U.S. patent application number 13/240562 was filed with the patent office on 2012-04-26 for gel compositions and methods of use.
This patent application is currently assigned to GALDERMA R&D SNC.. Invention is credited to Jean-Christophe BUGE, Cyril MEUNIER, Karine NADAU-FOURCADE.
Application Number | 20120101141 13/240562 |
Document ID | / |
Family ID | 44882481 |
Filed Date | 2012-04-26 |
United States Patent
Application |
20120101141 |
Kind Code |
A1 |
BUGE; Jean-Christophe ; et
al. |
April 26, 2012 |
GEL COMPOSITIONS AND METHODS OF USE
Abstract
Improved topical gel compositions for the treatment of skin
disorders are described. The gel compositions contain carbomer and
methylparaben, and are substantially free of methylparaben
crystalline particles after an extended period of storage.
Inventors: |
BUGE; Jean-Christophe;
(Nice, FR) ; NADAU-FOURCADE; Karine;
(Villeneuve-Loubet, FR) ; MEUNIER; Cyril;
(Mougins, FR) |
Assignee: |
GALDERMA R&D SNC.
Biot
FR
|
Family ID: |
44882481 |
Appl. No.: |
13/240562 |
Filed: |
September 22, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13158987 |
Jun 13, 2011 |
8053427 |
|
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13240562 |
|
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61405388 |
Oct 21, 2010 |
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Current U.S.
Class: |
514/401 ;
514/653; 514/772.1 |
Current CPC
Class: |
A61P 17/06 20180101;
A61Q 19/007 20130101; A61K 31/45 20130101; A61K 31/415 20130101;
A61K 31/135 20130101; A61K 31/535 20130101; A61P 17/00 20180101;
A61Q 19/08 20130101; A61P 29/00 20180101; A61K 9/1075 20130101;
A61K 8/4953 20130101 |
Class at
Publication: |
514/401 ;
514/772.1; 514/653 |
International
Class: |
A61K 31/4174 20060101
A61K031/4174; A61K 31/137 20060101 A61K031/137; A61P 29/00 20060101
A61P029/00; A61P 17/00 20060101 A61P017/00; A61P 17/06 20060101
A61P017/06; A61K 47/34 20060101 A61K047/34; A61K 31/4164 20060101
A61K031/4164 |
Claims
1. A topical gel composition, comprising: 0.05 to 0.20% (w/w)
methylparaben; a second preservative; 0.80 to 1.50% (w/w) carbomer;
9.0 to 13.0% (w/w) total polyol; and purified water; wherein the
topical gel composition has a pH of 4.5 to 7.5; and wherein when
the concentration of methylparaben is greater than 0.15% (w/w), the
concentration of carbomer is less than 1.25% (w/w).
2. The topical gel composition of claim 1, comprising about 4.5% to
6.5% (w/w) of a first polyol.
3. The topical gel composition of claim 1, further comprising an
alpha adrenergic receptor agonist.
4. The topical gel composition of claim 3, wherein the alpha
adrenergic receptor agonist is an alpha-1 or alpha-2 adrenergic
receptor agonist.
5. The topical gel composition of claim 4, wherein the alpha
adrenergic receptor agonist is selected from the group consisting
of oxymetazoline, phenylephrine, methoxyamine, tetrahydrozoline,
naphazoline, xylometazoline, epinephrine, and norepinephrine.
6. The topical gel composition of claim 1, further comprising 0.04
to 0.08% (w/w) of a water dispersible form of titanium dioxide.
7. The topical gel composition of claim 1, wherein the carbomer is
selected from the group consisting of carbomer 934P, carbomer 974P
and carbomer 980.
8. The topical gel composition of claim 1, wherein the second
preservative is selected from the group consisting of sodium
benzoate, phenoxyethanol, benzyl alcohol, imidazolidinyl urea, and
diazolidinyl urea.
9. A topical gel composition, comprising: 0.05 to 0.15% (w/w)
methylparaben; a second preservative selected from the group
consisting of sodium benzoate, phenoxyethanol, benzyl alcohol,
imidazolidinyl urea and diazolidinyl urea; 0.80 to 1.50% (w/w)
carbomer; 4.5 to 6.5% (w/w) propylene glycol; 4.5 to 6.5% (w/w)
glycerol; and purified water; wherein the pH of the topical gel
composition is adjusted to 5.0 to 6.5 by an adequate amount of
sodium hydroxide aqueous solution.
10. The topical gel composition of claim 9, wherein the second
preservative is phenoxyethanol, present at an amount greater than
0.3% (w/w) of the total weight of the topical gel composition.
11. The topical gel composition of claim 9, further comprising 0.04
to 0.08% (w/w) of a water dispersible form of titanium dioxide.
12. The topical gel composition of claim 9, further comprising an
alpha adrenergic receptor agonist.
13. The topical gel composition of claim 12, wherein the alpha
adrenergic receptor agonist is an alpha-1 or alpha-2 adrenergic
receptor agonist.
14. The topical gel composition of claim 13, wherein the alpha
adrenergic receptor agonist is selected from the group consisting
of oxymetazoline, phenylephrine, methoxyamine, tetrahydrozoline,
naphazoline, xylometazoline, epinephrine, and norepinephrine.
15. A method of treating or preventing a skin disorder in a
subject, comprising topically administering to a skin area of the
subject the topical gel composition of claim 1, wherein the gel
composition further comprises an alpha adrenergic receptor agonist
selected from the group consisting of oxymetazoline, phenylephrine,
methoxyamine, tetrahydrozoline, naphazoline, xylometazoline,
epinephrine, and norepinephrine, and wherein the skin area is, or
is prone to be, affected by the skin disorder.
16. The method of claim 15, wherein the skin disorder is rosacea,
erythema of rosacea, telangiectasia, psoriasis, purpura, erythema
of acne, eczema, non-rosacea-related inflammation of the skin,
flushing, skin sagging, creasing and/or wrinkling, or a symptom
associated therewith.
17. A method of treating or preventing a skin disorder in a
subject, comprising topically administering to a skin area of the
subject the topical gel composition of claim 9, wherein the gel
composition further comprises an alpha adrenergic receptor agonist
selected from the group consisting of oxymetazoline, phenylephrine,
methoxyamine, tetrahydrozoline, naphazoline, xylometazoline,
epinephrine, and norepinephrine, and wherein the skin area is, or
is prone to be, affected by the skin disorder.
18. The method of claim 17, wherein the skin disorder is rosacea,
erythema of rosacea, telangiectasia, psoriasis, purpura, erythema
of acne, eczema, non-rosacea-related inflammation of the skin,
flushing, skin sagging, creasing and/or wrinkling, or a symptom
associated therewith.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S. patent
application Ser. No. 13/158,987, filed on Jun. 13, 2011, which is
entitled to priority pursuant to 35 U.S.C. .sctn.119(e) to U.S.
Provisional Patent Application No. 61/405,388, filed Oct. 21, 2010,
the disclosures of which are hereby incorporated by reference
herein in its entirety.
BACKGROUND OF THE INVENTION
[0002] Parabens are esters of para-hydroxybenzoic acid. They are
used primarily for their bactericidal and fungicidal properties.
Examples of parabens include methylparaben, ethylparaben,
propylparaben, butylparaben, isobutylparaben, isopropylparaben,
benzylparaben and their salts. Because of their low costs, long
history of safe use and the inefficacy of natural alternatives,
parabens are widely used as preservatives in the cosmetic and
pharmaceutical industries. See Darbre et al., 24 J. Appl. Toxicol.
5-13 (2004) and references therein.
[0003] Carbomer is a generic name of Carbopol.RTM., a trademarked
product from Lubrizol. Carbomer and Carbopol.RTM. are used
interchangeably in the present application, referring to a
synthetic polymer of acrylic acid cross-linked with polyalkenyl
ethers or divinyl glycol. It can be a homopolymer of acrylic acid,
cross-linked with an allyl ether pentaerythritol, allyl ether of
sucrose, or allyl ether of propylene. Carbomers have been used as
vehicles for drug delivery. They have a long history of safe and
effective use in topical gels, creams, lotions, and ointments, as
supported by extensive toxicology studies. They have been shown to
have extremely low irritancy properties and are non-sensitizing
with repeat usage. Carbomers or carbomer copolymers have been used
in topical formulations, e.g., for thickening, emulsifying or
suspending.
[0004] Brimonidine is a selective alpha-2-adrenergic agonist. It
has been used as either monotherapy or as adjunctive therapy to
lower intraocular pressure (IOP) in the treatment of glaucoma and
ocular hypertension (OHT) since its approval in 1996. Brimonidine
has also been found to be useful in treating various skin
disorders, such as rosacea, erythema caused by rosacea, see, e.g.,
U.S. Ser. No. 10/853,585 to DeJovin et al.; U.S. Ser. No.
10/626,037 to Scherer; U.S. Ser. No. 12/193,098 to Theobald et al.;
telangiectasias, see, e.g., U.S. Patent Application Publication No.
2006/0264515. Topical gel compositions comprising brimonidine,
carbomer and paraben(s) for the treatment of skin disorders have
been described, see for example, U.S. Ser. No. 10/853,585 to
DeJovin et al.; U.S. Ser. No. 12/193,098 to Theobald et al.,
etc.
[0005] In the present invention, crystalline particles of
methylparaben have been unexpectedly observed in some brimonidine
topical gel formulations and placebo formulations containing
carbomer and methylparaben.
[0006] There is a need for topical gel compositions containing
carbomer and methylparaben that are substantially free of paraben
crystalline particles and meet the antimicrobial requirement over
an extended period of storage. Such compositions and related
methods and products are described in the present application.
BRIEF SUMMARY OF THE INVENTION
[0007] In one general aspect, embodiments of the present invention
relate to a topical gel composition comprising: [0008] 0.05 to
0.20% (w/w) methylparaben; [0009] one or more second preservatives;
[0010] 0.80 to 1.50% (w/w) carbomer; and [0011] 9.0 to 13.0% (w/w)
total polyol; [0012] wherein the topical gel composition has a pH
of 4.5 to 7.5; and [0013] wherein when the concentration of
methylparaben is greater than 0.15% (w/w), the concentration of
carbomer is less than 1.25% (w/w).
[0014] In another general aspect, embodiments of the present
invention relate to a topical gel composition comprising: 0.01 to
5% (w/w) brimonidine; [0015] 0.05 to 0.20% (w/w) methylparaben;
[0016] one or more second preservatives; [0017] 0.80 to 1.50% (w/w)
carbomer; and [0018] 9.0 to 13.0% (w/w) total polyol; [0019]
wherein the topical gel composition has a pH of 4.5 to 7.5; and
[0020] wherein when the concentration of methylparaben is greater
than 0.15% (w/w), the concentration of carbomer is less than 1.25%
(w/w).
[0021] Another general aspect of the present invention relates to a
topical gel composition comprising: [0022] 0.1 to 0.6% (w/w)
brimonidine tartrate; [0023] 0.05 to 0.15% (w/w) methylparaben;
[0024] one or more second preservatives selected from the group
consisting of sodium benzoate, phenoxyethanol, benzyl alcohol,
imidazolidinyl urea, and diazolidinyl urea; [0025] 0.80 to 1.50%
(w/w) carbomer; [0026] 4.5 to 6.5% (w/w) propylene glycol; [0027]
4.5 to 6.5% (w/w) glycerol; and [0028] purified water; [0029]
wherein the pH of the topical gel composition is adjusted to a pH
of 5.0 to 6.5 by an adequate amount of sodium hydroxide aqueous
solution.
[0030] In another general aspect, embodiments of the present
invention relate to a method of treating or preventing a skin
disorder in a subject. The method comprises topically administering
to a skin area of the subject a topical gel composition according
to an embodiment of the present invention, wherein the skin area
is, or is prone to be, affected by the skin disorder.
[0031] 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.
DETAILED DESCRIPTION OF THE INVENTION
[0032] 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 have 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.
[0033] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood to one of
ordinary skill in the art to which this invention pertains.
Otherwise, certain terms used herein have the meanings as set forth
in the specification. All patents, published patent applications
and publications cited herein are incorporated by reference as if
set forth fully herein. It must be noted that as used herein and in
the appended claims, the singular forms "a," "an," and "the"
include plural references unless the context clearly dictates
otherwise.
[0034] As used herein, "erythema or a symptom associated therewith"
is intended to encompass any type or classification of redness of
skin caused by hyperemia or congestion of the capillaries in the
lower layers of the skin, and any symptom associated therewith. The
term "erythema or a symptom associated therewith" encompasses skin
redness or rash resulting from any causes. For example, it can be
caused by skin injury, surgery and other procedures on the skin,
infection, inflammation, emotion, exercise, heat (erythema ab
igne), cold, photosensitivity, radiation therapy, allergy, hot
flush diseases, medications, etc. Examples of "erythema or a
symptom associated therewith" include, but are not limited to,
photosensitivity, erythema multiforme, and erythema nudism, and
their associated symptoms. Photosensitivity is caused by a reaction
to sunlight, which often occurs when some factors, such as an
infection or a medication, increase the sensitivity to ultraviolet
radiation. However, photosensitivity can also occur without any
increased sensitivity to ultraviolet radiation. Erythema multiforme
is characterized by raised spots or other lesions on the skin,
which are usually caused by a reaction to medications, infections,
or illness. Most erythema multiforme is associated with herpes
simplex or mycoplasma infections. Erythema nudism is a form of
erythema that is accompanied by tender lumps, usually on the legs
below the knees, and may be caused by certain medications or
diseases.
[0035] In one particular embodiment of the present invention, the
term "erythema or a symptom associated therewith" includes erythema
of rosacea, i.e., erythema or a symptom associated therewith in a
patient with rosacea. Rosacea is an inflammatory skin disorder that
generally affects the cheeks, nose, chin, and forehead of a
patient. The major symptom of rosacea is erythema, i.e., the
abnormal redness of the skin.
[0036] The term "erythema or a symptom associated therewith"
encompasses different degrees or grades of erythema or a symptom
associated therewith, from mild to severe.
[0037] In view of the present disclosure, a skin area that is
affected by erythema or that is prone to be affected by erythema
can be identified using any diagnostic signs or means known in the
art, and can be treated by methods according to embodiments of the
present invention.
[0038] As used herein, "telangiectasia or a symptom associated
therewith" refers to a visible, permanent abnormal dilation of
blood vessels, such as arterioles and venules. A visible blood
vessel is a blood vessel visually discernable as a line to an
observer without the aid of magnifying equipment (other than
spectacles normally used by the observer). In various aspects, a
telangiectatic blood vessel can have a diameter of at least about
0.5 mm. Telangiectasias can be associated with numerous conditions,
syndromes, diseases, and disorders. For example, a facial
telangiectasia can be associated with age, sun exposure, and
alcohol use. Other diseases, disorders, conditions, and syndromes
associated with telangiectasias include, in non-limiting example,
scleroderma, hereditary hemorrhagic telangiectasia (Olser-Rendu
syndrome), ataxia-telangiectasia, spider angioma, cutis marmorata
telangiectasia congenita, Bloom syndrome, Klippel-Trenaunay-Weber
syndrome, Sturge-Weber disease, xeroderma pigmentosa, nevus
flammeus, generalized essential telangiectasias (GET), angioma
serpiginosum, spider naevi, CREST syndrome, basal cell carcinoma,
and unilateral nevoid telangiectasia.
[0039] In one particular embodiment of the present invention, the
term "telangiectasia or a symptom associated therewith" includes
telangiectasia associated with rosacea, i.e., telangiectasia or a
symptom associated therewith in a patient with rosacea.
[0040] In another particular embodiment of the present invention,
the term "telangiectasia or a symptom associated therewith"
includes sun-induced/photodamage telangiectasia.
[0041] The term "telangiectasia or a symptom associated therewith"
encompasses different degrees or grades of telangiectasia or
symptoms associated therewith, from mild to severe.
[0042] In view of the present disclosure, a skin area that is
affected by telangiectasia or that is prone to be affected by
telangiectasia can be identified using any diagnostic signs or
means known in the art, and can be treated by methods according to
embodiments of the present invention.
[0043] As used herein, the term "brimonidine" refers to the
compound
(5-bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine
having the structure of Formula (I):
##STR00001##
and any pharmaceutically acceptable salt of the compound, such as
brimonidine tartrate.
[0044] The phrase "pharmaceutically acceptable salt(s)," as used
herein, means those salts of a compound of interest that are safe
and effective for topical use in mammals and that possess the
desired biological activity. Pharmaceutically acceptable salts
include salts of acidic or basic groups present in the specified
compounds. Pharmaceutically acceptable acid addition salts include,
but are not limited to, hydrochloride, hydrobromide, hydroiodide,
nitrate, sulfate, bisulfate, phosphate, acid phosphate,
isonicotinate, acetate, lactate, salicylate, citrate, tartrate,
pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucuronate, saccharate, formate,
benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate, and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain
compounds used in the present invention can form pharmaceutically
acceptable salts with various amino acids. Suitable base salts
include, but are not limited to, aluminum, calcium, lithium,
magnesium, potassium, sodium, zinc, and diethanolamine salts. For a
review on pharmaceutically acceptable salts see Berge et al., 66 J.
Pharm. Sci. 1-19 (1977), incorporated herein by reference.
[0045] 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.
[0046] The term "topical gel composition" or "topical gel
formulation," as used herein, means any gel formulation or
composition which is pharmaceutically and/or cosmetically
acceptable for topical delivery of the specified compound(s)
according to embodiments of the invention.
[0047] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredient in the
specified amount, as well as any product which results, directly or
indirectly, from combinations of the specified ingredient in the
specified amount.
[0048] As used herein, the term "subject" means any animal,
preferably a mammal, most preferably a human, to whom will be or
has been administered compounds or topical formulations according
to embodiments of the invention. The term "mammal" as used herein,
encompasses any mammal. Examples of mammals include, but are not
limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats,
rabbits, guinea pigs, monkeys, humans, etc., more preferably a
human. Preferably, a subject is in need of, or has been the object
of observation or experiment of, treatment or prevention of a skin
disorder, such as rosacea, erythema of rosacea, telangiectasia,
psoriasis, purpura, erythema of acne, eczema, non-rosacea-related
inflammation of the skin, flushing, skin sagging, creasing and/or
wrinkling, or a symptom associated therewith.
[0049] In one embodiment, "treatment" or "treating" refers to an
amelioration, prophylaxis, or reversal of a disease or disorder, or
of at least one discernible symptom thereof. 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.
[0050] In certain embodiments, compounds of interest 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 specified compounds are administered as a
preventative measure to a subject having a predisposition to a
disease or disorder even though symptoms of the disease or disorder
are absent or minimal.
[0051] In an embodiment of the present invention, methylparaben
crystalline particles have been observed in brimonidine topical gel
formulations containing 0.2% (w/w) or more methylparaben,
particularly in batch sizes of 300 g to 250 kg. See Example 1
below. This observation is surprising in view of the solubility of
methylparaben. According to a Material Safety Data Sheet (MSDS) of
methylparaben, the solubility of methylparaben in water is about
0.25% (w/w) at 20.degree. C. or about 0.30% (w/w) at 25.degree. C.
The solubility of methylparaben in propylene glycol is 1 in 5 at
25.degree. C., the solubility of methylparaben in warm glycerol is
about 1.4%, and see: MSDS, Chemicals & Laboratory Equipment,
Science Lab.com, World Wide Web:
sciencelab.com/msds.php?msdsId=9926083. Further, according to
Handbook of Pharmaceutical Excipients (supra), the solubility of
methylparaben in propylene glycol is 1 in 5 at 25.degree. C.,
[0052] In view of methylparaben's solubility in polyols and water,
it would have been reasonably expected that 0.30% (w/w) or less
methylparaben would remain completely soluble in a topical gel
composition comprising about 4.5 to 6.5% (w/w) of a first polyol in
which methylparaben is substantially soluble, about 4.5 to 6.5%
(w/w) of a second polyol, and about 90% (w/w) or less water. The
detection of methylparaben crystalline particles in the composition
is completely unexpected. Not wishing to be bound by theory, the
methylparaben crystalline particles observed in the brimonidine
topical gel and placebo compositions may have been caused by one or
more reasons, such as recrystallization of methylparaben during the
manufacturing process, or recrystallization of methylparaben during
storage resulting from excipient-excipient interaction. Without the
surprising observation made in the present invention, one would not
have reasonably expected the existence of methylparaben crystals in
the topical gel compositions, let alone to develop an improved
topical gel formulation free of the crystals.
[0053] Embodiments of the present invention relate to an improved
topical gel composition that is substantially free of crystalline
particles and has microbiological quality over an extended period
of storage. The improved topical gel composition according to an
embodiment of the present invention comprises: [0054] 0.05 to 0.20%
(w/w) methylparaben; [0055] one or more second preservatives;
[0056] 0.80 to 1.50% (w/w) carbomer; and [0057] 9.0% to 13.0% (w/w)
total polyol; [0058] wherein the topical gel composition has a pH
of 4.5 to 7.5; and [0059] wherein when the concentration of
methylparaben is greater than 0.15% (w/w), the concentration of
carbomer is less than 1.25% (w/w).
[0060] According to embodiments of the present invention, the
amount of methylparaben in the composition is about 0.05%, 0.075%,
0.10%, 0.125%, 0.15%, or 0.20% (w/w).
[0061] Suitable second preservatives that can be used in
embodiments of the present invention include any preservatives that
are suitable for topical application. Examples of the second
preservatives include, but are not limited to, sodium benzoate,
phenoxyethanol, benzyl alcohol, imidazolidinyl urea, or
diazolidinyl urea. Additional examples of the second preservatives
may include, quaternary ammonium compounds, such as benzalkonium
chloride, benzethonium chloride, cetrimide, dequalinium chloride,
and cetylpyridinium chloride; alcoholic agents, such as,
chlorobutanol; antibacterial esters, such as esters of
parahydroxybenzoic acid; and other anti-microbial agents such as
chlorhexidine, chlorocresol, benzoic acid, polymyxin, mupirocin,
erythromycin, clindamycin, gentamicin, polymyxin, bacitracin,
silver sulfadiazine, etc.
[0062] Preferably, the second preservative is effective in
inactivating challenge doses of Gram-negative and Gram-positive
microorganisms, as well as yeast.
[0063] According to embodiments of the present invention, the one
or more second preservatives comprise phenoxyethanol and the amount
of phenoxyethanol in the composition is, or is greater than 0.3%,
0.35%, 0.4%, 0.45%, or 0.5% (w/w).
[0064] According to embodiments of the present invention, the
carbomer is a synthetic polymer of acrylic acid cross-linked with
polyalkenyl ethers or divinyl glycol. It can be a homopolymer of
acrylic acid, cross-linked with an allyl ether pentaerythritol,
allyl ether of sucrose, or allyl ether of propylene. Examples of
carbomers that can be used in the present invention include, but
are not limited to, carbomer 910, 934P, 940, 941, 1342,
Carbopol.RTM. 974P (carbomer 974P), and Carbopol.RTM. 980 (carbomer
980).
[0065] Preferably, the carbomer is carbomer 934P, carbomer 974P, or
carbomer 980.
[0066] According to embodiments of the present invention, the
amount of the carbomer in the composition is about 0.8%, 0.85%,
0.95%, 1.05%, 1.15%, 1.25%, 1.35%, 1.45%, or 1.5% (w/w).
[0067] Polyol gel formulations with various ingredients solubilized
therein have been used to minimize irritation when applied to the
skin of a subject, while ensuring bioavailability of the active
agent in the formulation. See Other III et al., "Gels and Jellies,"
pp. 1327-1344 of Encyclopedia of Pharmaceutical Technology, vol. 3
(ed. by Swarbrick et al., pub. by Marcel Dekker, Inc., 2002); or
Pena, "Gel Dosage Forms: Theory, Formulation, and Processing," pp.
381-388 of Topical Drug Delivery Formulations, (ed. by Osborne et
al., pub. by Marcel Dekker, Inc., 1990). Polyols in gel
formulations can serve one or more functions, such as solubilizing
agents, moisturizers, emollients, skin humectant, skin-penetration
agents, etc. Suitable polyols that can be used in embodiments of
the present invention include, but are not limited to, glycerine,
propylene glycol, dipropylene glycol, hexylene glycol, butylene
glycol, and liquid polyethylene glycols, such as polyethylene
glycol 200 to 600, and glycerol.
[0068] According to embodiments of the present invention, the
amount of the total polyols in the composition is about 9.0% to
13.0% (w/w), for example about 9.0%, 9.5%, 10.0%, 10.5%, 11.0%,
11.5%, 12.0%, 12.5%, or 13.0% (w/w).
[0069] In an embodiment of the present invention, the topical gel
composition comprises at least a first polyol in which the
methylparaben is substantially soluble.
[0070] Preferably, the topical gel composition comprises the first
polyol and a second polyol, such as propylene glycol and glycerine,
respectively.
[0071] According to embodiments of the present invention, the
amount of each of the first and second polyols in the composition
is independently about 4.5% to 6.5% (w/w), for example 4.5%, 5.0%,
5.5%, 6.0%, or 6.5% (w/w).
[0072] In a preferred embodiment, a topical gel composition
according to embodiments of the invention further comprises a water
dispersible form of titanium dioxide (TiO.sub.2), 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. TiO.sub.2 may cause mild irritation and
reddening to the eyes, thus eye contact with the
TiO.sub.2-containing topically administrable composition should be
avoided. Titanium dioxide imparts a whiteness to the topically
administrable composition and helps to increase the opacity and
reduce the transparency of the composition. Titanium dioxide
absorbs, reflects, or scatters light (including ultraviolet
radiation in light), which can help protect products from
deterioration. Titanium dioxide can also be used as a sunscreen to
protect the user from the harmful effects of ultraviolet radiation
that is part of sunlight.
[0073] According to embodiments of the present invention, the
amount of water dispersible form of titanium dioxide in the
composition is about 0.04%, 0.0425%, 0.0525%, 0.0625%, 0.0725%, or
0.08% (w/w).
[0074] In another general aspect, a topical gel formulation
according to an embodiment of the present invention further
comprises an active pharmaceutical ingredient, such as an alpha
adrenergic receptor agonist or a pharmaceutically acceptable salt
thereof, that is effective to prevent or treat a skin disorder.
[0075] Alpha adrenergic receptor agonists are well known in the
art. In a preferred embodiment, the alpha adrenergic receptor
agonist may be an alpha-1 or alpha-2 adrenergic receptor agonist.
The alpha adrenergic receptor agonists included in the invention
may or may not show selectivity for either the alpha-1 or alpha-2
adrenergic receptors. For example, some may be considered as being
both alpha-1 and alpha-2 adrenergic receptor agonists. More
preferably, the alpha adrenergic receptor agonist may be a
selective alpha-1 or a selective alpha-2 adrenergic receptor
agonist.
[0076] Examples of selective alpha-1 adrenergic receptor agonists
include oxymetazoline, phenylephrine, and methoxyamine. Examples of
selective alpha-2 adrenergic receptor agonists include brimonidine,
tetrahydrozoline, naphazoline, xylometazoline, epinephrine, and
norepinephrine.
[0077] In an embodiment of the present invention, the active
pharmaceutical ingredient comprises 0.01 to 5% (w/w) brimonidine.
The active pharmaceutical ingredient can optionally include one or
more pharmaceutically active ingredients in addition to
brimonidine, including, but not limited to, medications used to
treat the skin disorder or the underlying disease that causes the
skin disorder, antihistamines to control itching, antibiotics,
corticosteroids, intravenous immunoglobulins, acetaminophen,
etc.
[0078] In a preferred embodiment, the brimonidine is brimonidine
tartrate.
[0079] According to embodiments of the present invention, the
amount of brimonidine in the topical gel composition is about 0.05%
to 0.1%, 0.1% to 0.4%, 0.4% to 0.7%, 0.7% to 1%, 1% to 2%, 2% to
3%, 3% to 4%, or 4% to 5% (w/w). Preferably, the amount of
brimonidine tartrate in the composition is about 0.1 to 0.6%
(w/w).
[0080] In a preferred embodiment of the present invention, a
topical gel composition comprises: [0081] 0.1 to 0.6% (w/w)
brimonidine tartrate; [0082] 0.05 to 0.15% (w/w) methylparaben;
[0083] one or more second preservatives selected from the group
consisting of sodium benzoate, phenoxyethanol, benzyl alcohol,
imidazolidinyl urea, and diazolidinyl urea; [0084] 0.80 to 1.50%
(w/w) carbomer; [0085] 4.5 to 6.5% (w/w) propylene glycol; [0086]
4.5 to 6.5% (w/w) glycerol; and [0087] purified water; [0088]
wherein the pH of the topical gel composition is adjusted to 5.0 to
6.5 by an adequate amount of sodium hydroxide aqueous solution.
[0089] According to an embodiment of the present invention, the
topical gel composition comprises greater than 0.3% (w/w)
phenoxyethanol as the second preservative when 0.15% (w/w) or less
methylparaben is used in the formulation.
[0090] A topical gel composition according to embodiments of the
present invention can comprise additional 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.
Examples of the additional excipients include, but are not limited
to, protectives, adsorbents, antioxidants, local anesthetics,
buffering agents, surfactants, flavorants, fragrances, dyes,
etc.
[0091] Suitable protective agents and/or cosmetic agents, and
adsorbents can include, but are not limited to, dusting powders,
zinc stearate, collodion, dimethicone, silicones, zinc carbonate,
aloe vera gel and other aloe products, vitamin E oil, allantoin,
petrolatum, titanium dioxide, and zinc oxide.
[0092] Suitable antioxidants can 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.
[0093] Suitable buffering agents can include, but are not limited
to, acetate buffers, citrate buffers, phosphate buffers, lactic
acid buffers, sodium buffer, and borate buffers.
[0094] A topical gel composition according to embodiments of the
present invention can further include local anesthetics and
analgesics, such as camphor, menthol, lidocaine, dibucaine, and
pramoxine; antifungals, such as ciclopirox, chloroxylenol,
triacetin, sulconazole, nystatin, undecylenic acid, tolnaftate,
miconazole, clotrimazole, oxiconazole, griseofulvin, econazole,
ketoconozole, and amphotericin B.
[0095] A topical gel composition according to embodiments of the
present invention can further include one or more antiseptics, such
as iodine, povidone-iodine, benzalkonium chloride, benzoic acid,
nitrofurazine, benzoyl peroxide, hydrogen peroxide,
hexachlorophene, phenol, resorcinol, and cetylpyridinium
chloride.
[0096] The topical gel composition according to embodiments of the
present invention can be prepared by mixing the ingredients of the
composition 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.
[0097] The pH of the topical gel formulations of the invention are
preferably within a physiologically acceptable pH range, e.g.,
within the range of about 4.5 to about 7.5, more preferably, of
about 5.0 to about 6.5, such as a pH of about 5.1, 5.15, 5.2, 5.25,
5.3, 5.35, 5.4, 5.45, 5.5, 5.55, 5.6, 5.65, 5.7, 5.75, 5.8, 5.85,
5.9, 5.95, 6.1, 6.15, 6.2, 6.25, 6.3, 6.35, 6.4, 6.45, or 6.5. To
stabilize the pH, preferably, an effective amount of a buffer is
included. Acids or bases can be used to adjust the pH as
needed.
[0098] In one general aspect, embodiments of the present invention
relate to a method of treating or preventing a skin disorder, such
as rosacea, erythema of rosacea, telangiectasia, psoriasis,
purpura, erythema of acne, eczema, non-rosacea-related inflammation
of the skin, flushing, skin sagging, creasing and/or wrinkling, or
a symptom associated therewith, in a subject by topically
administering to a skin area of the subject a topical gel
composition according to an embodiment of the present invention,
wherein the skin area is, or is prone to be, affected by the skin
disorder. The relevant disclosures, e.g., on using brimonidine to
treat the one or more of skin disorders, in U.S. Ser. No.
10/853,585 to DeJovin et al.; U.S. Ser. No. 10/626,037 to Scherer;
U.S. Ser. No. 10/607,439 to Gil et al.; U.S. Ser. No. 10/763,807 to
Shanler et al.; U.S. Ser. No. 12/193,098 to Theobald et al.; U.S.
Patent Application Publication No. 2006/0264515 to DeJovin et al.;
U.S. Ser. No. 12/621,942 to DeJovin et al.; U.S. Patent Application
Publication No. 2005/0020600 to Scherer; and U.S. Patent
Application Publication No. 2009/0130027 to Shanler et al., are
herein incorporated by reference as if set forth fully herein.
[0099] In an embodiment of the present invention, the topically
administrable composition comprises about 0.1% to 0.6% (w/w), such
as about 0.1%, about 0.15%, about 0.18%, about 0.2%, about 0.25%,
about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about
0.55%, or about 0.6% by weight of brimonidine tartrate.
[0100] To treat or prevent a skin disorder, in view of the present
disclosure, the topical gel compositions of the invention can be
topically applied directly to the affected area in any conventional
manner known in the art, e.g. by dropper, applicator stick, or
cotton swab, as a mist via an aerosol applicator, via an
intradermal or transdermal patch, or by simply spreading a
formulation of the invention onto the affected area with fingers, a
sponge, a pad, or wipes. Generally, the amount of a topical
formulation of the invention applied to the affected skin area
ranges from about 0.0001 g/cm.sup.2 of skin surface area to about
0.05 g/cm.sup.2, preferably 0.002 g/cm.sup.2 to about 0.005
g/cm.sup.2 of skin surface area. Typically, one to four
applications per day are recommended during the term of
treatment.
[0101] Methods of the present invention can be used in conjunction
with one or more other treatments and medications for the skin
disorder, such as the medications used to treat the underlying
disease that causes the skin disorder, antihistamines to control
itching, antibiotics, corticosteroids, intravenous immunoglobulins,
acetaminophen, etc.
[0102] 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 brimonidine, such that the
active ingredients or agents can act together to treat or prevent
the skin disorder. For example, the other medicament or treatment
and brimonidine can be administered in the same or separate
formulations at the same or different times.
[0103] 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.
[0104] 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
[0105] Observation of Methylparaben Crystalline Particles in
Topical Gel Compositions
[0106] Crystalline particles were first observed visually in a
sampling of 7 tubes of a batch of brimonidine topical gel
composition. These particles were isolated. The identity of the
particles was analyzed by several analytical methods, such as HPLC
test for identification by comparison of the retention time against
standards, differential scanning calorimetry (DSC) for
determination of melting point, NMR for a structural identification
(by 1H and 13C), mass/mass with UV detector and QTOF to separate
and identify the different masses, etc. Based on these analyses, it
has been concluded that the observed crystals are crystals of
methylparaben (hereinafter abbreviated as POBM or MPOB), which is a
preservative used in the composition. According to the process used
for manufacturing the batch, methylparaben was first dissolved in
propylene glycol at 50.degree. C. (122-140.degree. F.) in the
preservative phase.
[0107] Microscopic observations were performed on additional
representative batches of brimonidine topical gel compositions and
placebo gel compositions containing 1.25% (w/w) carbomer, POBM and
other ingredients. The observations have been done on one tube of
each batch, with the microscope Axiolab DRBKT Zeiss no. 023733.01
with a camera ICC Zeiss or the microscope Olympus BX60. The
microscopic observations were done at 5.degree. C. and room
temperature.
[0108] As shown in Table 1, methylparaben crystalline particles
were unpredictably observed in both brimonidine and placebo gel
compositions containing 0.2% or 0.3% by weight methylparaben
(POBM).
TABLE-US-00001 TABLE 1 Results of microscopic observations of
representative batches of gel composition Date of Microscopic No.
Tubes Date of Manufacturing Composition Observation Batch Size
Observed Observation April 2008 Placebo, 0.3% POBM Crystals 130 kg
7 December 2008 April 2008 Placebo, 0.3% POBM No crystal 130 kg 5
December 2008 Jul. 1, 2009 Placebo, 0.3% POBM Crystals 300 g-2 kg 1
October 2009 Aug. 25, 2009 Placebo, 0.3% POBM Crystals 300 g-2 kg 1
October 2009 0.03% Brimonidine 200-250 kg Sep. 2, 2009 0.3% POBM No
crystal 1 February 2010 0.06% Brimonidine 200-250 kg Sep. 7, 2009
0.3% POBM Crystals 1 February 2010 0.07% Brimonidine 200-250 kg
Jul. 6, 2009 0.3% POBM Crystals 1 February 2010 0.18% Brimonidine
300 g-2 kg Sep. 15, 2009 0.3% POBM Crystals 1 October 2009 0.5%
Brimonidine 200-250 kg Jul. 16, 2009 0.3% POBM Crystals 1 February
2010 1% Brimonidine 1% 200-250 kg Sep. 18, 2009 0.3% POBM No
crystal 1 February 2010 2% Brimonidine 2% 200-250 kg Sep. 29, 2009
0.3% POBM No crystal 1 February 2010 0.06% Brimonidine 300 g-2 kg
Sep. 10, 2009 0.3% POBM Crystals 1 October 2009 1% Brimonidine 300
g-2 kg Sep. 17, 2009 0.3% POBM No crystal 1 October 2009 Jan. 12,
2010 Placebo, 0.2% POBM Crystals 300 g 1 Feb. 4, 2010 0.18%
Brimonidine 800 g Feb. 10, 2010 Dec. 22, 2009 0.2% POBM No crystal
1
[0109] Assays were conducted to estimate the concentration of
methylparaben solubilized in a batch originally containing 0.3%
(w/w) of methylparaben, in which crystalline particles were
observed. Centrifugation was performed on the batch to collect
crystals at the bottom of the centrifuge tube, thus removing them
from the supernatant. The methylparaben concentration in the
supernatant was measured and found to be about 0.2% (w/w), which
was about 66% of the 0.3% (w/w) in the original formulation. The
reduction in the concentration of soluble methylparaben in the
composition raises non-conformity issues and may result in poor
microbiological quality of the composition over an extended period
of storage.
[0110] The presence of methylparaben crystalline particles in the
topical gel formulations is surprising in view of the solubility of
methylparaben. In order to find a solution to avoid the
crystallization problem, several hypotheses have been postulated
and evaluated to uncover the potential cause and possible solution
of the problem.
Example 2
Improved Topical Gel Compositions Free of Methylparaben Crystalline
Particles
[0111] Various changes to the formulation and the process of
manufacturing the formulation have been made in order to obtain
improved topical gel formulations that are free of the observed
paraben crystals and have acceptable microbiological quality. For
example, methylparaben, also named methyl parahydroxybenzoate
(POBM), was replaced with the more water soluble Na POBM, but
crystalline particles of Na POBM were still observed at 0.3% (w/w)
Na POBM. Addition of 0.1% of EDTA into the formulation resulted in
immediate recrystallization of the POBM at 0.3% (w/w) in the
formulation, suggesting that the 0.3% (w/w) concentration of POBM
may be too high.
[0112] Numerous formulations with different ingredients and varying
concentrations of the ingredients were made and tested for the
presence of the paraben crystals by microscopic observations. The
microbiological quality of the formulations was also analyzed by
using acceptance-test criteria in preservative-efficacy testing
(PET) in the United States Pharmacopeia (USP) and the European
Pharmacopoeia (EP).
[0113] Based on microscopic observations and PET analyses, it was
found that improved topical gel compositions containing 0.05% to
0.20% (w/w) methylparaben; one or more second preservatives, such
as 0.3% (w/w) or more phenoxyethanol; 0.80 to 1.50% (w/w) carbomer,
such as Carbopol.RTM.974P NF; 9.0% to 13.0% (w/w) total polyol,
such as 4.5 to 6.5% (w/w) of a first polyol, e.g., propylene
glycol, 4.5 to 6.5% (w/w) of a second polyol, e.g., glycerol; and
one or more other ingredients, such as purified water, titanium
dioxide, optionally an effective amount of brimonidine tartrate,
with a pH of 5.0 to 6.5 adjusted by an adequate amount of sodium
hydroxide, were free of methylparaben crystals after an extended
period of storage and passed criteria of EP and USP. See Table 2,
in which the concentration of carbomer in each of the formulations
was 1.25% (w/w).
TABLE-US-00002 TABLE 2 Results of microscopic observations and PET
of topical gel formulations Batch Period of Size Preservative
Storage Microscopic (kg) Concentration (w/w) (weeks) Observation
PET Result 2 0.1% MPOB 21 No crystal Failed criteria 0.3%
Phenoxyethanol A of EP at 48 hours 200 0.1% MPOB 24 No crystal
Passed EP 0.4% Phenoxyethanol and USP 2 0.125% MPOB 12 No crystal
Passed EP 0.4% Phenoxyethanol and USP 200 0.125% MPOB 7 No crystal
Passed EP 0.4% Phenoxyethanol and USP
[0114] It was further discovered that when the amount of
methylparaben was more than 0.15% (w/w), decreasing the amount of
carbomer reduced the formation of methylparaben crystals. See, for
example, Table 3.
TABLE-US-00003 TABLE 3 Results of microscopic observation of gel
compositions Batch Microscopic Size Composition Observation 300 G
POBM: 0.2 Crystals after one Phenoxyethanol: 0.3 month storage at
RT Carbopol .RTM. 980: 1.25 300 G POBM: 0.2 No crystal observed
Phenoxyethanol: 0.3 after one month Carbopol .RTM. 980: 0.8 storage
at RT
[0115] 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.
* * * * *