U.S. patent application number 15/486353 was filed with the patent office on 2017-08-03 for compounds, formulations, and methods for treating or preventing inflammatory skin disorders.
The applicant listed for this patent is Galderma Laboratories, L.P.. Invention is credited to Isabelle Jean DeJovin, Jack A. DeJovin.
Application Number | 20170216282 15/486353 |
Document ID | / |
Family ID | 33457481 |
Filed Date | 2017-08-03 |
United States Patent
Application |
20170216282 |
Kind Code |
A1 |
DeJovin; Jack A. ; et
al. |
August 3, 2017 |
Compounds, Formulations, and Methods for Treating or Preventing
Inflammatory Skin Disorders
Abstract
In methods, compounds, and topical formulations for treatment of
inflammatory skin disorders incorporating compounds represented by
the formulas below: ##STR00001## wherein each of R.sub.1, R.sub.2,
and R.sub.3 is independently hydrogen, hologen, alkyl, or alkoxy;
each of R.sub.4 and R.sub.5 is independently hydrogen, alkyl, or
alkoxy; and each of R.sub.6 and R.sub.7 is independently hydrogen,
nitro, alkyl, or alkoxy; wherein each of A.sub.1, A.sub.3, and
A.sub.4 is independently hydrogen or alkyl; and A.sub.2 is
independently hydrogen or hydroxy; and wherein each of B.sub.1,
B.sub.2, and B.sub.3 is independently hydrogen, hydroxy, or alkoxy;
and each of B.sub.4 and B.sub.5 is independently hydrogen or alkyl,
applying such compounds topically as sprays, mists, aerosols,
solutions, lotions, gels, creams, ointments, pastes, unguents,
emulsions, and suspensions to treat inflammatory skin disorders and
the symptoms associated therewith.
Inventors: |
DeJovin; Jack A.; (New
Brunswick, NJ) ; DeJovin; Isabelle Jean; (New
Brunswick, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Galderma Laboratories, L.P. |
Fort Worth |
TX |
US |
|
|
Family ID: |
33457481 |
Appl. No.: |
15/486353 |
Filed: |
April 13, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15091703 |
Apr 6, 2016 |
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15486353 |
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14672704 |
Mar 30, 2015 |
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15091703 |
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13775861 |
Feb 25, 2013 |
8993571 |
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14672704 |
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12545638 |
Aug 21, 2009 |
8426410 |
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13775861 |
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11137911 |
May 25, 2005 |
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12545638 |
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10853585 |
May 25, 2004 |
7439241 |
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11137911 |
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60473611 |
May 27, 2003 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 17/00 20180101;
A61K 45/06 20130101; A61K 31/137 20130101; Y02A 50/30 20180101;
A61K 31/4164 20130101; A61K 31/4174 20130101; A61K 31/00 20130101;
A61K 9/0014 20130101; A61P 29/00 20180101; A61P 17/10 20180101;
A61P 7/10 20180101; A61K 9/06 20130101; A61P 9/00 20180101; A61K
31/498 20130101; A61K 31/4174 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/498 20060101
A61K031/498; A61K 9/06 20060101 A61K009/06; A61K 31/137 20060101
A61K031/137; A61K 9/00 20060101 A61K009/00 |
Claims
1. A method of treating an inflammatory skin disorder and the
symptoms associated therewith, comprising topically administering
to the skin of a patient in need of such treatment or prevention a
composition comprising: a therapeutically effective amount of at
least one compound selected from the group consisting of
brimonidine, xylometazoline, epinephrine, norepinephrine,
phenylephrine, and methoxamine, and a pharmaceutically acceptable
salt thereof; and a pharmaceutically acceptable carrier; wherein
the inflammatory skin disorder is not rosacea.
2-4. (canceled)
5. The method according to claim 1, wherein the at least one
compound is administered in an amount sufficient to decrease blood
flow through the small arteries or arterioles of the skin of the
patient.
6. The method according to claim 1, wherein the pharmaceutically
acceptable carrier is selected from the group consisting of sprays,
mists, aerosols, solutions, lotions, gels, creams, ointments,
pastes, unguents, emulsions, and suspensions.
7. The method according to claim 1, wherein the composition acts
locally in the skin of the patient.
8-28. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to U.S. Patent Application
Ser. No. 60/574,142, filed May 25, 2004, which is incorporated
herein by reference. This application is also a divisional of U.S.
patent application Ser. No. 10/853,585, filed May 25, 2004, which
in turn claims priority from U.S. Patent Application Ser. No.
60/473,611, filed on May 27, 2003, both of which are incorporated
herein by reference.
FIELD OF THE INVENTION
[0002] The present invention is directed to compounds and methods
for treatment or prevention of inflammatory skin disorders. The
compounds and methods taught by the present invention are
particularly useful for treating or preventing inflammatory skin
disorders and the symptoms associated therewith.
BACKGROUND OF THE INVENTION
[0003] Many people are affected by inflammatory skin disorders that
result in unsightly and painful rashes, acne, persistent red veins,
and acne-like skin eruptions, such as macules, nodules, and
pustules that may ooze or crust Inflammatory skin disorders often
result in intense psychosocial distress. Rosacea is a common
inflammatory skin disorder affecting over 10 million people in the
United States. Rosacea generally involves the cheeks, nose, chin,
and forehead and the typical age of onset is 30 to 60 years. See
e.g., Zuber T. J., Rosacea: Beyond First Blush 32 HOSP. PRACT.
188-189 (1997); THE MERCK MANUAL 813-814 (Keryn A. G. Lane et al.
eds. 17.sup.th ed. 2001). Many people with early-stage rosacea
incorrectly assume that they suffer from adult acne, sun or
windburn, or the normal effects of aging.
[0004] Rosacea develops gradually starting as frequent blushing and
frequent irritation of the facial skin.
[0005] More advanced rosacea is characterized by a vascular stage
where patients display increasingly severe erythema (abnormal
redness of the skin) and telangiectasia (visible red lines due to
abnormal dilatation of capillary vessels and arterioles).
Pimple-like eruptions, which may be solid (called papules or
nodules) or puss filled (known as pustules) may develop. Such
eruptions often look like acne, but whiteheads or blackheads
(common symptoms of acne) are not normally present. Later-stage
rosacea is characterized by rhinophyma (enlargement of the nose).
If left untreated, rosacea can progress to irreversible
disfigurement. Rosacea symptoms are often aggravated by sun
exposure, changes or extremes in temperature, wind, and consumption
of certain foods, such as spicy foods, caffeine, and alcohol.
[0006] The exact pathogenesis of rosacea is unknown, but the
pathologic process is well described. For example, erythema
associated with rosacea is caused by dilation of the superficial
vasculature of the face. Zuber T. J., Rosacea: Beyond First Blush
32 HOSP. PRACT. 188-189 (1997).
[0007] There is no known cure for many inflammatory skin disorders
like rosacea. Current treatments, which are directed to control of
redness, inflammation, and skin eruptions, are of limited
effectiveness in many patients and, generally, can be used only for
a limited duration. Standard treatments include avoidance of
triggers such as sun exposure, wind exposure, alcohol consumption,
spicy foods, and irritating facial cleansers, lotions, and
cosmetics. Antibiotics are the traditional first line of therapy.
Long-term treatment (5 to 8 weeks or more) with oral antibiotics
such as tetracycline, minocycline, doxycycline or clarithromycin
may control skin eruptions. Alternative oral treatments include
vitamin A medications, such as isoretinoin and antifungal
medications. Unfortunately, such oral medications often cause side
effects and many people have limited tolerance. Topical treatments,
such at topically applied antibiotics and antifungals (such as
metronidazole) or steroids, are available but also have limited
effectiveness and cannot treat all symptoms. For example,
isoretinoin has serious teratogenic side-effects and female
patients of child bearing age must use effective birth control or
avoid the therapy. Topical treatments include topically applied
metronidazole, topically applied steroids, topically applied
azelaic acid, topically applied rentinoic acid or retinaldehyde,
and topical vitamin C preparations are available but have limited
effectiveness and cannot treat all symptoms. Surgery, such as the
laser elimination of blood vessels, is typically a last resort, but
may be prescribed if other treatments are ineffective. In patients
with nose hyperplasia, surgical reduction may improve the patient's
cosmetic appearance, but does not treat the disease itself. Mixed
light pulse (photoderm) therapy has proved somewhat effective for
symptoms associated with certain inflammatory skin orders like
rosacea in some patients. Thus, there remains a need for topical
formulations for treatment of inflammatory skin disorders like
rosacea and its symptoms.
[0008] Agonists of the .alpha..sub.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
(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).
[0009] Adrenoreceptor agonists such as clonidine have been
primarily used orally, though a patch formulation is known. The
goal of existing formulations is to deliver a systemic internal
dose of the compound to the patient. The .alpha..sub.2 agonists are
known to mediate vasoconstriction both in the core and periphery of
a patient. In particular .alpha..sub.2 adrenoceptor agonists are
known to cause vasoconstriction of peripheral arterioles, in
response to stimulation due to cold or stress.
[0010] A number of patents describe the use of brimonidine for
treating ophthalmic conditions and eye diseases. In Canadian patent
No. CA2326690, there is described the use of topical ophthalmic
preparations for use only in the eyes, to treat eye diseases. The
Canadian patent discusses the problems with ophthalmic preparations
taken topically (in the eye), orally or parenterally, and their
systemic effects, including some serious, that limit their use.
These systemic effects include, cardiopulmonary effects of
.beta.-blockers like timolol; dryness of mouth, flush, fever, tachy
cardia, urinary retention, convulsion and irritability with
atropine; hypertension with phenylephine; increased salivation,
nausea, vomiting, diarrhea, stomach cramps, bronchial secretions,
brionchial constriction, asthma, bradycardia, paresthesia with
miotics; hypotension with clonidine; and dry mouth, fatigue and
drowsiness with apraclonidine and brimonidine.
[0011] There has been no composition containing .alpha..sub.2
adrenoceptor agonists that can deliver a dose of the agonist to the
patient, ameliorating the symptoms of rosacea or other inflammatory
skin disorders, without causing systemic side effects. There has
also been no topical skin composition containing .alpha..sub.2
adrenoceptor agonists that can deliver a dose of the agonist to the
skin of the patient, ameliorating the symptoms of rosacea and/or
other inflammatory skin disorders, without causing systemic side
effects.
SUMMARY OF THE INVENTION
[0012] The present invention provides methods, compounds, and
topical skin formulations for treatment of inflammatory skin
disorders and their symptoms. The methods, compounds, and
formulations of the invention are particularly effective for
treatment of rosacea, but can be used to treat other inflammatory
skin diseases including but not limited to dermatitis, such as
contact dermatitis, atopic dermatitis, seborrheic dermatitis,
nummular dermatitis, generalized exfoliative dermatitis, statis
dermatitis, lichen simplex chronicus; disorders of hair follicles
and sebaceous glands, such as acne, rosacea and rhinophyma,
perioral dermatitis, and pseudofolliculitis barbae; and
inflammatory reactions, such as drug eruptions, erythema
multiforme, erythema nodosum, and granuloma annulare. Compounds of
the invention are .alpha..sub.2 adrenoceptor agonists that act on
the peripheral vasculature to cause vasoconstriction and thereby
ameliorate the symptoms of inflammatory skin disorders. The
compounds are delivered in a topical skin composition that insures
that the compounds are effective in the skin of a patient but do
not penetrate the skin in sufficient amounts to induce serious
systemic side effects.
[0013] Compounds of one embodiment of the invention are represented
by Formula I below:
##STR00002##
[0014] wherein each of R.sub.1, R.sub.2, and R.sub.3 is
independently hydrogen, halogen, alkyl, preferably, unsubstituted
alkyl, or alkoxy, preferably, unsubstituted alkoxy; each of R.sub.4
and R.sub.5 is independently hydrogen, alkyl, preferably,
unsubstituted alkyl, or alkoxy, preferably, unsubstituted alkoxy;
and each of R.sub.6 and R.sub.7 is independently hydrogen, nitro,
alkyl, preferably, unsubstituted alkyl, or alkoxy, preferably,
unsubstituted alkoxy. In a preferred embodiment of the compounds of
Formula I, R.sub.6 and R.sub.7 are both hydrogen. In another
preferred embodiment, R.sub.4 and R.sub.5 are both hydrogen.
[0015] To treat or prevent inflammatory skin disorders, according
to the methods of the invention, the compounds of this embodiment
of the invention are topically applied. Preferably the compounds of
the invention are delivered in a topical formulation. Formulations
for topical delivery of compounds of the invention are well-known
in the art, such as aqueous or non-aqueous solutions or
suspensions, creams, lotions, gels, or ointments.
[0016] Compounds of another embodiment of the invention are
represented by Formula II below:
##STR00003##
[0017] Compounds of another embodiment of the invention are
represented by Formula III below:
##STR00004##
[0018] Compounds of other embodiments of the invention are shown
below:
##STR00005##
[0019] These and other features, aspects, and advantages of the
present invention will become better understood with reference to
the following detailed description, examples, and claims.
[0020] These and other features, aspects, and advantages of the
invention will become better understood with reference to the
following detailed description, examples, and appended claims.
DETAILED DESCRIPTION
1.1 COMPOUNDS OF THE INVENTION
[0021] In one embodiment, the invention is directed to compounds of
the Formula I:
##STR00006##
[0022] wherein each of R.sub.1, R.sub.2, and R.sub.3 is
independently hydrogen, halogen, alkyl, preferably, unsubstituted
alkyl, or alkoxy, preferably, unsubstituted alkoxy; each of R.sub.4
and R.sub.5 is independently hydrogen, alkyl, preferably,
unsubstituted alkyl, or alkoxy, preferably, unsubstituted alkoxy;
and each of R.sub.6 and R.sub.7 is independently hydrogen, nitro,
alkyl, preferably, unsubstituted alkyl, or alkoxy, preferably,
unsubstituted alkoxy. In a preferred embodiment of the compounds of
Formula I, R.sub.6 and R.sub.7 are both hydrogen. In another
preferred embodiment, R.sub.4 and R.sub.5 are both hydrogen.
[0023] In another embodiment, the invention is directed to
compounds of the Formula Ia;
##STR00007##
[0024] wherein each of R.sub.1, R.sub.2, and R.sub.3 is
independently hydrogen, halogen, alkyl, preferably, unsubstituted
alkyl, or alkoxy, preferably, unsubstituted alkoxy; each of R.sub.4
and R.sub.5 is independently hydrogen, alkyl, preferably,
unsubstituted alkyl, or alkoxy, preferably, unsubstituted alkoxy;
and each of R.sub.6 and R.sub.7 is independently hydrogen, nitro,
alkyl, preferably, unsubstituted alkyl, or alkoxy, preferably,
unsubstituted alkoxy. In a preferred embodiment of the compounds of
Formula Ia, R.sub.6 and R.sub.7 are both hydrogen. In another
preferred embodiment, R.sub.4 and R.sub.5 are both hydrogen. In
still another preferred embodiment of the compounds of Formula Ia,
R.sub.2 and R.sub.3 are both hydrogen and R.sub.1 is halo,
preferably, bromo.
[0025] In another embodiment, the invention relates to compounds of
the Formula Ib:
##STR00008##
[0026] wherein each of R.sub.1, R.sub.2, and R.sub.3 is
independently hydrogen, halogen, alkyl, preferably, unsubstituted
alkyl, or alkoxy, preferably, unsubstituted alkoxy. In a preferred
embodiment of the compounds of Formula Ib, R.sub.2 and R.sub.3 are
both hydrogen and R.sub.1 is halo, preferably, bromo.
[0027] In another embodiment, the invention relates to compounds of
the Formula Ic:
##STR00009##
[0028] wherein R.sub.1 is hydrogen, halogen, alkyl, preferably,
unsubstituted alkyl, or alkoxy, preferably unsubstituted alkoxy. In
a preferred embodiment R.sub.1 is halo, more preferably, bromo; and
each of R.sub.4 and R.sub.5 is independently hydrogen, alkyl,
preferably, unsubstituted alkyl, or alkoxy, preferably,
unsubstituted alkoxy. In a preferred embodiment of the compounds of
Formula Ic, at least one of R.sub.4 and R.sub.5 is hydrogen.
[0029] In another embodiment, the invention relates to compounds of
the Formula Id:
##STR00010##
[0030] wherein R.sub.1 is hydrogen, halogen, alkyl, preferably,
unsubstituted alkyl, or alkoxy, preferably, unsubstituted alkoxy.
In a preferred embodiment, R.sub.1 is halo, more preferably,
bromo.
[0031] In another embodiment, the invention relates to compounds of
the Formula II:
##STR00011##
[0032] wherein each of A.sub.1, A.sub.3, and A.sub.4 is
independently hydrogen or alkyl, and A.sub.2 is hydrogen or
hydroxyl.
[0033] In another embodiment, the invention relates to compounds of
the Formula III:
##STR00012##
[0034] wherein each of B .sub.1, B.sub.2, and B.sub.3 is
independently hydrogen, hydroxy, or methoxy; each of B.sub.4 and
B.sub.5 is independently hydrogen or alkyl.
[0035] Preferred compounds of the invention are listed in Table 1
below.
TABLE-US-00001 TABLE 1 Compounds Of The Invention Compound of the
Invention Name ##STR00013##
(5-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H- imidazol-2-yl)-amine
(Brimonidine) ##STR00014##
(8-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H- imidazol-2-yl)-amine
##STR00015## (8-Bromo-quinoxalin-5-yl)-(4,5-dihydro-1H-
imidazol-2-yl)-amine ##STR00016##
(5-Bromo-3-methyl-quinoxalin-6-yl)-(4,5-dihydro-
1H-imidazol-2-yl)-amine ##STR00017##
(5-Bromo-2-methoxy-quinoxalin-6-yl)-(4,5-
dihydro-1H-imidazol-2-yl)-amine ##STR00018##
(4,5-dihydro-1H-imidazol-2-yl)-(8-methyl- quinoxalin-6-yl)-amine
##STR00019## (4,5-dihydro-1H-imidazol-2-yl)-quinoxalin-5-yl- amine
##STR00020## Tetrahydrozaline ##STR00021## Naphazoline ##STR00022##
Oxymetazoline ##STR00023## Xylometazoline ##STR00024## Epinephrine
##STR00025## Norepinephrine ##STR00026## Phenylephrine ##STR00027##
Methoxyamine
[0036] The most preferred compound is
(5-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine
(commonly referred to as brimonidine) and pharmaceutically
acceptable salts thereof, particularly the tartrate salt. Other
compounds of the invention include naphazoline, tetra-hydrozaline,
oxymetazoline, xylometazoline, epinephrine, norepinephrine,
phenylephrine and methoxamine and their pharmaceutically acceptable
salts.
[0037] The compounds of the invention are well known in the art to
be .alpha..sub.2 adrenergic receptor agonists. As such the
compounds have powerful vasoconstricting effects when introduced
into the body of mammals, particularly humans.
1.2 SYNTHESIS OF COMPOUNDS OF THE INVENTION
[0038] The compounds of the invention can be prepared in accordance
with well-known synthetic procedures, for example, using the
general synthetic procedures outlined in U.S. Pat. No. 3,890,319
(issued Jun. 17, 1975) and U.S. Pat. No. 4,029,792 (issued Jun. 14,
1977) both of which patents are hereby incorporated herein by
reference. Scheme 1 below illustrates one method to synthesize
compounds of Formula I.
##STR00028##
[0039] Compounds of the invention can be synthesized by reaction of
the appropriate quinoxalines 15 with thiophosgene 20 to form
corresponding isothiocyanates 25. The reaction with thiophosgene
can be carried out in aqueous solution or in dilute aqueous
hydrochloric acid at room temperature in a period of about 2 hours.
Alternatively, the thiophosgene 20 dissolved in a water-immiscible
solvent, such as chloroform, can be added to a basic aqueous
solution (sodium carbonate) of quinoxalines 15 and stirred for
about two hours. In the first alternative, isothiocyanates 25
precipitate from the reaction mixture. Precipitation can be
completed by neutralization with excess aqueous base. Precipitated
isothiocyanates 25 are recovered by filtration and dissolved in a
suitable solvent, e.g., chloroform, to form a solution. The
solution is dried (e.g., MgSO.sub.4), filtered, and concentrated to
yield the isothiocyanates 25.
[0040] Isothiocyanates 25 are treated with an excess of the
appropriately substituted ethylene diamine 30 to form the
corresponding 3-quinoxalin-6-yl-thioureas 35. Isothiocyanates 25
are reacted with an excess (e.g., 5 moles to 1 mole) of ethylene
diamine 30 in a suitable solvent, e.g., diethyl ether, benzene,
chloroform or dioxane. The reaction is carried out at room
temperature for about 2 hours. 3-Quinoxalin-6-yl-thioureas 35
precipitate and are recovered by filtration and washing the filter
cake with solvent.
[0041] Cyclization of 3-quinoxalin-6-yl-thioureas 35 to afford
compounds of the invention 10 is effected by heating a suspension
of thioureas 35 with mercuric or cupric oxide in a suitable organic
solvent, e.g., ethanol. The mercuric or cupric oxide can be
replaced by an organic soluble mercuric or cupric salt, e.g.,
mercuric or cupric acetate. The reaction mixture is filtered, to
remove the mercuric or cupric sulfide by-product, and the filtrate
is concentrated to give compounds 10 in crude form. Compounds 10
are recrystallized as the free base or converted to an
acid-addition salt by conventional reaction with a suitable acid.
In certain cases, cyclization can be effected by simply refluxing
the thioureas 35 in a suitable organic solvent, e.g., methanol, in
the absence of mercuric or cupric oxide.
[0042] Quinoxalines 15 are synthesized by well-known synthetic
procedures, for example, the procedures disclosed in J. A. JOULE ET
AL., HETEROCYCLIC CHEMISTRY 189-224 (3rd ed. 1995), hereby
incorporated herein by reference.
1.3 TOPICAL FORMULATIONS OF THE INVENTION
[0043] In one embodiment, the compounds of the invention are
delivered to the affected area of the skin in a pharmaceutically
acceptable topical carrier. As used herein, a pharmaceutically
acceptable topical carrier is any pharmaceutically acceptable
formulation 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. Topical formulations of the invention
are prepared by mixing a compound of the invention with a topical
carrier according to well-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.
[0044] The topical carriers useful for topical delivery of
compounds of the invention can be any carrier known in the art for
topically administering pharmaceuticals, for example, 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, such as standard ophthalmic
preparations.
1.3.1 Emulsions, Gels, and Ointments As Topical Carriers
[0045] In a preferred embodiment, the topical carrier used to
deliver a compound of the invention is an emulsion, gel, or
ointment. 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.
[0046] In another embodiment, the topical carrier used to deliver a
compound of the invention is 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.
[0047] Polymer thickeners (gelling agents) that may be used 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%.
[0048] "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.
[0049] In another preferred embodiment, the topical carrier used to
deliver a compound of the invention is 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.
1.3.2 Aqueous Topical Formulations of the Invention
[0050] In another embodiment, the topical carrier used in the
topical formulations of the invention is an aqueous solution or
suspension, preferably, an aqueous solution. Well-known ophthalmic
solutions and suspensions are suitable topical carriers for use in
the invention. Suitable aqueous topical formulations for use in the
invention are 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 are 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.
[0051] The pH of the aqueous topical formulations of the invention
are preferably within the range of from about 6 to about 8, more
preferably, of from about 6.3 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. Suitable buffering agents are listed below in
Section 1.3.3.
[0052] 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.
[0053] 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.
[0054] 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.
1.3.3 Excipients
[0055] The topical formulations 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.
[0056] Suitable protectives and adsorbents include, but are not
limited to, dusting powders, zinc sterate, collodion, dimethicone,
silicones, zinc carbonate, aloe vera gel and other aloe products,
vitamin E oil, allatoin, glycerin, petrolatum, and zinc oxide.
[0057] Suitable demulcents include, but are not limited to,
benzoin, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
and polyvinyl alcohol.
[0058] Suitable emollients include, but are not limited to, animal
and vegetable fats and oils, myristyl alcohol, alum, and aluminum
acetate.
[0059] 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.
[0060] Chlorine dioxide (ClO.sub.2), preferably, stabilized
chlorine dioxide, is a preferred preservative for use with topical
formulations of the invention. The term "stabilized chlorine
dioxide" is well known in the industry and by those skilled in the
art. Stabilized chlorine dioxide includes one or more chlorine
dioxide precursors such as one or more chlorine dioxide-containing
complexes and/or one or more chlorite-containing components and/or
one or more other entities capable of decomposing or being
decomposed in an aqueous medium to form chlorine dioxide. U.S. Pat.
No. 5,424,078 (issued Jun. 13, 1995), hereby incorporated herein by
reference, discloses a form of stabilized chlorine dioxide and a
method for producing same, which can be used as a preservative for
aqueous ophthalmic solutions and is useful in topical formulations
of the invention. The manufacture or production of certain
stabilized chlorine dioxide products is described in U.S. Pat. No.
3,278,447, hereby incorporated herein by reference. A commercially
available stabilized chlorine dioxide which can be utilized in the
practice of the present invention is the proprietary stabilized
chlorine dioxide of BioCide International, Inc. of Norman, Okla.,
sold under the trademark Purogene.TM. or Purite.TM.. Other suitable
stabilized chlorine dioxide products include that sold under the
trademark DuraKlor by Rio Linda Chemical Company, Inc., and that
sold under the trademark Antheium Dioxide by International Dioxide,
Inc.
[0061] Suitable antioxidants include, but are not limited to,
ascorbic acid and its esters, sodium bisulfite, butylated
hydroxytoluene, butylated hydroxyanisole, tocopherols, and
chelating agents like EDTA and citric acid.
[0062] Suitable moisturizers include, but are not limited to,
glycerin, sorbitol, polyethylene glycols, urea, and propylene
glycol.
[0063] Suitable buffering agents for use with the invention
include, but are not limited to, acetate buffers, citrate buffers,
phosphate buffers, lactic acid buffers, and borate buffers.
[0064] Suitable solubilizing agents include, but are not limited
to, quaternary ammonium chlorides, cyclodextrins, benzyl benzoate,
lecithin, and polysorbates.
[0065] Suitable skin-penetration agents include, but are not
limited to, ethyl alcohol, isopropyl alcohol,
octylphenylpolyethylene glycol, oleic acid, polyethylene glycol
400, propylene glycol, N-decylmethylsulfoxide, fatty acid esters
(e.g., isopropyl myristate, methyl laurate, glycerol monooleate,
and propylene glycol monooleate); and N-methyl pyrrolidone.
1.3.4 Pharmaceutical Additives
[0066] The topical formulations of the invention can include
pharmaceuticals or their pharmaceutically acceptable salts, for
example, but not limited to, topical 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.
1.4 DOSAGE
[0067] Dosages and dosing frequency will be determined by a trained
medical professional depending on the activity of the compound of
the invention, the characteristics of the particular topical
formulation, and the identity and severity of the dermatologic
disorder treated or prevented.
[0068] In general, a compound of the invention is present in a
formulation of the invention in an amount of from about 0.01
percent to about 5 percent of the total weight of the formulation,
preferably, of from about 0.05 percent to about 1 percent, more
preferably, of from about 0.1 percent to about 0.2 percent of the
total weight of the formulation.
[0069] To treat or prevent inflammatory skin disorders (e.g.,
rosacea), the topical formulations of the invention are topically
applied directly to the affected area in any conventional manner
well known in the art. For example, 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/cm.sup.2 of skin surface area to
about 5 g/cm.sup.2, preferably, 0.2 g/cm.sup.2 to about 0.5
g/cm.sup.2 of skin surface area. Typically, one to four
applications per day are recommended during the term of
treatment.
1.5 USE OF TOPICAL FORMULATIONS OF THE INVENTION IN COMBINATION
WITH OTHER SKIN-DISORDER TREATMENTS
[0070] The formulations of the invention can be used in combination
with other treatments and medications to provide more effective
treatment or prevention of inflammatory skin disorders (e.g.,
rosacea) and symptoms associated therewith. In a preferred
embodiment, the topical formulations of the invention are used in
combination with treatment regimens and medications well known for
treatment of dermatologic disorders, such as those disclosed in THE
MERCK MANUAL 811-830 (Keryn A. G. Lane et al. eds. 17.sup.th ed.
2001), hereby incorporated herein by reference.
[0071] Using a formulation or compound of the invention in
combination with another medicament or treatment means
administering a compound of the invention and the other medicament
or treatment to a subject in a sequence and within a time interval
such that they can act together to treat or prevent inflammatory
skin disorders (e.g., rosacea) and symptoms associated therewith.
For example, the compounds of the invention can be administered at
the same time as the other medicament in the same or separate
formulations or at different times.
[0072] 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. Thus, the formulations of the invention can be
administered together or at separate times with other medications
or treatments.
[0073] In one embodiment, the topical formulations of the invention
are used in combination with systemic administration of antibiotics
or retinoids including, but not limited to, orally dosed
antibiotics, such as tetracycline, minocin, minocycline,
erythromycin, and doxycycline, and orally dosed retinoids such as
isotretinoins (e.g., Accutane or Roaccutance).
[0074] In another embodiment, the topical formulations of the
invention are used in combination with other topical treatments
including, but not limited to, topical formulations consisting of
metronidizole, hydrogen peroxide, benzoyl peroxide, lipoic acid,
and azelaic acid, and sulfur preparations; topically dosed
antibiotics, such as metronidazole, clindamycin, and erythromycin;
topical retinoids such as tretinoin, adapalene, tazarotene; or
topical steroids.
[0075] In another embodiment, the topical formulations of the
invention are used in combination with mixed light pulse therapy
(photoderm), pulsed dye laser treatment, or electrosurgery.
1.6 ARTICLE OF MANUFACTURE
[0076] Another aspect of the invention is an article of manufacture
that comprises a topical formulation of the invention in a suitable
container with labeling and instructions for use. The container can
be a dropper or tube with a suitable small orifice size, such as an
extended tip tube made of any pharmaceutically suitable
material.
[0077] 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.
[0078] 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 inflammatory skin disorders
(e.g., rosacea) and symptoms associated therewith. The labeling
instructions are an important aspect of the invention in that
before a composition can be approved for any particular use, it
must be approved for marketing by the United States Food and Drug
Administration. Part of that process includes providing a label
that will accompany the pharmaceutical composition that is
ultimately sold. Preferably, the label includes the dosage and
administration instructions, the topical formulation's composition,
the clinical pharmacology, drug resistance, pharmacokinetics,
absorption, bioavailability, and contraindications.
1.7 EXAMPLES
[0079] The following examples are provided for illustrative
purposes only and are not to be construed as limiting the
invention's scope in any manner.
1.7.1 Example 1
Synthesis of
(5-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine
[0080] To a stirred solution of 6-amino-5-bromoquinoxaline
hydrobromide (10 g) in distilled water (150 ml) is added
thiophosgene (3 ml). The solution is stirred for two hours at room
temperature and the resultant precipitate is collected by
filtration, washed with water, and dried to afford
5-bromo-6-isothiocyanato-quinoxaline.
[0081] The 5-bromo-6-isothiocyanato-quinoxaline (3.5 g.) is
directly dissolved in benzene (400 ml) and added dropwise to a
well-stirred solution of ethylene diamine (15 g.) in benzene (50
ml). During a period of about two hours, an oil separates as a
lower layer. The upper benzene layer is poured off and the oil is
washed with diethyl ether and then dissolved in methanol (500 ml).
The methanolic solution is refluxed until hydrogen sulfide
evolution ceases. The methanolic solution is concentrated in vacuo
to a volume of approximately 100 ml upon which a yellow solid
precipitates. The precipitate is collected by filtration and
recrystallized from methanol to afford of
(5-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine:
m.p. 250-251 C.
1.7.2 Example 2
[0082] An aqueous solution topical formulation of the invention
comprises
(5-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine-L-tartrate
(brimonidine tartrate) (0.15 wt. %); Purite.RTM. (0.005%)
(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.
1.7.3 Example 3
[0083] A aqueous solution topical formulation of the invention
comprises
(5-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine-L-tartrate-
, (brimonidine tartrate) (0.15 wt. %); benzalkonium chloride (0.005
wt. %) 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.
1.7.4 Example 4
[0084] A possible cream topical formulation of the invention is
described in the Table below.
TABLE-US-00002 Possible Cream Formulation Of The Invention
(Hydrophilic Ointment USP) Ingredient Weight Percent Brimonidine
tartrate 0.15% 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
[0085] Melt the stearyl alcohol and the white petrolatum on a steam
bath, and warm to about 75 degrees C. Add the other ingredients,
previously dissolved in the water and warmed to 75 degrees C., and
stir the mixture until it congeals. With stirring, allow the
mixture to cool and add brimonidine tartrate as a concentrated
solution.
1.7.5 Example 5
[0086] A possible ointment topical formulation of the invention is
described in the Table below.
TABLE-US-00003 Possible Ointment Formulation of the Invention
(Hydrophilic Ointment USP) Ingredients Weight Brimonidine tartrate
10 g Cholesterol 30 g Stearyl Alcohol 30 g White Wax 80 g White
Petrolatum 850 g
[0087] Mix the stearyl alcohol and white wax together on a steam
bath, then add the cholesterol and stir until it completely
dissolves. Add the white petrolatum and mix. Remove from the bath,
and stir until the mixture congeals. Continue stirring and add
brimonidine tartrate as a concentrated slurry.
1.7.6 Example 6
[0088] A possible gel formulation of the invention is described in
the table below.
TABLE-US-00004 Possible Gel Formulation of the Invention
Ingredients Weight % Brimonidine tartrate 1.0% Methylparaben NF
0.15% Propylparaben NF 0.03% Hydroxyethylcellulose NF 1.25%
Disodium Edetate USP 0.05% Purified Water, USP QS 100%
1.7.7 Example 7
[0089] A possible gel formulation of the invention is described in
the Table below.
TABLE-US-00005 Possible Gel Formulation of the Invention
Ingredients Weight % Brimonidine tartrate 1.0% Methylparaben 0.20%
Propylparaben 0.05% Carbomer 934P NF 1.0% Sodium Hydroxide QS pH 7
Purified Water USP QS 100%
[0090] 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.
1.7.8 Example 8
[0091] A possible gel formulation of the invention is described in
the Table below.
TABLE-US-00006 Possible Gel Formulation of the invention
Ingredients Weight % Brimonidine tartrate 1.0% Methylparaben 0.2%
Propylparaben 0.05% "CARBOPOL .RTM." 1.0% Triethanolamine QS pH 7
Water QS 100%
[0092] The ingredients are mixed together and stirred.
Triethanolamine is added until a pH of about 7 is attained.
1.7.9 Example 9
[0093] Alphagan P (0.15% brimonidine tartrate in isotonic saline
and citrate buffer having a pH of 6.3 to 6.5) was supplied by
Allergan, Inc. having the composition disclosed in Example 2 above.
A study was conducted with four otherwise healthy persons who were
independently diagnosed with phase II rosacea (characterized by
transitory erythema of the mid-facial areas and early
telangiectasis). All subjects followed a morning protocol of
cleansing their face with soap and water. After a gentle towel
drying and air drying, Alphagan-P was administered by gently
rubbing onto areas of facial redness. The application area was
again allowed to air dry without any dressing.
[0094] Subject 1 is a 59 year old woman with a ten year history of
rosacea displaying symptoms of periodic redness flare-ups across
her cheeks that usually runs a course of three to four weeks before
subsiding under customary dermatological treatment. The subject
showed an immediate improvement after the first morning application
of Alphagan-P. All redness disappeared within 10 minutes and her
face remained symptom free for the entire first day. Daily
observation showed only mild return of redness after 24 hours.
Continued daily use resulted in completely eliminating the redness
due to rosacea in three days.
[0095] Subject 2 is a 54 year-old woman with an eight year history
of rosacea who suffers from everyday facial redness across her
cheeks with occasional severe flare-ups. The subject halted her
customary daily dermatological treatment to try the protocol
described above. The result was the same immediate removal of all
redness within ten minutes. The dramatic improvement lasted most of
the day with some mild redness re-occurring in the evening. For
this subject, redness returned the next day. Continued daily use
provided daily relief from redness.
[0096] Subject 3 is a 57 year-old man with a greater than ten-year
history of rosacea displaying symptoms of redness of the cheeks and
the nose. Although this subject's redness due to rosacea is always
present, his general ruddy complexion and lack of concern allows
him to forgo the daily use of customary dermatological treatment in
favor of occasional, ad hoc treatments. A single morning trial of
the Alphagan-P protocol described above resulted in dramatic
daylong relief of redness.
[0097] Subject 4 is a woman in her early forties with a diagnosis
of rosacea on her lower face and chin. Her condition includes some
thickening of skin. Upon trying the protocol, redness was greatly
reduced but not completely eliminated. Qualitatively the reduction
was described as 80% less red. An additional observation of reduced
skin thickening was reported.
[0098] These trials demonstrate that 0.15% brimonidine tartrate,
when used in a daily morning protocol, dramatically eliminates or
reduces redness due to rosacea. It is shown to be an effective
treatment to greatly accelerate the arrest of a rosacea flare-up.
It is further shown to be an effective daily treatment for chronic
rosacea redness.
1.7.10 Example 10
[0099] Use of Oxymetazoline
[0100] An oxymetazoline solution (Afrin.RTM., 0.05% solution.
Schering-Plough HealthCare Products) The solution was placed onto a
cotton tipped swab and applied to approximately 4 cm.sup.2 of
naso-facial skin displaying rosacea induced erythema. Twenty two
minutes after application a lessening of erythema was observed.
1.7.11 Example 11
[0101] Use of Epinephrine
[0102] An epinephrine solution (Epipen.RTM., trademark of Dey.RTM.,
L.P.) containing approximately 0.3 mg of epinephrine was placed in
a glass container. The solution was placed onto a cotton tipped
swab and then applied to approximately 4 cm.sup.2 of naso-facial
skin displaying rosacea induced erythema. Within 5 minutes of
application a mottled whitening of the skin was observed. No
whitening was observed in skin outside of the application area. The
whitening effect began to fade after approximately 30 minutes.
1.7.12 Example 12
[0103] A tetrahydrozoline solution (Visine.RTM., 0.05% solution,
Pfizer) The solution was placed onto a cotton-tipped swab and
applied to approximately 4 cm.sup.2 of naso-facial skin displaying
rosacea induced erythema. Visual observation indicated no erythema
reduction using this concentration of tetrahydrozoline.
1.7.13 Example 13
[0104] Testing Procedure for Prevention of Redness by
.alpha.-Adrenergic Agonists:
[0105] A number of a-adrenergic agonists were evaluated for their
ability to topically suppress erythema in human skin induced by
methyl nicotinate. The erythema produced in the skin results from
the vasodilatory effect on the dermal vasculature by methyl
nicotinate. In this model, the minimum erythemal dose (MED)
produced on the forearm by methyl nicotinate is determined for each
test subject. The MED is defined as the minimal dose that results
in a defined circle of erythema. The MED was determined by
saturating five 19 mm Hill Top Chambers with 220 .mu.l of 1, 2, 3,
4, and 5 mm methyl nicotinate. The Hill Top Chambers were applied
to the volar forearm of each test subject, removed after 30 seconds
and excess liquid lightly blotted from the skin. The MED of methyl
nicotinate was selected 10 minutes after application, by
determining the minimal dose that resulted in a defined circle of
erythema. The .alpha.-adrenergic agonists were dissolved in alcohol
and topically applied (2 .mu.l/cm.sup.2) to selected sites on the
contralateral volar forearm for 30 minutes prior to challenge with
methyl nicotinate. Hill Top Chambers (19 mm) were saturated with
220 .mu.l of the dose of methyl nicotinate determined to produce a
MED for each test subject. 6The chambers were applied to the volar
forearm treated with vehicle or test compounds, removed after 30
seconds and excess liquid was lightly blotted from the skin. Ten
minutes after application of methyl nicotinate the test sites were
evaluated for erythema. A numerical grading scale of 0 to 3 was
used: 0=none, 0.5=barely perceptible, 1.0=mild, 1.5=mild+ (mild to
moderate), 2.0=moderate, 2.5=moderate+ (moderate to severe),
3.0=severe.
[0106] The test results are shown in the table below and indicate
that each of the tested compounds reduced the formation of the
Methyl Nicotinate induced redness (erythema) in the test subjects.
With both Oxymetazoline HCl and Naphazoline HCl the redness was
fully blocked for two of the three subjects pursuant to the test
conditions as described above.
The Effect of .alpha.-Adrenergic Agonists on Methyl
Nicotinate-Induced Erythema
TABLE-US-00007 [0107] Pre-Treatment + Methyl Nicotinate N Mean
Erythema Grade Alcohol Vehicle Control 3 3.0 0.2% Naphazoline HCl 3
0.33 0.2% Oxymetazoline HCl 3 1.0 0.2% Brimonidine 3 0.83
1.8 DEFINITIONS
[0108] As used herein, the terms "an inflammatory skin disorder"
and "an inflammatory dermatologic disorder" mean any disease or
medical condition associated with the skin, nails, or mucosal
membranes displaying symptoms of redness, flushing, burning,
scaling, acne (pimples, papules, pustules (particularly in the
absence of blackheads)), telangiectasis, sores, surface irritation
or pain, itching, and/or inflammation Inflammatory dermatologic
disorders include, but are not limited to, dermatitis, such as
contact dermatitis, atopic dermatitis, seborrheic dermatitis,
nummular dermatitis, generalized exfoliative dermatitis, statis
dermatitis, lichen simplex chronicus; disorders of hair follicles
and sebaceous glands, such as acne, rosacea and rhinophyma,
perioral dermatitis, and pseudofolliculitis barbae; and
inflammatory reactions, such as drug eruptions, erythema
multiforme, erythema nodosum, and granuloma annulare. In a
preferred embodiment, the topical formulations of the invention are
used to treat or prevent inflammatory dermatologic disorders of the
face, such as rosacea.
[0109] The phrase "pharmaceutically acceptable salt(s)", as used
herein, means those salts of compounds of the invention 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 compounds of the
invention. 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 of the 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.
[0110] The term "pharmaceutically acceptable topical formulation"
as used herein means any formulation which is pharmaceutically
acceptable for topical delivery of the compounds of the invention.
According to the invention, a "topical formulation" will comprise
at least a compound of the invention. The choice of topical
formulation will depend on several factors, including the nature of
the symptoms to be treated or prevented, the physiochemical
characteristics of the particular compound of the invention and of
other excipients present, their stability in the formulation,
available manufacturing equipment, and cost constraints.
[0111] As used herein, a "therapeutically effective amount of a
compound of the invention" means the minimum amount of the compound
that is effective to treat or prevent an inflammatory dermatologic
disorder.
[0112] As used herein, the term "subject" means any animal,
preferably a mammal, to which will be or has been administered
compounds or topical formulations 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. Preferably, a subject is in need of
treatment or prevention of an inflammatory skin disorder and
symptoms associated therewith.
[0113] The term "analog" refers to a chemical compound that is
structurally similar to a parent compound and has chemical
properties or pharmaceutical activity in common with the parent
compound. Analogs include, but are not limited to, homologs, i.e.,
where the analog differs from the parent compound by one or more
carbon atoms in series; positional isomers; compounds that differ
by interchange of one or more atoms by a different atom, for
example, replacement of a carbon atom with an oxygen, sulfur, or
nitrogen atom; and compounds that differ in the identity of one or
more functional groups, for example, the parent compound differs
from its analog by the presence or absence of one or more suitable
substituents. Suitable substituents include, but are not limited
to, (C.sub.1-C.sub.8)alkyl; (C.sub.1-C.sub.8)alkenyl;
(C.sub.1-C.sub.8)alkynyl: aryl; (C.sub.2-C.sub.s)heteroaryl;
(C.sub.1C.sub.6)heterocycloalkyl; (C.sub.3-C.sub.7)cycloalkyl;
O--(C.sub.1-C.sub.8)alkyl; O--(C.sub.1-C.sub.8)alkenyl;
O--(C.sub.1-C.sub.8)alkynyl; O-aryl; CN; OH; oxo; halo, C(O)OH;
COhalo; O(CO)halo; CF.sub.3, N.sub.3; NO.sub.2, NH.sub.2;
NH((C.sub.1-C.sub.8)alkyl); N((C.sub.1-C.sub.8)alkyl).sub.2;
NH(aryl); N(aryl).sub.2 N((C.sub.1-C.sub.8)alkyl)(aryl);
(CO)NH.sub.2; (CO)NH((C.sub.1-C.sub.8)alkyl);
(CO)N((C.sub.1-C.sub.8)alkyl).sub.2; (CO)NH(aryl);
(CO)N(aryl).sub.2; O(CO)NH.sub.2; NHOH;
NOH((C.sub.1-C.sub.8)alkyl); NOH(aryl);
O(CO)NH((C.sub.1-C.sub.8)alkyl);
O(CO)N((C.sub.1-C.sub.8)alkyl).sub.2; O(CO)NH(aryl);
O(CO)N(aryl).sub.2; CHO; CO((C.sub.1-C.sub.8)alkyl); CO(aryl);
C(O)O((C.sub.1-C.sub.8)alkyl); C(O)O(aryl);
O(CO)((C.sub.1-C.sub.8)alkyl); O(CO)(aryl);
O(CO)O((C.sub.1-C.sub.8)alkyl); O(CO)O(aryl);
S--(C.sub.1-C.sub.8)alkyl; S--(C.sub.1-C.sub.8)alkenyl;
S--(C.sub.1-C.sub.8)alkynyl; S-aryl; S(O)--(C.sub.1-C.sub.8)alkyl;
S(O)--(C.sub.1-C.sub.8)alkenyl; S(O)--(C.sub.1-C.sub.8)alkynyl; and
S(O)-aryl; S(O).sub.2--(C.sub.1-C.sub.8)alkyl;
S(O).sub.2--(C.sub.1-C.sub.8)alkenyl;
S(O).sub.2--(C.sub.1-C.sub.8)alkynyl; and S(O).sub.2-aryl. One of
skill in the art can readily choose a suitable substituent based
upon the stability and pharmacological activity of the compound of
the invention.
[0114] The term "alkyl" means a saturated, monovalent, unbranched
or branched hydrocarbon chain. Examples of alkyl groups include,
but are not limited to, (C.sub.1-C.sub.3)alkyl groups, such as
methyl, ethyl, propyl, isopropyl and (C.sub.4-C.sub.8)alkyl groups,
such as 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,
3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,
2-methyl-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,
2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,
2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,
isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl, heptyl,
and octyl. An alkyl group can be unsubstituted or substituted with
one or two suitable attachments.
[0115] The term "alkenyl" means a monovalent, unbranched or
branched hydrocarbon chain having one or more double bonds therein.
The double bond of an alkenyl group can be unconjugated or
conjugated to another unsaturated group. Suitable alkenyl groups
include, but are not limited to (C.sub.2-C.sub.8)alkenyl groups,
such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl,
pentadienyl, hexadienyl,
2-ethylhexenyl,2-propyl-2-butenyl,4-(2-methyl-3-butene)-pentenyl.
An alkenyl group can be unsubstituted or substituted with one or
two suitable substituents.
[0116] The term"alkynyl" means monovalent, unbranched or branched
hydrocarbon chain having one or more triple bonds therein. The
triple bond of an alkynyl group can be unconjugated or conjugated
to another unsaturated group. Suitable alkynyl groups include, but
are not limited to, (C.sub.2-C.sub.8)alkynyl groups, such as
ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl,
4-methyl-1-butynyl,4-propyl-2-pentynyl, and 4-butyl-2-hexynyl. An
alkynyl group can be unsubstituted or substituted with one or two
suitable substituents.
[0117] The term "aryl" means a monocyclic or polycyclic-aromatic
group comprising carbon and hydrogen atoms. Examples of suitable
aryl groups include, but are not limited to, phenyl, tolyl,
anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as
benzo-fused carbocyclic moieties such as
5,6,7,8-tetrahydronaphthyl. An aryl group can be unsubstituted or
substituted with one or two suitable substituents. Preferably, the
aryl group is a monocyclic ring, wherein the ring comprises 6
carbon atoms, referred to herein as "(C.sub.6)aryl".
[0118] The term "heteroaryl" means a monocyclic- or polycyclic
aromatic ring comprising carbon atoms, hydrogen atoms, and one or
more heteroatoms, preferably, 1 to 3 heteroatoms, independently
selected from nitrogen, oxygen, and sulfur. As is well known to
those skilled in the art, heteroaryl rings have less aromatic
character than their all-carbon counter parts. Thus, for the
purposes of the invention, a heteroaryl group need only have some
degree of aromatic character. Illustrative examples of heteroaryl
groups include, but are not limited to, pyridinyl, pyridazinyl,
pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl,
(1,2,3,)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidinyl,
tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, phenyl,
isoxazolyl, and oxazolyl. A heteroaryl group can be unsubstituted
or substituted with one or two suitable substituents. Preferably, a
heteroaryl group is a monocyclic ring, wherein the ring comprises 2
to 5 carbon atoms and 1 to 3 heteroatoms, referred to herein as
"(C.sub.2-C.sub.5)heteroaryl".
[0119] The term "cycloalkyl" means a non-aromatic, monocyclic or
polycyclic ring comprising carbon and hydrogen atoms. A cycloalkyl
group can have one or more carbon-carbon double bonds in the ring
so long as the ring is not rendered aromatic by their presence.
Examples of cycloalkyl groups include, but are not limited to,
(C.sub.3-C.sub.7)cycloalkyl groups, such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated
cyclic and bicyclic terpenes and (C.sub.3-C.sub.7)cycloalkenyl
groups, such as cyclopropenyl, cyclobutenyl, cyclopentenyl,
cyclohexenyl, and cycloheptenyl, and unsaturated cyclic and
bicyclic terpenes. A cycloalkyl group can be unsubstituted or
substituted by one or two suitable substituents. Preferably, the
cycloalkyl group is a monocyclic ring or bicyclic ring.
[0120] The term "heterocycloalkyl" means a non-aromatic monocyclic
or polycyclic ring comprising carbon and hydrogen atoms and at
least one heteroatom, preferably, 1 to 4 heteroatoms selected from
nitrogen, oxygen, and sulfur. A heterocycloalkyl group can have one
or more carbon-carbon double bonds or carbon-heteroatoms double
bonds in the ring as long as the ring is not rendered aromatic by
their presence. Examples of heterocycloalkyl groups include
aziridinyl, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino,
piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl,
thiomorpholino, tetrahydrofuranyl, tetrahydrothiofuranyl,
tetrahydropyranyl, and pyranyl. A heterocycloalkyl group can be
unsubstituted or substituted with one or two suitable substituents.
Preferably, the heterocycloalkyl group is a monocyclic or bicyclic
ring, more preferably, a monocyclic ring, wherein the ring
comprises from 2 to 6 carbon atoms and from 1 to 3 heteroatoms,
referred to herein as (C.sub.1-C.sub.6)heterocycloalkyl.
[0121] The term "halogen" means fluorine, chlorine, bromine, or
iodine. Correspondingly, the term "halo" means fluoro, chloro,
bromo, and iodo.
[0122] The term "derivative" refers to an analog, as defined above,
that is synthesized in one or more chemical reactions from its
parent compound.
[0123] As used herein, the term "hydrate" means a compound of the
invention, 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.
[0124] In one embodiment, "treatment" or "treating" refers to an
amelioration, prophylaxis, or reversal of a disease or disorder, or
at least one discernible symptom thereof. For example, treating an
inflammatory skin disorder (e.g., rosacea) by lessening the redness
of the skin. In another embodiment, "treatment" or "treating"
refers to an amelioration, prophylaxis, or reversal of at least one
measurable physical parameter related to the disease or disorder
being treated, not necessarily discernible in or by the mammal. In
yet another embodiment, "treatment" or "treating" refers to
inhibiting or slowing the progression of a disease or disorder,
either physically, e.g., stabilization of a discernible symptom,
physiologically, e.g., stabilization of a physical parameter, or
both. In yet another embodiment, "treatment" or "treating" refers
to delaying the onset of a disease or disorder.
[0125] In certain embodiments, the compounds of the invention are
administered as a preventative measure. 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 compounds of the invention are administered as a
preventative measure to a subject having a predisposition to
rosacea even though symptoms of the disorder are absent or
minimal.
[0126] 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.
[0127] In view of the above Background, Summary, Figures, and
Detailed Description, it is clear that in certain embodiments, the
invention comprises a method of treating or preventing rosacea and
its symptoms, comprising topically administering to the skin of a
subject in need of such treatment or prevention a compound of a
formula:
##STR00029##
[0128] wherein each of R.sub.1, R.sub.2, and R.sub.3 is
independently hydrogen, hologen, alkyl, or alkoxy; each of R.sub.4
and R.sub.5 is independently hydrogen, alkyl, or alkoxy; and each
of R.sub.6 and R.sub.7 is independently hydrogen, nitro, alkyl, or
alkoxy;
[0129] wherein each of A.sub.1, A.sub.3, and A.sub.4 is
independently hydrogen or alkyl; and A.sub.2 is independently
hydrogen or hydroxy; and
[0130] wherein each of B.sub.1, B.sub.2, and B.sub.3 is
independently hydrogen, hydroxy, or alkoxy; and each of B.sub.4 and
B.sub.5 is independently hydrogen or alkyl.
[0131] All citations (e.g., scientific journal publications,
patents, and other reference material) mentioned herein are hereby
incorporated herein by reference to the same extent as if each
individual citation was specifically and individually indicated to
be incorporated by reference.
[0132] One of ordinary skill in the art can make many variations
and modifications to the above-described embodiments of the
invention without departing from the spirit or scope of the
appended claims. Accordingly, all such variations and modifications
are within the scope of the appended claims.
* * * * *