U.S. patent application number 10/189344 was filed with the patent office on 2003-07-03 for formulations and methods for reducing skin irritation.
Invention is credited to Hahn, Gary S., Thueson, David O..
Application Number | 20030124202 10/189344 |
Document ID | / |
Family ID | 46203134 |
Filed Date | 2003-07-03 |
United States Patent
Application |
20030124202 |
Kind Code |
A1 |
Hahn, Gary S. ; et
al. |
July 3, 2003 |
Formulations and methods for reducing skin irritation
Abstract
Compositions and methods are provided for inhibiting skin
irritations attributable to chemical irritants or environmental
conditions by the application of anti-irritant amounts of
aqueous-soluble divalent strontium cation.
Inventors: |
Hahn, Gary S.; (Cardiff by
the Sea, CA) ; Thueson, David O.; (Poway,
CA) |
Correspondence
Address: |
Cosmederm Technologies, LLC
4370 La Jolla Village Drive, Suite 960
San Diego
CA
92122
US
|
Family ID: |
46203134 |
Appl. No.: |
10/189344 |
Filed: |
July 3, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10189344 |
Jul 3, 2002 |
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10033194 |
Oct 24, 2001 |
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10033194 |
Oct 24, 2001 |
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09853282 |
May 11, 2001 |
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09853282 |
May 11, 2001 |
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09685992 |
Oct 10, 2000 |
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09685992 |
Oct 10, 2000 |
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08860993 |
Jun 23, 1997 |
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6139850 |
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08860993 |
Jun 23, 1997 |
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08362100 |
Dec 21, 1994 |
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5716625 |
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08860993 |
Jun 23, 1997 |
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PCT/US95/16985 |
Dec 21, 1995 |
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Current U.S.
Class: |
424/722 |
Current CPC
Class: |
A61Q 19/002 20130101;
A61Q 5/12 20130101; Y10S 514/881 20130101; Y10S 514/848 20130101;
A61K 2800/75 20130101; A61K 31/28 20130101; A61Q 9/02 20130101;
A61Q 19/00 20130101; A61Q 5/04 20130101; Y10S 514/847 20130101;
A61Q 1/06 20130101; A61Q 17/00 20130101; A61Q 19/10 20130101; A61Q
15/00 20130101; Y10S 514/859 20130101; A61K 33/24 20130101; A61K
8/365 20130101; A61K 8/20 20130101; A61K 8/19 20130101; A61Q 1/02
20130101; A61Q 5/00 20130101; Y10S 514/887 20130101 |
Class at
Publication: |
424/722 |
International
Class: |
A61K 033/00 |
Claims
What is claimed is:
1. A composition for topical application to an animal subject
comprising a topical vehicle; an irritant ingredient contained in
an amount capable of inducing skin irritation in said subject; and
an anti-irritant amount of aqueous-soluble divalent strontium
cation.
2. The composition of claim 1 comprising strontium cation in a
concentration of from about 10 mM to about 3000 mM.
3. The composition of claim 1 comprising strontium cation in a
concentration of from about 50 mM to about 2000 mM.
4. The composition of claim 1 comprising strontium cation in a
concentration of from about 100 mM to about 1000 mM.
5. The composition of claim 1 comprising strontium cation in a
concentration of from about 250 mM to about 500 mM.
6. The composition of claim 1 comprising an amount of strontium
cation capable of inhibiting mean cumulative skin irritation
attributable to said irritant ingredient in a susceptible human
population by at least about 20%
7. The composition of claim 6 wherein said inhibition of skin
irritation represents an average reduction in one or more of sting,
burn and itch in a susceptible human population upon topical
application of said composition, as compared to the level of
irritation induced in said population upon topical application of a
control formulation containing said irritant ingredient in a
vehicle without said strontium cation.
8. The composition of claim 1 comprising an amount of strontium
cation capable of inhibiting by at least about 40% the cumulative
skin irritation attributable to said irritant ingredient in at
least 10% of the susceptible human population.
9. The composition of claim 8 wherein said inhibition of skin
irritation represents an average reduction in one or more of sting,
burn and itch in at least 10% of the susceptible human population
upon topical application of said composition, as compared to the
level of irritation induced in said at least 10% of the population
upon topical application of a control formulation containing said
irritant ingredient in a vehicle without said strontium cation.
10. The composition of claim 1 wherein said composition is a
cosmetic product.
11. The composition of claim 10 wherein said composition comprises
a skin exfolient, skin peel or skin cell renewal agent.
12. The composition of claim 10 wherein said irritant ingredient is
selected from the group consisting of carboxylic acids, keto acids,
.alpha.-hydroxy acids, .beta.-hydroxy acids, retinoids, peroxides,
and organic alcohols.
13. The composition of claim 12 wherein said irritant ingredient
comprises lactic acid or a salt thereof.
14. The composition of claim 12 wherein said irritant ingredient
comprises glycolic acid or a salt thereof.
15. The composition of claim 12 wherein said irritant ingredient
comprises salicylic acid or a salt thereof.
16. The composition of claim 12 wherein said irritant ingredient
comprises a combination of lactic acid and salicylic acid, or salts
thereof.
17. The composition of claim 12 wherein said irritant ingredient
comprises capryloyl salicylic acid or a salt thereof.
18. The composition of claim 12 wherein said irritant ingredient
comprises citric acid or a salt thereof.
19. The composition of claim 12 wherein said irritant ingredient is
a retinoid selected from tretinoin, retinol, retinal and
derivatives thereof.
20. The composition of claim 12 wherein said irritant ingredient
comprises benzoyl peroxide.
21. The composition of claim 12 wherein said irritant ingredient
comprises acetic acid or a salt thereof.
22. The composition of claim 12 wherein said irritant ingredient
comprises one or more of the group consisting of
1-pyrrolidone-5-carboxylic acid, capryloyl salicyclic acid,
.alpha.-hydroxy decanoic acid, .alpha.-hydroxy octanoic acid,
gluconolactone, methoxypropyl gluconamide, oxalic acid, malic acid,
tartaric acid, mandelic acid, benzylic acid, gluconic acid, pyruvic
acid and phenol.
23. The composition of claim 12 wherein said irritant ingredient
comprises trichloroacetic acid of a salt thereof.
24. The composition of claim 12 wherein the pH of the composition
is in the range of 1 to 6.
25. The composition of claim 12 wherein the pH of the composition
is in the range of 3 to 5.
26. The composition of claim 12 having a concentration of said
irritant ingredient of from about 0.1% to about 50%
27. The composition of claim 12 having a concentration of said
irritant ingredient of from about 0.5% to about 20%
28. The composition of claim 1 wherein said composition is an
antiperspirant or deodorant product.
29. The composition of claim 1 wherein said composition is a
sunscreen, tanning or sunburn treatment product.
30. The composition of claim 1 wherein said composition is an
insect repellant product.
31. The composition of claim 10 wherein said composition is a
shaving or hair removal product selected from the group consisting
of depilatory, bracer, cream, foam, gel and aftershave
products.
32. The composition of claim 10 wherein said composition is a hair
care or hair treatment product.
33. The composition of claim 32 wherein said composition is
selected from the group consisting of shampoo, conditioner,
colorant, dye, bleach, permanent wave and hair straightener
products.
34. The composition of claim 10 wherein said composition is
selected from the group consisting of cleansers, astringents,
toners, rinses, serums and masks.
35. The composition of claim 10 wherein said composition is a
facial cosmetic product.
36. The composition of claim 10 wherein said composition is
selected from the group consisting of creams, lotions and
moisturizers.
37. The composition of claim 1 wherein said composition is selected
from the group consisting of soaps and detergents.
38. The composition of claim 1 wherein said composition is a
topical drug product.
39. The composition of claim 38 wherein said irritant ingredient is
capsaicin.
40. The composition of claim 38 wherein said composition is
selected from the group consisting of antibiotic, analgesic,
contraceptive, anti-acne and anti-dandruff products.
41. The composition of claim 40 wherein said irritant ingredient is
benzoyl peroxide.
42. The composition of claim 1 wherein said composition is
formulated as a rectal or vaginal suppository, foam, cream, gel or
ointment.
43. The composition of claim 1 wherein said composition is
formulated for administration to the mouth, throat or lip.
44. The composition of claim 43 formulated as a lozenge, mouthwash
or gargle.
45. The composition of claim 1 formulated as a liquid, gel, cream,
emulsion, suspension or stick.
46. The composition of claim 1 formulated with a physical
applicator.
47. The composition of claim 46 wherein said physical applicator is
selected from the group consisting of cloths, tissues, swabs,
bandages and wet wipes.
48. The composition of claim 1 further comprising, as counteranions
to said strontium cation, one or more topically acceptable anion
species.
49. The composition of claim 48 further comprising, as
counteranions to said strontium cation, one or more anion species
selected from the group consisting of nitrate, sulfate, halogen,
carbonate, bicarbonate, hydroxide, oxide, peroxide, nitrite,
sulfide, bisulfate, persulfate, glycerophosphate, hypophosphate,
borate and titanate inorganic anions, and carboxylic acid,
alkoxylate, amino acid, peptide, saturated and unsaturated organic
acid, and saturated and unsaturated fatty acid organic anions.
50. The composition of claim 48 wherein said one or more of said
counteranions is an organic anion selected from the group
consisting of citrate, oxalate, acetate, gluconate, lactate,
tartrate, maleate, benzoate, propionate, salicylate, ascorbate,
formate, succinate, folinate, aspartate, phthalate, oleate,
palmitate, stearate, lauryl sulfate, lanolate, myristate, behenate,
caseinate, cyclamate, pantothenate, polyaminopolycarboxylates,
saccharin, thioglycolate, laurate, methylparaben, propylparaben,
ricinoleate and sorbate organic anions.
51. The composition of claim 48 wherein said anion species includes
nitrate.
52. The composition of claim 48 wherein said anion species includes
sulfate.
53. The composition of claim 48 wherein said anion species includes
a halogen selected from chloride and fluoride anions.
54. The composition of claim 1 further comprising at least one
second anti-irritant agent.
55. The composition of claim 54 wherein the total amount of said
strontium cation and said second agent is capable of inhibiting
mean cumulative skin irritation attributable to said irritant
ingredient in a susceptible human population by at least about
20%
56. The composition of claim 54 wherein the total amount of said
strontium cation and said second agent is capable of inhibiting by
at least about 40% the cumulative skin irritation attributable to
said irritant ingredient in at least 10% of the susceptible human
population.
57. The composition of claim 54 wherein said second agent is
selected from the group consisting of potassium channel mediating,
regulating or blocking agents, calcium channel blocking or
regulatory agents, sodium channel blocking agents, steroids,
non-steroidal anti-inflammatory agents, aloe vera, chamomile,
.alpha.-bisabolol, cola nitada extract, green tea extract, tea tree
oil, licorice extract, allantoin, urea, caffeine and other
xanthenes, and glycyrrhizic acid and its derivatives.
58. An composition for inhibiting skin irritation in an animal
subject comprising an anti-irritant amount of aqueous-soluble
divalent strontium cation and a topical vehicle.
59. The composition of claim 58 comprising strontium cation in a
concentration of from about 10 mM to about 3000 mM.
60. The composition of claim 58 comprising strontium cation in a
concentration of from about 50 mM to about 2000 mM.
61. The composition of claim 58 comprising strontium cation in a
concentration of from about 100 mM to about 1000 mM.
62. The composition of claim 58 comprising strontium cation in a
concentration of from about 250 mM to about 500 mM.
63. The composition of claim 58 wherein said inhibition of skin
irritation represents a reduction in skin irritation attributable
to a pre-existing human skin disease or skin irritation
condition.
64. The composition of claim 63 wherein said skin irritation is
attributable to atopic or allergic contact dermatitis, eczema,
psoriasis or infectious disease.
65. The composition of claim 63 wherein said skin irritation is
attributable to environmental exposure to one or more of sunlight,
low humidity, wind, cold temperature, or hot and humid
conditions.
66. The composition of claim 63 wherein said skin irritation is
attributable to exposure to an irritating chemical agent.
67. The composition of claim 66 wherein said irritating chemical
agent exposure is attributable to application of a topical
product.
68. The composition of claim 67 wherein said product is selected
from the group consisting of antiperspirant, deodorant, sunscreen,
tanning, sunburn treatment, insect repellant, exfolient, skin peel,
skin cell renewal, fragrance, shaving or hair removal, hair care or
hair treatment, cleanser, astringent, toner, rinse, serum, masks,
facial cosmetic, cream, lotion, moisturizer, soap, detergent, and
topical drug products.
69. The composition of claim 67 wherein said composition is
packaged with instructions directing administration of said
composition before, with or following administration of said
topical product.
70. The composition of claim 66 wherein said irritating chemical
agent exposure is attributable to insect sting or bite, or to plant
exposure.
71. The composition of claim 63 wherein said skin irritation is
attributable to one or more of shaving, skin cleansing or bathing,
sweating, and physical skin trauma.
72. The composition of claim 58 wherein said skin irritation is
attributable to dry skin.
73. The composition of claim 58 comprising an amount of strontium
cation capable of inhibiting said skin irritation in subjects
experiencing the same by an average of at least about 20%
74. The composition of claim 58 comprising an amount of strontium
cation capable of inhibiting said skin irritation by at least about
40% in at least 10% of the subjects experiencing the same.
75. The composition of claim 58 wherein said composition is
formulated as a rectal or vaginal suppository, cream, foam, gel,
ointment, douche or enema.
76. The composition of claim 58 wherein said composition is
formulated for administration to the mouth, throat or lip.
77. The composition of claim 76 formulated as a lozenge, mouthwash
or gargle.
78. The composition of claim 58 formulated as a liquid, gel, cream,
emulsion, suspension or stick.
79. The composition of claim 58 formulated with a physical
applicator.
80. The composition of claim 58 further comprising, as
counteranions to said strontium cation, one or more topically
acceptable anion species.
81. The composition of claim 80 further comprising, as
counteranions to said strontium cation, one or more anion species
selected from the group consisting of nitrate, sulfate, halogen,
carbonate, bicarbonate, hydroxide, oxide, peroxide, nitrite,
sulfide, bisulfate, persulfate, glycerophosphate, hypophosphate,
borate and titanate inorganic anions, and carboxylic acid,
alkoxylate, amino acid, peptide, saturated and unsaturated organic
acid, and saturated and unsaturated fatty acid organic anions.
82. The composition of claim 80 wherein said one or more of said
counteranions is an organic anion selected from the group
consisting of citrate, oxalate, acetate, gluconate, lactate,
tartrate, maleate, benzoate, propionate, salicylate, ascorbate,
formate, succinate, folinate, aspartate, phthalate, oleate,
palmitate, stearate, lauryl sulfate, lanolate, myristate, behenate,
caseinate, cyclamate, pantothenate, polyaminopolycarboxylates,
saccharin, thioglycolate, laurate, methylparaben, propylparaben,
ricinoleate and sorbate organic anions.
83. The composition of claim 58 further comprising at least one
second anti-irritant agent.
84. The composition of claim 83 wherein said second agent is
selected from the group consisting of potassium channel mediating,
regulating or blocking agents, calcium channel blocking or
regulatory agents, sodium channel blocking agents, steroids,
non-steroidal anti-inflammatory agents, aloe vera, chamomile,
.alpha.-bisabolol, cola nitada extract, green tea extract, tea tree
oil, licorice extract, allantoin, urea, caffeine and other
xanthenes, and glycyrrhizic acid and its derivatives.
85. A method for inhibiting skin irritation associated with an
irritant ingredient contained in an applied topical formulation,
comprising topically administering to an human subject the
composition of claim 1.
86. A method for inhibiting skin irritation in a human subject
comprising topically administering to the subject the composition
of claim 58.
87. The method of claim 86 wherein said composition is administered
within about three hours prior to application to the subject of a
second topical formulation containing an irritant ingredient.
88. The method of claim 86 wherein said composition is administered
substantially simultaneously with application to the subject of a
second topical formulation containing an irritant ingredient.
89. The method of claim 86 wherein said composition is administered
to inhibit skin irritation attributable to a pre-existing human
skin disease or skin irritation condition.
90. The method of claim 89 wherein said skin irritation is
attributable to environmental exposure to one or more of sunlight,
low humidity, wind, cold temperature, or hot and humid
conditions.
91. The method of claim 89 wherein said skin irritation is
attributable to exposure to an irritating chemical agent.
92. The method of claim 89 wherein said skin irritation is
attributable to one or more of shaving, skin cleansing or bathing,
and physical skin trauma.
Description
BACKGROUND
[0001] Many substances are applied topically to the skin or mucous
membranes of humans or animals in order to alter the subject's
appearance, to protect the subject from the environment, or to
produce a biological change in the skin or other tissue for
therapeutic, preventive or cosmetic purposes. These substances may
generically be termed "topical products" and include such topically
applied substances as cosmetics, over-the-counter and prescription
topical drugs, and a variety of other products such as soaps and
detergents.
[0002] Topical products occur in a variety of forms, including
solids, liquids, suspensions, semisolids (such as creams, gels,
pastes or "sticks"), powders or finely dispersed liquids such as
sprays or mists. Examples of topical products commonly classified
as "cosmetics" include skin care products such as creams, lotions,
moisturizers and "treatment cosmetics" such as exfolients and/or
skin cell renewal agents; fragrances such as perfumes and colognes,
and deodorants; shaving-related products such as creams, "bracers"
and aftershaves; depilatories and other hair removal products; skin
cleansers, toners and astringents; pre-moistened wipes and
washcloths; tanning lotions and sunscreens; bath products such as
oils; eye care products such as eye lotions and makeup removers;
foot care products such as powders and sprays; skin colorant and
make-up products such as foundations, blushes, rouges, eye shadows
and liners, lip colors and mascaras; lip balms and sticks; hair
care and treatment products such as shampoos, conditioners,
colorants, dyes, bleaches, straighteners, and permanent wave
products; baby products such as baby lotions, oils, shampoos,
powders and wet wipes; feminine hygiene products such as deodorants
and douches; skin or facial peels applied by dermatologists or
cosmeticians; and others. Examples of topical products commonly
classified as "topical drugs" are many and varied, and include
over-the-counter and/or prescription products such as
antiperspirants, insect repellents, sunscreens and sunburn
treatments, anti-acne agents, antibiotics, therapeutic retinoids,
anti-dandruff agents, external analgesics such as capsaicin
products, topical contraceptives, topical drug delivery systems,
suppositories and enemas, hemorrhoid treatments, vaginal
treatments, lozenges, and many other products with therapeutic or
other effects. Other topical products include hand, facial and body
soaps and detergents and other forms of skin cleansers, as well as
household detergents and many other household products such as
solvents, propellants, polishes, lubricants, adhesives, waxes and
others which are either applied topically or are topically exposed
to the body during normal use.
[0003] In a large number of cases, topical products contain
chemicals which may produce irritation or inflammation when applied
to the skin or mucosa. The present invention is directed in part to
compositions and methods for inhibiting the irritation associated
with such topical products.
[0004] The occurrence, frequency and nature of
topical-product-induced irritation often varies from user to user.
The severity of irritation to the susceptible user may range from
subclinical to mild to severe. Typical symptoms of irritation
include itching (pruritus), stinging, burning, tingling,
"tightness," erythema (redness) or edema (swelling). The irritation
response may be due to the direct effect on the skin of certain
topical product chemicals or to a response by the immune system
directed toward the chemicals alone or in combination with skin
components (e.g. allergic dermatitis).
[0005] The sensation of itch is one of the most common skin
problems experienced by humans and animals. Itch can be defined as
a sensation which provokes the desire to scratch the site from
which the sensation originates. All skin contains sensory nerves
which transmit itch in response to chemical irritation,
environmental exposure or disease processes. Although the precise
population of itch producing nerves have not been identified, the
thinnest, unmyelinated nerve population, termed type C nociceptive
neurons are thought to be the most important in producing the
sensation. Itch: Mechanisms and Management of Pruritus. Jeffrey D.
Bernhard. McGraw-Hill, Inc. (San Francisco, 1994), pp. 1-22. The
itch-producing nerves of the skin can be considered to be a "final
common pathway" for the many irritating conditions which are
ultimately sensed as itch including chemical exposure,
environmental exposure (such as that which produces dry, itchy
skin) and disease processes such as atopic dermatitis. Many
chemical substances are able to produce itch when topically applied
to the skin. No matter what the ultimate cause of itch, the
sensation experienced is the same and provokes the desire to
scratch.
[0006] Many ingredients used in topical products are known
irritants or are potentially irritating, especially to people with
"sensitive skin". These irritating ingredients include fragrances,
preservatives, solvents, propellants and many other ingredients
that might otherwise be considered inert components of the
products. Additionally, many topical product active ingredients,
including chemicals that may also be classified as drugs, produce
irritation when applied to the skin. These include, but are not
limited to, such ingredients as exfoliants and skin cell renewal
agents, anti-acne drugs, antiperspirant compounds, antihistamines,
anti-inflammatory agents, skin protective agents, insect repellent
chemicals, sunscreens and many others. Where more than one chemical
irritant is present, their irritating effects may be additive.
Furthermore, chemical ingredients may react with one another, or in
the environment of the skin, to form new chemicals which are
irritating. The vehicles in which the active drug ingredients are
formulated may also produce irritation in sensitive people,
especially in drugs such as topical corticosteroids.
[0007] In addition to chemicals which directly trigger skin
irritation, some chemicals indirectly cause the skin to become more
sensitive to other chemicals or environmental conditions which
would not normally cause irritation. Many chemicals which act as
skin "exfoliants" such as retinoids (e.g. tretinoin, retinol and
retinal), carboxylic acids including .alpha.-hydroxy acids (e.g.
lactic acid, glycolic acid), .beta.-hydroxy acids (e.g. salicylic
acid), .alpha.-keto acids, acetic acid and trichloroacetic acid,
1-pyrrolidone-5-carboxylic acid, capryloyl salicylic acid,
.alpha.-hydroxy decanoic acid, .alpha.-hydroxy octanoic acid,
gluconolactone, methoxypropyl gluconamide, oxalic acid, malic acid,
tartaric acid, mandelic acid, benzylic acid, gluconic acid, benzoyl
peroxide and phenol, among others, may cause the skin to become
more sensitive to irritation triggered by other topically-applied
chemicals such as moisturizers, sunscreens, fragrances,
preservatives, surfactants (e.g. soaps, shaving cream) and other
topical products. Exfoliants and other ingredients may also
increase the skin's sensitivity to environmental conditions such as
sunlight, wind, cold temperature and dry air, or may exacerbate the
irritation attributable to a pre-existing skin disease.
[0008] Conversely, environmental influences may themselves increase
the skin's sensitivity to chemicals in topical products by reducing
the skin's "barrier function." The barrier function acts to
minimize absorption or passage of potentially irritating chemicals
through the outer "dead" cell layer into the living skin tissue.
Extremes of humidity, for example, can greatly increase irritation
from topically-applied products. A very common condition due to low
humidity is termed "winter itch" in which the very low humidity
characteristics of many cold climates (particularly when
accompanied by indoor heating) or long exposure to refrigerated air
from air conditioners in the summer produces itchy skin--especially
in older people--which can exacerbate the irritating effects of
topical products. Additionally, soaps, detergents, cleansing
products, shaving creams, alcohol and other products which remove
some of the skin's protective lipids and/or secretions may increase
the skin's permeability and sensitivity to topically-applied
chemicals which would otherwise not produce irritation. Normal
processes such as sweating may also increase the ability of
irritant materials, such as antiperspirants, deodorants or
sunscreens, to penetrate the skin through pores or glands, thus
exacerbating the potential for irritation. Exposure of the skin to
high humidity environments or liquids may also increase the ability
of potential irritants to penetrate the skin. Similarly, the skin
may become sensitized or inflamed due to infection, shaving
abrasion, repeated or excessive washing or bathing, sun exposure,
or other mechanical abrasion or injury, resulting in sensory
irritation responses upon subsequent application of underarm
deodorants, after-shaves or other topical products.
[0009] In addition to chemical and environmental causes of skin
irritation, many people have an inherent sensitivity or genetic
predisposition to skin irritants. People with respiratory
allergies, for example, tend to have excessively dry skin which
facilitates increased absorption of potentially irritating
chemicals. The excessively dry skin which accompanies atopic
dermatitis, for example, predisposes patients with this condition
to irritation from many topically-applied products. Other skin
diseases and conditions such as allergic or non-allergic contact
dermatitis, psoriasis, eczema, candida albicans, post-herpetic
neuralgia, infectious diseases manifested by, for example, sore
throat or skin lesions, insect bites and the like produce intrinsic
irritation which may be exacerbated by application of topical
products. Many other individuals exhibit sensitive skin as a
condition that is not related to an identifiable skin disease.
[0010] Whatever the exact cause of irritation, many attempts have
been made to reduce the irritation potential of topical products by
identifying chemicals which tend to cause irritation and reducing
their concentration or eliminating them from the products. Many of
these products are advertised to consumers as "hypoallergenic" or
the like to designate a product's reduced tendency to cause
irritation in consumers with sensitive skin. Most skin or mucosal
irritation responses, however, are not allergic in origin. In any
event, it is often not feasible or practical to identify or
eliminate all of the irritating chemical(s), particularly when the
irritating chemical(s) are the active ingredient of the product or
are required for formulation, preservative or other functional
reasons.
[0011] As one example, there is a substantial practical and
commercial need in the field of exfolients and related skin care
products for a composition or method that will reduce or prevent
the irritation caused by such products. Common exfolients include
.alpha.- and .beta.-hydroxy carboxylic acids such as lactic acid,
glycolic acid, salicylic acid and the like, .alpha.-keto acids such
as pyruvic acid, as well as assorted compounds such as acetic acid
and trichloroacetic acid, 1-pyrrolidone-5-carboxylic acid,
capryloyl salicylic acid, .alpha.-hydroxy decanoic acid,
.alpha.-hydroxy octanoic acid, gluconolactone, methoxypropyl
gluconamide, oxalic acid, malic acid, tartaric acid, mandelic acid,
benzylic acid, gluconic acid, peroxides, phenols, and skin cell
renewal agents such as retinoids. Such products are used as
exfoliants and/or cell renewal agents to reduce the occurrence or
severity of skin wrinkles, particularly facial wrinkles, or as
anti-acne, anti-"dry skin" or skin whitening agents. See U.S. Pat.
Nos. 4,105,782, 4,105,783, 4,246,261, and 5,091,171 (Yu et al.) and
5,262,153 (Mishima et al.); W. P. Smith, "Hydroxy Acids and Skin
Aging," Soap/Cosmetics/Chemical Specialties for September 1993, p.
54 (1993). Hydroxy acids, in concentrations high enough to
exfoliate, are well known often to cause skin irritation and
rashes. The danger of irritation is even higher for persons that
have sensitive skin.
[0012] Currently available methods reported by Yu et al. to reduce
the irritation caused by hydroxy- and keto-acids in topical
products include adding a strong alkali metal base such as sodium
hydroxide or potassium hydroxide, thereby raising the pH of the
preparation and reducing the acidity of the hydroxy acid. Such
methods have the reported drawback of reducing the ability of the
resulting hydroxy acid salt to penetrate the skin and thus
compromising the beneficial effects (particularly anti-acne or
anti-"dry skin" effects) of the hydroxy acid. Alternatively, Yu et
al. have proposed the approach of formulating the hydroxy acid with
a non-alkali metal base such as ammonium hydroxide or an organic
base such as a primary, secondary or tertiary organic amine,
thereby forming an amide or ammonium salt of the active ingredient
hydroxy (or keto) acid. See U.S. Pat. Nos. 4,105,782 and 4,105,783
(Yu et al.). The effect of such formulations is, again, to raise
the pH of preparation to a non-irritating level. However, the
increased pH (reduced acidity) of the resulting preparations
renders them less efficacious as exfoliating or anti-wrinkle
agents, which desirably have an acidity equivalent to pH 1-6, and
more preferably pH 3-5. See Smith, above, at Table 1. Other
approaches to reducing the irritation associated with exfolient
products include the use of slow-release topical formulations such
as polymer-based vehicles (see, e.g., Chess et al., U.S. Pat. No.
4,971,800) or microsponges, and inclusion of, e.g., plant-derived
anti-irritant components (see, e.g., Smith et al., U.S. Pat. No.
5,028,428).
[0013] Mishima, et al. have reported that certain alkali or
alkaline-earth metal salts of lactic acid were useful as
skin-whitening agents (U.S. Pat. No. 5,262,153), but no recognition
is expressed as to any need or ability to reduce irritation
effects; in addition, the particular formulations of Mishima were
typically "neutralized" or adjusted to pH 5.5 prior to screening or
skin-whitening testing (see Experiments 1 and 2). A clear need
exists, therefore, for a composition or method that prevents or
reduces the skin irritation caused by low-pH (high-acidity) organic
or inorganic acid products but that does not reduce the efficacy of
the acids as exfoliant/cell-renewal agents.
[0014] More generally, it would be highly desirable to identify
compounds with anti-irritant activities that would reduce the
irritation caused by a wide range of otherwise safe and effective
topical products, or to reduce the intrinsic irritation associated
with various skin diseases and conditions (such as atopic
dermatitis, eczema or psoriasis) or caused by exposure to
irritating chemicals or environmental conditions such as sun, wind
or extremes in humidity.
[0015] As explained in more detail below in the Detailed
Description, the present invention involves the surprising
discovery that the strontium metal cation of the invention is
useful in reducing the incidence and severity of irritation
associated with topically applied skin irritants. While the exact
mechanism (or mechanisms) of activity of this cation is not known
and the invention is not limited to any particular mechanism, it is
presently believed that the strontium cation may reduce irritation
by interacting with epidermal nerve cells to prevent or counteract
the sensation of irritation, and/or by interfering with
irritation-inducing components of skin cells that are triggered by
the application of the skin irritant. Thus, the cation may alter
the ability of epidermal nerve cells to depolarize or repolarize,
as for example by blocking or interfering with ion channel or pump
operation or by altering the transmembranal action potential, or
the cation may interfere with the transmission of nerve impulses
from one nerve cell to another (as by suppressing neurotransmitter
release). General descriptions of the function of channel proteins
are given in B. Hille (ed.), Ionic Channels of Excitable Membranes,
Sinauer Associates (Sunderland, Mass.: 2d Ed. 1992), and Siemen
& Hescheler (eds.), Nonselective Cation Channels: Pharmacology,
Physiology and Biophysics, Birkhauser Velgag (Basel, Switzerland:
1993). In addition, or alternatively, the strontium cation may act
to inhibit or modify the action of skin cell proteases or other
irritation-inducing biological molecules (such as eicosanoids or
cytokines) that may otherwise be activated by topical application
of skin irritants, or may alter "second-messenger" function within
sensory cells.
[0016] A number of ionic species, and certain metal cations in
particular, have been associated with various aspects of nerve cell
activity. For example, during the resting (polarized) state of a
typical nerve cell, the intracellular concentration of potassium in
the nerve axon is high relative to the extracellular potassium
concentration, and the intracellular concentration of sodium is low
relative to the extracellular sodium concentration. During the
process of nerve depolarization, potassium ions flow out of the
cell across the membrane, and sodium ions flow into the cell,
through pores created by axonal membrane proteins known as
"channels". Following depolarization, membranal proteins known as
ion "pumps" act to reestablish the resting, polarized state of the
cell.
[0017] Other metal ions have also been shown to influence nerve
function. For example, calcium (Ca.sup.2+) is carefully regulated
in higher eukaryotic organisms and is reported to have many
important effects on cellular and neuronal activity. Calcium
signaling pathways control many cellular processes, including
fertilization, cell growth, transformation, secretion, smooth
muscle contraction, sensory perception and neuronal signaling
(Berridge, Nature 361(6410), 315-25 (1993)). The wide diversity of
cells which display and use intercellular calcium waves and
regulate calcium concentrations inside and outside the cell
suggests that calcium levels provide a general mechanism by which
cells communicate (Sanderson et al., Mol. Cell. Endocrinol. 98(2),
173-87 (1994)).
[0018] More particularly, calcium ion is a transducer of
depolarization, and flows into the cell through a calcium channel
during depolarization, although the amount of current flow varies
from cell to cell (Stein, Nerve and Muscle--Membranes, Cells and
Systems, pp.33-64 at p.56 (Plenum Press 1980); Forsen & Kordel,
"Calcium in Biological Systems," in Bioinorganic Chemistry (Bertini
et al., eds.), University Science Books (Mill Valley, Calif.:
1993), pp. 107-166). Several messenger pathways of intracellular
calcium signal transduction also exist, such as inositol
triphosphate-induced release of intracellular stores of calcium
(Tsunoda, Biochim. Biophys. Acta. 1154(2), 105-56 (1993)). Calcium
is a critical second messenger in virtually all cell types, and the
signals generated by calcium can be single transients or prolonged
elevations of intracellular calcium concentrations. Signaling
patterns often vary from cell to cell and may contain more complex
features such as calcium oscillations. Sub-cellular calcium signals
and local concentration changes suggest even a further level of
complexity and control of cell function and specialization.
Nathanson, Gastroenterology 106(5), 1349-64 (1994).
[0019] Calcium also appears to modulate the release of
neurotransmitters and, in a variety of cells, elevated calcium
levels may result in stimulation of neurotransmitter release in
some experimental systems. The divalent cations strontium and
barium, while not normally found naturally in the body in
physiologically significant amounts, may, by virtue of their atomic
resemblance to calcium, similarly stimulate neurotransmitter
release, whereas magnesium and manganese cations may have an
inhibitory effect in the same system. Calcium is also involved in
the postsynaptic action of neurotransmitters, and may also alter
the activity of various nerve cell enzymes. Harris et al., J.
Pharmacol. Exp. Therap. 195, 488-498 (1975).
[0020] Calcium, strontium, barium and certain other divalent
cations have also been reported to modulate or block the gating
and/or conductance properties of certain ion transporting proteins
such as sodium and potassium channels (Shioya et al., Pflugers
Arch. 422, 427-435 (1993); Cukierman, Biophys. J. 65, 1168-73
(1993); Marrero & Orkland, Proc. R. Soc. Lond. B. 253, 219-224
(1993)). One mechanism that has been proposed to explain these
effects is that the cations may bind to the outer membrane of the
nerve cell, thus altering the electric field locally near the
membrane (Stein, above, at p. 57); others have proposed models
involving specific interactions between the divalent cations and
the channel gate and/or pore (Shioya et al., above; Cukierman,
above). Alternatively, the cations may regulate the function of
many calcium-binding regulatory proteins such as calmodulin or may
affect intracellular second messengers such as cyclic nucleotides
("Calcium: Controls and Triggers," in daSilva & Williams
(eds.), The Biological Chemistry of the Elements: The Inorganic
Chemistry of Life, Oxford University Press (New York: 1991), pp.
268-98).
[0021] Early studies involving selected nerve cell samples
indicated that certain divalent cations, including magnesium and
calcium, can have a "depressant" effect on nerve activity
(Frankenhaueser & Meves, J. Physiol. 142, 360-365 (1958);
Krnjevic, Brit. Med. Bull. 21, 10 (1965); Kato & Somjen, J.
Neurobiol. 2, 181-195 (1969); Kelly et al., J. Neurobiol. 2,
197-208 (1969)). These results were generally attributed to
post-synaptic membranal effects, as for example the inhibition of
potassium or sodium currents in nerve samples exposed to the
cations.
[0022] While laboratory studies such as these using cultured single
cells or microelectrode single-cell electrophysiological techniques
have done much to advance the understanding of nerve activity,
distinct challenges are presented in the clinical setting. A number
of factors make it difficult to predict what effects, if any,
particular agents (cationic or otherwise) may have on nerve
activity and sensation in intact animal bodies. For example, the
animal body (and particularly the human body) contains a wide
variety of nerve-containing tissues and organs adapted to perform
many different and specialized functions. Other cells in the
body--notably muscle cells and neuro-endocrine secretory
systems--are "excitable" in a manner akin to nerve cell excitation.
In order to achieve the disparate functions required in the animal
body, the various tissues and organs are differently disposed
within the body, and the nerves (and other excitable cells) within
a given tissue are typically highly specialized as well as uniquely
disposed within the particular tissue. As a result, different
nerve-containing tissues may respond differently to a given agent
depending on, for example, the type of nerve (or other excitable)
cell and its structural disposition within the tissue, the mode of
administration of the agent, the ability of the agent to penetrate
to the respective nerve site, and the rate at which the agent is
removed from the nerve site.
[0023] For example, while certain divalent cations including
magnesium and calcium have long been reported in laboratory studies
to have a "depressant" effect on nerves, clinical studies have
shown that intravenously-administered magnesium sulfate produces
neither anesthesia nor even analgesia in humans (Kato et al., Can.
Anaes. Soc. J. 15, 539-544 (1968)). Instead, the magnesium ion
induces paralysis of skeletal muscles, due perhaps to the
inhibitory effects of magnesium on muscle cell activity. Oral
ingestion of large doses of magnesium (e.g., magnesium sulfate as a
laxative) does not result in paralysis or depressed neural activity
in healthy individuals. On the other hand, when magnesium is
applied directly to the brains of test animals, depressed neural or
synaptic activity, and even a sleep-like state, reportedly result
(Kato et al. (1968), above).
[0024] In addition, the mechanisms underlying sensory stimulation
and perception in the animal body are diverse and exceedingly
complex. Even within a single tissue or organ, different nerve
groups having different organizations and functions may appear.
Depending on how they are disposed within the tissue, the various
nerve groups may be differently affected (or affected not at all)
by an applied agent. Moreover, to the extent that different types
of nerve cells occur within a tissue, they may have different
susceptibilities to a particular applied agent. This is
particularly true in the skin, which has nerves adapted to sense a
wide variety of sensory inputs.
[0025] Another complicating factor arises from the detailed nature
of nerve cell activity and response. The firing activity of an
individual nerve cell may be influenced in a complex fashion, and
may vary over time, depending on such factors as the extracellular
and intracellular concentration of nerve-related ions as sodium,
potassium, chloride, calcium and the like, as well as the time
course of exposure to such ions. Other bioactive agents, such as
prostaglandins present during inflammatory responses, may further
influence nerve sensitivity. In addition, nerves may respond to
non-chemical stimuli such as hydrodynamic pressure changes, which
in turn may depend on the nature of the tissue in which the nerve
is disposed. Such factors lead to considerable clinical uncertainty
as to how various agents may affect nervous responses such as pain
responses.
[0026] For example, studies have been undertaken over the last
several decades in an effort to identify and elucidate the effects
of various putative tooth-desensitizing agents and therapies. Tooth
nerves are disposed primarily in the central pulp of the tooth, but
also extend partially into the surrounding "dentin" material. The
dentin material is a mineralized collagen matrix containing
microscopic, fluid-filled "dentinal tubules." It has long been
known that tooth nerve activity (which is sensed as pain) may be
triggered by hydrodynamic pressure changes in the tubule fluid, as
may be caused for example by probing or air-blasting the tooth or
by applying an ionic solution having a high osmotic pressure
(particularly when the protective enamel surrounding the dentin is
degraded). Accordingly, one reportedly effective treatment for
tooth hypersensitivity involves sealing or occluding the dentinal
tubules using chemical or physical means (Scherman & Jacobsen,
J. Am. Dent. Ass. 123, 57-61 (1992)). In addition, potassium and
strontium salts, particularly potassium nitrate and strontium
chloride, have been employed in dentrifices and are reported to
reduce tooth sensitivity following two to six weeks of continuous
use (Scherman & Jacobsen, above; Silverman, Comp. Cont. Dent.
Educ. 6, 131-136 (1985)). One mechanism commonly advanced to
explain this putative desensitizing activity is that precipitated
potassium or strontium ions block or inhibit fluid flow within the
dentinal tubules (Scherman & Jacobsen, above; Knight et al., J.
Periodontal Res. 64, 366-373 (1993)). This explanation is
consistent with the chemical/physical sealing therapies noted
above, and also appears consistent with the clinical observation
that several weeks of treatment are required in order to achieve
substantial desensitizing effects.
[0027] A number of studies have attempted to elucidate other
possible effects of various ions on tooth nerve activity, and have
established that such effects may vary greatly depending on the
clinical or experimental system employed. For example, pain is
induced when potassium ion is applied to exposed tooth pulp but not
when applied to the dentin (Nahri et al., Arch. Oral Biol. 27,
1053-58 (1982). Hypertonic solutions of calcium and magnesium salts
have been reported to evoke pain and/or transient nerve electrical
activity when applied to the dentin, probably due to dentinal
tubule water movement induced by osmotic pressure effects
(Orchardson, in Lisney & Matthew (eds.), Current Topics in Oral
Biology, University of Bristol Press (Bristol: 1985), pp. 205-215;
Nahri, above; Markowitz & Kim, Proc. Finn. Dent. Soc. 88 (Supp.
1), 39-54 (1992)). On the other hand, electrical activity studies
undertaken on exposed tooth nerves (obtained, for example, by
deeply abrading the dentin material) have indicated that various
divalent cations (particularly calcium and magnesium) may suppress
nerve electrical responses, while monovalent potassium evokes a
transient electrical response followed by inhibition of
excitability (Markowitz & Kim, above; Orchardson, above). In
the final analysis, the Markowitz and Kim group concluded that it
is difficult to explain the clinical desensitizing effects of the
available ionic desensitizing dentrifices (which require several
weeks of treatment) in terms of a direct nerve cell membrane
function, and that studies undertaken with exposed nerves may not
reflect the pain-induction mechanisms observed clinically
(Markowitz & Kim, above).
[0028] The human skin presents a sensory and structural environment
that is much more complicated than that of the tooth. For example,
the skin contains nerves and highly specific sensory organs that
are specialized and disposed so as to differentiate the stimuli
leading to such distinct sensations as heat, cold, pressure, pain,
itch and the like. In addition to normal sensory stimuli, nerves in
the skin are also responsive to native or foreign chemicals such as
proteases, prostaglandins, complement-system molecules, allergens,
mitogens and the like which may be presented due to tissue injury
or environmental exposure. Agents which are effective to combat one
source of sensory stimulus--for example steroidal agents to treat
skin inflammation--are ineffective against other sensory stimuli
such as pressure, heat, or the transitory sting or itch caused by
an applied skin care product. Conversely, local anesthetic agents
which are effective to depress all sensory or even motor activity
in a treated region are not desirable if only a single
sensation--for example a transitory sting or itch--is sought to be
eliminated. To complicate the situation, the structural matrix of
the skin affords a "barrier function" which tends to exclude or
inhibit the entry of foreign material, including potentially
therapeutic agents.
[0029] Accordingly, it would be desirable to identify agents which
are effective in the skin to inhibit certain identified sensory
responses (as for example pain or itch) while not adversely
affecting other nervous responses in the same tissue (as for
example tactual sensations).
SUMMARY OF THE INVENTION
[0030] The present invention is directed to the use of the divalent
cation strontium (Sr.sup.2+) and salts thereof as ingredients to
provide fast-acting, efficient and safe topical skin anti-irritant
effects, and to formulations containing this cation. It is one
object of the present invention to provide ingredients,
formulations and methods of use which can suppress skin irritation
due to chemical or environmental exposure, or due to tissue
inflammation, injury or other skin pathology. The invention is
particularly useful for preventing, reducing or eliminating the
potential irritation caused by topical application of products
containing other irritating ingredients, including especially
cosmetics such as hydroxy acid or other exfolient containing
products, facial peels, shaving products, sunscreen products,
deodorants and other cosmetics as described above, as well as
topical drug products containing irritating active ingredients or
vehicles, and other products such as soaps, detergents, solvents
and the like which are either applied topically or are topically
exposed to the body during use. Thus, the present invention meets a
clear need for formulations and ingredients that will prevent or
reduce the potential skin irritation caused by topical products.
The invention is also useful for preventing, reducing or
eliminating the skin irritation caused by skin diseases or other
conditions such as environmental exposure to irritating chemicals
or influences such as wind, heat, cold and extremes in humidity,
including the intrinsic irritation associated with these conditions
as well as such irritation as may be exacerbated by the application
of a topical product.
[0031] Preferred embodiments of the present invention utilize an
anti-irritant amount of the strontium cation accompanied (as in the
form of a salt) by one or more ionizing anionic species, preferably
an acidic anion species such as a chloride, nitrate, sulfate,
acetate, gluconate or oxalate anion, dissolved or dispersed in an
appropriate vehicle. Investigations relating to the present
invention have shown that the anti-irritant effects of the cations
of the invention can be optimized by suitable selection of the
accompanying anionic species. Especially preferred cation-anion
pairs include strontium chloride, strontium nitrate, and strontium
acetate.
[0032] In the preferred embodiments, the cation of the invention is
included in a suitable topical vehicle at a concentration of about
10 to about 3000 mM, more preferably about 50 to about 2000 mM, and
most preferably about 100 to about 1000 mM. The most highly
preferred concentration range in many instances is from about 250
to about 500 mM, as for example where the formulation of the
invention includes an irritant ingredient such as an exfolient
ingredient. The appropriate cation concentration can be achieved,
for example, using a single strontium salt, or multiple different
cation salts may be combined to yield the total desired cation
concentration.
[0033] In another preferred embodiment, the strontium cation of the
invention is combined in a topical product formulation further
comprising a potentially irritating ingredient, the cation being
present in a total amount effective to reduce or eliminate
irritation due to the irritant ingredient.
[0034] In another preferred embodiment, the cation of the invention
is paired with one or more anionic species selected so as to
achieve a desired level of acidity or basicity in the formulated
composition, and a total cation concentration effective to reduce
skin irritation. In one such particularly preferred embodiment,
strontium is combined in a hydroxy acid or other exfolient
preparation accompanied by one or more suitable anionic species
such that the pH of the hydroxy acid preparation is maintained in
the range of pH 1-6, and more preferably in the range of pH 3-5. It
will be understood that, where the formulation employs an anhydrous
vehicle, the acidity of the formulation may not be expressible in
typical pH terms, but that such acidity will manifest itself upon
exposure of the formulation to the skin where water is present both
intracellularly and extracellularly.
[0035] In another embodiment, the cation of the present invention
may be combined in a formulation with other anti-irritants, such as
steroidal or non-steroidal anti-inflammatory agents or other
materials such as aloe vera, chamomile, .alpha.-bisabolol, cola
nitada extract, green tea extract, tea tree oil, licorice extract,
allantoin, urea, caffeine or other xanthenes, glycyrrhizic acid and
its derivatives, or with other anti-irritant species such as those
identified in co-pending patent application Ser. Nos. ______,
______, ______ and ______ (attorney docket numbers 210/181,
210/182, 210/183, and 210/184, entitled "Formulations and Methods
for Reducing Skin Irritation"), filed on Dec. 21, 1994 by the
present inventors, so as to achieve a multiple anti-irritant
effect.
[0036] The invention further provides methods of treating, reducing
or eliminating skin irritation comprising the topical application
of a formulation comprising an anti-irritant effective amount of
strontium. The cation formulation may further include one or more
potentially irritating components. Alternatively, the cation
formulation may be applied separately and prior to application of
another product containing a potentially irritating component, or
the cation formulation may be applied alone in order to prevent the
development of irritation or to treat a pre-existing irritation
attributable to conditions such as skin disease, chemical irritant
exposure or environmental exposure.
DETAILED DESCRIPTION
[0037] Human clinical trials undertaken in connection with the
present invention have established that the cation species
strontium(II) (Sr.sup.2+) is effective, when applied topically to
the skin in appropriate concentrations and vehicles, to suppress
the relatively severe stinging, burning, tingling, itching and/or
erythema induced by topical application of the hydroxy acid skin
irritant lactic acid as well as the skin irritants glycolic acid,
capsaicin, capryloyl salicylic acid, benzoyl peroxide, and
post-shaving-applied seawater. Formulations containing the
strontium cation are useful in suppressing a wide range of
topical-product-induced irritation responses attributable to
exfoliants, sunscreens, retinoids, anti-perspirants, deodorants,
anti-acne and other products which contain components potentially
capable of causing sensory irritation. For example, the cation of
the present invention is useful for preventing or reducing the skin
irritation caused by .alpha.- or .beta.-hydroxy acids, .alpha.-keto
acids and other carboxylic acids, as well as retinoids, phenols,
peroxides and similar irritants found in over-the-counter topical
products for home or cosmetologist use (such as,
1-pyrrolidone-5-carboxylic acid, capryloyl salicyclic acid,
.alpha.-hydroxy decanoic acid, .alpha.-hydroxy octanoic acid,
gluconolactone, methoxypropyl gluconamide, oxalic acid, malic acid,
tartaric acid, mandelic acid, benzylic acid, gluconic acid, as well
as in certain prescription topical drugs containing high (for
example, 12% w/w or even higher) dosage forms of such irritants.
The irritation attributable to combinations of such irritating
ingredients, such as lactic acid/salicyclic acid combinations and
hydroxy acid/retinoid combinations, as well as irritation
attributable to purified isomeric forms of such ingredients, can
also be inhibited by the formulations of the invention.
Additionally, formulations containing the cation are useful in
ameliorating irritation in conditions where the skin is inherently
hypersensitive to topical products (e.g. dry skin, "winter itch,"
and other inflammation or injury conditions) and in ameliorating
the irritation due to such conditions even in the absence of other
applied topical products. The formulations are also useful in
treating non-human animal skin irritation, as for example dog or
cat irritation and resultant scratching due to fleas or other skin
disease or condition.
[0038] An additional benefit of the present anti-irritant compounds
and formulations is that they do not have the undesirable
anesthetic side-effects exhibited by Lidocaine and other similar
skin local anesthetics. Upon application of a solution of the
compound used in the clinical trials described here, subjects
typically reported no sensations other than those sensations caused
by the vehicle alone, and no lack of normal sensations.
[0039] Formulations of the Invention
[0040] The anti-irritant topical formulations of the invention
comprise a topical vehicle suitable for administration to the
animal (particularly human) skin, and an amount of the strontium
cation effective to reduce, inhibit or eliminate existing or
potential skin irritation or inflammation. The cation component is,
of course, accompanied in the formulation by one or more
charge-neutralizing anionic counterions, although the cation-anion
pairs as originally incorporated into the vehicle may become
dissociated in the resulting formulation, or the strontium cations
may become associated in the formulation with other anionic species
appearing in the overall formulation. In one embodiment, the
anti-irritant topical formulations additionally contain an irritant
ingredient(s) that is itself capable of inducing skin irritation or
inflammation, as for example a cosmetic or skin care product
ingredient, or a pharmaceutically active ingredient or drug
ingredient.
[0041] The topical anti-irritant formulation of the invention
contains the divalent cation strontium (Sr.sup.2+) in a
concentration effective to prevent or reduce (hereafter, "inhibit")
the skin irritation and/or inflammation that is sought to be
eliminated. The formulation preferably contains this cation
component in a suitable topical vehicle at a total concentration of
about 10 to about 3000 mM, more preferably about 50 to about 2000
mM, and most preferably about 100 to about 1000 mM. The most highly
preferred concentration range in many instances is from about 250
to about 500 mM, as for example where the formulation of the
invention includes an irritant ingredient such as an exfolient
ingredient. These preferred concentration ranges correspond to
bioavailable forms of such cations within the formulation,
particularly, ionizable and aqueous-soluble forms of the strontium
cation as contrasted with insoluble or covalently-bonded forms of
the cation. If other anti-irritant compounds are included in the
formulation, then lower concentrations of the cations of the
invention may be utilized.
[0042] Preferred cation concentrations can also be expressed in
weight/volume or weight/weight percentage terms which will vary
somewhat depending on the density of the vehicle and other
components in the formulation. Thus, to take an example in which
the vehicle has a density of 0.93 g/ml (as in a 50:50 [by volume]
mixture of 95% ethyl alcohol and water) and the cation component is
incorporated in the form of strontium nitrate (formula weight 212),
represent molarity concentration values correspond approximately
to
1 10 mM: 0.21% (w/v) 0.23% (w/w) 50 mM: 1.05% (w/v) 1.14% (w/w) 100
mM: 2.1% (w/v) 2.28% (w/w) 250 mM: 5.3% (w/v) 5.7% (w/w) 500 mM:
10.5% (w/v) 11.4% (w/w) 1000 mM: 21.2% (w/v) 22.8% (w/w) 1500 mM:
31.7% (w/v) 34.2% (w/w)
[0043] The preferred concentration ranges expressed above
contemplate that a typical topical dosage will be approximately 0.5
grams of cation formulation over a 5 cm.times.5 cm area of skin (25
cm2). Clinical studies have shown that such preferred concentration
ranges are generally effective to inhibit skin irritation and, in
typical topical vehicles, are readily formulated and do not leave
any significant visible residue when applied to the skin. Higher
concentration formulations, such as saturated pastes or other
forms, may also be successfully used, particularly where visible
apeparance is not a limiting consideration (as in therapeutic
applications).
[0044] Furthermore, routine clinical assessments such as those
described below can readily be employed to optimize the cation
concentration and to ascertain if lower, or higher, concentrations
are appropriate for a given formulation or irritation indication.
For example, the concentration of cation may be adjusted to account
for the amount of formulation that is typically applied to a given
skin area by the user, which will depend to an extent on the
physical nature of the topical vehicle (e.g., lotion as compared to
liquid spray vehicles). Likewise, the amount of cation required may
be reduced in such cases where the formulation contains a skin
penetration-enhancing ingredient or other agent which increases the
ability of the cations to permeate the stratum corneum to their
site of anti-irritant activity. Preferably, the formulations of the
invention include an amount of anti-irritant cation capable of
inhibiting irritation in susceptible individuals by at least about
20% or more, as measured by a mean reduction in cumulative
irritation across a susceptible test population as exemplified in
the clinical protocols described below. Alternatively, the
formulations of the invention include an amount of anti-irritant
cation capable of inhibiting irritation by at least about 40% or
more in at least about 10% of the susceptible population, as
measured by a reduction in cumulative irritation on an
individual-by-individual basis (treated vs. control areas). This
latter measure of efficacy reflects the fact that the present
formulations, similar to many therapeutic products, may in some
cases be effective in delivering a significant benefit to some, but
not all, of the susceptible population.
[0045] The optimum concentration of a cation of the invention may
also be reduced below (or within) the preferred ranges set forth
above if some other anti-irritant component is included in the
formulation along with the cation component of the invention. In
particular, it is contemplated that lower (e.g. halved) amounts of
strontium (Sr.sup.2+) cations may be used, while still maintaining
comparable levels of anti-irritant activity, by further including
an approximately equal concentration of, for example, a potassium
channel mediating, regulating or blocking agent, a calcium channel
blocking or regulatory agent, or a sodium channel blocking agent,
or other anti-irritant agent such as a steroid or non-steroidal
anti-inflammatory agent. Examples of suitable additional
anti-irritant ingredients are described in applicants' co-pending
U.S. patent application Ser. Nos. _____, ______, and ______
(attorney docket numbers 210/181, 210/182, 210/183, and 210/184,
entitled "Formulations and Methods for Reducing Skin Irritation"),
filed Dec. 21, 1994 and incorporated by reference in their
entirety. Other anti-irritant ingredients, such as aloe vera,
chamomile, .alpha.-bisabolol, cola nitada extract, green tea
extract, tea tree oil, licorice extract, allantoin, urea, caffeine
or other xanthenes, and glycyrrhizic acid and its derivatives, may
also be beneficially incorporated into the formulations of the
invention in order further to inhibit irritation effects or
symptoms.
[0046] The cation component of the invention is typically
incorporated into the present formulations by mixing an appropriate
amount of a suitable salt form of the cation into the chosen
formulation vehicle, along with such other skin care components as
are desired. From a formulation standpoint, it is preferred that
the selected salt be sufficiently soluble in the formulation
vehicle as to allow a consistent formulation having the desired
physical and topical application characteristics. It will be
recognized that, depending on the formulation vehicle chosen, the
salt form of the cation of the invention may dissociate within the
formulation (and in this case may associate with other anions also
present in the formulation), or the salt form may remain
substantially associated. It is also highly preferred that the salt
(or salts) chosen be sufficiently aqueous-soluble such that, upon
application to the skin, the component cations (and corresponding
counteranions) can dissociate and be taken up into the
water-containing milieu of the skin. In addition, it will be clear
that the particular salt ingredient(s) chosen should be topically
acceptable and preferably will not themselves be irritating, toxic
or otherwise deleterious to the user.
[0047] With these considerations in mind, it will be recognized
that a variety of topically acceptable strontium/counteranion salt
ingredients may be utilized in the present formulations in order to
achieve the objectives of the invention. Such salts can be readily
identified by those skilled in the art in view of the present
disclosure based on known physical (e.g., solubility),
pharmacological and toxicological information and, if necessary, by
the application of routine experimentation.
[0048] Examples of potentially suitable counteranion components for
use with the strontium cations of the invention include a variety
of mono-, di- and trivalent inorganic and organic anions. Examples
of potentially suitable inorganic anions include nitrate, sulfate,
halogens (particularly F, Cl, Br and I), carbonate, bicarbonate,
hydroxide, oxide, peroxide, nitrite, sulfide, bisulfate,
persulfate, glycerophosphate, hypophosphate, borate and titanate.
Examples of potentially suitable organic anions include carboxylic
acids, alkoxylates, amino acids, peptides, saturated and
unsaturated organic acids, and saturated and unsaturated fatty
acids. Particular examples include citrate, oxalate, acetate,
gluconate, lactate, tartrate, maleate, benzoate, propionate,
salicylate, ascorbate, formate, succinate, folinate, aspartate,
phthalate, oleate, palmitate, stearate, lauryl sulfate, lanolate,
myristate, behenate, caseinate, cyclamate, pantothenate, EDTA and
other polyaminopolycarboxylates, saccharin, thioglycolate, laurate,
methylparaben, propylparaben, ricinoleate and sorbate anions. It
will be recognized in view of the foregoing disclosure that certain
of these suitable anion components, particularly various carboxylic
acid anions, are themselves known active ingredients in various
topical products (e.g. exfolient products), and it will be seen
accordingly that such active ingredients anions can be incorporated
into useful formulations along with the anti-irritant
counter-cations of the invention.
[0049] Clinical trials relating to the invention have established
that certain cation-anion pairs are particularly active as
anti-irritants. These include strontium chloride, strontium
nitrate, and strontium acetate.
[0050] Also preferred are these and other cation-anion pairs in
which the anionic species is acidic, because such pairs will
generally exhibit higher solubility in many common topical vehicles
and suitable ionization upon application to the skin. In addition,
strongly acidic anion components may be useful where it is desired
to maintain the pH of the resulting formulation at a relatively
acidic level, as for example in the case of hydroxy-acid or other
acidic exfolient products where the activity of the product to
reduce wrinkles or bring about other beneficial effects may be
reduced if the formulation is not relatively acidic. In any event,
however, the desired level of acidity in such cases can be achieved
by adjusting the formulation with a suitable acid (or base if
necessary).
[0051] In one such particularly preferred embodiment, the strontium
cation component of the present invention is combined in a hydroxy
acid or other exfolient preparation accompanied by one or more
suitable anionic or other acidic species such that the pH of the
hydroxy acid preparation is maintained in the range of pH 1-6, and
more preferably in the range of pH 3-5. It will be understood that,
where the formulation employs an anhydrous vehicle, the acidity of
the formulation may not be expressible in typical pH terms, but
that such acidity will manifest itself upon exposure of the
formulation to the skin where water is present both intracellularly
and extracellularly.
[0052] Suitable topical vehicles for use with the formulations of
the invention are well known in the cosmetic and pharmaceutical
arts, and include such vehicles (or vehicle components) as water;
organic solvents such as alcohols (particularly lower alcohols
readily capable of evaporating from the skin such as ethanol),
glycols (such as glycerin), aliphatic alcohols (such as lanolin);
mixtures of water and organic solvents (such as water and alcohol),
and mixtures of organic solvents such as alcohol and glycerin
(optionally also with water); lipid-based materials such as fatty
acids, acylglycerols (including oils, such as mineral oil, and fats
of natural or synthetic origin), phosphoglycerides, sphingolipids
and waxes; protein-based materials such as collagen and gelatin;
silicone-based materials (both non-volatile and volatile) such as
cyclomethicone, demethiconol and dimethicone copolyol (Dow
Corning); hydrocarbon-based materials such as petrolatum and
squalane; anionic, cationic and amphoteric surfactants and soaps;
sustained-release vehicles such as microsponges and polymer
matrices; stabilizing and suspending agents; emulsifying agents;
and other vehicles and vehicle components that are suitable for
administration to the skin, as well as mixtures of topical vehicle
components as identified above or otherwise known to the art. The
vehicle may further include components adapted to improve the
stability or effectiveness of the applied formulation, such as
preservatives, antioxidants, skin penetration enhancers, sustained
release materials, and the like. Examples of such vehicles and
vehicle components are well known in the art and are described in
such reference works as Martindale--The Extra Pharmacopoeia
(Pharmaceutical Press, London 1993) and Martin (ed.), Remington's
Pharmaceutical Sciences.
[0053] The choice of a suitable vehicle will depend on the
particular physical form and mode of delivery that the formulation
is to achieve. Examples of suitable forms include liquids
(including dissolved forms of the cations of the invention as well
as suspensions, emulsions and the like); solids and semisolids such
as gels, foams, pastes, creams, ointments, "sticks" (as in
lipsticks or underarm deodorant sticks), powders and the like;
formulations containing liposomes or other delivery vesicles;
rectal or vaginal suppositories, creams, foams, gels or ointments;
and other forms. Typical modes of delivery include application
using the fingers; application using a a physical applicator such
as a cloth, tissue, swab, stick or brush (as achieved for example
by soaking the applicator with the formulation just prior to
application, or by applying or adhering a prepared applicator
already containing the formulation--such as a treated or
premoistened bandage, wipe, washcloth or stick--to the skin);
spraying (including mist, aerosol or foam spraying); dropper
application (as for example with ear drops); sprinkling (as with a
suitable powder form of the formulation); and soaking.
[0054] Methodologies and materials for preparing formulations in a
variety of forms are also described in Anthony L. L. Hunting (ed.),
"A Formulary of Cosmetic Preparations (Vol. 2)--Creams, Lotions and
Milks," Micelle Press (England, N.J. 1993). See, for example,
Chapter 7, pp. 5-14 (oils and gels); Chapter 8, pp. 15-98 (bases
and emulsions); Chapter 9, pp. 101-120 ("all-purpose products");
Chapter 10, pp. 121-184 (cleansing masks, creams, lotions); Chapter
11, pp. 185-208 (foundation, vanishing and day creams); Chapter 12,
pp. 209-254 (emollients); Chapter 13, pp. 297-324 (facial treatment
products); Chapter 14, pp. 325-380 (hand products); Chapter 15, pp.
381-460 (body and skin creams and lotions); and Chapter 16, pp.
461-484 (baby products); the contents of which are incorporated
herein by reference.
[0055] The formulations of the invention are most preferably
formulated such that the cation component of the formulation (as
occurring with any accompanying anion counterion components) is
substantially invisible upon application to the skin. This is
particularly true in the case of many cosmetic formulations that
are applied to the face or other exposed parts of the body,
although it is also generally desirable that the cation (and anion)
component not be visible even if applied to non-exposed portions of
the body. It will be recognized that in some cases, particularly
with colored facial skin care products such as blushes, blemish
covers, lipsticks and the like, the formulation will be designed to
be visible on the skin; in such cases, it is desirable that the
cation component itself be "invisible," that is, that it not
adversely change the appearance of the overall formulation as
applied to the skin.
[0056] In this regard, clinical studies relating to the invention
have shown that anti-irritant effects can be achieved using cation
concentrations well below those concentrations that, as applied in
a typical topical vehicle, result in a visible cation (or salt)
residue on the skin. For example, a blended formulation of 500 mM
strontium nitrate in a silicone-based vehicle (Dow Corning
cyclomethicone [DC344]: cyclomethicone/dimethiconol [DC1401]:
cyclomethicone/dimethicone polyol [DC3225C]: water; 10:20:15:55)
results in an opaque white lotion which typically leaves no visible
residue when applied to the skin of a representative subject.
[0057] In another embodiment of the invention, the anti-irritant
cation of the invention can be be formulated in a form for topical
oral administration to treat pain or irritation in the mouth or
throat such as that due to sore throats, canker sores, gum
irritation or inflammation or the like, including such irritation
as may be exacerbated by spicy or acidic foods. Preliminary studies
related to the invention have suggested that the oral formulations
containing the strontium cation in a concentration comparable to
those described for external topical application are effective in
reducing sore throat pain. Furthermore, it is believed that the
strontium cation (and its suitable oral salts) are generally
tasteless at the concentrations described. Suitable forms for such
oral administration include liquids (e.g. mouthwash or gargle
solutions) and lozenges. As with other topical forms described
herein, the components used in such oral formulations (including
the cation salts) should be chosen to be non-toxic. Methods for
preparing oral formulations suitable for use in the present
invention are well known in the art.
[0058] Clinical Results
[0059] The anti-irritant efficacy of the formulations of the
present invention was tested and confirmed in numerous clinical
trials, the results of which are described in the examples below.
While these examples further illustrate various aspects and
preferred embodiments of the invention as described herein, they
are examples only, and should not be considered as limiting the
scope of the invention as set forth in the claims.
EXAMPLE 1
Clinical Studies of Anti-Irritation Activity
[0060] The objective of the clinical trials was to determine
whether and to what extent topical formulations of the strontium
cation reduced or prevented skin irritation caused by certain
severe skin irritants, including particularly lactic acid and
glycolic acid (which are hydroxy acids), capryloyl salicylic acid
(a .beta.-hydroxy acid ester) and capsaicin (an isolate from
cayenne and paprika known for its skin-irritating properties). The
trials were conducted in a double blind, randomized,
vehicle-controlled manner. Various formulations of the invention
were tested in over 740 people. The results confirm the highly
reproducible anti-irritant activity of the formulations of the
present invention.
[0061] a. Lactic Acid Irritation Trials
[0062] 1. Protocol
[0063] The majority of the trials were conducted using lactic acid
as the skin irritant, and proceeded generally as follows.
[0064] The subjects were women who had been screened and shown to
exhibit normal to above normal susceptibility to irritation by the
tested irritant. Tests were conducted in multiple panels of from 7
to 12 subjects each. Subjects were instructed not to wear any
makeup or facial lotions to the clinic the day of testing. The
subjects were instructed to wash their face with Ivory bar soap in
the clinic prior to application of test solutions.
[0065] Lactic acid skin-irritant compositions were formulated in an
appropriate vehicle prior to application to the skin of the
subjects. In the majority of the tests, the irritant composition
was 7.5% lactic acid dissolved in a 10% ethanol-in-water
solution.
[0066] Test anti-irritant formulations containing measured amounts
of strontium salts (concentration 250 mM) were applied either (a)
15 minutes prior to application to the skin of the skin-irritant
("pretreatment test") or (B) simultaneously with the application of
the skin-irritant ("time zero test"). In the case of the time zero
tests, the anti-irritant formulation included both the lactic acid
irritant and the cation anti-irritant ingredient of the invention,
whereas in the pretreatment tests the anti-irritant formulation was
separately formulated (typically in Elizabeth Arden "Visible
Difference Refining Toner," a commercially available alcohol-based
cosmetic solution) and applied 15 minutes before application of the
irritant composition. Controls were performed by applying
corresponding formulation(s) (pretreatment and/or skin-irritant
composition) with an equimolar amount of sodium chloride to a
contralateral portion of the subject's skin. Typically, the test
materials were applied to the face of the subject.
[0067] All test solutions (including controls) were applied in a
double blind, randomized fashion using the prepared solutions as
previously placed in coded vial designated for use on either the
right or left side of the face (or other test area). Solutions were
typically applied using a cotton swab (six strokes) or sponge
applicator to the face and cheek area extending from the midline of
the nose over to the center of the cheek and from the cheek bone
down to the jaw line. Application was made first to the right side
and then to the left.
[0068] Sensory assessment scores were recorded for each treated
side of the subject's skin every minute for 15 minutes or until
three consecutive scores of "zero" irritation were obtained. The
following scaled scores were used for sensory assessment:
2 Score Description of Irritation 0 NO irritation 1 SLIGHT
irritation - (Barely perceptible stinging, burning or itching) 2
MILD irritation - (Definite stinging, burning or itching) 3
MODERATE irritation - (Distinctly uncomfortable stinging, burning
or itching; constantly aware of irritation) 4 SEVERE irritation -
(Continuous stinging, burning or itching, and intensely
uncomfortable; would interfere with daily routine)
[0069] Symptom scores were cumulated, separately for the
cation-treated and control-treated areas, for each individual and
also for the panel as a whole. Individuals not reporting a
cumulative score of at least "7" on at least one treatment area
were excluded (in a blinded fashion) from further analysis in order
to ascertain anti-irritant efficacy with respect to the more
severely-susceptible test subjects. From a practical standpoint,
scores of "0" and "1" on the above scale would be considered highly
desirable for a commercial product because such a response would
likely not result in a consumer ceasing to use a product. Some
consumers, in fact, might view the "barely perceptible" sensations
represented by a score of 1 to be an indication that a facial
treatment skin care product (especially an exfoliant) was working
as advertised. By contrast, irritation scores of "2", "3" and "4"
would likely often result in a consumer never purchasing the
product again.
[0070] In those subjects and skin samples where an irritation was
sensed, the irritation commonly involved a spectrum of
burn-sting-itch reactions over time. For example, a subject might
at first experience a sting, but moments later might experience an
itch with no sting. Subjects experiencing higher levels of
irritation (e.g. scores of "3" or "4") occasionally exhibited
erythema (visually observable inflammation) in addition to sensory
irritation effects.
[0071] 2. Results
[0072] Clinical tests of over 740 subjects, performed as generally
described above, demonstrated that the strontium cation has
significant and reproducible anti-irritant effects, particularly if
administered simultaneously with an irritant compound. The average
inhibition of cumulative irritation for various cation salts of the
invention (at 250 mM) are shown in the following tables.
3 Cation Salt Percent Inhibition TIME ZERO TESTS Strontium chloride
60% Strontium nitrate 65% PRETREATMENT TESTS Strontium chloride 25%
Strontium nitrate 50% Strontium acetate 46%
[0073] A representative set of test results from several subject
panels, performed using cation concentrations of 250 mM, is set
forth in the following tables.
4 Percent Cation Anion Salt Formula Vehicle Inhibition PRETREATMENT
TESTS Strontium Chloride SrCl.sub.2 VIS DIFFERENCE 20 Strontium
Nitrate Sr(NO.sub.3).sub.2 VIS DIFFERENCE 56 Strontium Acetate
Sr(CH.sub.3CO.sub.2).sub.2 VIS DIFFERENCE 46 TIME ZERO TESTS
Strontium Chloride SrCl.sub.2 10% EtOH 58 Strontium Nitrate
Sr(NO.sub.3).sub.2 10% EtOH 64
[0074] FIGS. 1 through 4 show more detailed experimental data for
one panel test conducted using strontium nitrate (250 mM) as the
anti-irritant salt component of the subject formulation (time zero
test). FIG. 1 shows the time course of irritation responses for
both cation-treated and non-treated (control) skin portions for the
panel. FIG. 2 shows the cumulative irritation over time for the
same panel, while FIGS. 3 and 4 show cumulative irritation
suppression and treated/untreated irritation responses on a
subject-by-subject basis. While individual responses vary somewhat,
the overall efficacy of the subject formulation is clear.
[0075] b. Capsaicin Irritation Trials
[0076] Similar clinical trials were conducted to assess the
efficacy of the cation of the invention to inhibit irritation
induced by capsaicin. The clinical protocol was similar to that
conducted with lactic acid, with the irritant/anti-irritant and
control formulations being applied to the arms of the test
subjects. The test compounds of the invention were formulated in
Elizabeth Arden "Visible Difference Refining Toner", with the Toner
mixed with equimolar sodium chloride serving as the control. The
test solutions (and control) were provided in coded vials for
application to either the right or left arms. A template (1.5
in..times.4.0 in.) was placed on each forearm to mark the challenge
area. The pre-treatment solutions containing the anti-irritant
cation of the invention were applied to extend 1 inch beyond the
marked challenge area in all directions and were allowed to dry for
5 minutes. 0.5 ml of 0.15% capsaicin cream or a swab moistened with
capsaicin solution was thereafter applied to each arm by the
clinical technician, who rubbed in the cream using gloved fingers.
Application and scoring of test and control formulations was
performed sequentially for each arm. Scoring was recorded every
minute starting at 5 minutes post-application for 10 minutes and
then every 5 minutes for 15 minutes (30 minutes total) for the
cream, and every minute starting immediately for 15 minutes for the
solution. Assessment was made using the irritation scale described
above for the lactic acid test, and a simultaneous visual
assessment of erythema was made by the monitoring technician.
[0077] FIGS. 5 through 8 depict results from one representative
panel tested in this trial, in which the anti-irritant cation
component was applied in the form of strontium nitrate (250 mM).
FIG. 5 shows the time course of irritation responses for both
cation-treated and non-treated (control) skin portions for the
panel. FIG. 6 shows the cumulative irritation over time for the
same panel, while FIGS. 7 and 8 show cumulative irritation
suppression and treated/untreated irritation responses on a
subject-by-subject basis. Here again, while individual responses
vary somewhat, the overall efficacy of the subject formulation is
evident.
[0078] c. Glycolic Acid Irritation Trials
[0079] Following a protocol parallel to that of the lactic acid
irritant trials described above, glycolic acid (6.0% in 10%
ethanol-in-water) was applied as a skin irritant to subject panels.
Strontium nitrate was co-administered as an anti-irritant (time
zero testing), and was shown to inhibit cumulative irritation in
subject panels by 64% to 84% at concentrations ranging from 250 mM
to 500 mM. Time course and subject-by-subject data for one such
test (cation concentration 250 mM) are presented in FIGS. 9 through
12.
[0080] d. Benzoyl Peroxide Irritation Trials
[0081] In this test, male and female subjects were recruited who
had experienced a grade "2" or higher response in the
sting/burn/itch lactic acid irritation protocol described above.
Test subjects were limited to those who self-reported a sensitivity
(sting, burn, itch) to benzoyl peroxide.
[0082] Subjects were instructed not to wear makeup or facial
lotions on the day of testing. Those who had applied sunscreens to
the face within 24 hours prior to testing, or who had taken any
oral analgesic within 12 hours prior to testing, were disqualified.
Subjects were instructed to wash their face with Ivory bar soap
prior to application of test and control solutions. All materials
were applied and scored in a double-blind, randomized fashion.
[0083] Facial irritation was induced by application of a 10%
benzoyl peroxide wash product ("Oxy 10") to one side of the face.
The other side of the face was treated with the same irritant
composition containing 250 mM strontium nitrate as the test
anti-irritant. Inactive ingredients in the benzoyl peroxide product
included citric acid, cocamidopropyl betaine, diazolidinyl urea,
methylparaben, propylparaben, sodium citrate, sodium cocoyl
isethionate, sodium lauroyl sarcosinate, water, and xanthum
gum.
[0084] The respective compositions were applied (from coded
weighing vessels) using gloved fingers to the cheek area, first to
the right side and immediately thereafter to the left. In order to
maximize the irritation response above a baseline noise level, the
solutions were left on the face for the entire 10 minutes of the
study, rather than for only 1-2 minutes as instructed for the
commercial benzoyl peroxide product.
[0085] To allow for adequate quantitation of the relatively low
irritation levels in small numbers of subjects to be measured
reliably and true differences in irritation to be determined, a
differential scoring scale was developed. Using this method, each
subject was asked to rate the magnitude of the difference in
irritation response between the two sides of the face, as
follows:
5 Score Relative Subjective Irritation 0 No irritation on either
side of face, or No difference in irritation between the right and
left sides of face. 1 Slight difference in irritation between fight
and left sides of face; difference is barely noticeable and only
evident after thinking about it. 2 Clear difference in irritation
between right and left sides of face; difference is obvious and
immediately evident.
[0086] It was found that this simultaneous, differential scoring
approach allowed for accurate comparisons to be made for the low
levels of irritation associated with the present protocol, since it
was much easier for the subjects to quantify the difference in
irritation when both sides of the face were challenged
simultaneously than to rate irritation sequentially on an
"absolute" 0-4 scale as used in the lactic acid and glycolic acid
protocols. On the other hand, when high levels of irritation are
present, the use of sequential "absolute" scoring is preferred
because it avoids uncertainty and "carry-over" effects from one
side of the face to the other.
[0087] FIGS. 13 through 16 depict results obtained in this protocol
using strontium nitrate as the anti-irritant cation component (250
mM). FIG. 13 shows the time course of differential irritation
responses for both cation-treated and non-treated (control) skin
portions for the panel. FIG. 14 shows the cumulative irritation
over time for the same panel, while FIGS. 15 and 16 show cumulative
irritation suppression and treated/untreated irritation responses
on a subject-by-subject basis.
[0088] e. Post-Shaving Ocean Water Irritation
[0089] Ocean water is known to induce irritation in subjects with
sensitive skin, particularly if the skin has been abraded by
shaving or other means. The present test was performed to determine
the ability of the present cation formulations to inhibit
irritation of shaved skin due to ocean water.
[0090] Female subjects were instructed not to apply any sunscreen
to their legs within 24 hours prior to testing, and not to ingest
any oral analgesic medications within 12 hours prior to testing.
The subjects were instructed to shave the lateral portions of their
calves, spanning from the ankle to below the knee, with Ivory soap
and a disposable razor prior to application of test, control and
ocean water irritant solutions. All materials were applied and
scored in a double-blind, randomized fashion.
[0091] Following shaving, 1 ml of pretreatment solution (test or
control) was applied from coded vials to the respective right and
left calves using cosmetic sponges. The test cation solution
contained strontium nitrate (500 mM) in nanopure water (pH 4.5),
and the control vehicle was nanopure water (pH 5.5). The solutions
were allowed to dry for 2-3 minutes. Cosmetic sponges saturated
with ocean water (La Jolla, Calif.) were used to apply ocean water
challenge solutions to the right and left calves within the
pretreated areas. The subjects were asked to rate levels of
irritation (sting, burn or itch) on right and left calves, and
irritation scores were recorded every minute for 10 minutes. The
0-4 scoring scale described above for the lactic acid irritation
protocol was used in this test.
[0092] Irritation scores were cumulated for each individual and for
the panel as a whole. FIG. 17 shows the time course of differential
irritation responses for both cation-treated and non-treated
(control) skin portions for the panel. FIG. 18 shows the cumulative
irritation over time for the same panel, while FIGS. 19 and 20 show
cumulative irritation suppression and treated/untreated irritation
responses on a subject-by-subject basis.
[0093] f. Post-Shaving Lactic Acid Irritation
[0094] Following a protocol parallel to that of the post-shaving
ocean water irritation test described above, a commercial lotion
containing 5% lactic acid was applied to contralateral shaved
calves of the subject females. The control solution was Vaseline
Smooth Legs and Feet Lotion (containing water, lactic acid (5%),
glycerin, isopropyl palmitate, PEG-40 stearate, cetyl alcohol,
potassium hydroxide, steareth-2, magnesium aluminum silicate,
lecithin, soya sterol, tocopheryl acetate, tetinyl palmitate,
dimethicone, menthol, camphor, stearic acid, laureth-7, xanthan
gum, polyacrylamide, C13-14 isoparaffin, corn oil, fragrance, DMDM
hydantoin, iodopropynyl butylcarmamate, disodium EDTA, PG, and Ext.
violet 2); the cation test formulation included strontium nitrate
(500 mM) in the same Vaseline lactic acid lotion. 0.5 g of test and
control solutions were applied with gloved fingers to the right and
left calves. Subjects were asked to rate levels of irritation
(sting, burn or itch) on the right calves, and irritation scores
were recorded every minute for 10 minutes.
[0095] Irritation scores were cumulated for each individual and for
the panel as a whole. FIG. 21 shows the time course of differential
irritation responses for both cation-treated and non-treated
(control) skin portions for the panel. FIG. 22 shows the cumulative
irritation over time for the same panel, while FIGS. 23 and 24 show
cumulative irritation suppression and treated/untreated irritation
responses on a subject-by-subject basis.
EXAMPLE 2
Dose-Response Studies
[0096] Additional studies of anti-irritant activity using varying
concentrations of strontium cations were conducted in order to
assess the dose-response behavior of the present formulations. The
lactic acid irritation protocol described above was used, in which
the anti-irritant cation component was strontium nitrate (31-500
mM). Cumulative irritation inhibition data are set forth in the
following table, and are depicted graphically in FIG. 25.
6 Concentration (mM) Percent Inhibition 31 27 62 32 125 42 250 72
500 82
EXAMPLE 3
Additional Formulation Examples
[0097] Cation salts of the invention were formulated at various
concentrations in a number of commercially available topical
vehicles, and also in various commercially available topical
cosmetic products. The resulting mixtures generally did not alter
the texture, color, consistency or other physical properties of the
product, and could be used as formulations to inhibit topical
irritation.
[0098] a. Silicone-Based Vehicles
[0099] A 500 mM strontium nitrate topical lotion was prepared as
follows. 10.58 g of strontium nitrate was dissolved in 55 ml of
deionized water. This solution was combined with 10 ml
cyclomethicone (Dow Corning, "DC344"), 20 ml
cyclomethicone/dimethiconol (Dow Corning, "DC1401") and 15 ml
cyclomethicone/dimethicone copolyol (Dow Corning, "DC3225C") and
blended for 2-3 minutes. Imidizolidinyl urea (0.5%) was added as a
preservative. An opaque white lotion (100 ml) resulted which, when
applied to the skin of a fair (olive) skinned individual left no
visible residue.
[0100] A 500 mM strontium nitrate topical gel was prepared as
follows. 5.29 g of strontium nitrate was dissolved in 17 ml of
deionized water. This solution was combined with 10 ml
cyclomethicone (Dow Corning, "DC344"), 7.5 ml
cyclomethicone/dimethiconol (Dow Corning, "DC1401"), 7.5 ml
cyclomethicone/dimethicone copolyol (Dow Corning, "DC3225C") and 8
ml PEG-8 and blended for 2-3 minutes. Imidizolidinyl urea (0.5%)
was added as a preservative. A clear, thick gel resulted (50
ml).
[0101] A 1500 mM strontium nitrate topical gel was prepared as
follows. 31.75 g of strontium nitrate was dissolved in 50 ml of
deionized water. This solution was combined with 10 ml
cyclomethicone (Dow Corning, "DC344"), 20 ml
cyclomethicone/dimethiconol (Dow Corning, "DC1401") and 20 ml
cyclomethicone/dimethicone copolyol (Dow Corning, "DC3225C") and
blended for 2-3 minutes. Imidizolidinyl urea (0.5%) and benzyl
alcohol (1%) were added as preservatives. A clear, thick gel
resulted (100 ml) which, upon application to the skin of a
fair-skinned subject, left a visible white residue.
[0102] A 1500 mM strontium nitrate topical gel with a glycerin
component was prepared as follows. 31.75 g of strontium nitrate was
dissolved in 60 ml of deionized water. This solution was combined
with 5 ml cyclomethicone (Dow Corning, "DC344"), 10 ml
cyclomethicone/dimethiconol (Dow Corning, "DC1401"), 15 ml
cyclomethicone/dimethicone copolyol (Dow Corning, "DC3225C") and 10
ml glycerin and blended for 2-3 minutes. Imidizolidinyl urea (0.5%)
was added as a preservative. A clear, thick gel resulted (100
ml).
[0103] b. Commercial Cosmetic Vehicles
[0104] Topical solution forms of strontium nitrate, strontium
chloride and strontium acetate were prepared by combining various
amounts of the named salts with Elizabeth Arden Visible Difference
Refining Toner (an alcohol-containing solution). The concentrations
achieved were shown to be effective to inhibit skin irritation as
described in the protocols set forth above.
[0105] Similarly, other solution forms of strontium nitrate were
prepared by combining anti-irritant effective amounts of the salt
with Estee Lauder Clean Finish Purifying Toner Normal/Dry, Oil of
Olay Refreshing Toner Cleanser and Toner, Mary Kay Refining
Refreshener Formula 2, Clearasil Clearstick Max Strength, and
Oxy-10 Benzoyl Peroxide Wash.
[0106] Topical lotion forms of strontium nitrate were prepared by
combining anti-irritant effective amounts of the salt with
Cheseborough-Ponds Lotions (CCB-3-83-L15), Vaseline Intensive Care
Lotion Smooth Legs and Feet, and Lubriderm Moisture Recovery
Lotion. Similarly, serum and cream forms of strontium nitrate were
prepared by combining anti-irritant effective amounts of the salt
with Mary Kay Revival Serum (with 15% lactic acid) and L'Oreal
Vichy Novactia Cream (with 2% capryloyl salicylic acid),
respectively.
[0107] The foregoing examples are not intended to limit the scope
of the present invention, which is set forth in the following
claims. In particular, various equivalents and substitutions will
be recognized by those skilled in the art in view of the foregoing
disclosure, and these are contemplated to be within the scope of
the invention.
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