U.S. patent application number 12/811705 was filed with the patent office on 2011-05-26 for skincare treatment.
This patent application is currently assigned to RECKITT & COLMAN(OVERSEAS) LIMITED. Invention is credited to Rebecca Horne, Diene Kelly, Laurent Kirchhoffer, Richard Koontz, James Young.
Application Number | 20110121033 12/811705 |
Document ID | / |
Family ID | 39111155 |
Filed Date | 2011-05-26 |
United States Patent
Application |
20110121033 |
Kind Code |
A1 |
Horne; Rebecca ; et
al. |
May 26, 2011 |
Skincare Treatment
Abstract
The invention relates to a method of treating acne by the
topical administration of an acne active ingredient in the presence
of a) an anhydrous composition comprising a component that in the
presence of water generates heat, and b) water. The invention also
relates to an acne treatment kit comprising a first composition
which is anhydrous and comprises a component that in the presence
of water generates heat on the skin to which it is applied and a
second composition which comprises an aqueous carrier, at least one
of said compositions comprising an acne active ingredient, said
compositions being stored in isolation from each other and being
capable of generating heat when they are combined.
Inventors: |
Horne; Rebecca; (Hull,
GB) ; Kelly; Diene; (Hull, GB) ; Kirchhoffer;
Laurent; (Ludwigshafen, DE) ; Koontz; Richard;
(Hull, GB) ; Young; James; (Hull, GB) |
Assignee: |
RECKITT & COLMAN(OVERSEAS)
LIMITED
SLOUGH, BERKSHIRE
GB
|
Family ID: |
39111155 |
Appl. No.: |
12/811705 |
Filed: |
December 24, 2008 |
PCT Filed: |
December 24, 2008 |
PCT NO: |
PCT/GB08/04283 |
371 Date: |
November 30, 2010 |
Current U.S.
Class: |
222/145.1 ;
514/159 |
Current CPC
Class: |
A61P 17/10 20180101;
A61Q 19/00 20130101; A61K 33/06 20130101; A61K 45/06 20130101; A61K
2800/242 20130101; A61K 31/60 20130101; A61K 33/06 20130101; A61K
2800/31 20130101; A61K 8/368 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 8/36 20130101; A61K 31/60 20130101; A61K
2800/88 20130101 |
Class at
Publication: |
222/145.1 ;
514/159 |
International
Class: |
B67D 7/78 20100101
B67D007/78; A61K 31/60 20060101 A61K031/60; A61P 17/10 20060101
A61P017/10 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 4, 2008 |
GB |
0800145.5 |
Claims
1. A method of treating acne by the topical administration of an
acne active ingredient in the presence of an anhydrous composition
comprising a component that in the presence of water generates
heat, and water.
2. A method according to claim 1, wherein the administration of the
anhydrous composition and the aqueous composition is substantially
simultaneous.
3. A method according to claim 1, wherein said acne active
ingredient is present in said anhydrous composition.
4. A method according to claim 1, wherein said acne active
ingredient is present in said aqueous composition.
5. A method according to claim 1, wherein the acne active
ingredient is a keratolytic agent.
6. A method according to claim 1, wherein the acne active
ingredient is present in an amount of from 0.1% to 10% by weight of
the combined anhydrous and aqueous compositions.
7. A method according to claim 1, wherein the acne active
ingredient is present in an amount of 0.1% to 5% by weight of the
anhydrous composition.
8. A method according to claim 1, wherein the acne active
ingredient is present in an amount of 0.1% to 5% by weight of the
aqueous composition.
9. A method according to claim 1, wherein the component activatable
by water to generate heat on the skin is selected from the group
consisting of zeolites and bivalent metal halides.
10. A method according to claim 9, wherein the component
activatable by water to generate heat on the skin is magnesium
chloride.
11. A method according to claim 9, wherein said anhydrous
composition comprises from 5% to 60% by weight of said component
that generates heat in the presence of water.
12. A method according to claim 1, wherein the anhydrous
composition comprises an anhydrous carrier.
13. A method according to claim 12, wherein the anhydrous carrier
comprises a hydrocarbon material.
14. A method according to claim 13, wherein the anhydrous carrier
comprises mineral oil.
15. A method according to claim 1, wherein the anhydrous
composition comprises a surfactant.
16. A method according to claim 15, wherein the surfactant is
selected from the group consisting of alkyl sulphates, alkyl ether
sulphates, alpha-olefin sulphates, alkylsarcosinates and
aryl-sulphonated derivatives thereof.
17. A method according to claim 16, wherein the surfactant is
selected from the group consisting of sodium lauryl sulphate and
sodium dodecyl sulphate.
18. A method according to claim 15, wherein the anhydrous
composition comprises from 1% to 10% by weight surfactant.
19. A method according to claim 1, wherein the aqueous composition
is a cleansing composition comprising a surfactant.
20. An acne treatment kit comprising a first composition which is
anhydrous and comprises a component that in the presence of water
generates heat on the skin to which it is applied and a second
composition which comprises an aqueous carrier, at least one of
said compositions comprising an acne active ingredient, said
compositions being stored in isolation from each other and being
capable of generating heat when they are combined.
21. A skincare formulation obtained by mixing on, or prior to
application to, the skin comprising: a first composition which is
anhydrous and comprises a component that in the presence of water
generates heat; a second composition which comprises an aqueous
carrier; and at least one acne active ingredient.
22. An anhydrous composition for the treatment of acne comprising
an acne active ingredient, a component that in the presence of
water generates heat and a carrier therefor.
23. A composition according to claim 22, wherein the carrier
comprises a hydrocarbon.
24. A composition according to claim 23, wherein said composition
comprises a surfactant.
25. A composition according to claim 24, wherein said surfactant is
selected from the group consisting of alkyl sulphates and alkyl
ether sulphates.
26. A composition according to claim 22 comprising: 1-5% by weight
acne active ingredient; 20-40% by weight component that in the
presence of water generates heat; 50-85% by weight carrier; and
1-10% surfactant.
27. A composition according to claim 22 in the form of a thickened
liquid which does not flow off the skin.
28. An acne treatment package for dispensing a first and a second
composition onto the skin, said first composition being anhydrous
and comprising a component that in the presence of water generates
heat and said second composition comprising an aqueous component,
at least one of said compositions comprising an acne active
ingredient, wherein said package comprises a first chamber and a
second chamber, each of said first and second chambers having an
outlet, wherein said first composition is stored in said first
chamber and said second composition is stored in said second
chamber, said compositions being stored in isolation from each
other and the package being arranged such that said compositions
are combined after passing though said respective outlet.
29. A package according to claim 28 further comprising a dispensing
nozzle through which the combined compositions are dispensed onto
the skin.
30. A package according to claim 28 further comprising a receptacle
partitioned into first and second chambers.
31. A package according to claim 28 further comprising a tube
comprising said first or said second composition and an inner tube
comprising the other of said first or second composition.
32. A package according to claim 28, wherein the package is
squeezable to expel said first and second compositions.
33. A process to prepare an acne treatment kit comprising inserting
a first composition which is anhydrous and comprises a component
that in the presence of water generates heat into a first chamber
of a multi-chambered package and inserting a second composition
which comprises an aqueous carrier into a second chamber of said
package, at least one of said compositions comprising an acne
active ingredient, and providing means for combining said
compositions on, or prior to application to, the skin.
34. A process of dispensing an acne treatment onto the skin
comprising the application to the skin of a first composition which
is anhydrous and comprises a component that in the presence of
water generates heat, and a second composition which comprises an
aqueous carrier, at least one of said compositions comprising an
acne active ingredient and mixing said compositions to generate
heat on the skin.
35. A method for reducing the oily feel on the skin of an anhydrous
composition including a hydrocarbon carrier comprising the
incorporation of a surfactant in said composition.
36. A method according to claim 5, wherein the keratolytic agent is
salicylic acid.
37. A composition according to claim 23, wherein the hydrocarbon
comprises a mineral oil.
Description
[0001] The present invention relates to a method of treating acne,
to an acne treatment kit, to compositions and kits useful in such
methods and to processes to prepare said composition and/or
kits.
[0002] Acne vulgaris (acne) is a chronic inflammatory condition of
the pilosebaceous units of the skin, which is particularly
prevalent in adolescents. The condition generally causes the
formation, on the skin, of comedones, red papules, pustules and
sometimes cysts. This is unsightly and furthermore, if untreated,
acne can lead to scarring of the skin. The major causes of acne are
thought to be an increase in sebum production, an increased
presence of Propionibacterium acne (P. acne), blockage of the
pilosebaceus duct and the production of inflammation.
[0003] Remedies for the topical treatment of acne generally provide
for the application to the affected area of a skincare composition
comprising at least one ingredient effective to treat acne. Such
actives include the classes of topical retinoids, antibiotics,
anti-bacterials and keratolytic agents, for example tretinoin,
adapalene, tazarotene, clindamycin, erythromycin, azelaic acid,
benzoyl peroxide and salicylic acid.
[0004] It has now been found that an improved acne treatment may be
achieved by the topical administration of an acne active ingredient
in the presence of a component that generates heat on the skin.
[0005] It has been found that the above treatment provides improved
efficacy in the topical treatment of acne. For example, factors
including improved sebum removal and improved pore cleansing may
lead to a reduction in the number and intensity of acne
lesions.
[0006] Accordingly, the present invention provides a method of
treating acne comprising the topical administration of an acne
active ingredient in the presence of [0007] a) an anhydrous
composition comprising a component that in the presence of water
generates heat on the skin, and [0008] b) water.
[0009] In another aspect the present invention also provides an
acne treatment kit comprising a first composition which is
anhydrous and comprises a component that in the presence of water
generates heat and a second composition which comprises an aqueous
carrier, at least one of said compositions comprising an acne
active ingredient, said compositions being stored in isolation from
each other and being capable of generating heat when they are
combined.
[0010] In a yet further aspect the present invention provides a
skincare formulation obtained by mixing on, or prior to application
to, the skin comprising [0011] a) a first composition which is
anhydrous and comprises a component that in the presence of water
generates heat; [0012] b) a second composition which comprises an
aqueous carrier; and [0013] c) at least one acne active
ingredient.
[0014] In still a further aspect the present invention provides an
anhydrous composition for the treatment of acne comprising an acne
active ingredient, a component that in the presence of water
generates heat and a carrier therefor.
[0015] The invention also provides an acne treatment package for
dispensing a first and a second composition onto the skin, said
first composition being anhydrous and comprising a component that
in the presence of water generates heat and said second composition
comprising an aqueous component, at least one of said compositions
comprising an acne active ingredient, wherein said package
comprises a first chamber and a second chamber, each of said first
and second chambers having an outlet, wherein said first
composition is stored in said first chamber and said second
composition is stored in said second chamber, said compositions
being stored in isolation from each other and the package being
arranged such that said first and second compositions are combined
after passing though each respective outlet.
[0016] The invention also provides a process of dispensing an acne
treatment onto the skin comprising the application to the skin of a
first composition which is anhydrous and comprises a component that
in the presence of water generates heat, and a second composition
which comprises an aqueous carrier, at least one of said
compositions comprising an acne active ingredient, and mixing said
compositions to generate heat on the skin.
[0017] The invention also provides a process to prepare an acne
treatment kit, comprising inserting a first composition which is
anhydrous and comprises a component that in the presence of water
generates heat into a first chamber of a multi-chambered package
and inserting a second composition which comprises an aqueous
carrier into a second chamber of said package, at least one of said
compositions comprising an acne active ingredient, and providing
means for combining said compositions on, or prior to application
to, the skin.
[0018] Where reference is made herein to an anhydrous composition,
this means a composition which is substantially free of water; for
example, it will contain less than 2% by weight water preferably
less than 1% by weight water and most preferably less than 0.1% by
weight water.
[0019] In a method according to the invention, an acne active
ingredient is applied to the skin in the presence of an anhydrous
composition comprising a component that in the presence of water
generates heat and water. The heat is generated on the skin and is
useful to raise the temperature on the surface of the skin. The
amount of heat-generating component present in the anhydrous
composition is a level that the heat generated by the combination
of the anhydrous composition with the water is acceptable on the
skin of a user and does not burn the skin.
[0020] In accordance with the present invention, the anhydrous
composition may be applied to the skin and water applied thereto.
The water may be applied before, at the same time as, or after the
application of the anhydrous composition. Preferably the anhydrous
composition and water are combined by rubbing the ingredients
together. In this way the heat generating component is most
effectively combined with water to provide a heating effect on the
skin.
[0021] The water may be obtained from any suitable source, for
example a water tap. The water may also be provided in an aqueous
composition which may include one or more additional ingredients,
especially skincare ingredients. There may be sufficient water
already present on the skin to produce a suitable heating effect if
the anhydrous composition is rubbed into the skin with sufficient
vigour.
[0022] Preferably, the aqueous composition forms part of a package
in combination with the anhydrous composition, which allows a
measured amount of water to be applied to the skin thus allowing
more control of the heating effect.
[0023] In one embodiment, the administration of the anhydrous
composition and the aqueous composition on the skin is
substantially simultaneous. The anhydrous composition and aqueous
composition may be combined just prior to application to the skin
or they may be combined on the skin. For example, the anhydrous
composition and aqueous composition may be dispensed from separate
chambers within a package. The outlet of each chamber may allow the
compositions to be applied directly onto the skin and then combined
by the user rubbing the compositions on the surface of the skin or
the compositions may be combined as they pass through a dispensing
nozzle before application to the skin.
[0024] A skincare formulation is provided when said anhydrous
composition is combined with water. Heat is generated on the skin
which enhances the effect of the acne active ingredient. The
skincare formulation may be left on the skin in which case the heat
generated will gradually subside. Preferably the composition is
rinsed off the skin, leaving a therapeutically effective amount of
the acne active ingredient on the skin.
[0025] The acne active ingredient may be present separate from the
anhydrous composition or the aqueous composition, it may be present
in either the anhydrous and aqueous compositions or it may be
present in both the anhydrous and aqueous compositions.
[0026] The acne active ingredient may be selected from any class of
materials that are effective to treat acne, including topical
retinoids, antibiotics, anti-microbials, anti-bacterials,
anti-inflammatory agents and keratolytic agents, for example
tretinoin, adapalene, tazarotene, clindamycin, erythromycin,
azelaic acid, benzoyl peroxide, hydrogen peroxide and salicylic
acid. If desired two or more acne active ingredients may be
employed. The active ingredients may be present in the same or in
different compositions.
[0027] The active ingredient is present in the formulation in a
therapeutically effective amount, as generally known in the art.
For most active ingredients, a range from 0.001% to 10% by weight,
especially from 0.1% to 10% by weight, could be expected. Thus,
generally each composition may comprise the above recited amount of
acne active ingredient. Preferably, an acne active ingredient is
present in an amount of 0.1% to 5% by weight of the anhydrous
composition. Further preferably, an acne active ingredient is
present in an amount of 0.1% to 5% by weight of the aqueous
composition. However, it may be a benefit to reduce the total
amount of any one active in the anhydrous or aqueous compositions,
or to separate a plurality of actives, by including at least one
acne active ingredient in both compositions. Thus, in a preferred
embodiment, an acne active ingredient is present in an amount from
0.1% to 5% by weight of both aqueous and anhydrous
compositions.
[0028] In one embodiment, said acne active ingredient is a
keratolytic agent such as salicylic acid. Salicylic acid is
preferably incorporated into the composition according to the
invention as the free acid. However, the pH of the composition may,
and generally will, be such that the salicylic acid exists in the
composition in dissociated form. As the composition may well
contain cationic counterions, the salicylic acid may then be
thought of as being present in salt form. Alternatively, the
salicylic acid may be incorporated into the composition in salt
form, eg as a salt with a Group I metal, such as sodium salicylate.
As used herein, unless the context requires otherwise, any and all
references to salicylic acid should be taken to encompass
references to the acid and to dissociated forms and salts
thereof.
[0029] The total concentration of salicylic acid in the formulation
according to the invention, ie the combined anhydrous and aqueous
compositions, is preferably at least 0.1% by weight, more
preferably at least 0.5% by weight, most preferably at least 1.0%
and especially at least 1.5% by weight. The concentration of
salicylic acid is preferably less than 10% by weight, more
preferably less than 6% by weight, and most preferably less than 4%
by weight. Conveniently, the total concentration of salicylic acid
may fall in the range 0.1% to 10% by weight, preferably 0.5% to 10%
by weight, more preferably 1.0% to 6%, and most preferably 1.5% to
4.0% by weight. A particularly preferred total concentrations of
salicylic acid is approximately 1.5-2% by weight of the
composition.
[0030] In one embodiment, said acne active ingredient, preferably
salicylic acid, is present in the anhydrous and aqueous
compositions. The amount of acne active ingredient may be different
in each composition. However, preferably, the aqueous composition
comprises from 0.5% to 4% by weight, more preferably 1% to 3% by
weight, acne active ingredient. Further preferably, the anhydrous
composition comprises from 0.5% to 4% by weight, more preferably 1%
to 3% by weight, acne active ingredient.
[0031] In accordance with the invention, any pharmaceutically
acceptable component that generates heat in the presence of water
may be used. Preferred examples are selected from the group of
materials that generate heat within the classes of zeolites
(aluminosilicates); metal halides, sulphates, carbonates and
oxides; and polyhydric alcohols. Preferred classes of materials
include zeolites and bivalent metal halides. These materials are
well known to those skilled in the art. Examples of bivalent metal
halides and oxides may include magnesium chloride, iron chloride,
zinc chloride, magnesium oxide, calcium oxide, magnesium sulphate
and calcium chloride.
[0032] Such heat generating materials will suitably be present in
the anhydrous composition in an amount to heat the skin to
facilitate opening and cleansing of the pores. For example, such
materials my be used in an amount of up to 70% by weight of the
anhydrous composition, for example, from 1% to 70% by weight,
preferably from 1% to 40% by weight, more preferably from 1% to 25%
by weight and most preferably from 1% to 15% by weight.
[0033] The person skilled in the art will appreciate that the heat
generated must be less than that which will cause heat damage to
the skin. Preferably the temperature of the skin is raised by no
more than 50.degree. C. In order to be effective, preferably, the
temperature of the skin is raised by at least 2.degree. C., more
preferably at least 10.degree. C. Conveniently, the temperature of
the skin may be raised to a temperature in the range 4.degree. C.
to 70.degree. C., preferably 4.degree. C. to 15.degree. C.
[0034] Preferably, the component that in the presence of water
generates heat comprises a bivalent metal halide, further
preferably a metal halide selected from magnesium chloride, iron
chloride, zinc chloride and calcium chloride, most preferably
magnesium chloride.
[0035] In one embodiment of the invention, the anhydrous
composition comprises from 5% to 60% by weight, preferably from 10%
to 50% by weight, more preferably from 12% to 40% by weight and
most preferably from 15% to 35% by weight of said
water-activatable, heat-generating component.
[0036] In accordance with the invention, the anhydrous composition
comprises an anhydrous carrier. Conveniently, this may be an oily
material. A physiologically effective oil useful in accordance with
the present invention may be any cosmetically and/or
dermatologically acceptable synthetic or natural oil known to the
person skilled in the art. Such oils may also provide emollient
properties on the skin, for example to maintain the soft, smooth
and pliable appearance of the skin. Suitable ingredients include
hydrocarbons, silicone oils, triglycerides, waxes, fatty acids,
fatty acid alcohols and esters thereof, mineral oils, vegetable
oils and hydrogenated vegetable oils, lanolin or mixtures thereof.
Examples of hydrocarbons include paraffins (for example paraffinum
liquidum and white soft paraffin), petrolatum, hydrogenated
polyisobutene, alkyl benzoates, isohexadecane, isododecane,
isononyl isonanoate, diisopropylcyclohexane; examples of silicone
oils include dimethicone, cyclomethicone or cetyldimethicone;
examples of triglycerides include natural triglycerides and
synthetic or semi-synthetic triglycerides; examples of waxes
include vegetable waxes such as carnauba wax, animal waxes such as
beeswax, and mineral waxes such as paraffin wax, ozokerite;
examples of esters of fatty acids or alcohols include isopropyl
palmitate, isopropyl myristate, dioctylmaleate, glyceryl oleate and
cetostearyl isononanoate, octyl palmitate; examples of mineral oils
include Vaseline oil; examples of vegetable oils include jojoba
oil, soy bean oil, coconut oil, sunflower seed oil, apricot kernel
oil, shea butter, avocado oil and examples of hydrogenated
vegetable oils include hydrogenated palm oil.
[0037] Such materials may be used in an amount greater than 30% by
weight, more preferably greater than 35% by weight, advantageously
greater than 40% by weight and most preferably greater than 45% by
weight of the composition. The carrier generally provides the
largest component by weight of the anhydrous composition.
Preferably, the anhydrous composition comprises from 30% to 99% by
weight, preferably from 35% to 95% by weight, more preferably from
40% to 90% by weight and most preferably from 50% to 85% by weight
of said carrier.
[0038] In one embodiment, the anhydrous carrier comprises a mineral
oil. Preferably, the mineral oil is blended with a styrene
copolymer, for example a hydrogenated alkylene-styrene copolymer,
more preferably a hydrogenated butylene/ethylene/styrene copolymer
or a hydrogenated ethylene/propylene/styrene copolymer or a mixture
thereof. A particularly preferred source of a mineral oil/styrene
copolymer blend is available under the tradename Versagel from
Penreco, 138 Petrolia Karns City USA.
[0039] Preferably, mineral oil is combined with a hydrogenated
alkylene-styrene copolymer/mineral oil blend.
[0040] In preferred compositions which comprise mineral oil, the
total mineral oil is preferably present in an amount from 50% to
85% by weight, more preferably from 60% to 80% by weight, of the
anhydrous composition; conveniently this may be a blend comprising
mineral oil in an amount from 25% to 60% by weight (more preferably
from 35% to 50% by weight) and a mineral oil/styrene copolymer
blend in an amount from 20% to 40% by weight (more preferably from
24% to 32% by weight).
[0041] In another embodiment, the anhydrous composition comprises a
surfactant. This forms a particularly preferred aspect of the
present invention as it provides a composition with advantageous
viscosity and skin-feel properties. For example, it may provide a
less oily feel to the composition so that it is more pleasant to
apply and retain on the skin. For example, a greasy and/or oily
and/or sticky feel on the skin may be reduced. In particular, the
inclusion of a surfactant in a composition where the carrier is a
hydrocarbon (such as mineral oil) improves the aesthetic feel of
the composition on the skin. In this way, it has been found that
less expensive carriers may be employed in the anhydrous
composition. Furthermore, the anhydrous composition has good
viscosity properties as it is not too viscous to apply and does not
run off the skin when applied thereto. A suitable viscosity is that
of a thickened liquid such that it is thicker than water and
preferably remains in the area to which it is applied, even when
the user moves or applies it to a non-horizontal skin surface. It
is a preferred feature of the invention that the compositions have
a viscosity which allow them to be dispensed conveniently from a
package, especially through a dispensing nozzle. The viscosity
range values of such compositions will be known to those skilled in
the art. The inclusion of at least one surfactant may provide that
it may not be necessary to include a thickening component in the
composition. In one embodiment, the anhydrous composition comprises
a surfactant and does not include a thickening component.
[0042] The surfactant may be an anionic, non-ionic, cationic and
zwitterionic/amphoteric surfactant. Any conventionally used
pharmaceutically and cosmetically acceptable surfactant may be used
and these will be known to the person skilled in the art. Examples
of non-ionic surfactants include the class of ethoxylated fatty
alcohols and other surfactants such as oleth-5, PEG-5 cocamide,
polysorbate 20, PEG-40 hydrogenated castor oil, alkyl poly(ethylene
oxide), copolymers of poly(ethylene oxide) and poly(propylene
oxide) (commercially called Poloxamers or Poloxamines), alkyl
polyglucosides, including: octyl glucoside, decyl maltoside, fatty
alcohols, cetyl alcohol, oleyl alcohol; examples of anionic
surfactants includes the class of alkyl ether sulphates, such as
sodium lauryl sulphate, sodium laureth sulphate, sodium dodecyl
sulfate, ammonium lauryl sulfate, ammonium laureth sulphate, sodium
C12-15 pareth sulphate and disodium laureth sulfosuccinate, soaps
or fatty acid salts; examples of cationic surfactants include
cationic modified guar, alkyltrimethylammonium salts, for example
cetrimonium chloride, cetyl trimethylammonium bromide,
cetylpyridinium chloride, polyethoxylated tallow amine,
benzalkonium chloride, benzethonium chloride and behentrimonium
chloride; examples of amphoteric surfactants include the class of
alkylamido alkyl amines and dodecyl betaine, dodecyl dimethylamine
oxide, cocamidopropyl betaine, cocamidopropyl hydroxysultaine,
sodium lauroamphoacetate, cocoamphoglycinate or sodium
cocoamphoacetate. A further preferred group of classes of
surfactants are alkyl sulphates, alkyl ether sulphates,
alpha-olefin sulphates, alkylsarcosinates and aryl-sulphonated
derivatives thereof.
[0043] Preferably, the surfactant comprises an anionic surfactant,
optionally in combination with other surfactants. Most preferably,
the surfactant comprises an alkali metal sulphate, such as sodium
lauryl sulphate and/or sodium dodecyl sulphate.
[0044] Preferably, when present, the anhydrous composition
comprises from 1-20% by weight surfactant, further preferably from
1% to 10% by weight, more preferably from 3% to 15% by weight and
most preferably from 4% to 10% by weight surfactant.
[0045] In one embodiment, the present invention provides an
anhydrous composition comprising [0046] (a) 1% to 5% by weight
salicylic acid; [0047] (b) 10% to 35% by weight magnesium chloride;
[0048] (c) 4% to 10% by weight surfactant; and [0049] (d) 50% to
85% by weight carrier.
[0050] Further preferably, the anhydrous composition consists
essentially of the above ingredients.
[0051] In one embodiment of the present invention, the aqueous
composition is a cleansing composition comprising a surfactant. The
surfactant may be an anionic, non-ionic, cationic and
zwitterionic/amphoteric surfactant. Any conventionally used
pharmaceutically and cosmetically acceptable surfactant may be used
and these will be known to the person skilled in the art.
Particular surfactants may be as described above with respect to
the anhydrous composition. Preferably, the surfactant comprises an
anionic surfactant and/or a non-ionic surfactant. Preferred
materials include lauryl or laureth sulphates (such as sodium or
triethanolamine lauryl/laureth sulphates) and polypropyleneglycols,
polyethylene glycols and derivatives thereof.
[0052] In preferred compositions, it is desired that the total
surfactant concentration in the aqueous and anhydrous compositions
when combined to provide the formulation, is sufficient such that
when rubbed into the skin, a foam is produced which can be rinsed
off the skin.
[0053] The aqueous and anhydrous compositions may also include
other skincare ingredients as desired, for example emollients,
humectants, film formers, cooling agents, soothing agents,
anti-inflammatories.
[0054] In particular, the anhydrous and aqueous compositions may
also comprise thickening agents which increase the viscosity of the
composition. Examples include polyethylene glycols; polyoxyethylene
cetyl ethers; Acrylates/Vinyl Isodecanoate crosspolymer, polyamide
resins such as Sylvaclear (tradename), lanolin, stearyl alcohol and
salt.
[0055] In one embodiment, the present invention provides an aqueous
composition comprising [0056] (a) 1% to 5% by weight salicylic
acid; [0057] (b) 5% to 85% by weight surfactant; and [0058] (c) 10%
to 94% by weight water.
[0059] Further preferably, the aqueous composition consists
essentially of the above ingredients.
[0060] Preferably, when present, the anhydrous and/or aqueous
compositions comprise from 1-20% by weight thickener, more
preferably from 2% to 15% by weight and most preferably from 3% to
10% by weight thickener.
[0061] The aqueous and anhydrous compositions provided in
accordance with the present invention are suitably in the form of a
liquid or a gel, preferably as a viscous liquid.
[0062] In accordance with the present invention, the anhydrous and
aqueous compositions may comprise other conventional ingredients,
such as anti-microbial agents, sequestering agents, colouring
agents and perfumes. Such ingredients and the amounts in which they
are incorporated in the composition are within the knowledge of
those skilled in the art.
[0063] The present invention also provides an acne treatment
package for storing and dispensing the above described aqueous and
anhydrous compositions onto the skin. The package comprises a first
chamber and a second chamber, each chamber having an outlet
thereto, wherein said anhydrous composition is stored in said first
chamber and said aqueous composition is stored in said second
chamber, said compositions being stored in isolation from each
other and being arranged to be combined after passing though said
respective outlets onto the skin. On combination of the
compositions, heat is generated, effective to raise the temperature
of the skin.
[0064] In expelling a portion of the contents of the package, each
composition passes through the outlet of the chamber in which it is
stored. The outlets may be adjacent so that on expelling the
compositions from the package at the same time, they may be
combined after they pass through the outlets onto the skin. It may
be desired however to expel the compositions separately, for
example to apply one composition and then target the second
composition in the area of the first composition. In this case it
is not necessary that the outlets of each chamber are near to each
other. Although a heating effect is obtained as soon as the water
comes into contact with the component that generates heat on
contact with water, it is preferred to mix the compositions by
rubbing them into the skin.
[0065] In one embodiment, the package further comprises a
dispensing nozzle through which the combined compositions are
dispensed onto the skin. The aqueous and anhydrous compositions may
be combined in the dispensing nozzle or a chamber leading thereto
and then targeted onto the affected area of the skin.
[0066] In one embodiment the package comprises a receptacle
partitioned into first and second chambers. Preferably, the package
comprises a dispensing nozzle in which the aqueous and anhydrous
compositions may be combined before being expelled onto the
skin.
[0067] In another embodiment the package comprises a tube
comprising an anhydrous or aqueous composition and an inner tube
comprising the other of said anhydrous or aqueous composition.
Suitably, the inner tube is encompassed within an outer tube which
forms the packaging.
[0068] Preferably, the package is squeezable to expel said
anhydrous or aqueous compositions.
[0069] It will be appreciated that a method according to the
invention, including a method of treating acne comprising the
topical administration of an acne active ingredient in the presence
of a component that in the presence of water generates heat, may be
a therapeutic method, but will often be a primarily cosmetic
method, the objective of which is to reduce or eliminate externally
visible, and often unsightly, symptoms of acne.
[0070] The invention will now be described in more detail, by way
of illustration only, with reference to the accompanying
drawings.
[0071] In the drawings:
[0072] FIG. 1 shows a side view of a package comprising an inner
tube containing a first composition located within a clear outer
tube containing a second composition;
[0073] FIG. 2 shows a perspective view of one end of a tube
comprising a first dispensing nozzle;
[0074] FIG. 3 shows an end view of a second dispensing nozzle;
[0075] FIG. 4 shows a sectional view of a partitioned package
comprising first and second chambers;
[0076] FIG. 5 shows an expanded perspective view of the dispensing
nozzle from a partitioned package.
[0077] Referring firstly to FIG. 1, an acne treatment package (2)
for dispensing first and second compositions onto the skin
comprises an outer tube (4) which provides a first chamber and an
inner tube (6) which provides a second chamber, the contents of the
first chamber being isolated from the second chamber. The outer
tube has a cap (8).
[0078] An aqueous composition which comprises an acne active
ingredient is stored in said first (outer) chamber and an anhydrous
composition which comprises an acne active ingredient and a
component that in the presence of water generates heat on the skin
is stored in said second (inner) chamber.
[0079] In another embodiment, the anhydrous composition is present
in the outer tube and the aqueous composition is present in the
inner tube.
[0080] In a further embodiment, the acne active ingredient is
present in either one of the anhydrous or aqueous compositions.
[0081] In a further embodiment, at least one surfactant is present
in either one of or both of the anhydrous and aqueous
compositions.
[0082] Referring to FIG. 2, the package comprises a neck which
forms a dispensing nozzle (10). The inner tube has an outlet
leading into a central channel (12) of the dispensing nozzle. The
outer tube has an outlet leading to a plurality of openings (14)
around the periphery of the dispensing nozzle.
[0083] In use, the dispensing nozzle (10) is placed on or near the
affected area of the skin and the outer and inner tubes squeezed
simultaneously. The anhydrous composition is expelled through the
central channel (12) and the aqueous composition is expelled from
the plurality of openings (14). As the compositions are expelled
from the package they are combined as they pass onto the skin. The
combined compositions are rubbed together into the skin which
causes heat to be generated. The combined formulation is then
rinsed from the skin.
[0084] FIG. 3 shows an embodiment where the central passage (12) is
enlarged towards the periphery of the dispensing nozzle and allows
a greater amount of the composition in the inner tube to be
expelled at a given time in relation to the amount of composition
expelled from the openings (14) in the outer tube.
[0085] FIG. 4 shows a section view of a partitioned package (16)
providing first (18) and second (20) chambers. The anhydrous
composition is stored in the first chamber (18). The aqueous
composition is stored in the second chamber (20).
[0086] FIG. 5 shows a perspective view of one end of the
partitioned package (16) which is in the form of a tube. The
package comprises a neck which forms a dispensing nozzle (22). The
dispensing nozzle is divided down the middle to form two
semi-circular channels. A first channel connects the first chamber
(18) with a dispensing aperture (24). A second channel connects the
second chamber (20) with a dispensing aperture (26).
[0087] When it is desired to apply the combined compositions to the
skin, the dispensing nozzle (10) is placed on or near the affected
area of the skin and the tube (16) squeezed. The anhydrous
composition is expelled from the aperture (24) and the aqueous
composition is expelled from the aperture (26). As the compositions
are expelled from the package they are combined as they pass onto
the skin. The combined compositions are rubbed together into the
skin which causes heat to be generated. The combined formulation is
then rinsed from the skin.
[0088] In the following examples, there are described several
preferred embodiments to illustrate the invention. However, it is
to be understood that the invention is not to be limited to the
specific embodiments.
[0089] In the examples, the ingredients are available as follows;
Carrier.sup.1 is a blend of mineral oil and
ethylene/propylene/styrene copolymer and butylene/ethylene/styrene
copolymer is available from Penreco under the trade name Versagel
M-1600; Carrier.sup.2 is a blend of mineral oil and
ethylene/propylene/styrene copolymer and butylene/ethylene/styrene
copolymer and is available from Penreco under the trade name
Versagel R-500; Thickener.sup.1 is a combination of Glyceryl
Dibehenate, Tribehenin and Glyceryl Behenate and is available form
Gattefosse under the tradename Compritol ATO 888; Thickener.sup.2
is polyoxyethylene cetyl ether available under the tradename Brij
56; Acrylates/Vinyl Isodecanoate crosspolymer is available from 3V
under the tradename Stabylen-30; The polyamide resin is available
from Arizona Chemical under the tradename Sylvaclear AF1900V;
Triethanolamine laureth sulphate (TEA-LS) is available under the
tradename Sunform-T7; cocamidopropyl betaine is available under the
trade name Incronam 30; PEG-150 is available under the tradename
Crothix liquid; PEG-150 Pentaerythrityl Tetrastearate is available
from Crothix;
[0090] Any one of the heating compositions illustrated below may be
combined with any of the aqueous compositions illustrated below.
The compositions are rubbed together on the skin and after a
desired period may be rinsed off.
Heating Compositions
[0091] The ingredients listed in each example below were combined
by mixing according to conventional methods.
EXAMPLES 1-4
TABLE-US-00001 [0092] Examples Materials 1 2 3 4 Carrier.sup.1
38.5%.sup. 38.5%.sup. -- -- Carrier.sup.2 -- -- 38.5%.sup.
38.5%.sup. Light 45% 45% 45% 45% Mineral oil Salicylic 1.5% 1.5%
1.5% 1.5% acid MgCl.sub.2 15% -- 15% -- Zeolite -- 15% -- 15%
EXAMPLES 5-10
TABLE-US-00002 [0093] Examples Materials 5 6 7 8 9 10 Carrier.sup.2
38.5%.sup. .sup. 25% 15.5%.sup. 15.5%.sup. -- 13% Light 25% 31.8%
60% 60% 33.5%.sup. 35% Mineral oil Salicylic 1.5% 1.5% 1.5% 1.5%
1.5% 1.5% acid Butylene 20% 26.7% -- -- 30% 15.5%.sup. glycol
Thickener.sup.1 -- -- 8% 8% -- -- MgCl.sub.2 15% .sup. 15% -- 15%
-- -- Zeolite -- -- 15% -- 15% 15% PEG-8 -- -- -- -- 10% 10%
Thickener.sup.2 -- -- -- -- 10% 10%
EXAMPLES 11-14
TABLE-US-00003 [0094] Examples Materials 11 12 13 14 Carrier.sup.2
13.5%.sup. 13.5%.sup. 7% -- Light -- -- 68.5% 60.5% Mineral oil
Salicylic 1.5% 1.5% 1.5%.sup. 1.5% acid Butylene 50% 45% -- glycol
Thickener.sup.1 -- -- 8% 8% Zeolite 15% 30% 15% .sup. 30% PEG-8 10%
5% -- -- Brij 56 10% 5% -- --
EXAMPLES 15-17
TABLE-US-00004 [0095] Examples Materials 15 16 17 Salicylic acid
1.5% 1.5% 1.5% Butylene glycol 40% 26% 25% Glycerine 26% 40% 40%
Acrylates/Vinyl -- -- 1% Isodecanoate crosspolymer Zeolite 25% 25%
25% PEG-8 7.5% 7.5% 7.5%
EXAMPLES 18-20
TABLE-US-00005 [0096] Examples Materials 18 19 20 Salicylic acid
1.5% 1.5% 1.5% Butylene glycol 38.5%.sup. -- -- Light mineral oil
-- 59.5% 45.5%.sup. Carrier.sup.1 -- -- 15% MgCl.sub.2 35% .sup.
35% 35% PEG-8 5% -- -- polyamide resin 5% -- -- Polypropylene
glycol (PPG)-14 15% -- -- Thickener.sup.1 -- 4% 3%
EXAMPLES 21-25
TABLE-US-00006 [0097] Examples Materials 21 22 23 24 25 Salicylic
acid 1.5% 1.5% 1.5% 1.5% 1.5% Carrier.sup.1 27.5%.sup. 15% 15% 15%
15% Thickener.sup.1 6% 2.7% 8.2% 3% 6% Mineral oil 40% 45% 40% 45%
42.5%.sup. MgCl.sub.2 25% 35% 35% 35% 35% Fragrance -- 0.3% 0.3% --
--
EXAMPLES 26-28
TABLE-US-00007 [0098] Materials 26 27 28 Salicylic acid 1.5% 1.5%
1.5% Carrier.sup.1 15% 10% 10% Thickener.sup.1 -- 2.5% -- Mineral
oil 43.5%.sup. 48.5% 43.5%.sup. Sodium Dodecyl Sulfate 5% 2.5% 10%
MgCl.sub.2 35% 35% 35%
EXAMPLES 29-30
TABLE-US-00008 [0099] Materials 29 30 Salicylic acid 2% 2%
Carrier.sup.1 15% 30% Mineral oil 48% 43% Sodium Dodecyl Sulfate 5%
5% MgCl.sub.2 30% 20%
Aqueous Cleansing Compositions
[0100] The ingredients listed in each example below were combined
by mixing according to conventional methods.
EXAMPLES 31-34
TABLE-US-00009 [0101] Examples Materials 31 32 33 34 Water 27% 20%
25% 25% Salicylic acid 1.5% 1.5% 1.5% 1.5% Butylene glycol 15% --
-- -- Polyamide resin 3% -- -- -- Glycerol -- 25% 15% 15% Ethanol
45% 45% 45% 45% Menthol (L) 3.5% -- 3.5% -- Menthol (D/L) -- 3.5%
-- 3.5% TEA - Laureth Sulphate -- -- 5% 5% PEG - 8 5% 5% 5% 5%
EXAMPLES 35-40
TABLE-US-00010 [0102] Examples Materials 35 36 37 38 39 40
Salicylic acid 2% 2% 2% 2% 2% 2% Butylene glycol 35% 30% 20% 22% --
35% Glycerol 25% 20% 30% 30% 40% 25% PEG-7 glyceryl cocoate 2.5%
2.5% 4% 3% 2% 2% PEG-150 Pentaerythrityl 5% 5% 4% 4% 10% 3%
Tetrastearate PEG-8 2.5% 2.5% 4% 3% 2% 3% polyamide resin 5% 15% 3%
-- -- -- PPG -14 butyl ether -- -- 10% 13% 13% -- Water 13% 13% 13%
3% 21% 20% Sodium Lauryl Sulphate 10% 10% 10% 20% 10% -- (30% in
water) Cocamidopropyl Betaine -- -- -- -- -- 10%
EXAMPLES 41-44
TABLE-US-00011 [0103] Examples Materials 41 42 43 44 Salicylic acid
2% 2% 2% 2% Butylene glycol 35% 35% 30% 30% Glycerol 20% 20% 20%
20% PEG-7 glyceryl cocoate 2% 2% 2% 2% PEG-8 2% 2% 2% 2% Hydrolysed
milk protein 0.2%.sup. 0.2%.sup. 0.2%.sup. 0.2%.sup. PPG -14 butyl
ether 10% 10% 5% 6% cocamidopropyl betaine -- 2.3%.sup. 2.9%.sup.
2.8%.sup. Sodium Lauryl Sulphate 7.5%.sup. 5.3%.sup. 6.7%.sup.
6.7%.sup. (30% in water) Lanolin -- -- 1% 0.5%.sup. Stearyl alcohol
-- -- 2% 1.5%.sup. Sodium Chloride 1% 1% 1% 1% PEG - 150 -- -- 3%
3% Water to 100% to 100% to 100% to 100%
EXAMPLES 45-49
TABLE-US-00012 [0104] Examples Materials 45 46 47 48 49 Butylene
Glycol 30% 30% 30% 30% 30% Glycerine 20% 20% 20% 20% 20% PEG-7 1.5%
.sup. 2% .sup. 2% 2.5% 2.5%.sup. PEG-8 1.5% .sup. 2% .sup. 2% 2.5%
2.5%.sup. PPG-14 6.5% 6.5% 6.5% .sup. 5% 5% Lanolin .sup. 2% .sup.
2% .sup. 2% .sup. 2% 2% Stearyl Alcohol -- -- -- 0.5% 1% PEG-150
3.5% 2.5% 2.5% .sup. 3% 3% Sodium lauryl 6.7% 6.7% 6.7% 6.1%
6.1%.sup. sulphate cocamidopropyl 2.8% 2.8% 2.8% 2.8% 2.8%.sup.
betaine NaCl .sup. 1% .sup. 1% .sup. 1% .sup. 1% 1% Salicylic Acid
.sup. 2% .sup. 2% .sup. 2% .sup. 2% 2% Hydrolysed Milk 0.2% 0.2%
0.2% 0.2% 0.2%.sup. Protein Water to 100% to 100% to 100% to 100%
to 100%
EXAMPLES 50-54
TABLE-US-00013 [0105] Examples Materials 50 51 52 53 54 Butylene
Glycol 22.5 22.5 22.5 12.5 12.5 Glycerine 15 15 15 5 5 PEG-7 2.3
2.3 2.3 2.5 2.5 PEG-8 2.3 2.3 2.3 1.5 1.5 PPG-14 3.8 3.8 3.8 3.8
3.8 Lanolin 0.4 0.4 0.4 -- -- Protanal LF 10/60 0.4 -- -- -- --
Carrageenan -- 0.4 1.5 -- -- Carbopol polymer -- -- -- 1 3.8
Crothix Solid -- -- -- 1.5 -- Sodium lauryl 6.5 6.5 6.5 5 2
sulphate Incronam 2.1 2.1 2.1 2.1 2.1 NaCl 0.4 0.4 0.4 0.8 0.8
Salicylic Acid 1.5 1.5 1.5 1.5 1.5 Hydrolysed Milk 0.2 0.2 0.2 0.2
0.2 Protein Colour qs qs qs qs qs Fragrance qs qs qs qs qs water to
100% to 100% to 100% to 100% to 100%
[0106] Amounts are shown in g
EXAMPLES 55-56
TABLE-US-00014 [0107] Examples Materials 55 56 Butylene Glycol:
6.0000 6.0000 Glycerine: 3.0000 3.0000 PEG-7 1.5000 1.5000 PEG-8
1.5000 1.5000 PPG-14 3.0000 3.0000 S.L.S 7.5000 6.3750 Arrowroot
3.0000 4.5000 Incronam 1.0500 1.0500 Water: 44.6250 44.2500 Sodium
chloride 0.7500 0.7500 Salicylic Acid 1.5000 1.5000 Hydrolysed Milk
Protein 1.5000 1.5000 Colour qs qs Fragrance qs qs
EXAMPLES 57-60
TABLE-US-00015 [0108] Examples Materials 57 58 59 60 Sodium
hydroxide (25%) 0.86 0.86 0.34 0.8625 Carbopol CC polymer 3.75 3.75
-- 11.2500 Glycerine 4.36 11.25 4.5 8.4375 PEG-7 1.125 1.125 13.5
0.8438 PEG-8 1.125 1.125 0.15 0.8438 S.L.S (27%) 7.5 -- 1.13
22.5000 S.D.S solid -- 15 1.13 -- Cocamidopropyl 7.5 -- 11.25 --
betaine (30%) Water added 47.2 40.31 11.25 28.6875 Salicylic Acid
1.5 1.5 29.25 1.5000 Colour 0.0002 0.0002 1.5 0.0002 Fragrance
0.075 0.075 0.0002 0.0750
EXAMPLES 61-62
TABLE-US-00016 [0109] Examples Materials 61 62 Glycerine: 2.25 2.25
Water: 43.67 43.67 NaCl 0.94 0.94 Salicylic Acid 1.5 1.5 Hydrolysed
Milk Protein 0.15 0.15 Colour 0.0003 0.0003 Fragrance 0.15 0.15
Sodium hydroxide @ 25% 0.14 0.14 Plantacare 818 UP 6 6 Texapon NSO
20.25 -- Plantapon 611C -- 20.25
EXAMPLES 63-64
TABLE-US-00017 [0110] Materials 63 64 Salicylic Acid 2 2 Colour qs
qs Fragrance qs qs Cocoglucoside (50%) 8 8 Glycerin 2.7 2.7 Salt
(NaCl) 1.2 Sodium Laureth-2 Sulphate 52 67.7 (27%) Levomenthol 0.1
-- Hydrolysed milk protein 0.2 Sodium chloride 1.1 Water to 100% to
100%
Test Method
Skin Preparation:
[0111] A sheet of vitro-skin was accurately cut using a guillotine
into 10 equal pieces. Each of these pieces was then numbered and
weighed before the addition of sebum. Sebum was added to the skin
as a solid that could be rubbed across the whole of the skin
surface (matte side) until the whole surface was covered
(.about.0.2 g). Each piece of skin was then weighed once more
before being placed in the hydration chamber.
[0112] The hydration chamber was prepared by adding a mixture of
Glycerine (44 g) and DI water (256 g) to the bottom of it. The skin
was then placed on the contained shelves and allowed to stand, with
the lid tightly in place for approximately 24 hours at ambient
conditions in order to ensure a realistic level of vitro-skin
hydration.
Cleansing Method
[0113] After 24 hours the lid was removed and cleansing tests were
carried out on the skin. For all tests, the vitro-skin was placed
on a foam surface to mimic the non-solidity of skin.
[0114] For all samples, 5 ml of DI water at room temperature was
accurately syringed onto the surface of the vitro-skin. This was
then massaged into the skin using a gloved finger with small
circular movements for ten seconds. Once this was done the test
sample was applied and massaged into the skin.
[0115] After cleansing all skin samples were thoroughly rinsed
until for a minimum of 30 seconds, or until all visible products
had been removed (as would be the case in a realistic
situation).
[0116] After cleansing, the vitro-skin was left to dry on the
shelves provided in the hydration chamber.
[0117] After 24 hours the skin was then re-weighed providing the
information that was required to then calculate the percentage of
sebum removed from each piece of vitro-skin.
[0118] All testing carried out on vitro-skin was repeated 5 times
for each variable.
[0119] The test samples were: [0120] A: Water [0121] B: Part
1--Anhydrous composition comprising mineral oil, surfactant,
magnesium chloride and salicylic acid (2% w/w) as illustrated
herein. Part 2--Aqueous cleansing composition comprising surfactant
and salicylic acid (2% w/w) as illustrated herein [0122] C: Aqueous
cleansing composition comprising surfactant and salicylic acid (2%
w/w) as illustrated herein
[0123] The test results were as follows:
TABLE-US-00018 Mass of Mass of Skin + Mass of % Mass of Skin +
Sebum After Sebum Sebum Standard Skin. Sebum Cleansing Removed
Removed Average Deviation Confidence A 0.601 0.798 0.705 0.093
47.2081 32.7214 12.5944 11.039280 0.599 0.808 0.779 0.029 13.8756
0.590 0.794 0.735 0.059 28.9216 0.568 0.762 0.697 0.065 33.5052
0.561 0.768 0.685 0.083 40.0966 B 0.581 0.782 0.668 0.114 56.7164
78.6322 5.29019 3.4561965 0.563 0.771 0.619 0.152 73.0769 0.565
0.754 0.608 0.146 77.2487 0.604 0.800 0.629 0.171 87.2449 0.598
0.783 0.630 0.153 82.7027 0.463 0.661 0.515 0.146 73.7374 0.457
0.637 0.503 0.134 74.4444 0.444 0.626 0.479 0.147 80.7692 0.467
0.679 0.522 0.157 74.0566 0.455 0.641 0.484 0.157 84.4086 C 0.617
0.830 0.704 0.126 59.1549 44.9166 13.0069 11.400818 0.580 0.790
0.670 0.120 57.1429 0.560 0.751 0.669 0.082 42.9319 0.577 0.758
0.693 0.065 35.9116 0.552 0.749 0.691 0.058 29.4416
* * * * *