U.S. patent application number 16/798176 was filed with the patent office on 2020-06-18 for pharmaceutical cream compositions and methods of use.
The applicant listed for this patent is EPI Health, LLC. Invention is credited to Christopher Powala, Luis Rios, Stuart D. Shanler.
Application Number | 20200188517 16/798176 |
Document ID | / |
Family ID | 45346572 |
Filed Date | 2020-06-18 |
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United States Patent
Application |
20200188517 |
Kind Code |
A1 |
Shanler; Stuart D. ; et
al. |
June 18, 2020 |
PHARMACEUTICAL CREAM COMPOSITIONS AND METHODS OF USE
Abstract
Embodiments relating to cream formulations as well as
oxymetazoline creams and methods for treating rosacea and symptoms
associated with rosacea, including, for example, papules, pustules,
phymas (skin thickening), telangiectasias or erythema associated
with rosacea, other skin erythemas, telangiectasias, purpura or the
like, and other manifestations associated therewith; other
inflammatory conditions of the skin including, but not limited to,
keratosis pilaris, lupus miliaris dissemniatus faciei, eczema,
dermatitis, such as contact dermatitis, atopic dermatitis,
seborrheic dermatitis, nummular dermatitis, generalized exfoliative
dermatitis, statis dermatitis, neurodermatitis, lichen simplex
chronicus, xerosis and xerotic dermatitis, dyshidrosis and
dyshidrotic dermatitis, asteototic dermatitis or other conditions
characterized by sensitive skin or a disturbance of the epidermal
barrier; disorders characterized by rough, dry, cracked or fissured
skin, disorders characterized by hyperkeratotic skin such as
keratodermas and ichthyosisis and ichthyosiform dermatoses;
disorders of hair follicles and sebaceous glands, such as acne,
perioral dermatitis, and pseudofolliculitis barbae; disorders of
sweat glands, such as miliaria, including, but not limited to,
miliaria crystallina, miliaria rubra, miliaria profunda, miliaria
pustulosa; sunburn, chronic actinic damage, poikiloderma, radiation
dermatitis, actinic purpura ("solar purpura"); other inflammatory
dermatoses, reactions and conditions of the skin, including, but
not limited to, psoriasis, drug eruptions, erythema multiforme,
erythema nodosum, and granuloma annulare; diseases and conditions
characterized by bleeding or bruising such as petechiae,
ecchymosis, purpura and the like including any accumulation of
blood in the skin due to vascular extravasation, irrespective of
size or cause, bleeding or bruising due to any skin injury which
may include any trauma including surgical or procedural trauma;
infection, inflammatory dermatoses or inflammation due to any cause
using such creams are described herein.
Inventors: |
Shanler; Stuart D.;
(Malvern, PA) ; Powala; Christopher; (Radnor,
PA) ; Rios; Luis; (Pembroke Pines, FL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
EPI Health, LLC |
Charleston |
SC |
US |
|
|
Family ID: |
45346572 |
Appl. No.: |
16/798176 |
Filed: |
February 21, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14521094 |
Oct 22, 2014 |
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16798176 |
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13309403 |
Dec 1, 2011 |
8883838 |
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14521094 |
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61419693 |
Dec 3, 2010 |
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61419697 |
Dec 3, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/14 20130101;
A61K 31/4174 20130101; A61K 45/06 20130101; A61K 9/06 20130101;
A61K 9/0014 20130101; A61P 31/04 20180101; A61K 9/107 20130101;
A61P 9/00 20180101; A61P 17/00 20180101; A61K 47/10 20130101 |
International
Class: |
A61K 47/14 20060101
A61K047/14; A61K 45/06 20060101 A61K045/06; A61K 9/06 20060101
A61K009/06; A61K 31/4174 20060101 A61K031/4174; A61K 47/10 20060101
A61K047/10; A61K 9/107 20060101 A61K009/107; A61K 9/00 20060101
A61K009/00 |
Claims
1-17. (canceled)
18. A pharmaceutical composition comprising about 1% oxymetazoline
hydrochloride, greater than 10% of an emulsifier, an emollient, and
a buffering agent, wherein the composition is a cream and has a pH
of 4.3 to 4.7.
19. The pharmaceutical composition of claim 18, wherein the
buffering agent is selected from citric acid, sodium citrate,
sodium lactate, ammonium hydroxide, tris(hydroxymethyl)aminomethane
acetate salt, sodium borate, acetic acid, sodium acetate,
phosphoric acid, sodium phosphate, sodium citrate dihydrate, and
any combination of the foregoing.
20. The pharmaceutical composition of claim 18, wherein the
buffering agent comprises citric acid and sodium citrate.
21. The pharmaceutical composition of claim 19, wherein the buffer
capacity of the buffering agent ranges from about 5 mM to about 600
mM.
22. The pharmaceutical composition of claim 20, wherein the
emollient comprises medium chain triglycerides, diisopropyl
adipate, oleyl alcohol, and lanolin.
23. The pharmaceutical composition of claim 22, wherein the sole
oils in the emollient are the medium chain triglycerides,
diisopropyl adipate, oleyl alcohol, and lanolin.
24. The pharmaceutical composition of claim 18, wherein the
emulsifier comprises cetostearyl alcohol.
24. The pharmaceutical composition of claim 18, wherein the
composition, when packaged in a tube, maintains a pH of 4.3 to 4.7
after about 4 weeks of storage at about 25.degree. C. and 60%
relative humidity.
25. The pharmaceutical composition of claim 18, further comprising
a preservative, a chelating agent and an antioxidant.
26. A pharmaceutical composition comprising: (a) about 1%
oxymetazoline hydrochloride, (b) one or more ceteareth in
combination with a fatty acid alcohol selected from stearyl
alcohol, cetyl alcohol, and a combination thereof, (c) an
emollient, and (d) a buffering agent, wherein the composition is a
cream and has a pH of 4.3 to 4.7.
27. A pharmaceutical composition comprising: (a) about 1%
oxymetazoline hydrochloride, (b) one or more ceteareth in
combination with a fatty acid alcohol selected from stearyl
alcohol, cetyl alcohol, and a combination thereof, (c) an emollient
comprising medium chain triglycerides, diisopropyl adipate, oleyl
alcohol, and lanolin, and (d) a buffering agent, wherein the
composition is a cream and has a pH of 4.3 to 4.7.
Description
CROSS REFERENCE
[0001] This is a continuation of U.S. application Ser. No.
13/309,403 filed Dec. 1, 2011 which claims the benefit of U.S.
Provisional Patent Application Ser. No. 61/419,693 filed on Dec. 3,
2010, and U.S. Provisional Patent Application Ser. No. 61/419,697
filed on Dec. 3, 2010, the disclosures of which are incorporated
herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention is directed to cream compositions and
methods in which these cream compositions are administered to
patients for the treatment of one or more dermatological
conditions.
BACKGROUND OF THE INVENTION
[0003] Rosacea is a chronic disease most commonly characterized by
facial erythema (redness). There are at least four identified
rosacea subtypes and patients may have more than one subtype
present. The four most well recognized subtypes are
erythematotelangiectatic rosacea (ETR); papulopustular rosacea;
phymatous rosacea; and ocular rosacea. Other less common forms
exist and the signs and symptoms of each subtype are not unique to
that subtype and may overlap or coexist with any of the
manifestations of any other subtype. ETR may be characterized by
transient and/or permanent erythema with a tendency to flush and
blush easily and telangiectasias, which in its milder form may
resemble or present as erythema (redness) and in its more
pronounced state may manifest as discrete visible blood vessels on
the surface of the skin. Papulopustular rosacea may be
characterized by transient and/or permanent erythema with papules
(red bumps) and pustules (pus filled bumps). Without wishing to be
bound by theory, though the papules and other inflammatory lesions
(e.g. pustules) of papulopustular rosacea may be mistaken for acne,
it is believed that the papules and pustules of rosacea are
different from the papules and pustules of acne and arise from
different underlying pathophysiologic processes. Phymatous rosacea
may be characterized by thickening skin, irregular surface
nodularities, enlargement of facial areas (e.g. nose and cheeks),
erythema and telangiectasias. Ocular rosacea may be characterized
by red, dry and irritated eyes and eyelids. In each subtype,
erythema and telangiectasias of varying degree may be a
feature.
[0004] Rosacea patients may need topical or oral (systemic)
medication to alleviate their distress; however, a patient's skin
may be so sensitive that many products are irritating and, in fact,
may exacerbate the symptoms of rosacea and may cause more redness
and discomfort than patients can tolerate. Thus, rosacea can be
very difficult to effectively treat and thus may not only be
physically distressing but also psychologically distressing.
Accordingly, there is a need for a cosmetically and
pharmaceutically acceptable therapeutic which addresses the myriad
manifestations of rosacea including, but not limited to, the
erythema or redness associated with rosacea and the telangiectasias
associated with rosacea. Additionally, there is a need for a
cosmetically and pharmaceutically acceptable therapeutic which
addresses the inflammatory lesions and manifestations associated
with rosacea including the papules, pustules and phymas (skin
thickening).
[0005] U.S. Pat. No. 7,812,049 to Shanler et. al. describes the use
of oxymetazoline to treat erythema resulting from rosacea.
[0006] There exists a need in the art for a topical pharmaceutical
composition comprising oxymetazoline which is physically stable
(i.e. without phase separation) and chemically stable with the
active pharmaceutical agent and which optimizes the delivery of the
oxymetazoline to the skin in such a manner as to effectively treat
the pathologic condition.
[0007] There also exists a need in the art for a topical cream
formulation which is physically stable (i.e. without phase
separation) and chemically stable that is well tolerated by and
suitable for use in individuals with sensitive, reactive, easily
irritated or damaged skin.
BRIEF DESCRIPTION
[0008] Embodiments are generally directed to a cream formulation.
Certain embodiments may include a cream formulation of
oxymetazoline. Some embodiments may be directed to a cosmetically
acceptable formulation comprising oxymetazoline and a
pharmaceutically acceptable excipient, wherein the formulation is a
cream. Some embodiments may be directed to a formulation comprising
oxymetazoline and a pharmaceutically acceptable excipient, wherein
the formulation is a cream. Some embodiments may be directed to a
cream formulation comprising oxymetazoline in a therapeutically
effective amount and a pharmaceutically acceptable excipient. Some
embodiments of the invention are directed to a cream formulation
comprising oxymetazoline, an emulsifier and an emollient. Some
embodiments may be directed to a cream formulation comprising
oxymetazoline, an emulsifier and an emollient, wherein a ratio of
the emulsifier to the emollient comprises from about 0.1:1 to about
1.8:1. In other embodiments, the ratio of the emulsifier to the
emollient may comprise from about 0.2:1 to about 1.8:1, from about
0.3:1 to about 1.8:1, or from about 0.4:1 to about 1.8:1, or from
about 0.7:1 to about 1.8:1. In certain embodiments, the cream
formulation may have a pH from about 2.0 to about 7.0 at room
temperature. In further embodiments, the cream formulation may have
a pH from about 4.0 to about 5.5 at room temperature.
[0009] In some embodiments, the cream formulation may further
include a sunscreen or sun-blocking agent. In certain embodiments,
the sun-blocking agent may be zinc oxide, titanium dioxide or
combinations thereof.
[0010] Some embodiments may be directed to a cream formulation
comprising oxymetazoline in an amount of from about 0.0075% to
about 5% by weight and pharmaceutically acceptable excipients. In
some embodiments, the cream formulation may comprise oxymetazoline
in an amount from about 0.01% to about 2% by weight. Embodiments
may include one or more emulsifiers in a total amount of from about
1% to about 30% by weight of the pharmaceutical composition; and/or
one or more emollients in a total amount of from about 1% to about
50% by weight of the pharmaceutical composition. In some
embodiments the emollients are in an amount of from about 1% to
about 20% by weight of the pharmaceutical composition. In some
embodiments, the emulsifier may comprise Tefose 63.TM.. In some
embodiments, the emulsifier may comprise PEG-stearate, glycol
stearate or a combination thereof. In some embodiments, the
emulsifier may comprise ethoxylated fatty acids. In some
embodiments, the emulsifier may comprise cetostearyl alcohol. In
some embodiments, the formulation may further comprise additional
additives selected from the group consisting of preservatives,
emulsion stabilizers, pH adjusters, chelating agents, viscosity
modifiers, anti-oxidants, surfactants, emollients, opacifying
agents, skin conditioners, buffers, and combinations thereof. In
some embodiments, the formulation may further comprise a topically
active pharmaceutical or cosmetic agent.
[0011] In certain embodiments, a cream comprising oxymetazoline, a
vasoconstrictor and pharmaceutically acceptable excipients is
provided. In certain embodiments, a cream comprising oxymetazoline,
an alpha-adrenergic agonist and pharmaceutically acceptable
excipients is provided. In certain embodiments, a cream comprising
oxymetazoline, an imidazoline alpha-adrenergic agonist and
pharmaceutically acceptable excipients is provided. In certain
embodiments, a cream comprising oxymetazoline, a non-imidazoline
alpha-adrenergic agonist and pharmaceutically acceptable excipients
is provided. In certain embodiments, a cream comprising
oxymetazoline, an alpha-1 adrenergic agonist and pharmaceutically
acceptable excipients is provided. In certain embodiments, a cream
comprising oxymetazoline, an alpha-2 adrenergic agonist and
pharmaceutically acceptable excipients is provided. In certain
embodiments, a cream comprising oxymetazoline, a selective
alpha-adrenergic agonist and pharmaceutically acceptable excipients
is provided. In certain embodiments, a cream comprising
oxymetazoline, a non-selective alpha-adrenergic agonist and
pharmaceutically acceptable excipients is provided. In certain
embodiments, a cream comprising oxymetazoline, a selective alpha-1
adrenergic agonist and pharmaceutically acceptable excipients is
provided. In certain embodiments, a cream comprising oxymetazoline,
a selective alpha-2 adrenergic agonist and pharmaceutically
acceptable excipients is provided. In certain embodiments, a cream
comprising oxymetazoline, a non-selective alpha-1 adrenergic
agonist and pharmaceutically acceptable excipients is provided. In
certain embodiments, a cream comprising oxymetazoline, a
non-selective alpha-2 adrenergic agonist and pharmaceutically
acceptable excipients is provided.
[0012] In some embodiments, the cream formulation may be stable,
non-irritating, cosmetically acceptable, compatible with a wide
variety of APIs, or combinations thereof. In certain embodiments,
the cream formulation may be non-irritating to patients with
sensitive or "reactive" skin such as is commonly encountered in
patients with eczema, dermatitis or other conditions characterized
by sensitive skin or a disturbance of the epidermal barrier. In
certain embodiments, the cream formulation may be non-irritating to
individuals who are categorized as "stingers" or "burners," such as
patients with rosacea. Such individuals who are "stingers" or
"burners" may normally experience symptoms such as itching,
burning, stinging, prickling, tingling warmth or flushing to
external stimuli including external treatment. However, in certain
embodiments herein, the cream formulations may be non-irritating to
such individuals so that such symptoms are present in a reduced
fashion or are not present. In certain embodiments, the cream
formulation may be soothing to the skin. In some embodiments, the
soothing effect of the cream formulations of embodiments herein may
be long-lasting.
[0013] In some embodiments, the cream formulation does not contain
an active pharmaceutical ingredient. In some embodiments, the cream
formulation may be a vehicle to deliver a pharmacological agent or
drug topically. In some embodiments, the cream formulation
comprises an active pharmaceutical ingredient other than
oxymetazoline. Some embodiments may be directed to a formulation
comprising an active pharmaceutical ingredient other than
oxymetazoline and a pharmaceutically acceptable excipient. In
certain embodiments, a cream comprising an alpha-adrenergic agonist
and pharmaceutically acceptable excipients is provided. In certain
embodiments, a cream comprising an imidazoline alpha-adrenergic
agonist and pharmaceutically acceptable excipients is provided. In
certain embodiments, a cream comprising a non-imidazoline
alpha-adrenergic agonist and pharmaceutically acceptable excipients
is provided. In certain embodiments, a cream comprising an alpha-1
adrenergic agonist and pharmaceutically acceptable excipients is
provided. In certain embodiments, a cream comprising an alpha-2
adrenergic agonist and pharmaceutically acceptable excipients is
provided. In certain embodiments, a cream comprising a selective
alpha-adrenergic agonist and pharmaceutically acceptable excipients
is provided. In certain embodiments, a cream comprising a
non-selective alpha-adrenergic agonist and pharmaceutically
acceptable excipients is provided. In certain embodiments, a cream
comprising a selective alpha-1 adrenergic agonist and
pharmaceutically acceptable excipients is provided. In certain
embodiments, a cream comprising a selective alpha-2 adrenergic
agonist and pharmaceutically acceptable excipients is provided. In
certain embodiments, a cream comprising a non-selective alpha-1
adrenergic agonist and pharmaceutically acceptable excipients is
provided. In certain embodiments, a cream comprising a
non-selective alpha-2 adrenergic agonist and pharmaceutically
acceptable excipients is provided.
[0014] In some embodiments, a method of treating a skin condition,
including, but not limited to, rosacea, including, for example,
erythematotelangiectatic rosacea, papulopustular rosacea, phymatous
rosacea, ocular rosacea or combinations thereof; and symptoms
associated with rosacea, including, for example, papules, pustules,
phymas (skin thickening), telangiectasias or erythema associated
with rosacea, other skin erythemas, telangiectasias, purpura or the
like, and other manifestations associated therewith; other
inflammatory conditions of the skin including, but not limited to,
keratosis pilaris, lupus miliaris dissemniatus faciei, eczema,
dermatitis, such as contact dermatitis, atopic dermatitis,
seborrheic dermatitis, nummular dermatitis, generalized exfoliative
dermatitis, statis dermatitis, neurodermatitis, lichen simplex
chronicus, xerosis and xerotic dermatitis, dyshidrosis and
dyshidrotic dermatitis, asteototic dermatitis or other conditions
characterized by sensitive skin or a disturbance of the epidermal
barrier; disorders characterized by rough, dry, cracked or fissured
skin, disorders characterized by hyperkeratotic skin such as
keratodermas and ichthyosisis and ichthyosiform dermatoses;
disorders of hair follicles and sebaceous glands, such as acne,
perioral dermatitis, and pseudofolliculitis barbae; disorders of
sweat glands, such as miliaria, including, but not limited to,
miliaria crystallina, miliaria rubra, miliaria profunda, miliaria
pustulosa; sunburn, chronic actinic damage, poikiloderma, radiation
dermatitis, actinic purpura ("solar purpura"); other inflammatory
dermatoses, reactions and conditions of the skin, including, but
not limited to, psoriasis, drug eruptions, erythema multiforme,
erythema nodosum, and granuloma annulare; diseases and conditions
characterized by bleeding or bruising such as petechiae,
ecchymosis, purpura and the like including any accumulation of
blood in the skin due to vascular extravasation, irrespective of
size or cause, bleeding or bruising due to any skin injury which
may include any trauma including surgical or procedural trauma;
infection, inflammatory dermatoses or inflammation due to any cause
or combinations thereof comprising administering a cream
formulation of embodiments described herein is provided. In some
embodiments the cream formulation may also have a moisturizing,
hydrating, soothing, calming or protective effect on the skin of
the subject.
[0015] Certain embodiments may include a method of moisturizing,
hydrating, soothing, calming or protecting the skin comprising
administering a cream formulation, wherein the cream formulation
does not contain an API. In embodiments, the cream is
non-irritating. In some embodiments, the cream formulation may be
used to treat sensitive, irritated, dry or damaged skin. In some
embodiments, the sensitive, irritated, or dry skin may be found in
patients with rosacea, xerosis, eczema or dermatitis. In some
embodiments, the cream formulation without an API may relieve or
treat the symptoms of rosacea and symptoms associated with rosacea,
including, for example, papules, pustules, phymas (skin
thickening), telangiectasias or erythema associated with rosacea,
other skin erythemas, telangiectasias, purpura or the like, and
other manifestations associated therewith; other inflammatory
conditions of the skin including, but not limited to, keratosis
pilaris, lupus miliaris dissemniatus faciei, eczema, dermatitis,
such as contact dermatitis, atopic dermatitis, seborrheic
dermatitis, nummular dermatitis, generalized exfoliative
dermatitis, statis dermatitis, neurodermatitis, lichen simplex
chronicus, xerosis and xerotic dermatitis, dyshidrosis and
dyshidrotic dermatitis, asteototic dermatitis or other conditions
characterized by sensitive skin or a disturbance of the epidermal
barrier; disorders characterized by rough, dry, cracked or fissured
skin, disorders characterized by hyperkeratotic skin such as
keratodermas and ichthyosisis and ichthyosiform dermatoses;
disorders of hair follicles and sebaceous glands, such as acne,
perioral dermatitis, and pseudofolliculitis barbae; disorders of
the sweat glands, such as miliaria (including, but not limited to,
crystalline, rubra, profunda, or pustule); sunburn, chronic actinic
damage, poikiloderma, radiation dermatitis, actinic purpura ("solar
purpura"); other inflammatory dermatoses, reactions and conditions
of the skin, including, but not limited to, psoriasis, drug
eruptions, erythema multiforme, erythema nodosum, and granuloma
annulare; diseases and conditions characterized by bleeding or
bruising such as petechiae, ecchymosis, purpura and the like
including any accumulation of blood in the skin due to vascular
extravasation, irrespective of size or cause, bleeding or bruising
due to any skin injury which may include any trauma including
surgical or procedural trauma; infection, inflammatory dermatoses
or inflammation due to any cause.
[0016] In certain embodiments herein, the cream formulation may be
used to treat skin conditions of various types. For example, the
cream formulation may be used to treat rosacea, eczema, dermatitis,
atopic dermatitis, psoriasis, steroid-responsive dermatoses,
pruritis, or xerosis. In certain embodiments, the cream formulation
may be used to treat dry, irritated, erythematous or pruriginous
skin in subjects with no underlying skin disease, such as, for
example, after physical skin trauma or mechanical skin trauma such
as shaving (as a post-shave "healer") or tweezing, after bathing,
showering, sweating; or after exposure to extrinsic factors such as
"the elements", for example, sun, wind, cold temperature, low
humidity, hot and humid conditions, radiation, air pollution, smoke
or cigarette smoke; or treat said skin irritation or erythema that
is as a result of exposure to a topical irritant such as a chemical
agent, insect sting or bite, plant exposure, or application of a
topically applied drug product, medicament or topical product, such
as a fragrance, insect repellant, exfoliant, skin peeling agent,
shaving or depilatory preparation, skin or hair cleanser, soap,
detergent or conditioner, hair treatment or colorant,
antiperspirant, deodorant, sunscreen, tanning agent, moisturizer,
astringent, toner, moisturizer, serum, mask, facial or body
cosmetic, ointment, cream, lotion, gel, foam, solution, shake, or
powder.
[0017] The cream formulations of embodiments herein may have a
hydrating effect on the skin. In certain embodiments, the cream
formulations may be used to treat intrinsic or extrinsic aging of
the skin including, but not limited to, dermatoheliosis or
photoaging, blemishes, ephilides, age spots (solar lentigines),
solar keratoses, xerosis, roughness of the skin, dullness of the
skin, thinning of the skin, sagging of the skin, fine lines, fine
and deep facial lines or creases, wrinkles; or improve skin tone,
smoothness, softness, suppleness, radiance, skin flexibility, and
global skin comfort.
[0018] In certain embodiments, the cream formulation may be used as
a delivery vehicle for the topical delivery of pharmaceutically
active ingredients including, but not limited to, potentially
irritating active drug substances. In certain embodiments, these
potentially active drug substances may include, but are not limited
to, alpha hydroxy acids, retinoic acids, benzoyl peroxide,
calcipotriene, calcineurin inhibitors, sunscreens, sunblocks,
bleaching agents, depilitories, antiperspirants, or combinations
thereof. In some embodiments, the active drug may be anti-rosacea
agents such as metronidazole, precipitated sulfur, sodium
sulfacetamide, or azelaic acid; antibacterial agents (antibiotics)
such as clindamycin phosphate, erythromycin, or antibiotics from
the tetracycline family; antimycobacterial agents such as dapsone;
other antiacne agents such as retinoids, or benzoyl peroxide;
antiparasitic agents such as metronidazole, permethrin, crotamiton,
thiabendazole, ivermectin or pyrethroids; antifungal agents such as
compounds of the imidazole family such as miconazole, clotrimazole,
econazole, ketoconazole, or salts thereof, polyene compounds such
as amphotericin B, compounds of the allylamine family such as
terbinafine; steroidal anti-inflammatory agents such as
hydrocortisone triamcinolone, fluocinonide, betamethasone valerate
or clobetasol propionate, or non-steroidal anti-inflammatory agents
such as ibuprofen and salts thereof, naproxen and salts thereof, or
acetaminophen; anesthetic agents such as the "amide" and "ester"
anesthetics such as lidocaine, prilocaine, tetracaine,
hydrochloride and derivatives thereof; antipruriginous agents such
as thenaldine, trimeprazine, or pramoxine; antiviral agents such as
acyclovir; keratolytic agents such as alpha- and beta-hydroxy acids
such as glycolic acid or salicylic acid, or urea; anti-free radical
agents (antioxidants) such as Vitamin E (alpha tocopherol) and its
derivatives, Vitamin C (ascorbic acid), Vitamin A (retinol) and its
derivatives, and superoxide dismutases; antiseborrheic agents such
as zinc pyrithione and selenium sulfide; antihistamines such as
cyproheptadine or hydroxyzine; tricyclic antidepressants such as
doxepin hydrochloride; antipsoriatic agents such as calcipotriene,
anthralines, coal tar; immune modulating agents such as imiquimod;
calcineurin inhibitors pimecrolimus and tacrolimus; or
chemotherapeutic agents such as 5-fluorouracil, nitrogen mustard,
carmustine, bexarotene, mitomycin-c and combinations thereof.
[0019] The cream formulations of certain embodiments herein may
also be used as a delivery vehicle for topically administered
anti-infectives such as, but not limited to, antibiotics,
antifungals, antiparasitic, and antiviral agents, corticosteroids,
imiquimod or other immune modulating drugs, topical anesthetics,
topical chemotherapeutic, or topical photosensitizing agents.
[0020] Certain embodiments herein include a method of treating or
preventing a dermatosis such as acne, rosacea, xerosis, eczema, or
dermatitis comprising administering the cream formulation of
embodiments herein to a subject in need thereof. In certain
embodiments, the cream formulation may be administered topically to
a subject in need thereof. In particular embodiments, the subject
may be susceptible to a recurrence of the dermatosis.
[0021] In certain embodiments, the compositions may be used
therapeutically without an API. In some embodiments, the cream
formulation of embodiments herein may be used as a delivery vehicle
for the delivery of topical agents to a subject's nails.
DESCRIPTION OF DRAWINGS
[0022] For a fuller understanding of the nature and advantages of
embodiments described herein, reference should be made to the
following detailed description taken in connection with the
accompanying drawings, in which:
[0023] FIG. 1 is a bar graph showing the mean cosmetic
acceptability scores including appearance and sensorial evaluation
scores by category for creams of Trial 36, Trial 2, Trial 11 and
Trial 20.
[0024] FIG. 2 is a bar graph showing the mean cosmetic
acceptability scores including appearance and sensorial evaluation
scores for creams of Trial 36, Trial 2, Trial 11 and Trial 20 in
key categories.
[0025] FIG. 3 is a bar graph showing the total mean cosmetic
acceptability scores including appearance and sensorial evaluation
scores for each of the creams of Trial 36, Trial 2, Trial 11 and
Trial 20.
DETAILED DESCRIPTION
[0026] Before the present compositions and methods are described,
it is to be understood that this invention is not limited to the
particular processes, compositions, or methodologies described, as
these may vary. It is also to be understood that the terminology
used in the description is for the purpose of describing the
particular versions or embodiments only, and is not intended to
limit the scope of the present invention which will be limited only
by the appended claims. Unless defined otherwise, all technical and
scientific terms used herein have the same meaning as commonly
understood by one of ordinary skill in the art. Although any
methods and materials similar or equivalent to those described
herein can be used in the practice or testing of embodiments of the
present invention, the preferred methods, devices, and materials
are now described. All publications mentioned herein are
incorporated by reference in their entirety. Nothing herein is to
be construed as an admission that the invention is not entitled to
antedate such disclosure by virtue of prior invention.
[0027] It must also be noted that as used herein and in the
appended claims, the singular forms "a", "an", and "the" include
plural reference unless the context clearly dictates otherwise.
Thus, for example, reference to a "preservative" is a reference to
one or more preservatives and equivalents thereof known to those
skilled in the art, and so forth.
[0028] As used herein, the term "about" means plus or minus 10% of
the numerical value of the number with which it is being used.
Therefore, about 50% means in the range of 45%-55%.
[0029] "Administering", when used in conjunction with a
therapeutic, means to administer a therapeutic directly into or
onto a target tissue or to administer a therapeutic to a subject,
whereby the therapeutic positively impacts the tissue to which it
is targeted. Thus, as used herein, the term "administering", when
used in conjunction with a therapeutic, can include, but is not
limited to, providing a therapeutic to a subject systemically by,
for example, intravenous injection, whereby the therapeutic reaches
the target tissue. Administering a composition or therapeutic may
be accomplished by, for example, injection, oral administration,
topical administration, or by these methods in combination with
other known techniques. Such combination techniques may include
heating, radiation, ultrasound and the use of delivery agents.
Preferably, administering is a self-administration, wherein the
therapeutic or composition is administered by the subject
themselves. Alternatively, administering may be administration to
the subject by a health care provider.
[0030] "Providing", when used in conjunction with a therapeutic,
means to administer a therapeutic directly into or onto a target
tissue, or to administer a therapeutic to a subject whereby the
therapeutic positively impacts the tissue to which it is
targeted.
[0031] The term "animal" as used herein includes, but is not
limited to, humans and non-human vertebrates such as wild, domestic
and farm animals.
[0032] The term "patient" or "subject" as used herein is an animal,
particularly a human, suffering from an unwanted disease or
condition that may be treated by the therapeutic and/or
compositions described herein.
[0033] The term "improves" is used to convey that the present
invention changes either the characteristics and/or the physical
attributes of the tissue to which it is being provided, applied or
administered. The term "improves" may also be used in conjunction
with a diseased state such that when a diseased state is "improved"
the symptoms or physical characteristics associated with the
diseased state are diminished, reduced or eliminated.
[0034] The term "inhibiting" generally refers to prevention of the
onset of the symptoms, alleviating the symptoms, or eliminating the
disease, condition or disorder.
[0035] "Optional" or "optionally" means that the subsequently
described event or circumstance may or may not occur, and that the
description includes instances where the event occurs and instances
where it does not.
[0036] As used herein, "room temperature" means an indoor
temperature of from about 20.degree. C. to about 25.degree. C. (68
to 77.degree. F.).
[0037] Throughout the specification of the application, various
terms are used such as "primary," "secondary," "first," "second,"
and the like. These terms are words of convenience in order to
distinguish between different elements, and such terms are not
intended to be limiting as to how the different elements may be
utilized.
[0038] By "pharmaceutically acceptable," "physiologically
tolerable," and grammatical variations thereof, as they refer to
compositions, carriers, diluents, and reagents or other ingredients
of the formulation, can be used interchangeably and represent that
the materials are capable of being administered without the
production of undesirable physiological effects such as rash,
burning, irritation or other deleterious effects to such a degree
as to be intolerable to the recipient thereof.
[0039] As used herein, the term "cosmetically acceptable" and
grammatical variations thereof, as they refer to compositions,
carriers, diluents, and reagents or other ingredients of the
formulation, represent that the materials used and final
composition are not irritating or otherwise harmful to the patient
in general and to the skin, in particular, and preferably are
pleasant and well tolerated with respect to general appearance, pH,
color, smell and texture (feel), that they are not, for example,
unacceptably sticky (tacky), oily or drying, and that they do
spread easily, absorb into the skin at an acceptable rate of
absorption, and are generally moisturizing.
[0040] "Pharmaceutically acceptable salts" include both acid and
base addition salts. "Pharmaceutically acceptable acid addition
salt" refers to those salts that retain biological effectiveness
and properties of the free bases and that include inorganic acids
such as, for example, hydrochloric acid, hydrobromic acid, sulfuric
acid, nitric acid, carbonic acid, phosphoric acid, and the like.
Organic acids may be selected from aliphatic, cycloaliphatic,
aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic
classes of organic acids, such as formic acid, acetic acid,
propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic
acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic
acid, fumaric acid, tartaric acid, citric acid, aspartic acid,
ascorbic acid, glutamic acid, anthranilic acid, benzoic acid,
cinnamic acid, mandelic acid, embonic acid, phenylacetic acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,
salicyclic acid, and the like.
[0041] As used herein, the term "therapeutic" means an agent
utilized to treat, combat, ameliorate, prevent or improve an
unwanted condition or disease of a subject. In part, embodiments of
the present invention may be directed to the treatment of various
skin diseases, conditions or disorders or symptoms thereof,
including, but not limited to, rosacea and symptoms associated with
rosacea, including, for example, papules, pustules, phymas (skin
thickening), telangiectasias or erythema associated with rosacea,
other skin erythemas, telangiectasias, purpura or the like, and
other manifestations associated therewith; other inflammatory
conditions of the skin including, but not limited to, keratosis
pilaris, lupus miliaris dissemniatus faciei, eczema, dermatitis,
such as contact dermatitis, atopic dermatitis, seborrheic
dermatitis, nummular dermatitis, generalized exfoliative
dermatitis, statis dermatitis, neurodermatitis, lichen simplex
chronicus, xerosis and xerotic dermatitis, dyshidrosis and
dyshidrotic dermatitis, asteototic dermatitis or other conditions
characterized by sensitive skin or a disturbance of the epidermal
barrier; disorders characterized by rough, dry, cracked or fissured
skin, disorders characterized by hyperkeratotic skin such as
keratodermas and ichthyosisis and ichthyosiform dermatoses;
disorders of hair follicles and sebaceous glands, such as acne,
perioral dermatitis, and pseudofolliculitis barbae; disorders of
sweat glands, such as miliaria, including, but not limited to,
miliaria crystallina, miliaria rubra, miliaria profunda, miliaria
pustulosa; sunburn, chronic actinic damage, poikiloderma, radiation
dermatitis, actinic purpura ("solar purpura"); other inflammatory
dermatoses, reactions and conditions of the skin, including, but
not limited to, psoriasis, drug eruptions, erythema multiforme,
erythema nodosum, and granuloma annulare; diseases and conditions
characterized by bleeding or bruising such as petechiae,
ecchymosis, purpura and the like including any accumulation of
blood in the skin due to vascular extravasation, irrespective of
size or cause, bleeding or bruising due to any skin injury which
may include any trauma including surgical or procedural trauma;
infection, inflammatory dermatoses or inflammation due to any cause
or combinations thereof. In part, some embodiments may be directed
to a cream formulation that has moisturizing properties.
[0042] The terms "therapeutically effective" or "effective", as
used herein, may be used interchangeably and refer to an amount of
a therapeutic composition of embodiments of the present invention
(e.g., a composition comprising oxymetazoline). For example, a
therapeutically effective amount of a composition is an amount of
the composition, and particularly the active ingredient, such as
oxymetazoline, that generally achieves the desired effect.
[0043] A "therapeutically effective amount" or "effective amount"
of a composition is an amount necessary or sufficient to achieve
the desired result. The activity contemplated by the embodiments
herein includes medically therapeutic, cosmetically therapeutic
and/or prophylactic treatment, as appropriate. The specific dose of
a compound administered according to this invention to obtain
therapeutic and/or prophylactic effects will, of course, be
determined by the particular circumstances surrounding the case,
including, for example, the compound administered, the route of
administration, and the condition being treated. However, the
effective amount administered can be determined by the practitioner
or manufacturer or patient in light of the relevant circumstances
including the condition to be treated, the choice of compound to be
administered, and the chosen route of administration, and
therefore, the above dosage ranges are not intended to limit the
scope of the invention in any way. A therapeutically effective
amount of the compound of embodiments herein is typically an amount
such that when it is administered in a physiologically tolerable
excipient composition, it is sufficient to achieve an effective
systemic concentration or local concentration in or on the tissue
to achieve the desired therapeutic or clinical outcome.
[0044] The terms "treat," "treated," or "treating" as used herein
refers to therapeutic treatment, cosmetic treatment and/or
prophylactic or preventative measures, wherein the object is to
prevent or slow down (lessen) an undesired physiological condition,
disorder or disease, or to obtain beneficial or desired clinical
results. For the purposes of this invention, beneficial or desired
clinical results include, but are not limited to, alleviation of
symptoms; diminishment of the extent of the condition, disorder or
disease; stabilization (i.e., not worsening) of the state of the
condition, disorder or disease; delay in onset or slowing of the
progression of the condition, disorder or disease; amelioration of
the condition, disorder or disease state; and remission (whether
partial or total), whether detectable or undetectable, or
enhancement or improvement of the condition, disorder or disease.
Treatment includes eliciting a clinically significant response
without excessive levels of side effects.
[0045] As used herein, the term "consists of" or "consisting of"
means that the formulation includes only the elements, steps, or
ingredients specifically recited in the particular claimed
embodiment or claim.
[0046] As used herein, the term "consisting essentially of" or
"consists essentially of" means that the only active pharmaceutical
ingredient in the formulation or method that treats the specified
condition (e.g. erythema or redness associated with the particular
disease to be treated) is the specifically recited therapeutic in
the particular embodiment or claim.
[0047] Generally speaking, the term "tissue" refers to any
aggregation of similarly specialized cells which are united in the
performance of a particular function.
[0048] As used herein, the term "erythema" refers to any redness of
the skin due to hyperemia, congestion of the vasculature or
dilation of the vasculature of the skin and its surrounding
structures. Erythema may occur in many conditions of the skin
including, but not limited to, rosacea and symptoms associated with
rosacea, including, for example, papules, pustules, phymas (skin
thickening), telangiectasias or erythema associated with rosacea,
other skin erythemas, telangiectasias, purpura or the like, and
other manifestations associated therewith; other inflammatory
conditions of the skin including, but not limited to, keratosis
pilaris, lupus miliaris dissemniatus faciei, eczema, dermatitis,
such as contact dermatitis, atopic dermatitis, seborrheic
dermatitis, nummular dermatitis, generalized exfoliative
dermatitis, statis dermatitis, neurodermatitis, lichen simplex
chronicus, xerosis and xerotic dermatitis, dyshidrosis and
dyshidrotic dermatitis, asteototic dermatitis or other conditions
characterized by sensitive skin or a disturbance of the epidermal
barrier; disorders characterized by rough, dry, cracked or fissured
skin, disorders characterized by hyperkeratotic skin such as
keratodermas and ichthyosisis and ichthyosiform dermatoses;
disorders of hair follicles and sebaceous glands, such as acne,
perioral dermatitis, and pseudofolliculitis barbae; disorders of
sweat glands, such as miliaria, including, but not limited to,
miliaria crystallina, miliaria rubra, miliaria profunda, miliaria
pustulosa; sunburn, chronic actinic damage, poikiloderma, radiation
dermatitis, actinic purpura ("solar purpura"); other inflammatory
dermatoses, reactions and conditions of the skin, including, but
not limited to, psoriasis, drug eruptions, erythema multiforme,
erythema nodosum, and granuloma annulare; diseases and conditions
characterized by bleeding or bruising such as petechiae,
ecchymosis, purpura and the like including any accumulation of
blood in the skin due to vascular extravasation, irrespective of
size or cause, bleeding or bruising due to any skin injury which
may include any trauma including surgical or procedural trauma;
infection, inflammatory dermatoses; inflammation due to any cause
or a combination thereof.
[0049] Keratosis pilaris (KP) is a very common genetic follicular
condition that is manifested by the appearance of rough bumps on
the skin and may be accompanied by erythema. Lupus miliaris
disseminatus faciei (LMDF) is an uncommon, chronic dermatosis
characterized by red-to-yellow or yellow-brown papules of the
central face, particularly on and around the eyelids, that may be
accompanied by erythema.
[0050] As used herein, the term "purpura" refers to any
accumulation of blood in the skin due to vascular extravasation,
irrespective of size or cause. As used herein, "purpura" refers to
medical conditions commonly referred to as "petechiae" (pinpoint
spots), "ecchymoses" (larger macular (flat) patches) and "purpura"
(larger spots).
[0051] Purpura, in general, is hemorrhage of blood out of the
vascular spaces and into the skin or surrounding tissues of the
skin or mucous membranes. This hemorrhage results in a collection
of blood in the dermis and/or subdermal tissues of the skin that is
visible initially as a dark purple/red discoloration that changes
color as it breaks down and is resorbed.
[0052] In particular, purpura can be characterized as flat (macular
or non-palpable) or raised (palpable or papular). The definition of
macular purpuric subtypes include: petechiae-defined as small
purpura (less than 4-5 millimeters (mm) in diameter,
purpura-defined as greater than 4-5 mm and less than 1 cm
(centimeter) in diameter, and ecchymoses-defined as greater than 1
cm in diameter. The size divisions are not absolute but are useful
rules of thumb and there is often a range in size of clinical
purpuras in any one specific condition.
[0053] A bruise, also called a contusion or ecchymosis, is an
injury to biological tissue in which blood vessels such as the
capillaries are damaged, allowing blood to seep into the
surrounding tissue(s). Bruising is usually caused by a blunt impact
and its likelihood and its severity increases as one ages due to
thinning and loss of elasticity of the skin.
[0054] Certain embodiments herein are directed to pharmaceutical
compositions formulated for topical administration of
oxymetazoline. In certain embodiments, the pharmaceutical
compositions may be creams, and such creams may have any number and
quantity of additional components. Certain embodiments of the
invention are directed at a cream formulation comprising
oxymetazoline from about 0.0075% to about 5% and pharmaceutically
acceptable excipients. Some embodiments of the invention are
directed at a cream formulation consisting essentially of
oxymetazoline from about 0.0075% to about 5% and pharmaceutically
acceptable excipients. Some embodiments of the invention are
directed at a cream formulation consisting of oxymetazoline from
about 0.0075% to about 5% and pharmaceutically acceptable
excipients. Such formulations may be used to treat rosacea and
symptoms associated with rosacea, including, for example, papules,
pustules, phymas (skin thickening), telangiectasias or erythema
associated with rosacea, other skin erythemas, telangiectasias,
purpura or the like, and other manifestations associated therewith;
other inflammatory conditions of the skin including, but not
limited to, keratosis pilaris, lupus miliaris dissemniatus faciei,
eczema, dermatitis, such as contact dermatitis, atopic dermatitis,
seborrheic dermatitis, nummular dermatitis, generalized exfoliative
dermatitis, statis dermatitis, neurodermatitis, lichen simplex
chronicus, xerosis and xerotic dermatitis, dyshidrosis and
dyshidrotic dermatitis, asteototic dermatitis or other conditions
characterized by sensitive skin or a disturbance of the epidermal
barrier; disorders characterized by rough, dry, cracked or fissured
skin, disorders characterized by hyperkeratotic skin such as
keratodermas and ichthyosisis and ichthyosiform dermatoses;
disorders of hair follicles and sebaceous glands, such as acne,
perioral dermatitis, and pseudofolliculitis barbae; disorders of
sweat glands, such as miliaria, including, but not limited to,
crystallina, miliaria rubra, miliaria profunda, miliaria pustulosa;
sunburn, chronic actinic damage, poikiloderma, radiation
dermatitis, actinic purpura ("solar purpura"); other inflammatory
dermatoses, reactions and conditions of the skin, including, but
not limited to, psoriasis, drug eruptions, erythema multiforme,
erythema nodosum, and granuloma annulare; diseases and conditions
characterized by bleeding or bruising such as petechiae,
ecchymosis, purpura and the like including any accumulation of
blood in the skin due to vascular extravasation, irrespective of
size or cause, bleeding or bruising due to any skin injury which
may include any trauma including surgical or procedural trauma;
infection, inflammatory dermatoses, inflammation due to any cause
or the like. Such formulations may be used to treat or prevent
symptoms such as, but not limited to, papules, pustules, other
inflammatory lesions, phymas (skin thickening), telangiectasias or
erythema associated with rosacea and other inflammatory conditions
of the skin including, but not limited to, keratosis pilaris, lupus
miliaris dissemniatus faciei, eczema, dermatitis, such as contact
dermatitis, atopic dermatitis, seborrheic dermatitis, nummular
dermatitis, generalized exfoliative dermatitis, statis dermatitis,
neurodermatitis, lichen simplex chronicus, xerosis and xerotic
dermatitis, dyshidrosis and dyshidrotic dermatitis, asteototic
dermatitis or other conditions characterized by sensitive skin or a
disturbance of the epidermal barrier; disorders characterized by
rough, dry, cracked or fissured skin, disorders characterized by
hyperkeratotic skin such as keratodermas and ichthyosisis and
ichthyosiform dermatoses; disorders of hair follicles and sebaceous
glands, such as acne, perioral dermatitis, and pseudofolliculitis
barbae; disorders of sweat glands, such as miliaria, including, but
not limited to, miliaria crystallina, miliaria rubra, miliaria
profunda, miliaria pustulosa; sunburn, chronic actinic damage,
poikiloderma, radiation dermatitis, actinic purpura ("solar
purpura"); other inflammatory dermatoses, reactions and conditions
of the skin, including, but not limited to, psoriasis, drug
eruptions, erythema multiforme, erythema nodosum, and granuloma
annulare; diseases and conditions characterized by bleeding or
bruising such as petechiae, ecchymosis, purpura and the like
including any accumulation of blood in the skin due to vascular
extravasation, irrespective of size or cause, bleeding or bruising
due to any skin injury which may include any trauma including
surgical or procedural trauma; infection, inflammatory dermatoses
or inflammation due to any cause and other skin conditions
characterized by increased erythema of the skin. Such formulations
may also be used to treat or prevent purpura, which is a hemorrhage
of blood out of the vascular spaces and into the skin or
surrounding tissues of the skin or mucous membranes. In further
embodiments, the formulation is cosmetically acceptable.
[0055] Further embodiments are directed to methods of treating
erythema, redness or telangiectasias associated with rosacea
comprising administering a cream comprising oxymetazoline in a
therapeutically effective amount. Some embodiments are directed to
methods of treating papules, pustules, and other inflammatory
lesions associated with rosacea comprising administering a cream
comprising oxymetazoline in a therapeutically effective amount.
Some embodiments are directed to methods of treating skin erythema
comprising administering a cream comprising oxymetazoline in a
therapeutically effective amount. Some embodiments are directed to
methods of treating purpura comprising administering a cream
comprising oxymetazoline in a therapeutically effective amount.
Some embodiments are directed to methods of treating keratosis
pilaris, lupus miliaris disseminatus faciei or the like comprising
administering a cream comprising oxymetazoline in a therapeutically
effective amount. Some embodiments are directed to methods of
treating redness or erythema associated with rosacea, skin
erythemas, telangiectasias, purpura or the like, and other
manifestations associated therewith; other inflammatory conditions
of the skin including, but not limited to, keratosis pilaris, lupus
miliaris dissemniatus faciei, eczema, dermatitis, such as contact
dermatitis, atopic dermatitis, seborrheic dermatitis, nummular
dermatitis, generalized exfoliative dermatitis, statis dermatitis,
neurodermatitis, lichen simplex chronicus, xerosis and xerotic
dermatitis, dyshidrosis and dyshidrotic dermatitis, asteototic
dermatitis or other conditions characterized by sensitive skin or a
disturbance of the epidermal barrier; disorders characterized by
rough, dry, cracked or fissured skin, disorders characterized by
hyperkeratotic skin such as keratodermas and ichthyosisis and
ichthyosiform dermatoses; disorders of hair follicles and sebaceous
glands, such as acne, perioral dermatitis, and pseudofolliculitis
barbae; disorders of sweat glands, such as miliaria, including, but
not limited to, miliaria crystallina, miliaria rubra, miliaria
profunda, miliaria pustulosa; sunburn, chronic actinic damage,
poikiloderma, radiation dermatitis, actinic purpura ("solar
purpura"); other inflammatory dermatoses, reactions and conditions
of the skin, including, but not limited to, psoriasis, drug
eruptions, erythema multiforme, erythema nodosum, and granuloma
annulare; diseases and conditions characterized by bleeding or
bruising such as petechiae, ecchymosis, purpura and the like
including any accumulation of blood in the skin due to vascular
extravasation, irrespective of size or cause, bleeding or bruising
due to any skin injury which may include any trauma including
surgical or procedural trauma; infection, inflammatory dermatoses,
or inflammation due to any cause. In further embodiments, the
formulation is cosmetically acceptable.
[0056] Certain embodiments of the invention are directed to methods
of treating erythema or redness associated with rosacea comprising
administering a cream comprising oxymetazoline in an amount from
about 0.0075% to about 5% by weight of the cream and
pharmaceutically acceptable excipients. Embodiments are directed to
methods of treating inflammatory lesions including papules and
pustules associated with rosacea comprising administering a cream
comprising oxymetazoline in an amount from about 0.0075% to about
5% by weight of the cream and pharmaceutically acceptable
excipients. Embodiments are directed to methods of treating skin
thickening (phymas) associated with rosacea comprising
administering a cream comprising oxymetazoline in an amount from
about 0.0075% to about 5% by weight of the cream and
pharmaceutically acceptable excipients. Some embodiments of the
invention are directed to methods of treating erythema or redness
associated with telangiectasia comprising administering a cream
comprising oxymetazoline in an amount from about 0.0075% to about
5% by weight of the cream and pharmaceutically acceptable
excipients. Some embodiments of the invention are directed to
methods of treating telangiectasia comprising administering a cream
comprising oxymetazoline in an amount from about 0.0075% to about
5% by weight of the cream and pharmaceutically acceptable
excipients. Some embodiments of the invention are directed to
methods of treating erythema or redness associated with
erythemato-telangiectatic rosacea comprising administering a cream
comprising oxymetazoline in an amount from about 0.0075% to about
5% by weight of the cream. Some embodiments of the invention are
directed to methods of treating erythemato-telangiectatic rosacea
comprising administering a cream comprising oxymetazoline in an
amount from about 0.0075% to about 5% by weight of the cream and
pharmaceutically acceptable excipients. Some embodiments of the
invention are directed to methods of treating erythema or redness
associated with papulopustular rosacea comprising administering a
cream comprising oxymetazoline in an amount from about 0.0075% to
about 5% by weight of the cream. Some embodiments of the invention
are directed to methods of treating papules associated with
papulopustular rosacea comprising administering a cream comprising
oxymetazoline in an amount from about 0.0075% to about 5% by weight
of the cream. Some embodiments of the invention are directed to
methods of treating papulopustular rosacea comprising administering
a cream comprising oxymetazoline in an amount from about 0.0075% to
about 5% by weight of the cream and pharmaceutically acceptable
excipients. Embodiments of the invention are directed to methods of
treating symptoms associated with rosacea comprising administering
a cream comprising oxymetazoline in an amount from about 0.0075% to
about 5% by weight of the cream and pharmaceutically acceptable
excipients, wherein the symptoms are selected from the group
consisting of papules, pustules, erythema (redness), skin
thickening and telangiectasias. Some embodiments of the invention
are directed to methods of treating purpura comprising
administering a cream comprising oxymetazoline in an amount from
about 0.0075% to about 5% by weight of the cream and
pharmaceutically acceptable excipients. Embodiments are directed to
methods of treating keratosis pilaris, lupus miliaris disseminatus
faciei or the like comprising administering a cream comprising
oxymetazoline in an amount from about 0.0075% to about 5% by weight
of the cream and pharmaceutically acceptable excipients.
Embodiments are directed to methods of treating rosacea and
symptoms associated with rosacea, including, for example, papules,
pustules, phymas (skin thickening), telangiectasias or erythema
associated with rosacea, other skin erythemas, telangiectasias,
purpura or the like, and other manifestations associated therewith;
other inflammatory conditions of the skin including, but not
limited to, keratosis pilaris, lupus miliaris dissemniatus faciei,
eczema, dermatitis, such as contact dermatitis, atopic dermatitis,
seborrheic dermatitis, nummular dermatitis, generalized exfoliative
dermatitis, statis dermatitis, neurodermatitis, lichen simplex
chronicus, xerosis and xerotic dermatitis, dyshidrosis and
dyshidrotic dermatitis, asteototic dermatitis or other conditions
characterized by sensitive skin or a disturbance of the epidermal
barrier; disorders characterized by rough, dry, cracked or fissured
skin, disorders characterized by hyperkeratotic skin such as
keratodermas and ichthyosisis and ichthyosiform dermatoses;
disorders of hair follicles and sebaceous glands, such as acne,
perioral dermatitis, and pseudofolliculitis barbae; disorders of
sweat glands, such as miliaria, including, but not limited to,
miliaria crystallina, miliaria rubra, miliaria profunda, miliaria
pustulosa; sunburn, chronic actinic damage, poikiloderma, radiation
dermatitis, actinic purpura ("solar purpura"); other inflammatory
dermatoses, reactions and conditions of the skin, including, but
not limited to, psoriasis, drug eruptions, erythema multiforme,
erythema nodosum, and granuloma annulare; diseases and conditions
characterized by bleeding or bruising such as petechiae,
ecchymosis, purpura and the like including any accumulation of
blood in the skin due to vascular extravasation, irrespective of
size or cause, bleeding or bruising due to any skin injury which
may include any trauma including surgical or procedural trauma;
infection, inflammatory dermatoses, inflammation due to any cause
comprising administering a cream comprising oxymetazoline in an
amount from about 0.0075% to about 5% by weight of the cream and
pharmaceutically acceptable excipients. In further embodiments, the
formulation is cosmetically acceptable.
[0057] Certain embodiments of the invention are directed to methods
of treating erythema or redness associated with rosacea comprising
administering a cream consisting of oxymetazoline in an amount from
about 0.0075% to about 5% by weight of the cream and
pharmaceutically acceptable excipients. Some embodiments are
directed to methods of treating papules associated with rosacea
comprising administering a cream consisting of oxymetazoline in an
amount from about 0.0075% to about 5% by weight of the cream and
pharmaceutically acceptable excipients. Some embodiments of the
invention are directed to methods of treating symptoms associated
with rosacea comprising administering a cream consisting of
oxymetazoline in an amount from about 0.0075% to about 5% by weight
of the cream and pharmaceutically acceptable excipients, wherein
the symptoms are selected from the group consisting of papules,
pustules, erythema (redness), skin thickening, and telangiectasias.
Some embodiments of the invention are directed to methods of
treating erythema or redness associated with telangiectasia
comprising administering a cream consisting of oxymetazoline in an
amount from about 0.0075% to about 5% by weight of the cream and
pharmaceutically acceptable excipients. Some embodiments of the
invention are directed to methods of treating telangiectasia
comprising administering a cream consisting of oxymetazoline in an
amount from about 0.0075% to about 5% by weight of the cream and
pharmaceutically acceptable excipients. Some embodiments of the
invention are directed to methods of treating erythema or redness
associated with erythemato-telangiectatic rosacea comprising
administering a cream consisting of oxymetazoline in an amount from
about 0.0075% to about 5% by weight of the cream and
pharmaceutically acceptable excipients. Some embodiments of the
invention are directed to methods of treating
erythemato-telangiectatic rosacea comprising administering a cream
consisting of oxymetazoline in an amount from about 0.0075% to
about 5% by weight of the cream and pharmaceutically acceptable
excipients. Some embodiments of the invention are directed to
methods of treating erythema or redness associated with
papulopustular rosacea comprising administering a cream consisting
of oxymetazoline in an amount from about 0.0075% to about 5% by
weight of the cream. Some embodiments of the invention are directed
to methods of treating papules or pustules associated with
papulopustular rosacea comprising administering a cream consisting
of oxymetazoline in an amount from about 0.0075% to about 5% by
weight of the cream. Some embodiments of the invention are directed
to methods of treating papulopustular rosacea comprising
administering a cream consisting of oxymetazoline in an amount from
about 0.0075% to about 5% by weight of the cream and
pharmaceutically acceptable excipients. Some embodiments of the
invention are directed to methods of treating purpura comprising
administering a cream consisting of oxymetazoline in an amount from
about 0.0075% to about 5% by weight of the cream and
pharmaceutically acceptable excipients. Embodiments are directed to
methods of treating rosacea and symptoms associated with rosacea,
including, for example, papules, pustules, phymas (skin
thickening), telangiectasias or erythema associated with rosacea,
other skin erythemas, telangiectasias, purpura or the like, and
other manifestations associated therewith; other inflammatory
conditions of the skin including, but not limited to, keratosis
pilaris, lupus miliaris dissemniatus faciei, eczema, dermatitis,
such as contact dermatitis, atopic dermatitis, seborrheic
dermatitis, nummular dermatitis, generalized exfoliative
dermatitis, statis dermatitis, neurodermatitis, lichen simplex
chronicus, xerosis and xerotic dermatitis, dyshidrosis and
dyshidrotic dermatitis, asteototic dermatitis or other conditions
characterized by sensitive skin or a disturbance of the epidermal
barrier; disorders characterized by rough, dry, cracked or fissured
skin, disorders characterized by hyperkeratotic skin such as
keratodermas and ichthyosisis and ichthyosiform dermatoses;
disorders of hair follicles and sebaceous glands, such as acne,
perioral dermatitis, and pseudofolliculitis barbae; disorders of
sweat glands, such as miliaria, including, but not limited to,
miliaria crystallina, miliaria rubra, miliaria profunda, miliaria
pustulosa; sunburn, chronic actinic damage, poikiloderma, radiation
dermatitis, actinic purpura ("solar purpura"); other inflammatory
dermatoses, reactions and conditions of the skin, including, but
not limited to, psoriasis, drug eruptions, erythema multiforme,
erythema nodosum, and granuloma annulare; diseases and conditions
characterized by bleeding or bruising such as petechiae,
ecchymosis, purpura and the like including any accumulation of
blood in the skin due to vascular extravasation, irrespective of
size or cause, bleeding or bruising due to any skin injury which
may include any trauma including surgical or procedural trauma;
infection, inflammatory dermatoses, inflammation due to any cause
comprising administering a cream consisting of oxymetazoline in an
amount from about 0.0075% to about 5% by weight of the cream and
pharmaceutically acceptable excipients. In further embodiments, the
formulation is cosmetically acceptable.
[0058] Certain embodiments of the invention are directed to methods
of treating erythema or redness associated with rosacea comprising
administering a cream consisting essentially of oxymetazoline in an
amount from about 0.0075% to about 5% by weight of the cream and
pharmaceutically acceptable excipients. Some embodiments are
directed to methods of treating papules associated with rosacea
comprising administering a cream consisting essentially of
oxymetazoline in an amount from about 0.0075% to about 5% by weight
of the cream and pharmaceutically acceptable excipients. Some
embodiments of the invention are directed to methods of treating
symptoms associated with rosacea comprising administering a cream
consisting essentially of oxymetazoline in an amount from about
0.0075% to about 5% by weight of the cream and pharmaceutically
acceptable excipients, wherein the symptoms are selected from the
group consisting of papules, pustules, erythema (redness), skin
thickening, and telangiectasias. Some embodiments of the invention
are directed to methods of treating erythema or redness associated
with telangiectasia comprising administering a cream consisting
essentially of oxymetazoline in an amount from about 0.0075% to
about 5% by weight of the cream and pharmaceutically acceptable
excipients. Some embodiments of the invention are directed to
methods of treating telangiectasia comprising administering a cream
consisting essentially of oxymetazoline in an amount from about
0.0075% to about 5% by weight of the cream and pharmaceutically
acceptable excipients. Some embodiments of the invention are
directed to methods of treating erythema or redness associated with
erythemato-telangiectatic rosacea comprising administering a cream
consisting essentially of oxymetazoline in an amount from about
0.0075% to about 5% by weight of the cream and pharmaceutically
acceptable excipients. Some embodiments of the invention are
directed to methods of treating erythemato-telangiectatic rosacea
comprising administering a cream consisting essentially of
oxymetazoline in an amount from about 0.0075% to about 5% by weight
of the cream and pharmaceutically acceptable excipients. Some
embodiments of the invention are directed to methods of treating
erythema or redness associated with papulopustular rosacea
comprising administering a cream consisting essentially of
oxymetazoline in an amount from about 0.0075% to about 5% by weight
of the cream. Some embodiments of the invention are directed to
methods of treating papules or pustules associated with
papulopustular rosacea comprising administering a cream consisting
essentially of oxymetazoline in an amount from about 0.0075% to
about 5% by weight of the cream. Some embodiments of the invention
are directed to methods of treating papulopustular rosacea
comprising administering a cream consisting essentially of
oxymetazoline in an amount from about 0.0075% to about 5% by weight
of the cream and pharmaceutically acceptable excipients. Some
embodiments of the invention are directed to methods of treating
purpura comprising administering a cream consisting essentially of
oxymetazoline in an amount from about 0.0075% to about 5% by weight
of the cream and pharmaceutically acceptable excipients. Some
embodiments are directed to methods of treating keratosis pilaris,
lupus miliaris disseminatus faciei or the like comprising
administering a cream consisting essentially of oxymetazoline in an
amount from about 0.0075% to about 5% by weight of the cream and
pharmaceutically acceptable excipients. Some embodiments are
directed to methods of treating rosacea and symptoms associated
with rosacea, including, for example, papules, pustules, phymas
(skin thickening), telangiectasias or erythema associated with
rosacea, other skin erythemas, telangiectasias, purpura or the
like, and other manifestations associated therewith; other
inflammatory conditions of the skin including, but not limited to,
keratosis pilaris, lupus miliaris dissemniatus faciei, eczema,
dermatitis, such as contact dermatitis, atopic dermatitis,
seborrheic dermatitis, nummular dermatitis, generalized exfoliative
dermatitis, statis dermatitis, neurodermatitis, lichen simplex
chronicus, xerosis and xerotic dermatitis, dyshidrosis and
dyshidrotic dermatitis, asteototic dermatitis or other conditions
characterized by sensitive skin or a disturbance of the epidermal
barrier; disorders characterized by rough, dry, cracked or fissured
skin, disorders characterized by hyperkeratotic skin such as
keratodermas and ichthyosisis and ichthyosiform dermatoses;
disorders of hair follicles and sebaceous glands, such as acne,
perioral dermatitis, and pseudofolliculitis barbae; disorders of
sweat glands, such as miliaria, including, but not limited to,
miliaria crystallina, miliaria rubra, miliaria profunda, miliaria
pustulosa; sunburn, chronic actinic damage, poikiloderma, radiation
dermatitis, actinic purpura ("solar purpura"); other inflammatory
dermatoses, reactions and conditions of the skin, including, but
not limited to, psoriasis, drug eruptions, erythema multiforme,
erythema nodosum, and granuloma annulare; diseases and conditions
characterized by bleeding or bruising such as petechiae,
ecchymosis, purpura and the like including any accumulation of
blood in the skin due to vascular extravasation, irrespective of
size or cause, bleeding or bruising due to any skin injury which
may include any trauma including surgical or procedural trauma;
infection, inflammatory dermatoses, inflammation due to any cause
comprising administering a cream consisting essentially of
oxymetazoline in an amount from about 0.0075% to about 5% by weight
of the cream and pharmaceutically acceptable excipients. In further
embodiments, the formulation is cosmetically acceptable.
[0059] Oxymetazoline is the common name for
3-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2,4-dimethyl-6-tert-butyl-phenol,
which has the chemical structure:
##STR00001##
[0060] As used herein, oxymetazoline includes both oxymetazoline
free base and an acid addition salt of oxymetazoline. For example,
in some embodiments, the oxymetazoline used in the preparation of
the pharmaceutical composition may include a pharmaceutical salt,
such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, carbonic acid, phosphoric acid, and the like, or an organic
acid such as formic acid, acetic acid, propionic acid, glycolic
acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic
acid, maleic acid, maloneic acid, succinic acid, fumaric acid,
tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic
acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid,
embonic acid, phenylacetic acid, methanesulfonic acid,
ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid, and
the like. In certain embodiments, the pharmaceutical salt may be
hydrochloric acid
[0061] A "cream," as used herein, refers to a semi-solid emulsion,
i.e. a dispersed system having at least two immiscible phases where
one phase is dispersed in another, with droplets ranging in
diameter from about 0.1 .mu.m to about 100 .mu.m that is capable of
penetrating the stratum corneum layer of skin. The creams of
various embodiments can have a viscosity of from about 2,500
centipoises (cP) to about 150,000 cP at about 25.degree. C. In some
embodiments, the creams described herein can exhibit a melting
point of greater than about 25.degree. C., greater than about
30.degree. C., greater than about 35.degree. C., greater than about
40.degree. C., from about 25.degree. C. to about 80.degree. C.,
from about 25.degree. C. to about 60.degree. C., from about
30.degree. C. to about 80.degree. C., from about 30.degree. C. to
about 60.degree. C., from about 35.degree. C. to about 80.degree.
C., from about 35.degree. C. to about 60.degree. C., from about
35.degree. C. to about 50.degree. C., from about 35.degree. C. to
about 40.degree. C., from about 40.degree. C. to about 80.degree.
C., or from about 40.degree. C. to about 60.degree. C.
[0062] In certain embodiments of the present invention a cream
comprising oxymetazoline, as the active pharmaceutical ingredient
(API), and pharmaceutically acceptable excipients is provided. In
some embodiments, the cream may comprise from about 0.0075% to
about 5%, from about 0.0075% to about 2.5%, from about 0.0075% to
about 2%, from about 0.0075% to about 1.5%, from about 0.0075% to
about 1%, from about 0.0075% to about 0.5%, from about 0.0075% to
about 0.25%, from about 0.0075% to about 0.15%, from about 0.0075%
to about 0.1%, from about 0.0075% to about 0.025%, from about
0.0075% to about 0.075%, from about 0.0075% to about 0.06%, from
about 0.0075% to about 0.05%, from about 0.01% to about 5%, from
about 0.01% to about 2.5%, from about 0.01% to about 2%, from about
0.01% to about 1.5%, from about 0.01% to about 1%, from about 0.01%
to about 0.5%, from about 0.01% to about 0.25%, from about 0.01% to
about 0.15%, from about 0.01% to about 0.1%, from about 0.01% to
about 0.025%, from about 0.05% to about 5%, from about 0.05% to
about 2.5%, from about 0.05% to about 2%, from about 0.05% to about
1%, from about 0.05% to about 0.5%, from about 0.05% to about
0.25%, from about 0.05% to about 0.15%, from about 0.05% to about
0.1%, from about 0.05% to about 0.075% from about 0.1% to about 5%,
from about 0.1% to about 2.5%, from about 0.1% to about 2%, from
about 0.1% to about 1.5%, from about 0.1% to about 1%, from about
0.1% to about 0.5%, from about 0.1% to about 0.25%, from about 0.1%
to about 0.15%, from about 0.15% to about 5%, from about 0.15% to
about 2.5%, from about 0.15% to about 2%, from about 0.15% to about
1.5%, from about 0.15% to about 1%, from about 0.15% to about 0.5%,
from about 0.15% to about 0.25% by weight of oxymetazoline and
pharmaceutically acceptable excipients. In some embodiments, the
cream may comprise about 0.0075%, about 0.01%, about 0.025%, about
0.05%, about 0.06%, about 0.075%, about 0.1%, about 0.15%, about
0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about
0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about
0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about
0.95%, about 1%, about 1.05%, about 1.1%, about 1.15%, about 1.2%,
about 1.25%, about 1.3%, about 1.35%, about 1.4%, about 1.45%,
about 1.5%, about 1.55%, about 1.6%, about 1.65%, about 1.7%, about
1.75%, about 1.8%, about 1.85%, about 1.9%, about 1.95%, about 2%,
about 2.05%, about 2.1%, about 2.15%, about 2.2%, about 2.25%,
about 2.3%, about 2.35%, about 2.4%, about 2.45%, about 2.5%, about
2.55%, about 2.6%, about 2.65%, about 2.7%, about 2.75%, about
2.8%, about 2.85%, about 2.9%, about 2.95%, about 3%, about 3.5%,
about 4%, about 4.5%, or about 5% by weight of oxymetazoline and
pharmaceutically acceptable excipients. In some embodiments, the
cream may comprise less than about 5% by weight of oxymetazoline
and pharmaceutically acceptable excipients. In some embodiments,
the cream may comprise less than about 2.5% by weight of
oxymetazoline and pharmaceutically acceptable excipients. In some
embodiments, the cream may comprise less than about 2% by weight of
oxymetazoline and pharmaceutically acceptable excipients. In some
embodiments, the cream may comprise less than about 1% by weight of
oxymetazoline and pharmaceutically acceptable excipients. In
certain embodiments, a cream comprising oxymetazoline, a
vasoconstrictor and pharmaceutically acceptable excipients is
provided. In certain embodiments, a cream comprising oxymetazoline,
an alpha-adrenergic agonist and pharmaceutically acceptable
excipients is provided. In certain embodiments, a cream comprising
oxymetazoline, an imidazoline alpha-adrenergic agonist and
pharmaceutically acceptable excipients is provided. In certain
embodiments, a cream comprising oxymetazoline, a non-imidazoline
alpha-adrenergic agonist and pharmaceutically acceptable excipients
is provided. In certain embodiments, a cream comprising
oxymetazoline, an alpha-1 adrenergic agonist and pharmaceutically
acceptable excipients is provided. In certain embodiments, a cream
comprising oxymetazoline, an alpha-2 adrenergic agonist and
pharmaceutically acceptable excipients is provided. In certain
embodiments, a cream comprising oxymetazoline, a selective
alpha-adrenergic agonist and pharmaceutically acceptable excipients
is provided. In certain embodiments, a cream comprising
oxymetazoline, a non-selective alpha-adrenergic agonist and
pharmaceutically acceptable excipients is provided. In certain
embodiments, a cream comprising oxymetazoline, a selective alpha-1
adrenergic agonist and pharmaceutically acceptable excipients is
provided. In certain embodiments, a cream comprising oxymetazoline,
a selective alpha-2 adrenergic agonist and pharmaceutically
acceptable excipients is provided. In certain embodiments, a cream
comprising oxymetazoline, a non-selective alpha-1 adrenergic
agonist and pharmaceutically acceptable excipients is provided. In
certain embodiments, a cream comprising oxymetazoline, a
non-selective alpha-2 adrenergic agonist and pharmaceutically
acceptable excipients is provided.
[0063] In certain embodiments of the present invention a cream
consisting essentially of oxymetazoline and pharmaceutically
acceptable excipients is provided. In some embodiments, the cream
may consist essentially of from about 0.0075% to about 5%, from
about 0.0075% to about 2.5%, from about 0.0075% to about 2%, from
about 0.0075% to about 1.5%, from about 0.0075% to about 1%, from
about 0.0075% to about 0.5%, from about 0.0075% to about 0.25%,
from about 0.0075% to about 0.15%, from about 0.0075% to about
0.1%, from about 0.0075% to about 0.025%, from about 0.0075% to
about 0.075%, from about 0.0075% to about 0.06%, from about 0.0075%
to about 0.05%, from about 0.01% to about 5%, from about 0.01% to
about 2.5%, from about 0.01% to about 2%, from about 0.01% to about
1.5%, from about 0.01% to about 1%, from about 0.01% to about 0.5%,
from about 0.01% to about 0.25%, from about 0.01% to about 0.15%,
from about 0.01% to about 0.1%, from about 0.01% to about 0.025%,
from about 0.05% to about 5%, from about 0.05% to about 2.5%, from
about 0.05% to about 2%, from about 0.05% to about 1.5%, from about
0.05% to about 1%, from about 0.05% to about 0.5%, from about 0.05%
to about 0.25%, from about 0.05% to about 0.15%, from about 0.05%
to about 0.1%, from about 0.05% to about 0.075% from about 0.1% to
about 5%, from about 0.1% to about 2.5%, from about 0.1% to about
2%, from about 0.1% to about 1.5%, from about 0.1% to about 1%,
from about 0.1% to about 0.5%, from about 0.1% to about 0.25%, from
about 0.1% to about 0.15%, from about 0.15% to about 5%, from about
0.15% to about 2.5%, from about 0.15% to about 2%, from about 0.15%
to about 1.5%, from about 0.15% to about 1%, from about 0.15% to
about 0.5%, from about 0.15% to about 0.25% by weight of
oxymetazoline and pharmaceutically acceptable excipients. In some
embodiments, the cream may consist essentially of about 0.0075%,
about 0.01%, about 0.025%, about 0.05%, about 0.06%, about 0.075%,
about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about
0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about
0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about
0.85%, about 0.9%, about 0.95%, about 1%, about 1.05%, about 1.1%,
about 1.15%, about 1.2%, about 1.25%, about 1.3%, about 1.35%,
about 1.4%, about 1.45%, about 1.5%, about 1.55%, about 1.6%, about
1.65%, about 1.7%, about 1.75%, about 1.8%, about 1.85%, about
1.9%, about 1.95%, about 2%, about 2.05%, about 2.1%, about 2.15%,
about 2.2%, about 2.25%, about 2.3%, about 2.35%, about 2.4%, about
2.45%, about 2.5%, about 2.55%, about 2.6%, about 2.65%, about
2.7%, about 2.75%, about 2.8%, about 2.85%, about 2.9%, about
2.95%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% by
weight of oxymetazoline and pharmaceutically acceptable excipients.
In some embodiments, the cream may consist essentially of less than
about 5% by weight of oxymetazoline and pharmaceutically acceptable
excipients. In some embodiments, the cream may consist essentially
of less than about 2.5% by weight of oxymetazoline and
pharmaceutically acceptable excipients. In some embodiments, the
cream may consist essentially of less than about 2% by weight of
oxymetazoline and pharmaceutically acceptable excipients. In some
embodiments, the cream may consist essentially of less than about
1% by weight of oxymetazoline and pharmaceutically acceptable
excipients. In certain embodiments, a cream consisting essentially
of oxymetazoline, a vasoconstrictor and pharmaceutically acceptable
excipients is provided. In certain embodiments, a cream consisting
essentially of oxymetazoline, an alpha-adrenergic agonist and
pharmaceutically acceptable excipients is provided. In certain
embodiments, a cream consisting essentially of oxymetazoline, an
imidazoline alpha-adrenergic agonist and pharmaceutically
acceptable excipients is provided. In certain embodiments, a cream
consisting essentially of oxymetazoline, a non-imidazoline
alpha-adrenergic agonist and pharmaceutically acceptable excipients
is provided. In certain embodiments, a cream consisting essentially
of oxymetazoline, an alpha-1 adrenergic agonist and
pharmaceutically acceptable excipients is provided. In certain
embodiments, a cream consisting essentially of oxymetazoline, an
alpha-2 adrenergic agonist and pharmaceutically acceptable
excipients is provided. In certain embodiments, a cream consisting
essentially of oxymetazoline, a selective alpha-adrenergic agonist
and pharmaceutically acceptable excipients is provided. In certain
embodiments, a cream consisting essentially of oxymetazoline, a
non-selective alpha-adrenergic agonist and pharmaceutically
acceptable excipients is provided. In certain embodiments, a cream
consisting essentially of oxymetazoline, a selective alpha-1
adrenergic agonist and pharmaceutically acceptable excipients is
provided. In certain embodiments, a cream consisting essentially of
oxymetazoline, a selective alpha-2 adrenergic agonist and
pharmaceutically acceptable excipients is provided. In certain
embodiments, a cream consisting essentially of oxymetazoline, a
non-selective alpha-1 adrenergic agonist and pharmaceutically
acceptable excipients is provided. In certain embodiments, a cream
consisting essentially of oxymetazoline, a non-selective alpha-2
adrenergic agonist and pharmaceutically acceptable excipients is
provided.
[0064] In certain embodiments of the present invention a cream
consisting of oxymetazoline and pharmaceutically acceptable
excipients is provided. In some embodiments, the cream may consist
of from about 0.0075% to about 5%, from about 0.0075% to about
2.5%, from about 0.0075% to about 2%, from about 0.0075% to about
1.5%, from about 0.0075% to about 1%, from about 0.0075% to about
0.5%, from about 0.0075% to about 0.25%, from about 0.0075% to
about 0.15%, from about 0.0075% to about 0.1%, from about 0.0075%
to about 0.025%, from about 0.0075% to about 0.075%, from about
0.0075% to about 0.06%, from about 0.0075% to about 0.05%, from
about 0.01% to about 5%, from about 0.01% to about 2.5%, from about
0.01% to about 2%, from about 0.01% to about 1.5%, from about 0.01%
to about 1%, from about 0.01% to about 0.5%, from about 0.01% to
about 0.25%, from about 0.01% to about 0.15%, from about 0.01% to
about 0.1%, from about 0.01% to about 0.025%, from about 0.05% to
about 5%, from about 0.05% to about 2.5%, from about 0.05% to about
2%, from about 0.05% to about 1.5%, from about 0.05% to about 1%,
from about 0.05% to about 0.5%, from about 0.05% to about 0.25%,
from about 0.05% to about 0.15%, from about 0.05% to about 0.1%,
from about 0.05% to about 0.075% from about 0.1% to about 5%, from
about 0.1% to about 2.5%, from about 0.1% to about 2%, from about
0.1% to about 1.5%, from about 0.1% to about 1%, from about 0.1% to
about 0.5%, from about 0.1% to about 0.25%, from about 0.1% to
about 0.15%, from about 0.15% to about 5%, from about 0.15% to
about 2.5%, from about 0.15% to about 2%, from about 0.15% to about
1.5%, from about 0.15% to about 1%, from about 0.15% to about 0.5%,
from about 0.15% to about 0.25% by weight of oxymetazoline and
pharmaceutically acceptable excipients. In some embodiments, the
cream may consist of about 0.0075%, about 0.01%, about 0.025%,
about 0.05%, about 0.06%, about 0.075%, about 0.1%, about 0.15%,
about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about
0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about
0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about
0.95%, about 1%, about 1.05%, about 1.1%, about 1.15%, about 1.2%,
about 1.25%, about 1.3%, about 1.35%, about 1.4%, about 1.45%,
about 1.5%, about 1.55%, about 1.6%, about 1.65%, about 1.7%, about
1.75%, about 1.8%, about 1.85%, about 1.9%, about 1.95%, about 2%,
about 2.05%, about 2.1%, about 2.15%, about 2.2%, about 2.25%,
about 2.3%, about 2.35%, about 2.4%, about 2.45%, about 2.5%, about
2.55%, about 2.6%, about 2.65%, about 2.7%, about 2.75%, about
2.8%, about 2.85%, about 2.9%, about 2.95%, about 3%, about 3.5%,
about 4%, about 4.5%, or about 5% by weight of oxymetazoline and
pharmaceutically acceptable excipients. In some embodiments, the
cream may consist of less than about 5% by weight of oxymetazoline
and pharmaceutically acceptable excipients. In some embodiments,
the cream may consist of less than about 2.5% by weight of
oxymetazoline and pharmaceutically acceptable excipients. In some
embodiments, the cream may consist of less than about 2% by weight
of oxymetazoline and pharmaceutically acceptable excipients. In
some embodiments, the cream may consist of less than about 1% by
weight of oxymetazoline and pharmaceutically acceptable excipients.
In certain embodiments, a cream consisting of oxymetazoline, a
vasoconstrictor and pharmaceutically acceptable excipients is
provided. In certain embodiments, a cream consisting of
oxymetazoline, an adrenomimetic and pharmaceutically acceptable
excipients is provided. In certain embodiments, a cream consisting
of oxymetazoline, an alpha-adrenergic agonist and pharmaceutically
acceptable excipients is provided. In certain embodiments, a cream
consisting of oxymetazoline, an imidazoline alpha-adrenergic
agonist and pharmaceutically acceptable excipients is provided. In
certain embodiments, a cream consisting of oxymetazoline, a
non-imidazoline alpha-adrenergic agonist and pharmaceutically
acceptable excipients is provided. In certain embodiments, a cream
consisting of oxymetazoline, an alpha-1 adrenergic agonist and
pharmaceutically acceptable excipients is provided. In certain
embodiments, a cream consisting of oxymetazoline, an alpha-2
adrenergic agonist and pharmaceutically acceptable excipients is
provided. In certain embodiments, a cream consisting of
oxymetazoline, a selective alpha-adrenergic agonist and
pharmaceutically acceptable excipients is provided. In certain
embodiments, a cream consisting of oxymetazoline, a non-selective
alpha-adrenergic agonist and pharmaceutically acceptable excipients
is provided. In certain embodiments, a cream consisting of
oxymetazoline, a selective alpha-1 adrenergic agonist and
pharmaceutically acceptable excipients is provided. In certain
embodiments, a cream consisting of oxymetazoline, a selective
alpha-2 adrenergic agonist and pharmaceutically acceptable
excipients is provided. In certain embodiments, a cream consisting
of oxymetazoline, a non-selective alpha-1 adrenergic agonist and
pharmaceutically acceptable excipients is provided. In certain
embodiments, a cream consisting of oxymetazoline, a non-selective
alpha-2 adrenergic agonist and pharmaceutically acceptable
excipients is provided.
[0065] In some embodiments, the cream may comprise an API other
than oxymetazoline in an amount that is clinically effective. In
some embodiments, the cream may comprise from about 0.0075% to
about 50%, from about 0.0075% to about 40%, from about 0.0075% to
about 35%, from about 0.0075% to about 30%, from about 0.0075% to
about 25%, from about 0.0075% to about 20%, from about 0.0075% to
about 15%, from about 0.0075% to about 10%, from about 0.0075% to
about 5%, from about 0.0075% to about 4%, from about 0.0075% to
about 3%, from about 0.0075% to about 2.5%, from about 0.0075% to
about 2%, from about 0.0075% to about 1%, from about 0.0075% to
about 0.5%, from about 0.0075% to about 0.25%, from about 0.0075%
to about 0.15%, from about 0.0075% to about 0.1%, from about
0.0075% to about 0.075%, from about 0.0075% to about 0.06%, from
about 0.0075% to about 0.05%, from about 0.0075% to about 0.025%,
from about 0.01% to about 40%, from about 0.01% to about 35%, from
about 0.01% to about 30%, from about 0.01% to about 25%, from about
0.01% to about 20%, from about 0.01% to about 15%, from about 0.01%
to about 10%, from about 0.01% to about 5%, from about 0.01% to
about 4%, from about 0.01% to about 3%, from about 0.01% to about
2.5%, from about 0.01% to about 2%, from about 0.01% to about 1%,
from about 0.01% to about 0.5%, from about 0.01% to about 0.25%,
from about 0.01% to about 0.15%, from about 0.01% to about 0.1%,
from about 0.01% to about 0.05%, from about 0.01% to about 0.025%,
from about 0.05% to about 40%, from about 0.05% to about 35%, from
about 0.05% to about 30%, from about 0.05% to about 25%, from about
0.05% to about 20%, from about 0.05% to about 15%, from about 0.05%
to about 10%, from about 0.05% to about 5%, from about 0.05% to
about 4%, from about 0.05% to about 3%, from about 0.05% to about
2.5%, from about 0.05% to about 2%, from about 0.05% to about 1%,
from about 0.05% to about 0.5%, from about 0.05% to about 0.25%,
from about 0.05% to about 0.15%, from about 0.05% to about 0.1%,
from about 0.05% to about 0.075%, from about 0.1% to about 40%,
from about 0.1% to about 35%, from about 0.1% to about 30%, from
about 0.1% to about 25%, from about 0.1% to about 20%, from about
0.1% to about 15%, from about 0.1% to about 10%, from about 0.1% to
about 5%, from about 0.1% to about 4%, from about 0.1% to about 3%,
from about 0.1% to about 2.5%, from about 0.1% to about 2%, from
about 0.1% to about 1%, from about 0.1% to about 0.5%, from about
0.1% to about 0.25%, from about 0.1% to about 0.15%, from about
0.15% to about 40%, from about 0.15% to about 35%, from about 0.15%
to about 30%, from about 0.15% to about 25%, from about 0.15% to
about 20%, from about 0.15% to about 15%, from about 0.15% to about
10%, from about 0.15% to about 5%, from about 0.15% to about 4%,
from about 0.15% to about 3%, from about 0.15% to about 2.5%, from
about 0.15% to about 2%, from about 0.15% to about 1%, from about
0.15% to about 0.5%, from about 0.15% to about 0.25% by weight of
an API other than oxymetazoline and pharmaceutically acceptable
excipients. In some embodiments, the cream may comprise about
0.0075%, about 0.01%, about 0.025%, about 0.05%, about 0.06%, about
0.075%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about
0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about
0.75%, about 1%, about 2%, about 2.5% or about 5% by weight of an
API other than oxymetazoline and pharmaceutically acceptable
excipients.
[0066] In certain embodiments, a cream comprising an API other than
oxymetazoline, an alpha-adrenergic agonist and pharmaceutically
acceptable excipients is provided. In certain embodiments, a cream
comprising an API other than oxymetazoline, an imidazoline
alpha-adrenergic agonist and pharmaceutically acceptable excipients
is provided. In certain embodiments, a cream comprising an API
other than oxymetazoline, a non-imidazoline alpha-adrenergic
agonist and pharmaceutically acceptable excipients is provided. In
certain embodiments, a cream comprising an API other than
oxymetazoline, an alpha-1 adrenergic agonist and pharmaceutically
acceptable excipients is provided. In certain embodiments, a cream
comprising an API other than oxymetazoline, an alpha-2 adrenergic
agonist and pharmaceutically acceptable excipients is provided. In
certain embodiments, a cream comprising an API other than
oxymetazoline, a selective alpha-adrenergic agonist and
pharmaceutically acceptable excipients is provided. In certain
embodiments, a cream comprising an API other than oxymetazoline, a
non-selective alpha-adrenergic agonist and pharmaceutically
acceptable excipients is provided. In certain embodiments, a cream
comprising an API other than oxymetazoline, a selective alpha-1
adrenergic agonist and pharmaceutically acceptable excipients is
provided. In certain embodiments, a cream comprising an API other
than oxymetazoline, a selective alpha-2 adrenergic agonist and
pharmaceutically acceptable excipients is provided. In certain
embodiments, a cream comprising an API other than oxymetazoline, a
non-selective alpha-1 adrenergic agonist and pharmaceutically
acceptable excipients is provided. In certain embodiments, a cream
comprising an API other than oxymetazoline, a non-selective alpha-2
adrenergic agonist and pharmaceutically acceptable excipients is
provided.
[0067] In certain embodiments, the cream may comprise a formulation
having a buffer system. In some embodiments, the cream may comprise
a buffering agent. In some embodiments, the buffering agent may be
selected from a group consisting of citric acid, sodium citrate,
sodium lactate, ammonium hydroxide, trizma acetate, sodium borate,
acetic acid, sodium acetate, phosphoric acid, sodium phosphate,
sodium citrate dehydrate and the like. In certain embodiments, the
buffer capacity may be from about 0 mM to about 600 mM; from about
0 mM to about 600 mM; from about 5 mM to about 600 mM; from about 5
mM to about 400 mM; from about 5 mM to about 300 mM; from about 5
mM to about 200 mM; from about 200 mM to about 400 mM; about 0 mM,
about 100 mM, about 200 mM, about 300 mM, about 400 mM, about 500
mM, or about 600 mM.
[0068] In certain embodiments, the cream may comprise the
formulation of any of Trials 1-51 described herein with
oxymetazoline as the API. In other embodiments the cream may
comprise the formulation of any of Trials 1-51 with an API other
than oxymetazoline. In certain embodiments of the present
invention, the cream may comprise the formulation of any of Trials
22, 24, 25, or 35-51 as described herein. In one embodiment of the
present invention, the cream consists essentially of the
formulation of any of Trials 22, 24, 25, or 35-51 as described
herein. In one embodiment of the present invention, the cream
consists of the formulation of any of Trials 22, 24, 25, or 35-51
as described herein. In some embodiments, the cream formulation
comprises Trial 38 as a base formulation.
[0069] In certain embodiments the cream formulations are not only
"non-irritating" to the sensitive skin of patients with rosacea,
but are calming, or "soothing" to the skin. In addition, the
calming or soothing and moisturizing effect of the cream
formulation of certain embodiments herein may last for an extended
period of time. In some embodiments, the soothing effect may last
up to at least about four hours, at least about five hours, at
least about six hours, at least about seven hours, at least about
eight hours, at least about ten hours, at least about 12 hours, at
least about 15 hours, at least about 18 hours, at least about 21
hours, at least about 24 hours, or at least about 48 hours with a
single application. In some embodiments, the soothing effect may
last for from about 1 to about 48 hours; from about 1 to about 24
hours; from about 1 to about 21 hours; from about 1 to about 18
hours; from about 1 to about 16 hours; from about 1 to about 12
hours; from about 1 to about 10 hours; from about 1 to about 8
hours; from about 2 to about 824 hours; from about 2 to about 16
hours; from about 2 to about 12 hours; from about 2 to about 8
hours; from about 4 to about 24 hours; from about 4 to about 16
hours; from about 4 to about 12 hours; from about 4 to about 8
hours; from about 6 to about 24 hours; from about 6 to about 16
hours; from about 6 to about 12 hours; from about 4 to about 8
hours; from about 6 to about 8 hours; from about 2 to about 6
hours; from about 4 to about 6 hours, or combinations thereof. In
some embodiments, this soothing effect may be maintained with daily
application of the cream formulation to the skin. In some
embodiments, this soothing effect may be maintained for as long as
the cream formulation is applied to the skin daily. In some
embodiments, this soothing effect may be maintained with daily
application of the cream formulation for at least about 1 month, at
least about 2 months, at least about 3 months, at least about 4
months, at least about 5 months, at least about 6 months, at least
about 9 months, or at least about 12 months.
[0070] The cream formulation of certain embodiments is cosmetically
acceptable to both patients with rosacea, a disorder characterized
by a defect in the epidermal barrier and by normal controls.
[0071] In certain embodiments the cream formulation is a soothing,
long-lasting moisturizer that is cosmetically elegant and well
tolerated even in subjects with extremely sensitive and highly
reactive skin.
[0072] In some embodiments, the cream may include an emulsifying
agent, or emulsifier. The emulsifier can be provided to adjust the
properties of the cream, such as density, viscosity, the melting
point, and/or droplet size; and in some embodiments, the emulsifier
may increase the stability of the cream. Various emulsions suitable
for embodiments described herein and methods for preparing such
emulsions are well known in the art and are described in, for
example, Remington's Pharmaceutical Sciences, Mack Publishing Co.,
Easton, Pa., USA, which is hereby incorporated by reference in its
entirety. In some embodiments, the cream may include an emulsifier
in an amount from about 1% to about 30%, from about 1% to about
25%, from about 1% to about 20%, or from about 4% to about 12%
emulsifier. In some embodiments, the cream may include emulsifier
in an amount greater than 8%. In some embodiments, the cream may
include from about 8% to about 30% emulsifier. In some embodiments,
the cream may include from about 8% to about 25% emulsifier. In
other embodiments, the cream may include from about 8% to about 20%
emulsifier. In still other embodiments, the cream may include from
about 8% to about 10% emulsifier. If more than one emulsifier is
used, the cream may include from about 1% to about 30% of each
emulsifier, from about 2% to about 30% of each emulsifier or from
about 2% to about 25% of each emulsifier.
[0073] The creams of various embodiments may include any
emulsifiers or combination of emulsifiers. For example, in some
embodiments, the cream may be a common oil-in-water or water-in-oil
emulsion including oxymetazoline and water or one or more common
oils such as, for example, cottonseed, groundnut, corn, germ,
olive, castor, soybean, mineral, and sesame oils. In other
embodiments, the cream may include one or more emulsifiers, such
as, for example, sesquioleates such as sorbitan sesquioleate or
polyglyceryl-2-sesquioleate, ethoxylated esters of derivatives of
natural oils such as the polyethoxylated ester of hydrogenated
castor oil, silicone emulsifiers such as silicone polyols, anionic
emulsifiers, fatty acid soaps such as potassium stearate and fatty
acid sulphates like sodium cetostearyl sulphate, ethoxylated fatty
alcohols, sorbitan esters, ethoxylated sorbitan esters, ethoxylated
fatty acid esters such as ethoxylated stearates, ethoxylated mono,
di-, and triglycerides, non-ionic self-emulsifying waxes,
ethoxylated fatty acids, methylglucose esters such as
polyglycerol-3 methyl glucose distearate, and mixtures thereof. In
particular embodiments, the emulsifier may be an ethoxylated fatty
acid such as, for example, the mixture of PEG-6/PEG-32/glycol
stearate marketed under the trademark TEFOSE.TM. 63 by Gattefosse.
As used herein, TEFOSE.TM. 63 is considered an emulsifier and, in
certain embodiments described herein, shall be considered a mixture
of one or more polyethylene glycol (PEG) stearates and one or more
glycol stearates. In some embodiments, the emulsifier may comprise
a polyethylene glycol (PEG) stearate, a glycol stearate or a
mixture thereof. In some embodiments, the cream may include from
about 1% to about 30% TEFOSE.TM. 63. In some embodiments, the cream
may include from about 1% to about 20% TEFOSE.TM. 63. In other
embodiments, the cream may include from about 1% to less than about
20% TEFOSE.TM. 63. In embodiments, the cream may include from about
4% to about 12% TEFOSE.TM. 63. In some embodiments, the cream may
include greater than about 8% TEFOSE.TM. 63. In other embodiments,
the cream may include from about 8% to about 10% TEFOSE.TM.. In
still other embodiments, the cream may include from about 8% to
less than about 10% TEFOSE.TM. 63. In some embodiments, the cream
may comprise TEFOSE.TM. 63 in an amount from about 1% to about 20%.
In various embodiments, the cream may comprise TEFOSE.TM. 63 in an
amount from about 3% to about 15%, from about 5% to about 10%, from
about 7% to about 10%, about 9% or about 8%. In some embodiments
the cream may comprise about 7.1%, about 7.2%, about 7.3%, about
7.4%, about 7.5%, about 7.6%, about 7.7%, about 7.8%, about 7.9%,
about 8%, about 8.1%, about 8.2%, about 8.3%, about 8.4%, or about
8.5% by weight of TEFOSE.TM. 63. In certain embodiments, TEFOSE.TM.
63 is comprised of PEG-6 stearate, glycol stearate, and PEG-32
stearate. In embodiments, the cream comprises PEG-6 stearate,
glycol stearate, and PEG-32 stearate added as TEFOSE.TM. 63 in an
about from about 1% to about 20%, from about 3% to about 15%, from
about 5% to about 10%, from about 7% to about 10%, about 9% or
about 8%. In some embodiments, the cream comprises PEG-6 stearate,
glycol stearate and PEG-32 stearate. In embodiments, the cream may
comprise PEG-6 stearate, glycol stearate and PEG-32 stearate in a
ratio of about 63:18.5:18.5, about 75:12.5:12.5, about 50:25:25,
about 75:15:10 or ranges of such ratios. In embodiments, the cream
may comprise PEG-6 stearate, glycol stearate and PEG-32 stearate in
a combined amount of from about 1% to about 30%, from about 1% to
about 20%, from about 3% to about 15%, from about 5% to about 10%,
from about 7% to about 10%, about 9% or about 8%. In embodiments,
the cream may comprise PEG-6 stearate in an about from about 1% to
about 20% by weight, from about 1% to about 10% by weight, from
about 4% to about 10% by weight or from about 4% to about 6% by
weight. In some embodiments, the cream may comprise glycol stearate
in an amount from about 0.1% to about 10%, from about 0.1% to about
8%, from about 0.5% to about 5%, from about 0.5% to about 3%, from
about 0.5% to about 2%, or from about 0.8% to about 2%. In some
embodiments, the cream may comprise PEG-32 stearate in an amount
from about 0.1% to about 10%, from about 0.1% to about 8%, from
about 0.5% to about 5%, from about 0.5% to about 3%, from about
0.5% to about 2%, or from about 0.8% to about 2%. In some
embodiments, the cream may comprise PEG-6 may be present in an
amount of about 5% w/w; glycol stearate may be present in an amount
of about 1.5% w/w, PEG-32 stearate may be present in an amount of
about 1.5% w/w.
[0074] In some embodiments, the hydrophilic-lipophilic balance
("HLB") of the oil phase (or internal phase) of the cream may be
very closely matched with the HLB values of the blend of
emulsifiers in the cream. For example, the ingredients in the oil
phase may include HLB values of:
TABLE-US-00001 Ingredient HLB value* Medium chain triglycerides
10.0 diisopropyl adipate 9.0 oleyl alcohol 14.0 lanolin 12.0 *HLB
values are approximate and may vary by about .+-. 1 unit.
Also, as example, the blend of emulsifiers may include HLB values
of:
TABLE-US-00002 Ingredient HLB value* TEFOSE .TM. 63 9.0-10.0
cetostearyl alcohol 15.5 Macrogol (6) cetostearyl ether 10.0-12.0
Macrogol (25) cetostearyl ether 15.0-17.0 *HLB values are
approximate and may vary by about .+-. 1 unit.
[0075] In some embodiments, the cream may comprise an emulsifier
having a hydrophilic-lipophilic balance of from about 9.0 to about
17.0. In some embodiments, the hydrophilic-lipophilic balance is
determined by Griffin's method. For example, in Trial 38, the HLB
values for the oil phase and the emulsifier blend is as
follows:
TABLE-US-00003 Oil Phase Component Desired HLB Percent in Formula
Contribution Medium chain 10.0 7.0 0.70 triglycerides Diisopropyl
adipate 9.0 7.0 0.63 Oleyl alcohol 14.0 7.0 0.98 Lanolin 12.0 2.0
0.24 Oil Phase SUM 2.55 Emulsifier Blend Component HLB Value*
Percent in Formula Contribution Tefose 63 9 to 10 8.0 0.76
Cetostearyl alcohol 15.5 8.0 1.24 Macrogol (6) 10 to 12 2.0 0.22
cetostearyl ether Macrogol (25) 15 to 17 2.0 0.32 cetostearyl ether
Emulsifier Blend SUM 2.54 *For HLB value ranges, the mid value was
used to execute the calculation.
[0076] It may be understood from the above calculations that where
percentages of the oil phase ingredients are varied, physically
stable emulsions may be obtained by varying the percentages of
blend emulsifiers so that the required HLB of the oil phase remains
closely matched. In embodiments, the HLB may be matched within +/-1
HLB value, within +1-0.5 HLB value or within +/-0.1 HLB value.
[0077] Without wishing to be bound by theory, it is surprising
that, for example, in Trial 38, using four neutral to hydrophilic
emulsifiers, such as TEFOSE 63.TM. (having an HLB value from about
9.0 to about 10.0) or Macrogol (25) cetostearyl ether (having an
HLB value from about 15.0 to about 17.0), in the concentrations or
proportions described, results in a cosmetically acceptable
emulsion that is non-irritating. Non-ionic surfactants such as
those used in embodiments herein may contain irritants such as
polyethylene glycol (PEG). Such PEGylated or PEG containing
surfactants may be irritating and may cause contact dermatitis at
high levels. In some embodiments, the cream formulation may
comprise an emulsifier having an HLB value of from about 9.0 to
about 17.0 in cream embodiments described herein wherein the cream
formulation is cosmetically acceptable and non-irritating. In
embodiments, the cream formulation may be non-irritating to even
patients with extremely reactive and/or sensitive skin, such as,
but not limited to, that typically seen in patients with rosacea,
eczema, dermatitis, and other conditions of the skin characterized
by a disturbance of the epidermal barrier.
[0078] Furthermore, it is surprising that in some embodiments, the
cream may further produce a long lasting soothing effect on the
skin. The term "soothing", as used herein, means that the
formulation is moisturizing, softening, cosmetically appealing,
non-irritating or generally calming and comforting to the skin or
may decrease any erythema (or redness), if present.
[0079] Thus, in some embodiments, the cream formulation is soothing
to the skin. In some embodiments, the soothing effect of the cream
formulations of embodiments herein may be long-lasting. In some
embodiments, the soothing effect may last up to at least about four
hours, at least about five hours, at least about six hours, at
least about seven hours, at least about eight hours, at least about
ten hours, at least about 12 hours, at least about 15 hours, at
least about 18 hours, at least about 21 hours, at least about 24
hours or at least about 48 hours with a single application. In some
embodiments, the soothing effect may last for from about 1 to about
48 hours; from about 1 to about 24 hours; from about 1 to about 21
hours; from about 1 to about 18 hours; from about 1 to about 16
hours; from about 1 to about 12 hours; from about 1 to about 10
hours; from about 1 to about 8 hours; from about 2 to about 24
hours; from about 2 to about 16 hours; from about 2 to about 12
hours; from about 2 to about 8 hours; from about 4 to about 24
hours; from about 4 to about 16 hours; from about 4 to about 12
hours; from about 4 to about 8 hours; from about 6 to about 24
hours; from about 6 to about 16 hours; from about 6 to about 12
hours; from about 6 to about 8 hours; from about 2 to about 6
hours; from about 4 to about 6 hours, or combinations thereof. In
some embodiments, this soothing effect may be maintained with daily
application of the cream formulation to the skin. In some
embodiments, this soothing effect may be maintained for as long as
the cream formulation is applied to the skin daily. In some
embodiments, this soothing effect may be maintained with daily
application of the cream formulation for at least about 1 month, at
least about 2 months, at least about 3 months, at least about 4
months, at least about 5 months, at least about 6 months, at least
about 9 months, or at least about 12 months.
[0080] In some embodiments described herein, the cream formulation
is cosmetically elegant and highly stable. Without wishing to be
bound by theory, it is believed that such cosmetically elegant and
stable emulsions may restore and reinforce the epidermal barrier
function ordinarily provided by healthy stratum corneum, ceramides,
cholesterol and epidermal lipids, providing protection and
restoring hydration to the skin.
[0081] In some embodiments, the cream formulation comprises an
emulsifier in an amount of greater than about 5% and is
non-irritating. In some embodiments, the cream formulation
comprises an emulsifier in an amount of greater than about 10% and
is non-irritating. In some embodiments, the cream formulation
comprises an emulsifier in an amount of greater than about 15% and
is non-irritating. In some embodiments, the cream formulation
comprises an emulsifier in an amount of greater than about 20% and
is non-irritating. In some embodiments, the cream formulation
comprises an emulsifier in an amount of greater than about 25% and
is non-irritating. In some embodiments, the cream formulation
comprises an emulsifier in an amount of greater than about 30% and
is non-irritating. In some embodiments, the cream formulation
comprises propylene glycol and is non-irritating. In some
embodiments, the cream formulation comprises propylene glycol in an
amount of greater than about 4% and is non-irritating.
[0082] The creams of various embodiments may include any number of
additional components such as, for example, preservatives, emulsion
stabilizers, pH adjusters, chelating agents, viscosity modifiers,
antioxidants, surfactants, emollients, opacifying agents, skin
conditioners, buffers, fragrances and combinations thereof. In some
embodiments, such additional components may provide a dual purpose.
For example, certain surfactants may also act as emulsifiers,
certain emollients may also act as opacifying agents, and certain
buffering agents may also act as chelating agents.
[0083] In certain embodiments of the invention, the formulation may
further comprise a topically active pharmaceutical or cosmetic
agent other than oxymetazoline, destined in part, to have a
synergistic effect or a therapeutic effect associated with another
skin complaint, condition or affliction. Examples of these agents
include: anti-rosacea agents such as metronidazole, precipitated
sulfur, sodium sulfacetamide, or azelaic acid; antibacterial agents
(antibiotics) such as clindamycin phosphate, erythromycin, or
antibiotics from the tetracycline family; antimycobacterial agents
such as dapsone; other antiacne agents such as retinoids, or
benzoyl peroxide; antiparasitic agents such as metronidazole,
permethrin, crotamiton, thiabendazole, ivermectin or pyrethroids;
antifungal agents such as compounds of the imidazole family such as
miconazole, clotrimazole, econazole, ketoconazole, or salts
thereof, polyene compounds such as amphotericin B, compounds of the
allylamine family such as terbinafine; steroidal anti-inflammatory
agents such as hydrocortisone triamcinolone, fluocinonide,
betamethasone valerate or clobetasol propionate, or non-steroidal
anti-inflammatory agents such as ibuprofen and salts thereof,
naproxen and salts thereof, or acetaminophen; anesthetic agents
such as the "amide" and "ester" anesthetics, including, but not
limited to, lidocaine, prilocaine, tetracaine, hydrochloride and
derivatives thereof; antipruriginous agents such as thenaldine,
trimeprazine, or pramoxine; antiviral agents such as acyclovir;
keratolytic agents such as alpha- and beta-hydroxy acids such as
glycolic acid or salicylic acid, or urea; anti-free radical agents
(antioxidants) such as Vitamin E (alpha tocopherol) and its
derivatives, Vitamin C (ascorbic acid), Vitamin A (retinol) and its
derivatives, and superoxide dismutases; antiseborrheic agents such
as zinc pyrithione and selenium sulfide; antihistamines such as
cyproheptadine or hydroxyzine; tricyclic antidepressants such as
doxepin hydrochloride; antipsoriatic agents such as calcipotriene,
anthralines, coal tar; immune modulating agents such as imiquimod,
or the calcineurin inhibitors pimecrolimus and tacrolimus, and
chemotherapeutic agents such as 5-fluorouracil, nitrogen mustard,
carmustine, bexarotene, mitomycin-c or combinations thereof.
[0084] The topically active pharmaceutical or cosmetic agent may
include, without limitation, one or more of hydroxyacids,
polyhydroxy acids, polyhydroxy lactones, ketoacids and related
compounds; phenyl alpha acyloxyalkanoic acids and derivatives;
N-acyl-aldosamines, N-acylamino acids and related N-acyl compounds;
N-(phosphonoalkyl)-aminocarbohydrates, N-(phosphonoalkyl)-amino
acids and their related N-(phosphonoalkyl)-compounds; local
analgesics and anesthetics; anti-acne agents; antibacterial agents;
anti-yeast agents; anti-fungal agents; anti-viral agents;
anti-infective agents; anti-dandruff agents; anti-dermatitis
agents; anti-eczema agents; anti-histamine agents; anti-pruritic
agents; anti-emetics; anti-motion sickness agents;
anti-inflammatory agents; anti-hyperkeratotic agents;
antiperspirants; anti-psoriatic agents; anti-rosacea agents;
antiseborrheic agents; hair conditioners and hair treatment agents;
anti-aging and anti-wrinkle agents; anti-anxiety agents;
anti-convulsant agents; anti-depressant agents; sunblock and
sunscreen agents; skin lightening agents; depigmenting agents;
astringents; cleansing agents; corn, callus and wart removing
agents; skin plumping agents; skin volumizing agents; skin firming
agents; matrix metalloproteinase (MMP) inhibitors; topical
cardiovascular agents; wound-healing agents; gum disease or oral
care agents; amino acids; peptides; dipeptides; tripeptides;
glutathione and its derivatives; oligopeptides; polypeptides;
carbohydrates; aminocarbohydrates; vitamins; corticosteroids;
tanning agents; hormones, retinoids or combinations thereof.
[0085] In some embodiments, the topically active pharmaceutical or
cosmetic agent may include, without limitation, abacavir,
acebutolol, acetaminophen, acetaminosalol, acetazolamide,
acetohydroxamic acid, acetylsalicylic acid, N-acylglutathione ethyl
ester and other esters, N-acyl proline ethyl ester and other
esters, acitretin, aclovate, acrivastine, actiq, acyclovir,
adalimumab, adapalene, adefovir dipivoxil, adenosine, albuterol,
alefacept, alfuzosin, allopurinol, alloxanthine, almotriptan,
alprazolam, alprenolol, aluminum acetate, aluminum chloride,
aluminum chlorohydroxide, aluminum hydroxide, amantadine,
amiloride, aminacrine, p-aminobenzoic acid, aminocaproic acid,
aminolevulinic acid, aminosalicylic acid, amiodarone,
amitriptyline, amlodipine, amocarzine, amodiaquin, amorolfine,
amoxapine, amphetamine, ampicillin, anagrelide, anastrozole,
anthralin, apomorphine, aprepitant, arbutin, aripiprazole, ascorbic
acid, ascorbyl palmitate, atazanavir, atenolol, atomoxetine,
atropine, azathioprine, azelaic acid, azelastine, azithromycin,
bacitracin, beclomethasone dipropionate, bemegride, benazepril,
benzilic acid, bendroflumethiazide, benzocaine, benzonatate,
benzophenone, benzoyl peroxide, benztropine, bepridil,
betamethasone dipropionate, betamethasone valerate, botulinum
toxin, brimonidine, brompheniramine, bupivacaine, buprenorphine,
bupropion, burimamide, butenafine, butoconazole, cabergoline,
caffeic acid, caffeine, calcipotriene, camphor, candesartan
cilexetil, capsaicin, carbamazepine, carbamide peroxide, cefditoren
pivoxil, cefepime, cefpodoxime proxetil, celecoxib, cetirizine,
cevimeline, chitosan, chlordiazepoxide, chlorhexidine, chloroquine,
chlorothiazide, chloroxylenol, chlorpheniramine, chlorpromazine,
chlorpropamide, ciclopirox, cilostazol, cimetidine, cinacalcet,
ciprofloxacin, citalopram, citric acid, cladribine, clarithromycin,
clemastine, clindamycin, clioquinol, clobetasol propionate,
clocortolone pivalate, clomiphene, clonidine, clopidogrel,
clotrimazole, clozapine, cocaine, codeine, cromolyn, crotamiton,
cyclizine, cyclobenzaprine, cycloserine, cytarabine, dacarbazine,
dalfopristin, dapsone, daptomycin, daunorubicin, deferoxamine,
dehydroepiandrosterone, delavirdine, desipramine, desloratadine,
desmopressin, desoximetasone, dexamethasone, dexmedetomidine,
dexmethylphenidate, dexrazoxane, dextroamphetamine, diazepam,
diclofenac, dicyclomine, didanosine, dihydrocodeine,
dihydromorphine, diltiazem, 6,8-dimercaptooctanoic acid
(dihydrolipoic acid), diphenhydramine, diphenoxylate, dipyridamole,
disopyramide, dobutamine, dofetilide, dolasetron, donepezil, dopa
esters, dopamide, dopamine, dorzolamide, doxepin, doxorubicin,
doxycycline, doxylamine, doxypin, duloxetine, dyclonine, econazole,
efalizumab, eflornithine, eletriptan, emtricitabine, enalapril,
ephedrine, epinephrine, epinine, epirubicin, eptifibatide,
ergotamine, erythromycin, escitalopram, esmolol, esomeprazole,
estazolam, estradiol, etanercept, ethacrynic acid, ethinyl
estradiol, ethyl pyruvate, etidocaine, etomidate, famciclovir,
famotidine, felodipine, fentanyl, ferulic acid, fexofenadine,
finasteride, flecamide, fluconazole, flucytosine, fluocinolone
acetonide, fluocinonide, 5-fluorouracil, fluoxetine, fluphenazine,
flurazepam, fluticasone propionate, fluvoxamine, formoterol,
furosemide, galactarolactone, galactonic acid, galactonolactone,
galantamine, gatifloxacin, gefitinib, gemcitabine, gemifloxacin,
glucarolactone, gluconic acid, gluconolactone, glucuronic acid,
glucuronolactone, glycolic acid, griseofulvin, guaifenesin,
guanethidine, N-guanylhistamine, haloperidol, haloprogin,
hexylresorcinol, homatropine, homosalate, hydralazine,
hydrochlorothiazide, hydrocortisone, hydrocortisone 21-acetate,
hydrocortisone 17-butyrate, hydrocortisone 17-valerate, hydrogen
peroxide, hydromorphone, hydroquinone, hydroquinone monoether,
hydroxyzine, hyoscyamine, hypoxanthine, ibuprofen, ichthammol,
idarubicin, imatinib, imipramine, imiquimod, indinavir,
indomethacin, infliximab, irbesartan, irinotecan, isoetharine,
isoproterenol, itraconazole, kanamycin, ketamine, ketanserin,
ketoconazole, ketoprofen, ketotifen, kojic acid, labetalol, lactic
acid, lactobionic acid, lamivudine, lamotrigine, lansoprazole,
letrozole, leuprolide, levalbuterol, levofloxacin, lidocaine,
linezolid, lobeline, loratadine, loperamide, losartan, loxapine,
lysergic diethylamide, mafenide, malic acid, maltobionic acid,
mandelic acid, maprotiline, mebendazole, mecamylamine, meclizine,
meclocycline, memantine, menthol, meperidine, mepivacaine,
mequinol, mercaptopurine, mescaline, metanephrine, metaproterenol,
metaraminol, metformin, methadone, methamphetamine, methotrexate,
methoxamine, methyldopa esters, methyldopamide,
3,4-methylenedioxymethamphetamine, methyllactic acid, methyl
nicotinate, methylphenidate, methyl salicylate, metiamide,
metolazone, metoprolol, metronidazole, mexiletine, miconazole,
midazolam, midodrine, miglustat, minocycline, minoxidil,
mirtazapine, mitoxantrone, moexiprilat, molindone, monobenzone,
morphine, moxifloxacin, moxonidine, mupirocin, nadolol, naftifine,
nalbuphine, nalmefene, naloxone, naproxen, nefazodone, nelfinavir,
neomycin, nevirapine, nicardipine, nicotine, nifedipine,
nimodipine, nisoldipine, nitrofurantoin, nizatidine,
norepinephrine, nystatin, octopamine, octreotide, octyl
methoxycinnamate, octyl salicylate, ofloxacin, olanzapine,
olmesartan medoxomil, olopatadine, omeprazole, ondansetron,
oxiconazole, oxotremorine, oxybenzone, oxybutynin, oxycodone,
oxymetazoline, padimate O, palonosetron, pantothenic acid, pantoyl
lactone, paroxetine, pemoline, penciclovir, penicillamine,
penicillins, pentazocine, pentobarbital, pentostatin,
pentoxifylline, pergolide, perindopril, permethrin, phencyclidine,
phenelzine, pheniramine, phenmetrazine, phenobarbital, phenol,
phenoxybenzamine, phentolamine, phenylephrine, phenylpropanolamine,
phenyloin, N-(phosphonomethyl)-glycine,
N-(phosphonomethyl)-creatine, N-(phosphonomethyl)-tyramine,
physostigmine, pilocarpine, pimecrolimus, pimozide, pindolol,
pioglitazone, pipamazine, piperonyl butoxide, pirenzepine,
podofilox, podophyllin, povidone iodine, pramipexole, pramoxine,
prazosin, prednisone, prenalterol, prilocalne, procainamide,
procaine, procarbazine, praline, promazine, promethazine,
promethazine propionate, propafenone, propoxyphene, propranolol,
propylthiouracil, protriptyline, pseudoephedrine, pyrethrin,
pyrilamine, pyrimethamine, quetiapine, quinapril, quinethazone,
quinidine, quinupristin, rabeprazole, reserpine, resorcinol,
retinal, 13-cis retinoic acid, retinoic acid, retinol, retinyl
acetate, retinyl palmitate, ribavirin, ribonic acid, ribonolactone,
rifampin, rifapentine, rifaximin, riluzole, rimantadine, risedronic
acid, risperidone, ritodrine, rivastigmine, rizatriptan,
ropinirole, ropivacaine, salicylamide, salicylic acid, salmeterol,
scopolamine, selegiline, selenium sulfide, serotonin,
sertaconazole, sertindole, sertraline, shale tar, sibutramine,
sildenafil, sotalol, streptomycin, strychnine, sulconazole,
sulfacetamide, sulfabenz, sulfabenzamide, sulfabromomethazine,
sulfacetamide (sodium sulfacetamide), sulfachlorpyridazine,
sulfacytine, sulfadiazine, sulfadimethoxine, sulfadoxine,
sulfaguanole, sulfalene, sulfamethizole, sulfamethoxazole,
sulfanilamide, sulfapyrazine, sulfapyridine, sulfasalazine,
sulfasomizole, sulfathiazole, sulfisoxazole, sulfur, tacrolimus,
tadalafil, tamsulosin, tartaric acid, tazarotene, tegaserol,
telithromycin, telmisartan, temozolomide, tenofovir disoproxil,
terazosin, terbinafine, terbutaline, terconazole, terfenadine,
tetracaine, tetracycline, tetrahydrozoline, thalidomide,
theobromine, theophylline, thiabendazole, thioctic acid (lipoic
acid), thioridazine, thiothixene, thymol, tiagabine, timolol,
tinidazole, tioconazole, tirofiban, tizanidine, tobramycin,
tocamide, tolazoline, tolbutamide, tolnaftate, tolterodine,
tramadol, tranylcypromine, trazodone, triamcinolone acetonide,
triamcinolone diacetate, triamcinolone hexacetonide, triamterene,
triazolam, triclosan, triflupromazine, trimethoprim, trimipramine,
tripelennamine, triprolidine, tromethamine, tropic acid, tyramine,
undecylenic acid, urea, urocanic acid, ursodiol, vardenafil,
venlafaxine, verapamil, vitamin E acetate, voriconazole, warfarin,
wood tar, xanthine, zafirlukast, zaleplon, zinc pyrithione,
ziprasidone, zolmitriptan, zolpidem or combinations thereof.
[0086] Embodiments are not limited by the number or type of
preservatives used in the creams described herein. For example,
preservatives useful in embodiments may include, but are not
limited to, pentylene glycol, ethylene diamine tetra acetate (EDTA)
and its salts, chlorhexidine and its diacetate, dihydrochloride,
digluconate derivatives, 1,1,1-trichloro-2-methyl-2-propanol,
parachlorometaxylenol, polyhexamethylenebiguanide hydrochloride,
dehydroacetic acid, diazolidinyl urea, 2,4-dichlorobenzyl alcohol,
4,4-dimethyl-1,3-oxazolidine, formaldehyde, glutaraldehyde,
dimethylidantoin, imidazolidinyl urea,
5-chloro-2-methyl-4-isothiazolin-3-one, ortho-phenylphenol, benzyl
alcohol, benzoic acid and its salts, 4-hydroxybenzoic acid and its
methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-esters
(parabens), methylparaben, propylparaben, isopropylparabens,
isobutylparabens, butylparabens, ethylparaben, trichlosan,
2-phenoxyethanol, phenyl mercuric acetate, quaternium-15,
methylsalicylate, salicylic acid and its salts, sorbic acid and its
salts, iodopropanyl butylcarbamate, calcium sorbate, zinc
pyrithione, 5-bromo-Snitro-1,3-dioxane,
2-bromo-2-nitropropane-1,3-diol, sulfites, bisulfites, and
benzalkonium chloride, phenoxyethanol, 2-phenoxyethanol,
chloroxylenol, diazolidinyl urea, and combinations thereof. In
embodiments, the cream may include any preservative, including, but
not limited to. those listed above or a combination thereof. In
certain embodiments, the cream may include a combination of
methylparaben, propylparaben, and 2-phenoxyethanol.
[0087] Preservatives may be provided in any concentration known in
the art. For example in some embodiments, the cream may include
from about 0.01% to about 3% by weight of any one preservative, and
in other embodiments, the cream may include from about 0.05% to
about 1.2% by weight of any one preservative. Thus, in creams that
include more than one preservative each preservative may be
provided at about 0.01% to about 3% by weight or from about 0.05%
to about 1.2% by weight. In some embodiments the cream may comprise
each preservative in an amount of about 0.05%, about 0.1%, about
0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about
0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about
0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about
0.9%, about 0.95%, or about 1% by weight.
[0088] The creams of various embodiments may include any chelating
agent or combination of chelating agents. Examples of the chelating
agents useful in various embodiments include, but are not limited
to, alanine, sodium polyphosphate, sodium metaphosphate, citric
acid, phosphoric acid, tartaric acid, ethylenediamine tetra acetic
acid (Edetate, EDTA) and derivatives and salts thereof,
dihydroxyethyl glycine, and mixtures thereof. In particular
embodiments, the chelating agent may be EDTA or edetate disodium,
dihydrate.
[0089] The chelating agents may be provided in any effective
amount. For example, in some embodiments, the cream may include
from about 0.001% to about 2% by weight chelating agent, and in
other embodiments, the cream may include from about 0.05% to about
1% by weight chelating agent. In some embodiments the cream may
comprise about 0.001%, about 0.002%, about 0.003%, about 0.004%,
about 0.005%, about 0.006%, about 0.007%, about 0.008%, about
0.009%, about 0.01%, about 0.011%, about 0.012%, about 0.013%,
about 0.014%, about 0.015%, about 0.016%, about 0.017%, about
0.018%, about 0.019%, about 0.02%, about 0.025%, about 0.03%, about
0.035%, about 0.04%, about 0.045%, or about 0.05% by weight
chelating agent.
[0090] In some embodiments, the cream may include one or more
viscosity modifiers. The viscosity modifier of such embodiments may
generally include a high molecular weight compound such as, for
example, carboxyvinyl polymer, carboxymethyl cellulose, polyvinyl
pyrrolidone, hydroxyethyl cellulose, methyl cellulose, natural gum
such as gelatin and tragacanth gum, and various alcohols such as
polyvinyl alcohol. In other embodiments, the viscosity modifier may
include ethanol or isopropyl alcohol. In some embodiments, the
viscosity modifier may be a high molecular weight saturated and
unsaturated fatty alcohol such as, but are not limited to,
carbitol, lauryl alcohol, myristyl alcohol, cetyl alcohol, isocetyl
alcohol, stearyl alcohol, isostearyl alcohol, hydroxystearyl
alcohol, oleyl alcohol, ricinoleyl alcohol, behenyl alcohol, erucyl
alcohol, 2-octyldodecanyl alcohol, cetearyl alcohol, lanolin
alcohol, and the like, and in certain embodiments, the viscosity
modifier may be oleyl alcohol.
[0091] The viscosity modifier may be provided in any amount
necessary to create a cream that fits within the viscosity
described above, and in certain embodiments, the cream may include
from about 0.1% to about 30% by weight viscosity modifier. In some
embodiments, the cream may include from about 0.5% to about 20% by
weight viscosity modifier. In some embodiments, the cream may
include from about 0.5% to about 10% by weight viscosity modifier.
In some embodiments, the cream may include a viscosity modifier in
an amount from about 2% to about 10% by weight. In some embodiments
the cream may comprise about 2%, about 2.5%, about 3%, about 3.5%,
about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%,
about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%,
or about 10% by weight viscosity modifier.
[0092] The cream of certain embodiments may include one or more
antioxidants. Numerous antioxidants are known in the art, and any
such antioxidant may be used to prepare the oxymetazoline creams
described herein. Examples of suitable antioxidants include, but
are not limited to, amino acids such as glycine, histidine,
tyrosine, trytophan and derivatives thereof, imidazoles such as
urocanic acid and derivatives thereof, peptides, such as
D,L-carnosine, D-carnosine, L-carnosine and derivatives thereof
such as anserine, carotinoids, carotenes such as .alpha.-carotone,
.beta.-carotene, lycopene, and derivatives thereof, chlorogenic
acid and derivatives thereof, lipoic acid and derivatives thereof
such as dihydrlipoic acid, aurothioglycose, propylthiouracil and
other thiols such as thioredoxin, glutathione, cysteine, cystine,
cystamine and glycosyl, N-acetyl, methyl, ethyl, propyl, amyl,
butyl, lauryl, palmitoyl, oleyl, .alpha.-linoleyl, cholesteryl and
glyceryl esters and salts thereof, dilauryl thiodipropionate,
distearyl thiodipropionate, thiodipropionic acid and derivatives
thereof such as esters, ethers, peptides, lipids, nucleotides,
nucleosides, and salts, sulfoximine compounds such as buthionine
sulfoximines, homocysteine sulfoximine, buthionine sulfones,
penta-, hexa-, hepta-thionine sulfoximine, unsaturated fatty acids
and derivatives thereof such as .alpha.-linolenic acid, linoleic
acid, oleic acid, folic acid and derivatives thereof, ubiquinone
and ubiquinol and derivatives thereof, vitamin C and derivatives
there of such as ascorbyl palmitate, magnesium ascorbyl phosphate,
ascorbyl acetate, tocopherals and derivatives such as vitamin E
acetate, vitamin A and derivatives such as vitamin A palmitate,
vitamin B and derivatives thereof, coniferyl benzoate of benzoin
resin, rutinic acid and derivatives thereof, .alpha.-glycosylrutin,
ferulic acid, furfurylidene glucitol, carnosine, butyl
hydroxytoluene, trihydroxy-butyrophenone, uric acid and derivatives
thereof, mannose and derivatives thereof, superoxide dismutase,
zinc and derivatives thereof such as ZnO, ZnSO.sub.4, selenium and
derivatives thereof such as selenium methionine, stilbene and
derivatives thereof such as stilbene oxide, trans-stilbene oxide
and the like. In particular exemplary embodiments, the one or more
antioxidants may include vitamin B, nordihydroguaiaretic acid,
butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),
propyl gallate, erythorbate acid, sodium erythorbate, ascorbir
palmitate, and ascorbir stearate. butyl hydroxyanisole, and gallic
esters, and in some embodiments, the one or more antioxidants may
include BHT.
[0093] The one or more antioxidants may be provided in any suitable
amount. For example in some embodiments, one or more antioxidants
may be from about 0.001% to about 3% by weight of the cream, and in
other embodiments, the one or more antioxidants may be from about
0.01% to about 1% by weight of the cream or from about 0.01% to
about 0.50% by weight of the cream. In some embodiments the cream
may comprise about 0.01%, about 0.015%, about 0.02%, about 0.025%,
about 0.03%, about 0.035%, about 0.04%, about 0.045%, about 0.05%,
about 0.055%, about 0.06%, about 0.065%, about 0.07%, about 0.075%,
about 0.08%, about 0.085%, about 0.09%, about 0.095%, or about 0.1%
by weight antioxidant.
[0094] In some embodiments, oxymetazoline creams described herein
may include one or more surfactants. Such embodiments are not
limited by type of surfactant used; for example, in some
embodiments, the one or more surfactants may be anionic surfactants
such as alkyl sulfates, alkylether sulfates, alkylsulfonates,
alkylaryl sulfonates, alkyl succinates, alkyl sulfosuccinates,
N-alkoylsarcosinates, acyl taurates, acyl isethionates, alkyl
phosphates, alkyl ether phosphates, alkyl ether carboxylates,
.alpha.-olefinsulfonates, and the alkali metal and alkaline earth
metal salts and ammonium and triethanolamine salts thereof. Such
alkyl ether sulfates, alkyl ether phosphates and alkyl ether
carboxylates can have between 1 and 10 ethylene oxide or propylene
oxide units, and in some embodiments, 1 to 3 ethylene oxide units,
per molecule. More specific examples include, but are not limited
to, sodium lauryl sulfate, ammonium lauryl sulfate, sodium lauryl
ether sulfate, ammonium lauryl ether sulfate, sodium lauryl
sarcosinate, sodium oleyl succinate, ammonium lauryl
sulfosuccinate, sodium dodecylbenzene sulfonate, triethanolamine
dodecylbenzenesulfonate. In other embodiments, the one or more
surfactants may be amphoteric surfactants such as, for example,
alkylbetaines, alkylamidopropylbetaines, alkylsulfobetaines,
alkylglycinates, alkylcarboxyglycinates, alkylamphoacetates or
.alpha.-propionates, alkylamphodiacetates or .alpha.-dipropionates,
and more specifically, cocodimethylsulfopropylbetaine, lauryl
betaine, cocamidopropylbetaine or sodium cocamphopropionate.
[0095] In certain embodiments, the one or more surfactants may be
non-ionic surfactants such as, for example, the reaction products
of aliphatic alcohols or alkylphenols having 6 to 20 carbon atoms
in a linear or branched alkyl chain with ethylene oxide and/or
propylene oxide where the alkylene oxide may be from about 6 moles
to about 60 moles per mole of alcohol. In particular embodiments,
non-ionic surfactants may include alkylamine oxides, mono- and
dialkylalkanolamides, fatty acid esters of polyethylenenglycols,
ethoxylated fatty acids amides, saturated fatty acid alcohols
reacted with ethylene oxide, alkyl polyglycosides, and sorbitan
ether esters, and in some embodiments, the non-ionic surfactant may
be ceteareth-2, ceteareth-3, ceteareth-4, ceteareth-5, ceteareth-6,
ceteareth-7, ceteareth-8, ceteareth-9, ceteareth-10, ceteareth-11,
ceteareth-12, ceteareth-13, ceteareth-14, ceteareth-15,
ceteareth-16, ceteareth-17, ceteareth-18, ceteareth-20,
ceteareth-22, ceteareth-23, ceteareth-24, ceteareth-25,
ceteareth-27, ceteareth-28, ceteareth-29, ceteareth-30,
ceteareth-33, ceteareth-34, ceteareth-40, ceteareth-50,
ceteareth-55, ceteareth-60, ceteareth-80, ceteareth-100, and the
like or combinations thereof, or one or more ceteareth in
combination with a fatty acid alcohol such as stearyl alcohol,
oleyl alcohol, linoleyl alcohol, arachidyl alcohol, cetyl alcohol,
and the like. In certain embodiments, the one or more surfactants
may be a commercially available ceteareth containing surfactants
such as CREMOPHOR EL.RTM., CREMOPHOR A-6.RTM., CREMPHOR A-25.RTM.
or combinations thereof.
[0096] The one or more surfactants of various embodiments may make
up from about 0.1% to about 50% by weight of the cream and in some
embodiments, from about 0.5% to about 20% by weight of the cream.
In embodiments in which more than one surfactant is provided in the
oxymetazoline cream, each surfactant may be from about 0.5% to
about 12% by weight of the cream, and in some embodiments, each
surfactant of the oxymetazoline cream containing two or more
surfactants may be from about 0.5% to about 5% by weight of the
cream. In some embodiments the cream may comprise each surfactant
in an amount of about 0.5%, about 1%, about 1.5%, about 2%, about
2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% by
weight.
[0097] In some embodiments, the oxymetazoline cream may include one
or more emollients. Generally, emollients function enable the cream
and by extension the active agent to remain on the skin surface or
in the stratum corneum. Emollients are well known in the art and
are listed, for example, the International Cosmetic Ingredient
Dictionary, Eighth Edition, 2000, which is hereby incorporated by
reference in its entirety. In certain embodiments, the one or more
emollient may be fatty esters, fatty alcohols, or combinations
thereof including, but not limited to, diisopropyl adipate, oleyl
alcohol, lanolin, isopropyl myristate, isopropyl palmitate,
caprylic/capric triglycerides, cetyl lactate, cetyl palmitate,
hydrogenated castor oil, glyceryl esters, hydroxycetyl isostearate,
hydroxy cetyl phosphate, isopropyl isostearate, isostearyl
isostearate, diisopropyl sebacate, polyoxypropylene (5)
poloxyethylene (20) cetyl ether (PPG-5-Ceteth-20), 2-ethylhexyl
isononoate, 2-ethylhexyl stearate, C.sub.12 to C.sub.16 fatty
alcohol, C.sub.12 to C.sub.16 fatty alcohol lactate, isopropyl
lanolate, 2-ethylhexyl salicylate, and mixtures thereof. In some
embodiments, the one or more emollients may be a combination of
fatty alcohols. In certain embodiments, the one or more emollients
may be 1-hexadecanol, acetylated lanolin, behenocyl dimethicone,
C.sub.12-15 alkyl benzoate, cetearyl octanoate, cocoglycerides,
dicaprylate/dicaprate dimethicone copolyol, dimethiconol, dioctyl
adipate, glyceryl stearate, isocetyl alcohol, isohexadecane,
isopentylcyclohexanone, isopropyl palmitate, lauryl lactate,
mineral oil, methoxy peg-22/dodecyl glycol copolymer, myristyl
lactate, ocryldodecyl neopentanoate, octyl cocoate, octyl
palmitate, octyl stearate, octyldodecyl neopentanoate,
polyglyceryl-4 isosterate, polyoxyl 40 stearate, polyoxymethylene
urea, potassium sorbate, propylene glycol, propylene glycol
isoceth-3 acetate, and propylene glycol myristyl ether acetate.
[0098] The emollient may be provided in any suitable amount. For
example, in some embodiments, the one or more emollient may be from
about 1% to about 50% by weight of the cream, and in other
embodiments, the emollient may be from about 2% to about 7% by
weight of the oxymetazoline cream. In some embodiments the cream
may comprise each emollient in an amount of about 1%, about 1.5%,
about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%,
about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%,
or about 8% by weight. As indicated above, the emollient may also
be provided in an amount sufficient to provide a ratio of
emulsifier to emollient of from about 0.002:1 to about 50:1. In
some embodiments, the ratio of emulsifier to emollient is from
about 0.1:1 to about 1.8:1, from about 0.2:1 to about 1.8:1, from
about 0.3:1 to about 1.8:1, from about 0.4:1 to about 1.8:1, from
about 0.5:1 to about 1.8:1, from about 0.7:1 to about 1.8:1, about
0.3:1 to about 1.5:1, about 0.3:1 to about 1.285:1, about 0.3 to
about 1:1, about 0.4:1 to about 1.5:1, about 0.4:1 to about
1.285:1, about 0.4:1 to about 1:1, about 0.7:1 to about 1.8:1,
about 0.7:1 to about 1.5:1, about 0.7:1 to about 1.285:1, about
0.7:1 to about 1:1, about 0.73:1 to about 1.8:1, about 0.73:1 to
about 1.5:1, about 0.73:1 to about 1.285:1, about 0.73:1 to about
1:1, about 0.87:1 to about 1.5:1, about 0.87:1 to about 1.285:1,
about 0.87:1 to about 1:1, about 1:1 to about 1.285:1, about 1:1 to
about 1.25:1, about 1:1 to about 1.2:1, about 1:1, about 0.87:1,
about 0.73:1, or about 0.7:1, or combinations thereof. In such
embodiments, the percentage by weight of emollient in the cream
will fall within these ranges. In some embodiments, the emulsifier
may comprise TEFOSE.TM. 63, cetostearyl alcohol macrogol (6)
cetostearyl ether, macrogol(25) cetostearyl ether or combinations
thereof. In some embodiments, the cream may comprise an emulsifier
of low molecular weight polyethylene glycol(s) or its esters (e.g.
PEG-32 stearate, PEG-6 stearate). In some embodiments, the ratio of
TEFOSE.TM. 63 to cetostearyl alcohol is from about 0.7:1 to about
1.8:1, about 0.7:1 to about 1.5:1, about 0.7:1 to about 1.285:1,
about 0.7 to about 1:1, about 0.73:1 to about 1.8:1, about 0.73:1
to about 1.5:1, about 0.73:1 to about 1.285:1, about 0.73:1 to
about 1:1, about 0.87:1 to about 1.5:1, about 0.87:1 to about
1.285:1, about 0.87:1 to about 1:1, about 1:1 to about 1.285:1,
about 1:1 to about 1.25:1, about 1:1 to about 1.2:1, about 1:1,
about 0.87:1, about 0.73:1, or about 0.7:1 or combinations thereof.
In some embodiments, the emollient may comprise triglycerides
medium chain, diisopropyl adipate, oleyl alcohol, lanolin or
combinations thereof.
[0099] Without wishing to be bound by theory, from the standpoint
of emulsion stability, if an ester is not properly emulsified, the
emulsion will exhibit "creaming": separation of the non-polar phase
to the top of the cream and aqueous layer underneath. It is
believed that the embodiments described herein contain no "true"
oil phase and the medium chain triglycerides, diisopropyl adipate
and oleyl alcohol are not "true" oils, thus forming an
oil-phase-less emulsion. This may make the cream formulation of
embodiments herein extremely difficult to emulsify and it may
explain why there are so many varied emulsifiers.
[0100] In certain embodiments, the oxymetazoline cream may include
one or more opacifying agents. Opacifying agents provide color or
whiteness to a composition that may otherwise be clear of would
have an undesirable color. In some embodiments, components such as,
for example, emollients, surfactants, and/or emulsifiers may
provide sufficient opaqueness. In other embodiments, one or more
additional opacifying agents may be provided to the cream.
Opacifying agents are well known in the art and include, but are
not limited to, higher fatty alcohols such as cetyl, stearyl,
cetostearyl alcohol, arachidyl and behenyl alcohols, solid esters
such as cetyl palmitate, glyceryl laurate, stearamide MEA-stearate,
high molecular weight fatty amides and alkanolamides and various
fatty acid derivatives such as propylene glycol and polyethylene
glycol esters. In other embodiments, opacifying agents may include
inorganic materials such as, for example, magnesium aluminum
silicate, zinc oxide, titanium dioxide or other sunblocking
agents.
[0101] In embodiments in which an opacifying agent is used, the
opacifying agent may be provided in any amount necessary to provide
the desired opaqueness. In such embodiments, the opacifying agent
may generally be from about 0.01% to about 20% by weight of the
cream, and in some embodiments, the opacifying agent may be from
about 0.01% to about 5% or about 0.02% to about 2% by weight of the
cream. In some embodiments the cream may comprise about 2%, about
2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about
5.5%, about 6%, about 6.5%, about 7%, about 7.1%, about 7.2%, about
7.3%, about 7.4%, about 7.5%, about 7.6%, about 7.7%, about 7.8%,
about 7.9%, about 8%, about 8.1%, about 8.2%, about 8.3%, about
8.4%, about 8.5%, about 8.6%, about 8.7%, about 8.8%, about 8.9%,
about 9%, about 9.5%, about 10%, about 10.5%, about 11%, about
11.5%, or about 12% by weight opacifying agent.
[0102] In some embodiments, the oxymetazoline cream may include one
or more skin conditioners. Skin conditioners are components that
may generally improve moisture retention in the skin, retard
evaporation of water from the skin, and cause
plasticization/softening of the skin. Common skin conditioners
include, for example, mineral oil, petrolatum, aliphatic alcohols,
lanolin and its derivatives, fatty acids, glycol fatty acids,
sugars, glycerin, propylene glycol, sorbitols, and polyethylene
glycols, vitamins and herbal derivatives. Additional skin
conditioners can be found in CTFA Cosmetic Ingredient Handbook, 1st
Ed., 1988, which is hereby incorporated herein by reference in its
entirety. In some embodiments, the one or more skin conditioners
may include, but are not limited to, humectants, such as fructose,
glucose, glycerin, propylene glycol, glycereth-26, mannitol and
urea, pyrrolidone carboxylic acid, hydrolyzed lecithin,
coco-betaine, cysteine hydrochloride, glutamine, polyoxypropylene
(15) polyoxyethylene (PPG-15), sodium gluconate, potassium
aspartate, oleyl betaine, thiamine hydrochloride, sodium laureth
sulfate, sodium hyaluronate, hydrolyzed proteins, hydrolyzed
keratin, amino acids, amine oxides, water-soluble derivatives of
vitamins A, E and D, amino-functional silicones, ethoxylated
glycerin, .alpha.-hydroxy acids and salts thereof, water-soluble
fatty oil derivatives, such as PEG-24 hydrogenated lanolin, almond
oil, grape seed oil and castor oil; numerous other water-soluble
skin conditioners listed, and mixtures thereof. In certain
embodiments, the skin conditioners may include lanolin or lanolin
derivatives, caprylic capric/triglyceride, diisopropyl adipate, and
combinations thereof.
[0103] Skin conditioners may be provided to the creams of various
embodiments in any amount known in the art, and the amount of skin
conditioner provided may vary depending upon the type of skin
condition or combination of skin conditioners used. In general, the
creams of embodiments may include a conditioner in an amount from
about 1% to about 50% by weight of the cream or from about 1% to
about 25% by weight of the cream. In some embodiments the cream may
comprise each skin conditioner in an amount of about 1%, about
1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%,
about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about
3%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%,
about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about
4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 6.6%, about
6.7%, about 6.8%, about 6.9%, about 7%, about 7.1%, about 7.2%,
about 7.3%, about 7.4%, about 7.5%, about 8%, about 8.5%, about 9%,
about 9.5%, or about 10% by weight.
[0104] The oxymetazoline creams of various embodiments may be of
neutral to mildly acidic pH to allow for comfortable application to
the subject's skin, particularly in light of the disease state or
condition suffered by the subject. For example, in various
embodiments, the pH of the creams may be from about 2.5 to about
7.0, from about 4.0 to about 7.0, or from about 4.0 to about 5.5 at
room temperature. In other embodiments, the pH of such creams may
be about 4.5 to about 5.5 at room temperature, and in particular
embodiments, the pH of the creams may be about 4.5 at room
temperature. Any components or combination of components known and
useful in the art may be used to achieve an appropriate pH such as,
for example, pH regulators including, but not limited to, lactic
acid, citric acid, sodium citrate, glycolic acid, succinic acid,
phosphoric acid, monosodium phosphate, disodium phosphate, oxalic
acid, dl-malic acid, calcium carbonate, sodium hydroxide and sodium
carbonate, sodium hydrogen carbonate, and ammonium hydrogen
carbonate. In certain embodiments the pH regulators comprise
anhydrous citric acid and sodium citrate dihydrate In various
embodiments, the total buffer capacity may be from about from about
0 mM to about 600 mM; from about 0 mM to about 600 mM; from about 5
mM to about 600 mM; from about 5 mM to about 400 mM; from about 5
mM to about 300 mM; from about 5 mM to about 200 mM; from about 200
mM to about 400 mM; about 0 mM, about 100 mM, about 200 mM, about
300 mM, about 400 mM, about 500 mM, or about 600 mM. In some
embodiments the cream comprises each pH regulator in an amount of
about 0.05%, about 0.1%, about 0.15%, about 0.16%, about 0.17%,
about 0.18%, about 0.19%, about 0.2%, about 0.21%, about 0.22%,
about 0.23%, about 0.24%, about 0.25%, about 0.26%, about 0.27%,
about 0.28%, about 0.29%, about 0.3%, about 0.31%, about 0.32%,
about 0.33%, about 0.34%, about 0.35%, about 0.36%, about 0.37%,
about 0.38%, about 0.39%, about 0.4%, about 0.45%, about 0.5%,
about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%,
about 0.8%, about 0.85%, about 0.9%, about 0.95%, or about 1% by
weight.
[0105] Embodiments of the invention also include methods for
preparing pharmaceutical compositions as described above by, for
example, conventional mixing and the like. For example, in some
embodiments, oxymetazoline may be combined with any combination of
components described above in purified water using conventional
mixing, and after a stable emulsion has formed, the pH and
viscosity may be adjusted using known methods to achieve a cream
having an appropriate pH. In other embodiments, various
combinations of components may be combined in purified water by
conventional mixing and oxymetazoline may then be added to the
mixture. The pH, viscosity, opaqueness, and/or density may be
adjusted to achieve a cream which is cosmetically acceptable.
[0106] Certain embodiments are directed to methods of making the
cream formulation comprising making a first solution comprising the
steps of dissolving preservatives, such as methylparaben and
propylparaben, into a solvent, such as polyethylene glycol 300,
mixing with a magnetic stirrer until the mixture becomes
homogeneous, adding other preservatives, such as 2-phenoxyethanol,
to the mixture; making a second solution comprising the steps of
heating purified water, and a chelating agent, such as disodium
edetate (EDTA); making an oil phase comprising adding emulsifiers,
such as Tefose 63, cetostearyl alcohol, Cremophor A-6 and Cremaphor
A-25; antioxidants, such as butylated hydroxytoluene; emollients,
such as lanolin, diisopropyl adipate, triglycerides medium chain;
and viscosity modifiers, such as cetostearyl alcohol; heating and
mixing the oil phase; dissolving oxymetazoline into the second
solution to create an aqueous phase; adding the first solution to
the aqueous phase to make an aqueous phase solution; and adding the
aqueous phase solution to the oil phase to make a cream.
[0107] Certain embodiments are directed to methods of making the
cream formulation comprising a "one-pot" process. In the one-pot
process, the batch may be manufactured in one vessel, kettle or
container that can be heated by means of a steam or a heated fluid.
First, an oil phase may be made comprising adding emulsifiers, such
as Tefose 63, cetostearyl alcohol, Cremophor A-6 and Cremaphor
A-25; antioxidants, such as butylated hydroxytoluene; emollients,
such as lanolin, diisopropyl adipate, triglycerides medium chain;
and viscosity modifiers such as cetostearyl alcohol, heating and
mixing the oil phase, then separately in a small container
preparing a side-mix by dissolving preservatives, such as
methylparaben and propylparaben, into a solvent, such as
polyethylene glycol 300, mixing with a magnetic stirrer until the
mixture becomes homogeneous, adding other preservatives, such as
2-phenoxyethanol, to the mixture; and a chelating agent, such as
disodium edetate (EDTA) and adding this solution to the oil phase,
mixing and heating this solution to high temperature and then
adding slowly the purified water, the water is added at a rate that
the temperature in the pot is maintained at above about 70 degrees
C.; once all the water has been added and the cream has been made,
dissolving the API (e.g. oxymetazoline) into the cream.
Alternatively, the API may be added at any time during the process
which is feasible or where it is conventionally added.
[0108] Yet other embodiments are directed to methods for using the
pharmaceutical compositions. In general, the oxymetazoline creams
of certain embodiments described herein may be administered
topically to the skin, and in some embodiments, the oxymetazoline
creams may be applied to portions of the skin that exhibit or may
be prone to papules, pustules, other inflammatory lesions, phymas
(skin thickening) or erythema associated with rosacea, purpura,
telangiectasias, keratosis pilaris, lupus miliaris disseminatus
faciei or the like. In other embodiments, oxymetazoline cream may
be applied over an entire skin area including those areas not
currently exhibiting or prone to papules, pustules, other
inflammatory lesions, phymas (skin thickening) or erythema
associated with rosacea, purpura, telangiectasias, keratosis
pilaris, lupus miliaris disseminatus faciei or the like. In certain
embodiments, the pharmaceutical compositions may be provided in an
effective amount to a skin area exhibiting or prone to a skin
condition (e.g. dryness).
[0109] In various embodiments, the pharmaceutical compositions may
be applied to provide an effective amount of oxymetazoline to the
subject, and in certain embodiments, the pharmaceutical
compositions may be provided in an effective amount to a skin area
exhibiting or prone to the symptoms of rosacea, telangiectasias,
skin thickening, pustules, papules, other skin erythemas, purpura,
keratosis pilaris, lupus miliaris disseminatus faciei or the like.
In some embodiments, an effective amount of the cream (e.g.
oxymetazoline cream) may be applied to the skin of the subject in
need of treatment as the result from a single application. In other
embodiments, the cream (e.g. oxymetazoline cream) may be reapplied
over the course of, for example, a day, a week, a month, several
months, or several years or until the condition is resolved. For
example, in one exemplary embodiment, a therapeutic method may
include applying the oxymetazoline creams described herein to a
skin area exhibiting or prone to symptoms of rosacea, skin
thickening, telangiectasias, pustules, papules, other skin
erythemas, purpura, keratosis pilaris, lupus miliaris disseminatus
faciei or the like once per day as long as the symptoms persist. In
other embodiments, the oxymetazoline cream may be applied as a
maintenance therapy, wherein the cream is continuously applied as
needed or applied on a scheduled basis over time while the subject
is in need of such treatment. In embodiments, a therapeutic method
may include applying the cream once per day, 2 times per day, 3
times per day, 4 times per day or as needed or prescribed. In some
embodiments, a therapeutic method may include applying the cream
pro re nata (PRN or as needed). In other embodiments, a therapeutic
method may include applying the oxymetazoline cream 2 times per
day, for example, every 4 hours, as long as the symptoms persist.
In other exemplary embodiments, a therapeutic method may include
applying the oxymetazoline creams 2 or more times, for example,
every 6 hours or every 12 hours, per day as long as the symptoms
persist. In such embodiments, application of the oxymetazoline
creams may be carried out until the symptoms of rosacea, skin
thickening, telangiectasias, pustules, papules, other skin
erythemas, purpura, keratosis pilaris, lupus miliaris disseminatus
faciei or the like have been substantially reduced or eliminated,
and in some embodiments, the amount of oxymetazoline cream applied
or the frequency of application may be modified throughout the
course of treatment based on the subject's reaction to the
pharmaceutical composition and the clinician's recommendations. For
example, after symptom reduction or elimination is observed, the
amount of oxymetazoline cream applied or the frequency of
applications may be modified to maintain a therapeutic effect.
[0110] The creams of various embodiments may be applied by any
method. For example, in some embodiments, the oxymetazoline cream
may be applied by hand by the subject or another person, such as a
clinician. In other embodiments, the cream may be packaged with an
applicator such as a wand, swath of cloth, or applicator pad, and
in still other embodiments, measured doses of the cream may be
packaged for application by hand. Without wishing to be bound by
theory, providing the cream with a prepackaged applicator or in
measured doses may provide a more controlled dose. In general, the
subject and/or clinician will ensure that the cream is applied
evenly over the skin area to be treated.
[0111] In one embodiment a formulation comprises oxymetazoline and
a pharmaceutically acceptable excipient, wherein the formulation is
a cream. In one aspect the formulation comprises a therapeutically
effective amount of oxymetazoline. In one aspect, the formulation
is cosmetically acceptable. In one aspect the formulation comprises
an emulsifier and an emollient. In a further aspect the
hydrophilic-lipophilic balance of the emulsifier is from about 9.0
to about 17.0. In a further aspect the emulsifier is present in a
total amount of from about 1% to about 30% by weight. In a further
aspect the emulsifier comprises Tefose 63.TM.. In a further aspect
the emulsifier comprises a PEG-stearate, a glycol stearate or a
mixture thereof. In a further aspect the emulsifier is polyethylene
glycol 6 (PEG-6), polyethylene glycol 32 (PEG-32), and glycol
stearate. In a further aspect the emulsifier comprises ethoxylated
fatty acids. In a further aspect the emollient is present in a
total amount of from about 1% to about 50% by weight. In a further
aspect the emollient comprises cetostearyl alcohol. In a further
aspect the ratio of the emulsifier to the emollient comprises from
about 0.7:1 to about 1.8:1. In a further aspect the ratio of the
emulsifier to the emollient comprises from about 0.7:1 to about
1.5:1. In one aspect the formulation comprises an additive selected
from the group consisting of preservatives, emulsion stabilizers,
pH adjusters, chelating agents, viscosity modifiers, anti-oxidants,
surfactants, emollients, opacifying agents, skin conditioners,
buffers, and combinations thereof. In a further aspect the one or
more preservatives is present in an amount of from about 0.01% to
about 5% by weight. In a further aspect the one or more chelating
agents is present in an amount of about 0.001% to about 2% by
weight. In a further aspect the one or more viscosity modifiers is
present in an amount of from about 0.5% to about 30% by weight. In
a further aspect the one or more antioxidants is present in an
amount of from about 0.01% to about 3% by weight. In a further
aspect the one or more surfactants is present in an amount of from
about 0.1% to about 50% by weight. In a further aspect the one or
more opacifying agents is present in an amount of from about 0.01%
to about 20% by weight. In a further aspect the one or more skin
conditioners is present in an amount of from about 1% to about 50%
by weight. In a further aspect the one or more pH regulators is
present in an amount sufficient to provide a pH of from about 2.5
to about 7.0 for the formulation. In one aspect the formulation
further comprises a topically active pharmaceutical agent or
cosmetic agent. In a further aspect the topically active
pharmaceutical agent is selected from the group consisting of an
antimycobacterial agent, an anti-rosacea agent, and a mixture
thereof. In a further aspect the formulation further comprises
dapsone or metronidazole. In one aspect the formulation comprises a
pH from about 2.0 to about 7.0 at room temperature. In one aspect
the pH of the formulation does not decrease after about 4 weeks
storage at about 25.degree. C./60% RH, about 30.degree. C./75% RH
or about 40.degree. C./75% RH. In one aspect the pH of the
formulation does not decrease after about 1 week storage (e.g.
where cream formulation is packaged into tubes--for example into 30
g polyethylene tubes or 30 g glaminate tubes) at about 60.degree.
C. In one aspect the pH of the formulation is unchanged after about
4 weeks storage at about 25.degree. C./60% RH, about 30.degree.
C./75% RH or about 40.degree. C./75% RH. In one aspect the pH of
the formulation is unchanged after about 1 week storage at about
60.degree. C. In one aspect the formulation maintains a pH of from
about 4.30 to about 4.70 after about 4 weeks storage at about
25.degree. C./60% RH, about 30.degree. C./75% RH or about
40.degree. C./75% RH. In one aspect the formulation maintains a pH
of from about 4.30 to about 4.70 after about 1 week storage at
about 60.degree. C. In one aspect the formulation maintains a pH of
from about 4.30 to about 4.70 after about 9 months storage at about
25.degree. C./60% RH, or after about 6 months storage at about
40.degree. C./75% RH. In one aspect the formulation maintains a pH
of from about 4.10 to about 4.60 after about 3 months storage at
about 25.degree. C./60% RH or after about 3 months at about
40.degree. C./75% RH. In one aspect the formulation maintains a pH
of about 4.5 after about 4 weeks storage at about 25.degree. C./60%
RH, about 30.degree. C./75% RH or about 40.degree. C./75% RH. In
one aspect the formulation maintains a pH of about 4.5 after about
1 week storage at about 60.degree. C. In one aspect the appearance
(e.g. viscosity, consistency and/or color) of the formulation is
unchanged after about 4 weeks storage at about 25.degree. C./60%
RH, about 30.degree. C./75% RH or about 40.degree. C./75% RH. In
one aspect the appearance of the formulation is unchanged after
about 1 week storage at about 60.degree. C. In one aspect the
oxymetazoline is present in an amount of from about 0.0075% to
about 5% by weight. In one aspect the oxymetazoline is present in
an amount of about 0.5%, about 1.0% or about 1.5% by weight. In one
aspect the formulation comprises a vasoconstrictor. In a further
aspect the vasoconstrictor is an alpha-adrenergic agonist. In a
further aspect the vasoconstrictor is an imidazoline type
alpha-adrenergic agonist, a non-imidazoline type alpha-adrenergic
agonist, an alpha-1 adrenergic agonist, an alpha-2 adrenergic
agonist, a selective alpha-adrenergic agonist, a non-selective
alpha-adrenergic agonist, a selective alpha-1 adrenergic agonist, a
selective alpha-2 adrenergic agonist, a non-selective alpha-1
adrenergic agonist, a non-selective alpha-2 adrenergic agonist or a
combination thereof.
[0112] In one embodiment a cream formulation comprises an active
pharmaceutical ingredient other than oxymetazoline, an emulsifier
and an emollient. In one aspect the ratio of the emulsifier to the
emollient is from about 0.7:1 to about 1.8:1. In a further aspect,
the formulation comprises an emulsifer in a total amount of from
about 1% to about 30% by weight. In a further aspect, the
emulsifier comprises Tefose 63.TM.. In a further aspect the
emulsifier comprises a PEG-stearate, a glycol stearate or a
combination thereof. In a further aspect the emulsifier is
polyethylene glycol 6 (PEG-6), polyethylene glycol 32 (PEG-32), and
glycol stearate. In a further aspect the hydrophilic-lipophilic
balance of the emulsifier is from about 9.0 to about 17.0. In a
further aspect the emulsifier comprises ethoxylated fatty acids. In
a further aspect the emulsifier comprises cetostearyl alcohol. In a
further aspect, the formulation comprises an emulsifer and an
emollient, and the ratio of the emulsifier to the emollient
comprises from about 0.7:1 to about 1.5:1. In a further aspect, the
formulation further comprises an additive selected from the group
consisting of preservatives, emulsion stabilizers, pH adjusters,
chelating agents, viscosity modifiers, anti-oxidants, surfactants,
emollients, opacifying agents, skin conditioners, buffers,
fragrances and combinations thereof. In a further aspect, the
active pharmaceutical ingredient is a topically active
pharmaceutical or cosmetic agent. In a further aspect the active
pharmaceutical ingredient is a systemically active pharmaceutical
or cosmetic agent. In a further aspect the formulation comprises a
pH from about 2.0 to about 7.0 at room temperature. In a further
aspect the formulation comprises a pH from about 4.0 to about 5.5
at room temperature. In a further aspect the active pharmaceutical
ingredient is in an amount of from about 0.0075% to about 50% by
weight. In a further aspect, the active pharmaceutical ingredient
is an imidazoline alpha-adrenergic agonist, a non-imidazoline
alpha-adrenergic agonist, an alpha-1 adrenergic agonist, an alpha-2
adrenergic agonist, a selective alpha-adrenergic agonist, a
non-selective alpha-adrenergic agonist, a selective alpha-1
adrenergic agonist, a selective alpha-2 adrenergic agonist, a
non-selective alpha-1 adrenergic agonist, a non-selective alpha-2
adrenergic agonist or a combination thereof.
[0113] In one embodiment, a cream formulation comprises an
emulsifier and an emollient, wherein a ratio of the emulsifier to
the emollient is from about 0.7:1 to about 1.8:1 and wherein the
formulation does not contain an active pharmaceutical
ingredient.
[0114] In one embodiment, a pharmaceutical composition comprises an
API other than oxymetazoline; an emulsifier; and an emollient;
wherein a ratio of the emulsifier to the emollient comprises from
about 0.7:1 to about 1.8:1, and wherein the composition is a
cream.
[0115] In one embodiment, a pharmaceutical composition comprises an
API other than oxymetazoline in an amount of from about 0.0075% to
about 50% by weight of the pharmaceutical composition; an
emulsifier in an amount of about 1% to about 30% by weight of the
pharmaceutical composition; and an emollient in an amount of from
about 1% to about 50% by weight of the pharmaceutical
composition.
[0116] At least one embodiment provides a method of treating a skin
condition selected from the group consisting of rosacea and
symptoms associated with rosacea, including, for example, papules,
pustules, phymas, telangiectasias or erythema associated with
rosacea, other skin erythemas, telangiectasias, purpura or the
like, and other manifestations associated therewith; other
inflammatory conditions of the skin including, but not limited to,
keratosis pilaris, lupus miliaris dissemniatus faciei, eczema,
dermatitis, such as contact dermatitis, atopic dermatitis,
seborrheic dermatitis, nummular dermatitis, generalized exfoliative
dermatitis, statis dermatitis, neurodermatitis, lichen simplex
chronicus, xerosis and xerotic dermatitis, dyshidrosis and
dyshidrotic dermatitis, asteototic dermatitis or other conditions
characterized by sensitive skin or a disturbance of the epidermal
barrier; disorders characterized by rough, dry, cracked or fissured
skin, disorders characterized by hyperkeratotic skin such as
keratodermas and ichthyosisis and ichthyosiform dermatoses;
disorders of hair follicles and sebaceous glands, such as acne,
perioral dermatitis, and pseudofolliculitis barbae; disorders of
sweat glands, such as miliaria, including, but not limited to,
miliaria crystallina, miliaria rubra, miliaria profunda, miliaria
pustulosa; sunburn, chronic actinic damage, poikiloderma, radiation
dermatitis, actinic purpura; other inflammatory dermatoses,
reactions and conditions of the skin, including, but not limited
to, psoriasis, drug eruptions, erythema multiforme, erythema
nodosum, and granuloma annulare; diseases and conditions
characterized by bleeding or bruising such as petechiae,
ecchymosis, purpura and the like including any accumulation of
blood in the skin due to vascular extravasation, irrespective of
size or cause, bleeding or bruising due to any skin injury which
may include any trauma including surgical or procedural trauma;
infection, inflammatory dermatoses or inflammation due to any cause
comprising administering a cream formulation of an embodiment
described herein.
EXAMPLES
[0117] Although the present invention has been described in
considerable detail with reference to certain preferred embodiments
thereof, other versions are possible. Therefore, the spirit and
scope of the appended claims should not be limited to the
description and the preferred versions contained within this
specification. Various aspects of the present invention will be
illustrated with reference to the following non-limiting
examples.
Example 1
[0118] The amount per batch (kg) for each component of the
oxymetazoline cream prepared as described below are provided with
their concentration by weight of the total cream in Table 1. Table
2 illustrates a function and amount per batch (kg) for each
component of the cream prepared as described below with each
component's concentration by weight of the total cream wherein
Tefose.TM. 63 is replaced by a mixture of PEG-6 Stearate, Glycol
Stearate and PEG-32 Stearate.
[0119] Solution 1: In a 2 L glass beaker, 44.0 g of methylparaben,
NF and 11.0 g of propylparaben, NF was dissolved into 880 g of
polyethylene glycol by mixing with a magnetic stirrer until the
mixture became homogeneous. Once the parabens were dissolved, 176.0
g of phenoxyethanol Ph Eur was added to the mixture.
[0120] Solution 2: In a separate 36 L capacity stainless steel
beaker, heat purified 11305 g of purified water was heated to
75.degree. C. to 78.degree. C. using a hot plate, and 2.2 g of
disodium edetate (EDTA), USP, 44.0 g of anhydrous citric acid, USP,
and 66.0 g of sodium citrate dehydrate, USP was added to the heated
water using a low mixing speed (450 rpm) while maintaining the
temperature of the solution at 75.degree. C. to 78.degree. C.
[0121] Oil Phase: Into a reactor vessel, preferably an anchor-type,
propeller-equipped reactor vessel, 11.0 g of butylated
hydroxytoluene, NF, 1760 g of Tefose.TM. 63 (PEG-& glycol &
PEG-32 Stearate), 1760 g of cetostearyl alcohol, NF, 1540 g of
triglycerides medium chain, NF (caprylic capric triglycerides),
1540 g of diisopropyl adipate, 1540 g of oleyl alcohol, NF, 440 g
of lanolin, USP, 440 g of macrogol (6) cetostearyl ether (Cremophor
A-6), Ph Eur, and 440 g of macrogol (25) cetostearyl ether
(Cremophor A-25), Ph Eur was added, and the mixture was heated to
73.degree. C. to 75.degree. C. while mixing at a low mixing speed
(50 rpm).
[0122] While the oil phase was melting, oxymetazoline
hydrochloride, USP was dissolved into Solution 2 to create the
aqueous phase, and evaporated water was replaced by adding 10.9 g
of purified water to the stainless steel beaker. Solution 1 was
then added to the aqueous phase while the temperature was
maintained at 75.degree. C. to 78.degree. C. with low speed mixing
(250 rpm). The resulting aqueous phase solution was than added at a
moderate speed to the oil phase in the reactor vessel, preferably
an anchor-type, propeller-equipped reactor vessel, with low speed
mixing (50 rpm), and stirring was continued until the temperature
in the reactor was 40.degree. C. The mixing speed was then lowered
to 30 rpm, and the temperature was reduced to 35.degree. C. When
35.degree. C. was reached, the mixing speed was again lowered to 20
rpm. The resulting white cream was manually discharged from the
reactor and stored in a two 12 L stainless steel beakers.
TABLE-US-00004 TABLE 1 COMPOSITION OF OXYMETAZOLINE CREAM TRIAL 36
Amount per Ingredient % W/W Batch (g) Oxymetazoline hydrochloride,
USP 0.01 2.2 2-Phenoxyethanol, Ph Eur 0.80 176 Methylparaben, NF
0.20 44 Propylparaben, NF 0.05 11 Edetate Disodium, Dihydrate, USP
0.01 2.2 Butylated Hydroxytoluene, NF 0.05 11 Polyethylene Glycol
300, NF 4.0 880 Tefose 63 8.0 1760 Cetostearyl alcohol, NF 8.0 1760
Triglycerides medium chain, NF 7.0 1540 (caprylic
capric/triglycerides) Diisopropyl adipate 7.0 1540 Oleyl alcohol,
NF 7.0 1540 Lanolin, USP 2.0 440 Cremophor A-6 2.0 440 Cremophor
A-25 2.0 440 Purified Water, USP (1) 51.38 11305.8 Purified Water,
USP (2) QS QS Anhydrous Citric Acid, USP 0.20 44 Sodium Citrate
Dihydrate, USP 0.30 66
TABLE-US-00005 TABLE 2 COMPOSITION OF OXYMETAZOLINE CREAM TRIAL 36
% W/W Ingredients Function QS Oxymetazoline Hydrochloride, Active
USP 0.80 Phenoxyethanol, Ph Eur Antimicrobial preservative 0.20
Methylparaben, NF Antimicrobial preservative 0.05 Propylparaben, NF
Antimicrobial preservative 0.01 Disodium Edetate, USP Chelating
agent 0.05 Butylated Hydroxytoluene, NF Anti-oxidant 4.00
Polyethylene Glycol 300, NF Humectant 5.00 PEG-6 Stearate
Emulsifier 1.50 Glycol Stearate Emulsifier 1.50 PEG-32 Stearate
Emulsifier 8.00 Cetostearyl alcohol, NF Emollient, stiffening agent
and emulsion stabilizer 7.00 Triglycerides medium chain, NF
Emollient, oil component (Caprylic capric triglycerides) 7.00
Diisopropyl adipate Emollient, oil component 7.00 Oleyl Alcohol, NF
Emollient, oil component 2.00 Lanolin, USP Emollient, oil component
2.00 Macrogol (6) Cetostearyl Ether Non-ionic o/w emulsifier,
(Cremophor A-6), Ph Eur consistency enhancer 2.00 Macrogol (25)
Cetostearyl Ether Non-ionic o/w emulsifier, (Cremophor A-25), Ph
Eur consistency enhancer 51.38 Purified Water, USP Vehicle 0.20
Anhydrous Citric Acid, USP Buffering agent 0.30 Sodium Citrate
Dihydrate, USP Buffering agent 100.00
Example 2
[0123] Oxymetazoline creams having a variety of formulations were
prepared as described in Example 1 in order to obtain a cream which
was cosmetically acceptable and had enough consistency to support
prolonged exposure at 40.degree. C. without losing its physical
integrity. Trial 1 was a base formulation without any API. Trial 2
included 0.1% API to determine the impact that the API would have
on the base formulation. The consistency (Viscosity value) revealed
that there was no immediate physical impact of the active at 0.1%
concentration on the physical integrity of the cream base as
compared to the plain base in Trial 1. Trials 3, 5 and 6 were
formulations prepared during development work. Trials 7-11 were
formulations prepared for the first stability study. Trials 12-13
were formulations containing higher concentrations of oxymetazoline
(2% and 1%, respectively). Trials 15-18 were formulations made for
toxicology studies. Batches A and B were the same and were combined
to make a larger batch for the toxicology studies. Trial 19 was a
formulation without preservatives for analytical method
development. Trials 20-34 were the first round of optimization
formulations. Trials 35-37 were buffered at pH 4.5 and included a
high content of cetostearyl alcohol and Tefose.TM. 63. Trials 38-41
further optimized the Trial 36 formulation with 0.5%, 1%, 2% API
and a placebo. Trials 42-43 further optimized the Trial 36
formulation with 0.01%, and 0.15% API and were used in the
permeation flux studies. Trial 45 was a large engineering batch of
the Trial 36 formulation. Trial 46-48 and 51 were made for
analytical method development. Trials 49-50 were made for
toxicology studies and contain 0.05% and 0% API, respectively.
TABLE-US-00006 TABLE 3 PREPARATION OF OXYMETAZOLINE CREAM: TRIALS
1-7A (% W/W) Trial Trial Trial Trial Trial Trial Trial Trial 1 2 3
4 5 6 7 7A Oxymetazoline HCl 0.000 0.100 0.025 NA 0.100 0.050 0.150
0.025 Phenoxyethanol 0.800 0.800 0.800 NA 0.800 0.800 0.800 0.800
Methylparaben 0.200 0.200 0.200 NA 0.200 0.200 0.200 0.200
Propylparaben 0.050 0.050 0.050 NA 0.050 0.050 0.050 0.050 Disodium
Edetate 0.010 0.010 0.010 NA 0.010 0.010 0.010 0.010 Butylated
Hydroxytoluene 0.050 0.050 0.050 NA 0.050 0.050 0.050 0.050
Polyethylene Glycol 300 4.000 4.000 4.000 NA 4.000 4.000 4.000
4.000 Tefose 63 7.500 7.500 8.000 NA 8.000 8.000 8.000 8.000
Cetostearyl alcohol 4.000 4.000 5.000 NA 5.000 5.000 5.000 5.000
Triglycerides medium chain 7.000 7.000 7.000 NA 7.000 7.000 7.000
7.000 Diisopropyl adipate 7.000 7.000 7.000 NA 7.000 7.000 7.000
7.000 Oleyl Alcohol 7.000 7.000 7.000 NA 7.000 7.000 7.000 7.000
Lanolin 2.000 2.000 2.000 NA 2.000 2.000 2.000 2.000 Macrogol (6)
Cetostearyl 2.000 2.000 2.000 NA 2.000 2.000 2.000 2.000 Ether
Macrogol (25) Cetostearyl 2.000 2.000 2.000 NA 2.000 2.000 2.000
2.000 Ether Anhydrous Citric Acid 0.000 0.000 0.000 NA 0.000 0.000
0.000 0.000 Sodium Citrate Dihydrate 0.000 0.000 0.000 NA 0.000
0.000 0.000 0.000 Hydroxyethyl Cellulose 0.000 0.000 0.000 NA 0.000
0.000 0.000 0.000 Lipoid S-75 0.000 0.000 0.000 NA 0.000 0.000
0.000 0.000 Trizma 0.000 0.000 0.000 NA 0.000 0.000 0.000 0.000
Purified Water 56.390 56.290 54.865 NA 54.790 54.840 54.740
54.865
TABLE-US-00007 TABLE 4 PREPARATION OF OXYMETAZOLINE CREAM: TRIALS
8-15A (% W/W) Trial Trial Trial Trial Trial Trial Trial Trial 8 9
10 11 12 13 14 15A Oxymetazoline HCl 0.100 0.050 0.150 0.010 2.000
1.000 NA 2.000 Phenoxyethanol 0.800 0.800 0.800 0.800 0.800 0.800
NA 0.800 Methylparaben 0.200 0.200 0.200 0.200 0.200 0.200 NA 0.200
Propylparaben 0.050 0.050 0.050 0.050 0.050 0.050 NA 0.050 Disodium
Edetate 0.010 0.010 0.010 0.010 0.010 0.010 NA 0.010 Butylated
Hydroxytoluene 0.050 0.050 0.050 0.050 0.050 0.050 NA 0.050
Polyethylene Glycol 300 4.000 4.000 4.000 4.000 4.000 4.000 NA
4.000 Tefose 63 8.000 8.000 8.000 8.000 8.000 8.000 NA 8.000
Cetostearyl alcohol 5.000 5.000 5.000 5.000 5.000 5.000 NA 5.000
Triglycerides medium chain 7.000 7.000 7.000 7.000 7.000 7.000 NA
7.000 Diisopropyl adipate 7.000 7.000 7.000 7.000 7.000 7.000 NA
7.000 Oleyl Alcohol 7.000 7.000 7.000 7.000 7.000 7.000 NA 7.000
Lanolin 2.000 2.000 2.000 2.000 2.000 2.000 NA 2.000 Macrogol (6)
Cetostearyl 2.000 2.000 2.000 2.000 2.000 2.000 NA 2.000 Ether
Macrogol (25) Cetostearyl 2.000 2.000 2.000 2.000 2.000 2.000 NA
2.000 Ether Anhydrous Citric Acid 0.000 0.000 0.000 0.000 0.000
0.000 NA 0.000 Sodium Citrate Dihydrate 0.000 0.000 0.000 0.000
0.000 0.000 NA 0.000 Hydroxyethyl Cellulose 0.000 0.000 0.000 0.000
0.000 0.000 NA 0.000 Lipoid S-75 0.000 0.000 0.000 0.000 0.000
0.000 NA 0.000 Trizma 0.000 0.000 0.000 0.000 0.000 0.000 NA 0.000
Purified Water 54.790 54.840 54.740 54.880 52.890 53.890 NA
52.890
TABLE-US-00008 TABLE 5 PREPARATION OF OXYMETAZOLINE CREAM: TRIALS
15B-19 (% W/W) Trial Trial Trial Trial Trial Trial Trial Trial 15B
16A 16B 17A 17B 18A 18B 19 Oxymetazoline HCl 2.000 1.000 1.000
0.500 0.500 0.000 0.000 0.150 Phenoxyethanol 0.800 0.800 0.800
0.800 0.800 0.800 0.800 0.000 Methylparaben 0.200 0.200 0.200 0.200
0.200 0.200 0.200 0.000 Propylparaben 0.050 0.050 0.050 0.050 0.050
0.050 0.050 0.000 Disodium Edetate 0.010 0.010 0.010 0.010 0.010
0.010 0.010 0.010 Butylated Hydroxytoluene 0.050 0.050 0.050 0.050
0.050 0.050 0.050 0.050 Polyethylene Glycol 300 4.000 4.000 4.000
4.000 4.000 4.000 4.000 4.000 Tefose 63 8.000 8.000 8.000 8.000
8.000 8.000 8.000 8.000 Cetostearyl alcohol 5.000 5.000 5.000 5.000
5.000 5.000 5.000 5.000 Triglycerides medium chain 7.000 7.000
7.000 7.000 7.000 7.000 7.000 7.000 Diisopropyl adipate 7.000 7.000
7.000 7.000 7.000 7.000 7.000 7.000 Oleyl Alcohol 7.000 7.000 7.000
7.000 7.000 7.000 7.000 7.000 Lanolin 2.000 2.000 2.000 2.000 2.000
2.000 2.000 2.000 Macrogol (6) Cetostearyl 2.000 2.000 2.000 2.000
2.000 2.000 2.000 2.000 Ether Macrogol (25) Cetostearyl 2.000 2.000
2.000 2.000 2.000 2.000 2.000 2.000 Ether Anhydrous Citric Acid
0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 Sodium Citrate
Dihydrate 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000
Hydroxyethyl Cellulose 0.000 0.000 0.000 0.000 0.000 0.000 0.000
0.000 Lipoid S-75 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000
Trizma 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 Purified
Water 52.890 53.890 53.890 54.390 54.390 54.890 54.890 55.790
TABLE-US-00009 TABLE 6 PREPARATION OF OXYMETAZOLINE CREAM: TRIALS
20-27 (% W/W) Trial Trial Trial Trial Trial Trial Trial Trial 20 21
22 23 24 25 26 27 Oxymetazoline HCl 0.010 0.150 0.010 0.010 0.010
0.010 0.010 0.010 Phenoxyethanol 0.800 0.800 0.800 0.800 0.800
0.800 0.800 0.800 Methylparaben 0.200 0.200 0.200 0.200 0.200 0.200
0.200 0.200 Propylparaben 0.050 0.050 0.050 0.050 0.050 0.050 0.050
0.050 Disodium Edetate 0.010 0.010 0.010 0.010 0.010 0.010 0.010
0.010 Butylated Hydroxytoluene 0.050 0.050 0.050 0.050 0.050 0.050
0.050 0.050 Polyethylene Glycol 300 4.000 4.000 4.000 4.000 4.000
4.000 4.000 4.000 Tefose 63 8.000 8.000 8.000 8.000 8.000 8.000
10.000 10.000 Cetostearyl alcohol 5.000 5.000 5.000 5.000 5.000
5.000 8.000 10.000 Triglycerides medium chain 7.000 7.000 7.000
7.000 7.000 7.000 7.000 7.000 Diisopropyl adipate 7.000 7.000 7.000
7.000 7.000 7.000 7.000 7.000 Oleyl Alcohol 7.000 7.000 7.000 7.000
7.000 7.000 7.000 7.000 Lanolin 2.000 2.000 2.000 2.000 2.000 2.000
2.000 2.000 Macrogol (6) Cetostearyl Ether 2.000 2.000 2.000 2.000
2.000 2.000 2.000 2.000 Macrogol (25) Cetostearyl 2.000 2.000 2.000
2.000 2.000 2.000 2.000 2.000 Ether Anhydrous Citric Acid 0.000
0.000 0.200 0.000 0.100 0.200 0.000 0.000 Sodium Citrate Dihydrate
0.000 0.000 0.300 0.000 0.450 0.300 0.000 0.000 Hydroxyethyl
Cellulose 0.000 0.000 0.000 0.500 0.000 0.500 0.000 0.000 Lipoid
S-75 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 Trizma 0.000
0.000 0.000 0.000 0.000 0.000 0.000 0.000 Purified Water 54.880
54.740 54.380 54.380 54.330 53.880 49.880 47.880
TABLE-US-00010 TABLE 7 PREPARATION OF OXYMETAZOLINE CREAM: TRIALS
28-35 (% W/W) Trial Trial Trial Trial Trial Trial Trial Trial 28 29
30 31 32 33 34 35 Oxymetazoline HCl 0.010 0.010 0.010 0.010 0.010
0.150 0.150 0.010 Phenoxyethanol 0.800 0.800 0.800 0.800 0.800
0.800 0.800 0.800 Methylparaben 0.200 0.200 0.200 0.200 0.200 0.200
0.200 0.200 Propylparaben 0.050 0.050 0.050 0.050 0.050 0.050 0.050
0.050 Disodium Edetate 0.010 0.010 0.010 0.010 0.010 0.010 0.010
0.010 Butylated Hydroxytoluene 0.050 0.050 0.050 0.050 0.050 0.050
0.050 0.050 Polyethylene Glycol 300 4.000 4.000 4.000 4.000 4.000
4.000 4.000 4.000 Tefose 63 8.000 8.000 8.000 8.000 8.000 8.000
8.000 10.000 Cetostearyl alcohol 5.000 5.000 5.000 5.000 5.000
5.000 5.000 10.000 Triglycerides medium chain 3.500 10.500 7.000
7.000 7.000 3.500 10.500 7.000 Diisopropyl adipate 3.500 10.500
7.000 7.000 7.000 3.500 10.500 7.000 Oleyl Alcohol 14.000 0.000
0.000 0.000 7.000 14.000 0.000 7.000 Lanolin 2.000 2.000 2.000
2.000 2.000 2.000 2.000 2.000 Macrogol (6) Cetostearyl 2.000 2.000
2.000 2.000 1.000 2.000 2.000 2.000 Ether Macrogol (25) Cetostearyl
2.000 2.000 2.000 2.000 1.000 2.000 2.000 2.000 Ether Anhydrous
Citric Acid 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.200 Sodium
Citrate Dihydrate 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.300
Hydroxyethyl Cellulose 0.000 0.000 0.000 0.000 0.000 0.000 0.000
0.000 Lipoid S-75 0.000 0.000 2.000 0.000 0.000 0.000 0.000 0.000
Trizma 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 Purified
Water 54.880 54.880 59.880 61.880 56.880 54.740 54.740 47.380
TABLE-US-00011 TABLE 8 PREPARATION OF OXYMETAZOLINE CREAM: TRIALS
36-40A (% W/W) Trial Trial Trial Trial Trial Trial Trial Trial 36
37 38 38A 39 39A 40 40A Oxymetazoline HCl 0.010 0.010 0.000 0.000
0.500 0.500 1.000 1.000 Phenoxyethanol 0.800 0.800 0.800 0.800
0.800 0.800 0.800 0.800 Methylparaben 0.200 0.200 0.200 0.200 0.200
0.200 0.200 0.200 Propylparaben 0.050 0.050 0.050 0.050 0.050 0.050
0.050 0.050 Disodium Edetate 0.010 0.010 0.010 0.010 0.010 0.010
0.010 0.010 Butylated Hydroxytoluene 0.050 0.050 0.050 0.050 0.050
0.050 0.050 0.050 Polyethylene Glycol 300 4.000 4.000 4.000 4.000
4.000 4.000 4.000 4.000 Tefose 63 8.000 9.000 8.000 8.000 8.000
8.000 8.000 8.000 Cetostearyl alcohol 8.000 7.000 8.000 8.000 8.000
8.000 8.000 8.000 Triglycerides medium chain 7.000 7.000 7.000
7.000 7.000 7.000 7.000 7.000 Diisopropyl adipate 7.000 7.000 7.000
7.000 7.000 7.000 7.000 7.000 Oleyl Alcohol 7.000 7.000 7.000 7.000
7.000 7.000 7.000 7.000 Lanolin 2.000 2.000 2.000 2.000 2.000 2.000
2.000 2.000 Macrogol (6) Cetostearyl 2.000 2.000 2.000 2.000 2.000
2.000 2.000 2.000 Ether Macrogol (25) Cetostearyl 2.000 2.000 2.000
2.000 2.000 2.000 2.000 2.000 Ether Anhydrous Citric Acid 0.200
0.200 0.200 0.200 0.200 0.200 0.200 0.200 Sodium Citrate Dihydrate
0.300 0.300 0.300 0.300 0.300 0.300 0.300 0.300 Hydroxyethyl
Cellulose 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 Lipoid
S-75 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 Trizma 0.000
0.000 0.000 0.000 0.000 0.000 0.000 0.000 Purified Water 51.380
51.380 51.390 51.390 50.890 50.890 50.390 50.390
TABLE-US-00012 TABLE 9 PREPARATION OF OXYMETAZOLINE CREAM: TRIALS
41-47 (% W/W) Trial Trial Trial Trial Trial Trial Trial Trial 41
41A 42 43 44 45 46 47 Oxymetazoline HCl 2.000 2.000 0.010 0.150 NA
0.000 0.500 0.250 Phenoxyethanol 0.800 0.800 0.800 0.800 NA 0.800
0.800 0.800 Methylparaben 0.200 0.200 0.200 0.200 NA 0.200 0.200
0.200 Propylparaben 0.050 0.050 0.050 0.050 NA 0.050 0.050 0.050
Disodium Edetate 0.010 0.010 0.010 0.010 NA 0.010 0.010 0.010
Butylated Hydroxytoluene 0.050 0.050 0.050 0.050 NA 0.050 0.050
0.050 Polyethylene Glycol 300 4.000 4.000 4.000 4.000 NA 4.000
4.000 4.000 Tefose 63 8.000 8.000 8.000 8.000 NA 8.000 8.000 8.000
Cetostearyl alcohol 8.000 8.000 8.000 8.000 NA 8.000 8.000 8.000
Triglycerides medium chain 7.000 7.000 7.000 7.000 NA 7.000 7.000
7.000 Diisopropyl adipate 7.000 7.000 7.000 7.000 NA 7.000 7.000
7.000 Oleyl Alcohol 7.000 7.000 7.000 7.000 NA 7.000 7.000 7.000
Lanolin 2.000 2.000 2.000 2.000 NA 2.000 2.000 2.000 Macrogol (6)
Cetostearyl 2.000 2.000 2.000 2.000 NA 2.000 2.000 2.000 Ether
Macrogol (25) Cetostearyl 2.000 2.000 2.000 2.000 NA 2.000 2.000
2.000 Ether Anhydrous Citric Acid 0.200 0.200 0.200 0.200 NA 0.200
0.200 0.200 Sodium Citrate Dihydrate 0.300 0.300 0.300 0.300 NA
0.300 0.300 0.300 Hydroxyethyl Cellulose 0.000 0.000 0.000 0.000 NA
0.000 0.000 0.000 Lipoid S-75 0.000 0.000 0.000 0.000 NA 0.000
0.000 0.000 Trizma 0.000 0.000 0.000 0.000 NA 0.000 0.000 0.000
Purified Water 49.390 49.390 51.380 51.240 NA 51.390 50.890
51.140
TABLE-US-00013 TABLE 10 PREPARATION OF OXYMETAZOLINE CREAM: TRIALS
48-51 (% W/W) Trial 48 Trial 49 Trial 50 Trial 51 Oxymetazoline HCl
0.100 0.050 0.000 0.150 Phenoxyethanol 0.800 0.800 0.800 0.800
Methylparaben 0.200 0.200 0.200 0.200 Propylparaben 0.050 0.050
0.050 0.050 Disodium Edetate 0.010 0.010 0.010 0.010 Butylated
Hydroxytoluene 0.050 0.050 0.050 0.050 Polyethylene Glycol 300
4.000 4.000 4.000 4.000 Tefose 63 8.000 8.000 8.000 8.000
Cetostearyl alcohol 8.000 8.000 8.000 8.000 Triglycerides medium
chain 7.000 7.000 7.000 7.000 Diisopropyl adipate 7.000 7.000 7.000
7.000 Oleyl Alcohol 7.000 7.000 7.000 7.000 Lanolin 2.000 2.000
2.000 2.000 Macrogol (6) Cetostearyl Ether 2.000 2.000 2.000 2.000
Macrogol (25) Cetostearyl Ether 2.000 2.000 2.000 2.000 Anhydrous
Citric Acid 0.200 0.200 0.200 0.000 Sodium Citrate Dihydrate 0.300
0.300 0.300 0.000 Hydroxyethyl Cellulose 0.000 0.000 0.000 0.000
Lipoid S-75 0.000 0.000 0.000 0.000 Trizma 0.000 0.000 0.000 0.000
Purified Water 51.290 51.340 51.390 51.740
[0124] The purpose of this protocol was to perform a stability
study on Oxymetazoline Topical Creams, 0.05%, 0.10% and 0.15%. The
creams were packaged into two packaging configurations; 30-g
polyethylene tubes and 30-g glaminate tubes. Approximately 120
tubes of each cream concentration were prepared. The creams were
placed on stability for up to 36 months at the nominal storage
condition of 25.degree. C./60% RH and for 6 months at accelerated
conditions of 40.degree. C./75% RH. Some samples were also stored
at the intermediate condition, 30.degree. C./75% RH. The results of
this stability study can be found in Tables 11-13. The pH of the
product exhibited a tendency to decrease over time. This tendency
appeared to be more pronounced in the samples stored at 40.degree.
C./75% RH. The observed appearance of the product at 40.degree.
C./75% RH indicated that there was a portion of the cream that
melted to the point of becoming a liquid. Both of these issues
represented a concern for the long term stability of the cream
formulation. It is noted from the stand point of chemical stability
of the drug, there was no appreciable drop in potency and there was
a very low presence of impurities on the samples tested.
TABLE-US-00014 TABLE 11 STABILITY STUDY RESULTS - PRODUCT STORED IN
POLYETHYLENE TUBES Initial @ 40.degree.' C./75% 40.degree.' C./75%
25.degree.' C./60% 30.degree.' C./65% Room RH,. 2 RH,. 1 RH,. 1
RH,. 1 Parameters Temperature Weeks Month Month Month Oxymetazoline
HCl Creams 0.01% Assay (% LC) 101.0 102.0 96.0 101.5 N/R pH 4.45
4.23 4.03 4.05 4.22 Oxymetazoline HCl Creams 0.05% Assay (% LC)
104.3 101.3 101.3 101.8 100.6 CP (% Area) 0.5 0.6 0.3 0.4 N/R pH
4.29 4.16 3.98 4.09 4.14 Oxymetazoline HCl Creams 0.10%. Assay (%
LC) 104.1 104.5 106.8 101.6 101.8 CP (% Area) 0.3 0.4 0.1 0.2 N/R
pH 4.39 4.22 3.98 4.05 4.11 Oxymetazoline HCl Creams 0.15% Assay (%
LC) 100.9 99.2 102.1 99.8 100.1 CP (% Area) 0.2 0.3 0.1 0.2 N/R pH
4.42 4.22 3.87 4.04 4.08 N/R = not reported
TABLE-US-00015 TABLE 12 STABILITY STUDY RESULTS - PRODUCT STORED IN
GLAMINATE TUBES Initial @ Room 40.degree.' C./75% Parameters
Temperature RH,. 2 Weeks Avg % RSD Oxymetazoline HCl Creams 0.01%
Assay (% LC) 101.5 101.0 101.3 0.3 pH 4.38 4.11 4.2 4.5
Oxymetazoline HCl Creams 0.05% Assay (% LC) 102.8 105.0 103.9 1.5
CP (% Area) 0.7 0.8 NA NA pH 4.12 4.01 4.1 1.9 Oxymetazoline HCl
Creams 0.10%. Assay (% LC) 102.1 104.0 103.1 1.3 CP (% Area) 0.5
0.5 NA NA pH 4.13 4.01 4.1 2.1 Oxymetazoline HCl Creams 0.15% Assay
(% LC) 100.2 101.4 100.8 0.8 CP (% Area) 0.4 0.3 NA NA pH 4.10 3.98
4.0 2.1 The appearance of the samples stored for 1 month at
30.degree. C. is within specification (White viscous cream); the
homogeneous creams are similar to the samples stored at 25.degree.
C.
TABLE-US-00016 TABLE 13 STABILITY STUDY RESULTS - APPEARANCE OF
PRODUCT IN POLYETHYLENE TUBES AND GLAMINATE TUBES Sample
Description Condition Appearance Polyethylene Tubes Oxymetazoline
HCl 25.degree. C./60% White viscous cream Creams 0.01% RH, 1 Month
Oxymetazoline HCl 25.degree. C./60% White viscous cream Creams
0.05% RH, 1 Month Oxymetazoline HCl 25.degree. C./60% White viscous
cream Creams 0.10% RH, 1 Month Oxymetazoline HCl 25.degree. C./60%
White viscous cream Creams 0.15% RH, 1 Month Glaminate tubes
Oxymetazoline HCl 40.degree. C./75% White viscous cream Creams
0.01% RH, 1 Month (not homogeneous) (A portion of the cream was
transferred from the tube to a glass culture tube, a different
consistency was observed) Oxymetazoline HCl 40.degree. C./75% White
viscous cream Creams 0.05% RH, 1 Month (not homogeneous) (A portion
of the cream was transferred from the tube to a glass culture tube,
a different consistency was observed) Oxymetazoline HCl 40.degree.
C./75% White viscous cream Creams 0.10% RH, 1 Month (not
homogeneous) (A portion of the cream was transferred from the tube
to a glass culture tube, a different consistency was observed)
Oxymetazoline HCl 40.degree. C./75% White viscous cream Creams
0.15% RH, 1 Month (not homogeneous) (A portion of the cream was
transferred from the tube to a glass culture tube, a different
consistency was observed)
[0125] Creams from Trials 20-34 were packaged into 30-g glaminate
tubes. The creams were placed on stability for up to 4 weeks at
storage condition of 25.degree. C./60% RH at accelerated conditions
of 60.degree. C. and 40.degree. C./75% RH and at the intermediate
condition 30.degree. C./75% RH. Trials 20-34 were tested initially
and after 1 week. Viscosity was measure using a Brookfield RVT,
C/P, Spindle CPE-52, 25 rpm, RT. The results are outlined in Table
14.
TABLE-US-00017 TABLE 14 STUDY RESULTS Viscosity pH pH Appearance
Appearance Sample ID cPs (Initial) (1 week).sup.2 (Initial) (1
week).sup.2 Trial #20 1836 4.45 4.58 White Viscous Cream White
Viscous Cream (Homogeneous) (Homogeneous) 4.32 White Viscous Cream
(Homogeneous) 4.16 White Viscous Cream (Homogeneous) Trial #21 2367
3.92 3.89 White Viscous Cream White Viscous Cream (Homogeneous)
(Homogeneous) 3.74 White Viscous Cream (Homogeneous) 3.58 White
Viscous Cream (Homogeneous) Trial #22 3450 4.57 4.55 White Viscous
Cream White Viscous Cream (Homogeneous) (Homogeneous) 4.57 White
Viscous Cream (Homogeneous) 4.54 White Viscous Cream (Homogeneous)
Trial #23 6895 4.24 4.15 White Viscous Cream White Viscous Cream
(Homogeneous) (Homogeneous) 4.05 White Viscous Cream (Homogeneous)
3.93 White Viscous Cream with oily spots Trial #24 1608 5.58 5.51
White Viscous Cream White Viscous Cream (Homogeneous) (Homogeneous)
5.51 White Cream-Lotion 5.48 White Viscous Cream (Homogeneous)
Trial #25 19183.sup.1 4.66 4.58 White Viscous Cream White Viscous
Cream (Homogeneous) (Homogeneous) 4.58 White Viscous Cream
(Homogeneous) 4.58 White Viscous Cream (Homogeneous) Trial #26
8458.sup.1 3.94 3.69 White Viscous Cream White Viscous Cream
(Homogeneous) (Homogeneous) 3.72 White Viscous Cream (Homogeneous)
3.64 White Viscous Cream (Homogeneous) Trial #27 21067 4.44 4.17
White Viscous Cream White Viscous Cream (Homogeneous) (Homogeneous)
4.04 White Viscous Cream (Homogeneous) 3.87 White Viscous Cream
(Homogeneous) Trial #28 4695 4.61 4.54 White Viscous Cream White
Viscous Cream (Homogeneous) (Homogeneous) 4.38 White Viscous Cream
(Homogeneous) 4.18 White Viscous Cream (Homogeneous) Trial #29 4686
4.53 4.41 White Viscous Cream White Viscous Cream (Homogeneous)
(Homogeneous) 4.26 White Viscous Cream (Homogeneous) 4.23 White
Cream-Lotion Trial #30 6931 3.64 3.65 Off-White Viscous Off-White
Viscous Cream Cream (Homogeneous) (Homogeneous) 3.56 Off-White
Viscous Cream (Homogeneous) 3.55 Off-White Viscous Cream
(Homogeneous) Trial #31 1700 5.65 5.50 White Viscous Cream White
Viscous Cream (Homogeneous) (Homogeneous) 5.36 White Viscous Cream
(Homogeneous) 5.04 White Cream-Lotion Trial #32 7269 3.75 3.69
White Viscous Cream White Viscous Cream (Homogeneous) (Homogeneous)
3.56 White soft Cream 3.62 White Lotion Trial #33 2580 4.25 4.23
White Viscous Cream White Viscous Cream (Homogeneous) (Homogeneous)
4.07 White Cream-Lotion 3.87 White Viscous Cream (Homogeneous)
Trial #34 5639 4.09 4.03 White Viscous Cream White Viscous Cream
(Homogeneous) (Homogeneous) 3.95 White Cream-Lotion 3.84 White
Cream-Lotion .sup.1Modified Method used Speed #10 RPM .sup.2Order:
25.degree. C./60% RH 40.degree. C./75%/RH 60.degree. C.
[0126] Based on the stability studies of Trials 20-34, it appears
that buffer systems stabilize the pH of the formulation.
Formulations with high content of Cetostearyl Alcohol and
Tefose.TM. 63 show a higher viscosity and a stable physical
consistency when exposed to 60.degree. C. temperature for 1 week.
While not wishing to be bound by theory, this may be explained due
to the two excipients' wax-like consistency and as such they impart
a more rigid structure to the cream. Further evaluation of the
stability data pointed to formulations which were optimized by
buffers and higher wax-like material content. A buffer that could
maintain a pH of about 4.5 was selected for Trials 35-37.
Example 3
[0127] Oxymetazoline creams formulated as Trials 35-37 were filled
into 30 gram tubes and stored at 25.degree. C., 30.degree. C.,
40.degree. C., and 60.degree. C. Each cream was initially tested
for appearance (Ap), melting point (mDSC), zeta potential (ZP), pH,
and viscosity (V), and each sample was reevaluated once per week
for 4 weeks to evaluate stability as follows:
[0128] Initial: Ap; mDSC; ZP; pH; and V
[0129] Week-1 (25; 40; 60): Ap; mDSC; ZP; pH; and V (if Ap
passes)
[0130] Week-2 (25; 40): Ap; mDSC; ZP; pH; and V (if Ap passes)
[0131] Week-4 (25; 40): Ap; mDSC; pH; and V (if Ap passes)
[0132] A sensorial evaluation was conducted by a blinded panel. The
panel's evaluation of cosmetic acceptability was based on the
criteria provided in Table 15:
TABLE-US-00018 TABLE 15 CRITERIA FOR COSMETIC ACCEPTABILITY
EVALUATION Test Category Scale General Appearance 7 = Pleasant 1 =
Unpleasant Color 7 = Pleasant 1 = Unpleasant Smell 7 = Pleasant 1 =
Unpleasant Tackiness 7 = Not Sticky 1 = Very Sticky Oiliness 7 =
Not Oily 1 = Very Oily Cosmetic Elegance 7 = Very elegant 1 = Not
Elegant Ease of Application 7 = Spreads Easily 1 = Not Well Speed
of Absorption 7 = Very Quickly 1 = Very Slowly Overall Application
7 = Very Pleasant 1 = Very Unpleasant Irritation/Stinging 7 = Not
Irritating 1 = Very Irritating Dry Skin 7 = Not Drying 1 = Very
Drying Moisturizing 7 = Moisturizing 1 = Not Moisturizing Can I put
Make-up 7 = Strongly Agree 1 = Strongly Disagree Over Cream Overall
Impression 7 = Excellent Product 1 = Terrible Product
[0133] Mean scores by category are provided in FIG. 1, and the mean
results for key evaluation categories are provided in FIG. 2. The
total mean score is provided in FIG. 3. As indicated in FIG. 1-3,
each formulation exhibited acceptable appearance. Overall, the
panel selected the formulation of Trial 36 as containing the best
sensorial attributes according to the criteria under Table 15.
[0134] Modulated Differential Scanning calorimetry (mDSC) and Zeta
Potential (ZP) determinations were performed on samples of the
Trials 20 through 34 and for the three high wax content
formulations Trials 36, 37 and 38. Samples of the creams were
subjected to mDSC cycles of heating and cooling from about
7.degree. C. to 60.degree. C. and back. It was found that an
optimal formulation combines a buffer system at pH 4.5, such as
Trial 22, with a high content of wax-like material (Cetostearyl
alcohol and Tefose 63) which demonstrated a physically stable
formulation.
[0135] Confirmatory studies of mDSC and Zeta Potential were
conducted on the formulation of Trial 36. The formulation of Trial
36 was compared with the formulation of Trial 27. Results: Trial 36
formulation showed that no major changes are taking place with
respect to the compound structure until 42.5.degree. C. except
changes in physical properties of the material after 39.degree. C.
in first heat and after 33.degree. C. in second heat. Trial 27
formulation showed that the initial mDSC at 25.degree. C. and after
1 week were less stabile than the formulations of Trial 36. The
physical changes are present from about 26.degree. C. and the
structural changes show an increased activity after about
40.degree. C. At the same time, the plot of Trial 36 formulation is
very similar with the Trial 27 formulation plotted after 1 week at
60.degree. C. stability. The improvement in mDSC of Trial 36
appears to be related to the combined result of adjusting the ratio
of cetostearyl alcohol to Tefose.TM. 63 to 1:1, optimization of the
concentrations of Tefose and cetostearyl alcohol, and optimization
of the overall total concentrations and ratio of emulsifier to
emollient.
[0136] The pH of Trial 36 was adjusted to 4.5 using anhydrous
citric acid (0.2% by weight) and sodium citrate dihydrate (0.3% by
weight), and the zeta potential of this formula was -5.
Example 4
[0137] The formulation of Trial 36 was selected for a formal
accelerated stability study. For this study Trials 42 at 0.01% API
and Trial 43 at 0.15% API were prepared. The purpose of this
protocol was to perform a stability study on Oxymetazoline Topical
Creams, 0.01% and 0.15% based on Trial 36. The creams were packaged
into 30-g glaminate tubes. Approximately 60 tubes of each cream
concentration was prepared. The creams were placed on stability at
the nominal storage condition of 25.degree. C./60% RH and at
accelerated conditions of 40.degree. C./75% RH. Samples were also
stored at the intermediate condition, 30.degree. C./75% RH.
Viscosity was measured using a Brookfield RVT, C/P, Spindle CPE-52,
25 rpm, RT.
[0138] RESULTS: The appearance, viscosity, pH & assay results
of the samples were consistent for the sub-samples from top, middle
and bottom of the tube as well as the composite sample. This shows
that the manufacturing procedure was carried out efficiently. The
results indicate the preparation to be a stable formulation.
Example 5
[0139] An in vitro permeation procedure for oxymetazoline cream was
developed using the 0.01 and 0.10% w/w oxymetazoline cream. The in
vitro experiments were conducted using Hanson Microette Franz Cell
apparatus and 0.01N PBS (pH 7.4) as the receiving medium. Other
critical parameters were evaluated such as the type of
semi-synthetic membrane, sample timing (time dependent
release-permeability profile), method sensitivity, specificity and
linearity.
[0140] Permeation characterization of oxymetazoline cream of
different strengths (0.01% w/w, 0.05% w/w, 0.10% w/w and 0.15% w/w)
was based on flux study across two different artificial membranes
(cellulose acetate and polysulfone). The concentration of
oxymetazoline which permeated through the membranes was measured
using an HPLC assay.
[0141] RESULTS: The oxymetazoline permeation rate over the
concentration range studied exhibited a dump and die profile,
reaching a peak after 0.5 hours of the cream application. After
this period, the drug release gradually declined for the next 24
hours. Oxymetazoline permeability (AUC.sub.0-24h) linearly
increased in the concentration range 0.01-0.10% w/w. Further
increase of drug concentration (0.10-0.15% w/w), did not lead to a
proportional increase in the amount of drug delivered across the
membrane. The in vitro membrane transport reached saturation above
the 0.1% w/w level irrespective the membrane type used.
[0142] Permeability efficiency across the cellulose acetate and
polysulfone membranes (expressed as a percent of total drug
permeated as a function of time) was similar for all four strengths
(30-40%) after the 24 hours application period. Lower oxymetazoline
release was observed in the case of polysulfone at the lowest 0.01%
w/w level. Without wishing to be bound by theory, this effect may
be caused by drug binding to this membrane at this low
concentration level.
Example 6
[0143] Additional formulations were made using Trial 38 as the base
formulation and varying the amount of oxymetazoline. Such
formulations included oxymetazoline at 0.01%, 0.05%, 0.06%, 0.1%,
0.15%, 0.25%, 0.5%, 1% and 2.5%, and were found to be stable.
Example 7
[0144] Stability studies were done on oxymetazoline creams: 0.01%
cream, 0.10% cream, and 0.15% cream, after 9 months at 25.degree.
C./60% RH, and after 6 months at 40.degree. C./75% RH.
[0145] RESULTS: The appearance for all samples at normal and
accelerated conditions is in conformance with the initial
appearance indicating no change of the appearance from initial. The
assay results (potency of API) of the samples at 25.degree. C./60%
RH and 40.degree. C./75% RH are all above 100% indicating chemical
stability of the drug in the formulation. The pH values at both
storage conditions are within the narrow range of 4.30 and 4.70
indicating that the buffer system is maintaining the pH of the
formulation. No microbial issues are reported showing that the
preservative is efficacious. The viscosity samples at both storage
conditions seem to go up and in some cases down. This is not
unusual for emulsion systems containing a waxy matrix. In such
systems melting and re-crystallization of lipids produce a mixture
of wax materials of different crystalline forms that have an impact
on the rheological behavior of the cream. Ref: Theory and Practice
of Industrial Pharmacy. Lachman, Lieberman and Kanig).
Example 8
[0146] Stability studies were done on oxymetazoline creams: 0.25%
and 0.50% creams, after 3 months at 25.degree. C./60% RH and after
3 months at 40.degree. C./75% RH.
[0147] RESULTS: The appearance of all samples at normal and
accelerated conditions is in conformance with the initial
appearance indicating no change in appearance from initial. The
assay results (potency of API) of the samples at 25.degree. C./60%
RH and 40.degree. C./75% RH are all above 100% indicating chemical
stability of the drug in the formulation. The pH values at both
storage conditions are within the narrow range of 4.10 and 4.60
indicating that the buffer system is maintaining the pH of the
formulation. No microbial issues are reported showing that the
preservative is efficacious. The viscosity samples at both storage
conditions seem to go up and in some cases down. This is not
unusual for emulsion systems containing a waxy matrix. In such
systems melting and re-crystallization of lipids produce a mixture
of wax materials of different crystalline forms that have an impact
on the rheological behavior of the cream (Ref: Theory and Practice
of Industrial Pharmacy. Lachman, Lieberman and Kanig).
Example 9
[0148] The following formulations were made and were found to be
stable.
TABLE-US-00019 TABLE 16 Oxymetazoline Formulations COMPONENT % W/W
Oxymetazoline 0.5 1.0 1.5 Phenoxy ethanol 0.8 0.8 0.8 Methyl
paraben 0.2 0.2 0.2 Propyl paraben 0.05 0.05 0.05 EDTA 0.01 0.01
0.01 BHT 0.05 0.05 0.05 PEG 300 4.0 4.0 4.0 Tefose-63 (PEG &
Glycol & 8.0 8.0 8.0 PEG-32 stearate) Cetostearyl alcohol 8.0
8.0 8.0 Med chain triglycerides 7.0 7.0 7.0 (caprylic capric
triglycerides) Diisopropyl adipate 7.0 7.0 7.0 Oleyl alcohol 7.0
7.0 7.0 Lanolin 2.0 2.0 2.0 Cremophor A-25 2.0 2.0 2.0 Cremophor
A-6 2.0 2.0 2.0 Anhydrous Citric acid 0.2 0.2 0.2 Sodium citrate
dihydrate 0.3 0.3 0.3 Purified Water, USP QS 100% QS 100% QS
100%
Example 10
[0149] A single-center, two-way crossover relative bioavailability
study of V-101 (oxymetazoline) cream 0.50% administered topically,
and oxymetazoline HCl solution (Afrin.RTM.) 0.05% administered
intranasally to subjects with moderate to severe erythematous
rosacea, was conducted.
[0150] Objectives: To assess the relative bioavailability of V-101
cream 0.50% and oxymetazoline nasal spray 0.05% under conditions of
maximum use and to evaluate the safety of V-101 cream 0.50%
administered topically to the face in male and female subjects with
moderate to severe erythematous rosacea under maximum use
conditions.
[0151] Methodology: This was a double-blind, randomized, 2-way
crossover study of V-101 cream 0.50% and oxymetazoline nasal spray
0.05% administered in adult subjects with moderate to severe
erythematous rosacea. Subjects were seen for screening up to 28
days before Treatment Visit 1. Subjects who were eligible for
randomization had 2 treatment visits separated by a washout period
of 6 to 21 days. At Treatment Visit 1 subjects were treated with
one 0.5 g facial application of V 101 cream 0.50% plus 3 sprays of
control (normal saline) nasal spray in each nostril (Treatment A)
or one 0.5 g facial application of vehicle cream plus 3 sprays of
oxymetazoline nasal spray 0.05% in each nostril (Treatment B). The
treatment sequence (A then B or B then A) was randomized. Subjects
received the opposite treatment at Treatment Visit 2. Evaluations
and blood sampling for determination of plasma concentrations of
oxymetazoline took place through 12 hours after dosing at each
treatment visit.
[0152] Number of Subjects (Planned and Analyzed): Approximately 28
subjects (14 per treatment sequence) were planned to ensure that at
least 20 subjects completed 2 treatment visits; 28 subjects were
randomized and included in the analyses.
[0153] Diagnosis and Main Criteria for Inclusion: Diagnosis:
Moderate to severe erythematous rosacea. Main Inclusion Criteria:
Males and females age .gtoreq.18 years in good general health with
a clinical diagnosis of erythematous rosacea, Subject's Self
Assessment (SSA) and Clinician's Erythema Assessment (CEA) scores
of .gtoreq.3, .ltoreq.3 inflammatory lesions (papules and/or
pustules) within the treatment area, intraocular pressure
(TOP).gtoreq.10 mm Hg and .ltoreq.21 mm Hg, and females with
negative pregnancy test who were non lactating, and using an active
method of birth control.
[0154] Test Product, Dose and Mode of Administration, Batch Number:
V-101 (oxymetazoline) cream 0.50% (lot B10013) was applied
topically to the face by a site staff member at a dose of 0.5 g
after the subject administered the assigned nasal spray.
[0155] Duration of Treatment: The study included 2 treatments
separated by a washout period of 6 to 21 days. Treatment A was
V-101 cream 0.50% and control saline nasal spray. Treatment B was
vehicle cream and oxymetazoline nasal spray 0.05%.
[0156] Criteria for Evaluation: Efficacy was evaluated as the
overall severity of erythema on the treatment area at the study
visits by the subject, using the 5-point SSA scale and by the
investigator, using the 5-point CEA scale at 0 (just prior to the
study medication dose), 2, 3, 4, 6, 9, and 12 hours post dose.
Pharmacokinetics and relative bioavailability were to be evaluated
based on quantitation of oxymetazoline levels from blood samples
collected at each treatment visit at 0 (just prior to the study
medication dose), 1, 2, 3, 4, 6, 9, and 12 hours post-dose. Safety
was evaluated by treatment-emergent adverse events (AEs),
laboratory evaluations, vital signs, electrocardiograms (ECGs), and
intraocular pressure (TOP).
[0157] Analysis of Efficacy: Clinician's Erythema Assessment (CEA):
The primary efficacy variable, the mean change from pre-dose in AUC
for CEA, was -9.107 following treatment with V-101 cream 0.50% and
control nasal spray compared to -0.411 following treatment with
vehicle cream and oxymetazoline nasal spray 0.05%. The difference
between the treatments was statistically significant, p<0.001.
Across both treatment sequences combined, the CEA pre-dose and
change from pre-dose values are summarized in Table 17.
Statistically significantly greater improvement was seen following
treatment with V-101 cream 0.50% and control nasal spray compared
to vehicle cream and oxymetazoline nasal spray 0.05% at all time
points from 2 through 12 hours post dose (p.ltoreq.0.003).
TABLE-US-00020 TABLE 17 Clinician's Erythema Assessment: Mean
Pre-Dose and Mean Change from Pre-Dose for Subjects Completing the
Study (Treatment Sequences Combined) Mean (Standard Deviation)
V-101 Cream + Vehicle Cream + Control Spray Oxy 0.05% Spray Time (N
= 28) (N = 28) P-value.sup.1 Pre-dose 3.214 (0.418) 3.214 (0.418)
NA 2 Hours Change -1.214 (0.833) -0.143 (0.448) <0.001 3 Hours
Change -1.571 (0.920) -0.036 (0.331) <0.001 4 Hours Change
-1.036 (0.793) -0.036 (0.189) <0.001 6 Hours Change -0.893
(0.832) 0.000 (0.272) <0.001 9 Hours Change -0.500 (0.694)
-0.036 (0.189) <0.001 12 Hours Change -0.286 (0.460) 0.000
(0.272) 0.003 Avg Hrs 3-6 Change -1.107 (0.832) -0.036 (0.189)
<0.001 Avg = average, NA = not applicable, Oxy = oxymetazoline
.sup.1P-values were calculated using analysis of covariance based
on change from pre dose and variables were analyzed as continuous
variables.
[0158] An analysis was performed in which treatment success was
defined as a score of 0 or 1 or a reduction from baseline of at
least 2 grades on the CEA. The success rate was statistically
significantly greater for treatment with V-101 cream 0.50% and
control nasal spray than for treatment with vehicle cream and
oxymetazoline nasal spray 0.05% from 2 through 6 hours
(p.ltoreq.0.010 by the chi-square test. For the averaged Hours 3-6
score, where success rate was defined as a score of 0 or 1 or a
reduction from baseline of at least 1.5 grades on the CEA, 9 of 28
(32%) subjects following treatment with V-101 cream 0.50% and
control nasal spray and none of 28 subjects (0%) following
treatment with vehicle cream and oxymetazoline nasal spray 0.05%
achieved treatment success (p=0.010 by the chi square test).
[0159] Subject's Self-Assessment (SSA): The mean change from
pre-dose in AUC for SSA was 6.661 following treatment with V 101
cream 0.50% and control nasal spray compared to 0.339 following
treatment with vehicle cream and oxymetazoline nasal spray 0.05%.
The difference between the treatments was statistically
significant, p<0.001.
[0160] Across both treatment sequences combined, the SSA pre-dose
and change from pre-dose values are summarized in Table 18.
Statistically significantly greater improvement was seen following
treatment with V-101 cream 0.50% and control nasal spray compared
to vehicle cream and oxymetazoline nasal spray 0.05% at all time
points from 2 through 12 hours post dose (p<0.001).
TABLE-US-00021 TABLE 18 Subject's Self-Assessment: Mean Pre-Dose
and Mean Change from Pre-Dose for Subjects Completing the Study
(Treatment Sequences Combined) Mean (Standard Deviation) V-101
Cream + Vehicle Cream + Control Spray Oxy 0.05% Spray Time (N = 28)
(N = 28) P-value.sup.1 Pre-dose 3.071 (0.262) 3.107 (0.315) NA 2
Hours Change -0.500 (0.638) 0.000 (0.000) <0.001 3 Hours Change
-0.607 (0.629) 0.036 (0.189) <0.001 4 Hours Change -0.643
(0.731) 0.036 (0.189) <0.001 6 Hours Change -0.643 (0.731) 0.036
(0.189) <0.001 9 Hours Change -0.607 (0.737) 0.036 (0.189)
<0.001 12 Hours Change -0.607 (0.786) 0.036 (0.189) <0.001
Avg Hrs 3-6 Change -0.643 (0.731) 0.036 (0.189) <0.001 Avg =
average, NA = not applicable, Oxy = oxymetazoline .sup.1P-values
were calculated using analysis of covariance based on change from
pre dose and variables were analyzed as continuous variables.
[0161] An analysis was performed in which treatment success was
defined as a score of 0 or 1 or a reduction from baseline of at
least 2 grades on the SSA. The success rate was higher for
treatment with V-101 cream 0.50% and control nasal spray than for
treatment with vehicle cream and oxymetazoline nasal spray 0.05%
from 2 through 12 hours but the between-treatment differences were
not statistically significant. For the averaged Hours 3-6 score,
where success rate was defined as a score of 0 or 1 or a reduction
from baseline of at least 1.5 grades on the SSA, 2 of 28 (7%)
subjects following treatment with V-101 cream 0.50% and control
nasal spray and none of 28 subjects (0%) following treatment with
vehicle cream and oxymetazoline nasal spray 0.05% achieved
treatment success.
[0162] In an analysis defining treatment success as a score of 0 or
1 or a reduction from baseline of at least 2 grades on both the CEA
and the SSA, the success rate was higher for treatment with V-101
cream 0.50% and control nasal spray than for treatment with vehicle
cream and oxymetazoline nasal spray 0.05% from 2 through 12 hours
but the between-treatment differences were not statistically
significant. For the averaged Hours 3-6 score, where success rate
was defined as a score of 0 or 1 or a reduction from baseline of at
least 1.5 grades on both the CEA and the SSA, 2 of 28 (7%) subjects
following treatment with V 101 cream 0.50% and control nasal spray
and none of 28 subjects (0%) following treatment with vehicle cream
and oxymetazoline nasal spray 0.05% achieved treatment success.
[0163] Pharmacokinetics: In general, minimal systemic exposure of
oxymetazoline was observed following topical facial application of
V-101 cream 0.50% in subjects with moderate to severe erythematous
rosacea. The mean maximum observed plasma concentration (C.sub.max)
and area under the plasma concentration-time curve from 0 hour to
the last measurable plasma concentration (AUC.sub.0-t) following
treatment with V-101 cream 0.50% and control nasal spray were 34.7
pg/mL and 295 pghr/mL respectively. Following treatment with
vehicle cream and oxymetazoline nasal spray 0.05%, the median time
to C.sub.max (T.sub.max) was 3.00 hours and mean C.sub.max,
AUC.sub.0-t, area under the plasma-concentration-time curve
extrapolated to infinity (AUC.sub.0-.infin.), apparent terminal
phase rate constant (.lamda..sub.Z), and apparent plasma terminal
phase half-life (t.sub.1/2) were 245 pg/mL, 1741 pghr/mL, 1859
pghr/mL, 0.143 (1/hr), and 4.99 hours, respectively.
[0164] Conclusion: A single topical facial administration of V-101
cream 0.50% under maximum use conditions in subjects with moderate
to severe erythematous rosacea resulted in minimal systemic
exposure when compared with a single administration of Afrin Nasal
Spray 0.05%. Topical facial application of V-101 cream 0.50% was
well tolerated and significantly reduced erythema from 2 to 12
hours post-dose.
* * * * *