically acceptable carrier
suitable for local application.
[0170] 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.
[0171] In other embodiments, the anticancer therapeutic agent can
be a taxane, such as docetaxel or paclitaxel.
[0172] 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.
[0173] The compositions of the present invention may be packaged
for single use or multiple uses, 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.
[0174] 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.
[0175] The compositions of the present invention can also usefully
be packaged in kits. The kits of the present invention can, for
example, usefully comprise a protectant composition and an orally
administrable anticancer therapeutic agent or precursor.
[0176] 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 tegafar, 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.
6.2.2. General Treatment of Dermatoses
[0177] In other embodiments, the invention encompasses the
surprising and unexpected effect of treating, managing, or
preventing the onset or progression of various dermatoses.
Dermatoses are known in the art to encompass disorders of the skin
or dermis. By way of example, dermatoses may include atopic
dermatitis, irritant contact dermatitis, radiation-induced
dermatitis, dry skin dermatitis, papulopustular rashes, xerosis,
pruritus, actinic keratosis, genital warts, superficial basal cell
carcinoma, and combinations thereof.
[0178] In certain embodiments, the invention is directed to the
surprising discovery that compositions including uracil or a
metabolite thereof are useful in treating and/or preventing
dermatoses. Dermatoses may include any disorder or disease of the
skin.
[0179] In other embodiments, compositions including a
therapeutically or prophylactically effective amount of uracil or a
metabolite thereof may further be of use for treating, preventing,
or managing Atopic Dermatitis (AD or eczema). In other embodiments,
the compositions including uracil or a metabolite thereof are
useful in treating, preventing, or managing dry, itchy, inflamed
and scaly skin.
[0180] As used herein and unless otherwise indicated, the terms
"therapeutically," "treatment," or "treating" refers to an
amelioration of a disease or disorder associated with a dermatosis,
or at least one discernible symptom thereof. In yet another
embodiment, "treatment" or "treating" refers to inhibiting the
progression of a disease or disorder associated with a dermatosis,
either physically (e.g., stabilization of a discernible symptom),
physiologically (e.g., stabilization of a physical parameter), or
both. In yet another embodiment, "treatment" or "treating" refers
to delaying the onset of a disease or disorder associated with a
dermatosis.
[0181] As used herein and unless otherwise indicated, the phrase
"therapeutically effective amount" of a Compound or Composition of
the Invention or a pharmaceutically acceptable salt, solvate,
metabolite, or prodrug thereof is measured by the therapeutic
effectiveness of a compound of the invention, wherein at least one
adverse effect of a disorder associated with dermatosis is
ameliorated or alleviated. In one embodiment, the term
"therapeutically effective amount" mean an amount of a drug or
Compound of the Invention that is sufficient to provide the desired
local or systemic effect and performance at a reasonable
benefit/risk ratio attending any medical treatment. In one
embodiment, the phrase "therapeutically effective amount" of a
composition of the invention is measured by the therapeutic
effectiveness of a compound of the invention to alleviate at least
one symptom associated with dermatosis.
[0182] As used herein and unless otherwise indicated, the term
"prophylactically effective" refers to an amount of a Compound or
Composition of the Invention or a pharmaceutically acceptable salt,
solvate, metabolite, or prodrug thereof causing a reduction of the
risk of acquiring a given disease or disorder associated with
dermatosis. Accordingly, the Compounds of the Invention may be used
for the prevention of one disease or disorder and concurrently
treating another (e.g., prevention of HFS, while treating
pruritus). In certain embodiments, the compositions of the
invention are administered to a patient, preferably a human, as a
preventative measure against such diseases. As used herein,
"prevention" or "preventing" refers to a reduction of the risk of
acquiring a given disease or disorder associate with
dermatosis.
[0183] In other embodiments, compositions including uracil or a
metabolite thereof may further be used for treating or preventing
radiation induced dermatitis. Patients undergoing radiation
treatment often suffer radiation dermatitis, resulting in an
interruption in their course of radiation. Radiation dermatitis
manifests with dryness and itchiness in the affected area, pain or
soreness of the skin, as well as breakdown and blistering.
[0184] In other embodiments, compositions including uracil or a
metabolite thereof may further be used for treating patients with
End-Stage Renal Disease who have pruritus associated with the
disease. Persons undergoing hemodialysis treatment for end-stage
renal disease may suffer from dry, cracked skin and moderate to
severe pruritus. It is another facet of the invention that the
protectant may alleviate the problems stimulated by recurrent
hemodialysis.
[0185] In other embodiments, compositions including uracil or a
metabolite thereof may further be used for treating premature
infants often suffer skin disorders as they often lack a fully
developed skin barrier, which puts them at higher risk for skin
infections and divert a portion of their caloric intake to
thermoregulation. The use of the present invention may provide
treatment to alleviate the dermatological perils premature infants
may face.
[0186] In some embodiments, compositions including uracil or a
metabolite thereof may be applied topically to the skin to treat
the skin suffering from a dermatosis. In other aspects, the
compositions will be applied topically to prevent or protect the
skin. By way of example, application of uracil or its metabolities
or analogs thereof to the skin of a subject is useful for treating
or protecting the skin from dermatoses.
[0187] In certain embodiments, compositions including uracil or a
metabolite thereof are useful for patient suffering from a disease
that can manifest with periodic outbreaks on the skin, such as
genital warts. The compositions of the invention may be useful in
preventing skin outbreaks. It will also be apparent to those
skilled in the art that the compositions may be applied to prevent
or treat acne outbreaks.
[0188] In particular embodiments, the compositions are combined
with other topical agents to assist in treating or prevent a skin
disease. By way of example, the uracil or metabolite thereof may be
combined with anti-viral or anti-bacterial agents and applied
together to the skin. Those skilled in the art will appreciate that
restrictions on dosing, as well as other factors such as
convenience, may provide for the topical application of other
agents at separate times and/or intervals as the application of the
compositions of the invention.
6.3 Kits
[0189] 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. The
kit can comprise at least one dose of an orally administrable
anticancer therapeutic agent or precursor thereof; an 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, 8-1, or Emitefur.
[0190] 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%.
[0191] 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.
[0192] 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.
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.
[0193] 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.
[0194] The invention additionally provides a metered-dose package
for coadministration of a first and a second component of a
therapeutic agent. The metered-dose package includes a first
plurality of fluidly noncommunicating chambers, each of the
chambers sealably containing an individual dose of the first
component, and a second plurality of chambers, each of the chambers
capable of reversibly receiving at least one dose of the second
component.
[0195] The metered-dose package of the invention can include any of
the kit embodiments described above and/or the safety or compliance
systems described further below.
[0196] In one embodiment, the first and second component of a
therapeutic agent includes, respectively, a protectant agent of the
invention and an anticancer therapeutic of the invention. These
therapeutics and protectant agents have been described above, any
of which can be included in the metered-dose package of the
invention. The first and second component of a metered-dose package
of the invention is coadministered as described above. Therefore,
all of the various combinations and permutations of a systemic
anticancer therapeutic and a protectant agent above described or
understood by one skilled in the art given the teachings and
guidance provided herein are appropriate for inclusion in
combination, for coadministration, in a metered-dose package of the
invention.
[0197] A metered-dose package of the invention is particularly
useful for associating the first and second components of a
therapeutic agent where at least one of the components is to be
administered in a predetermined dose--such as a maximal acceptable
dose--or formulation, and the second component is to be
administered in a variable, or individualized, dose, depending on
patient factors with a dose prescribed by a physician.
[0198] In this regard, the metered-dose package of the invention
includes a plurality first and second chambers. Such chambers can
be, for example, the containers of the dispensers described further
below. One plurality of chambers can be preloaded with a first
component corresponding to the medicament having a predetermined,
such as maximally acceptable, dose. The second plurality of
chambers can be empty, or capable of reversibly receiving the
medicament having a prescribed and variable dose. The second
plurality of chambers can, for example, be filled by a pharmacist
according to an individualized patient prescription.
[0199] In one specific example of the invention, the preloaded
first component is a protectant agent of the invention, such as a
uracil topical ointment. The empty chamber is designated for
receiving a systemic anticancer therapeutic of the invention such
as an orally administrable dose of capecitabine. The first
plurality can be sealable chambers that are fluidly
noncommunicating.
[0200] The above exemplary metered-dose package format is useful
for efficient and effective dosing of both the systemic anticancer
therapeutic and the protectant agent of the invention because it
allows precise packaging of a predetermined dose, which dose may be
a maximally acceptable dose, together with a variable dose.
[0201] This exemplary format also is beneficial for prescription
accuracy and patient compliance of coadministered medicaments
because it places the coadministered medicaments in association
with each other in a concise and organized package easily
understood by a patient. In this regard, a metered-dose package can
be viewed as a precursor package for a safety or compliance system
of the invention, later to be filled--or partially filled--with the
prescribed anticancer therapeutic. Therefore, all of the
attributes, characteristics, formats and permutations described
below with reference to a safety or compliance system of the
invention are equally applicable to a metered-dose package of the
invention.
[0202] In further embodiments, a metered-dose package of the
invention can include a first plurality of chambers that are
capable of separately releasing their contained dose of first
component. The wall bounding each of the first plurality of
chambers can include an openable member. The openable member can be
responsive to a variety forces including, for example, being
openably responsive to the pressure within its respective chamber.
In this latter embodiment, the wall member can open outwards in
response to an increase in pressure within its respective chamber.
In certain of these embodiments, for example, the wall member can
open in response to pressures that exceed a threshold pressure, the
threshold pressure being achievable by manual application of inward
pressure to a site of the respective chamber's bounding wall
positioned at a distance from the openable member. In various
embodiments, the openable member can be pierceable.
[0203] In yet further embodiments, the first component can be
flowable. Each dose of the flowable first component can be further
constrained within a nonflowable dosage form, the constrained
nonflowable dosage form being sealably contained with the chamber.
For example, the flowable first component can be constrained within
a breakable gel or gel capsule, each such gel or gel capsule being
contained within one of the first plurality of chambers.
[0204] In some embodiments, the flowable component can be
formulated for topical cutaneous administration. In other
embodiments, which need not be mutually exclusive, the flowable
component can be formulated for topical administration to
oropharyngeal mucosae.
[0205] As described above and below, a metered-dose package of the
invention can contain in each of the first plurality of chambers an
identical dose of the first component. For example, the first
component of the therapeutic agent can comprise uracil. The dosage
of uracil can be any of the doses described above.
[0206] A metered-dose package of the invention also can be
formatted to have each of the second plurality of chambers to be
capable of reversibly receiving at least one solid dosage form of
the second component. As with the first plurality of chambers, the
second plurality of chambers also can include a bounding wall
having an openable member. The openable member can be reversibly
sealable. The second plurality of chambers also can be optionally
filled with the second component. The second component can be any
of the systemic anticancer therapeutics of the invention including,
for example, capecitabine, Carmofur, tegafur, doxifluridine, S-1
and emitefur.
[0207] In one specific embodiment, the metered-dose package of the
invention is capecitabine and the dose is either 150 mg or 500 mg.
Accordingly, the plurality of doses of capecitabine includes a
plurality of 150 mg and a plurality of 500 mg doses. In further
specific embodiments, the plurality of first and/or second
therapeutic agent component is sufficient, for example, for at
least a one week course of therapy, al least a two week course of
therapy, or at least a three week course of therapy.
[0208] Also provided is a safety or compliance system. The safety
or compliance system includes at least one dispenser having a
plurality of individual doses of a systemic anticancer therapeutic
associated with a plurality of individual doses of a protectant
agent formulated for nonsystematic delivery, each individual dose
of the systemic anticancer therapeutic associated with each
individual dose of the protectant agent enclosed in one or more
individual compartments, the dispenser having suitable indicia
marked in association with each individual compartment, thereby
identifying each compartment with the day or time when the enclosed
systemic anticancer therapeutic and protectant agent should be
administered. The anticancer therapeutic can be capecitabine and
the protectant agent can be a uracil topical ointment.
[0209] Patient compliance has been defined as "the extent to which
an individual's behavior coincides with medical or health advice."
(Remington's Pharmaceutical Sciences Chapter 103, Volume II, page
1796 (19th Edition (1995)). Conversely, non-compliance encompasses
a variety of behaviors including drug underuse, which encompasses
taking too low a dose or skipping a dose. Non-compliance also
encompasses drug overuse such as taking too high a dose or taking a
dose too frequently. Medication compliance is effected by the
physician's and pharmacists relationship with the patient, and, in
particular, how clearly the physician or pharmacist explains the
treatment regimen to the patient. Non-compliance is generally
higher in the elderly population than in other groups; for patients
over the age of 65, about 20% of all non-elective hospital
admissions are due to mismanagement of prescription medications.
The increased incidence of non compliance in the elderly population
may be due, for example, to declining mental function, increasing
numbers of medications prescribed or an increase in side effects or
drug interactions associated with multiple drug regimens (Murray et
al., DICP 20:146 (1986)). Unfortunately, counseling, education and
behavior modification techniques have achieved only limited success
in boosting patient compliance. Pharmaceutical non-compliance is a
particularly argent problem in the case of antineoplastic chemical
compound therapies, a class of drug which can be fatal when
ingested at excessive doses.
[0210] The present invention provides a safety or compliance system
useful for home administration of a therapeutic agent such as the
antimetabolites or anthracyclines described above in combination
with one or more protectant agents. In particular, the invention
provides a safety or compliance system that contains at least one
dispenser including plurality of individual doses of a systemic
anticancer therapeutic and a plurality of individual doses of a
protectant agent formulated for nonsystemic delivery or
administration, each individual dose of the systemic anticancer
therapeutic is associated with each individual dose of the
protectant agent and is enclosed in one or more individual
compartments. Such a dispenser can have, for example, suitable
indicia marked in association with each individual compartment,
thereby identifying each compartment with the day or lime when the
enclosed systemic anticancer therapeutic and/or protectant agent
should be administered.
[0211] In a safety or compliance system of the invention, the
dispenser can include, for example, at least two individual doses
of systemic anticancer therapeutic and at least individual doses of
protectant agent. A dispenser included in a safety or compliance
system of the invention also can include, for example, a plurality
of individual doses of systemic anticancer therapeutic in
association with a comparable plurality of individual doses of
protectant agent that corresponds to a prescribed treatment
period.
[0212] It is understood that the safety or compliance systems of
the invention can be useful for any patient prescribed a systemic
anticancer therapeutic and protectant agent including, but not
limited to, any outpatient-prescribed anticancer therapy and
protectant agent that is associated with side effects due to the
anticancer therapeutic. One skilled in the an understands that a
safety or compliance system of the invention can be useful for
patients suffering from any of a variety of disorders including,
but not limited to, any of those described above such as breast
cancer, colorectal cancer, head and neck cancer, and other
neoplastic conditions.
[0213] A safety or compliance system of the invention contains at
least one dispenser that includes a plurality of individual doses
of systemic anticancer therapeutic in association with a plurality
of individual doses of a protectant agent, each individual dose of
systemic anticancer therapeutic and protectant agent are enclosed
or positioned in one or more individual compartments. Such a safety
or compliance system can have, for example, a single dispenser that
includes a single daily dose, a weekly dose, a biweekly dose or a
monthly dose of systemic anticancer therapeutic and protectant
agent. Thus, a safety or compliance system of the invention is a
pharmaceutical system that can contain any desired treatment regime
of a systemic anticancer therapeutic and a protectant agent as one
individual unit.
[0214] Systemic anticancer therapeutics can be prescribed in a
variety of different treatment regimes. For example, capecitabine
is typically prescribed as a daily individual dose for an interval
of two weeks. The amount of capecitabine is determined by the
surface area of the patient, and is typically administered orally
using combinations of pills selected from 150 mg and 500 mg dosage
strengths. A protectant agent such as uracil topical ointment can
be administered in any of the dog dosages described above. A
particularly useful ointment contains a concentration of about
0.1-1% uracil, with a dose in the range of about 0.4-2 g. As
described above, protectant agents of the invention can be
administered as a single dose once, twice or thrice daily, for
example, for the duration of the anticancer treatment regiment.
Applying a protectant agent in a nonsystemic delivery formulation
such as a topical ointment beneficially raises the local
concentration at the site of protection while the systemic
concentration remains sufficiently low so as not to interfere with
the systemic anticancer therapeutic effects.
[0215] The plurality of individual doses provided in a dispenser of
the invention which corresponds to a daily, weekly, biweekly or
monthly treatment regime of a systemic anticancer therapeutic
included in a safety or compliance system of the invention is
provided in an effective amount. Such an amount generally is the
minimum dose necessary to achieve the desired reduction in severity
of one or more symptoms of the condition to be treated over the
course of the treatment, such as that amount roughly necessary to
reduce the discomfort caused by the condition to tolerable levels
or to result in a significant reduction in the discomfort caused by
the condition. Such amounts generally are in the range of 0.1-5000
mg/day and can be, for example, in the range of 0.1-500 mg/day,
0.5-500 mg/day, 0.5-100 mg/day, 0.5-50 mg/day, 0.5-30 mg/day, 1-20
mg/day, 2.5-20 mg/day or 2.5-15 mg/day, with the actual amount to
be prescribed and included in the safety or compliance system
determined by a physician taking into account the relevant
circumstances including the severity and type of condition to be
treated, the age and weight of the patient, the patient's general
physical condition, the cumulative dose, the characteristics of the
active compounds and pharmaceutical formulation, and the route or
routes of administration.
[0216] As used herein in reference to a systemic anticancer
therapeutic or protectant agent of the invention, the term "daily,"
"weekly," "biweekly" or "monthly" dose means the total amount of
systemic anticancer therapeutic and/or protectant agent prescribed
or determined to be taken within the referenced treatment period
(one day, seven days, 14 days or about 30 days). It is understood
that individual doses can be prescribed to be administered, for
example, as a single individual dose, or can be prescribed to be
administered in two, three, or more individual doses, or can be
prescribed to be administered in daily, twice daily or thrice daily
individual doses to be taken every day of the week. Thus, where,
within a biweekly treatment period (14 days), 2,100 mg capecitabine
is prescribed to be administered as daily individual doses of equal
amounts, the biweekly dose of capecitabine is 2,100 mg but the
individual daily doses are 150 mg. Similarly, where, within a
biweekly treatment period, 7,000 mg is prescribed to be
administered as daily individual doses of equal amounts, the
biweekly dose of capecitabine is 7,000 mg but the individual daily
doses are 500 mg. It is understood that, where a dose for a
particular treatment period is administered as a single dose, the
dose for the referenced period will be the same as the individual
dose, defined herein below.
[0217] Daily, weekly, biweekly or monthly doses of the systemic
anticancer therapeutics of the invention are well known in the art
and prescribed by a physician. Any of such doses can be included in
the dispenser as, for example, a single individual dose, two or
more individual doses, daily individual doses to be administered
every day of the week, or twice daily individual doses to be
administered every day of the week. In particular embodiments, any
of such doses for a desired treatment period are included in the
dispenser as daily individual doses to be administered every day of
the week. In further embodiments, any of such doses are included in
the dispenser as twice daily individual doses to be administered
every day of the week, or as thrice daily individual doses to be
administered every day of the week.
[0218] Daily, weekly, biweekly or monthly doses of a protectant
agent formulated, for example, in a nonsystemic composition such as
a topical ointment have been described above. Any of such doses can
be associated with the chosen systemic anticancer therapeutic in a
dispenser of the invention as, for example, a single individual
dose, two or more individual doses, daily individual doses to be
administered every day of the week, or twice daily individual doses
to be administered every day of the week. In particular
embodiments, any of such doses for a desired treatment period of
protection are included in the dispenser as daily individual doses
to be administered every day of the week. In further embodiments,
any of such doses are included in the dispenser as twice daily
individual doses to be administered every day of the week, or as
thrice daily individual doses to be administered every day of the
week. One skilled in the art understands that the dosages and
treatment regimes exemplified herein for a systemic anticancer
therapeutic associated with a protectant agent for dual
administration and action are encompassed by the safety or
compliance systems of the invention.
[0219] As used herein in reference to a systemic anticancer
therapeutic or a protectant agent the term "individual dose" means
the total amount of therapeutic and analog prescribed to be
administered at a particular time, for example, on a particular day
or particular hour of a particular day. Thus, an individual dose is
defined by the time at which it is prescribed to be taken; such a
dose can be provided, for example, as a single pill or multiple
pills, which can be packaged together in the same compartment or
packaged in two or more individual compartments, provided that the
multiple pills are prescribed to be taken by the patient at the
same time. In view of the above, it is understood that an
individual dose can be composed of a single pill, tablet, capsule,
spoonful, vial, ampule etc., or can be composed of multiple pills,
tablets, capsules, spoonfuls, vials, ampules, etc., or a
combination thereof. Two different individual doses are typically
prescribed to be administered at two times separated by two or more
hours such as, without limitation, four hours, eight hours, 12
hours, 24 hours or more. In specific embodiments, such an
individual dose is administered one daily, twice daily or thrice
daily.
[0220] The term "daily individual dose," as used herein in
reference to a dose of a systemic anticancer therapeutic or a
protectant agent, means an individual dose prescribed to be taken
once a day. A daily individual dose is typically prescribed to be
taken for several days in a row and can be prescribed to be taken
at the same time of day.
[0221] As a non limiting example, an individual dose of a systemic
anticancer therapeutic can be provided as a single tablet in a
single compartment, or as multiple tablets packaged in a single or
multiple individual compartments to be taken by the patient at the
same time. As a further non limiting example, an individual dose of
a systemic anticancer therapeutic and a protectant agent can be
associated by packaging together in a single compartment or in two
individual compartments, where the systemic anticancer therapeutic
and protectant agent are prescribed to be administered together at
the same time. As a further non limiting example, two or more
individual doses of a systemic anticancer therapeutic can each be
provided as a single tablet in two or more individual compartments
to be administered, for example, two or more times daily, with
protectant agent packaged together in the same compartment or
associated with one or more daily doses of the systemic anticancer
therapeutic. Generally, an individual dose of protectant agent of
the invention will be administered with each individual dose of a
systemic anticancer therapeutic and therefore have an association
with each individual dose of the therapeutic.
[0222] As described above, the association between systemic
anticancer therapeutic and protectant agent formulated for
nonsystemic delivery can be in the same compartment or in different
compartments. For example, pills, tablets, vials and the like of
systemic anticancer therapeutic can be placed in a sealable
container together with an individual dose of a protectant agent.
The protectant agent can similarly be confined in a capsule, vial,
gel cap and the like appropriate for the mode of nonsystemic
administration. Alternatively, association of the individual doses
for a systemic anticancer therapeutic and a protectant agent of the
invention can be accomplished by, for example, structuring the
dispenser of the safety or compliance system of the invention to
contain pairs of containers in an organizational association that
spatially associates the coadministered individual doses.
Similarly, and as described further below, association of
individual doses for a systemic anticancer therapeutic and a
protectant agent of the invention also can be accomplished by, for
example, inclusion of suitable indicia marked in association with
each individual compartment that identifies each compartment with
the day or time when the enclosed systemic anticancer therapeutic
and protectant agent should be administered.
[0223] Although exemplified above with reference to individual
doses deposited in single containers or in pairs of containers for
association of a systemic anticancer therapeutic dose and a
protectant agent dose, given the teachings and guidance provided
herein, those skilled in the art will understand that such
associations can be performed with three or more as well as larger
pluralities of individual doses that are to be associated in the
system of the invention for administration at the same time and
date. Similarly, those skilled in the art also will understand that
the associations described herein are only exemplary and that there
exists a variety of other formats and permutations of compartmental
structure, spatial at arrangements, indicia markings and all
combinations thereof that can be routinely designed to achieve the
same outcome and purpose of the various associations exemplified
herein. Accordingly, the safety and compliance system of the
invention provides the requisite association of an individual dose
of a systemic anticancer therapeutic and of an individual dose of a
protectant agent for a prescribed treatment regime and/or treatment
period.
[0224] The term "dispenser," as used herein, means a structure that
includes individual compartments, which are means for retaining and
physically separating individual doses, or portions therefore, of a
systemic anticancer therapeutic, a protectant agent or the combined
individual doses for a systemic anticancer therapeutic and a
protectant agent. It is understood that a dispenser is amenable to
removal of an individual dose and that the individual compartments
of a dispenser can open reversibly or irreversibly. In one
embodiment, each individual compartment is located at a fixed
position relative to the other individual compartments. A dispenser
useful in the invention can optionally include, if desired, a
visual or recordable means for indicating when individual
compartments are opened.
[0225] In view of the definition of an individual dose, one skilled
in the art understands that each individual compartment in a
dispenser contains at most one individual dose of either a systemic
anticancer therapeutic, a protectant agent or both a systemic
anticancer therapeutic and a protectant agent but and never
contains two or more individual doses of the same medicament
together. In certain embodiments, an individual compartment can
contain a portion of an individual dose as exemplified
previously.
[0226] A variety of dispensers are useful in a safety or compliance
system of the invention including, without limitation, a blister
pack composed of for example, disposable cardboard or paper or a
reusable plastic card; a surface with doses of medicament removably
affixed thereto; a circular or substantially circular dispenser
with compartments for every day of the month; a dispenser
containing predetermined dose injection units; or a credit-card
style medication package containing a month's worth of medication.
Dispensers known in the art and suitable for use in the safety or
compliance systems of the invention further include, but are not
limited to, those described in U.S. Pat. No. 4,736,849; U.S. Pat.
No. 4,889,236; U.S. Pat. No. 5,265,728; U.S. Pat. No. 6,039,208;
U.S. Pat. No. 6,138,866; U.S. Pat. No. 6,439,422; GB 2 237 204 A;
publication 0 393 942 A1; and WO 01/68454 A2. Commercially
available dispensers also are useful in the invention such as,
without limitation, SlidePack7, E Ztear (PCI Services, Inc.;
Cardinal Health), Pill Pak.TM., and DialPak7 tablet dispensers
(Ortho Pharmaceutical Corporation; Raritan, N.J.). One skilled in
the art understands that these and other disposable or refillable
dispensers, including electronic dispensers and those with audio or
visual cues, can be useful in the safety or compliance systems of
the invention.
[0227] A safety or compliance system of the invention can include a
plurality of dispensers. As non-limiting examples, a safety or
compliance system can include one, two, three, four, five, six,
seven, eight, nine, ten, eleven or twelve dispensers each
containing a complete daily, weekly, biweekly or monthly dose of a
systemic anticancer therapeutic associated with a like plurality of
daily, weekly, biweekly or monthly doses of a protectant agent.
Where multiple dispensers are packaged together in a safety or
compliance system, the dispensers can be of the same or different
types, and further can be of the same type containing identical or
different individual doses of systemic anticancer therapeutic or
protectant agent.
[0228] A blister pack is a dispenser which can be useful in the
safety or compliance systems of the invention. As used herein, the
term "blister pack" is a dispenser in which each compartment is an
individual cavity having a rupturable backing. In one embodiment,
the cavities or "pockets" are translucent. In a blister pack,
individual doses of medication are dispensed by pushing the
medication through the rupturable backing. In certain embodiments
where the protectant agent of the invention is, for example, a
topical ointment, the ointment can be directly loaded into the
compartment extruded therefrom for administration. Alternatively,
the protectant agent can be contained in a vial, gel cap or the
like that can be removed from the compartment at the time of
administration. The vial, gel cap or the like can be opened such as
by tearing a perforated edge and the ointment can be extruded for
topical or local application. The vial, gel cap or the like also
can be removably attached to the inside of the compartment.
[0229] In one embodiment, a blister pack dispenser useful in the
invention includes a first sheet having a plurality of apertures,
each aperture defining an opening having an area large enough for
the individual dose of systemic anticancer therapeutic or
protectant agent to pass through; and a second sheet overlapping a
portion of the first sheet, said second sheet forming a plurality
of hollow cavities, said hollow cavities sealed with a rupturable
backing to form a plurality of blister compartments arranged in a
pattern on the sheet, with each rupturable backing arranged to
overlap each aperture.
[0230] The first sheet generally is made of a moderately rigid
material such as cardboard or coated cardboard, or plastic such as,
without limitation, polyvinyl chloride of a thickness of about 0.5
mm to about 1 mm. The apertures can be of a variety of shapes, for
example, circular, elliptical or of another shape appropriate to
the egress of the anti folate therapeutic or folic acid analog. The
second sheet is typically formed of a thin, flexible material such
as clear polyvinyl chloride or other flexible material including,
but not limited to, other translucent materials. The hollow
cavities can be formed, for example, by thermal vacuum-drawing of
the second sheet in accordance with standard practices in the
packaging art. The rupturable backing can be formed, for example,
of a thin layer of any of a variety of frangible materials such as
metal foil. As one example, aluminum foil, of a thickness of
between about 0.25 mm to 0.15 mm can be used as the rupturable
backing. In one embodiment, a blister pack is of a size that can be
conveniently accommodated in a shirt or other pocket. Such a
blister pack can be, for example, of a size of 3 to 4 inches by 4
to 5 inches. A variety of blister packs are known in the art and
have been described hereinabove.
[0231] As another non limiting example, a dispenser can be a
DialPak7 tablet dispenser in which tablets are arrayed circularly
and rotated one at a time to an aperture through which a selected
tablet can be expelled from the package, with days of the week
provided as indicia to guide the user to the appropriate tablet for
the current day.
[0232] A dispenser useful in the invention optionally includes a
visual or other recordable means for compliance monitoring, such
dispensers are well known in the art and encompass, without
limitation, U.S. Pat. No. 4,617,557; U.S. Pat. No. 5,289,157; U.S.
Pat. No. 5,852,408; U.S. Pat. No. 6,401,991; WO 02/083057 A1; as
well as the Medic.TM., ECM.TM., available from Information Mediary
Corporation (Ontario, Canada). A recordable means for compliance
monitoring also car be included in a safety or compliance system of
the invention in a form separate from the dispenser. Non-limiting
examples of separate recordable means can be found described in,
for example, U.S. Pat. No. 6,075,755 or U.S. Pat. No.
4,837,719.
[0233] A dispenser useful in a safety or compliance system of the
invention can be optionally marked with suitable indicia in
association with each compartment. Such indicia can be, for
example, the days of the week or the month or abbreviations
therefore such as "M" "T" "W" "Th" "F" "S" "S" or, for example,
"Day 1," "Day 2," etc. through "Day 7" or "Day 1," "Day 2," etc.
through "Day 14" and/or "Day 31." Suitable indicia also can
include, for example, the time of day such as, without limitation
"morning" and "evening;" "breakfast" and "dinner;" "lunch" and
"bedtime," "breakfast," "lunch," "dinner" and "bedtime;" or "A.M."
and "P.M." In some cases, the indicia may apply to multiple
compartments. As one example, a bracket or equivalent symbol can be
used to indicate the same dose of systemic anticancer therapeutic
and/or protectant agent included in multiple compartments. As a
further example, in a calendar pack containing a month's worth of
medication, the designation "Monday" placed above a column of four
compartments can refer to each of the four compartments.
[0234] In particular embodiments, multiple dispensers are included
in a safety or compliance system of the invention, with each
dispenser containing, for example, medication exactly for a daily,
weekly, biweekly or monthly treatment regime divided into
individual doses and associated for coadministration of the
systemic anticancer therapeutic and the protectant agent. In cases
in which a safety or compliance system contains multiple
dispensers, each separate dispenser can be optionally marked with
"Week 1," "Week 2," "Week 3," "Week 4" etc. Alternatively, each
dispenser can be optionally marked with "1", "2," "3," and "4" or
"Dispenser 1," "Dispenser 2," "Dispenser 3," and "Dispenser 4" or
other equivalent language. It is understood that multiple
dispensers included together in a safety or compliance system of
the invention may not be marked so as to be distinguishable from
each other.
[0235] The suitable indicia marked in association with each
compartment can include, if desired, the name of the systemic
anticancer therapeutic or name of the protectant agent or
appropriate abbreviation. As another option, the dose of one or
both of the systemic anticancer therapeutic and protectant agents
also can be marked on the dispenser in association with the
appropriate compartment.
[0236] All of the elements of a safety or compliance system of the
invention can be optionally packaged in an outer container made of
any suitable material. Such an outer container can be constructed,
for example, of any appropriate paper or plastic material, or a
combination thereof. The outer container typically is of a size to
accommodate standard pharmacy prescription labels and can have,
without limitation, a rectangular or square shape.
[0237] It further is understood that a safety or compliance system
of the invention, with or without an outer container, can be
packaged in a child resistant manner or tamper-evident manner or
both. Child resistant blister packages can incorporate, for
example, at least one of the child-resistant features described in
ASTM D 3475, or another feature which meets standard requirements
for child resistance. Well known child-resistant blister cards
included SlidePack7 and E-Ztear packages. Additional child
resistant packaging, including child resistant blister packaging,
also is well known in the art, as described, for example, in U.S.
Pat. Nos. 3,503,493; 3,809,220; 3,809,221; 3,924,746; 3,924,747;
4,011,949; 4,398,634; and 4,537,312. One skilled in the art
understands that these and other child-resistant and tamper-evident
dispensers and outer containers can be useful in a safety or
compliance system of the invention.
[0238] A safety or compliance system of the invention optionally
includes one or more reminder aids. Such a reminder aid can be,
without limitation, one or any combination of reminder cards with
information to remind the patient when to take a dose of
medication; adhesive stickers with information to remind the
patient when to take a dose of medication; or a visual or
recordable means that is activated at the time an individual dose
should be taken. It is understood that such recordable means
encompass those to be set by the patient as well as those set, for
example, by the manufacturer or pharmacist.
[0239] A safety or compliance system of the invention further
optionally includes patient information provided separately from
any outer container and the one or more dispensers. Such patient
information can be provided, for example, as a paper insert or
booklet and generally includes dosing information. The patient
information provided cat further optionally include, without
limitation, side effect information, patient incentive information
or information on the disease being treated. The term "patient
information," as used herein, means any information of interest to
a patient being treated with a systemic anticancer therapeutic and
a protectant agent. Such patient information includes, but is not
limited to, any or all of the following: dosage information;
importance of complying with dosage and administration
instructions; side effect information, optionally including when
during therapy side effects typically occur or how to manage side
effects; anticipated benefits of therapy; and information regarding
the disease or condition being treated. The patient information can
additionally include, if desired, instructions regarding how and
when to make up any missed doses as well as patient incentive
information such as statements that encourage compliance by
highlighting the benefits of proper administration. Patient
information also can include, for example, warnings regarding
possible drug interactions as well as conditions that may be
inconsistent with the prescribed treatment or which may require a
special dosage or special monitoring. The information is generally
provided in a form which avoids complex and difficult medical
terminology, using simple words appropriate to all educational
levels.
[0240] The safety or compliance systems of the invention include
both a systemic anticancer therapeutic and a protectant agent
enclosed in a dispenser in association with each other. For
convenience, the term "medicament" is used herein to mean either a
systemic anticancer therapeutic or a protectant agent as described
above and further below.
[0241] A safety or compliance system of the invention can
optionally include any of a variety of drugs or other active
compounds in addition to the systemic anticancer therapeutics and
protectant agents of the invention. Such a drug or active compound
can be for example, any drug or compound beneficial to an
individual incurring cancer therapy and/or susceptible to side
effects of such treatment.
[0242] A safety or compliance system of the invention can
optionally include one or more placebos. A placebo lacks the
anticancer therapeutic or the protectant agent or both and
generally is any substance lacking significant pharmacological
activity. In one embodiment, a safety or compliance system of the
invention includes a placebo for every day on which no systemic
anticancer therapeutic or protectant agent is prescribed.
[0243] As described previously, any of the systemic anticancer
therapeutics and protectant agents of the invention can be included
in a safety or compliance system of the invention in any of a
variety of convenient or beneficial formulations. In one specific
embodiment, the systemic anticancer therapeutic is formulated for
oral administration as a pill and the protectant agent is
formulated for nonsystemic delivery as a topical ointment. However,
given the teachings and guidance provided herein, a systemic
anticancer therapeutic and a protectant agent of the invention also
can be formulated for other routes of administration, depending,
for example, on the type and severity of condition to be treated,
and the history, risk factors and symptoms of the subject. The
formulations can be for the same or different routes of
administration and associated in a dispenser of a safety or
compliance system of the invention as exemplified previously. As
described above, such formulations can be, for example, formulated
for systemic administration for the anticancer therapeutic and for
local or nonsystemic administration for the protectant agent.
Formulations include, for example, compositions for oral
administration or for administration by dermal patch; topical
drops, creams, gels or ointments; or for parenteral administration;
for subcutaneous, intramuscular, intravenous or other injection;
and as extended release formulations. Acceptable dosage forms
include, without limitation, tablets, pills, capsules, GelCaps
(gelatin coated capsules) and other solid formulations, gels,
creams, ointments, suppositories, powders, liquids, suspensions,
emulsions, pre-filled syringes, aerosols and the like.
[0244] 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.
6.4. Combination Therapy
[0245] The compositions of the invention, which include a
therapeutically or prophlactically effective amount of uracil or a
metabolite thereof, can further include a therapeutically or
prophlactically effective amount of a second active agent for
treating, preventing or managing skin conditions.
[0246] In some aspects, the compositions further include a
therapeutically or prophlactically effective amount of one or more
antiviral compounds when the dermatosis is based on a viral
infection, such as with herpes simplex-1 and -2, as well as fifth
disease or other parvovirus B19 diseases. By way of example, the
protectant agent may be used with antiviral agents such as
abacavir, aciclovir, acyclovir, adefovir, amantadine, amprenavir,
arbidol, atazanavir, brivudine, cidofovir, combivir, darunavir,
delavirdine, didanosine, docosanol, edoxudine, efavirenz,
emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen,
fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine,
immunovir, idoxuridine, indinavir, inosine, integrase inhibitors,
interferon type III, interferon type II, interferon type I,
lamivudine, lopinavir, maraviroc, moroxydine, nelfinavir,
nevirapine, nexavir, nucleoside analogues, oseltamivir,
penciclovir, peramivir, pleconaril, podophyllotoxin, protease
inhibitors, ribavirin, rimantadine, ritonavir, saquinavir,
stavudine, tenofovir, tenofovir disoproxil, tipranavir,
trifluridine, trizivir, tromantadine, valaciclovir, valganciclovir,
vidarabine, viramidine, zalcitabine, zanamrivir, or zidovudine.
[0247] In other embodiments, the compositions further include a
therapeutically or prophlactically effective amount of one or more
anti-inflammatory agents, such as acetylsalicylic acid, NSAIDs,
corticosteroids, anti-arthritics, gold or gold salts, DMARDs,
methotrexate, cyclophosphamide, sulfasalazine, minocycline,
azathipine cyclosporin, penicillamine, hydroxychloroquine,
leflunomide, ibuprofen, naproxen, leukotriene inhibitors, COX-1
and/or COX-2 inhibitors, paracetamol, cortisone, corticosterone,
arylalkanoic acids, 2-arylpropionic acids, N-arylanthranilic acids,
pyrazolidine derivatives, oxicams, or sulfonanilides.
[0248] In other embodiments, the compositions further include a
therapeutically or prophlactically effective amount of one or more
anti-bacterial agents such as antispetics, antibiotics, alcohols,
boric acid, azelaic acid, quaternary ammonium compounds,
chlorohexidine gluconate, zinc, hydrogen peroxide, iodine, sodium
hypochlorite, mercurochrome, octenidine dihydrochloride, phenol,
sodium chloride, aminoglycosides, ansamycins, carbacephams,
carbapenems, cephalosporins (first on, second, third, third,
fourth, or fifth generation), macrolides, glycopeptides,
monobactams, penicillins, polypeptides, quinolones, sulfonamides,
chloramphenicol, tetracyclines, clindamycin, lincomycin,
antifungals, metronidazole, rifampin, or isoniazid.
7. EXAMPLES
[0249] The following examples are offered by way of illustration
only, and not by way of limitation.
7.1. Example 1
[0250] 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.
[0251] 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 UFT. Thus, the mean systemic uracil exposure with
uracil ointment averages about 0.00005 (0.005%) that of UFT.
[0252] 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.
7.2. Example 2
[0253] 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.. FIGS. 3A, 3B and 3C
illustrate the incidence of Hand and Foot syndrome in patients
treated with Xeloda.RTM..
[0254] Table 1 below summarizes results on this patient.
TABLE-US-00001 TABLE 1 Course q3wk 1 2 3 4 5 6 7 8 Xeloda dose 1250
mg/m.sup.2 Same D/C 1000 mg/m.sup.2 1250 mg/m.sup.2 Same Same Same
14/21 days bid .times. 14 after 4 days bid .times. 14 bid .times.
14 Taxotere + + + + + + + + 75 mg/m.sup.2 Marker tumor 12 .times.
12 8 .times. 8 7 .times. 7 7 .times. 7 9 .times. 9 8.5 .times. 8.5
8 .times. 8 8.5 .times. 8.5 size cm- progression prior to rx on
lower dose Xeloda .RTM. 1% uracil 0 0 0 0 + + + + ointment
Hand-foot ND* ND ++++ ++ 0 0 0 0 syndrome *ND: Not described
[0255] The 1% uracil ointment allowed a re-escalation of the dose
of Xeloda.RTM. with antitumor 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.
7.3 Example 3
[0256] 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.
7.4. Example 4
[0257] 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.
[0258] 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.
[0259] 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.
7.5. Example 5
[0260] 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.
[0261] 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..
[0262] 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.
7.6. Example 6
[0263] 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.
[0264] 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.
7.7. Example 7
[0265] 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).
[0266] The patient manifests skin toxicity.
[0267] 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.
7.8. Example 8
[0268] 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 t-DNA complex and prevent religation of single-strand
breaks.
[0269] 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- 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.
7.9. Example 9
[0270] The metabolism of uracil or analogs and derivative thereof
to urea is useful for rehydrating the skin. It has previously been
examined by Strahlenther (Onkol 179: 708-712, 2003) whether urea
could effect radiation-induced skin toxicity. Briefly, Strahlenther
observed 88 patients with carcinomas of the head and neck
undergoing radiotherapy with curative intent (mean total dose 60
Gy, range: 50-74 Gy) were evaluated weekly for acute skin reactions
according to the RTOG-CTC score. In 63 patients, moist skin care
with a 3% urea lotion was performed. The control group consisted of
25 patients receiving conventional dry skin care. The incidence of
grade I, II, and III reactions and the radiation dose at occurrence
of a particular reaction were determined and statistically analyzed
using the log-rank test. The dose-time relations of individual skin
reactions are described.
[0271] At some point of time during radiotherapy, all patients
suffered from acute skin reactions grade 1, >90% from grade II
reactions. 50% of patients receiving moist skin care experienced
grade I reactions at 26 Gy as compared to 22 Gy in control patients
(p=0.03). Grade II reactions occurred at 51 Gy versus 34 Gy
(p=0.006). Further, 22% of the patients treated with moist skin
care suffered from acute skin toxicity grade III as compared to 56%
of the controls (p=0.0007).
[0272] Moist skin care with 3% urea lotion delays the occurrence
and reduces the grade of acute skin reactions in percutaneously
irradiated patients with head and neck tumors.
7.10. Example 10
[0273] Hand foot syndrome (Palmar plantar crythrodysesthesia) is
common side effect of capecitabine. FIG. 4 illustrates the
frequency with which capecitabine treatment results in Hand and
Foot syndrome, Grade II-III toxicity is seen in 10-50% of the
patients and may lead to discomfort with activities of daily
living. Interruption in the treatment and dose reductions are very
frequent due to this toxicity. FIG. 5 shows the approach to coping
with Hand and Foot syndrome through dose reduction. A study
reported at the ASCO Annual Meeting in 2004 (Vol. 22, No. 14S at
page 8105) analyzed the efficacy of local application of
keratolytic agent urea (12.5%) (Cotoryl.RTM.) on capecitabine
induced toxicity.
[0274] This study showed that patients on capecitabine were
followed for signs of hand foot syndrome. Thirteen such episodes
were recorded. Out of theses 4 episodes were of grade III and 9 of
grade II toxicity. All had dry furrowed skin, rash, desquamation on
the palms of the hands and soles of the feet. Patients with grade
III toxicity had additionally painful erythema, discomfort with
activities of daily living. All patients were asked to apply
locally, twice a day, urea containing moisturizing ointment. The
same preparation was used prophylactically in 7 cycles of
capecitabine.
[0275] This application reportedly had a dramatic impact on
dermatological complications within 2-3 days of initiation. The
effect lasted till continuation of the application and lead to
reduction in desquamation, pain, and comfort level of all the
patients improved. Neurological symptoms reportedly improved as
well. All patients were able to complete the chemotherapy cycle as
per the schedule and without interruption or delays. Efficacy was
seen in patients where it was used prophylactically. 5/7 did not
develop cutaneous manifestation and two had grade I toxicity.
[0276] Urea containing preparation appears to be excellent choice
for the prevention and treatment of capecitabine induced hand foot
syndrome. This minimizes drag delays, schedule interruptions and
maintains the dose density. Owing to reduced morbidity, the drug
tolerance and acceptance is considerably improved.
7.11. Example 11
[0277] UFT.RTM. is a mixture of 5FU ad uracil in molar proportions
of 1:4, which was chosen based on preclinical models that suggested
maximal tumor selectivity with these relative concentrations.
Uracil acts as a modulator on the catabolism of FU as it is a
natural substrate for DPD, uracil will compete with 5FU.
Furthermore, as its molar concentration is much higher than that of
5FU, little 5-FU is degraded by DPD, and thus, more is available to
the anabolic route of activation.
[0278] Co-administration of 5FU and uracil may therefore produce a
constant reserve of 5 FU and its active metabolites and to minimize
production of inactive and potentially toxic metabolites.
7.12. Example 12
[0279] Ten patients have been treated from one to six months, with
reports of complete efficacy in preventing Hand and Foot syndrome.
Further, there have been no reports of toxicity. The projected
systemic absorption of uracil from the claimed invention is
described in Table 2. The calculations are based on topical
application of 1 g of cream to the hands and 1 g to the feet twice
a day, totaling 4 g. Uracil is at a concentration of 1% of the
cream. A volume of distribution (Vd) of 50 L is assumed.
TABLE-US-00002 TABLE 2 Percent Absorption Total mg in body
Concentration (ng/mL) 100 40 800 10 4 80 5 2 40 1 0.4 8
[0280] Given the chemistry of uracil, it is unlikely that more than
5% will be typically absorbed, indicating the concentration will be
below 40 ng/mL. The normal level of uracil is reported to be
33.6+/-12 ng/mL (Ochoa et al. Annals of Oncology 10: 1313-1322,
2000). Accordingly, the present invention while efficacious for
topical treatment, will not substantially increase the patient's
systemic levels of uracil.
[0281] 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.
[0282] 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.
* * * * *