U.S. patent application number 14/021723 was filed with the patent office on 2014-01-09 for use of allopurinol for the treatment of palmar plantar erythrodysesthesia.
This patent application is currently assigned to NOBERA PHARMA, S.L.. The applicant listed for this patent is Yolanda Rodemer. Invention is credited to Yolanda Rodemer.
Application Number | 20140011820 14/021723 |
Document ID | / |
Family ID | 38512579 |
Filed Date | 2014-01-09 |
United States Patent
Application |
20140011820 |
Kind Code |
A1 |
Rodemer; Yolanda |
January 9, 2014 |
USE OF ALLOPURINOL FOR THE TREATMENT OF PALMAR PLANTAR
ERYTHRODYSESTHESIA
Abstract
Use of allopurinol or a pharmaceutically acceptable salt thereof
for the treatment or prevention of palmar plantar
erythrodysesthesia induced by chemotherapy. The allopurinol or its
salt is administered topically to the affected areas, palms and
soles, preferably in the form of a cream.
Inventors: |
Rodemer; Yolanda;
(Wilhemshaven Rustersiel, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Rodemer; Yolanda |
Wilhemshaven Rustersiel |
|
DE |
|
|
Assignee: |
NOBERA PHARMA, S.L.
Tres Cantos
ES
|
Family ID: |
38512579 |
Appl. No.: |
14/021723 |
Filed: |
September 9, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13114768 |
May 24, 2011 |
8557829 |
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14021723 |
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12227807 |
Jun 22, 2009 |
7973046 |
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PCT/EP2007/055367 |
May 31, 2007 |
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13114768 |
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Current U.S.
Class: |
514/262.1 |
Current CPC
Class: |
A61P 17/02 20180101;
A61P 25/04 20180101; A61P 17/00 20180101; A61P 35/00 20180101; A61P
17/16 20180101; A61K 31/519 20130101 |
Class at
Publication: |
514/262.1 |
International
Class: |
A61K 31/519 20060101
A61K031/519 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 1, 2006 |
EP |
EP06011432.9 |
May 8, 2007 |
EP |
EP07107744.0 |
Claims
1-13. (canceled)
14. A method for treating or preventing palmar plantar
erythrodysesthesia (PPE) induced by fluoropyrimidine chemotherapy
or by pegylated doxorubicin in a patient in need thereof comprising
administering to the patient a medicament having an amount of
allopurinol or a pharmaceutically acceptable salt thereof which is
therapeutically effective to treat or prevent PPE.
15. A pharmaceutical composition for the topical administration to
the skin, comprising from 1-10% by weight of the total composition
of allopurinol or a pharmaceutically acceptable salt thereof,
wherein the pharmaceutical composition is formulated to topical
administration to the skin, and is free of methylsulphonylmethane
or cetomacrogol.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to the field of therapy,
especially in oncology. It relates to the use of allopurinol or its
pharmaceutically acceptable salts for the treatment or prevention
of chemotherapy-induced palmar plantar erythrodysesthesia (PPE). It
also relates to pharmaceutical compositions comprising allopurinol
and to methods for the treatment of PPE.
BACKGROUND OF THE INVENTION
[0002] Cancer is a group of diseases in which abnormal cells divide
without control. Cancer cells can invade nearby tissues and can
spread through the bloodstream and lymphatic system to other parts
of the body. There are several main types of cancer. Carcinoma is
cancer that begins in the skin or in tissues that line or cover
internal organs. Sarcoma is cancer that begins in bone, cartilage,
fat, muscle, blood vessels, or other connective or supportive
tissue. Leukemia is cancer that starts in blood-forming tissue such
as the bone marrow, and causes large numbers of abnormal blood
cells to be produced and enter the bloodstream. Lymphoma and
multiple myeloma are cancers that begin in the cells of the immune
system.
[0003] Several treatments are available for cancer, including
surgery and radiation for localised disease, and drugs that destroy
cancer cells (chemotherapy). Chemotherapy plays a significant part
in cancer treatment, as it is required for the treatment of
advanced cancers with distant metastasis and often helpful for
tumor reduction before surgery (neoadjuvant therapy). It is also
used following surgery or radiation (adjuvant therapy) to destroy
any remaining cancer cells or prevent recurrence of the cancer.
[0004] Many anti- cancer drugs have been developed based on various
modes of action: alkylating agents that act directly on the DNA
(such as cisplatin, carboplatin, oxaliplatin, busulfan,
chlorambucil, cyclophosphamide, ifosfamide, dacarbazine);
antimetabolites that interfere with DNA and RNA synthesis (such as
5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate,
gemcitabine, cytarabine (ara-C), fludarabine); anthracyclines that
interfere with enzymes involved in DNA replication (such as
daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone);
microtubule disrupters (taxanes such as paclitaxel and docetaxel or
Vinca alkaloids such as vinblastine, vincristine, and vinorelbine);
topoisomerase inhibitors (such as etoposide, doxorubicin, topotecan
and irinotecan); hormone therapy (such as tamoxifen, flutamide) and
recently introduced targeted therapy (such as the inhibitors of
EGFR cetuximab, gefitinib or the protein tyrosine kinase inhibitor
imatinib) are the most frequently used.
[0005] Cancer chemotherapy may consist of a single drug or
combinations of drugs that are delivered in cycles. A cycle
consists of treatment with one or more drugs followed by a period
of rest.
[0006] The development of chemotherapy in the last decades has
significantly improved the treatment of cancer, resulting in
effective treatments in some types of cancers, and improved
survival or time to progression in others. Currently, most
chemotherapy is administered intravenously; however, oral
chemotherapy drugs are gaining wider use.
[0007] Unfortunately, most chemotherapy drugs cannot difference
between a cancer cell and a healthy cell. Therefore, chemotherapy
often affects the body's normal tissues and organs which results in
complication of treatments, or side effects. In addition to the
problems they cause, side effects can prevent doctors from
delivering the prescribed dose of chemotherapy, reducing the
probability of a correct treatment of cancer. Most frequent side
effects of chemotherapy are anemia, neutropenia, thrombocytopenia,
fatigue, alopecia, nausea and vomiting, mucositis and pain.
[0008] Palmar plantar Erythrodysesthesia (PPE) was first described
by Zuehlke in 1974 as a erythematous eruption of the palms and
soles associated with mitotane therapy (Zuehlke, R. K.
Dermatologica, 1974, 148(2), 90-92). PPE is a distinctive and
relatively frequent toxic reaction related to some chemotherapeutic
agents. It is a painful swelling and erythematous rash, located in
the palms and soles, often preceded by dysesthesia, usually in the
form of a tingling sensation, and often associated with edema. The
rash may become bollous and then desquamate without scarring, and
pain gradually increases. Erythema may also occur in periungal
areas. Generally it is confined to the hands and feet, the hands
are usually more severely affected than the feet.
[0009] Histologically PPE shows mild spongiosis, scattered necrotic
and dyskeratotic keratynocites and vacuolar degeneration of the
basal layer. Dermal changes in most cases include dilated blood
vessels, papillary edema, and a sparse superficial perivascular
limphohistiocytic infiltrate that can be found in varying degrees
in the epidermis.
[0010] PPE is clearly distinct from other adverse skin reactions
and is reviewed in Nagore E. et al, Am J Clin Dermatol. 2000, 1(4),
225-234 which is incorporated herein by reference in its
entirety.
[0011] The severity of PPE can be classified according to the
following WHO grades: [0012] 1. Dysesthesiaiparesthesia, tingling
in the hands and feet. [0013] 2. Discomfort in holding objects and
upon walking, painless swelling or erythema. [0014] 3. painful
erythema and swelling of palms and soles, periungual erythema and
swelling. [0015] 4. Desquamation, ulceration, blistering, severe
pain.
[0016] Another grading is based on the US National Cancer Institute
criteria: [0017] 1. Skin changes or dermatitis without pain (E.g
erythema, peeling) [0018] 2. Skin changes with pain, not
interfering with function [0019] 3. Skin changes with pain
interfering with function
[0020] Among the agents that have been reported to cause PPE,
Fluorouracil (5-FU), Capecitabine (Xeloda.RTM.), pegylated
Liposomal doxorubicin (Caelyx.RTM./Doxil.RTM.), Cytarabine
(Cytosar-U.RTM.), Floxuridine (FUDR.RTM.), Tegafur and Idarubicin
(Idamycin.RTM.) are the most frequent inducers.
[0021] Fluorouracil is a fluorinated pyrimidine that is metabolized
intracellularly to its active form, fluorouridine monophosphate,
that inhibits DNA synthesis. It is indicated for several types of
cancer, among others as adjuvant or palliative therapy in breast,
colorectal, gastric and pancreatic cancer. The benefits of
fluorouracil based adjuvant chemotherapy in reducing the risk of
relapse and prolonging survival in patients with resected colon
cancer are well established, particularly in stage III disease.
Survival advantages were demonstrated with bolus intravenous
fluorouracil (425 mg/m.sup.2) plus leucovorin (a biomodulator)
according to the Mayo Clinic regimen (five days, monthly, for six
months), or the Roswell par regimen (weekly bolus, six of every
eight weeks, for eight months) (Sun W. et al Curr Oncol Rep. 2005
May; 7(3):181-5). For metastatic colon cancer a 24 hour continuous
infusion of high dose 5-FU (2600 mg/m.sup.2) and leucovorin weekly
for 6 weeks followed by a 1 or 2 week rest period (AIO protocol)
showed improved progression free survival compared with the Mayo
protocol (Kohne et al J Clin Oncol, 2003, vol 21, no. 20,
3721-3728).
[0022] New combinations of fluorouracil are emerging, such as with
oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) showing survival
benefits in the treatment of colorectal cancer (Goldberg,
Oncologist 2005; 10 Suppl 3:40-8. Review). Most of these
combinations use infusional fluorouracil.
[0023] In spite of the obvious benefits of Fluorouracil as a
chemotherapy, the incidence of PPE is frequent with the bolus and
high dose continuous infusion regimens. This is a reason for dose
reduction or interruption of the treatment, In metastatic colon
cancer, the prolonged 5-FU.sub.24H/LV schedule resulted in higher
incidence of PPE (34%) compared with the Mayo protocol (13%) (J
Clin Oncol, 1998, vol 16, 3537-3541). Infusional fluorouracil is
also responsible for PPE in the treatment of breast cancer, see for
example Smith I E et al. Ann. Oncol. 2004, 15(5) 751-758.
[0024] Capecitabine (Xeloda.RTM.) is a prodrug, an oral
fluoropyrimidine carbonate that is activated into fluorouracil in
tumor tissue by thymidine phosphorylase. It is used as adjuvant
therapy for the treatment of colon cancer, as first line therapy
for metastatic colorectal cancer, and for the treatment of advanced
or metastatic breast cancer. In a recently reported phase III
study, capecitabine was compared with fluorouracilfleucovorin (Mayo
protocol) as adjuvant treatment for stage III colon cancer (Twelves
C. et al., N Engl J Med 2005, 352, 2696-2704). Concerning efficacy,
capecitabine was shown to be equivalent to fluorouracil+leucovorin.
As first line treatment for metastatic colorectal cancer,
capecitabine achieved response rates superior to those achieved
with the Mayo Clinic regimen with equivalent progression free
survival and overall survival (Van Cutsem E. et al. Br J Cancer
2004, 90:1190-1197).
[0025] Concerning toxicity, in both cases capecitabine showed less
incidence of severe grade 3 or 4 stomatitis and neutropenia.
However, the incidence of hand-foot syndrome (PPE) was
significantly higher with capecitabine than with
tluorouracil+leucovorin, being as high as 49-60% for all grades and
17% for severe grades. This resulted in dose reduction, delay or
interruption of the treatment. In metastatic breast cancer the same
situation arises, capecitabine alone or in combination with
docetaxel showed improved efficacy versus docetaxel, but one of the
most common dose limiting adverse effecs is PPE.
[0026] In view of the above, although capecitabine has the
important advantage of being an oral drug and more convenient for
the patient, in particular in combination treatments, palmar planar
erythrodysesthesia remains one of the main causes for concern when
using this drug.
[0027] Another drug that is frequently associated with PPE is
pegylated liposomal doxorubicin, i.e. doxorubicin hydrochloride
encapsulated in long-circulating stealth liposomes with surface
bound methoxypolyethylene glycol. The pegylation protects the
liposomes from detection by the inmune system allowing them to
reach a tissue or organ characterized by a higher permeability of
the endothelium, such as a tumor. Liposomal doxorubicin is used for
the treatment of advanced ovarian cancer and of metastatic breast
cancer. PPE with this drug is related to the schedule, and the
incidence is relatively high: 37.4% for all grades, with 16.4% for
severe grades were reported in ovarian cancer. Toxicity can be
reduced by a reduction in dose intensity (for example from 50
mg/m.sup.2 every 4 weeks to 40 mg/m.sup.2, Rose P G, The
Oncologist, 2005, 10: 205-214).
[0028] Palmar plantar erythrodysesthesia is thus an important side
effect for the mentioned chemotherapeutic agents. However, little
is known of its causes and at present there is no therapy or
prophylaxis for PPE proved to be effective. Chemotherapy reduction,
delay or withdrawal can be effective in reducing or eliminating
PPE, but at the cost of seriously compromising the chemotherapeutic
treatment of cancer.
[0029] Some of the few treatments that have been proposed are: cold
compresses or ice packs, especially during chemotherapy; elevating
hands or feet; skin hydration; emollient skin creams containing
lanolin, lactic acid, petrolleum jelly (for example Bag Balm.RTM.
petroleum lanolin based ointment with hydroxyquinoline sulfate as
antiseptic ingredient, or Aquaphor.RTM.), and topical or oral
corticosteroids such as dexamethasone, Pyridoxine (vitamin B6) has
been used to decrease the pain from PPE (Fabian et al. Invest. New
Drugs 1990, 8:57-63; Lauman M K et al. ASCO Proceedings, 2001,
abstract 1565) and it appears to provide some symptomatic benefit
in patients being treated with capecitabine.
[0030] Amifostine, a cytoprotective agent, has been used to try to
prevent PPE in patients being traeated with liposomal doxorubicin
(Lyass O. et al, ASCO Proceedings, 2001, abstract 2148).
[0031] U.S. Pat. No. 6,060,083 discloses the use of topical DMSO
for the treatment of PPE, in particular when caused by pegylated
liposomal doxorubicin.
[0032] U.S. Pat. No. 6,979,688 describes the topical use of uracil
ointment for the treatment of PPE induced by fluorouracil or a
precursor thereof.
[0033] None of the proposed treatments has yet been able to
effectively treat or prevent PPE. It is clear that an effective
treatment of PPE is still needed, in order to untie the full
potential of chemotherapeutic agents such as fluorouracil,
capecitabine or pegylated liposomal doxorubicin and the different
regimens and combinations in which they are used.
[0034] Allopurinol is a structural isomer of hypoxanthine, that
inhibits xanthine oxidase, an enzyme that converts oxypurines to
uric acid. By blocking the production of uric acid, this agent
decreases serum and urine concentrations of uric acid, thereby
providing protection against uric acid-mediated end organ damage in
conditions associated with excessive production of uric acid. It
has been used for many years for the treatment or prevention of
gout, hyperuricemia and kidney stones, through oral or parenteral
systemic administration.
[0035] Allopurinol has also been reported for the treatment of
mucositis, a frequent chemotherapy- or radiation-induced damage to
the rapidly dividing cells lining the mouth, throat and
gastrointestinal (GI) tract. Allupurinol is used in the form of
mouthwashes (dispersion in water) (porta C. et al, Am J clin Oncol.
1994, Vol 17, no. 3, 246-247). An improved formulation for
mouthwashes comprising allopurinol, carboxymethylcellulose and
water is described in JP-3106817. Hanawa et al. in Drug Dev Ind
Pharm 2004, 30(2) 151-161 describe another mouthwash comprising
allopurinol, polyethyleneoxide and carrageenan.
[0036] Dagher et al., canadian journal of Hospital pharmacy, vol.
40, no. 5 1987, page 189 discloses the use of allopurinol mouthwash
and vaginal 0.1% cream for the treatment of 5-FU-Induced
mucositis.
[0037] Allopurinol has also been administered systemically to
modulate the 5-fluorouracil myelosuppresion, in particular
granulocytopenia (Woolley at al. J. of Clinical Oncology, 1985 vol.
3, no. 1, 103-109). However, preclinical studies showed antagonism
between the two drugs.
[0038] EP278040 describes the use of pteridines or xanthine oxidase
inhibitors, among other allopurinol, for the treatment of
genetically caused, degenerative retina diseases such as
retinopathia pigmentosa, in the form of topically administrable eye
drops or eye creams. There is no specific disclosure in this
document of a topical composition containing allopurinol.
[0039] WO94/05293 and WO94/05291 describe synergistic compositions
comprising methylsuphonylmethane (MSM) and at least one of
oxypurinol or allopurinol and their use for the treatment of skin
conditions, diseases and injuries such as burns, dermatitis,
hyperkeratosis, sun exposure, skin ageing, etc. Oxypurinol or
allopurinol are described as enhancing the skin healing or
repairing properties of MSM.
[0040] None of the cited documents mentions or suggests that
allopurinol would be useful for the treatment or prevention of
palmar planar erythrodysesthesia.
SUMMARY OF THE INVENTION
[0041] The inventor has surprisingly found that allopurinol, when
applied topically to the palms and soles of the patient, is very
effective in the treatment and prevention of palmar planar
erythrodysesthesia induced by fluoropyrimidine chemotherapy. As
show in the examples, topical application of allopurinol to cancer
patients being treated with chemotherapy completely avoided the
appearance of PPE.
[0042] In one aspect the invention is directed to use of
allopurinol or a pharmaceutically acceptable salt thereof in the
manufacture of a medicament for the treatment or prevention of
palmar plantar erythrodysesthesia induced by fluoropyrimidine
chemotherapy.
[0043] In a second aspect, the invention is directed to a
pharmaceutical composition for the topical administration to the
hands and feet, comprising from 1-10% by weight of allopurinol or a
pharmaceutically acceptable salt thereof, with the proviso that it
does not comprise methylsulphonylmethane or cetomacrogol.
[0044] In a third aspect, the invention is directed to a method for
treating or preventing palmar plantar erythrodysesthesia induced by
fluoropyrimidine chemotherapy in a patient affected or likely to be
affected by this syndrome, comprising topically applying to the
hands and feet a therapeutically effective amount of allopurinol or
a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0045] Palmar plantar erythrodysesthesia (PPE) is also known as
acral erythema, hand-foot syndrome, palmar planar erythema,
Burgorf's syndrome, and toxic erythema of the palms and soles. In
the context of the present invention, the term palmar plantar
erythrodysesthesia include all these synonyms when they describe
conditions related to chemotherapy as described above.
[0046] In the context of the present invention the term allopurinol
refers also to the different tautomers of the compound, since it is
a tautomeric mixture of lH-pyrazolo[3,4-d]pyrimidin-4-ol and
1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one:
##STR00001##
[0047] As mentioned above, the topical application of allopurinol
or one of its pharmaceutically acceptable salt has surprisingly
been found to be useful for the treatment and prevention of
PPE.
[0048] Thus, in one aspect the invention is directed to use of
allopurinol or a pharmaceutically acceptable salt thereof in the
manufacture of a medicament for the treatment or prevention of
palmar plantar erythrodysesthesia induced by fluoropyrimidine
chemotherapy.
[0049] In one embodiment the medicament is in the form of a cream.
Preferably the cream is an hydrophylic cream.
[0050] In another embodiment the medicament is for the treatment of
PPE induced by fluorouracil, capecitabine, either alone or in
combination with other agents.
[0051] The medicament is thus useful for the treatment of patients
suffering from cancer, preferably from colorectal cancer, ovarian
cancer, breast cancer, gastric gastric and pancreatic cancer and
receiving chemotherapy, either as adjuvant, neoadjuvant or
palliative. Example of patients and chemotherapies inducing PPE
have been discussed in the section background of the invention and
is incorporated herein. The medicament for the treatment of PPE is
particularly useful in patients receiving or about to receive
infusional 5-FU, capecitabine, either alone or in combination with
other agents.
[0052] In another embodiment, the medicament for the treatment of
PPE induced by pegylated doxorubicin, particularly in patients
receiving or about to receive pegylated doxorubicin.
[0053] Without willing to be bound by theory, it is believed that
when applied topically to the palms and soles, allopurinol acts
locally at the level of the epidermis, inhibiting the metabolism of
the cytotoxic drugs.
[0054] The toxicity to the palms and soles, characteristic of PPE,
may be due to a specific local enzymatic activity of this skin
area, the enzymes being probably involved in the metabolism of the
cytotoxic drugs. Keratinocytes made up 90% of epidermal cells. It
is important to note that the keratinocytes of the palms and soles
have a specific phenotype, such as production of keratin 9,
hypopigmentation and thick suprabasal layers that diferenciates
them from the keratinocytes of other parts of the skin.
[0055] Schwartz et al, in Biochem Pharmacol, 1988, 37,353-355 have
shown that human keratinocytes have a higher Thymidine
Phosphorylase (TP) activity, that is not present in other animals.
This activity is responsible of the salvage of thymidine for DNA
synthesis. Other studies show a strong expression of TP in the
basal layer of the epidermis.
[0056] Thymidine phosphorylase is an enzyme involved in the
activation of 5'DFUR (a metabolite of capecitabine) into 5-FU, It
can also be involved in the activation of 5-FU, Thymidine
phosphorylase (TP) is markedly upregulated in many solid tumors
such as colorectal, breast and kidney cancers, locally activating
prodrugs of fluoropyrimidines that "target" the tumors. This enzyme
is also known as the angiogenic platelet-derived endothelial cell
growth factor (PD-ECGF), that stimulates endothelial cell migration
in vitro and angiogenesis in vivo and plays an important role in
tumour progression and metastasis.
[0057] Fischel et al. Anti Cancer Drugs 2004, 15 969-974 propose
that capecitabine toxicity in the palms and soles may be due to the
elevated TP activity in the skin, in particular in these areas
where it is known that epidermal renewal is particularly active.
According to this hypothesis high levels of cell proliferation and
TP activity can be present in this cutaneous area, inducing
angiogenesis and drug metabolism. Thus, if the tissue of the palms
and soles shows similarities with tumor tissue, it is plausible
that the chemotherapeutic agents have increased specific toxic
activity against the keratinocytes of the palms and soles in the
same way as they target proliferating tumor tissue.
[0058] Our hypothesis is that when administered topically
allopurinol acts directly or indirectly inhibiting the enzyme
thymidine phosphorylase. Interestingly, Allopurinol has been
described in Gallo et al. J Biological Chemistry 1968, vol. 243,
4943-4951, to be a selective inhibitor of deoxythymidine
phosphorylase, another name for the enzyme thymidine phosphorylase.
It inhibits TP but not uridine phophorylase.
[0059] Allopurinol could be acting by a reduction of the local
production of active toxic metabolites that can be responsible for
the symptoms of PPE. Local application allows an effective
targeting of the affected areas, and avoids the toxicities and
complications that systemic allopurinol can provoke in cancer
patients, in particular it avoids interfering with the
chemotherapy.
[0060] In one embodiment the treatment is for reducing or
preventing PPE in patients being treated systemically with
chemotherapy comprising an agent selected from Fluorouracil (5-FU)
or Capecitabine (Xeloda.RTM.).
[0061] In another embodiment the treatment is for reducing or
preventing PPE in patients being treated systemically with
chemotherapy comprising Liposomal pegylated doxorubicin
(Doxil.RTM., Caelyx.RTM.).
[0062] The invention further relates to a topical pharmaceutical
composition for the treatment of the hands and feet, comprising
from 1%-10% by weight of allopurinol or a pharmaceutically
acceptable salt thereof, together with at least one topically
acceptable carrier material, with the proviso that it does not
comprise methylsulphonylmethane or cetomacrogol.
[0063] Allopurinol is a compound very slightly soluble in water and
alcohol; practically insoluble in chloroform and in ether; it
dissolves in dilute solutions of alkali hydroxides. It can be used
as such, or, to improve the solubility in water, a salt such as the
sodium salt can be used instead of the base.
[0064] In the topical compositions of the invention, allopurinol or
its salt is typically present in an amount of from about 1 up to
10%, in particular form 1-8%, more particularly from l-6%,
especially from 1 up to 5%. Below 1% the concentration of
allopurinol is not sufficient to treat or prevent effectively PPE,
In concentrations above 10% the allopurinol can have undesired side
effects for the skin of the patient.
[0065] A preferred range is from 2 up to 5%, more preferably from
2-4% of the total composition on a weight basis. An amount of about
3% has given good results and is especially preferred. All
percentages given are weight-% (w/w), if not indicated
otherwise.
[0066] Pharmaceutical compositions of the invention, suitable for
topical administration to the hands and feet, preferably to the
palms and soles, are for example creams, lotions, ointments,
microemulsions, fatty ointments, gels, emulsion-gels, pastes,
foams, tinctures, solutions, patches, bandages and transdermal
therapeutic systems. Most preferred are creams or
emulsion-gels.
[0067] Creams or lotions are oil-in-water emulsions. Oily bases
that can be used are fatty alcohols, especially those containing
from 12 to 18 carbon atoms, for example lauryl, cetyl or stearyl
alcohol, fatty acids, especially those containing from 10 to 18
carbon atoms, for example palmitic or stearic acid, fatty acid
esters, e.g. glyceryl tricaprilocaprate (neutral oil) or cetyl
palmitate, liquid to solid waxes, for example isopropyl myristate,
wool wax or beeswax, and/or hydrocarbons, especially liquid,
semi-solid or solid substances or mixtures thereof, for example
petroleum jelly (petrolatum, Vaseline) or paraffin oil. Suitable
emulsifiers are surface-active substances having predominantly
hydrophilic properties, such as corresponding non-ionic
emulsifiers, for example fatty acid esters of polyalcohols and/or
ethylene oxide adducts thereof, especially corresponding fatty acid
esters with (poly)ethylene glycol, (poly)propylene glycol or
sorbitol, the fatty acid moiety containing especially from 10 to 18
carbon atoms, especially partial glycerol fatty acid esters or
partial fatty acid esters of polyhydroxyethylene sorbitan, such as
polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty
acid esters (Tweens), and also polyoxyethylene fatty alcohol ethers
or fatty acid esters, the fatty alcohol moiety containing
especially from 12 to 18 carbon atoms and the fatty acid moiety
especially from 10 to 18 carbon atoms, such as
polyhydroxyethyleneglycerol fatty acid ester (for example Tagat S),
or corresponding ionic emulsifiers, such as alkali metal salts of
fatty alcohol sulfates, especially having from 12 to 18 carbon
atoms in the fatty alcohol moiety, for example sodium lauryl
sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are
usually used in the presence of fatty alcohols, for example cetyl
alcohol or stearyl alcohol. Additives to the aqueous phase are,
inter alia agents that prevent the creams from drying out, for
example humectants, such as polyalcohols, such as glycerol,
sorbitol, propylene glycol and/or polyethylene glycols, and also
preservatives, perfumes, gelling agents, etc.
[0068] Ointments are water-in-oil emulsions that contain up to 70%,
but preferably from approximately 20% to approximately 50%, water
or aqueous phase. Suitable as fatty phase are especially
hydrocarbons, for example petroleum jelly, paraffin oil and/or hard
paraffins, which, in order to improve the water-binding capacity,
preferably contain suitable hydroxy compounds, such as fatty
alcohols or esters thereof, for example cetyl alcohol or wool wax
alcohols, or wool wax or beeswax. Emulsifiers are corresponding
lipophilic substances, for example of the type indicated above,
such as sorbitan fatty acid esters (Spans), for example sorbitan
oleate and/or sorbitan isostearate. Additives to the aqueous phase
are, inter alia humectants, such as polyalcohols, for example
glycerol, propylene glycol, sorbitol and/or polyethylene glycol,
and also preservatives, perfumes, etc
[0069] Microemulsions are isotropic systems based on the following
four components: water, a surfactant, for example a tensioactive, a
lipid, such as a non-polar or polar oil, for example paraffin oil,
natural oils such as olive or maize oil, and an alcohol or
polyalcohol containing lipophilic groups, for example
2-octyldodecanol or ethoxalated glycerol or polyglycerol esters. If
desired, other additives may be added to the microemulsions.
Microemulsion have micelles or particlaes with sizes below 200 nm
and are transparent or translucid systems, the form spontaneoulsy
and are stable.
[0070] Fatty ointments are water-free and contain as base
especially hydrocarbons, for example paraffin, petroleum jelly
and/or liquid paraffins, also natural or partially synthetic fat,
such as fatty acid esters of glycerol, for example coconut fatty
acid triglyceride, or preferably hardened oils, for example
hydrogenated groundnut oil, castor oil or waxes, also fatty acid
partial esters of glycerol, for example glycerol mono- and
di-stearate, and also, for example, the fatty alcohols increasing
the water-absorption capacity, emulsifiers and/or additives
mentioned in connection with the ointments.
[0071] With gels, a distinction is made between aqueous gels,
water-free gels and gels having a low water content, which gels
consist of swellable, gel-forming materials. There are used
especially transparent hydrogels based on inorganic or organic
macromolecules. High molecular weight inorganic components having
gel-forming properties are predominantly water-containing
silicates, such as aluminium silicates, for example bentonite,
magnesium aluminium silicates, for example Veegum, or colloidal
silicic acid, for example Aerosil. As high molecular weight organic
substances there are used, for example, natural, semisynthetic or
synthetic macromolecules. Natural and semi-synthetic polymers are
derived, for example, from polysaccharides containing a great
variety of carbohydrate components, such as celluloses, starches,
tragacanth, gum arabic and agar-agar, and gelatin, alginic acid and
salts thereof, for example sodium alginate, and derivatives
thereof, such as lower alkylcelluloses, for example methyl- or
ethyl-cellulose, carboxy- or hydroxy-lower alkylcelluloses, for
example carboxymethyl- or hydroxyethyl-cellulose. The components of
synthetic gel-forming macromolecules are, for example, suitably
substituted unsaturated aliphatic compounds such as vinyl alcohol,
vinylpyrrolidine, acrylic or methacrylic acid.
[0072] Emulsion-gels - also called "emulgels"--represent topical
compositions which combine the properties of a gel with those of an
oil-in-water emulsion. In contrast to gels, they contain a lipid
phase which due to its fat-restoring properties enables the
formulation to be massaged in whilst, at the same time, the direct
absorption into the skin is experienced as a pleasant property.
Furthermore, one can observe an increased solubility for lipophilic
active ingredients. One advantage of emulsion-gels over
oil-in-water emulsions resides in the enhanced cooling effect which
is brought about by the coldness due to evaporation of the
additional alcohol component, if present.
[0073] Foams are administered, for example, from pressurised
containers and are liquid oil-in water emulsions in aerosol form;
unsubstituted hydrocarbons, such as alkanes, for example propane
and/or butane, are used as propellant. As oil phase there are used,
inter alia hydrocarbons, for example paraffin oil, fatty alcohols,
for example cetyl alcohol, fatty acid esters, for example isopropyl
myristate, and/or other waxes. As emulsifiers there are used, inter
alia, mixtures of emulsifiers having predominantly hydrophilic
properties, such as polyoxyethylene sorbitan fatty acid esters
(Tweens), and emulsifiers having predominantly lipophilic
properties, such as sorbitan fatty acid esters (Spans). The
customary additives, such as preservatives, etc., are also
added.
[0074] Tinctures and solutions generally have an ethanolic base, to
which water may be added and to which there are added, inter alia,
polyalcohols, for example glycerol, glycols and/or polyethylene
glycol, as humectants for reducing evaporation, and fat-restoring
substances, such as fatty acid esters with low molecular weight
polyethylene glycols, propylene glycol or glycerol, that is to say
lipophilic substances that are soluble in the aqueous mixture, as a
replacement for the fatty substances removed from the skin by the
ethanol, and, if necessary, other adjuncts and additives. Suitable
tinctures or solutions may also be applied in spray form by means
of suitable devices. In this case, due to the solubility problems
of allopurinol, a salt is more appropriate for tinctures or
solutions.
[0075] Transdermal therapeutic systems with -in particular- local
delivery of allopurinol contain an effective amount allopurinol
optionally together with a carrier. Useful carriers comprise
absorbable pharmacological suitable solvents to assist passage of
the active ingredient through the skin. Transdermal delivery
systems are, for example, in the form of a patch comprising (a) a
substrate (=backing layer or film), (b) a matrix containing the
active ingredient, optionally carriers and optionally (but
preferably) a special adhesive for attaching the system to the
skin, and normally (c) protection foil (=release liner), The matrix
(b) is normally present as a mixture of all components or may
consist of separate layers.
[0076] All these systems are well known to the person skilled in
the art. The manufacture of the topically administrable
pharmaceutical preparations is effected in a manner known per se,
for example by dissolving or suspending allopurinol in the base or,
if necessary, in a portion thereof.
[0077] The compositions according to the invention may also
comprise conventional additives and adjuvants for dermatological
applications, such as preservatives, especially paraben esters like
methylparaben, ethylparaben, propylparaben, butylparaben, or
quaternary ammonium compounds like benzalkonium chloride, or
formaldehyde donors like imidazonidinyl urea, or alcohols like
benzyl alcohol, phenoxyethanol or acids like benzoic acid, sorbic
acid; acids or bases used as pH buffer excipients; antioxidants,
especially phenolic antioxidants like hydroquinone, tocopherol and
derivatives thereof, as well as flavonoids, or miscellaneous
antioxidants like ascorbic acid,ascorbyl palmitat ; perfumes;
fillers such as kaolin or starch; pigments or colorants;
UV-screening agents; moisturizers, especially glycerin, butylen
glycol, hexylen glycol, urea, hyaluronic acid or derivatives
thereof; anti-free radical agents such as vitamin E or derivatives
thereof; penetration enhancers especially propylene glycol;
ethanol; isopropanol; dimethylsulfoxide; N-methyl-2- pyrrolidone;
fatty acids/alcohols such as oleic acid, oleyl alcohol; terpenes
such as limonen, menthol, 1-8 cineole; alkyl esters such as ethyl
acetate, butyl acetate; ion pairing agents such as salicylic
acid.
[0078] Further details concerning suitable topical formulations may
be obtained by reference to standard textbooks such as Banker and
Rhodes (Ed) Modern Pharmaceutics 4.sup.th ed. (2002) published by
Marcel Dekker Inc.; Harry's Cosmeticology (2000), 8th Edition,
Chemical Publishing Co.; Remington's Pharmaceutical Sciences
20.sup.th ed Mack Publishing Co. (2000).
[0079] In a preferred embodiment allopurinol is formulated as a
cream, preferably in an emollient base provided the emollient base
is suitable for topical application on the skin, is substantially
non-toxic and provides a suitable carrier for allopurinol or its
pharmaceutically acceptable salts. A properly chosen emollient base
may also provide a certain amount of relief in itself. In a
particular case, a moisturizing cream is preferred as a base.
[0080] Emollients may be e.g. fatty alcohols, hydrocarbons,
triglycerides, waxes, esters, silicone oils and lanolin containing
products. Fatty alcohols are e.g. cetyl alcohol, octyldodecanol,
stearyl alcohol and oleyl alcohol. Hydrocarbons include mineral
oil, petrolatum, paraffin, squalene, polybutene, polyisobuten,
hydrogenated polyisobutene, cerisin and polyethylene. Triglycerides
are e.g. castor oil, caprylic/capric triglyceride, hydrogenated
vegetable oil, sweet almond oil, wheat germ oil, sesame oil,
hydrogenated cottonseed oil, coconut oil, wheat germ glycerides,
avocado oil, corn oil, trilaurin, hydrogenated castor oil, shea
butter, cocoa butter, soybean oil, mink oil, sunflower oil,
safflower oil, macadamia nut oil, olive oil, apricot kernel oil,
hazelnut oil and borage oil. Waxes include e.g. camauba wax,
beeswax, cadelilla wax paraffin. Japan wax, microcrystalline wax,
jojoba oil, cetyl esters wax, and synthetic jojoba oil. Esters
include e. g. isopropyl myristate, isopropyl palmitate, octyl
palmitate, isopropyl linoleate, 12-15 alcohol benzoates, cetyl
palmitate, myristyl myristate, myristyl lactate, cetyl acetate,
propylene glycoldicaprylate/caprate, decyl oleate, stearyl
heptanoate, diisostearyl malate, octylhydroxystearate and isopropyl
isostearate. Silicone oils are e. g. dimethicone(dimethyl
polysiloxane) and cyclomethicone. Lanolin containing products are
e. g. lanolin, lanolin oil, isopropyl lanolate,acetylated lanolin
alcohol, acetylated lanolin, hydroxylated lanolin, hydrogenated
lanolin and lanolin wax.
[0081] In a preferred embodiment allopurinol is prepared by mixing
it with a commercial basic cream such as Bag Balm or Basiscreme DAC
(Deutsches Arzneimittel codex).
[0082] The daily dosage of the topical formulation comprising
allopurinol or its pharmaceutically acceptable salts may depend on
various factors, such as sex, age, weight and individual condition
of the patient, as well as the chemotherapy he is being or will be
given.
[0083] The topical pharmaceutical compositions, e. g. in the form
of creams, emulsion-gels or gels may be applied once, twice or
three times daily, but also more frequent daily applications such
as 5 to 10 times a day are possible provided that the symptoms of
PPE are avoided. The dosage may be variable, in function of the
severity of the PPE symptoms, or the cycles or dosages of the
chemotherapeutic treatment.
[0084] The pharmaceutical composition of the invention is
administered to patients already suffering from PPE in its
different grades, or as a preventive treatment to patients
susceptible to develop PPE as a consequence of a chemotherapeutic
treatment that is administered or about to be administered.
[0085] The administration can be intensified shorlty before, during
and after chemotherapeutic treatment, when the risks of developing
PPE are higher, and can be reduced during periods of rest between
cycles.
[0086] The invention will be further illustrated by means of
examples, they should no be taken as limiting the scope of the
invention as defined by the claims.
EXAMPLE
Example 1
[0087] Preparation of a Topical Formulation Comprising
Allopurinol
[0088] A formulation was prepared by suspending allopurinol base
(3% by weight of total formulation) in 5% water and then adding
Basiscreme DAC (92%) and mixing.
[0089] The composition of the Basic cream DAC is as follows:
[0090] Glycerolmonostearate: 4.0
[0091] Cetylalcohol 6.0
[0092] Medium chain triglyceride 7.5
[0093] White Vaseline 25.5
[0094] Polyoxyethylenglycerol monostearate 7.0
[0095] Propylenglycol 10.0
[0096] Water 40.0
[0097] The resulting cream is distributed in suitable containers
and stored. The cream is easily applicable by the patients.
Example 2
[0098] Treatment of Palmar Planar Erythrodysesthesia
[0099] Patients with colorectal carcinoma were administered
chemotherapy (adjuvant or palliative) following the usual
protocols. As soon as the first symptoms of palmar planar
erythrodysesthesia appeared after starting chemotherapy, the
patients were administered the cream prepared in example 1.
[0100] The characteristics of the patients treated with the cream
and the chemotherapeutic regimen that they were administered were
as follow:
[0101] Patients with advanced or metastatic colorectal cancer:
8
[0102] Patients with resected stage III colon cancer: 2
[0103] Chemotherapy: [0104] 5FU+LV bolus (Mayo protocol): 1 patient
[0105] 5FU-LV infusional (AIO protocol): 7 patients [0106]
Capecitabine monotherapy: 2 patients
[0107] The cream was applied 5 times per day, to the palms and
soles, as long as the chemotherapy was applied. The frequency was
reduced in between cycles and increased shortly before and during
chemotherapy administration.
[0108] Results: following the topical treatment with allopurinol,
the symptoms of PPE disappeared and the chemotherapy could be
completed without any dose reduction or delay in the treatment due
to PPE. This is most remarkable in the case of patients being
treated with high dose infusional SFU.sub.24H +leucovorin, were the
incidence of PPE has been reported to be as high as 34%.
Example 3
[0109] Treatment of Palmar Planar Erythrodysesthesia
[0110] Patients suffering from colon cancer or breast cancer were
treated from January 2005 up to March 2007 with the following
standard chemotherapy: [0111] AIO protocol: high dose infusion
5FU.sub.24H+leucovorin [0112] FOLFOX 4 protocol: day 1:
oxaliplatin, 85 mg/m2, and leucovorin, 200 mg/m2, concurrently
i.v., then 5-FU, 400 mg/m2 i.v. bolus followed by 600 mg/m2
continuous i.v.; day 2: leucovorin, 200 mg/m2 i.v., then 5-FU, 400
mg/m2 i.v. bolus, followed by 600 mg/m2 continuous i.v.; repeated
every 2 weeks. [0113] Oral capecitabine.
[0114] The patient characteristics are summarized in table 1.
TABLE-US-00001 TABLE 1 Patients characteristics n Patients 35 Age
Median 67 range (42-83) ECOG performance 0 21 1 14 2 0 Sex Male 11
female 24 Tumor type Breast Cancer 8 Colon Cancer 27 Prior
Chemotherapy Yes 10 No 25 Regimes Therapie 5-FU: AIO 16 FOLFOX 4 7
Capecitabine 12
[0115] Palmar plantar erythrodysesthesia (PPE) appeared in 30% of
the patients treated with 5-FU and in 66% of those treated with
capecitabine. The time of appearance and the severity of the
symptoms was variable, it is summarized in table 2.
TABLE-US-00002 TABLE 2 Palmar plantar erythrodysesthesia n %
Patients Total 35 PPE symptoms 15(35) 42% AIO 5(16) 31% FOLFOX 4
2(7) 28% Capecitabine 8(12) 66% PPE Toxicity grade (NCI) 1 1 6.6% 2
5 33% 3 9 60% Cumulative Dosis 5-FU regimen until appearance of PPE
AIO Median 42.000 mg Range (23.000 mg-64.800 mg) FOLFOX 4 Median
40.000 mg Range (38.000 mg-42.000 mg) Cumulative dosis with
capecitabine until apprearance of PPE Median 81.000 mg Range
(35.000 mg-180.000 mg)
[0116] These data correlate well with the reported incidence of
PPE.
[0117] The cream comprising allopurinol as prepared in example 1
was topically applied by the patients 4-5 times a day to the hands
and feet. In case of no response to this treatment and persistence
of PPE symptoms, the dosage of chemotherapy was reduced and some
cases interrupted. The response is summarized in table 3.
TABLE-US-00003 TABLE 3 Response to allopurinol treatment n %
PPEPatients 15 (TR) 13 86.6%.sup. (CR) 10 66.6%.sup. (PR) 3
20.0%.sup. (NR) 2 13.3%.sup. AIO 5 (TR) 5 100% (CR) 4 80% (PR) 1
20% (NR) 0 0% FOLFOX-4 2 (TR) 1 50% (CR) 0 (PR) 1 50% (NR) 1 50%
Capecitabine 8 (TR) 7 87% (CR) 5 62.5%.sup. (PR) 2 25% (NR) 1 12.5
TR: total response CR: complete remission PR: Partial remission NR:
no response
[0118] In 86% of the patients there was a response to the
treatment, with a reduction of the symptoms in 20% and complete
dissapearance in 66% .
[0119] No toxics effects associated to the topical allopurinol
treatment were observed, and the compliance of the patients and
improvements of the PPE symptoms were surprising. As a result
quality of life significantly improved.
[0120] In 86% of the patients that had developed PPE, the treatment
with allopurinol allowed the completion of chemotherapy as
planned.
* * * * *