U.S. patent application number 15/090398 was filed with the patent office on 2016-07-28 for compositions and methods of treatment of inflammatory skin conditions using allantoin.
This patent application is currently assigned to Scioderm, Inc.. The applicant listed for this patent is Scioderm, Inc.. Invention is credited to Elliott FARBER, Robert RYAN.
Application Number | 20160213649 15/090398 |
Document ID | / |
Family ID | 50547852 |
Filed Date | 2016-07-28 |
United States Patent
Application |
20160213649 |
Kind Code |
A1 |
FARBER; Elliott ; et
al. |
July 28, 2016 |
Compositions And Methods Of Treatment Of Inflammatory Skin
Conditions Using Allantoin
Abstract
Embodiments herein provide formulations and methods for
treatment of inflammatory skin diseases using allantoin in an
amount from about 0.5% to about 15.0% by weight. Inflammatory skin
diseases treated by embodiments herein include, without limitation,
cutaneous porphyria, sclerodema, epidermolysis bulosa, psoriasis,
decubitus ulcers, pressure ulcers, diabetic ulcers, venous stasis
ulcers, sickle cell ulcers, ulcers caused by burns, eczema,
urticaria, atopic dermatitis, dermatitis herpetiform, contact
dermatitis, arthritis, gout, lupus erythematosus, acne, alopecia,
carcinomas, psoriasis, rosacea, miliaria, skin infections,
post-operative care of incisions, post-operative skin care
following any variety of plastic surgery operations, skin care
following radiation treatment, care of dry, cracked or aged skin
and skin lines as well as other conditions affecting the skin and
having an inflammatory component, symptoms thereof, or a
combination thereof. Symptoms treated may include pain,
inflammation, redness, itching, scarring, skin thickening, milia,
or a combination thereof.
Inventors: |
FARBER; Elliott; (Apple
Valley, MN) ; RYAN; Robert; (Durham, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Scioderm, Inc. |
Cranbury |
NJ |
US |
|
|
Assignee: |
Scioderm, Inc.
Cranbury
NJ
|
Family ID: |
50547852 |
Appl. No.: |
15/090398 |
Filed: |
April 4, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14789173 |
Jul 1, 2015 |
9339492 |
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15090398 |
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14062295 |
Oct 24, 2013 |
9095574 |
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14789173 |
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13019039 |
Feb 1, 2011 |
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14062295 |
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61300627 |
Feb 2, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/107 20130101;
A61K 9/0014 20130101; A61K 47/12 20130101; A61P 17/00 20180101;
A61P 29/00 20180101; A61K 9/06 20130101; A61K 47/20 20130101; A61K
47/44 20130101; A61K 47/10 20130101; A61K 47/14 20130101; A61K
31/4166 20130101 |
International
Class: |
A61K 31/4166 20060101
A61K031/4166; A61K 9/00 20060101 A61K009/00; A61K 47/10 20060101
A61K047/10; A61K 47/14 20060101 A61K047/14; A61K 47/20 20060101
A61K047/20; A61K 47/12 20060101 A61K047/12; A61K 47/18 20060101
A61K047/18; A61K 9/107 20060101 A61K009/107; A61K 47/44 20060101
A61K047/44 |
Claims
1-27. (canceled)
28. A composition comprising an oil-in-water emulsion comprising:
(a) about 6% allantoin; (b) about 40% to about 90% water; (c) about
8% to about 30% an emollient; (d) about 1% to about 15% an
emulsifier; (e) about 0.01% to about 1% a pH modifier; (f) about 1%
to about 10% a viscosity agent; (g) about 1% to about 20% a
solubilizing agent selected from the group consisting of propylene
glycol, glycerin, and a combination thereof; (h) about 0.01% to
about 2% a chelating agent selected from the group consisting of
alanine, sodium polyphosphate, sodium methaphosphate, citric acid,
phosphoric acid, tartaric acid, dihydroxyethyl glycine,
ethylenediamine tetra acetic acid (EDTA) and derivatives and salts
thereof, and a combination thereof; (i) about 0.001% to about 3% an
antioxidant selected from the group consisting of vitamin B,
nordihydroguaiaretic acid, butylated hydroxyanisole (BHA),
butylated hydroxytoluene (BHT), propyl gallate, erythorbate acid,
sodium erythorbate, ascorbir palmitate, ascorbir stearate, butyl
hydroxyanisole, and gallic esters; and (j) about 0.01% to about
3.0% a preservative.
29. The composition of claim 28 comprising: (a) about 6% allantoin;
(b) about 40% to about 90% water; (c) about 8% to about 30%
emollient selected from the group consisting of lanolin oil, cod
liver oil, mineral oil, an alcohol, and any combination thereof;
(d) about 1% to about 15% emulsifier selected from the group
consisting of sodium lauryl sulfate, a white wax, and a combination
thereof; (e) about 0.01% to about 1% pH modifier selected from the
group consisting of citric acid, lactic acid, and a combination
thereof; (f) about 1% to about 10% viscosity enhancing agent
selected from the group consisting of cetyl alcohol, stearyl
alcohol, and a combination thereof; (g) about 1% to about 20%
solubilizing agent selected from the group consisting of propylene
glycol, glycerin, and a combination thereof; (h) about 0.01% to
about 2% chelating agent selected from the group consisting of
alanine, sodium polyphosphate, sodium methaphosphate, citric acid,
phosphoric acid, tartaric acid, dihydroxyethyl glycine,
ethylenediamine tetra acetic acid (EDTA) and derivatives and salts
thereof, and a combination thereof; (i) 0.01% to about 1%
antioxidant selected from the group consisting of vitamin B,
nordihydroguaiaretic acid, butylated hydroxyanisole (BHA),
butylated hydroxytoluene (BHT), propyl gallate, erythorbate acid,
sodium erythorbate, ascorbir palmitate, ascorbir stearate, butyl
hydroxyanisole, and gallic esters; and (j) about 0.01% to about
3.0% preservative selected from the group consisting of
methylparaben, propylparaben, and a combination thereof.
30. The composition of claim 29, comprising: (a) about 6%
allantoin; (b) about 40% to about 90% water; (c) about 1% to about
6% cetyl alcohol; (d) about 1% to about 3% stearyl alcohol; (e)
about 1.5% to about 3% beeswax; (f) about 1.5% to about 3% sodium
lauryl sulfate in a 30% solution; (g) about 0.05% to about 0.2%
citric acid; (h) about 5% to about 15% lanolin oil; (i) about 2% to
about 8% propylene glycol; (j) about 0.05% to about 0.5%
tetrasodium EDTA; (k) about 0.05% to about 5% cod liver oil; (l)
about 0.05% to about 1% butylated hydroxytoluene; (m) about 0.05%
to about 0.5% methylparaben; and (n) about 0.05% to about 0.5%
propylparaben.
31. The composition of claim 30, comprising: (a) about 42% to about
68% water; (b) about 2% to about 6% cetyl alcohol; (c) about 1% to
about 3% stearyl alcohol; (d) about 1.5% to about 3% beeswax; (e)
about 1.5% to about 3% sodium lauryl sulfate in a 30% solution; (f)
about 0.06% to about 0.1% citric acid; (g) about 5% to about 15%
lanolin oil; (h) about 2% to about 8% propylene glycol; (i) about
0.05% to about 0.35% tetrasodium EDTA; (j) about 0.05% to about 5%
cod liver oil; (k) about 0.05% to about 1% butylated
hydroxytoluene; (l) about 0.05% to about 0.5% methylparaben; and
(m) about 0.05% to about 0.5% propylparaben.
32. The composition of claim 31, comprising: (a) about 65.11%
water; (b) about 3.6% cetyl alcohol; (c) about 1.7% stearyl
alcohol; (d) about 2.0% beeswax; (e) about 2.0% sodium lauryl
sulfate in a 30% solution; (f) about 0.09% citric acid; (g) about
10.6% lanolin oil; (h) about 5.7% propylene glycol; (i) about 0.15%
tetrasodium EDTA; (j) about 2% cod liver oil; (k) about 0.5%
butylated hydroxytoluene; (l) about 0.3% methylparaben; and (m)
about 0.25% propylparaben.
33. The composition of claim 28 further comprising a fragrance.
34. A method for treating epidermolysis bulosa in a patient in need
thereof, comprising contacting the patient's skin with an effective
amount of the composition of claim 28.
35. The method of claim 34, wherein the composition is administered
to the patient daily.
36. The method of claim 34, wherein the composition results in
penetration of the allantoin across the skin membrane of the
patient in a dose dependent manner.
37. The method of claim 34, wherein the composition results in
penetration of the allantoin across the skin membrane of the
patient without an increase in systemic blood levels of allantoin
in the patient.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. Provisional
Application No. 61/300,267 filed Feb. 2, 2010 entitled
"Compositions and Methods for Treatment of Inflammatory Skin
Conditions Using Allantoin," which is incorporated herein by
reference in its entirety.
GOVERNMENT INTERESTS
[0002] Not applicable
PARTIES TO A JOINT RESEARCH AGREEMENT
[0003] Not applicable
INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED ON A COMPACT
DISC
[0004] Not applicable
BACKGROUND
[0005] Not applicable
BRIEF SUMMARY OF THE INVENTION
[0006] Embodiments of the present invention relate generally to
compositions comprising allantoin that can be used to treat
individuals affected with inflammatory skin conditions. The
compositions are preferably formulated as topical formulations.
[0007] In one aspect, formulations of allantoin comprising from
about 2.5% to about 15% of allantoin by weight and a
pharmaceutically acceptable excipient are provided. In some
embodiments, the amount of allantoin is not 1.5% by weight or less
of the composition. In some embodiments, the amount of allantoin is
not 2.0% by weight or less of the composition. In embodiments, the
formulation further comprises an emollient, an emulsifier, a
solvent, a pH modifier, a solubilizing agent, an antioxidant, a
preservative, a chelating agent, an additive, a viscosity agent or
a combination thereof. In some embodiments, the formulation
comprises, allantoin in an amount from about 2.5% to about 15% by
weight of the formulation, water, cetyl alcohol, stearyl alcohol,
beeswax, sodium lauryl sulfate in an about 30% solution, citric
acid, lanolin oil, propylene glycol, cod liver oil, butylated
hydroxytoluene, methylparaben, propylparaben or a combination
thereof. In an embodiment, the formulation may comprise allantoin
in an amount of from about 2.5% to about 15%; water in an amount
from about 40% to about 90%; cetyl alcohol in an amount from about
0.5% to about 15%; stearyl alcohol in an amount from about 1% to
about 3%; beeswax in an amount from about 1.5% to about 3%; sodium
lauryl sulfate in a 30% solution in an amount from about 1.5% to
about 3%; citric acid in an amount from about 0.5% to about 0.2%;
lanolin oil in an amount from about 5% to about 15%; propylene
glycol in an amount from about 2% to about 8%; tetrasodium EDTA in
an amount from about 0.05% to about 0.5%; cod liver oil in an
amount from about 0.05% to about 5%; butylated hydroxytoluene in an
amount from about 0.05% to about 1%; methylparaben in an amount
from about 0.05% to about 0.5%; propylparaben in an amount from
about 0.05% to about 0.5% by weight of the formulation or a
combination thereof. In embodiments, the formulation optionally
includes tetrasodium EDTA. In embodiments, the tetrasodium EDTA may
be present in an amount from about 0.05% to about 0.5% by weight of
the formulation. In embodiments, the formulation optionally
includes a fragrance. In some embodiments, allantoin may be present
in an amount from about 1.5% to about 15%, from about 2.0% to about
15%, from about 2.5% to about 15% or from about 3.0% to about 15%
by weight of the formulation. In some embodiments, the amount of
allantoin is not 1.5% by weight or less of the composition. In some
embodiments, the amount of allantoin is not 2.0% by weight or less
of the composition.
[0008] In another aspect, formulations of allantoin comprising
about 3.0% of allantoin, water, cetyl alcohol, stearyl alcohol,
beeswax, sodium lauryl sulfate in an about 30% solution, citric
acid, lanolin oil, propylene glycol, tetrasodium EDTA, cod liver
oil, butylated hydroxytoluene, methylparaben, and propylparaben are
provided. In another aspect, formulations of allantoin comprising
about 6.0% of allantoin, water, cetyl alcohol, stearyl alcohol,
beeswax, sodium lauryl sulfate in an about 30% solution, citric
acid, lanolin oil, propylene glycol, tetrasodium EDTA, cod liver
oil, butylated hydroxytoluene, methylparaben, and propylparaben are
provided. In another aspect, formulations of allantoin comprising
about 9.0% of allantoin, water, cetyl alcohol, stearyl alcohol,
beeswax, sodium lauryl sulfate in a about 30% solution, citric
acid, lanolin oil, propylene glycol, tetrasodium EDTA, cod liver
oil, butylated hydroxytoluene, methylparaben, and propylparaben are
provided.
[0009] In another aspect, embodiments describe methods of treatment
of inflammatory skin conditions comprising administrating a
composition comprising from about 2.5% to about 15% allantoin and a
pharmaceutically acceptable excipient. In some embodiments, the
amount of allantoin is not 1.5% by weight or less of the
composition. In some embodiments, the amount of allantoin is not
2.0% by weight or less of the composition. In embodiments, the
composition further comprises an emollient, an emulsifier, a
solvent, a pH modifier, a solubilizing agent, an antioxidant, a
preservative, a chelating agent, an additive, a viscosity agent or
a combination thereof. In some embodiments, the formulation
comprises allantoin, water, cetyl alcohol, stearyl alcohol,
beeswax, sodium lauryl sulfate in an about 30% solution, citric
acid, lanolin oil, propylene glycol, cod liver oil, butylated
hydroxytoluene, methylparaben, propylparaben or a combination
thereof. In some embodiments, the formulation comprises allantoin
in an amount from about 2.5% to about 15%, water in an amount from
about 40% to about 90%; cetyl alcohol in an amount from about 0.5%
to about 15%; stearyl alcohol in an amount from about 1% to about
3%; beeswax in an amount from about 1.5% to about 3%; sodium lauryl
sulfate in a 30% solution in an amount from about 1.5% to about 3%;
citric acid in an amount from about 0.5% to about 0.2%; lanolin oil
in an amount from about 5% to about 15%; propylene glycol in an
amount from about 2% to about 8%; cod liver oil in an amount from
about 0.05% to about 5%; butylated hydroxytoluene in an amount from
about 0.05% to about 1%; methylparaben in an amount from about
0.05% to about 0.5%; propylparaben in an amount from about 0.05% to
about 0.5% by weight of the formulation or a combination thereof.
In embodiments, the formulation optionally includes tetrasodium
EDTA. In embodiments, the tetrasodium EDTA may be present in an
amount from about 0.05% to about 0.5% by weight of the formulation.
In embodiments, the formulation optionally includes a fragrance. In
some embodiments, allantoin may be present in an amount from about
1.5% to about 15%, from about 2.0% to about 15%, from about 2.5% to
about 15% or from about 3.0% to about 15% by weight of the
formulation.
[0010] In another aspect, embodiments describe methods of treatment
of inflammatory skin conditions comprising administering a
composition comprising about 3.0% allantoin and a pharmaceutical
excipient. In another aspect, embodiments describe methods of
treatment of inflammatory skin conditions comprising administering
a composition comprising about 6.0% allantoin and a pharmaceutical
excipient. In another aspect, embodiments describe methods of
treatment of inflammatory skin conditions comprising administering
a composition comprising about 9.0% allantoin and a pharmaceutical
excipient.
[0011] In some aspects, the inflammatory skin condition may be
characterized by ulceration, inflammation, or blistering of the
skin. In some embodiments, the inflammatory skin condition may be
characterized by a genetic component, an autoimmune component, a
circulatory component or combinations thereof. In some embodiments,
the inflammatory skin condition may be selected from a group
consisting of cutaneous porphyria, sclerodema, epidermolysis
bulosa, psoriasis, decubitus ulcers, pressure ulcers, diabetic
ulcers, venous stasis ulcers, sickle cell ulcers, ulcers caused by
burns, eczema, urticaria, atopic dermatitis, dermatitis
herpetiform, contact dermatitis, arthritis, gout, lupus
erythematosus, acne, alopecia, carcinomas, psoriasis, rosacea,
miliaria, inflammation due to skin infections, post-operative care
of incisions, post-operative inflammation, inflammation following
radiation treatment, inflammation due to dry, cracked or aged skin,
skin lines, a combination thereof and a symptom thereof. In some
embodiments, the symptom may be selected from pain, inflammation,
itching, scarring, milia, skin thickening, redness, or a
combination thereof.
[0012] In another aspect, embodiments describe methods of treatment
of Epidermolysis bullosa comprising the topical administration of
an about 3.0% allantoin containing composition.
[0013] In another aspect, embodiments describe methods of treatment
of Epidermolysis bullosa comprising the topical administration of
an about 6.0% allantoin containing composition.
[0014] In another aspect, embodiments describe methods of treatment
of Epidermolysis bullosa comprising the topical administration of
an about 9.0% allantoin containing composition.
[0015] In another aspect, embodiments describe methods of treatment
of psoriasis comprising the topical administration of an about 3.0%
allantoin containing composition.
[0016] In another aspect, embodiments describe methods of treatment
of psoriasis comprising the topical administration of an about 6.0%
allantoin containing composition.
[0017] In another aspect, embodiments describe methods of treatment
of psoriasis comprising the topical administration of an about 9.0%
allantoin containing composition.
[0018] In another aspect, embodiments describe methods of treatment
of diabetic ulcers comprising the topical administration of an
about 3.0% allantoin containing composition.
[0019] In another aspect, embodiments describe methods of treatment
of diabetic ulcers comprising the topical administration of an
about 6.0% allantoin containing composition.
[0020] In another aspect, embodiments describe methods of treatment
of diabetic ulcers comprising the topical administration of an
about 9.0% allantoin containing composition.
[0021] In another aspect, embodiments describe methods of treatment
of atopic dermatitis comprising the topical administration of an
about 3.0% allantoin containing composition.
[0022] In another aspect, embodiments describe methods of treatment
of atopic dermatitis comprising the topical administration of an
about 6.0% allantoin containing composition.
[0023] In another aspect, embodiments describe methods of treatment
of atopic dermatitis comprising the topical administration of an
about 9.0% allantoin containing composition.
[0024] These and other features provided by the present disclosure
are set forth herein.
DESCRIPTION OF DRAWINGS
[0025] For a fuller understanding of the nature and advantages of
the present invention, reference should be had to the following
detailed description taken in connection with the accompanying
drawings, in which:
[0026] FIG. 1 illustrates exemplary formulations of allantoin
according to embodiments disclosed herein.
[0027] FIG. 2 illustrates an exemplary embodiment of a method of
manufacture of pharmaceutical compositions disclosed herein.
[0028] FIG. 3 includes summary tables detailing percutaneous
absorption through various barriers over 48 hours from a single
application of different formulations of allantoin.
[0029] FIG. 4 is a summary graph detailing percutaneous absorption
through various barriers over 48 hours from a single application of
different formulations of allantoin.
[0030] FIG. 5 is a summary graph detailing percutaneous absorption
through dermatomed human cadaver skin over 48 hours from a single
application of formulations of 9% allantoin.
[0031] FIG. 6 is a graph of the results of membrane release of
different formulations of allantoin through a porous membrane.
[0032] FIG. 7 includes tables detailing the results of membrane
release of different formulations of allantoin through a porous
membrane.
[0033] FIG. 8 is a graph of the results for the percutaneous
absorption of different formulations of allantoin through abraded
and unabraded porcine cadaver skin.
[0034] FIG. 9 includes tables of the results for percutaneous
absorption of different formulations of allantoin through abraded
and unabraded porcine cadaver skin.
[0035] FIG. 10 is a graph summarizing the percutaneous absorption
of different formulations of allantoin through full thickness human
cadaver skin.
[0036] FIG. 11 includes tables detailing results for percutaneous
absorption of different formulations of allantoin through full
thickness human cadaver skin.
[0037] FIG. 12 is a graph summarizing the percutaneous absorption
of different formulations of allantoin through the isolated dermis
layer from human cadaver skin.
[0038] FIG. 13 includes tables detailing results for percutaneous
absorption of different formulations of allantoin through the
isolated dermis layer from human cadaver skin.
[0039] FIG. 14 is a graph summarizing the percutaneous absorption
of 9% allantoin through the isolated dermis layer from human
cadaver skin.
[0040] FIG. 15 includes tables detailing results for percutaneous
absorption of 9% allantoin through the isolated dermis layer from
human cadaver skin.
1. DETAILED DESCRIPTION
[0041] 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 meanings 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.
[0042] 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 "fibroblast" is a reference to
one or more fibroblasts and equivalents thereof known to those
skilled in the art, and so forth.
[0043] As used herein, the term "about" means plus or minus 10% of
the numerical value of the number with which it is being used. In
other aspects, the term "about" means plus or minus 1% of the
numerical value of the number with which it is being used.
Therefore, about 50%, means in the range of 45%-55% or 49.5%-50.5%
as described herein.
[0044] 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.
[0045] 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. Epidermolysis bullosa, psoriasis, atopic
dermatitis, diabetic ulcers or the like) is the specifically
recited therapeutic in the particular embodiment or claim.
[0046] The term "inhibiting" includes the administration of a
compound of the present invention to prevent the onset of the
symptoms, alleviating the symptoms, or eliminating the disease,
condition or disorder.
[0047] By "pharmaceutically acceptable", it is meant the carrier,
diluent or excipient must be compatible with the other ingredients
of the formulation and not deleterious to the recipient
thereof.
[0048] 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.).
[0049] Unless otherwise indicated, the term "skin" means that outer
integument or covering of the body, consisting of the dermis and
the epidermis and resting upon subcutaneous tissue.
[0050] The term "improves" is used to convey that the present
invention changes either the appearance, form, characteristics
and/or the physical attributes of the tissue to which it is being
provided, applied or administered. The change in form may be
demonstrated by any of the following alone or in combination:
enhanced appearance of the skin; decreased inflammation of the
skin, prevention of inflammation or blisters, decreased spread of
blisters, decreased ulceration of the skin, decreased redness,
reduction of scarring, reduction in lesions, healing of blisters,
reduced skin thickening, closure of wounds and lesions, a reduction
in symptoms including, but not limited to, pain, inflammation,
itching, milia or other symptoms associated with inflammatory
disease or the like.
[0051] As used herein, the term "sole active ingredient" means that
the active ingredient or active compound (identified as such) is
the only effective therapeutic in the formulation to treat the
disease or disorder. In some embodiments, allantoin is the sole
active ingredient in formulation for the treatment of inflammatory
skin diseases such as Epidermolysis bullosa, psoriasis, atopic
dermatitis, diabetic ulcers, or the like. As an example, in
embodiments where a formulation used for the treatment of psoriasis
contains allantoin as the sole active ingredient, the formulation
does not contain another active ingredient, such as, for example,
coal tar.
[0052] As used herein, the term "therapeutic" means an agent
utilized to treat, combat, ameliorate, prevent or improve an
unwanted condition or disease of a patient. In part, embodiments of
the present invention are directed to the treatment of various skin
conditions or disorders, such as inflammatory skin conditions or
disorders.
[0053] A "therapeutically effective amount" or "effective amount"
of a composition is a predetermined amount calculated to achieve
the desired effect, i.e., to enhance appearance of skin, to
alleviate inflammation or blisters, or to prevent the skin
condition from worsening. The activity contemplated by the present
methods includes both medical 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, it will be understood
that the effective amount administered will be determined by the
physician in the 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 compound of this
invention 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 the tissue.
[0054] The terms "treat," "treated," or "treating" as used herein
refers to both therapeutic treatment and 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.
[0055] For example, in some aspects, the invention is directed to a
method of treating a disease using a pharmaceutical composition
comprising a compound, as defined above, and a pharmaceutically
acceptable carrier or diluent, or an effective amount of a
pharmaceutical composition comprising a compound as defined
above.
[0056] Compounds. The structure of allantoin is:
##STR00001##
[0057] Encompassed within this disclosure is all forms of
allantoin, or a salt thereof, including, but not limited to,
crystals, polymorphs, clathrates, solvates, hydrates, amorphous
forms, co-crystals, and anhydrous forms. As used herein,
"allantoin" includes salts thereof (as described below), crystals,
polymorphs, clathrates, solvates, hydrates, amorphous forms,
co-crystals, and anhydrous forms unless otherwise specified.
[0058] Embodiments of the present disclosure also relate to the
salts of allantoin. The acids which are used to prepare the salts
of the aforementioned compound are those which form non-toxic
salts, i.e., salts containing pharmacologically acceptable anions,
such as the hydrochloride, acetate, trifluoroacetic acid, tosylate,
picrate, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,
phosphate, acid phosphate, lactate, citrate, acid citrate,
tartrate, bitartrate, succinate, maleate, fumarate, gluconate,
saccharate, benzoate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate and pamoate salts.
[0059] Inflammatory skin disease, particularly chronic inflammatory
skin disease, is still a major source of morbidity. Such
inflammatory skin diseases are disfiguring and cause severe
physical and psychological harm to patients, disrupting their
quality of life substantially. Inflammatory skin diseases may be
selected from genetic inflammatory skin diseases, circulatory
inflammatory skin diseases and auto-immune inflammatory skin
diseases. Such diseases include cutaneous porphyria, sclerodema,
epidermolysis bulosa, psoriasis, decubitus ulcers, pressure ulcers,
diabetic ulcers, venous stasis ulcers, sickle cell ulcers, and
ulcers caused by burns, as well as other conditions affecting the
skin and having an inflammatory component such as eczema,
urticaria, atopic dermatitis, dermatitis herpetiform, contact
dermatitis, arthritis, gout, and lupus erythematosus. Other skin
conditions having an inflammatory component for which improved
treatments are needed include acne, alopecia, carcinomas,
psoriasis, rosacea, miliaria, skin infections, post-operative care
of incisions, post-operative skin care following any variety of
plastic surgery operations, skin care following radiation
treatment, care of dry, cracked or aged skin and skin lines. Such
skin diseases tend to be chronic and difficult to treat,
particularly in patients with poor circulation or other underlying
disease states. Symptoms of such diseases may include, without
limitation, pain, inflammation, itching, milia, blisters,
ulceration, redness, scarring or the like.
[0060] Among the most difficult to treat of these diseases is
epidermolysis bullosa. Epidermolysis bullosa (EB) is a rare genetic
disorder caused by a mutation in the keratin gene. The disorder is
characterized by the presence of extremely fragile skin, severe
inflammation, recurrent blister formation and scarring, resulting
from minor mechanical friction or trauma. Epidermolysis bullosa is
difficult to treat by conventional means.
[0061] Many allantoin compositions are prepared as emulsions,
particularly oil-in-water emulsions. One emulsifier system used
with such compositions is a combination of sodium lauryl sulfate
and beeswax. Although solutions of sodium lauryl sulfate are
alkaline with an approximate pH of 9.5, the simultaneous use of
beeswax with its organic acids produces a complex neutralized
system with a pH of about 6.8 to about 7.5. However, in such a
system with a pH range of 6.8 to 7.5, allantoin degrades
significantly with time and in accelerated stability tests at
40.degree. C. Because preparations designed for application to the
skin are typically stored by users at room temperature, and room
temperatures can fluctuate with climactic conditions, such a degree
of stability is undesirable. Therefore, there is a need for an
oil-in-water emulsified composition containing allantoin in which
the stability of allantoin is increased.
[0062] In general, embodiments herein describe a method of treating
inflammatory skin conditions or diseases comprising applying to the
skin an allantoin comprising composition in a therapeutically
effective amount. It was unexpectedly found that stabilized
oil-in-water emulsions containing allantoin optionally plus other
pharmaceutically acceptable ingredients as described herein provide
a high degree of relief for inflammatory skin conditions
characterized by ulceration, inflammation, or blistering of skin.
Such skin conditions may include, without limitation, cutaneous
porphyria, sclerodema, epidermolysis bullosa, psoriasis, decubitus
ulcers, pressure ulcers, diabetic ulcers, venous stasis ulcers,
sickle cell ulcers, ulcers caused by burns, eczema, urticaria,
atopic dermatitis, dermatitis herpetiform, contact dermatitis,
arthritis, gout, lupus erythematosus, acne, alopecia, carcinomas,
psoriasis, rosacea, miliaria, skin infections, post-operative care
of incisions, post-operative skin care following any variety of
plastic surgery operations, skin care following radiation
treatment, care of dry, cracked or aged skin and skin lines as well
as other conditions affecting the skin and having an inflammatory
component. Administration of formulations of allantoin described in
embodiments herein may cause a reduction in symptoms of such
diseases such as, without limitation, pain, scarring, inflammation,
redness, milia, itching, skin thickening, blisters, or other
symptoms associated with inflammatory disease. In some embodiments,
inflammatory skin disease may comprise epidermolysis bullosa,
psoriasis, atopic dermatitis, and diabetic ulcers. The
allantoin-containing composition comprises an oil-in-water emulsion
as may be described below.
[0063] Furthermore, formulations of allantoin in embodiments
described herein may impart long lasting stability at room
temperature (where refrigeration is not needed) to the formulation.
In some embodiments, the formulation may be stable for about 4 to
about 10 years, for about 4 to about 8 years, for about 4 to about
7 years, for about 4 to about 6 years, for about 5 to about 10, for
about 5 to about 8 years, for about 5 to about 7 years, for about 5
to about 6 years, for about 6 to about 10 years, for about 6 to
about 8 years, or for about 6 to about 7 years. In some
embodiments, stability may include, without limitation, physical
stability, chemical stability, resistance to microbial agents or
combinations thereof. In some embodiments, stability refers to a
stability of allantoin. In some embodiments, stability refers to a
period where there is no degradation of allantoin at room
temperature. In some embodiments, stability refers to a period
where there may be about 1% or less degradation of allantoin at
room temperature. In some embodiments, stability refers to a period
where there is no decrease in concentration. In some embodiments,
stability refers to a period where there is less than about 1%
decrease in concentration. In some embodiments, stability refers to
a period of resistance to microbiological growth at room
temperature. In some embodiments, stability refers to a period
where the formulation falls within the normal bioburden ranges for
said formulation at room temperature. In some embodiments, the
formulations of allantoin in embodiments described herein may
impart better absorption of the active pharmaceutical across a skin
barrier. In some embodiments, the skin barrier comprises intact
skin. In some embodiments, the formulations of allantoin in
embodiments described herein may deliver more allantoin across
intact skin barrier than formulations of prior art.
[0064] Embodiments of the present disclosure relate to formulations
of allantoin and methods of treatment of inflammatory skin
conditions. In some embodiments, the formulation comprises about
0.5% or more of allantoin and a pharmaceutically acceptable
excipient. In some embodiments, the formulation consists
essentially of about 0.5% or more of allantoin and a
pharmaceutically acceptable excipient. In some embodiments, the
formulation consists of about 0.5% or more of allantoin and a
pharmaceutically acceptable excipient. In some embodiments, the
formulation comprises about 1.5% or more of allantoin and a
pharmaceutically acceptable excipient. In some embodiments, the
formulation consists essentially of about 1.5% or more of allantoin
and a pharmaceutically acceptable excipient. In some embodiments,
the formulation consists of about 1.5% or more of allantoin and a
pharmaceutically acceptable excipient. In some embodiments, the
formulation comprises about 2.0% or more of allantoin and a
pharmaceutically acceptable excipient. In some embodiments, the
formulation consists essentially of about 2.0% or more of allantoin
and a pharmaceutically acceptable excipient. In some embodiments,
the formulation consists of about 2.0% or more of allantoin and a
pharmaceutically acceptable excipient. In some embodiments, the
formulation comprises about 2.5% or more of allantoin and a
pharmaceutically acceptable excipient. In some embodiments, the
formulation consists essentially of about 2.5% or more of allantoin
and a pharmaceutically acceptable excipient. In some embodiments,
the formulation consists of about 2.5% or more of allantoin and a
pharmaceutically acceptable excipient. In some embodiments, the
formulation comprises about 3.0% or more of allantoin and a
pharmaceutically acceptable excipient. In some embodiments, the
formulation consists essentially of about 3.0% or more of allantoin
and a pharmaceutically acceptable excipient. In some embodiments,
the formulation consists of about 3.0% or more of allantoin and a
pharmaceutically acceptable excipient.
[0065] Embodiments describe a composition comprising allantoin in
an amount from about 0.5% to about 15% by weight and a
pharmaceutically acceptable excipient. In some embodiments, the
composition comprises allantoin in an amount from about 1.5% to
about 15% by weight and a pharmaceutically acceptable excipient. In
some embodiments, the composition comprises allantoin in an amount
from about 2.0% to about 15% by weight and a pharmaceutically
acceptable excipient. In some embodiments, the composition
comprises allantoin in an amount from about 2.5% to about 15% by
weight and a pharmaceutically acceptable excipient. In some
embodiments, the composition comprises allantoin in an amount from
about 3.0% to about 15% by weight and a pharmaceutically acceptable
excipient. In some embodiments, the composition comprises allantoin
in an amount from about 3.0% to about 10% by weight and a
pharmaceutically acceptable excipient. In some embodiments, the
composition comprises allantoin in an amount from about 3.0% to
about 9.0% by weight and a pharmaceutically acceptable excipient.
In some embodiments, the composition comprises allantoin in an
amount from about 3.0% to about 6.0% by weight and a
pharmaceutically acceptable excipient. In some embodiments, the
composition comprises allantoin in an amount from about 6.0% to
about 15.0% by weight and a pharmaceutically acceptable excipient.
In some embodiments, the composition comprises allantoin in an
amount from about 6.0% to about 10.0% by weight and a
pharmaceutically acceptable excipient. In some embodiments, the
composition comprises allantoin in an amount from about 6.0% to
about 9.0% by weight and a pharmaceutically acceptable
excipient.
[0066] Embodiments describe a composition consisting essentially of
allantoin in an amount from about 0.5% to about 15% by weight and a
pharmaceutically acceptable excipient. In some embodiments, the
composition consists essentially of allantoin in an amount from
about 1.5% to about 15% by weight and a pharmaceutically acceptable
excipient. In some embodiments, the composition consists
essentially of allantoin in an amount from about 2.0% to about 15%
by weight and a pharmaceutically acceptable excipient. In some
embodiments, the composition consists essentially of allantoin in
an amount from about 2.5% to about 15% by weight and a
pharmaceutically acceptable excipient. In some embodiments, the
composition consists essentially of allantoin in an amount from
about 3.0% to about 15% by weight and a pharmaceutically acceptable
excipient. In some embodiments, the composition consists
essentially of allantoin in an amount from about 3.0% to about 10%
by weight and a pharmaceutically acceptable excipient. In some
embodiments, the composition consists essentially of allantoin in
an amount from about 3.0% to about 9.0% by weight and a
pharmaceutically acceptable excipient. In some embodiments, the
composition consists essentially of allantoin in an amount from
about 3.0% to about 6.0% by weight and a pharmaceutically
acceptable excipient. In some embodiments, the composition consists
essentially of allantoin in an amount from about 6.0% to about
15.0% by weight and a pharmaceutically acceptable excipient. In
some embodiments, the composition consists essentially of allantoin
in an amount from about 6.0% to about 10.0% by weight and a
pharmaceutically acceptable excipient. In some embodiments, the
composition consists essentially of allantoin in an amount from
about 6.0% to about 9.0% by weight and a pharmaceutically
acceptable excipient.
[0067] Embodiments describe a composition consisting of allantoin
in an amount from about 0.5% to about 15% by weight and a
pharmaceutically acceptable excipient. In some embodiments, the
composition consists of allantoin in an amount from about 1.5% to
about 15% by weight and a pharmaceutically acceptable excipient. In
some embodiments, the composition consists of allantoin in an
amount from about 2.0% to about 15% by weight and a
pharmaceutically acceptable excipient. In some embodiments, the
composition consists of allantoin in an amount from about 2.5% to
about 15% by weight and a pharmaceutically acceptable excipient. In
some embodiments, the composition consists of allantoin in an
amount from about 3.0% to about 15% by weight and a
pharmaceutically acceptable excipient. In some embodiments, the
composition consists of allantoin in an amount from about 3.0 to
about 10% by weight and a pharmaceutically acceptable excipient. In
some embodiments, the composition consists of allantoin in an
amount from about 3.0% to about 9.0% by weight and a
pharmaceutically acceptable excipient. In some embodiments, the
composition consists of allantoin in an amount from about 3.0% to
about 6.0% by weight and a pharmaceutically acceptable excipient.
In some embodiments, the composition consists of allantoin in an
amount from about 6.0% to about 15.0% by weight and a
pharmaceutically acceptable excipient. In some embodiments, the
composition consists of allantoin in an amount from about 6.0% to
about 10.0% by weight and a pharmaceutically acceptable excipient.
In some embodiments, the composition consists of allantoin in an
amount from about 6.0% to about 9.0% by weight and a
pharmaceutically acceptable excipient.
[0068] In other embodiments, the formulation comprises more than
about 1.5% by weight of allantoin, but not 1.5% or less of
allantoin, and a pharmaceutically acceptable excipient. In some
embodiments, the formulation comprises about 2.0% by weight or more
of allantoin, but not 1.5% or less of allantoin, and a
pharmaceutically acceptable excipient. In some embodiments, the
formulation comprises about 2.5% by weight or more of allantoin,
but not 1.5% or less of allantoin, and a pharmaceutically
acceptable excipient. In some embodiments, the formulation
comprises about 2.5% by weight or more of allantoin, but not less
than 2.0% of allantoin, and a pharmaceutically acceptable
excipient. In some embodiments, the formulation comprises about
3.0% by weight or more of allantoin, but not less than 2.5% of
allantoin, and a pharmaceutically acceptable excipient. In some
embodiments, the formulation comprises about 3.0% by weight or more
of allantoin, but not less than 2.0 of allantoin, and a
pharmaceutically acceptable excipient. In other embodiments, the
formulation comprises about 3.0% by weight or more of allantoin,
but not 1.5% or less of allantoin and a pharmaceutically acceptable
excipient. In other embodiments, the formulation consists
essentially of more than about 1.5% by weight of allantoin, but not
1.5% or less of allantoin, and a pharmaceutically acceptable
excipient. In some embodiments, the formulation consists
essentially of about 2.0% by weight or more of allantoin, but not
1.5% or less of allantoin, and a pharmaceutically acceptable
excipient. In some embodiments, the formulation consists
essentially of about 2.5% by weight or more of allantoin, but not
1.5% or less of allantoin, and a pharmaceutically acceptable
excipient. In some embodiments, the formulation consists
essentially of about 2.5% by weight or more of allantoin, but not
less than 2.0% of allantoin, and a pharmaceutically acceptable
excipient. In other embodiments, the formulation consists
essentially of about 3.0%, by weight or more of allantoin, but not
less than 2.5% of allantoin, and a pharmaceutically acceptable
excipient. In some embodiments, the formulation consists
essentially of about 3.0% by weight or more of allantoin, but not
less than 2.0% of allantoin and a pharmaceutically acceptable
excipient. In other embodiments, the formulation consists
essentially of about 3.0% by weight or more of allantoin but not
1.5% or less of allantoin and a pharmaceutically acceptable
excipient. In other embodiments, the formulation consists of more
than about 1.5% by weight of allantoin, but not 1.5% or less of
allantoin, and a pharmaceutically acceptable excipient. In some
embodiments, the formulation consists of about 2.0% by weight or
more of allantoin, but not 1.5% or less of allantoin, and a
pharmaceutically acceptable excipient. In some embodiments, the
formulation consists of about 2.5% by weight or more of allantoin,
but not 1.5% or less of allantoin, and a pharmaceutically
acceptable excipient. In some embodiments, the formulation consists
of about 2.5% by weight or more of allantoin, but not less than
2.0% of allantoin, and a pharmaceutically acceptable excipient. In
some embodiments, the formulation consists of about 3.0% by weight
or more of allantoin but not less than 2.5% of allantoin, and a
pharmaceutically acceptable excipient. In some embodiments, the
formulation consists of about 3.0% by weight or more of allantoin,
but not less than 2.0% of allantoin, and a pharmaceutically
acceptable excipient. In other embodiments, the formulation
consists of about 3.0% by weight or more of allantoin, but not 1.5%
or less of allantoin, and a pharmaceutically acceptable
excipient.
[0069] Embodiments herein describe formulations of allantoin
comprising an oil-in-water emulsion comprising allantoin, an
emollient, an emulsifier and a solvent. In some embodiments, the
formulation further comprises a pH modifier, a solubilizing agent,
an antioxidant, a preservative, a chelating agent, an additive, a
viscosity agent or a combination thereof. In some embodiments, the
formulation comprises allantoin, an emollient, an emulsifier, a pH
modifier, a solubilizing agent, an antioxidant, a preservative and
a solvent. In some embodiments, the formulation consists
essentially of allantoin, an emollient, an emulsifier, a pH
modifier, a solubilizing agent, an antioxidant, a preservative and
a solvent. In some embodiments, the formulation consists of
allantoin, an emollient, an emulsifier, a pH modifier, a
solubilizing agent, an antioxidant, a preservative and a
solvent.
[0070] The formulations of various embodiments may include any
number of additional components such as, for example,
preservatives, emulsion stabilizers, pH adjusters, chelating
agents, viscosity modifiers, anti-oxidants, 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 viscosity modifiers, and certain buffering agents
may also act as chelating agents.
[0071] In particular, embodiments of the present disclosure relate
to formulations of allantoin comprising an oil-in-water emulsion
comprising allantoin; a solvent; an emollient such as, without
limitation, lanolin oil, cod liver oil or an alcohol used as a
thickening agent; an emulsifier such as, without limitation, sodium
laurate sulfate or a white wax; an antioxidant such as, without
limitation, butylated hydroxytoluene; a preservative such as,
without limitation, methylparaben or propylparaben; a pH modifier
such as, without limitation, citric acid or lactic acid; and a
solubilizing agent such as, without limitation, glycerin or
propylene glycol. In some embodiments, the formulation may further
comprise a fragrance, an herbal extract, a viscosity agent such as,
without limitation, cetyl alcohol or stearyl alcohol, a chelating
agent such as, without limitation, tetrasodium EDTA, or a
combination thereof. In some embodiments, the formulation of
allantoin comprises any formulation disclosed in FIG. 1. In some
embodiments, the formulation of allantoin consists essentially of
any formulation disclosed in FIG. 1. In some embodiments, the
formulation of allantoin consists of any formulation disclosed in
FIG. 1. In some embodiments, the formulation of allantoin comprises
a formulation selected from the group consisting of 1-206A, 1-192A,
1-196A and 1-204A as shown in FIG. 1. In some embodiments, the
formulation of allantoin consists essentially of a formulation
selected from the group consisting of 1-206A, 1-192A, 1-196A and
1-204A as shown in FIG. 1. In some embodiments, the formulation of
allantoin consists of a formulation selected from the group
consisting of 1-206A, 1-192A, 1-196A and 1-204A as shown in FIG. 1.
In an embodiment, a formulation of allantoin comprises an
oil-in-water emulsion comprising allantoin, water, cetyl alcohol,
stearyl alcohol, beeswax, sodium lauryl sulfate in a 30% solution,
citric acid, lanolin oil, propylene glycol, tetrasodium EDTA, cod
liver oil, butylated hydroxytoluene, methylparaben, and
propylparaben.
[0072] In some embodiments, the formulation may include an
emulsifying agent, or emulsifier. In embodiments, the emulsifier
may be, for example, sodium lauryl sulfate, white waxes such as
beeswax or paraffin wax, 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
combinations thereof. 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 formulation may include an emulsifier in an amount
from about 1% to about 15%, and in other embodiments, the
formulation may include from about 1% to about 10%, or from about
1% to about 5% emulsifier. If more than one emulsifier is used, the
formulation may include from about 1% to about 5% or from about
1.5% to about 3% by weight of the formulation of each
emulsifier.
[0073] In some embodiments, the formulations 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.
[0074] 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. The surfactant of various embodiments may make up
from about 0.1% to about 20% by weight of the formulation and in
some embodiments, from about 0.5% to about 20% by weight of the
formulation. In embodiments in which more than one surfactant is
provided in the formulation, each surfactant may be from about 0.5%
to about 10% by weight of the formulation, and in some embodiments,
each surfactant of the formulation may be from about 0.5% to about
6% by weight of the formulation.
[0075] In some embodiments, the formulation may comprise emollients
in an amount from about 8% to about 30% by weight of the
formulation. In formulations that include more than one emollient,
each emollient may be provided at about 0.05% to about 15% by
weight of any one emollient. 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 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-ethyl-hexyl salicylate, and combinations 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, lauryllactate, 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. In some embodiments, the emollient
may be a high molecular weight saturated and unsaturated fatty
alcohol such as, but 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, or the
like. In particular embodiments, the emollient may be selected from
cetyl alcohol, stearyl alcohol, lanolin oil, cod liver oil, or a
combination thereof. In some embodiments, the formulation may
comprise an emollient such as, without limitations, cetyl alcohol
in an amount from about 2% to about 6%, stearyl alcohol in an
amount from about 1% to about 3%, lanolin in an amount from about
5% to about 15%, cod liver oil in an amount from about 0.05% to
about 5% or combinations thereof.
[0076] In some embodiments, the formulation may include one or more
viscosity modifiers. In some embodiments, the formulation may
comprise from about 1% to about 10% or from about 1% to about 6% of
each viscosity modifier. 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 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
cetyl alcohol, stearyl alcohol or a combination thereof. In some
embodiments, the formulation may comprise a viscosity modifier such
as, without limitations, cetyl alcohol in an amount from about 2%
to about 6%, stearyl alcohol in an amount from about 1% to about
3%, or combinations thereof.
[0077] Formulations of embodiments herein may further include a
preservative. 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, quatemium-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
certain embodiments, the formulation may include a combination of
methylparaben and propylparaben. Preservatives may be provided in
any concentration known in the art. For example in some
embodiments, the formulation may include preservatives in an amount
from about 0.01% to about 3% by weight; and, in embodiments, the
formulation may include from about 0.05% to about 1% or from about
0.05% to about 0.5% by weight of any one preservative.
[0078] The formulations of various embodiments may further include
a 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
methaphosphate, citric acid, phosphoric acid, tartaric acid,
ethylenediamine tetra acetic acid (Edetate, EDTA) and derivatives
and salts thereof, dihydroxyethyl glycine, and combinations
thereof. In particular embodiments, the chelating agent may be
tetrasodium EDTA. The chelating agents may be provided in any
effective amount. For example, in some embodiments, the formulation
may include from about 0.01% to about 2% by weight chelating agent,
and in other embodiments, the formulation may include from about
0.05% to about 0.5% or from about 0.05% to about 0.35% by weight
chelating agent.
[0079] The formulations 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 formulations
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-camosine, D-camosine, L-camosine and derivatives thereof such
as anserine, carotinoids, carotenes such as .alpha.-carotene,
.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 some embodiments, the 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
particular embodiments, the one or more antioxidants may include
BHT. The antioxidant 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 formulation, and in other
embodiments, the one or more antioxidants may be from about 0.01%
to about 1% by weight of the formulation or from about 0.05% to
about 1% by weight of the formulation.
[0080] In some embodiments, the formulation may include a
solubilizing agent. In embodiments, the solubilizers may be, for
example, hydrochloric acid, sodium hydroxide, glycine,
cyclodextrin, liquid paraffin, hydrogenated castor oil, ethanol,
glycerin, propylene glycol, dilute hydrochloric acid, hydrogenated
oils, purified water, physiological saline, water for injection,
Macrogol 4000, Polysorbate 80, or a combination thereof. In
particular embodiments, the solubilizing agent may be propylene
glycol, glycerin or a combination thereof. In embodiments, the
solubilizing agent comprises from about 1% to about 20%, from about
1% to about 10% or from about 2% to about 8% by weight of the
formulation.
[0081] In certain embodiments, the formulation may include one or
more opacifying agents. In some embodiments, components such as,
for example, emollients, surfactants, and/or emulsifiers may
provide sufficient opaqueness. In other embodiments, an additional
opacifying agent may be provided to the formulation. 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, glyceryllaurate, 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 and other sun-blocking
agents. 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
formulation, and in some embodiments, the opacifying agent may be
from about 0.01% to about 10% or about 0.02% to about 5% by weight
of the formulation.
[0082] In some embodiments, the formulation may include one or more
skin conditioners. 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
combinations thereof. In certain embodiments, the skin conditioners
may include lanolin or lanolin derivatives, caprylic
capric/triglyceride, diisopropyl adipate, and combinations thereof.
Skin conditioners may be provided to 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 formulations
of embodiments may include a conditioner in an amount from about 1%
to about 30% by weight of the formulation or from about 1% to about
25% by weight of the formulation.
[0083] The pH of various embodiments may be of neutral to mildly
acidic pH to allow for comfortable application to a 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
formulations 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 formulations may be about 4.0 to
about 5.0 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 particular embodiments, the
formulation may include, for example, citric acid or lactic acid as
a pH modifier. In embodiments, the pH modifier may comprise from
about 0.01% to about 1%, from about 0.05% to about 0.5%, from about
0.06% to about 0.15%, from about 0.06% to about 0.11%, or from
about 0.06% to about 0.1% by weight of the formulation.
[0084] In embodiments, the formulation may further comprise a
solvent. In some embodiments, the solvent may include one or more
ingredients therein, with water being preferred in certain
embodiments. Generally, the quantity of water used as a solvent may
depend on the various other ingredients used. The solvent may be
present in certain embodiments in a range of from about 10% to
about 95% by weight, with certain embodiments including from about
40% to about 90%, from about 42% to about 87%, from about 42% to
about 80%, from about 42% to about 75%, from about 42% to about
70%, or from about 42% to about 68% by weight of the formulation.
The exact quantity of solvent may be dependent on the form of the
product. For example, a product in lotion form may in certain
preferred embodiments include more water than a product in spray
form and a product in cream or butter form may include less water
than a product in spray form. Deionized water is generally
preferred. Other suitable solvent materials may also be used.
[0085] In embodiments, the formulation of embodiments herein may be
physically and chemically stable. In some embodiments, the
formulation of embodiments herein may be resistant to microbial
agents for up to 4 years, up to 6 years, up to 8 years, up to 10
years, up to 12 years or up to 20 years. In some embodiments, the
formulation of embodiments herein may be resistant to microbial
agents for from about 4 to about 20 years, from about 4 to about 12
years, from about 4 to about 10 years, from about 4 to about 8
years, from about 4 to about 6 years, from about 6 to about 20
years, from about 6 to about 12 years, from about 6 to about 10
years, from about 6 to about 8 years, from about 8 to about 20
years, from about 8 to about 12 years, or from about 8 to about 10
years.
[0086] One embodiment relates to formulations of allantoin
comprising an oil-in-water emulsion comprising about 3.0% of
allantoin, water, cetyl alcohol, stearyl alcohol, beeswax, sodium
lauryl sulfate in a 30% solution, citric acid, lanolin oil,
propylene glycol, tetrasodium EDTA, cod liver oil, butylated
hydroxytoluene, methylparaben, and propylparaben. In further
embodiments, the formulation consists essentially of about 3.0% of
allantoin, water, cetyl alcohol, stearyl alcohol, beeswax, sodium
lauryl sulfate in a 30% solution, citric acid, lanolin oil,
propylene glycol, tetrasodium EDTA, cod liver oil, butylated
hydroxytoluene, methylparaben, and propylparaben. In certain
embodiments, the formulation consists of about 3.0% of allantoin,
water, cetyl alcohol, stearyl alcohol, beeswax, sodium lauryl
sulfate in a 30% solution, citric acid, lanolin oil, propylene
glycol, tetrasodium EDTA, cod liver oil, butylated hydroxytoluene,
methylparaben, and propylparaben. In certain embodiments, the
formulation further includes a fragrance. In some embodiments, the
fragrance comprises from about 0.01% to about 5%, from about 0.01%
to about 3%, from about 0.01% to about 2%, from about 0.01% to
about 1% from about 0.01% to about 0.5%, from about 0.05% to about
3%, from about 0.05% to about 2%, from about 0.05% to about 1% from
about 0.05% to about 0.5% by weight of the formulation. In certain
embodiments, the formulation does not contain a fragrance. In
embodiments, the formulation may further include an herbal extract.
In certain embodiments, the formulation does not contain any herbal
extracts.
[0087] In another embodiment, formulations of allantoin comprising
an oil-in-water emulsion comprising about 6.0% of allantoin, water,
cetyl alcohol, stearyl alcohol, beeswax, sodium lauryl sulfate in a
30% solution, citric acid, lanolin oil, propylene glycol,
tetrasodium EDTA, cod liver oil, butylated hydroxytoluene,
methylparaben, and propylparaben are provided. In certain
embodiments, the formulation does not contain a fragrance. In
certain embodiments, the formulation does not contain any herbal
extracts. In further embodiments, the formulations consist
essentially of about 6.0% of allantoin, water, cetyl alcohol,
stearyl alcohol, beeswax, sodium lauryl sulfate in a 30% solution,
citric acid, lanolin oil, propylene glycol, tetrasodium EDTA, cod
liver oil, butylated hydroxytoluene, methylparaben, and
propylparaben. In certain embodiments, the formulations consist of
about 6.0% of allantoin, water, cetyl alcohol, stearyl alcohol,
beeswax, sodium lauryl sulfate in a 30% solution, citric acid,
lanolin oil, propylene glycol, tetrasodium EDTA, cod liver oil,
butylated hydroxytoluene, methylparaben, and propylparaben. In
certain embodiments, the formulation further includes a fragrance.
In certain embodiments, the formulation does not contain a
fragrance. In embodiments, the formulation may further include an
herbal extract. In certain embodiments, the formulation does not
contain any herbal extracts.
[0088] In another embodiment, formulations of allantoin comprising
an oil-in-water emulsion comprising about 9.0% of allantoin, water,
cetyl alcohol, stearyl alcohol, beeswax, sodium lauryl sulfate in a
30% solution, citric acid, lanolin oil, propylene glycol,
tetrasodium EDTA, cod liver oil, butylated hydroxytoluene,
methylparaben, and propylparaben are provided. In certain
embodiments, the formulation does not contain a fragrance. In
certain embodiments, the formulation does not contain any herbal
extracts. In further embodiments, the formulation consists
essentially of about 9.0% of allantoin, water, cetyl alcohol,
stearyl alcohol, beeswax, sodium lauryl sulfate in a 30% solution,
citric acid, lanolin oil, propylene glycol, tetrasodium EDTA, cod
liver oil, butylated hydroxytoluene, methylparaben, and
propylparaben. In certain embodiments, the formulation consists of
about 9.0% of allantoin, water, cetyl alcohol, stearyl alcohol,
beeswax, sodium lauryl sulfate in a 30% solution, citric acid,
lanolin oil, propylene glycol, tetrasodium EDTA, cod liver oil,
butylated hydroxytoluene, methylparaben, and propylparaben. In
certain embodiments, the formulation further includes a fragrance.
In certain embodiments, the formulation does not contain a
fragrance. In embodiments, the formulation may further include an
herbal extract. In certain embodiments, the formulation does not
contain any herbal extracts.
[0089] In another embodiment, the formulation comprises about 3.0%
allantoin; about 67.01% water; about 3.5% cetyl alcohol; about 1.7%
stearyl alcohol; about 2.5% beeswax; about 0.09% citric acid; about
10.6% lanolin oil; about 5.7% propylene glycol; about 0.15%
tetrasodium EDTA; about 2% cod liver oil; about 0.5% butylated
hydroxytoluene; about 0.3% methylparaben; about 0.25%
propylparaben; about 0.2% fragrance; and about 2.5% sodium lauryl
sulfate in a 30% solution. In further embodiments, the formulations
consist essentially of about 3.0% allantoin; about 67.01% water;
about 3.5% cetyl alcohol; about 1.7% stearyl alcohol; about 2.5%
beeswax; about 0.09% citric acid; about 10.6% lanolin oil; about
5.7% propylene glycol; about 0.15% tetrasodium EDTA; about 2% cod
liver oil; about 0.5% butylated hydroxytoluene; about 0.3%
methylparaben; about 0.25% propylparaben; about 0.2% fragrance; and
about 2.5% sodium lauryl sulfate in a 30% solution. In certain
embodiments, the formulations consist of about 3.0% allantoin;
about 67.01% water; about 3.5% cetyl alcohol; about 1.7% stearyl
alcohol; about 2.5% beeswax; about 0.09% citric acid; about 10.6%
lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodium
EDTA; about 2% cod liver oil; about 0.5% butylated hydroxytoluene;
about 0.3% methylparaben; about 0.25% propylparaben; about 0.2%
fragrance; and about 2.5% sodium lauryl sulfate in a 30%
solution.
[0090] In another embodiment, the formulation comprises about 3.0%
allantoin; about 67.41% water; about 4.2% cetyl alcohol; about 2%
stearyl alcohol; about 1.9% beeswax; about 0.09% citric acid; about
10.6% lanolin oil; about 5.7% propylene glycol; about 0.15%
tetrasodium EDTA; about 2% cod liver oil; about 0.5% butylated
hydroxytoluene; about 0.3% methylparaben; about 0.25%
propylparaben; and about 1.9% sodium lauryl sulfate in a 30%
solution. In further embodiments, the formulation consists
essentially of about 3.0% allantoin; about 67.41% water; about 4.2%
cetyl alcohol; about 2% stearyl alcohol; about 1.9% beeswax; about
0.09% citric acid; about 10.6% lanolin oil; about 5.7% propylene
glycol; about 0.15% tetrasodium EDTA; about 2% cod liver oil; about
0.5% butylated hydroxytoluene; about 0.3% methylparaben; about
0.25% propylparaben; and about 1.90% sodium lauryl sulfate in a 30%
solution. In certain embodiments, the formulation consists of about
3.0% allantoin; about 67.41% water; about 4.2% cetyl alcohol; about
2% stearyl alcohol; about 1.9% beeswax; about 0.09% citric acid;
about 10.6% lanolin oil; about 5.7% propylene glycol; about 0.15%
tetrasodium EDTA; about 2% cod liver oil; about 0.5% butylated
hydroxytoluene; about 0.3% methylparaben; about 0.25%
propylparaben; and about 1.9% sodium lauryl sulfate in a 30%
solution.
[0091] In another embodiment, the formulation comprises about 3.0%
allantoin; about 67.41% water; about 4.2% cetyl alcohol; about 2%
stearyl alcohol; about 1.9% beeswax; about 0.09% citric acid; about
10.6% lanolin oil; about 5.7% propylene glycol; about 0.15%
tetrasodium EDTA; about 2% cod liver oil; about 0.5% butylated
hydroxytoluene; about 0.3% methylparaben; about 0.25%
propylparaben; and about 1.5% sodium lauryl sulfate in a 30%
solution. In further embodiments, the formulations consist
essentially of about 3.0% allantoin; about 67.41% water; about 4.2%
cetyl alcohol; about 2% stearyl alcohol; about 1.90% beeswax; about
0.09% citric acid; about 10.6% lanolin oil; about 5.7% propylene
glycol; about 0.15% tetrasodium EDTA; about 2% cod liver oil; about
0.5% butylated hydroxytoluene; about 0.3% methylparaben; about
0.25% propylparaben; and about 1.5% sodium lauryl sulfate in a 30%
solution. In certain embodiments, the formulations consist of about
3.00 allantoin; about 67.41% water; about 4.2% cetyl alcohol; about
2% stearyl alcohol; about 1.9% beeswax; about 0.09% citric acid;
about 10.6% lanolin oil; about 5.7% propylene glycol; about 0.15%
tetrasodium EDTA; about 2% cod liver oil; about 0.5% butylated
hydroxytoluene; about 0.3% methylparaben; about 0.25%
propylparaben; and about 1.5% sodium lauryl sulfate in a 30%
solution.
[0092] In another embodiment, the formulation comprises about 3.0%
allantoin; water; cetyl alcohol; stearyl alcohol; beeswax; about
0.09% citric acid; about 10.6% lanolin oil; about 5.7% propylene
glycol; about 0.15% tetrasodium EDTA; about 2% cod liver oil; about
0.5% butylated hydroxytoluene; about 0.3% methylparaben; about
0.25% propylparaben; and about 2.0% sodium lauryl sulfate in a 30%
solution. In further embodiments, the formulation consists
essentially of about 3.0% allantoin; water; cetyl alcohol; stearyl
alcohol; beeswax; about 0.09% citric acid; about 10.6% lanolin oil;
about 5.7% propylene glycol; about 0.15% tetrasodium EDTA; about 2%
cod liver oil; about 0.5% butylated hydroxytoluene; about 0.3%
methylparaben; about 0.25% propylparaben; and about 2.0% sodium
lauryl sulfate in a 30% solution. In certain embodiments, the
formulation consists of about 3.0% allantoin; water; cetyl alcohol;
stearyl alcohol; beeswax; about 0.09% citric acid; about 10.6%
lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodium
EDTA; about 2% cod liver oil; about 0.5% butylated hydroxytoluene;
about 0.3% methylparaben; about 0.25% propylparaben; and about 2.0%
sodium lauryl sulfate in a 300 solution.
[0093] In another embodiment, the formulation comprises about 6.0%
allantoin; about 63.98% water; about 3.23% cetyl alcohol; about
1.5% stearyl alcohol; about 2.75% beeswax; about 0.09% citric acid;
about 10.6% lanolin oil; about 5.7% propylene glycol; about 0.15%
tetrasodium EDTA; about 2% cod liver oil; about 0.5% butylated
hydroxytoluene; about 0.3% methylparaben; about 0.25%
propylparaben; about 0.2% fragrance; and about 2.75% sodium lauryl
sulfate in a 30% solution. In further embodiments, the formulations
consist essentially of about 6.0% allantoin; about 63.98% water;
about 3.23% cetyl alcohol; about 1.5% stearyl alcohol; about 2.75%
beeswax; about 0.09% citric acid; about 10.6% lanolin oil; about
5.7% propylene glycol; about 0.15% tetrasodium EDTA; about 2% cod
liver oil; about 0.5% butylated hydroxytoluene; about 0.3%
methylparaben; about 0.25% propylparaben; about 0.2% fragrance; and
about 2.75% sodium lauryl sulfate in a 30% solution. In certain
embodiments, the formulations consist of about 6.0% allantoin;
about 63.98% water; about 3.23% cetyl alcohol; about 1.5% stearyl
alcohol; about 2.75% beeswax; about 0.09% citric acid; about 10.6%
lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodium
EDTA; about 2% cod liver oil; about 0.5% butylated hydroxytoluene;
about 0.3% methylparaben; about 0.25% propylparaben; about 0.2%
fragrance; and about 2.75% sodium lauryl sulfate in a 30%
solution.
[0094] In another embodiment, the formulation comprises about 6.0%
allantoin; about 64.81% water; about 3.5% cetyl alcohol; about 1.5%
stearyl alcohol; about 2.3% beeswax; about 0.09% citric acid; about
10.6% lanolin oil; about 5.7% propylene glycol; about 0.15%
tetrasodium EDTA; about 2% cod liver oil; about 0.5% butylated
hydroxytoluene; about 0.3% methylparaben; about 0.25%
propylparaben; and about 2.3% sodium lauryl sulfate in a 30%
solution. In further embodiments, the formulations consist
essentially of about 6.0% allantoin; about 64.81% water; about 3.5%
cetyl alcohol; about 1.5% stearyl alcohol; about 2.3% beeswax;
about 0.09% citric acid; about 10.6% lanolin oil; about 5.7%
propylene glycol; about 0.15% tetrasodium EDTA; about 2% cod liver
oil; about 0.5% butylated hydroxytoluene; about 0.3% methylparaben;
about 0.25% propylparaben; and about 2.3% sodium lauryl sulfate in
a 30% solution. In certain embodiments, the formulations consist of
about 6.0% allantoin; about 64.81% water; about 3.5% cetyl alcohol;
about 1.5% stearyl alcohol; about 2.3% beeswax; about 0.09% citric
acid; about 10.6% lanolin oil; about 5.7% propylene glycol; about
0.15% tetrasodium EDTA; about 2% cod liver oil; about 0.5%
butylated hydroxytoluene; about 0.3% methylparaben; about 0.25%
propylparaben; and about 2.3% sodium lauryl sulfate in a 30%
solution.
[0095] In another embodiment, the formulation comprises about 6.0%
allantoin; about 65.11% water; about 3.6% cetyl alcohol; about 1.7%
stearyl alcohol; about 2.0% beeswax; about 0.09% citric acid; about
10.6% lanolin oil; about 5.7% propylene glycol; about 0.15%
tetrasodium EDTA; about 2% cod liver oil; about 0.5% butylated
hydroxytoluene; about 0.3% methylparaben; about 0.25%
propylparaben; and about 2.0% sodium lauryl sulfate in a 30%
solution. In further embodiments, the formulations consist
essentially of about 6.0% allantoin; about 65.11% water; about 3.6%
cetyl alcohol; about 1.7% stearyl alcohol; about 2.0% beeswax;
about 0.09% citric acid; about 10.6% lanolin oil; about 5.7%
propylene glycol; about 0.15% tetrasodium EDTA; about 2% cod liver
oil; about 0.5% butylated hydroxytoluene; about 0.3% methylparaben;
about 0.25% propylparaben; and about 2.0% sodium lauryl sulfate in
a 30% solution. In certain embodiments, the formulations consist of
about 6.0% allantoin; about 65.11% water; about 3.6% cetyl alcohol;
about 1.7% stearyl alcohol; about 2.0% beeswax; about 0.09% citric
acid; about 10.6% lanolin oil; about 5.7% propylene glycol; about
0.15% tetrasodium EDTA; about 2% cod liver oil; about 0.5%
butylated hydroxytoluene; about 0.3% methylparaben; about 0.25%
propylparaben; and about 2.0% sodium lauryl sulfate in a 30%
solution.
[0096] In another embodiment, the formulation comprises about 6.0%
allantoin; water; cetyl alcohol; stearyl alcohol; beeswax; about
0.09% citric acid; about 10.6% lanolin oil; about 5.7% propylene
glycol; about 0.15% tetrasodium EDTA; about 2% cod liver oil; about
0.5% butylated hydroxytoluene; about 0.3% methylparaben; about
0.25% propylparaben; and about 1.5% sodium lauryl sulfate in a 30%
solution. In further embodiments, the formulations consist
essentially of about 6.0% allantoin; water; cetyl alcohol; stearyl
alcohol; beeswax; about 0.09% citric acid; about 10.6% lanolin oil;
about 5.7% propylene glycol; about 0.15% tetrasodium EDTA; about 2%
cod liver oil; about 0.5% butylated hydroxytoluene; about 0.3%
methylparaben; about 0.25% propylparaben; and about 1.5% sodium
lauryl sulfate in a 30% solution. In certain embodiments, the
formulations consist of about 6.0% allantoin; water; cetyl alcohol;
stearyl alcohol; beeswax; about 0.09% citric acid; about 10.6%
lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodium
EDTA; about 2% cod liver oil; about 0.5% butylated hydroxytoluene;
about 0.3% methylparaben; about 0.25% propylparaben; and about 1.5%
sodium lauryl sulfate in a 30% solution.
[0097] In another embodiment, the formulation comprises about 9.0%
allantoin; about 61.78% water; about 2.7% cetyl alcohol; about 1.2%
stearyl alcohol; about 2.75% beeswax; about 0.12% citric acid;
about 10.6% lanolin oil; about 5.7% propylene glycol; about 0.15%
tetrasodium EDTA; about 2% cod liver oil; about 0.5% butylated
hydroxytoluene; about 0.3% methylparaben; about 0.25%
propylparaben; about 0.2% fragrance; and about 2.75% sodium lauryl
sulfate in a 30% solution. In further embodiments, the formulations
consist essentially of about 9.0% allantoin; about 61.78% water;
about 2.7% cetyl alcohol; about 1.2% stearyl alcohol; about 2.75%
beeswax; about 0.12% citric acid; about 10.6% lanolin oil; about
5.7% propylene glycol; about 0.15% tetrasodium EDTA; about 2% cod
liver oil; about 0.5% butylated hydroxytoluene; about 0.3%
methylparaben; about 0.25% propylparaben; about 0.2% fragrance; and
about 2.75% sodium lauryl sulfate in a 30% solution. In certain
embodiments, the formulations consist of about 9.0% allantoin;
about 61.78% water; about 2.7% cetyl alcohol; about 1.2% stearyl
alcohol; about 2.75% beeswax; about 0.12% citric acid; about 10.6%
lanolin oil; about 5.7% propylene glycol; about 0.15% tetrasodium
EDTA; about 2% cod liver oil; about 0.5% butylated hydroxytoluene;
about 0.3% methylparaben; about 0.25% propylparaben; about 0.2%
fragrance; and about 2.75% sodium lauryl sulfate in a 300
solution.
[0098] In another embodiment, the formulation comprises about 9.0%
allantoin; about 63.71% water; about 2.5% cetyl alcohol; about 1.2%
stearyl alcohol; about 2.0% beeswax; about 0.09% citric acid; about
10.6% lanolin oil; about 5.7% propylene glycol; about 0.15%
tetrasodium EDTA; about 2% cod liver oil; about 0.5% butylated
hydroxytoluene; about 0.3% methylparaben; about 0.25%
propylparaben; and about 2.0% sodium lauryl sulfate in a 30
solution. In further embodiments, the formulations consist
essentially of about 9.0% allantoin; about 63.71% water; about 2.5%
cetyl alcohol; about 1.2% stearyl alcohol; about 2.0% beeswax;
about 0.09% citric acid; about 10.6% lanolin oil; about 5.7%
propylene glycol; about 0.15% tetrasodium EDTA; about 2% cod liver
oil; about 0.5% butylated hydroxytoluene; about 0.3% methylparaben;
about 0.25% propylparaben; and about 2.0% sodium lauryl sulfate in
a 30% solution. In certain embodiments, the formulations consist of
about 9.0% allantoin; about 63.71% water; about 2.5% cetyl alcohol;
about 1.2% stearyl alcohol; about 2.0% beeswax; about 0.09% citric
acid; about 10.6% lanolin oil; about 5.7% propylene glycol; about
0.15% tetrasodium EDTA; about 2% cod liver oil; about 0.5%
butylated hydroxytoluene; about 0.3% methylparaben; about 0.25%
propylparaben; and about 2.0% sodium lauryl sulfate in a 30%
solution.
[0099] In another embodiment, the formulation comprises about 9.0%
allantoin; water; cetyl alcohol; stearyl alcohol; beeswax; citric
acid; about 10.6% lanolin oil; about 5.7% propylene glycol; about
0.15% tetrasodium EDTA; about 2% cod liver oil; about 0.5%
butylated hydroxytoluene; about 0.3% methylparaben; about 0.25%
propylparaben; and 1.5% sodium lauryl sulfate in a 30% solution. In
further embodiments, the formulations consist essentially of about
9.0% allantoin; water; cetyl alcohol; stearyl alcohol; beeswax;
citric acid; about 10.6% lanolin oil; about 5.7% propylene glycol;
about 0.15% tetrasodium EDTA; about 2% cod liver oil; about 0.5%
butylated hydroxytoluene; about 0.3% methylparaben; about 0.25%
propylparaben; and 1.5% sodium lauryl sulfate in a 30% solution. In
certain embodiments, the formulations consist of about 9.0%
allantoin; water; cetyl alcohol; stearyl alcohol; beeswax; citric
acid; about 10.6% lanolin oil; about 5.7% propylene glycol; about
0.15% tetrasodium EDTA; about 2% cod liver oil; about 0.5%
butylated hydroxytoluene; about 0.3% methylparaben; about 0.25%
propylparaben; and 1.5% sodium lauryl sulfate in a 30%
solution.
[0100] In another embodiment, the formulation comprises about 9.0%
allantoin; water; cetyl alcohol; stearyl alcohol; beeswax; citric
acid; about 10.6% lanolin oil; about 5.7% propylene glycol; about
0.15% tetrasodium EDTA; about 2% cod liver oil; about 0.5%
butylated hydroxytoluene; about 0.3% methylparaben; about 0.25%
propylparaben; and sodium lauryl sulfate in a 30% solution. In
further embodiments, the formulations consist essentially of about
9.0% allantoin; water; cetyl alcohol; stearyl alcohol; beeswax;
citric acid; about 10.6% lanolin oil; about 5.7% propylene glycol;
about 0.15% tetrasodium EDTA; about 2% cod liver oil; about 0.5%
butylated hydroxytoluene; about 0.3% methylparaben; about 0.25%
propylparaben; and sodium lauryl sulfate in a 30% solution. In
certain embodiments, the formulations consist of about 9.0%
allantoin; water; cetyl alcohol; stearyl alcohol; beeswax; citric
acid; about 10.6% lanolin oil; about 5.7% propylene glycol; about
0.15% tetrasodium EDTA; about 2% cod liver oil; about 0.5%
butylated hydroxytoluene; about 0.3% methylparaben; about 0.25%
propylparaben; and sodium lauryl sulfate in a 30% solution.
[0101] Embodiments herein are also directed to methods of treating
inflammatory skin conditions comprising administering a composition
comprising an oil-in-water emulsion comprising allantoin in an
amount from about 0.5% to about 15% by weight and a
pharmaceutically acceptable excipient. In some embodiments, the
formulation of allantoin comprises an oil-in-water emulsion
comprising allantoin, an emollient, an emulsifier and a solvent. In
some embodiments, the formulation further comprises a pH modifier,
a solubilizing agent, an antioxidant, a preservative, a chelating
agent, an additive, a viscosity agent or a combination thereof. In
some embodiments, the formulation comprises allantoin, an
emollient, an emulsifier, a pH modifier, a solubilizing agent, an
antioxidant, a preservative and a solvent. In some embodiments, the
formulation consists essentially of allantoin, an emollient, an
emulsifier, a pH modifier, a solubilizing agent, an antioxidant, a
preservative and a solvent. In some embodiments, the formulation
consists of allantoin, an emollient, an emulsifier, a pH modifier,
a solubilizing agent, an antioxidant, a preservative and a solvent.
In some embodiments, a method of treating inflammatory skin
conditions in a patient in need thereof comprises administering a
formulation comprising allantoin, a solvent, an emollient, an
emulsifier, an antioxidant, a preservative, a pH modifier and a
solubilizing agent, wherein the allantoin is present in an amount
of about 0.5% to about 15% by weight. In some embodiments, a method
of treating inflammatory skin conditions in a patient in need
thereof comprises administering a formulation consisting
essentially of allantoin, a solvent, an emollient, an emulsifier,
an antioxidant, a preservative, a pH modifier and a solubilizing
agent, wherein the allantoin is present in an amount of about 0.5%
to about 15% by weight. In some embodiments, a method of treating
inflammatory skin conditions in a patient in need thereof comprises
administering a formulation consisting of allantoin, a solvent, an
emollient, an emulsifier, an antioxidant, a preservative, a pH
modifier and a solubilizing agent, wherein the allantoin is present
in an amount of about 0.5% to about 15% by weight.
[0102] In another embodiment, a method of treating Epidermolysis
bullosa comprises administering a formulation of allantoin
comprising an oil-in-water emulsion comprising allantoin, an
emollient, an emulsifier, a solvent and a pharmaceutically
acceptable excipient. In some embodiments, the formulation further
comprises a pH modifier, a solubilizing agent, an antioxidant, a
preservative, a chelating agent, an additive, a viscosity agent or
a combination thereof. In some embodiments, the formulation
comprises allantoin, an emollient, an emulsifier, a pH modifier, a
solubilizing agent, an antioxidant, a preservative, a solvent and a
pharmaceutically acceptable excipient. In some embodiments, the
formulation consists essentially of allantoin, an emollient, an
emulsifier, a pH modifier, a solubilizing agent, an antioxidant, a
preservative, a solvent and a pharmaceutically acceptable
excipient. In some embodiments, the formulation consists of
allantoin, an emollient, an emulsifier, a pH modifier, a
solubilizing agent, an antioxidant, a preservative, a solvent and a
pharmaceutically acceptable excipient. In some embodiments, a
method of treating Epidermolysis bullosa in a patient in need
thereof comprises administering a formulation comprising allantoin,
a solvent, an emollient, an emulsifier, an antioxidant, a
preservative, a pH modifier, a solubilizing agent and a
pharmaceutically acceptable excipient, wherein the allantoin is
present in an amount of about 0.5% to about 15% by weight. In some
embodiments, a method of treating Epidermolysis bullosa in a
patient in need thereof comprises administering a formulation
consisting essentially of allantoin, a solvent, an emollient, an
emulsifier, an antioxidant, a preservative, a pH modifier, a
solubilizing agent and a pharmaceutically acceptable excipient,
wherein the allantoin is present in an amount of about 0.5% to
about 15% by weight. In some embodiments, a method of treating
Epidermolysis bullosa in a patient in need thereof comprises
administering a formulation consisting of allantoin, a solvent, an
emollient, an emulsifier, an antioxidant, a preservative, a pH
modifier, a solubilizing agent and a pharmaceutically acceptable
excipient, wherein the allantoin is present in an amount of about
0.5% to about 15% by weight.
[0103] In another embodiment, a method of treating psoriasis
comprises administering a formulation of allantoin comprising an
oil-in-water emulsion comprising allantoin, an emollient, an
emulsifier, a solvent and a pharmaceutically acceptable excipient.
In some embodiments, the formulation further comprises a pH
modifier, a solubilizing agent, an antioxidant, a preservative, a
chelating agent, an additive, a viscosity agent or a combination
thereof. In some embodiments, the formulation comprises allantoin,
an emollient, an emulsifier, a pH modifier, a solubilizing agent,
an antioxidant, a preservative, a solvent and a pharmaceutically
acceptable excipient. In some embodiments, the formulation consists
essentially of allantoin, an emollient, an emulsifier, a pH
modifier, a solubilizing agent, an antioxidant, a preservative, a
solvent and a pharmaceutically acceptable excipient. In some
embodiments, the formulation consists of allantoin, an emollient,
an emulsifier, a pH modifier, a solubilizing agent, an antioxidant,
a preservative, a solvent and a pharmaceutically acceptable
excipient. In some embodiments, a method of treating psoriasis in a
patient in need thereof comprises administering a formulation
comprising allantoin, a solvent, an emollient, an emulsifier, an
antioxidant, a preservative, a pH modifier, a solubilizing agent
and a pharmaceutically acceptable excipient, wherein the allantoin
is present in an amount of about 0.5% to about 15% by weight. In
some embodiments, a method of treating psoriasis in a patient in
need thereof comprises administering a formulation consisting
essentially of allantoin, a solvent, an emollient, an emulsifier,
an antioxidant, a preservative, a pH modifier, a solubilizing agent
and a pharmaceutically acceptable excipient, wherein the allantoin
is present in an amount of about 0.5% to about 15% by weight. In
some embodiments, a method of treating psoriasis in a patient in
need thereof comprises administering a formulation consisting of
allantoin, a solvent, an emollient, an emulsifier, an antioxidant,
a preservative, a pH modifier, a solubilizing agent and a
pharmaceutically acceptable excipient, wherein the allantoin is
present in an amount of about 0.5% to about 15% by weight. As shown
in Example 11, it is believed that formulations containing above
1.5% allantoin are better able to treat psoriasis than formulations
of 1.5% or below. Accordingly, embodiments herein include a method
of treating psoriasis disclosed herein wherein allantoin is present
an amount greater than about 1.5% to about 15%.
[0104] In another embodiment, a method of treating diabetic ulcers
comprises administering a formulation of allantoin comprising an
oil-in-water emulsion comprising allantoin, an emollient, an
emulsifier, a solvent and a pharmaceutically acceptable excipient.
In some embodiments, the formulation further comprises a pH
modifier, a solubilizing agent, an antioxidant, a preservative, a
chelating agent, an additive, a viscosity agent or a combination
thereof. In some embodiments, the formulation comprises allantoin,
an emollient, an emulsifier, a pH modifier, a solubilizing agent,
an antioxidant, a preservative, a solvent and a pharmaceutically
acceptable excipient. In some embodiments, the formulation consists
essentially of allantoin, an emollient, an emulsifier, a pH
modifier, a solubilizing agent, an antioxidant, a preservative, a
solvent and a pharmaceutically acceptable excipient. In some
embodiments, the formulation consists of allantoin, an emollient,
an emulsifier, a pH modifier, a solubilizing agent, an antioxidant,
a preservative, a solvent and a pharmaceutically acceptable
excipient. In some embodiments, a method of treating diabetic
ulcers in a patient in need thereof comprises administering a
formulation comprising allantoin, a solvent, an emollient, an
emulsifier, an antioxidant, a preservative, a pH modifier, a
solubilizing agent and a pharmaceutically acceptable excipient,
wherein the allantoin is present in an amount of about 0.5% to
about 15% by weight. In some embodiments, a method of treating
diabetic ulcers in a patient in need thereof comprises
administering a formulation consisting essentially of allantoin, a
solvent, an emollient, an emulsifier, an antioxidant, a
preservative, a pH modifier, a solubilizing agent and a
pharmaceutically acceptable excipient, wherein the allantoin is
present in an amount of about 0.5% to about 15% by weight. In some
embodiments, a method of treating diabetic ulcers in a patient in
need thereof comprises administering a formulation consisting of
allantoin, a solvent, an emollient, an emulsifier, an antioxidant,
a preservative, a pH modifier, a solubilizing agent and a
pharmaceutically acceptable excipient, wherein the allantoin is
present in an amount of about 0.5% to about 15% by weight.
[0105] In another embodiment, a method of treating atopic
dermatitis comprises administering a formulation of allantoin
comprising an oil-in-water emulsion comprising allantoin, an
emollient, an emulsifier, a solvent and a pharmaceutically
acceptable excipient. In some embodiments, the formulation further
comprises a pH modifier, a solubilizing agent, an antioxidant, a
preservative, a chelating agent, an additive, a viscosity agent or
a combination thereof. In some embodiments, the formulation
comprises allantoin, an emollient, an emulsifier, a pH modifier, a
solubilizing agent, an antioxidant, a preservative, a solvent and a
pharmaceutically acceptable excipient. In some embodiments, the
formulation consists essentially of allantoin, an emollient, an
emulsifier, a pH modifier, a solubilizing agent, an antioxidant, a
preservative, a solvent and a pharmaceutically acceptable
excipient. In some embodiments, the formulation consists of
allantoin, an emollient, an emulsifier, a pH modifier, a
solubilizing agent, an antioxidant, a preservative, a solvent and a
pharmaceutically acceptable excipient. In some embodiments, a
method of treating atopic dermatitis in a patient in need thereof
comprises administering a formulation comprising allantoin, a
solvent, an emollient, an emulsifier, an antioxidant, a
preservative, a pH modifier, a solubilizing agent and a
pharmaceutically acceptable excipient, wherein the allantoin is
present in an amount of about 0.5% to about 15% by weight. In some
embodiments, a method of treating atopic dermatitis in a patient in
need thereof comprises administering a formulation consisting
essentially of allantoin, a solvent, an emollient, an emulsifier,
an antioxidant, a preservative, a pH modifier, a solubilizing agent
and a pharmaceutically acceptable excipient, wherein the allantoin
is present in an amount of about 0.5% to about 15% by weight. In
some embodiments, a method of treating atopic dermatitis in a
patient in need thereof comprises administering a formulation
consisting of allantoin, a solvent, an emollient, an emulsifier, an
antioxidant, a preservative, a pH modifier, a solubilizing agent
and a pharmaceutically acceptable excipient, wherein the allantoin
is present in an amount of about 0.5% to about 15% by weight.
[0106] Embodiments of the present disclosure also relate to the use
of formulations of allantoin in connection with excipients or
stabilizers. Stabilizers include carbohydrates, amino acids, fatty
acids, and surfactants and are known to those skilled in the
art.
[0107] Compositions according to the embodiments described herein
can contain other, optional ingredients. For example, compositions
according to the present embodiments can contain glycerin, lactic
acid, lipid-soluble components such as, but not limited to,
caprylic/capric triglycerides; steareth-2; steareth-21;
polygrlyceryl-3 beeswax; a branched-carboxylic acid ester of a
branched-chain alcohol selected from the group consisting of
isononyl isononanoate, isodecyl isononanoate, isooctyl
isononanotate, isooctyl isooctanoate, isononyl isooctanoate,
isodecyl isooctanoate, isononyl isodecanoate, isooctyl
isodecanoate, and isodecyl isodecanoate; an
acrylates/C.sub.10-C.sub.30 alkyl acrylates cross-polymer;
methylgluceth-20; a glyceryl ester of a long chain fatty acid
selected from the group consisting of glyceryl monostearate,
glyceryl monopalmitate, and glyceryl monoarachidate; hydrogenated
vegetable oil; squalane; C.sub.12-C.sub.15 alkyl benzoates;
di-C.sub.12-C.sub.15 alkyl fumarate; cholesterol; lanolin alcohol;
octyldodecanol, isostearic acid; a branched-chain neopentanoate
selected from the group consisting of octyldodecyl neopentanoate,
heptyldodecyl neopentanoate, nonyldodecyl neopentanoate,
octylundecyl neopentanoate, heptylundecyl neopentanoate,
nonylundecyl neopentanoate, octyltridecyl neopentanoate,
heptyltridecyl neopentanoate, and nonyltridecyl neopentanoate; an
arachidyl ester of a short-chain carboxylic acid selected from the
group consisting of arachidyl propionate, arachidyl acetate,
arachidyl butyrate, and arachidyl isobutyrate; a long-chain fatty
acid ester of a medium-chain alcohol selected from the group
consisting of octyl palmitate, octyl myristate, octyl stearate,
heptyl palmitate, heptylmyristate, heptyl stearate, nonyl
palmitate, nonyl myristate, and nonyl stearate; jojoba oil; a
myristyl ester of a long-chain fatty acid selected from the group
consisting of myristyl myristate, myristyl laurate, and myristyl
palmitate; bisabolol; hydrogenated jojoba oil; jojoba esters;
methyl-gluceth-20 sesquistearate; PPG-14 butyl ether; PPG-15
stearyl ether; PPG-1-isoceteth-3-accetate; laureth-2-benzoate;
diisostearyl dimmer dilinoleate; a long-chain cis-monounsaturated
fatty acid ester of a medium-chain alcohol; a medium-chain
saturated carboxylic acid ester of a long-chain alcohol;
hydrogenated soy glycerides; a long-chain fatty acid ester of cetyl
alcohol selected from the group consisting of cetyl palmitate,
cetyl stearate, and cetyl myristate; palm kernel oil; palm oil; and
an arachidyl ester such as arachidyl acetate, arachidyl propionate,
arachidyl butyrate, or arachidyl isobutyrate.
[0108] In addition, the composition can further comprise other
ingredients that are generally used in the cosmetic art and in the
art of over-the-counter skin preparations. These ingredients
include, but are not limited to: (1) other plant extracts, such as
horsetail extract, horse chestnut extract, rose extract, or
lavender extract; (2) a short-chain carboxylic acid ester of
tocopherol selected from the group consisting of tocopheryl
acetate, tocopheryl propionate, tocopheryl butyrate, and tocopheryl
isobutyrate; (3) a long-chain fatty acid ester of ascorbic acid
selected from the group consisting of ascorbyl myristate, ascorbyl
palmitate, and ascorbyl stearate; (4) a long-chain fatty acid ester
of retinol or a retinol derivative or analogue wherein the acyl
moiety of the ester is selected from the group consisting of
myristic acid, palmitic acid, and stearic acid; and (5) a
sunscreen, which can be at least one compound selected from the
group consisting of octyl methoxycinnamate, p-aminobenzoate,
glyceryl p-aminobenzoate, p-dimethylaminobenzoic acid, methyl
anthranilate, menthyl anthranilate, phenyl anthranilate, benzyl
anthranilate, phenylethyl anthranilate, linalyl anthranilate,
terpinyl anthranilate, cyclohexenyl anthranilate, amyl salicylate,
phenyl salicylate, benzyl salicylate, menthyl salicylate, glyceryl
salicylate, dipropyleneglycol salicylate, methyl cinnamate, benzyl
cinnamate, .alpha.-phenyl cinnamonitrile, butyl cinnamoylpyruvate,
umbelliferone, methylacetoumbelliferone, esculetin,
methylesculetin, daphnetin, esculin, daphnin, diphenylbutadiene,
stilbene, dibenzalacetone, benzalacetophenone, sodium
2-naphthol-3,6-disulfonate, sodium 2-naphthol-6,8-disulfonate,
dihydroxynaphthoic acid, salts of dihydroxynaphthoic acid,
o-hydroxybiphenyldisulfonates, p-hydroxybiphenyldisulfonates,
7-hydroxycoumarin, 7-methylcoumarin, 3-phenyl-coumarin,
2-acetyl-3-bromoindazole, phenylbenzoxazole, methylnaphthoxazole,
arylbenzothiazoles, quinine bisulfate, quinine sulfate, quinine
chloride, quinine oleate, quinine tannate, 8-hydroxyquinoline
salts, 2-phenylquinoline, hydroxyl-substituted benzophenones,
methoxy-substituted benzophenones, uric acid, vilouric acid, tannic
acid, tannic acid hexaethylether, hydroquinone, oxybenzone,
sulisobenzone, dioxybenzone, benzoresorcinol,
2,2',4,4'-tetrahydroxybenzophenone,
2,2'-dihydroxy-4,4-dimethoxybenzophenone, octabenzone,
butylmethoxydibenzoylmethane, etocrylene, and
4-isopropyldibenzoylmethane. Other ingredients can also optionally
be included, such as colorants, pigments, opacifiers, and the
like.
[0109] Methods according to the embodiments described herein
provide rapid improvement, are well tolerated by patients, are easy
to apply, and can be used alone or with other methods for treatment
of skin conditions. Alternative formulations with reduced sodium
lauryl sulfate, reduced beeswax and no fragrance are better suited
to treat diseases such as Epidermolysis bullosa, where the skin is
fragile and sensitive to irritants. It was unexpectedly found that
these formulations, though they have reduced sodium lauryl sulfate
and reduced beeswax, have a stable emulsion in room temperatures
and are effective in treating inflammatory skin conditions. In
particular, formulations of embodiments herein have better
penetration of intact skin and are able to deliver the active (i.e.
allantoin) across intact skin.
[0110] In any of the foregoing embodiments, the composition can
further include fragrance. The use of fragrance is well known in
the art of over-the-counter drug formulation, and many suitable
fragrances are known in the art. The stability and function of the
composition is not altered by the presence or absence of fragrance.
In many alternatives, it may be desirable to avoid the use of
fragrance which may trigger allergic reaction in patients
predisposed to such reactions. Accordingly, in certain embodiments,
the composition excludes a fragrance.
[0111] The compositions can further include other ingredients, such
as proteins, humectants, other preservatives, essential oils, other
vitamins, colorants, hydroxyacids, other plant extracts,
sunscreens, sodium hyaluronate, lipids, fatty acids, thickeners,
panthenol, and the like. The use of such components is conventional
in the over-the-counter drug art. Typical sunscreens are octyl
methoxycinnamate and benzophenone-3.
[0112] In any of the foregoing embodiments, the term "inflammatory
skin conditions" is used interchangeably with "inflammatory skin
diseases" and includes cutaneous porphyria, sclerodema,
epidermolysis bullosa, psoriasis, decubitus ulcers, pressure
ulcers, diabetic ulcers, venous stasis ulcers, sickle cell ulcers,
ulcers caused by burns, eczema, urticaria, atopic dermatitis,
dermatitis herpetiform, contact dermatitis, arthritis, gout, lupus
erythematosus, acne, alopecia, carcinomas, psoriasis, rosacea,
miliaria, skin infections, post-operative care of incisions,
post-operative skin care following any variety of plastic surgery
operations, skin care following radiation treatment, care of dry,
cracked or aged skin and skin lines as well as other conditions
affecting the skin and having an inflammatory component. The term
may also include symptoms associated with such diseases such as,
without limitation, pain, scarring, inflammation, redness, milia,
itching, skin thickening, blisters, or other symptoms associated
with inflammatory disease.
[0113] Pharmaceutical Compositions.
[0114] Pharmaceutical compositions provided by the present
disclosure may comprise formulations of allantoin and in certain
embodiments, in purified form, together with a suitable amount of
one or more pharmaceutically acceptable vehicles, so as to provide
a composition for proper administration to a patient with an
inflammatory skin disease. Suitable pharmaceutical vehicles also
include excipients such as starch, glucose, lactose, sucrose,
gelatin, malt, rice, flour, chalk, silica gel, sodium stearate,
glycerol monostearate, talc, sodium chloride, dried skim milk,
glycerol, propylene, glycol, water, ethanol, and the like. The
present compositions may also contain wetting agents, emulsifying
agents, and/or pH buffering agents. In addition, auxiliary,
stabilizing, thickening, lubricating, and/or coloring agents may be
used. Other examples of suitable pharmaceutical vehicles are
described in the art (see, for example, "Remington's Pharmaceutical
Sciences," Lippincott Williams & Wilkins, 21st Edition,
2005).
[0115] Pharmaceutical compositions disclosed herein may be prepared
by standard mixing techniques, such as are conventional in the
cosmetic art and in the art of over-the-counter drug formulation
for blending lipid-soluble components and water-soluble components.
These mixing techniques include both manual and mechanical mixing,
and include homogenization mixing and sweep mixing. The mixing
techniques to be used can be chosen by one of ordinary skill in the
art based on variables such as the viscosity of the components to
be mixed and the volume of those components, as well as the
relative proportion of lipid-soluble and water-soluble ingredients.
The composition can be mixed in two or more batches, such as one
batch containing lipid-soluble ingredients and another batch
containing water-soluble ingredients, and the batches can then be
mixed at the final state of preparation.
[0116] For example, pharmaceutical compositions disclosed herein
may be manufactured by following these steps: (1) mix and heat
water, 30% solution of sodium lauryl sulfate, propylene glycol,
tetrasodium EDTA and citric acid in one container ("Container 1");
(2) in another container ("Container 2"), mix and heat lanolin oil,
beeswax, stearyl alcohol and cetyl alcohol; (3) when both
containers reach about 170-180.degree. F., add contents of
Container 2 to Container 1; (4) add cod liver oil and butyl
hydroxytoluene (BHT); (5) mix for about thirty minutes; (6) add
allantoin; (7) mix for about thirty minutes; (8) cool contents to
about 120.degree. F.; (9) add methylparaben and propylparaben; (10)
mix for about ten minutes; (11) remove the mixer and insert the
homogenizer; (12) activate the homogenizer for about five minutes;
(13) remove the homogenizer and insert mixer; (14) mix for about
thirty minutes while maintaining temperature range of about
115-120.degree. F.; (15) continue mixing while contents are cooled
to about 115.degree. F.; (16) stop mixing when contents reach about
115.degree. F.; (17) remove mixer and cover drum; (18) store cream
overnight at room temperature; and (19) package the cream into
finished product containers.
[0117] Pharmaceutical compositions may be formulated in a
conventional manner using one or more physiologically acceptable
carriers, diluents, excipients, or auxiliaries, which facilitate
processing of allantoin and one or more pharmaceutically acceptable
vehicles into formulations that can be used pharmaceutically.
Proper formulation is dependent upon the route of administration
chosen.
[0118] Pharmaceutical compositions provided by the present
disclosure may be administered for therapeutic or prophylactic
treatments. A therapeutic amount is an amount sufficient to remedy
a disease state or symptoms, or otherwise prevent, hinder, retard,
or reverse the progression of disease or any other undesirable
symptoms in any way whatsoever. In prophylactic applications,
pharmaceutical compositions or the present disclosure may be
administered to a patient susceptible to or otherwise at risk of a
particular disease or infection. Hence, a prophylactically
effective amount is an amount sufficient to prevent, hinder or
retard a disease state or its symptoms.
[0119] Specific modes of administration will depend on the
indication. The selection of the specific route of administration
and the dose regimen is to be adjusted or titrated by the clinician
according to methods known to the clinician in order to obtain the
optimal clinical response. The amount of compound to be
administered is that amount which is therapeutically effective. The
dosage to be administered will depend on the characteristics of the
subject being treated, e.g., the particular animal treated, age,
weight, health, types of concurrent treatment, if any, and
frequency of treatments, and can be easily determined by one of
skill in the art (e.g., by the clinician).
[0120] Pharmaceutical formulations containing the above-described
compound and a suitable carrier can be topical dosage forms which
include, but are not limited to, solutions, powders, fluid
emulsions, fluid suspensions, semi-solids, ointments, pastes,
creams, gels and jellies, and foams comprising an effective amount
of a polymer or copolymer of the present embodiment. It is also
known in the art that the active ingredients can be contained in
such formulations with pharmaceutically acceptable diluents,
fillers, disintegrants, binders, lubricants, surfactants,
hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers,
humectants, moisturizers, solubilizers, preservatives and the like.
The means and methods for administration are known in the art and
an artisan can refer to various pharmacologic references for
guidance. For example, Modem Pharmaceutics, Banker & Rhodes,
Marcel Dekker, Inc. (1979); and Goodman & Gilman's The
Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan
Publishing Co., New York (1980) can be consulted.
[0121] The embodiments illustrating the methods and materials used
may be further understood by reference to the following
non-limiting examples.
Example 1
[0122] A formulation containing 3.0% allantoin; 67.01% water; 3.5%
cetyl alcohol; 1.7% stearyl alcohol; 2.5% beeswax; 0.09% citric
acid; 10.6% lanolin oil; 5.7% propylene glycol; 0.15% tetrasodium
EDTA; 2% cod liver oil; 0.5% butylated hydroxytoluene; 0.3%
methylparaben; 0.25% propylparaben; 0.2% fragrance; and 2.5% sodium
lauryl sulfate in a 30% solution was made. The pH of this
formulation is 4.58.
Example 2
[0123] A formulation containing 3.0% allantoin; 67.41% water; 4.2%
cetyl alcohol; 2% stearyl alcohol; 1.9% beeswax; 0.09% citric acid;
10.6% lanolin oil; 5.7% propylene glycol; 0.15% tetrasodium EDTA;
2% cod liver oil; 0.5% butylated hydroxytoluene; 0.3%
methylparaben; 0.25% propylparaben; and 1.9% sodium lauryl sulfate
in a 30% solution was made. The pH of this formulation is 4.54. It
is desirous to reduce irritants due to the indications of these
inflammatory skin conditions; thus we reduced the amounts of
beeswax, and sodium lauryl sulfate and removed the fragrance. It
was unexpected that such a reduction of these ingredients created
an effective composition because lowering the emulsifier
concentration may not result in a system that demonstrates
long-term stability.
Example 3
[0124] A formulation containing 3.0% allantoin; water; cetyl
alcohol; stearyl alcohol; beeswax; 0.09% citric acid; 10.6% lanolin
oil; 5.7% propylene glycol; 0.15% tetrasodium EDTA; 2% cod liver
oil; 0.5% butylated hydroxytoluene; 0.3% methylparaben; 0.25%
propylparaben; and 1.5% sodium lauryl sulfate in a 30% solution was
made. It is desirous to reduce irritants due to the indications of
these inflammatory skin conditions; thus we reduced the amounts of
beeswax, and sodium lauryl sulfate and removed the fragrance. It
was unexpected that such a reduction of these ingredients created
an effective composition because lowering the emulsifier
concentration may not result in a system that demonstrates
long-term stability at room temperature.
Example 4
[0125] A formulation containing 6.0% allantoin; 63.98% water; 3.23%
cetyl alcohol; 1.5% stearyl alcohol; 2.75% beeswax; 0.09% citric
acid; 10.6% lanolin oil; 5.7% propylene glycol; 0.15% tetrasodium
EDTA; 2% cod liver oil; 0.5% butylated hydroxytoluene; 0.3%
methylparaben; 0.25% propylparaben; 0.2% fragrance; and 2.75%
sodium lauryl sulfate in a 30% solution was made. The pH of this
formulation is 4.62.
Example 5
[0126] A formulation containing 6.0% allantoin; 64.81% water; 3.5%
cetyl alcohol; 1.5% stearyl alcohol; 2.3% beeswax; 0.09% citric
acid; 10.6% lanolin oil; 5.7% propylene glycol; 0.15% tetrasodium
EDTA; 2% cod liver oil; 0.5% butylated hydroxytoluene; 0.3%
methylparaben; 0.25% propylparaben; and 2.3% sodium lauryl sulfate
in a 30% solution was made. The pH of this formulation is 4.51. It
is desirous to reduce irritants due to the indications of these
inflammatory skin conditions; thus we reduced the amounts of
beeswax, and sodium lauryl sulfate and removed the fragrance. It
was unexpected that such a reduction of these ingredients created
an effective composition because lowering the emulsifier
concentration may not result in a system that demonstrates
long-term stability at room temperature.
Example 6
[0127] A formulation containing 6.0% allantoin; 65.11% water; 3.6%
cetyl alcohol; 1.7% stearyl alcohol; 2.0% beeswax; 0.09% citric
acid; 10.6% lanolin oil; 5.7% propylene glycol; 0.15% tetrasodium
EDTA; 2% cod liver oil; 0.5% butylated hydroxytoluene; 0.3%
methylparaben; 0.25% propylparaben; and 2.0% sodium lauryl sulfate
in a 30% solution was made. It is desirous to reduce irritants due
to the indications of these inflammatory skin conditions; thus we
reduced the amounts of beeswax, and sodium lauryl sulfate and
removed the fragrance. It was unexpected that such a reduction of
these ingredients created an effective composition because lowering
the emulsifier concentration may not result in a system that
demonstrates long-term stability at room temperature.
Example 7
[0128] This formulation contained 9.0% allantoin; 61.78% water;
2.7% cetyl alcohol; 1.2% stearyl alcohol; 2.75% beeswax; 0.12%
citric acid; 10.6% lanolin oil; 5.7% propylene glycol; 0.15%
tetrasodium EDTA; 2% cod liver oil; 0.5% butylated hydroxytoluene;
0.3% methylparaben; 0.25% propylparaben; 0.2% fragrance; and 2.75%
sodium lauryl sulfate in a 30% solution. The pH of this formulation
is 4.07.
Example 8
[0129] This formulation contained 9.0% allantoin; water; cetyl
alcohol; stearyl alcohol; beeswax; citric acid; 10.6% lanolin oil;
5.7% propylene glycol; 0.15% tetrasodium EDTA; 2% cod liver oil;
0.5% butylated hydroxytoluene; 0.3% methylparaben; 0.25%
propylparaben; and sodium lauryl sulfate in a 30% solution. It is
desirous to reduce irritants due to the indications of these
inflammatory skin conditions; thus we reduced the amounts of
beeswax, and sodium lauryl sulfate and removed the fragrance. It
was unexpected that such a reduction of these ingredients created
an effective composition because lowering the emulsifier
concentration may not result in a system that demonstrates
long-term stability at room temperature.
Example 9
[0130] This formulation contained 90% allantoin; 63.71% water; 2.5%
cetyl alcohol; 1.2% stearyl alcohol; 2.0% beeswax; 0.09% citric
acid; 10.6% lanolin oil; 5.7% propylene glycol; 0.15% tetrasodium
EDTA; 2% cod liver oil; 0.5% butylated hydroxytoluene; 0.3%
methylparaben; 0.25% propylparaben; and 2.0% sodium lauryl sulfate
in a 30% solution. It is desirous to reduce irritants due to the
indications of these inflammatory skin conditions; thus we reduced
the amounts of beeswax, and sodium lauryl sulfate and removed the
fragrance. It was unexpected that such a reduction of these
ingredients created an effective composition because lowering the
emulsifier concentration may not result in a system that
demonstrates long-term stability at room temperature.
Example 10
[0131] The formulations A.S. 1-139E, A.S. 1-81B, A.S. 1-135C, A.S.
1-1350, and A.S. 1-81G were tested on a minimum of triplicate
sections from three different cadaver skin donors and three
different porcine skin donors for the percutaneous absorption of
allantoin over a 48-hour dose period. The intent of this study was
to mimic the absorption of allantoin directly into the capillary
bed, while the dermis only study attempted to mimic the loss of
skin barrier function due to broken skin or blisters. In addition,
each formulation was tested in at least triplicate membrane
chambers. At preselected times after dosing, the dermal receptor
solution was removed in its entirety, replaced with fresh receptor
solution, and an aliquot saved for subsequent analysis. The samples
were analyzed for the allantoin using high performance liquid
chromatography with UV and MS detection (HPLC-UV-MS). The summary
results are presented in FIG. 3 and FIG. 4. The bottom table of
FIG. 3 lists a remanufacture of the 9% allantoin cream (A.S.
1-153H) to achieve a better viscosity of the final product. That
table demonstrates that the initial results with A.S. 1-81G were
lower than expected and unreliable due to problems in the
manufacture of this lot. The remanufacture of the new A.S. 1-153H
9% lot demonstrated no viscosity issues, and was retested in the
full thickness skin model only, demonstrating that the penetration
of allantoin with this concentration was two times that of the 6%
formulation (A.S. 1-135G). It can also be inferred based on this
result that the 9% cream results in the top table of FIG. 3 may be
higher than reported with A.S. 1-81G and dose related to the other
formulation concentrations in all percutaneous models.
[0132] Conclusions: Analysis of the mass delivered through the
porous membrane over 24 hours (FIGS. 6-7) showed that
9%>6%>3%>1.5%>0.5% (p<0.05). Area under the curve
presented graphically demonstrated a dose-related increase in
allantoin penetration across the membrane. Analysis of the mass
delivered through full thickness human cadaver skin (FIGS. 10-11)
showed that 6% delivered more than 0.5% (p<0.05), and that
penetration across the skin was related to the concentration of
allantoin in the formulation. The accuracy of the formulation's
manufacturing impacted the ability of the formulation to deliver
allantoin across the skin, as demonstrated by a 2.times. increase
in allantoin delivered across the intact skin with the new 9% lot
(A.S. -153H) versus the previous 9% lot (A.S. 1-81G), which was
outside of specifications in terms of physical appearance and
consistency.
[0133] Statistical analysis of the mass delivered through dermis
only human cadaver skin (FIGS. 12-15) showed that
9%>6%>3%>1.5%>0.5% (p<0.05). It is well known from
studies with dermal formulations that the lack of efficacy of
dermal products is due to lack of penetration of the active
ingredient across the stratum corneum, which is an effective
barrier, however the formulations described above delivered
allantoin across this stratum corneum in a dose related manner,
unexpectedly. When the skin's barrier has been damaged or removed
(as seen with the isolated dermis in FIGS. 12-15), the penetration
of allantoin increases significantly.
[0134] Blood and urine collection and analysis for the presence of
allantoin demonstrated no increase in basal levels of allantoin in
either the blood or urine from EB patients treated with 1.5%
allantoin daily for a period greater than 1 year. In addition, data
derived from various skin penetration models (dermis and full
thickness cadaver skin, abraded porcine skin, and membrane)
demonstrated a dose-related increase in allantoin concentrations
across various skin models, which was clearly unexpected due to
lack of penetration enhancers in the formulation. Specifically,
allantoin levels increased from 1.5 to 3.times. across the dermis
in the 3%, 6%, and 9% formulations; 2.5 to 7.times. across the full
thickness skin; and 2-4.times. across the membrane, as compared to
a 1.5% formulation. Additionally, it was unexpected that the
allantoin formulations result in penetration of allantoin across
the skin membrane without any increase in systemic blood
levels.
[0135] The results of the penetration studies with the various
concentration of the active ingredient, allantoin, was clearly
unexpected, given the robustness of the protection of the skin from
penetration of topical products. This formulation was able to
deliver allantoin across all skin models in a dose-related manner
over a sustained period of time. The inability of deliver of active
ingredients across the intact skin and dermal barriers is the
reason why topical products typically only work on superficial skin
diseases.
Example 11
[0136] In vitro tests confirm the protein dispersing activity of
allantoin as measured by the concentration of reactive sulphydryl
groups released from the protein of skin samples. Keratolytic
activity on psoriatic scales was demonstrated in vitro by
incubation with concentrations as low as 0.2% allantoin solution.
(Fisher A 1981; Cajkovac et al 1992). Keratolysis is a process
whereby horny cells are dispersed with a release of non-keratinous
material such as free amino acids and acid mucopolysaccharides
which contributes to the horny layer associated with psoriasis
(Flesch 1958). Other studies have further demonstrated the ability
of allantoin to remove or reduce calluses and other forms of
hyperkeratization by dissolving the cement holding the cornified
cells together, or loosening of the desmosomes as lower
concentrations (<1%)(protein bridges) (Mecca SB 1976). All of
these in vitro studies have suggested that allantoin could be
effective in psoriasis, but no published clinical data to date with
allantoin administration topically have demonstrated efficacy in
psoriasis. Results from testing of this topical formulation at a
concentration of allantoin up to 1.5% in clinical psoriasis was
consistent with published data on the lack of human clinical
efficacy with topically administered allantoin. However,
unexpectedly, evaluation of allantoin at a daily administration of
this formulation at a higher concentration (3%), which has been
shown to deliver allantoin across the skin barriers, demonstrated
complete clearing of psoriatic plaques in addition to prevention of
reoccurrence of plaque formation.
[0137] The results of the 3% study demonstrate the ability of
allantoin to effectively close wounds and lesions, and
significantly lower than body surface area coverage of lesions and
wounds in patients with this indication. Two patients in this study
had previously used the 1.5% formulation for an extended period of
time, and noted that, while the 1.5% formulation was effective,
application of the 3% cream was more effective in closure of wounds
and the healing time was faster. These results are consistent with
the findings from the percutaneous skin studies, in that allantoin
can be delivered to the active site more effectively at higher
cream concentrations resulting in improved efficacy.
Example 12
[0138] Eight patients 6 months to 4 years of age were enrolled an
open study with a 3 month treatment period involving daily
administration of 3% allantoin cream to all areas of the body
containing blisters, skin erosions and open wounds: 3 patients with
EB Simplex; 3 patients with Junctional EB; 2 patients with
Recessive Dystrophic EB. All patients had between 25-75% of body
surface area affected by the disease.
[0139] Measurements: The key measurements were based on a change in
disease condition from baseline/screening evaluations: (1) the
change from baseline in size of an index lesion/wound measured by
area, cm squared; (2) the change from baseline in affected body
surface area (BSA) including head, upper limbs, lower limbs, and
trunk; physicians global assessment of improvement from baseline
measured on a 6 point scale (Clear; Excellent; Marked; Good; None;
Worsening).
[0140] Results: The findings of the study indicated that there were
clinically significant improvements in BSA and Index lesion scores
compared with baseline. Following 3 months of treatment, there was
a 55% reduction in BSA ratings from baseline and in most patients
one or more index lesions were totally healed/cleared. The
Physicians Global Assessment of Improvement indicated that all
patients improved from baseline with some patients showing as much
as a 75% improvement. In addition, the cream appeared to prevent
the recurrence of newly formed blisters and erosions.
[0141] Conclusions: The findings of the study indicated that a 3%
concentration of allantoin in a cream formulation induces a
clinically significant change in the severity of the disease
including wound closures and an overall reduction of body blisters
and skin erosions. A number of these patients had been exposed
previously to a 1.5% concentration of allantoin cream which was
felt to be less efficacious. The current formulation promotes the
penetration of allantoin across the skin barrier thereby increasing
effectiveness in a dose related manner. Based on the dose-related
effects seen with this formulation, it is likely that higher
concentrations may confer even better efficacy.
[0142] Although the present invention has been described in
considerable detail with reference to certain preferred embodiments
thereof, other versions are possible. Accordingly, the present
embodiments are to be considered as illustrative and not
restrictive. Therefore the spirit and scope of the appended claims
should not be limited to the description and the preferred versions
contained within this specification.
* * * * *