U.S. patent application number 17/650270 was filed with the patent office on 2022-05-26 for methods and compositions for reducing side effects in chemotherapeutic treatments.
The applicant listed for this patent is Galderma Research and Development. Invention is credited to Philippe ANDRES, Mario LACOUTURE.
Application Number | 20220160708 17/650270 |
Document ID | / |
Family ID | |
Filed Date | 2022-05-26 |
United States Patent
Application |
20220160708 |
Kind Code |
A1 |
LACOUTURE; Mario ; et
al. |
May 26, 2022 |
Methods and Compositions for Reducing Side Effects in
Chemotherapeutic Treatments
Abstract
The present invention relates to a method of preventing or
reducing dermatological side effects of the therapeutic agents in a
subject without substantial loss in efficacy, where the therapeutic
agents would otherwise have significant effects. In particular,
this beneficial effect is achieved by using an alpha-2 adrenergic
agonist to isolate body areas from pharmacological effects of the
therapeutic agents, such as a chemotherapeutic agent, and to
prevent or reduce inflammatory processes.
Inventors: |
LACOUTURE; Mario; (New York,
NY) ; ANDRES; Philippe; (Peymeinade, FR) |
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Applicant: |
Name |
City |
State |
Country |
Type |
Galderma Research and Development |
Lausanne |
|
CH |
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Appl. No.: |
17/650270 |
Filed: |
February 8, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16630989 |
Jan 14, 2020 |
11278548 |
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PCT/US2018/041952 |
Jul 13, 2018 |
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17650270 |
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62532442 |
Jul 14, 2017 |
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International
Class: |
A61K 31/498 20060101
A61K031/498; A61P 17/00 20060101 A61P017/00; A61K 31/137 20060101
A61K031/137; A61K 31/4174 20060101 A61K031/4174; A61K 31/7048
20060101 A61K031/7048 |
Claims
1. A method of preventing or reducing an unwanted dermatological
side effect of a chemotherapeutic agent in a skin body part of a
human subject, comprising administering to the subject an effective
amount of a pharmaceutical composition comprising an alpha-2
adrenergic agonist having more affinity for an alpha-2
adrenoreceptor than for an alpha-1 adrenoreceptor, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
2. The method according to claim 1, wherein the skin body part is
selected from the group consisting of: scalp, face, neck,
shoulders, back, torso, belly, genitals, arms, forearms, legs,
hands, and feet.
3. The method of claim 1, wherein the pharmaceutical composition
further comprises an avermectin.
4. The method of claim 3, wherein the avermectin is emamectin or
ivermectin.
5. The method of claim 1, wherein the pharmaceutical composition is
topically administered to the skin body part of the human
subject.
6. The method of claim 1, wherein the pharmaceutical composition is
administered before administration of the chemotherapeutic
agent.
7. The method of claim 1, wherein the pharmaceutical composition is
administered during administration of the chemotherapeutic
agent.
8. The method of claim 1, wherein the pharmaceutically acceptable
carrier comprises a gelling agent and a polyol.
9. A method of claim 1, further comprising administration of the
pharmaceutical composition without dosing interruptions of the
chemotherapeutic agent for at least 12 weeks.
10. The method of claim 1, further comprising administration of the
pharmaceutical composition without the administration of an
antibiotic or a corticosteroid to the skin body part of the human
subject for at least 12 weeks.
11. The method of claim 1, wherein the pharmaceutical composition
comprises brimonidine or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable carrier.
12. The method of claim 11, wherein the brimonidine or a
pharmaceutically acceptable salt thereof is about 0.1% (w/w) to
about 0.6% (w/w) of the pharmaceutical composition.
13. The method of claim 1, wherein the pharmaceutical composition
comprises brimonidine tartrate and a pharmaceutically acceptable
carrier.
14. The method of claim 12, wherein the brimonidine tartrate is
about 0.1% (w/w) to about 10.0% (w/w) of the pharmaceutical
composition.
15. A method of preventing or reducing dermatological side effects
of in a skin body part of a human subject induced by a
chemotherapeutic agent, comprising administering to the subject an
effective amount of a pharmaceutical composition comprising an
alpha-2 adrenergic agonist having more affinity for the alpha-2
adrenoreceptor than for an alpha-1 adrenoreceptor, or a
pharmaceutically acceptable salt thereof; wherein the
chemotherapeutic agent is selected from the group consisting of: an
anti-EGFR compound, an MEK inhibitor compound, and an mTOR
inhibitor compound.
16. The method according to claim 15, wherein the chemotherapeutic
agent is an anti-EGFR compound selected from the group consisting
of: cetuximab, gefitinib, erlotinib, necitumumab, neratinib,
panitumumab, vandetanib, osimertinib, and lapatinib.
17. The method according to claim 15, wherein the chemotherapeutic
agent is an MEK inhibitor compound selected from the group
consisting of: trametinib, selumetinib, binimetinib, refametinib,
pimasertib, and cobimetinib.
18. The method according to claim 15, wherein the chemotherapeutic
agent is an mTOR inhibitor compound selected from the group
consisting of: rapamycin (sirolimus), temsirolimus, everomilus,
ridaforolimus, dactolisib (NVP-BEZ235), GSK2126458, XL765, AZD8055,
sapanisertib (INK128), OS1027, and rapalink-1.
19. The method of claim 15, wherein the pharmaceutical composition
comprises brimonidine or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable carrier.
20. The method of claim 15, wherein the pharmaceutical composition
comprises brimonidine tartrate and a pharmaceutically acceptable
carrier.
21. The method of claim 1, wherein the dermatological side effect
is one of papulopustular rash, dry skin, flushing,
hyperpigmentation, unwanted nail changes and photosensitivity.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser.
No. 16/630,989, filed on Jan. 14, 2020, which claims priority to
International Application No. PCT/US2018/041952, filed on Jul. 13,
2018, which published in the English language on Jan. 17, 2019
under International Publication No. WO2019/014518, which claims
priority to U.S. Provisional Application No. 62/532,442, filed on
Jul. 14, 2017, the disclosures of which are incorporated herein by
reference in its entirety.
TECHNICAL FIELD AND BACKGROUND ART
[0002] The present invention relates to preventing or reducing
dermatological side effects of therapeutic agents in a subject
without substantial loss in efficacy, where the therapeutic agents
would otherwise have significant side effects. This beneficial
effect is achieved by using an alpha-2 adrenergic agonist to
isolate body areas from pharmacological effects of the therapeutic
agents, such as a chemotherapeutic agent, and to prevent or reduce
inflammatory processes.
[0003] Side effects are the hallmark of many chemotherapeutic
agents which otherwise are effective in reducing tumor size. Among
known chemotherapeutic agents, EGFR inhibitors have shown to be
active antitumor agents against a variety of solid tumors including
but not limited to colorectal carcinoma, non-small cell lung
cancer, head and neck cancer and malignant gliomas (Conen et al.,
2003; Lage et al., 2003; Lorusso, 2003; Vanhoefer et al., 2004).
Clinical benefit defined as relief of symptoms or prolongation of
survival has been so far demonstrated with the anti-EGFR antibody
cetuximab (Erbitux.RTM.) and the EGFR tyrosine kinase (TK)
inhibitors gefitinib (Iressa.RTM.) and erlotinib (Tarceva.RTM.).
Many additional agents belonging to this class are being developed.
As of today, FDA approved indications include, e.g.,
chemorefractory colorectal carcinoma and non-small cell lung
cancer, head and neck carcinoma, and pancreatic carcinoma. Many
clinical studies using these agents alone or in combination, for
refractory or chemo naive patients with a variety of other
malignant diseases are in progress.
[0004] Undesired adverse effects common to anti-EGFR agents include
undesired dermatological side-effects, such as papulopustular rash,
usually on the face, upper back and upper torso, which generally
develops in a dose-dependent manner. Findings suggest that there is
a relationship between the development of rash and response and/or
survival. Although most patients only see mild to moderate skin
toxicity, clinical benefit of increasing the dose of the various
EGFR inhibitors or maintaining their full dose, is expected.
Histological data indicate that rash is caused directly by EGFR
inhibition in skin.
[0005] The above described adverse reactions of EGFR therapy very
often lead to drug discontinuation or dose reduction, impairs the
quality of life of the patients, puts patients at risk of
superinfection and moreover reduces their chances to survive.
[0006] Serial biopsies of skin before and after treatment revealed
two main reaction patterns: a superficial dermal inflammatory cell
infiltrate surrounding hyperkeratotic and ectatic follicular
infundibula, and a suppurative superficial folliculitis. Follicular
accumulation of neutrophilic granulocytes is considered
characteristic for the skin lesion observed after EGFR inhibition.
Otherwise, however, little is known about the etiology of this
rash, and there are no clear evidence-based management
recommendations. Most of the actual management of skin rash
resulting from chemotherapies is achieved through treatment rather
than preventing the anti-EGFR adverse effects.
[0007] Treatment of skin related adverse reactions is currently
limited to oral or topical antibiotics, general skin care and
hygiene recommendations. The use of other treatment options, such
as topical steroids is controversial because of secondary side
effects and the higher risk of superinfection in these EGFR-induced
rashes, especially on the face. Topical retinoids are not
recommended because of the further increase in skin dryness and
peeling, and they have never demonstrated efficacy in this
indication. Systemic steroids for treatment of severe skin or
gastrointestinal adverse reactions are problematic, since they may
interfere with EGFR inhibition. Oral antibiotics, although
generally well tolerated, can lead to severe gastro-intestinal side
effects, drug-drug interaction and bacterial resistance.
[0008] Thus, there is an unmet need for novel therapeutic and/or
prophylactic strategies to manage adverse skin reactions in
patients treated with chemotherapies, such as EGFR inhibitors,
especially by preventing or reducing such adverse reactions with a
distinct mechanism of action and devoid of additive toxicities.
[0009] Therefore, it is the aim of the present invention to provide
pharmaceutical compositions for preventing or reducing one or more
adverse reactions caused by treatment with a chemotherapeutic
agent, such as an EGFR inhibitor.
SUMMARY OF THE INVENTION
[0010] The present invention relates to the use of alpha adrenergic
agonist, in particular alpha-2 adrenergic agonist, to exclude a
skin body part from undesired dermatological side-effects of a
chemotherapeutic agent, such as an EGFR inhibitor.
[0011] Accordingly, in one general aspect, the invention relates to
method of preventing or reducing unwanted dermatological side
effects of a chemotherapeutic agent in a skin body part of a
subject. The method comprises administering to the subject,
preferably topically administering to the skin body part of the
subject, an effective amount of a pharmaceutical composition
comprising an alpha-2 adrenergic agonist or a pharmaceutically
acceptable salt thereof and a pharmaceutically acceptable carrier.
The pharmaceutical composition is administered to the subject prior
to, simultaneously with, or after the administration of the
chemotherapeutic agent to the subject. According to an embodiment
of the invention, the method further comprises administering to the
subject another pharmaceutical active ingredient. Preferably, the
other pharmaceutical active ingredient is an avermectin, such as an
ivermectin or an emamectin, and is topically administering to the
skin body part together with the alpha-2 adrenergic agonist in one
or separate compositions, or the alpha-2 adrenergic agonist and the
avermectin are topically applied to the skin body part
sequentially.
[0012] In another general aspect, the invention relates to the use
of an alpha adrenergic agonist, in particular an alpha-2 adrenergic
agonist, for the prevention or reduction of undesired
dermatological side-effects of a chemotherapy, such as an EGFR
treatment, in a subject in need thereof, in particular for the
prevention or reduction of rash caused by the chemotherapy.
[0013] According to an embodiment of the invention, the subject in
need of a treatment of the invention is undergoing, or is enrolled
to undergo a chemotherapy, such as an anti-EGFR treatment. The
method comprises administering an effective amount of an alpha-2
adrenergic agonist to the subject, preferably topically
administering an effective amount of an alpha-2 adrenergic agonist
to a skin body part of the subject, more preferably, prior to
administering the chemotherapeutic agent to the subject.
[0014] The invention also relates to the use of an alpha-2
adrenergic agonist for the preparation of a pharmaceutical
composition for preventing or reducing an undesired dermatological
side-effect in an individual undergoing, or enrolled to undergo a
chemotherapy, such as an anti-EGFR treatment.
[0015] In a further aspect, the invention relates to a composition
suitable for use in a method of the invention, comprising an
alpha-2 adrenergic agonist, wherein said alpha-2 adrenergic agonist
is present in an amount sufficient to reduce and/or prevent one or
more undesired dermatological side-effects of the chemotherapy,
such as the anti-EGFR agent.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] The foregoing summary, as well as the following detailed
description of preferred embodiments of the present application,
will be better understood when read in conjunction with the
appended drawings. It should be understood, however, that the
application is not limited to the precise embodiments shown in the
drawings.
[0017] FIG. 1 shows the bar graph of Acneiform rash (e.g., rash
grade) outcome of patients treated with brimonidine gel.
[0018] FIG. 2 shows the bar graph of Aceniform rash outcome (e.g.,
clear, stable, or partial improvement) of patients treated with
brimonidine gel when compared to baseline.
[0019] FIGS. 3A-3B show a patient with metastatic colorectal cancer
treated on panitumumab treated with brimonidine gel. FIG. 3A shows
a grade 2 rash at baseline, and FIG. 3B shows a grade 1 rash in 2
month follow up.
DETAILED DESCRIPTION OF THE INVENTION
[0020] Definitions
[0021] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood to one of
ordinary skill in the art to which this invention pertains.
Otherwise, certain terms used herein have the meanings as set forth
in the specification. All patents, published patent applications
and publications cited herein are incorporated by reference as if
set forth fully herein. It must be noted that as used herein and in
the appended claims, the singular forms "a," "an," and "the"
include plural references unless the context clearly dictates
otherwise.
[0022] As used herein, the term "skin body part" refers to an
external location on the human skin that can be defined either by
surface or location on the body. A non-limiting list of "skin body
part" includes, e.g., scalp, face, neck, shoulders, back (upper and
lower), torso, belly, genitals, arm, forearm, leg(s), hand(s) and
foot/feet more preferably hand(s), foot/feet, fingers, toes, or the
face.
[0023] As used herein, the term "excluding a skin body part" refers
to excluding the skin body part from a pharmacological activity of
a chemotherapeutic agent, more preferably, denying, reducing or
limiting access of the chemotherapeutic agent to the blood stream
of the specific body surface.
[0024] As used herein, the phrase "unwanted dermatological side
effects" refers to any unwanted reactions of a skin body part to a
drug therapy, such as a chemotherapy (e.g., a treatment with an
anti-EGFR, an MEK inhibitor, an mTOR inhibitor, or a combination
thereof). Examples of such unwanted reactions include, but are not
limited to, rash, such as papulopustular rash, dry skin, flushing,
hyperpigmentation, unwanted nail changes, and photosensitivity. The
"unwanted dermatological side effects" usually develop on the face,
upper back and upper torso, but can also occur on other body part.
The side effects generally develop in a dose-dependent manner, but
can also be dose-independent.
[0025] As used herein, the term "chemotherapy" refers to a type of
cancer treatment that uses one or more anti-cancer drugs
(chemotherapeutic agents) to kill cancer cells. Chemotherapy may be
given with a curative intent, or it may aim to prolong life or to
reduce symptoms.
[0026] As used herein, the term "chemotherapeutic agent" or
"chemotherapeutic compound" refers to any agent that can be used to
treat a disease or disorder of a subject. Preferably, a
"chemotherapeutic agent" or "chemotherapeutic compound" is used to
treat a tumor or cancer. Conventional chemotherapy uses
non-specific cytotoxic drugs to inhibit cell division (mitosis).
Hormone therapy is one type of cancer treatment that inhibits
growth-promoting signals from classic endocrine hormones, primarily
estrogens for breast cancer and androgens for prostate cancer. By
contrast, targeted therapy is another type of cancer treatment that
inhibits growth-signals like those associated with receptor
tyrosine kinases.
[0027] Based on their principal mechanism of action, conventional
chemotherapeutics can be broadly subdivided into: 1) alkylating
agents; 2) antimetabolites; 3) topoisomerase inhibitors; 4)
microtubular poisons; and 5) cytotoxic antibiotics.
[0028] Hormone therapy falls into two broad groups, those that
block the body's ability to produce hormones and those that
interfere with how hormones behave in the body.
[0029] Most chemotherapeutic agents in targeted therapy are either
small-molecule drugs or monoclonal antibodies. Small-molecule drugs
are small enough to enter cells easily, so they are used for
targets that are inside cells. Monoclonal antibodies are drugs that
attach to specific targets on the outer surface of cancer cells.
Examples of chemotherapeutic agents for target therapy include, but
are not limited to an anti-EGFR compound, an MEK inhibitor and an
mTOR inhibitor.
[0030] As used herein, the term "anti-EGFR compound" refers to an
active ingredient having an anti-EGFR pharmacological activity. In
a preferred embodiment, the compound having an anti-EGFR activity
is selected from the group consisting of cetuximab, gefitinib,
erlotinib, necitumumab, neratinib, panitumumab, vandetanib,
osimertinib, and lapatinib.
[0031] As used herein, the term "MEK inhibitor" refers to an active
ingredient that inhibits the mitogen-activated protein kinase
enzymes MEK1 and/or MEK2. In a preferred embodiment, the MEK
inhibitor compound is selected from the group consisting of
trametinib, selumetinib, binimetinib, refametinib, pimasertib, and
cobimetinib.
[0032] As used herein, the term "mTOR inhibitor" refers to an
active ingredient that inhibits the mechanistic target of rapamycin
(mTOR). In a preferred embodiment, the mTOR inhibitor compound is
selected from the group consisting of rapamycin (sirolimus),
temsirolimus, everomilus, ridaforolimus, dactolisib (NVP-BEZ235),
GSK2126458, XL765, AZD8055, sapanisertib (INK128), OSI027, and
rapalink-1.
[0033] As used herein, the term "alpha adrenergic receptor" refers
to any of an alpha-1 and alpha-2 adrenergic receptors that were
distinguished from each other in the 1970's. During the same
decade, alpha 2 adrenergic receptors were found to occur on
vascular smooth muscles and exhibit mediation of vasoconstrictor
response (Docherty, "Subtypes of functional .alpha.1- and
.alpha.2-adrenoceptors," European Journal of Pharmacology, 1998,
361: 1 -15). Thus, molecules exhibiting alpha adrenergic agonism,
advantageously alpha 2 adrenergic agonism, possess peripheral
vasoconstrictive activity. Among the alpha receptors, the agonist
can be an agonist of both alpha-1 and alpha-2 receptors, or can be
specific for alpha-1 or alpha-2. Preferably, the chosen molecule
displays more affinity for the alpha-2 than for the alpha1
receptor, and will generally be named, in the rest of the
application, "an alpha-2 adrenergic receptor agonist."
[0034] Agonists of the alpha-2 adrenoceptors have been used
therapeutically for a number of conditions including hypertension,
congestive heart failure, angina pectoris, spasticity, glaucoma,
diarrhea, and for the suppression of opiate withdrawal symptoms
(Heible and Ruffolo, "Therapeutic Applications of Agents
Interacting with .alpha.-Adrenoceptors," in Progress in Basic and
Clinical Pharmacology, Vol. 8, p. 180-206, P. Lomax and E. S.
Vesell Ed., Karger, 1991). Adrenoceptor agonists such as clonidine
have been primarily used orally, though a patch formulation is
known. The alpha-2 agonists are known to mediate vasoconstriction
both in the core and periphery of a patient. In particular alpha-2
adrenoceptor agonists are known to cause vasoconstriction of
peripheral arterioles, in response to stimulation due to cold or
stress.
[0035] The most preferred compound is
(5-bromo-quinoxalin-6-yl)-(4,5-dihydro-IH-imidazol-2-yl)-amine
(commonly referred to as brimonidine) and pharmaceutically
acceptable salts thereof, particularly the tartrate salt. Other
adrenoceptor agonists useful in the invention include naphazoline,
tetra-hydrozaline, oxymetazoline, xylometazoline, epinephrine,
norepinephrine, phenylephrine and methoxamine and their
pharmaceutically acceptable salts.
[0036] As used herein, the term "brimonidine" refers to the
compound
(5-bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine
having the structure of Formula (I):
##STR00001##
and any pharmaceutically acceptable salt of the compound, such as
brimonidine tartrate.
[0037] The phrase "pharmaceutically acceptable salt(s)," as used
herein, means those salts of a compound of interest that are safe
and effective for topical use in mammals and that possess the
desired biological activity. Pharmaceutically acceptable salts
include salts of acidic or basic groups present in the specified
compounds. Pharmaceutically acceptable acid addition salts include,
but are not limited to, hydrochloride, hydrobromide, hydroiodide,
nitrate, sulfate, bisulfate, phosphate, acid phosphate,
isonicotinate, acetate, lactate, salicylate, citrate, tartrate,
pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucuronate, saccharate, formate,
benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate, and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain
compounds used in the present invention can form pharmaceutically
acceptable salts with various amino acids. Suitable base salts
include, but are not limited to, aluminum, calcium, lithium,
magnesium, potassium, sodium, zinc, and diethanolamine salts. For a
review on pharmaceutically acceptable salts see Berge et al., 66 J.
Pharm. Sci. 1-19 (1977), incorporated herein by reference.
[0038] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredient in the
specified amount, as well as any product which results, directly or
indirectly, from combinations of the specified ingredient in the
specified amount.
[0039] The term "topically administrable composition," a "topical
composition," or a "topical formulation," as used herein, means any
formulation or composition which is pharmaceutically and/or
cosmetically acceptable for topical delivery of the specified
compounds according to embodiments of the invention. Exemplary
forms of formulation that can be used for topical administration in
embodiments of the present invention include, but are not limited
to, sprays, mists, aerosols, solutions, lotions, gels, creams,
ointments, pastes, unguents, emulsions and suspensions.
[0040] The term "topically administrable composition" as used
herein, also encompasses locally applied and locally acting
formulations such as formulations for use with implants,
injections, or patches.
[0041] As used herein, the term "subject" means any animal,
preferably a mammal, most preferably a human, to whom will be or
has been administered compounds or topical formulations according
to embodiments of the invention. The term "mammal" as used herein,
encompasses any mammal. Examples of mammals include, but are not
limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats,
rabbits, guinea pigs, monkeys, humans, etc., more preferably a
human.
[0042] As used herein, "prevention" or "preventing" refers to a
reduction of the risk of acquiring a given disease or disorder. In
a preferred mode of the embodiment, the specified compounds are
administered as a preventative measure to a subject having a
predisposition to a disease or disorder even though symptoms of the
disease or disorder are absent or minimal.
Embodiments of the Invention
[0043] The invention relates to a method of preventing or reducing
undesired dermatological side-effects of a chemotherapeutic
compound and symptoms associated therewith in a subject in need
thereof. The method comprises administering to the subject,
preferably topically administering to a skin body part of the
subject, a pharmaceutical composition comprising an alpha-2
adrenergic receptor agonist or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable carrier before, during,
and/or after the course of the chemotherapy.
[0044] In a preferred embodiment of the invention, the
chemotherapeutic compound is an anti-EGFR compound, an MEK
inhibitor compound, a mTOR inhibitor compound, or a combination
thereof.
[0045] In a preferred embodiment of the invention, the alpha-2
adrenergic receptor agonist is brimonidine or one of its
pharmaceutically acceptable salt, such as brimonidine tartrate.
[0046] The undesired side-effect(s) or adverse effect(s) of a
chemotherapy, such as an anti-EGFR treatment, that are prevented or
reduced by administration of the alpha adrenergic receptor agonist,
are of any type of dermatological side-effect of such treatment,
such as rash, folliculitis, dry skin or nail changes, e.g.,
paronychia. However, in a preferred embodiment, the undesired
dermatological side-effect that is reduced or prevented by the
alpha adrenergic receptor agonist is rash, such as follicular
rash.
[0047] Rash can be quantified using methods known in the art in
view of the present disclosure. For example, a reduction in rash,
e.g., of 10%, when used herein indicates that is a statistically
significant reduction of 10% in the total score of a representative
population, as compared to the same treatment with the chemotherapy
(such as an anti-EGFR agent) alone, i.e. without administration of
an alpha adrenergic receptor agonist. The reduction can be the
result of prevention and/or treatment, preferably through
prevention.
[0048] In a preferred embodiment of the method or use of the
invention, the rash is reduced by at least 10%, such as at least
20%, e.g., at least 30%, such as at least 40%, e.g., at least 50%,
such as at least 60%, e.g., at least 70%, such as at least 80%,
e.g., at least 90%, such as least 95%
[0049] Another embodiment of the present invention relates to a
method of limiting the progression of undesired dermatological
side-effects of EGFR treatment in a subject by excluding a skin
body part, which comprises topically administering to the skin body
part a composition comprising a therapeutically effective amount of
an alpha-2 adrenergic receptor agonist and a pharmaceutically
acceptable carrier. While not wishing to be bound by theories, it
is believed that, due to its vasoconstriction function, the
effective amount of alpha-2 adrenergic receptor agonist excludes
the skin body part from the pharmacological activity of the
chemotherapeutic agent, for example, by denying, reducing or
limiting access of the chemotherapeutic agent to the blood stream
of the specific body surface, and such exclusion contributes to the
prevention or reduction of the undesired dermatological
side-effects of the chemotherapeutic compound. Narrowing the blood
vessels does also limit the inflammatory processes such as
leukocyte recruitment and subsequent cytokine production and
release.
[0050] According to a preferred embodiment of the present
invention, a method of preventing or limiting the progression of an
undesired dermatological side-effect of chemotherapeutic agent,
such as an anti-EGFR compound, an MEK inhibitor, or an mTOR
inhibitor, in a subject, comprises administering to the subject,
preferably topically administering to a skin body part of the
subject, an effective amount of a pharmaceutical composition
comprising brimonidine or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable carrier.
[0051] More preferably the present invention relates to a method of
preventing or limiting the progression of skin rash associated with
a chemotherapeutic agent treatment in a subject in need thereof.
The method comprises topically administering to the subject an
effective amount of a composition comprising brimonidine or a
pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable carrier.
[0052] According to embodiments of the invention, the method
further comprises administering to the subject one or more
additional active pharmaceutical ingredient for reducing or
treating the undesired dermatological side-effect of
chemotherapeutic agent. The additional active pharmaceutical
ingredients can be administered together with the alpha-2
adrenergic receptor agonist in the same pharmaceutical composition
or in a separate pharmaceutical composition. The additional active
pharmaceutical ingredients and the alpha-2 adrenergic receptor
agonist can also be administered to the subject sequentially.
Preferably, the additional active pharmaceutical ingredient is an
avermectin, such as an ivermectin or an emamectin. More preferably,
the avermectin is topically administered to the subject with the
alpha-2 adrenergic receptor agonist in one pharmaceutical
composition.
Dosage Regimens
[0053] In the method and use of the invention, the alpha adrenergic
receptor agonist is given in an effective amount, i.e. in an amount
effective, at dosages and for periods of time necessary, to achieve
a desired result.
[0054] A therapeutically effective amount can vary according to
factors such as the disease state, age, sex, and weight of the
individual, and the ability of the agent to elicit a desired
response in the individual.
[0055] To treat or prevent undesired dermatological side-effects of
chemotherapeutic treatments or a symptom associated therewith, the
topically administrable compositions of the invention can be
topically applied directly to the skin body part to be excluded
from chemotherapeutic treatment in any conventional manner known in
the art, e.g., by dropper, applicator stick, or cotton swab, as a
mist via an aerosol applicator, via an intradermal or transdermal
patch, or by simply spreading a formulation of the invention onto
the affected area with fingers, a sponge, a pad, or wipes.
[0056] Generally, the amount of a topical formulation of the
invention applied to the affected skin area ranges from about
0.0001 g/cm.sup.2 of skin surface area to about 0.05 g/cm.sup.2,
preferably, 0.002 g/cm.sup.2 to about 0.005 g/cm.sup.2 of skin
surface area.
[0057] In various aspects, an application of a topical composition
can noticeably prevent undesired dermatological side-effects of
chemotherapeutic treatments and can be maximally effective at about
30 minutes after application, and the ameliorative effects can last
up to about 2 hours, up to about 4 hours, up to about 8 hours, up
to about 12 hours, up to about 18 hours, or up to about 24 hours,
or longer.
[0058] Accordingly, in some aspects, a composition can be topically
applied to skin body part at a site to be excluded from
chemotherapeutic treatment symptoms once per day, twice per day, or
three or more times per day.
Formulation, Additives and Mode-of-Administration
[0059] In one embodiment, the alpha adrenergic receptor agonist of
the invention is preventively delivered to a skin body part in a
pharmaceutically acceptable topical carrier. As used herein, a
"pharmaceutically acceptable topical carrier" is any
pharmaceutically acceptable carrier that can be applied to the skin
surface for topical, dermal, intradermal, or transdermal delivery
of a pharmaceutical or medicament. The combination of a
pharmaceutically acceptable topical carrier and a compound of the
invention is termed a topical formulation of the invention.
[0060] In view of the present disclosure, the pharmaceutical
compositions and agents can be formulated with pharmaceutically
acceptable carriers or diluents as well as any other known
adjuvants and excipients in accordance with conventional
techniques, such as those disclosed in Remington: The Science and
Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing
Co., Easton, Pa., 1995.
[0061] The pharmaceutically acceptable carriers or diluents as well
as any other known adjuvants and excipients should be suitable for
the chosen composition of the present invention and the chosen mode
of administration. Suitability for carriers and other components of
pharmaceutical compositions is determined based on the lack of
significant negative impact on the desired biological properties of
the chosen compound or pharmaceutical composition of the present
invention, e.g., less than a substantial impact (10% or less
relative inhibition, 5% or less relative inhibition, etc.) on the
desired biological properties of an alpha agonist used in the
present invention.
[0062] A pharmaceutical composition of the present invention can
also include diluents, fillers, salts, buffers, detergents (e.g., a
nonionic detergent, such as Tween-80), stabilizers, stabilizers
(e.g., sugars or protein-free amino acids), preservatives, tissue
fixatives, solubilizers, and/or other materials suitable for
inclusion in a pharmaceutical composition.
[0063] The actual dosage levels of the active ingredients in the
pharmaceutical compositions of the present invention can be varied
so as to obtain an amount of the active ingredient which is
effective to achieve the desired therapeutic response for a
particular patient, composition, and mode of administration,
without being toxic to the patient.
[0064] The selected dosage level will depend upon a variety of
pharmacokinetic factors including the activity of the particular
compositions of the present invention employed, or the ester, salt
or amide thereof, the route of administration, the time of
administration, the rate of excretion of the particular compound
being employed, the duration of the treatment, other drugs,
compounds and/or materials used in combination with the particular
compositions employed, the age, sex, weight, condition, general
health and prior medical history of the patient being treated, and
like factors well known in the medical arts.
[0065] The pharmaceutical composition may be administered by any
suitable route and mode. Suitable routes of administering a
composition in vivo and in vitro are well known in the art and may
be selected by those of ordinary skill in the art. Preferably, the
pharmaceutical composition containing an alpha-2 adrenergic agonist
is administered to a skin body part of interest by topical
administration.
[0066] Brimonidine and its pharmaceutically acceptable salts are
preferred embodiments of the invention. Preferably, the active
ingredient of the composition is brimonidine tartrate.
[0067] In an embodiment of the present invention, the topically
administrable composition comprises about 0.1%, 0.2%, 0.3%, 0.5%,
1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%,
6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5% or 10.0%, by weight of an
alpha-2 adrenergic agonist, preferably brimonidine, such as
brimonidine tartrate.
[0068] In another embodiment of the present invention, the
topically administrable composition comprises about 0.15%, about
0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about
0.45%, about 0.5%, about 0.55% or about 0.6%, by weight of an
alpha-2 adrenergic agonist, preferably brimonidine, such as
brimonidine tartrate.
[0069] In a preferred embodiment, the topical composition comprises
about 0.5% by weight of an alpha-2 adrenergic agonist, preferably
brimonidine, such as about 0.5% by weight of brimonidine
tartrate.
[0070] In one embodiment of the invention, the topical composition
is contained within one suitable container, such as a dropper, a
jar, or a tube with a suitable small orifice size, such as an
extended tip tube, made of any pharmaceutically suitable material.
The topical formulations according to embodiments of the invention
can be filled and packaged into a plastic squeeze bottle or tube.
Suitable container-closure systems for packaging topical
formulations of the invention are commercially available for
example, from Wheaton Plastic Products, 1101 Wheaton Avenue,
Millville, N.J. 08332. Optionally, an applicator can be provided in
or attached to the container, or separately from the container.
[0071] In one embodiment of the invention, the instructions are,
for example, a pamphlet or package label. The instructions explain
how to administer topical formulations of the invention, in an
amount and for a period of time sufficient to provide a safe and
effective treatment of erythema or a symptom associated therewith.
Preferably, the instructions include, for example, the dosage and
administration instructions, the topical formulation's composition,
the clinical pharmacology, drug resistance, pharmacokinetics,
absorption, bioavailability, and contraindications.
[0072] Another aspect of the present invention relates to a topical
gel composition for preventing or reducing unwanted dermatological
side effects in a skin body part due to administration of a
chemotherapeutic agent in a subject. The topical gel composition
comprises:
[0073] about 0.1% (w/w) to about 10.0% (w/w) an alpha-2 adrenergic
agonist, preferably brimonidine, such as brimonidine tartrate;
[0074] about 0.20% (w/w) to about 4.0% (w/w) gelling agent; and
[0075] about 5.0% (w/w) to about 30.0% (w/w) at least one
polyol.
[0076] According to an embodiment of the invention, the topical
administration of the topical gel composition to a skin body part
excludes the skin body part from a pharmacological activity of a
chemotherapeutic agent, thereby preventing unwanted dermatological
side effects in the skin body part due to administration of a
chemotherapeutic agent.
[0077] The topically administrable composition are prepared by
mixing a pharmaceutically acceptable carrier with the safe and
effective amount of an alpha-2 adrenergic agonist, such as
brimonidine, according to known methods in the art, for example,
methods provided by standard reference texts such as, REMINGTON:
THE SCIENCE AND PRACTICE OF PHARMACY 1577-1591, 1672-1673, 866-885
(Alfonso R. Gennaro ed. 19th ed. 1995); Ghosh, T. K.; et al.
TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS (1997), both of which
are hereby incorporated herein by reference.
[0078] In a preferred embodiment, the topical gel composition
comprises about 0.1% to about 0.6% by weight of an alpha-2
adrenergic agonist, preferably brimonidine, more preferably, 0.5%
by weight of brimonidine tartrate.
[0079] Suitable gelling agents known in the art, including those
used in the two-phase or single-phase gel systems, can be used in
the present invention. Some examples of suitable gelling agents are
disclosed in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY
1517-1518 (Alfonso R. Gennaro ed. 19th ed. 1995), which is hereby
incorporated herein by reference. The gelling agents used in
embodiments of the present invention, include, but are not limited
to, one or more hydrophilic and hydroalcoholic gelling agents used
in the cosmetic and pharmaceutical industries. Preferably, the
hydrophilic or hydroalcoholic gelling agent comprises
"CARBOPOL.RTM." (B.F. Goodrich, Cleveland, Ohio), "HYPAN.RTM."
(Kingston Technologies, Dayton, N.J.), "NATROSOL.RTM." (Aqualon,
Wilmington, Del.), "KLUCEL.RTM." (Aqualon, Wilmington, Del.), or
"STABILEZE.RTM." (ISP Technologies, Wayne, N.J.). The preferred
compositional weight percent range for "CARBOPOL.RTM." is between
about 0.5% to about 2%, while the preferred weight percent range
for "NATROLSOL.RTM." and "KLUCEL.RTM." is between about 0.5% to
about 4%. The preferred compositional weight percent range for both
"HYPAN.RTM." and "STABILEZE.RTM." is between 0.5% to about 4%.
Other preferred gelling agents include hydroxyethylcellulose,
cellulose gum, MVE/MA decadiene crosspolymer, PVM/MA copolymer,
glycerine polyacrylate, or a combination thereof.
[0080] Examples of carbomers that can be used in the present
invention include, but are not limited to, Carbomer 910, 934P, 940,
941, 980 and 1342, and Carbopol.RTM. 974P and Carbopol.RTM. 980.
Preferably, the carbomer is Carbomer 934P or Carbopol.RTM. 974P,
and Carbopol.RTM. 980.
[0081] According to embodiments of the present invention, the
amount of the carbomer in the composition is about 0.5%, 0.6%,
0.7%, 0.8%, 0.85%, 0.95%, 1.05%, 1.15%, 1.25%, 1.35%, 1.45%, 1.5%,
1.6%, 1.7%, 1.8%, 1.9% or 2.0% (w/w).
[0082] The following examples are offered to illustrate, but not to
limit the claimed invention.
EXAMPLE 1
Formulations
[0083] Exemplary formulations useful in the present invention are
prepared using methods known in the art, e.g., by mixing the
following ingredients at the specified concentrations:
[0084] Formulation 1
TABLE-US-00001 % relative to the total weight of the Ingredient
composition Brimonidine tartrate 0.20% Ivermectin 1.00% EDTA 0.1%
Polysorbate 80 8.0% Propylene glycol 20.0% Benzyl alcohol 3% Water
QS TOTAL 100%
[0085] Formulation 2
TABLE-US-00002 % relative to the total weight of the Ingredient
composition Brimonidine tartrate 0.3% Emamectin 0.5% Codex
petroleum jelly 56.0% Liquid petroleum jelly 43.0%
[0086] Formulation 3
TABLE-US-00003 % relative to the total weight of the Ingredient
composition Oxymetazoline hydrochloride 0.20% Ivermectin 1.4%
Glycerol 4.0% Steareth-2 1.0% Steareth-21 2.0% Aluminum magnesium
1.0% silicate/titanium dioxide/silica Methyl para-hydroxybenzoate
0.2% Propyl para-hydroxybenzoate 0.1% Disodium EDTA 0.05% Citric
acid monohydrate 0.05% Isopropyl palmitate 4.0% Glyceryl/PEG 100
stearate 2.0% Self-emulsifiable wax 1.0 Palmitostearic acid 2.0%
Dimethicone 200-350 cS 0.5% Propylene glycol 4.0% Glyceryl
triacetate 1.0% Phenoxyethanol 0.5% 10% sodium hydroxide qs pH
Water QS TOTAL 100%
[0087] Formulation 4
TABLE-US-00004 % relative to the total weight of the Ingredient
composition [% (w/w)] Brimonidine tartrate 0.15% Ivermectin 0.03%
Polysorbate 80 2.00% Benzalkonium chloride 0.05% EDTA 0.05% Buffer
system pH 6.3 Water QS TOTAL 100%
[0088] Additional Formulations
TABLE-US-00005 Ingredient % (w/w) % (w/w) % (w/w) Brimonidine
tartrate 0.3-1% 0.6-3.0% 3.0-10% Carbomer 934P 1.25% 1.0% 1.5%
Methylparaben 0.2% 0.15% 0.20% Phenoxyethanol 0.4% 0.35% 0.4%
Glycerol 5.5% 10% 15% Kowet titanium dioxide 0.0625% 0.0725%
0.0825% Propylene glycol 5.5% 10% 15% DI Water QS QS QS TOTAL 100%
100% 100%
EXAMPLE 2
[0089] A retrospective analysis was conducted on epidermal growth
factor receptor-inhibition (EGFRI)-treated patients receiving
brimonidine gel for acneiform rash. The characteristics of these
patients were reviewed in 2 centers. Demographics, primary tumor,
anticancer therapy agent, and treatment of acneiform rash were
summarized. Documentation on grading of rash using the Common
Terminology Criteria for Adverse Events v4.0 (CTCAE) (Chen, et al.,
Journal of the American Academy of Dermatology, 2012,
67(5):1025-39) was gathered. Data was reported using descriptive
statistics.
[0090] Materials and Methods
[0091] A total of 18 patients were identified, with a median age of
53 years, predominantly male patients (n=10, 55.6%), and most
presented with a solid tumor (n=16, 88.9%), primarily lung cancer
(n=5, 27.8%). Grade.gtoreq.2 rash at presentation (Common
Terminology Criteria for Adverse Events v4.0) was observed in 83.3%
(n=15) of patients. Causal agents were monoclonal antibodies
(n=101, 34%) and small molecules (n=101, 34%). Patients on
brimonidine were followed for 12 to 24 weeks
[0092] Results
[0093] FIG. 1 and FIG. 2 demonstrated that the majority of treated
patients had a decrease in rash severity (n=17, 94%), and did not
require dose modification of anticancer therapies. FIGS. 3A-3B
compared the rash in a patient between the baseline and 2 month
follow up. Adverse events to brimonidine were not reported.
[0094] This data demonstrates an improvement in acneiform rash in
all patients. It is noted that 83% of patients were also receiving
systemic antibiotics (72%) and topical antibiotics or
corticosteroids (83%).
[0095] This analysis demonstrated that the addition of brimonidine
gel had a therapeutic benefit for the acneiform rash from targeted
cancer therapies. In addition, no adverse events to brimonidine
were reported by patients reported herein. All of which suggested
that the addition of brimonidine can improve quality of life and
prevent dosing interruptions or decreases in the dosing of
anticancer agents.
[0096] It will be appreciated by those skilled in the art that
changes could be made to the embodiments described above without
departing from the broad inventive concept thereof. It is
understood, therefore, that this invention is not limited to the
particular embodiments disclosed, but it is intended to cover
modifications within the spirit and scope of the present invention
as defined by the appended claims.
* * * * *