U.S. patent application number 14/570276 was filed with the patent office on 2015-04-09 for method for preventing or treating skin tumor.
The applicant listed for this patent is GALDERMA RESEARCH & DEVELOPMENT. Invention is credited to Guy BOUVIER, Michael GRAEBER, Matthew James LEONI.
Application Number | 20150098917 14/570276 |
Document ID | / |
Family ID | 44629521 |
Filed Date | 2015-04-09 |
United States Patent
Application |
20150098917 |
Kind Code |
A1 |
BOUVIER; Guy ; et
al. |
April 9, 2015 |
METHOD FOR PREVENTING OR TREATING SKIN TUMOR
Abstract
Methods, compositions and products for preventing skin tumor
formation or inhibiting the development of an existing skin tumor
in a subject are described. The methods involve administering to
the subject a composition containing an .alpha.2 adrenergic
receptor agonist, such as brimonidine.
Inventors: |
BOUVIER; Guy; (Biot, FR)
; LEONI; Matthew James; (Hampton, NJ) ; GRAEBER;
Michael; (Lawrenceville, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GALDERMA RESEARCH & DEVELOPMENT |
Biot |
|
FR |
|
|
Family ID: |
44629521 |
Appl. No.: |
14/570276 |
Filed: |
December 15, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13821145 |
Jun 6, 2013 |
8911713 |
|
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PCT/EP11/60939 |
Jun 29, 2011 |
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14570276 |
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61344333 |
Jun 30, 2010 |
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Current U.S.
Class: |
424/59 ;
544/353 |
Current CPC
Class: |
A61K 9/0014 20130101;
A61K 8/4946 20130101; A61K 31/502 20130101; A61K 47/06 20130101;
A61Q 17/04 20130101; A61P 17/00 20180101; A61K 47/32 20130101; A61P
35/00 20180101; A61K 2800/78 20130101; A61K 9/12 20130101; A61K
47/10 20130101; A61K 31/137 20130101; A61K 47/38 20130101; A61K
31/4174 20130101 |
Class at
Publication: |
424/59 ;
544/353 |
International
Class: |
A61K 8/49 20060101
A61K008/49; A61Q 17/04 20060101 A61Q017/04 |
Claims
1. A method for protecting the skin, the lips, or the scalp of a
subject against the damaging effects of UV-radiation, comprising
administering to the subject a composition comprising a safe and
effective amount of an .alpha.2 adrenergic receptor agonist.
2. The method according to claim 1, wherein the .alpha.2 adrenergic
receptor agonist is selected from the group consisting of:
brimonidine,
(8-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,
(8-Bromo-quinoxalin-5-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,
(5-Bromo-3-methyl-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,
(5-Bromo-2-methoxy-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,
(4,5-dihydro-1H-imidazol-2-yl)-(8-methyl-quinoxalin-6-yl)-amine,
(4,5-dihydro-1H-imidazol-2-yl)-quinoxalin-5-yl-amine, naphazoline,
tetrahydrozaline, oxymetazoline, xylometazoline, epinephrine,
norepinephrine, phenylephrine, and methoxamine.
3. The method according to claim 1, wherein the composition
comprises from about 0.01% to about 5% by weight of the .alpha.2
adrenergic receptor agonist.
4. The method according to claim 3, wherein the composition
comprises from about 0.1% to about 2% by weight of the .alpha.2
adrenergic receptor agonist.
5. The method according to claim 1, wherein the composition is
administered to the subject through the route of topical,
epicutaneous, transdermal, subcutaneous, or intramuscular
delivery.
6. The method according to claim 5, wherein the composition is
administered to the subject by subcutaneous delivery to the skin
area in need such administration.
7. The method according to claim 5, wherein the composition is
administered to the subject by topical application onto the skin in
need such administration.
8. The method according to claim 1, wherein the subject is under a
tanning treatment and the composition further comprises a safe
amount of a tanning agent.
9. The method according to claim 1, wherein the .alpha.2 adrenergic
receptor agonist is brimonidine.
10. A cosmetic product comprising: (1) a topical composition
comprising a safe and effective amount of an .alpha.2 adrenergic
receptor agonist; and (2) instructions on applying the topical
composition to the skin, the lips, or the scalp of a subject
against the damaging effects of UV-radiation.
11. The cosmetic product of claim 10, wherein the topical
composition further comprises a safe and effective amount of a sun
screening agent.
12. The cosmetic product of claim 10, wherein the cosmetic product
is for tanning the skin of a subject, and the topical composition
further comprises a safe and effective amount of a tanning
agent.
13. The cosmetic product of claim 12, wherein the tanning agent is
selected from the group consisting of tyrosine, riboflavin,
collagen hydrolysate, and combinations thereof.
14. The cosmetic product of claim 10, wherein the .alpha.2
adrenergic receptor agonist is selected from the group consisting
of: brimonidine,
(8-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,
(8-Bromo-quinoxalin-5-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,
(5-Bromo-3-methyl-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,
(5-Bromo-2-methoxy-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,
(4,5-dihydro-1H-imidazol-2-yl)-(8-methyl-quinoxalin-6-yl)-amine,
(4,5-dihydro-1H-imidazol-2-yl)-quinoxalin-5-yl-amine, naphazoline,
tetrahydrozaline, oxymetazoline, xylometazoline, epinephrine,
norepinephrine, phenylephrine, and methoxamine.
15. The cosmetic product according to claim 14, wherein the topical
composition comprises from about 0.01% to about 5% by weight of the
.alpha.2 adrenergic receptor agonist.
16. The cosmetic product according to claim 15, wherein the topical
composition comprises from about 0.1% to about 2% by weight of the
.alpha.2 adrenergic receptor agonist.
17. The cosmetic product according to claim 14, wherein the
.alpha.2 adrenergic receptor agonist is brimonidine.
18. The cosmetic product according to claim 12, wherein the
.alpha.2 adrenergic receptor agonist is brimonidine.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation of U.S. application Ser.
No. 13/821,145, which is a Section 371 of International Application
No. PCT/EP2011/060939, filed Jun. 29, 2011, which was published in
the English language on Jan. 5, 2012, under International
Publication No. WO 2012/001065 A1, and the disclosure of which is
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] UV radiation has been shown to be a cause for a wide
spectrum of skin damage, from premature aging to skin cancer, the
most prevalent of all cancers in the United States. Skin cancer is
a malignant neoplasm of the epidermis/dermis, i.e., it has
uncontrolled growth, invades nearby tissue, and if left untreated,
may spread throughout the body, metastasizing and eventually
killing the host. Basal cell and squamous cell carcinomas represent
the majority of skin cancer cases. The leading cause of death due
to skin cancer is from malignant melanoma. It is estimated that
over the lifetime 20% of United States population will develop skin
cancer.
[0003] Besides skin cancer, there are also benign skin tumors and
pre-malignant skin tumors. A benign skin tumor will not transform
into skin cancer. Examples of benign skin tumors include, but are
not limited to, moles, seborrheic keratoses, acrochordons (also
called skin tags), epidermoid or sebaceous cysts, and
dermatofibroma. A pre-malignant skin tumor is a confined mass that
does not invade surrounding tissue, and is thus not yet cancerous
by definition. However, over time they can dedifferentiate and
become malignant. One common form of pre-malignant cancer is
carcinoma in situ, where the cells are neoplastic and continue to
multiply, but do not leave their confined space.
[0004] Skin tumors can be treated by various therapies, such as
surgical removal or destruction via excision, cryosurgery,
electro-cautery, chemo-cautery, and radiation or topical cytotoxic
agents. If the malignant skin tumors are detected early, treatment
is usually effective. However, the treatment can still be
invasive.
[0005] An alpha adrenergic agonist is a drug that selectively
stimulates alpha adrenergic receptors. The alpha-adrenergic
receptor has two subclasses .alpha.1 and .alpha.2. Complete
selectivity between receptor agonism is rarely achieved, some
agents have partial selectivity.
[0006] The .alpha. adrenoceptor agonists 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 (J.
P. Heible and R. R. Ruffolo Therapeutic Applications of Agents
Interacting with .alpha.-Adrenoceptors, p. 180-206 in Progress in
Basic and Clinical Pharmacology Vol. 8, P. Lomax and E. S. Vesell
Ed., Karger, 1991).
[0007] It was reported that activation of alpha-adrenoceptors with
alpha-adrenoceptor agonists (e.g., clonidine, oxymetazoline,
dexmedetomidine, etc) was associated with enhanced proliferation of
human tumor epithelial breast cell lines or mouse mammary tumor
cell line. See, e.g., Vazquez et al., Cancer Chemother Pharmacol.
2006 July; 58(1):50-61. Epub 2005 Nov. 15; and Bruzzone et al., Br
J Pharmacol. 2008 October; 155(4):494-504. Epub 2008 Jul. 7. It was
also reported that the alpha2-adrenoceptor antagonist yohimbine
inhibited the proliferation and induced apoptosis of pancreatic
cancer cells, suggesting that yohimbine can be used as an
anticancer drug for pancreatic cancer. Shen et al., World J
Gastroenterol. 2008 Apr. 21; 14(15):2358-63. It was further
reported that stimulation of alpha 2-adrenergic receptor inhibited
cholangiocarcinoma, a cancer of the bile ducts. Kanno et al.,
Hepatology, 2002, Volume 35, Issue 6 (p 1329-1340). The current
literature, while not extensive, does indicate that that
alpha-adrenergic receptors may play a role in tumorogenesis, and
that stimulation or antagonism of the these receptors can lead to
either increased growth or suppression of tumor tissue, depending
on the underlying cellular sub-type.
[0008] There is a need of improved noninvasive methods and
compositions that would effectively prevent skin tumor formation or
reduces skin tumor development, particularly for skin tumors
induced by UV radiation. The present invention relates to such
improved methods and compositions.
BRIEF SUMMARY OF THE INVENTION
[0009] It is now surprisingly discovered that treatment with an
.alpha.2 adrenergic receptor agonist has resulted in a significant
delay of skin tumor formation and a significant regression in skin
tumor growth in subjects exposed to UV radiation.
[0010] In one general aspect, embodiments of the present invention
relate to a method of preventing skin tumor formation in a subject.
The method comprises administering to the subject a composition
comprising an effective amount of an .alpha.2 adrenergic receptor
agonist and a pharmaceutically acceptable carrier.
[0011] In another general aspect, embodiments of the present
invention relate to a method of inhibiting the progression of an
existing skin tumor in a subject, comprising administering to the
subject a composition comprising a therapeutically effective amount
of an .alpha.2 adrenergic receptor agonist and a pharmaceutically
acceptable carrier.
[0012] In another general aspect, embodiments of the present
invention relate to a method of inducing the death or inhibiting
the growth of a skin tumor cell, comprising contacting the skin
tumor cell with a composition comprising an .alpha.2 adrenergic
receptor agonist in an amount sufficient to induce the death or
inhibit the growth of the skin tumor cell, respectively.
[0013] In another general aspect, embodiments of the present
invention relate to a method for protecting the skin, the lips, or
the scalp of a subject against the damaging effects of
UV-radiation. The method comprises administering to the subject a
composition comprising a safe and effective amount of an .alpha.2
adrenergic receptor agonist.
[0014] In another general aspect, embodiments of the present
invention relate to a method of tanning the skin of a subject,
wherein the method comprises administering to the subject a
composition comprising a safe and effective amount of an .alpha.2
adrenergic receptor agonist.
[0015] Another aspect of the present invention relates to a
cosmetic product, comprising:
[0016] (1) a topical composition comprising a safe and effective
amount of an .alpha.2 adrenergic receptor agonist; and
[0017] (2) instructions on applying the topical composition to the
skin, the lips, or the scalp of a subject against the damaging
effects of UV-radiation.
[0018] Yet another aspect of the present invention relates to a
topical composition for tanning the skin of a subject,
comprising:
[0019] (1) a safe and effective amount of an .alpha.2 adrenergic
receptor agonist and;
[0020] (2) a safe amount of a tanning agent.
[0021] Other aspects, features and advantages of the invention will
be apparent from the following disclosure, including the detailed
description of the invention and its preferred embodiments and the
appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1A. Prevalence by Week of First Perceptible Tumors
Sexes combined
[0023] FIG. 1B. Prevalence by Week of First 1 mm Tumors Sexes
combined
[0024] FIG. 1C. Prevalence by Week of First 2 mm Tumors Sexes
combined
[0025] FIG. 1D. Prevalence by Week of First 4 mm Tumors Sexes
combined
DETAILED DESCRIPTION OF THE INVENTION
[0026] Various publications, articles and patents are cited or
described in the background and throughout the specification; each
of these references is herein incorporated by reference in its
entirety. Discussion of documents, acts, materials, devices,
articles or the like which has been included in the present
specification is for the purpose of providing context for the
present invention. Such discussion is not an admission that any or
all of these matters form part of the prior art with respect to any
inventions disclosed or claimed.
[0027] 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 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 reference unless the context clearly dictates otherwise.
[0028] As used herein, an ".alpha.2 adrenergic receptor agonist" or
"agonist of .alpha.2 adrenoceptor" means a compound that binds to
and stimulates alpha adrenergic receptor subclass .alpha.2.
[0029] As used herein, the name of a compound is intended to
encompass all possible existing isomeric forms (e.g., optical
isomer, enantiomer, diastereomer, racemate or racemic mixture),
esters, prodrugs, metabolite forms, or pharmaceutically acceptable
salts, of the compound. For example, "brimonidine" can be the
compound
(5-bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine, and
any pharmaceutically acceptable salt of the compound, such as
brimonidine tartrate.
[0030] 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, glucaronate, saccharate, formate,
benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzensulfonate, 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.
[0031] As used herein, the term "hydrate" means a compound of
interest, or a pharmaceutically acceptable salt thereof that
further includes a stoichiometric or non-stoichiometric amount of
water bound to it by non-covalent intermolecular forces.
[0032] In an embodiment of the present invention, the .alpha.2
adrenergic receptor agonists include, but are not limited to, the
.alpha.2 adrenergic receptor agonists disclosed in the published US
Patent Application US20050276830, which is herein incorporated by
reference in its entirety.
[0033] Representative .alpha.2 adrenergic receptor agonists that
can be used in the present invention include, but are not limited
to, those listed in Table 1.
TABLE-US-00001 TABLE 1 Representative .alpha.2 adrenergic receptor
agonists Compound Formula Compound Name ##STR00001##
(5-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H- imidazol-2-yl)-amine
(Brimonidine) ##STR00002##
(8-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H- imidazol-2-yl)-amine
##STR00003## (8-Bromo-quinoxalin-5-yl)-(4,5-dihydro-1H-
imidazol-2-yl)-amine ##STR00004##
(5-Bromo-3-methyl-quinoxalin-6-yl)-(4,5-
dihydro-1H-imidazol-2-yl)-amine ##STR00005##
(5-Bromo-2-methoxy-quinoxalin-6-yl)-(4,5-
dihydro-1H-imidazol-2-yl)-amine ##STR00006##
(4,5-dihydro-1H-imidazol-2-yl)-(8-methyl- quinoxalin-6-yl)-amine
##STR00007## (4,5-dihydro-1H-imidazol-2-yl)-quinoxalin- 5-yl-amine
##STR00008## Tetrahydrozaline ##STR00009## Naphazoline ##STR00010##
Oxymetazoline ##STR00011## Xylometazoline ##STR00012## Epinephrine
##STR00013## Norepinephrine ##STR00014## Phenylephrine ##STR00015##
Methoxyamine
[0034] The most preferred .alpha.2 adrenergic receptor agonist is
brimonidine,
(5-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine and
pharmaceutically acceptable salts thereof, such as the tartrate
salt of brimonidine.
[0035] Other examples of .alpha.2 adrenergic receptor agonists that
can be used in the present invention include, but are not limited
to, Dexmedetomidine, Medetomidine, Romifidine, Clonidine,
Detomidine, Lofexidine, Xylazine, Tizanidine, Guanfacine, and
Amitraz.
[0036] According to the present invention, .alpha.2 adrenergic
receptor agonists can be administered to the subject through the
routes of topical, epicutaneous, transdermal, subcutaneous, or
intramuscular deliveries. In a preferred embodiment, .alpha.2
adrenergic receptor agonists are delivery to the site of the tumor
or the skin area subject to UV damages by subcutaneous delivery or
topical application on the skin.
[0037] As used herein, "topical application" and "topically
applying" means directly laying on or spreading on the skin in need
of treatment, e.g., by use of the hands or an applicator.
[0038] As used herein, "subcutaneous delivery" means directly
depositing in or underneath the skin, or in the subcutaneous fat
layer, by use of an applicator such as a needle, a multi-needle
array, an energy-based delivery system capable of subcutaneous
delivery, a pressure-based delivery system capable of subcutaneous
delivery, a needleless delivery system capable of subcutaneous
delivery, or a similar medical device.
[0039] As used herein, an "skin tumor" includes a skin cancer, a
benign skin tumor and pre-malignant skin tumor. Skin cancers
include, but are not limited to, basal cell and squamous cell
carcinomas and malignant melanoma. Examples of benign skin tumors
include, but are not limited to, moles, seborrheic keratoses,
acrochordons (also called skin tags), epidermoid or sebaceous
cysts, and dermatofibroma. Pre-malignant skin tumors include, but
are not limited to carcinoma in situ.
[0040] One embodiment of the present invention relates to a method
of preventing skin tumor formation in a subject, which comprises
administering to the subject a composition comprising an effective
amount of an .alpha.2 adrenergic receptor agonist and a
pharmaceutically acceptable carrier.
[0041] As used herein, an "effective amount of an .alpha.2
adrenergic receptor agonist" means the amount of the .alpha.2
adrenergic receptor agonist that is sufficient to prevent or delay
the formation of skin tumors in a tissue system, mammal or
human.
[0042] As used herein, the term "subject" means any mammal,
preferably a human, to whom will be or has been administered
compounds or topical formulations according to embodiments of the
invention.
[0043] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combinations of the specified ingredients in
the specified amounts.
[0044] As used herein, "prevention" or "preventing" refers to a
reduction of the risk of acquiring a skin tumor. In a preferred
mode of the embodiment, the specified compounds are administered as
a preventative measure to a subject having a predisposition to a
skin tumor, even though symptoms of the disorder are absent or
minimal.
[0045] As used herein, a "pharmaceutically-acceptable carrier"
means a carrier that is suitable for the application of the present
invention without undue toxicity, incompatibility, instability,
irritation, allergic response, and the like. This term is not
intended to limit the ingredient which it describes.
[0046] Another embodiment of the present invention relates to a
method of inhibiting the progression of an existing skin tumor in a
subject, which comprises administering to the subject a composition
comprising a therapeutically effective amount of an .alpha.2
adrenergic receptor agonist and a pharmaceutically acceptable
carrier.
[0047] As used herein, a "therapeutically effective amount of an
.alpha.2 adrenergic receptor agonist" means the amount of the
.alpha.2 adrenergic receptor agonist that is sufficient to prevent
or delay the progression of skin tumors in a tissue system, mammal
or human.
[0048] One skilled in the art will recognize that the
therapeutically effective amount of the .alpha.2 adrenergic
receptor agonist to be used in the instant invention can vary with
factors, such as the particular subject, e.g., age, diet, health,
etc., degree of UV radiation exposed to, severity and complications
of the skin tumor sought to be treated or prevented, the
formulation used, etc. In view of the present disclosure, standard
procedures can be performed to evaluate the effect of the
administration of a composition to a subject, thus allowing a
skilled artisan to determine the therapeutically effective amount
of the .alpha.2 adrenergic receptor agonist to be administered to
the subject. For example, the clinically observable beneficial
effect of the .alpha.2 adrenergic receptor agonist in preventing
the formation or preventing or delaying the progression of a skin
tumor.
[0049] The clinically observable beneficial effect can be a
situation that, when a composition of the present invention is
administered to a subject after signs and/or symptoms related to a
skin tumor are observable, the signs and/or symptoms are prevented
from further development or aggravation, or develop to a lesser
degree than without administration of the specified composition
according to embodiments of the present invention. The clinically
observable beneficial effect can also be that, when a composition
of the present invention is administered to a subject before signs
and/or symptoms related to a skin tumor are observable, the signs
and/or symptoms are prevented from occurring or subsequently occur
to a lesser degree than without administration of the composition
of the present invention.
[0050] In another embodiment, a therapeutically effective amount of
the .alpha.2 adrenergic receptor agonist will reduce of the
discomfort of the subject associated with the skin tumor or a sign
and/or symptom associated therewith.
[0051] Methods of the present invention can be used in conjunction
with one or more other treatments or medications for preventing the
formation of a skin tumor or inhibiting the progression, or
treating an existing skin tumor or a sign and/or symptom associated
therewith.
[0052] For example, a therapeutically effective amount of an
.alpha.2 adrenergic receptor agonist can be used in conjunction
with a therapy for treating a skin tumor, such as surgery-scalpel,
cryosurgery, electro-surgery, chemo-surgery, or radiation and
cytotoxic agents, such as alkylating agents, e.g., nitrogen
mustard, ethyleneimine, fluorouracil, icyclophosphamide;
anti-metabolites, e.g., 8-azaguinine, 6-mercaptopurine,
aminopterin, methotrexate; antibiotics, e.g., sarcomycin,
adinomycin, carcinophyrin, mitomycin-C, chromomycin, bleomycin,
vinblastine; hormones, e.g., sex hormones, ACTH, corticosteroids;
radio-isotopes--P 32, I 131, Co 60, Au 190; or plant derivatives,
e.g., podophyllin, colchicin, milkweed, or Abrus precatorius.
[0053] The other medicament or treatment can be administered to the
subject simultaneously with, or in a sequence and within a time
interval of, the administration of the .alpha.2 adrenergic receptor
agonist, such that the active ingredients or agents can act
together to treat or prevent skin tumor and signs and/or symptoms
associated therewith. For example, the other medicament or
treatment and the .alpha.2 adrenergic receptor agonist can be
administered in the same or separate formulations at the same or
different times.
[0054] Any suitable route of administration can be employed to
deliver the additional treatment or medication including, but not
limited to, oral, intraoral, rectal, parenteral, topical,
epicutaneous, transdermal, subcutaneous, intramuscular, intranasal,
sublingual, buccal, intradural, intraocular, intrarespiratory, or
nasal inhalation.
[0055] Another embodiment of the present invention relates to a
method of inducing the death or inhibiting the growth of a skin
tumor cell, which comprises contacting the skin tumor cell with a
composition comprising an .alpha.2 adrenergic receptor agonist in
an amount sufficient to induce the death or inhibit the growth of
the skin tumor cell, respectively. The cell under the treatment can
be in a cell culture in vitro, or a cell within an mammal in
vivo.
[0056] The present invention also relates to a method for
protecting the skin, the lips or the scalp of a subject against the
damaging effects of UV-radiation, wherein the method comprises
administering to the subject a composition comprising a safe and
effective amount of an .alpha.2 adrenergic receptor agonist.
[0057] As used herein, safe and effective amount of an .alpha.2
adrenergic receptor agonist refers to an amount of an .alpha.2
adrenergic receptor agonist sufficient to protect the skin against
the damaging effects of UV-radiation, specifically the UV-induced
skin tumors, but low enough to avoid serious side effects. The safe
and effective amount of .alpha.2 adrenergic receptor agonist will
vary with the age, health and environmental UV exposure of the
subject, the duration and nature of the treatment, the specific
ingredient, or composition employed, the particular
pharmaceutically-acceptable carrier utilized, and like factors.
[0058] The .alpha.2 adrenergic receptor agonist can be administered
together with a safe and effective amount of a sun screening agent,
an agent that absorbs or reflects some of the UV radiation in
sunlight to thus help protect the skin against sun or UV
damages.
[0059] As used herein, "safe and effective" refers to an amount of
a sun screening agent sufficient to provide photo protection when
the composition is applied but not so much as to cause any
unacceptable side effects or skin reactions. The amount varies
depending upon the sun screening agent chosen and the desired Sun
Protection Factor (SPF). Commercially available sunscreen products
have SPF values ranging from 2 to 40 or more. According to
embodiments of the present invention, a topical composition
comprises a safe and UV-damage protectively effective amount of an
.alpha.2 adrenergic receptor agonist, and about 1% to about 20%, by
weight, of a sun screening agent.
[0060] The suitable sun screening agent is capable of being
commingled with the .alpha.2 adrenergic receptor agonist used in
the present invention in a manner such that there is no interaction
which would substantially reduce the efficacy of the composition
for skin tumor prevention and/or treatment and photoprotection.
Numerous sun screening agents are suitable for use in combination
with .alpha.2 adrenergic receptor agonist, including, but not
limited to: p-Aminobenzoic acid, its salts and its derivatives
(ethyl, isobutyl, glyceryl esters; p-dimethylaminobenzoic acid);
Anthranilates (i.e., o-aminobenzoates; methyl, menthyl, phenyl,
benzyl, phenylethyl, linalyl, terpinyl, and cyclohexenyl esters);
Salicylates (amyl, phenyl, benzyl, menthyl, glyceryl, and
dipropyleneglycol esters); Cinnamic acid derivatives (menthyl and
benzyl esters, .alpha.-phenyl cinnamonitrile; butyl cinnamoyl
pyruvate); Dihydroxycinnamic acid derivatives (umbelliferone,
methylumbelliferone, methylaceto-umbelliferone);
Trihydroxy-Trihydroxycinnamic acid derivatives (esculetin,
methylesculetin, daphnetin, and the glucosides, esculin and
daphnin); Hydrocarbons (diphenylbutadiene, stilbene);
Dibenzalacetone and benzalacetophenone; Naphtholsulfonates (sodium
salts of 2-naphthol-3,6-disulfonic and of 2-naphthol-6,8-disulfonic
acids); Dihydroxy-naphthoic acid and its salts; o- and
p-Hydroxybiphenyldisulfonates; Coumarin derivatives (7-hydroxy,
7-methyl, 3-phenyl); Diazoles (2-acetyl-3-bromoindazole, phenyl
benzoxazole, methyl naphthoxazole, various aryl benzothiazoles);
Quinine salts (bisulfate, sulfate, chloride, oleate, and tannate);
Quinoline derivatives (8-hydroxyquinoline salts,
2-phenylquinoline); Hydroxy- or methoxy-substituted benzophenones;
Uric and vilouric acids; Tannic acid and its derivatives (e.g.,
hexaethylether); (Butyl carbityl) (6-propyl piperonyl) ether;
Hydroquinone; Benzophenones (Oxybenzene, Sulisobenzone,
Dioxybenzone, Benzoresorcinol, 2,2',4,4'-Tetrahydroxybenzophenone,
2,2'-Dihydroxy-4,4'-dimethoxybenzophenone, Octabenzone;
4-Isopropyldibenzoylmethane; Butylmethoxydibenzoylmethane;
Etocrylene; and 4-isopropyl-di-benzoylmethane. See, e.g., Segarin,
et al., at Chapter VIII, pages 189 et seq., of Cosmetics Science
and Technology.
[0061] Preferred sun screening agents useful in the compositions of
the present invention include, e.g., 2-ethylhexyl
p-methoxycinnamate, butyl methoxydibenzoylmethane,
2-hydroxy-4-methoxybenzophenone, octyl dimethyl p-aminobenzoic acid
and mixtures thereof.
[0062] Another aspect of the present invention relates to a
compositon and a method of tanning the skin of a subject, wherein
the method comprises administering to the subject the composition
comprising a safe and effective amount of an .alpha.2 adrenergic
receptor agonist.
[0063] As used herein, safe and effective amount of an .alpha.2
adrenergic receptor agonist refers to an amount of an .alpha.2
adrenergic receptor agonist sufficient to protect the skin against
the damaging effects of UV-radiation, specifically the UV-induced
skin tumors, but low enough to avoid serious side effects. The safe
and effective amount of .alpha.2 adrenergic receptor agonist will
vary with the tanning agent and the concentration thereof used with
herein, the duration and nature of UV exposure by the subject, the
duration and nature of the treatment, the specific ingredient, or
composition employed, the particular pharmaceutically-acceptable
carrier utilized, and like factors.
[0064] The .alpha.2 adrenergic receptor agonist can be administered
together with a safe amount of a tanning agent, an agent that helps
to increase and/or prolong skin tanning after exposure to natural
or artificial sunlight. According to an embodiment of the present
invention, a topical composition for tanning the skin of a subject
comprises a safe and effective amount of an .alpha.2 adrenergic
receptor agonist and a safe amount of a tanning agent.
[0065] The suitable tanning agent is capable of being commingled
with the .alpha.2 adrenergic receptor agonist used in the present
invention in a manner such that there is no interaction which would
substantially reduce the efficacy of the composition for skin tumor
prevention and/or treatment and skin tanning. Examples of the
tanning agent that can be used in the present invention include,
but are not limited to, tyrosine, riboflavin, collagen hydrolysate,
and combinations thereof.
[0066] A composition according to embodiments of the present
invention comprises an effective amount, or a therapeutically
effective amount, or a safe and effective amount of an .alpha.2
adrenergic receptor agonist and a pharmaceutically acceptable
carrier.
[0067] In view of the present disclosure, the composition can be
formulated for various delivery routes, such as topical,
epicutaneous, transdermal, subcutaneous, or intramuscular
deliveries. In a preferred embodiment, the .alpha.2 adrenergic
receptor agonists is formulated as a subcutaneous or topical
formulation.
[0068] One embodiment of the present invention relates to a topical
composition comprising a pharmaceutically acceptable carrier and a
therapeutically effective amount of an .alpha.2 adrenergic receptor
agonist. The carriers useful for topical delivery of the specified
compounds according to embodiments of the invention can be any
carrier known in the art for topically administering
pharmaceuticals, including, but not limited to, pharmaceutically
acceptable solvents, such as a polyalcohol or water; emulsions
(either oil-in-water or water-in-oil emulsions), such as creams or
lotions; micro emulsions; gels; ointments; liposomes; powders; and
aqueous solutions or suspensions. The pharmaceutically acceptable
carrier includes necessary and inert pharmaceutical excipients,
including, but not limited to, binders, suspending agents,
lubricants, flavorants, preservatives, dyes, and coatings.
[0069] The topical composition according to embodiments of the
present invention are prepared by mixing a pharmaceutically
acceptable carrier with a therapeutically effective amount of an
.alpha.2 adrenergic receptor agonist 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.
[0070] In one embodiment, the topical composition of the invention
is in the form of an emulsion. Emulsions, such as creams and
lotions are suitable topical formulations for use in the invention.
An emulsion is a dispersed system comprising at least two
immiscible phases, one phase dispersed in the other as droplets
ranging in diameter from 0.1 .mu.m to 100 .mu.m. An emulsifying
agent is typically included to improve stability. When water is the
dispersed phase and an oil is the dispersion medium, the emulsion
is termed a water-in-oil emulsion. When an oil is dispersed as
droplets throughout the aqueous phase as droplets, the emulsion is
termed an oil-in-water emulsion. Emulsions, such as creams and
lotions that can be used as topical carriers and their preparation
are disclosed in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY
282-291 (Alfonso R. Gennaro ed. 19th ed. 1995), hereby incorporated
herein by reference.
[0071] In another embodiment, the topical composition of the
invention is in the form of a gel, for example, a two-phase gel or
a single-phase gel. Gels are semisolid systems consisting of
suspensions of small inorganic particles or large organic molecules
interpenetrated by a liquid. When the gel mass comprises a network
of small discrete inorganic particles, it is classified as a
two-phase gel. Single-phase gels consist of organic macromolecules
distributed uniformly throughout a liquid such that no apparent
boundaries exist between the dispersed macromolecules and the
liquid. Suitable gels for use in the invention are disclosed in
REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1517-1518 (Alfonso
R. Gennaro ed. 19th ed. 1995), hereby incorporated herein by
reference. Other suitable gels for use with the invention are
disclosed in U.S. Pat. No. 6,387,383 (issued May 14, 2002); U.S.
Pat. No. 6,517,847 (issued Feb. 11, 2003); and U.S. Pat. No.
6,468,989 (issued Oct. 22, 2002), each of which patents is hereby
incorporated herein by reference.
[0072] In an embodiment, the topical composition further comprises
an aqueous gel comprising water and a water-gelling amount of a
pharmaceutically acceptable gelling agent selected from the group
consisting of carbomers, glycerine polyacrylate, and mixtures
thereof, and the topical composition has a physiologically
acceptable pH.
[0073] As used herein, "carbomer" is the USP designation for
various polymeric acids that are dispersible but insoluble in
water. When the acid dispersion is neutralized with a base a clear,
stable gel is formed. Carbomer 934P is physiologically inert and is
not a primary irritant or sensitizer. Other carbomers include 910,
940, 941, and 1342. Polymer thickeners (gelling agents) that may be
used in compositions according to embodiments of the present
invention include those known to one skilled in the art, such as
hydrophilic and hydroalcoholic gelling agents frequently 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.). Preferably the
gelling agent comprises between about 0.2% to about 4% by weight of
the composition. More particularly, 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%.
[0074] "CARBOPOL.RTM." is one of numerous cross-linked acrylic acid
polymers that are given the general adopted name carbomer. These
polymers dissolve in water and form a clear or slightly hazy gel
upon neutralization with a caustic material such as sodium
hydroxide, potassium hydroxide, triethanolamine, or other amine
bases. "KLUCEL.RTM." is a cellulose polymer that is dispersed in
water and forms a uniform gel upon complete hydration. Other
preferred gelling polymers include hydroxyethylcellulose, cellulose
gum, MVE/MA decadiene crosspolymer, PVM/MA copolymer, or a
combination thereof.
[0075] In another preferred embodiment, the topical composition of
the invention is in the form of an ointment. Ointments are
oleaginous semisolids that contain little if any water. Preferably,
the ointment is hydrocarbon based, such as a wax, petrolatum, or
gelled mineral oil. Suitable ointments for use in the invention are
well known in the art and are disclosed in REMINGTON: THE SCIENCE
AND PRACTICE OF PHARMACY 1585-1591 (Alfonso R. Gennaro ed. 19th ed.
1995), hereby incorporated herein by reference.
[0076] In an embodiment of the present invention, the topical
composition of the invention comprises at least one of a cream and
an ointment, each comprising an agent selected from the group
consisting of stearic acid, stearyl alcohol, cetyl alcohol,
glycerin, water, and mixtures thereof, and the topical composition
has a physiologically acceptable pH.
[0077] In another embodiment, the topical composition of the
invention is in the form of an aqueous solution or suspension,
preferably, an aqueous solution. Suitable aqueous topical
formulations for use in the invention include those disclosed in
REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1563-1576 (Alfonso
R. Gennaro ed. 19th ed. 1995), hereby incorporated herein by
reference. Other suitable aqueous topical carrier systems include
those disclosed in U.S. Pat. No. 5,424,078 (issued Jun. 13, 1995);
U.S. Pat. No. 5,736,165 (issued Apr. 7, 1998); U.S. Pat. No.
6,194,415 (issued Feb. 27, 2001); U.S. Pat. No. 6,248,741 (issued
Jun. 19, 2001); U.S. Pat. No. 6,465,464 (issued Oct. 15, 2002), all
of which patents are hereby incorporated herein by reference.
[0078] The pH of the topical formulations of the invention are
preferably within a physiologically acceptable pH, e.g., within the
range of about 5 to about 8, more preferably, of about 5.5 to about
6.5. To stabilize the pH, preferably, an effective amount of a
buffer is included. In one embodiment, the buffering agent is
present in the aqueous topical formulation in an amount of from
about 0.05 to about 1 weight percent of the formulation. Acids or
bases can be used to adjust the pH as needed.
[0079] Tonicity-adjusting agents can be included in the aqueous
topical formulations of the invention. Examples of suitable
tonicity-adjusting agents include, but are not limited to, sodium
chloride, potassium chloride, mannitol, dextrose, glycerin, and
propylene glycol. The amount of the tonicity agent can vary widely
depending on the formulation's desired properties. In one
embodiment, the tonicity-adjusting agent is present in the aqueous
topical formulation in an amount of from about 0.5 to about 0.9
weight percent of the formulation.
[0080] Preferably, the aqueous topical formulations of the
invention have a viscosity in the range of from about 15 cps to
about 25 cps. The viscosity of aqueous solutions of the invention
can be adjusted by adding viscosity adjusting agents, for example,
but not limited to, polyvinyl alcohol, povidone, hydroxypropyl
methyl cellulose, poloxamers, carboxymethyl cellulose, or
hydroxyethyl cellulose.
[0081] In a preferred embodiment, the aqueous topical formulation
of the invention is isotonic saline comprising a preservative, such
as benzalkonium chloride or chlorine dioxide, a viscosity-adjusting
agent, such as polyvinyl alcohol, and a buffer system such as
sodium citrate and citric acid.
[0082] The topical composition according to embodiments of the
invention can comprise pharmaceutically acceptable excipients such
as those listed in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY
866-885(Alfonso R. Gennaro ed. 19th ed. 1995; Ghosh, T. K.; et al.
TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS (1997), hereby
incorporated herein by reference, including, but not limited to,
protectives, adsorbents, demulcents, emollients, preservatives,
antioxidants, moisturizers, buffering agents, solubilizing agents,
skin-penetration agents, and surfactants.
[0083] In an embodiment, the topical composition of the invention
further comprises one or more agent selected from the group
consisting of a preservative, a local anesthetic and a skin
humectant.
[0084] Suitable preservatives include, but are not limited to,
quaternary ammonium compounds, such as benzalkonium chloride,
benzethonium chloride, cetrimide, dequalinium chloride, and
cetylpyridinium chloride; mercurial agents, such as phenylmercuric
nitrate, phenylmercuric acetate, and thimerosal; alcoholic agents,
for example, chlorobutanol, phenylethyl alcohol, and benzyl
alcohol; antibacterial esters, for example, esters of
parahydroxybenzoic acid; and other anti-microbial agents such as
chlorhexidine, chlorocresol, benzoic acid and polymyxin.
[0085] The topical composition according to embodiments of the
invention can include pharmaceuticals or their pharmaceutically
acceptable salts, such as an .alpha.2 adrenergic receptor agonist,
and optionally one or more other pharmaceutically active
ingredients, including, but not limited to, corticosteroids and
other anti-inflammatory agents, such as betamethasone, diflorasone,
amcinonide, fluocinolone, mometasone, hydrocortisone, prednisone,
and triamcinolone; local anesthetics and analgesics, such as
camphor, menthol, lidocaine, and dibucaine, and pramoxine;
antifungals, such as ciclopirox, chloroxylenol, triacetin,
sulconazole, nystatin, undecylenic acid, tolnaftate, miconizole,
clotrimazole, oxiconazole, griseofulvin, econazole, ketoconozole,
and amphotericin B; antibiotics and anti-infectives, such as
mupirocin, erythromycin, clindamycin, gentamicin, polymyxin,
bacitracin, and silver sulfadiazine; and antiseptics, such as
iodine, povidine-iodine, benzalkonium chloride, benzoic acid,
chlorhexidine, nitrofurazine, benzoyl peroxide, hydrogen peroxide,
hexachlorophene, phenol, resorcinol, and cetylpyridinium
chloride.
[0086] In a preferred embodiment, a topical composition according
to embodiments of the invention further comprises titanium dioxide
(TiO2), preferably at an amount that is sufficient to mask the
color of brimonidine or another colored ingredient in the
formulation, but would not cause irritation to the skin. TiO2 may
cause mild irritation and reddening to the eyes, thus eye contact
with the TiO2--containing topically administrable composition
should be avoided.
[0087] Dosages and dosing frequency will be determined by a trained
medical professional depending on the activity of the compounds
used, the characteristics of the particular topical formulation,
and the identity and severity of the dermatologic disorder treated
or prevented.
[0088] In an embodiment of the present invention, the topical
composition comprises 0.01% to 5% by weight of the .alpha.2
adrenergic receptor agonist. For example, the composition can
comprise, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%,
0.8%, 0.9%, 1%, 2%, 3%, 4% or 5%, by weight, of the .alpha.2
adrenergic receptor agonist.
[0089] To treat or prevent a skin tumor in view of the present
disclosure, for example, the topical compositions of the invention
are topically applied directly to the area exposed to sunlight or
the otherwise affected area in any conventional manner well known
in the art, e.g., by dropper or applicator stick, 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. Generally the amount of a topical formulation of
the invention applied to the affected skin area ranges from about
0.1 g/cm2 of skin surface area to about 5 g/cm2, preferably, 0.2
g/cm2 to about 0.5 g/cm2 of skin surface area. Typically, one to
four applications per day are recommended during the term of
treatment.
[0090] Another embodiment of the present invention relates to a
cosmetic product, comprising:
[0091] (1) a topical composition comprising a safe and effective
amount of an .alpha.2 adrenergic receptor agonist; and
[0092] (2) instructions on applying the topical composition to the
skin, the lips, or the scalp of a subject against the damaging
effects of UV-radiation.
[0093] As used herein, the term "instructions" when used in the
context of a kit includes a publication, a recording, a diagram or
any other medium of expression which can be used to communicate the
usefulness of the kit for its designated use. The instructions can,
for example, be affixed to or included within a container for the
kit.
[0094] The cosmetic product can further comprise a second topical
composition comprising a safe and effective amount of a sun
screening agent.
[0095] The .alpha.2 adrenergic receptor agonist and the sun
screening agent can be formulated in the same or separate topical
compositions contained in one or two separate containers, 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.
[0096] The topical formulations of the invention can be filled and
packaged into a plastic squeeze bottle or tube. Suitable
container-closure systems for packaging a topical formulations of
the invention are commercially available for example, from Wheaton
Plastic Products, 1101 Wheaton Avenue, Millville, N.J. 08332.
[0097] Preferably, instructions are packaged with the formulations
of the invention, for example, a pamphlet or package label. The
labeling instructions explain how to administer topical
formulations of the invention, in an amount and for a period of
time sufficient to treat or prevent a skin tumor and signs and/or
symptoms associated therewith. Preferably, the label includes the
dosage and administration instructions, the topical formulation's
composition, the clinical pharmacology, drug resistance,
pharmacokinetics, absorption, bioavailability, and
contraindications.
[0098] This invention will be better understood by reference to the
non-limiting examples that follow, but those skilled in the art
will readily appreciate that the examples are only illustrative of
the invention as described more fully in the claims which follow
thereafter.
Example 1
Aqueous Topical Formulations
[0099] This example illustrates aqueous topical formulations that
can be used in the present invention.
[0100] A first aqueous solution topical formulation comprises:
brimonidine tartrate (0.01% to 5% w/w); Puriteg (0.005% w/w)
(stabilized chlorine dioxide) as a preservative; and the inactive
ingredients: boric acid; calcium chloride; magnesium chloride;
potassium chloride; purified water; sodium borate; sodium
carboxymethylcellulose; sodium chloride; with hydrochloric acid
and/or sodium hydroxide to adjust the pH to 5.6 to 6.6. The
osmolality is in the range of 250-350 mOsmol/kg.
[0101] A second aqueous solution topical formulation comprises
brimonidine tartrate (0.2% to 2% w/w); benzalkonium chloride
(0.005% w/w.) as a preservative; and the inactive ingredients:
boric acid; calcium chloride; magnesium chloride; potassium
chloride; purified water; sodium borate; sodium
carboxymethylcellulose; sodium chloride; with hydrochloric acid
and/or sodium hydroxide to adjust the pH to 5.6 to 6.6. The
osmolality is in the range of 250-350 mOsmol/kg.
Example 2
Cream or Ointment Topical Formulations
[0102] This example illustrates cream or ointment topical
formulations that can be used in the present invention.
[0103] A first cream topical formulation (hydrophilic ointment) is
described in Table 2 below.
TABLE-US-00002 TABLE 2 Ingredient Weight Percent Brimonidine
tartrate 0.01% to 5% Stearic acid 7% Stearyl alcohol 5% Cetyl
alcohol 2% Glycerin 10% Sodium lauryl sulfate 1% Propylparaben
0.05% Methylparaben 0.25% Disodium edetate 0.055% Distilled water
QS TOTAL 100%
[0104] To make the formulation, the stearyl alcohol and the white
petrolatum are melted on a steam bath, and warmed to about 75
degrees C. The other ingredients, previously dissolved in the water
and warmed to 75 degrees C., are then added, and the mixture is
stirred until it congeals. The mixture is then allowed to cool with
stirring, and brimonidine tartrate is then added as a concentrated
solution.
[0105] An ointment topical formulation (hydrophilic ointment) is
described in Table 3 below.
TABLE-US-00003 TABLE 3 Ingredients Weight Brimonidine tartrate 20 g
Cholesterol 30 g Stearyl Alcohol 30 g White Wax 80 g White
Petrolatum 820-800 g
[0106] To make the formulation, the stearyl alcohol and white wax
are mixed together on a steam bath. The cholesterol is then added
and stirred until it completely dissolved. The white petrolatum is
then added and mixed. The mixture is removed from the bath, and
stirred until it congeals. With continuous stirring, brimonidine
tartrate is added as a concentrated slurry.
Example 3
Gel Topical Formulations
[0107] This example illustrates gel topical formulations that can
be used in the present invention.
[0108] A first gel formulation is described in Table 4 below.
TABLE-US-00004 TABLE 4 Ingredients Weight % Brimonidine tartrate
0.01-5% Methylparaben NF 0.15% Propylparaben NF 0.03%
Hydroxyethylcellulose NF 1.25% Disodium Edetate USP 0.05% Purified
Water, USP QS TOTAL 100%
[0109] A second gel formulation is described in Table 5 below.
TABLE-US-00005 TABLE 5 Ingredients Weight % Brimonidine tartrate
0.5% Methylparaben 0.20% Propylparaben 0.05% Carbomer 934P NF 1.0%
Sodium Hydroxide QS pH 7 Purified Water, USP QS TOTAL 100%
[0110] The ingredients are mixed together and aqueous sodium
hydroxide is slowly added to the mixture until a pH of about 7 is
reached and the gel is formed.
[0111] A third gel formulation is described in Table 6 below.
TABLE-US-00006 TABLE 6 Ingredient Weight Percent Brimonidine
tartrate 0.1-2% Carbomer 934P 1.25% Methylparaben 0.3%
Phenoxyethanol 0.4% Glycerin 5.5% 10% Titanium dioxide 0.625%
Propylene glycol 5.5% 10% NaOH Solution 6.5% DI Water QS TOTAL
100%
[0112] A fourth gel formulation is described in Table 7 below.
TABLE-US-00007 TABLE 7 Ingredients Weight % Brimonidine tartrate
0.01-5% Methylparaben 0.2% Propylparaben 0.05% "CARBOPOL .RTM."
1.0% Triethanolamine QS pH 7 Water QS TOTAL 100%
[0113] The ingredients are mixed together and stirred.
Triethanolamine is added until a pH of about 7 is attained.
Example 4
Foam Topical Formulations
[0114] This example illustrates foam topical formulations that can
be used in the present invention.
[0115] A first foam formulation is described in Table 8 below.
TABLE-US-00008 TABLE 8 Ingredients Amount (Weight %) Brimonidine
tartrate 0.01-5 Stearic Acid 4.2 Laureth-23 1.4 Sodium Lauryl
Sulfate 0.5 Triethanolamine 2.2 Butylated hydroxytoluene (BHT) 0.01
Fragrance 0.5 Aeron A-31 Propellant 3 Water QS TOTAL 100
[0116] The water is heated to 80-85.degree. C., after which stearic
acid is added. Once the stearic acid is melted, the laureth-23 is
added, melted, and mixed well. Next, triethanolamine is added and
the resulting composition is mixed well for about 30 minutes to
form a soap. The resulting soap is then cooled to about 65.degree.
C., after which sodium lauryl sulfate is added. The composition is
then mixed well. Next, the BHT and the Brimonidine tartrate are
added, followed by mixing. The resulting composition is then cooled
to room temperature and the fragrance added. The product is
packaged with the Aeron A-31 propellant in an aerosol can using
conventional techniques and mechanically shaken for 5 minutes. The
product dispenses as a cone-shaped spray that deposits onto the
skin as a layer of rich lather that quickly covers a wide area of
skin, and begins to relieve symptoms within about 2 minutes after
application.
[0117] A second foam formulation is described in Table 9 below.
TABLE-US-00009 TABLE 9 Ingredient Amount (Weight %) Brimonidine
tartrate 0.2-2 Water QS Palmitic Acid 2.12 Laureth-23 0.93
Triethanolamine (99%) 1.13 Cetyl Dimethicone Copolyol 0.19 Mineral
Oil 0.31 Stearyl Alcohol 0.31 Lauramide DEA 0.15 PEG-150 Distearate
0.05 Imidazolidinyl Urea 0.0016 Methylparaben 0.0005 Propylparaben
0.00003 Freeze Dried Aloe Powder 0.0015 Fragrance 0.50 Aeron A-31
Propellant 3.00 TOTAL 100
[0118] The aqueous phase is prepared as follows. The water is
heated to 80.degree. C., after which palmitic acid is added. Once
the palmitic acid is melted, the laureth-23 is added, melted, and
mixed well. Next, triethanolamine is added and the resulting
composition is mixed well for about 15 minutes to form a soap.
[0119] Stearyl alcohol, mineral oil, lauramide DEA, cetyl
dimethicone copolyol, PEG-1 50 distearate, and BHT are mixed and
heated at 55.degree. C. to form the oil phase. The oil phase is
combined with the aqueous phase at 80.degree. C. and mixed well for
about 15 minutes. The resulting mixture is then cooled to room
temperature and the imidazolidinyl urea, methylparaben, and
propylparaben are added, and then mixed well. The brimonidine
tartrate is then added, and mixed well. Next, the fragrance is
added, followed by gentle mixing. The aloe is then dissolved in
make-up water and added with slow mixing to form the product
formulation which is then packaged in an aerosol can as described
for the first foam formulation.
[0120] The product dispenses as a cone-shaped spray that deposits
onto the skin as a layer of rich lather that quickly covers a wide
area of skin, and begins to relieve symptoms within about 2 minutes
after application.
[0121] A third non-soapy foam formulation is described in Table 10
below.
TABLE-US-00010 TABLE 10 Ingredient Amount (Weight %) Brimonidine
tartrate 0.4-0.6 Ethanol 6 Ethyl Ester of PVM/MA 4 Copolymer
Dimethicone Copolyol 0.1 Water QS PVP/VA Copolymer 1 Sodium Lauryl
Sulfate 1 Oleth-20 0.5 Cocamide MEA 0.05 Methyl Paraben 0.1
Aminomethyl Propanol 0.53 Stearalkonium Chloride 0.05 Steareth-16
0.1 Panthenol 0.5 Fragrance 0.5 Aeron A-46 5 TOTAL 100
[0122] The alcohol phase is prepared by dissolving ethyl ester of
PVM/MA copolymer in ethanol, after which dimethicone is added and
mixed well. The aqueous phase is prepared by heating the water to
65.degree. C., after which the PVP/VA copolymer is added and mixed
well. The oil phase is prepared by mixing the oleth-20, cocamide
MEA, and steareth-16 at 60.degree. C. to form a blend. The oil
phase is then added to the aqueous phase at 65.degree. C. and mixed
well. Next, the methylparaben is added to the mixture, followed by
mixing, after which the aminomethyl propanol, stearalkonium
chloride, and panthenol are added and mixed until uniform. The
resulting composition is cooled to room temperature, after which
the alcohol phase is added and mixed well. The fragrance is then
added and mixed gently to form the product. The product is then
packaged in an aerosol can.
[0123] The product dispenses as a cone-shaped spray that deposits
onto the skin as a layer of rich lather that quickly covers a wide
area of skin, and begins to relieve symptoms within about 2 minutes
after application.
Example 5
Photo Carcinogenicity Study with Brimonidine
[0124] Albino hairless SKH1-hr mice (36/sex/group) were treated for
40 weeks with UVR and brimonidine gel or vehicle according to the
design in table 11. Mice were further observed for 12 weeks without
treatment. Topical treatments were performed approximately one hour
before UVR on Monday, Wednesday and Friday of each week and
approximately one hour after UVR Tuesday and Thursday of each week.
See table 11.
[0125] All procedures involving animals were conducted in a fully
accredited animal facility and in accordance with the preapproved
protocols.
TABLE-US-00011 TABLE 11 Solar- Duration of Add'l Period w/o
Brimonidine Administration Frequency of simulated Treatment or
treatment or Dosage tartrate (.mu.L/mouse, administration UVR dose
exposure UVR exposure Group Conc. (%) on 25 cm.sup.2 BSA) (days per
wk)* (RBU/week) (weeks) (weeks) 1 Vehicle 100 5 600 40 12 2 0.18
100 5 600 40 12 3 1 100 5 600 40 12 4 2 100 5 600 40 12 5 N/A N/A
N/A 600 40 12 6 N/A N/A N/A 1200 40 12 N/A: NOT APPLICABLE RBU:
Robertson-Berger Unit (a measure of effectiveness of UVR; 400 RBU
approximates one minimal erythema dose in previously untanned human
skin) *Monday, Wednesday and Friday of each week: exposure to UVR
approximately one hour after test item application. Tuesday and
Thursday of each week: exposure to UVR approximately one hour
before test item application.
[0126] As the results shown in Table 12, topical application of
Brimonidine at 0.18%, 1%, and 2% concentrations surprisingly slowed
down development of skin tumor lesions. Brimonidine resulted in a
dose-dependent delay in UV-induced skin tumor formation.
TABLE-US-00012 TABLE 12 Group Comparisons of Tumor Onset for Tumors
.gtoreq.1 mm Group 1 Group 2 Group 3 Group 4 Group 5 (No Group 6
(No Vehicle + 0.18% + 1% + 2% + treatment) treatment) Parameter 600
RBU 600 RBU 600 RBU 600 RBU 600 RBU 1200 RBU Median 40.5 48 >52
>52 40.5 26 Week(a) to Tumor (.gtoreq.1 mm) Tumor Yield 4.57
2.40 0.85 0.49 4.00 7.61 (b) (.gtoreq.1 mm) (a)The time at which
one-half of the members of the groups have acquired one or more
qualifying tumors. (b) Average number of tumors per survivor
[0127] The delay was observed in median week to tumor (.gtoreq.1
mm). In fact, the 1% and 2% Brimonidine were so effective that less
than one-half of the members of the groups acquired one or more
qualifying tumors within the 52-week study period. The delay was
also observed in tumor yield (.gtoreq.1 mm). Compared to the
vehicle group, 0.18% Brimonidine reduced the tumor yield by 1.7-
fold, 1% Brimonidine by 4.7-fold; and 2% Brimonidine by 8.1-fold.
These results represent a significant delay in onset tumor
formation.
[0128] Furthermore, FIG. 1 shows group comparisons of tumor
prevalence. Note that the number next each line denotes the
treatment group number shown in Tables 11 and 12. As shown in FIG.
1, with increasing Brimonidine concentration, the sizes of tumors
were also reduced. This indicates that topical Brimonidine promote
tumor regression as well.
[0129] 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.
* * * * *