Note: Descriptions are shown in the official language in which they were submitted.
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MILD, LEAVE-ON ANTIMICROBIAL COMPOSITIONS
TECHNICAL FIELD
The present invention relates to leave-on, topical antimicrobial compositions
which
provide improved antimicrobial effectiveness when they are applied to the
skin. Specifically,
the leave-on antimicrobial compositions of the invention provide provide
previously unseen
residual effectiveness against transient Gram negative bacteria, previously
unseen levels of
residual effectiveness against Gram positive bacteria, provide improved
immediate germ
reduction on the skin compared to prior art compositions.
BACKGROUND OF THE INVENTION
Human health is impacted by many microbial entities. Inoculation by viruses
and bacteria
cause a wide variety of sicknesses and ailments. Media attention to cases of
food poisoning,
strep infections, and the like is increasing public awareness of microbial
issues.
It is well known that the washing of hard surfaces, food (e.g. fruit or
vegetables) and skin,
especially the hands, with antimicrobial or non-medicated soap, can remove
many viruses and
bacteria from the washed surfaces. Removal of the viruses and bacteria is due
to the surfactancy
of the soap and the mechanical action of the wash procedure. Therefore, it is
known and
recommended that people wash frequently to reduce the spread of viruses and
bacteria.
Bacteria found on the skin can be divided into two groups: resident and
transient bacteria.
Resident bacteria are Gram positive bacteria which are established as
permanent microcolonies
on the surface and outermost layers of the skin and play an important, helpful
role in preventing
the colonization of other, more harmful bacteria and fungi.
Transient bacteria are bacteria which are not part of the normal resident
flora of the skin,
but can be deposited when airborne contaminated material lands on the skin or
when
contaminated material is brought into physical contact with it. Transient
bacteria are typically
divided into two subclasses: Gram positive and Gram negative. Gram positive
bacteria include
pathogens such as Staphylococcus aureus, Streptococcus pyogenes and
Clostridium botulinum.
Gram negative bacteria include pathogens such as Salmonella, Escherichia coli,
Klebsiella,
Haemophilus, Pseudomonas aeruginosa, Proteus and Shigella dysenteriae. Gram
negative
bacteria are generally distinguished from Gram positive by an additional
protective cell
membrane which generally results in the Gram negative bacteria being less
susceptible to topical
antibacterial actives.
Antimicrobial cleansing products have been marketed in a variety of forms, for
some time.
Forms include antibacterial soaps, hard surface cleaners, and surgical
disinfectants. Rinse-off
antimicrobial soaps have been formulated to provide bacteria removal during
washing.
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2
Antimicrobial liquid cleansers are disclosed in U.S. Patent Numbers:
4,847,072, Bissett et al.,
issued July I I, 1989, 4,939,284, Degenhardt, issued July 3, 1990 and
4,820,698, Degenhardt,
issued April 11, 1989-. Finally, these
traditional aritimicrobial soaps have been developed for use in a washing
process with water.
This limits their use to locations with available water.
Some of these traditional products, especially the hard surface cleaners,
surgical
disinfectants, and some alcohol-based leave-on lotions (e.g. Purellm), utilize
high levels of
alcohol and/or harsh surfactants which have been shown to dry out and irritate
skin tissues.
Ideal persona) cleansers should gently cleanse the skin, cause little or no
irritation, and_not leave
the skin overly dry after frequent use and preferably should provide a
moisturizing bereft to the
skin.
Leave-on, topical lotions, foams and gels have been used, in the past, to
moisturize skin,
along with a variety of other purposes. However, these leave-on compositions
provide minimal
antimicrobial effectiveness.
PC? application WO 92/18100, Keegan et al., published October 29, 1992 and PCT
application WO 95132705, Fujiwara. et al., published December 7, 1995 teach
liquid skin
cleansers comprising mild surfactants, antibacterial agents and acidic
compounds to buffer the
pH, which provide improved germ hostility. However, the use of the acid
compounds for only
pH adjustment therein, result in compositions which do not deliver the
undissociated acid
required to ~pcovide good aatimicrobia) effectiveness. 'Ibis situation is
compounded in Keegan
and Fujiwara by the preference of mild surfactants, including nonionic
surfactants. Neither
Keegan nor Fujiwsra teach the use of their compositions in a form which can be
used without
available water, e.g. a leave-on lotion. .
U.S. Palest Number 3,141,821. issued to Campesu July 21, 1964 and Irgasan DP
300
(Trichraam) technical literawte from Cibs-Giegy, Inc., "Basic Formulation for
Hand
Disinfectiaa 89142/01" teach the use of aaionie surfactants, antimicrobial
actives and acids in
aatibactaial skin clansas. However, the xla:yon of highly active surfactants
result in leave-
on eompositioas which are drying u~d hanlt to the skin. Here, also, neither
rcfen~ce teaches
the ux of aatimicrobial compositions in s form which can be used without
available water, e.g.
a a ksvc-on lotion.
Given the heahh impa~aaeg~ttixe bacteria lt'ke Surlmonella, Erclrtrichia cell
and
Slrigella ark of Gram positive fit like Staphylxoccirs a~reus, Streptococcus
pywgenu and
Closrridiran borulprurr:, it would be highly desirable to formulate leave-on,
topical antimicrobial
compositions which provide improved rrsidual effactivenas versus these
transient ~ Gram
negative bactais, improved residual effectiveness versus these resident and
transient Gram
positive bacteria, or provide improved immediate germ reduction on the skin
during application;
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3
which are also mild to the skin and which can be used without water. Existing
products have
been unable to deliver all of these benefits.
Applicants have found that leave-on, topical antimicrobial compositions which
provide
such mildness and antimicrobial effectiveness can be formulated by using known
antimicrobial
actives in combination with specific organic and/or inorganic acids as proton
donating agents,
and specific anionic surfactants, all of which are deposited on the skin. The
deposited proton
donating agent and anionic surfactant work in combination with the selected
active, to provide a
new level of hostility to bacteria contacting the skin.
SUMMARY OF THE INVENTION
The present invention relates to a leave-on antimicrobial composition
characterized in that
it comprises from 0.001% to 5% of an antimicrobial active; from 0.05% to 10%
of an anionic
surfactant; from 0.1 % to 10% of a proton donating agent; and from 0% to
99.85% of water;
wherein the composition is adjusted to a pH of from 3.0 to 6.0; wherein the
leave-on
antimicrobial composition has a Gram Negative Residual Effectiveness Index of
greater than
0.3; and wherein the leave-on antimicrobial composition has a Mildness Index
of greater than
0.3.
The present invention also relates to a leave-on antimicrobial cleansing
composition
which has a Gram Positive Residual Effectiveness Index of greater than 0.5. It
also relates to a
leave-on antimicrobial cleansing composition which has a One-wash Immediate
Germ
Reduction Index of greater than 1Ø
The present invention also relates to methods for decreasing the spread of
transient Gram
positive bacteria using the leave-on antimicrobial compositions described
herein.
DETAILED DESCRIPTION OF THE INVENTION
The leave-on antimicrobial compositions of the present invention are highly
efficacious
for providing residual antimicrobial effectiveness versus Gram negative
bacteria, residual
antimicrobial effectiveness versus transient Gram positive bacteria, or for
reducing the number
of germs on the skin; and are mild to the skin.
The term "leave-on antimicrobial composition" is used herein to mean products
suitable
for application to the human skin for the purpose controlling the growth and
viability of
transient bacteria on the skin.
By "residual effectiveness" it is meant that bacteria growth on a surface is
controlled for
some period of time following the washinglrinsing process.
The compositions of the present invention can also be useful for treatment of
acne. As
used herein "treating acne" means preventing, retarding and/or arresting the
process of acne
formation in mammalian skin.
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4
The compositions of the invention can also potentially be useful for providing
an
essentially immediate (i.e., acute) visual improvement in skin appearance
following application
of the composition to the skin. More particularly, the compositions of the
present invention are
useful for regulating skin condition, including regulating visible and/or
tactile discontinuities in
skin, including but not limited to visible and/or tactile discontinuities in
skin texture and/or
color, more especially discontinuities associated with skin aging. Such
discontinuities may be
induced or caused by internal and/or external factors. Extrinsic factors
include ultraviolet
radiation (e.g., from sun exposure), environmental pollution, wind, heat, low
humidity, harsh
surfactants, abrasives, and the like. Intrinsic factors include chronological
aging and other
biochemical changes from within the skin.
Regulating skin condition includes prophylactically andlor therapeutically
regulating
skin condition. As used herein, prophylactically regulating skin condition
includes delaying,
minimizing and/or preventing visible and/or tactile discontinuities in skin.
As used herein,
therapeutically regulating skin condition includes ameliorating, e.g.,
diminishing, minimizing
and/or effacing, such discontinuities. Regulating skin condition involves
improving skin
appearance and/or feel, e.g., providing a smoother, more even appearance
and/or feel. As used
herein, regulating skin condition includes regulating signs of aging.
"Regulating signs of skin
aging" includes prophylactically regulating and/or therapeutically regulating
one or more of
such signs (similarly, regulating a given sign of skin aging, e.g., lines,
wrinkles or pores,
includes prophylactically regulating and/or therapeutically regulating that
sign).
"Signs of skin aging" include, but are not limited to, all outward visibly and
tactilely
perceptible manifestations as well as any other macro or micro effects due to
skin aging. Such
signs may be induced or caused by intrinsic factors or extrinsic factors,
e.g., chronological aging
and/or environmental damage. These signs may result from processes which
include, but are not
limited to, the development of textural discontinuities such as wrinkles,
including both fine
superficial wrinkles and coarse deep wrinkles, skin lines, crevices, bumps,
large pores (e.g.,
associated with adnexal structures such as sweat gland ducts, sebaceous
glands, or hair follicles),
scaliness, flakiness and/or other forms of skin unevenness or roughness, loss
of skin elasticity
(loss and/or inactivation of functional skin elastin), sagging (including
puffiness in the eye area
and jowls), loss of skin firmness, loss of skin tightness, loss of skin recoil
from deformation,
discoloration (including undereye circles), blotching, sallowness,
hyperpigmented skin regions
such as age spots and freckles, keratoses, abnormal differentiation,
hyperkeratinization,
elastosis, collagen breakdown, and other histological changes in the stratum
corneum, denmis,
epidermis, the skin vascular system (e.g., telangiectasia or spider vessels),
and underlying
tissues, especially those proximate to the skin.
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All percentages and ratios used herein, unless otherwise indicated, are by
weight and all
measurements made are at 25°C, unless otherwise designated. The
invention hereof can
comprise, consist of, or consist essentially of, the essential as well as
optional ingredients and
components described therein.
I. INGREDIENTS
The leave-on antimicrobial compositions of the present invention comprise an
antimicrobial active, an anionic surfactant, and a proton donating agent.
These components are
selected so that the efficacy and mildness requirements hereinafter defined
for the compositions
herein are met. The selection of each component is necessarily dependent on
the selection of
each of the other components. For example, if a weak acid is selected as the
proton donating
agent, then in order to realize an efficacious composition, either a more
biologically active (but
possibly less mild) surfactant must be employed, and/or a high level of acid
within the
prescribed range must be used and/or a particularly efficacious active must be
employed.
Similarly, if a mild, but nonefficacious surfactant is employed, then a
stronger acid and/or a high
level of acid may be necessary to realize an efficacious composition. If a
harsh surfactant is
utilized, then a mildness agent may have to be utilized. Guidelines for the
selection of the
individual components are provided herein.
A. ANTIMICROBIAL ACTIVE
The leave-on antimicrobial composition of the present invention comprises from
0.001%
to 5%, preferably from 0.05% to 1%, more preferably from 0.05% to 0.5% and
more preferably
from 0.1% to 0.25%, by weight of the leave-on antimicrobial composition, of an
antimicrobial
active. The exact amount of antibacterial active to be used in the
compositions will depend on
the particular active utilized since actives vary in potency. Non-cationic
actives are required in
order to avoid interaction with the anionic surfactants of the invention.
Given below are examples of non-cationic antimicrobial agents which are useful
in the
present invention .
Pyrithiones, especially the zinc complex (ZPT)
Octopirox~
Dimethyldimethylol Hydantoin (Glydant~)
Methylchloroisothiazolinone/methylisothiazolinone (Kathon CG~)
Sodium Sulfite
Sodium Bisulfate
Imidazolidinyl Urea (German 115~)
Diazolidinyl Urea (Germaill II~)
Benzyl Alcohol
2-Bromo-2-nitropropane-1,3-diol (Bronopol~)
Formalin (formaldehyde)
Iodopropenyl Butylcarbamate (Polyphase P100~)
Chloroacetamide
Methanamine
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Methyldibromonitrile Glutaronitrile (1,2-Dibromo-2,4-dicyanobutane or
Tektamer~)
Glutaraldehyde
5-bromo-5-nitro-1,3-dioxane (Bronidox~)
Phenethyl Alcohol
o-Phenylphenol/sodium o-phenylphenol
Sodium Hydroxymethylglycinate (Suttocide A~)
Polymethoxy Bicyclic Oxazolidine (Nuosept C~)
Dimethoxane
Thimersal
Dichlorobenzyl Alcohol
Captan
Chlorphenenesin
Dichlorophene
Chlorbutanol
Glyceryl Laurate
Halogenated biphenyl Ethers
2,4,4'-trichloro-2'-hydroxy-diphenyl ether (Triclosan~ or TCS)
2,2'-dihydroxy-5,5'-dibromo-diphenyl ether
Phenolic Compounds
Phenol
2-Methyl Phenol
3-Methyl Phenol
4-Methyl Phenol
4-Ethyl Phenol
2,4-Dimethyl Phenol
2,5-Dimethyl Phenol
3,4-Dimethyl Phenol
2,6-Dimethyl Phenol
4-n-Propyl Phenol
4-n-Butyl Phenol
4-n-Amyl Phenol
4-tert-Amyl Phenol
4-n-Hexyl Phenol
4-n-Heptyl Phenol
Mono- and Poly-Alkyl and Aromatic Halophenols
p-Chlorophenol
Methyl p-Chlorophenol
Ethyl p-Chlorophenol
n-Propyl p-Chlorophenol
n-Butyl p-Chlorophenol
n-Amyl p-Chlorophenol
sec-Amyl p-Chlorophenol
n-Hexyl p-Chlorophenol
Cyclohexyl p-Chlorophenol
n-Heptyl p-Chlorophenol
n-Octyl p-Chlorophenol
o-Chloropheno!
Methyl o-Chlorophenol
Ethyl o-Chlorophenol
n-Propyl o-Chlorophenol
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n-Butyl o-Chlorophenol
n-Amyl o-Chlorophenol
tent-Amyl o-Chlorophenol
n-Hexyl o-Chlorophenol
n-Heptyl o-Chlorophenol
o-Benzyl p-Chlorophenol
o-Benxyl-m-methyl p-Chlorophenol
o-Benzyl-m, m-dimethyl p-Chlorophenol
o-Phenylethyl p-Chlorophenol
o-Phenylethyl-m-methyl p-Chloropheno)
3-Methyl p-Chlorophenol
3,5-Dimethyl p-Chlorophenol
6-Ethyl-3-methyl p-Chlorophenol
6-n-Propyl-3-methyl p-Chlorophenol
6-iso-Propyl-3-methyl p-Chlorophenol
2-Ethyl-3,5-dimethyl p-Chlorophenol
6-sec-Butyl-3-methyl p-Chlorophenol
2-iso-Propyl-3,5-dimethyl p-Chlorophenol
6-Diethylmethyl-3-methyl p-Chlorophenol
6-iso-Propyl-2-ethyl-3-methyl p-Chlorophenol
2-sec-Amyl-3,5-dimethyl p-Chlorophenol
2-Diethylmethyl-3,5-dimethyl p-Chlorophenol
6-sec-Octyl-3-methyl p-Chlorophenol
p-Chloro-m-cresol
p-Bromophenol
Methyl p-Bromophenol
Ethyl p-Bromophenol
n-Propyl p-Bromophenol
n-Butyl p-Bromophenol
n-Amyl p-Bromopheno)
sec-Amyl p-Bromophenol
n-Hexyl p-Bromophenol
Cyclohexyl p-Bromophenol
o-Bromophenol
tert-Amyl o-Bromophenol
n-Hexyl o-Bromophenol
n-Propyl-m,m-Dimethyl o-Bromophenol
2-PhenylPhenol
4-Chloro-2-methyl phenol
4-Chloro-3-methyl phenol
4-Chloro-3,5-dimethyl phenol
2,4-Dichloro-3,5-dimethylphenol
3,4,5,6-Terabromo-2-methylphenol
5-Methyl-2-pentylphenol
4-Isopropyl-3-methylphenol
Para-chloro-meta-xylenol (PCMX)
Chlorothymol
Phenoxyethanol
Phenoxyisopropanol
5-Chloro-2-hydroxydiphenylmethane
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8
Resorcinol and its Derivatives
Resorcinol
Methyl Resorcinol
Ethyl Resorcinol
n-Propyl Resorcinol
n-Butyl Resorcinol
n-Amyl Resorcinol
n-Hexyl Resorcinol
n-Heptyl Resorcinol
n-Octyl Resorcinol
n-Nonyl Resorcinol
Phenyl Resorcinol
Benzyl Resorcinol
Phenylethyl Resorcinol
Phenylpropyl Resorcinol
p-Chlorobenzyl Resorcinol
5-Chloro 2,4-Dihydroxydiphenyl Methane
4'-Chloro 2,4-Dihydroxydiphenyl Methane
5-Bromo 2,4-Dihydroxydiphenyl Methane
4' -Bromo 2,4-Dihydroxydiphenyl Methane
Bisphenolic Compounds
2,2'-Methylene bis (4-chlorophenol)
2,2'-Methylene bis (3,4,6-trichlorophenol)
2,2'-Methylene bis (4-chloro-6-bromophenol)
bis (2-hydroxy-3,5-dichlorophenyl) sulphide
bis (2-hydroxy-5-chlorobenzyl)sulphide
Benzoic Esters (Parabens)
Methylparaben
Propylparaben
Butylparaben
Ethylparaben
Isopropylparaben
Isobutylparaben
Benzylparaben
Sodium Methylparaben
Sodium Propylparaben
Halogenated Carbanilides
3,4,4'-Trichlorocarbanilides (Triclocarban~or TCC)
3-Trifluoromethyl-4,4'-dichlorocarbanilide
3,3',4-Trichlorocarbanilide
Another class of antibacterial agents, which are useful in the present
invention, are the so-
called "natural" antibacterial actives, referred to as natural essential oils.
These actives derive
their names from their natural occurrence in plants. Typical natural essential
oil antibacterial
actives include oils of anise, lemon, orange, rosemary, wintergreen, thyme,
lavender, cloves,
hops, tea tree, citronella, wheat, barley, lemongrass, cedar leaf, cedarwood,
cinnamon, fleagrass,
geranium, sandalwood, violet, cranberry, eucalyptus, vervain, peppermint, gum
benzoin, basil,
fennel, fir, balsam, menthol, ocmea origanum, Hydastis carradensis,
Berberidaceae daceae,
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9
Ratanhiae and Curcuma Tonga. Also included in this class of natural essential
oils are the key
chemical components of the plant oils which have been found to provide the
antimicrobial
benefit. These chemicals include, but are not limited to anethol, catechole,
camphene, carvacol,
eugenol, eucaiyptol, ferulic acid, farnesol, hinokitioi, tropolone, limonene,
menthol, methyl
salicylate, thymol, terpineol, verbenone, berberine, ratanhiae extract,
caryophellene oxide,
citroneliic acid, curcumin, nerolidol and geraniol.
Additional active agents are antibacterial metal salts. This class generally
includes salts of
metals in groups 3b-7b, 8 and 3a-Sa. Specifically are the salts of aluminum,
zirconium, zinc,
silver, gold, copper, lanthanum, tin, mercury; bismuth, selenium, strontium,
scandium, yttrium,
cerium, praseodymium, neodymium, promethum, samarium, europium, gadolinium,
terbium,
dysprosium. holmium, erbium, thulium, ytterbium, lutetium and mixtures
thereof.
Preferred antimicrobial agents for use herein are the broad spectrum actives
selected from
the group consisting of Triclosan~, Triclocarban~, Octopirox~, PCMX, ZPT,
natural essential
oils and their key ingredients, and mixtures thereof. The most prefcis~ed
antimicrobial active for
use in the present invention ,is Triclosan~.
B: ANIONIC SURFACTANT
The leave-on antimicrobial composition of the present invention comprise from
0.05% to
.10, preferably from 0:1 to 2%, and more preferably from 0.2% to I %, by
weight of the leave-on
composition, of an anionic surfactant. Without being limited by theory, it is
believed that the
anionic surfactant disrupts the lipid in the cell membrane of the bacteria.
The particular acid
used herein reduces the negative charges on the cell wall of the bacteria,
crosses through the cell
membrane, weakened by the surfactant, and acidifies the cytoplasm of the
bacteria. The
antimicrobial active can then pass more easily through the weakened cell wall,
and more
ef~lciently poison the bacteria.
Nonlimiting examples of anionic latheratg surfactants useful in the
compositions of the
present invention are disclosed in McCuutseocs's, l~tenu and Ernulsi~ers.
North American
edition ( I99Qj, published by The Manufa~etuting Confectioner Publishing Co.;
.MeCutcheon's,
Functional Materials, Nerds Amaicxrs Edition (1992); and U.S. Patent No.
3,929,678, to
Laughlin et al., issued December 30,1975,.
A wide variety of anionic surfactants are potentially useful herein.
Noniimiting examples
of anionic lathering surfactants include those selected from the group
consisting of alkyl and
alkyl ether sulfates, sulfated monoglycaides, sulfonated olefins, alkyl aryl
sulfonates, primary
or secondary alkasse sutfonates, alkyl suifosuccinates, aryl taurates, acyi
isethionates, ,alkyl
gtycerylether sulfonatr, sulfonatted methyl esters, suifonated fatty acids,
alkyl phosphates, acyl
glutamates, acyl sarcosinata, alkyl suifoalcetates, acylat~ed peptides, alkyl
ether carboxylates,
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acyl lactylates, anionic fluorosurfactants, and mixtures thereof. Mixtures of
anionic surfactants
can be used effectively in the present invention.
Anionic surfactants for use in the leave-on compositions include alkyl and
alkyl ether
sulfates. These materials have the respective formulae RIO-S03M and
R1(CH2H40)X
O-S03M, wherein RI is a saturated or unsaturated, branched or unbranched alkyl
group from 8
to 24 carbon atoms, x is I to 10, and M is a water-soluble cation such as
ammonium, sodium,
potassium, magnesium, triethanolamine, diethanolamine and monoethanolamine.
The alkyl
sulfates are typically made by the sulfation of monohydric alcohols (having
from 8 to 24 carbon
atoms) using sulfur trioxide or other known sulfation technique. The alkyl
ether sulfates are
typically made as condensation products of ethylene oxide and monohydric
alcohols (having
from 8 to 24 carbon atoms) and then sulfated. These alcohols can be derived
from fats, e.g.,
coconut oil or tallow, or can be synthetic. Specific examples of alkyl
sulfates which may be
used in the cleanser compositions are sodium, ammonium, potassium, magnesium,
or TEA salts
of iauryl or myristyl sulfate. Examples of alkyl ether sulfates which may be
used include
ammonium, sodium, magnesium, or TEA laureth-3 sulfate.
Another suitable class of anionic surfactants are the sulfated monoglycerides
of the form
R1C0-O-CH2-C(OH)H-CH2-O-S03M, wherein RI is a saturated or unsaturated,
branched or
unbranched alkyl group from 8 to 24 carbon atoms, and M is a water-soluble
cation such as
ammonium, sodium, potassium, magnesium, triethanolamine, diethanolamine and
monoethanolamine. These are typically made by the reaction of glycerin with
fatty acids
(having from 8 to 24 carbon atoms) to form a monoglyceride and the subsequent
sulfation of
this monoglyceride with sulfur trioxide. An example of a sulfated
monoglyceride is sodium
cocomonoglyceride sulfate.
Other suitable anionic surfactants include olefin sulfonates of the form RI
S03M, wherein
RI is a mono-olefin having from 12 to 24 carbon atoms, and M is a water-
soluble cation such as
ammonium, sodium, potassium, magnesium, triethanolamine, diethanolamine and
monoethanolamine. These compounds can be produced by the sulfonation of alpha
olefins by
means of uncomplexed sulfur trioxide, followed by neutralization of the acid
reaction mixture in
conditions such that any sultones which have been formed in the reaction are
hydrolyzed to give
the corresponding hydroxyalkanesulfonate. An example of a sulfonated olefin is
sodium
C I 4~C 16 alpha olefin sulfonate.
Other suitable anionic surfactants are the linear alkylbenzene sulfonates of
the form RI-
C6H4-S03M, wherein RI is a saturated or unsaturated, branched or unbranched
alkyl group
from 8 to 24 carbon atoms, and M is a water-soluble cation such as ammonium,
sodium,
potassium, magnesium, triethanolamine, diethanolamine and monoethanolamine.
These are
CA 02291249 2003-02-21
formed by the sulfonation of linear alkyl benzene with sulfur trioxide. An
example of this
anionic surfactant is sodium dodecylbenzene sulfonate.
Still other anionic surfactants suitable for this leave-on composition include
the primary or
secondary alkane sulfonates of the form R1S03M, wherein RI is a saturated or
unsaturated,
branched or unbranched alkyl chain from 8 to 24 carbon atoms, and M is a water-
soluble cation
such as ammonium, sodium, potassium, magnesium, triethanolamine,
diethanoiamine and
monoethanolamine. These are commonly formed by the sulfonation of paraffins
using sulfur
dioxide in the presence of chlorine and ultraviolet light or another known
sulfonation method.
The sulfonation can occur in either the secondary or primary positions of the
alkyl chain. An
example of an alkane sulfonate useful herein is alkali metal or ammonium C 13-
C 1 ~ paraffin
sulfonates.
Still other suitable anionic surfactants are the alkyl sulfosuccinates, which
include
disodium N-octadecylsulfosuccinamate; diammonium lauryl sulfosuccinate;
tetrasodium N-(1,2-
dicarboxyethyl}-N-octadecylsulfosuccinate; diamyl ester of sodium
sulfosuccinic acid; dihexyl
ester of sodium sulfosuccinic acid; and dioctyl. esters of sodium
sulfosuccinic acid.
Also useful are taurates which are based on taurine, which is also known as 2-
aminoethanesulfonic acid. Examples of taurates include N-alkyltaurines such as
the one
prepared by reacting dodecylamine with sodium isethionate according to the
teaching of U.S.
Patent .'.,b58,072 . Other examples based
flntaurine include the acyl taurines formed by the reaction of n-methyl
taurine with fatty acids
(having from 8 to 24 carbon atoms).
Another class of anionic surfactants suitable for use in the leave-on
composition are the
acyl isethionates. The aryl isethionstes typicslly have the formula R1C0-O-
CH2CH2S03M
wherein R1 is a sattuatod or unsaturated, branched or unbcanched alkyl group
having from 10 to
30 carbon atoms, and M is a cuion. These are typically formed by the reactioh
of fatty acids
(having from 8 to 30 carbon atoms) with as alkali metal isethionate.
Nonlimiting examples of
these aryl isahiooates include ammonium cocoyl isethionate, sodium cocoyl
isethionate,
sodium lauroyl isethioaate, and mixtures thereof.
Still otha suitable anionic surfactants are the alkylglyceryl ether sulfonates
of the form
R1-OCHZ-C(OH~I-CHZ-S03M, wheetin R1 is a saturated or unsaturated, branched or
unbranched alkyl group from 8 to 24 carbon atoms, and M is a water-soluble
canon such as
ammonium, sodium, potassium, magnesium, triethanolamine, diethanolamine and
monoethanolamine. These can be formed by the reaction of epichtorohydrin and
sodiuiti
bisulfite with fatty alcohols (hsving from 8 to 24 carbon atoms) or other
known methods. One
example is sodium cocoglyceryl etha sulfonate.
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WO 98/55081 PCT/US98/10978
12
Other suitable anionic surfactants include the sulfonated fatty acids of the
form R1-
CH(S04)-COOH and sulfonated methyl esters of the from R1-CH(S04)-CO-O-CH3,
where R1
is a saturated or unsaturated, branched or unbranched alkyl group from 8 to 24
carbon atoms.
These can be formed by the sulfonation of fatty acids or alkyl methyl esters
(having from 8 to 24
carbon atoms) with sulfur trioxide or by another known sulfonation technique.
Examples
include alpha sulphonated coconut fatty acid and lauryl methyl ester.
Other anionic materials include phosphates such as monoalkyl, dialkyl, and
trialkylphosphate salts formed by the reaction of phosphorous pentoxide with
monohydric
branched or unbranched alcohols having from 8 to 24 carbon atoms. These could
also be
formed by other known phosphation methods. An example from this class of
surfactants is
sodium mono or dilaurylphosphate.
Other anionic materials include acyl glutamates corresponding to the formula
R1C0-
N(COOH)-CH2CH2-C02M wherein RI is a saturated or unsaturated, branched or
unbranched
alkyl or alkenyl group of 8 to 24 carbon atoms, and M is a water-soluble
cation. Nonlimiting
examples of which include sodium iauroyl glutamate and sodium cocoyl
glutamate.
Other anionic materials include alkanoyl sarcosinates corresponding to the
formula
RICON{CH3)-CH2CH2-C02M wherein R1 is a saturated or unsaturated, branched or
unbranched alkyl or alkenyl group of 10 to 20 carbon atoms, and M is a water-
soluble canon.
Nonlimiting examples of which include sodium lauroyl sarcosinate, sodium
cocoyl sarcosinate,
and ammonium lauroyl sarcosinate.
Other anionic materials include alkyl ether carboxylates corresponding to the
formula Rl-
(OCH2CH2~-OCH2-C02M wherein R1 is a saturated or unsaturated, branched or
unbranched
alkyl or alkenyl group of 8 to 24 carbon atoms, x is 1 to 10, and M is a water-
soluble cation.
Nonlimiting examples of which include sodium laureth carboxyiate.
Other anionic materials include acyl lactylates corresponding to the formula
R1C0-[O-
CH(CH3)-CO]x-C02M wherein R1 is a saturated or unsaturated, branched or
unbranched alkyl
or alkenyl group of 8 to 24 carbon atoms, x is 3, and M is a water-soluble
cation. Nonlimiting
examples of which include sodium cocoyl lactylate.
Other anionic materials include the carboxylates, nonIimiting examples of
which include
sodium lauroyl carboxylate, sodium cocoyl carboxylate, and ammonium lauroyl
carboxylate.
Anionic flourosurfactants can also be used.
The chain length of the anionic surfactant of the present invention can range
from 8 to 24
carbon atoms, preferably from 10 to 18 carbon atoms and most preferably from
12 to 16 carbon
atoms. Without being limited by theory, it is believed that surfactants with a
chain length of 12
to 16 optimally interact with the biology of the cell membrane.
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WO 98/55081 PCT/US98/I0978
13
Any counter cation, M, can be used on the anionic surfactant. Preferably the
counter
cation is selected from the group consisting of sodium, potassium, ammonium,
monoethanolamine, diethanolamine, and triethanolamine. More preferably the
counter cation is
ammonium.
Two factors must be taken into account when selecting the surfactant or
surfactants to be
employed in the leave-on antimicrobial compositions herein: 1 ) the activity
of the surfactant
molecule at the cell membrane of the bacteria; and 2) the mildness of the
surfactant insofar as it
affects the Mildness Index (hereinafter described) for the antibacterial
composition.
Biological Activity/Mildness of Surfactant
In general, the higher the biological activity of the surfactant, the more
residual
effectiveness is provided by the composition comprising the surfactant.
Typically, however, the
biological activity of a surfactant and the mildness of a surfactant are
inversely proportional; the
higher the biological activity of the surfactant, the harsher the surfactant
and the lower the
biological activity of the surfactant, the milder the surfactant. Whether a
bioiogically active, but
harsh surfactant or a mild, but biologically inactive surfactant is desired
will, of course, depend
on (or influence) the selection of the other components.
The biological activity/mildness of a pure surfactant can measured directly
via a Microtox
Response Test hereinafter described in the Analytical Methods section and can
be reported as a
Microtox Response Index. By "pure surfactant" it is meant a chemical
composition consisting
essentially of a single surfactant entity, wherein the entity has essentially
one chain length, head
group and salt counter ion. From a standpoint of high biological activity,
preferred anionic
surfactants of the leave-on antimicrobial compositions of the present
invention have a Microtox
Response Index of less that 150, more preferably less than 100 and most
preferably less than 50.
From a standpoint of mildness, preferred anionic surfactants of the leave-on
antimicrobial
compositions of the present invention have a Microtox Response Index of
greater than 25, more
preferably greater than SO and most preferably greater than 100. Surfactants
with a Microtox
Response Index ranging from 25 to 150 are typically moderately biologically
active and
moderately mild.
For surfactant compositions which are mixtures of surfactants rather than pure
surfactants
(this includes "commercial grade" surfactants which typically comprise
mixtures of entities with
different chain lengths and potentially have higher levels of impurities), the
Microtox Response
Index for any individual surfactant component is not a reliable measurement of
biological
activity or mildness. In the case of mixtures, the Microtox Index of each
individual component
can be determined and the weighted average used as the Index for the mixture
if all the
individual components of the mixture are known. If the individual components
of a mixture are
CA 02291249 2003-02i 21
14
not known, then the primary head group and chain lengths of the surfactant
mixture are better
indicators of biological activity/mildness.
Anionic surfactants or mixtures of surfactants with a chain length primarily
in the range
of from 8 to 24 carbon atoms, preferably primarily from 10 to 18 carbon atoms
and most
preferably primarily from 12 to 16 carbon atoms are preferred from the
standpoint of high
biological activity. As used herein "primarily" means at least 50%. From a
standpoint of
mildness, it is preferable to minimize C12.
From the standpoint of biological activity, it is 'preferred that the head
group 'of the
anionic surfactant be less than I S Angstroms, preferably ltss than 10
Angstoms, and more
preferably less than 7 Angstoms. The "head group" is defined as the
hydrophilic portion (non-
hydrocarbon) of the anionic surfactant, measured from the first polar atom to
the end of the
molecule. The head group size is estimated from the Van der Waals radius of
the atoms arid the
configuration of the surfactant molecule. Head groups with sizes less than 7
Angstroms include
sulfates, sulfonates, and phosphates. From the standpoint of mildness, it is
preferred that the
head group size is greater than 7 Angstoms, and pr~erably greater than 10
Angstoms. Head
groups with sizes greater than 10 Angstroms include ethoxylated sulfates;
glyceryl ether
sulfonates, and isethionates. It is believed that as the head group size
increases, more stearic
hindrance at the cell wall prevents disruption by the surfactant and, thus,
biological activity is
dccrtased and mildness is increased.
The mildness of a surfactant or mixturt of surfactants can also be determined
by a number
of other known, conventional methods for measuring surfactant mildness. For
example, the
Bacreer Destruction Test set forth in T. J. Franz, J. Invest. ~ermatol.. 1975,
64, pp. 190-195 and
in U.S. Patent 4,673.525 to Small et al; issued June 16, 1987, -
is a way of measuring mildness of surfactants. In general, the milder
the surfaeiant, the less skin barrier that is dauoycd in the barrier
destruction test Skin barrier
des~trwtioo is measured by relative amount of radiotabeled water which passes
from the test
solution t3trvugit the skin epidermis into ttte physiological butler contained
in the diffusate
charttba. Surfactants having a Relative Skin Baaia Penetration Value of as
close to um as
possibk up w 75 are considerod mild for purposes herein. Surfactants having a
Relative Skin
Barrier Penetration Value of than 75 are considered harsh for purposes herein.
In order for the atttimicrobia! coatposition herein to be effective, oø~l the
biological
activity of ttte surfsctant and the mildness of the surfa,ctaat and acid
employed in the
composition must be taken into account
For example, ammonium lauryl sulfate, ALS, is very biologically active
(Microtox Index
= 1.0). Compositions comprising ALS are capable of prrnriding very effective
residual
antibacterial effectiveness due to its activity, even with Lower levels of
antibacterial active and
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WO 98/55081 PCT/US98/10978
proton donating agent. However, compositions containing ALS may require the
addition of co-
surfactants or polymers, described herein in the Optional Ingredient Section,
to achieve most
preferred mildness levels for the present invention.
A selection of ammonium laureth-3 sulfate (Microtox = 120) as a surfactant
will result in
compositions which are very mild, but which would require higher levels of
proton donating
agent and antimicrobial active in order to achieve the residual effectiveness
of the present
invention.
Paraffin sulfonate, a commercial grade surfactant sold under the name Hastapur
SAS~
from Hoechst Celanese, with a small head group and average chain length of
15.5 is a relatively
active surfactant. Compositions comprising lower levels of active and acid can
be used with
higher levels of paraffin sulfonate, where the surfactant provides a larger
component of residual
effectiveness. Alternately, compositions comprising lower levels of paraffin
sulfonate can be
combined with even higher levels of active to achieve a mild and effective
composition.
Nonlimiting examples of preferred anionic surfactants useful herein include
those selected
from the group consisting of sodium and ammonium alkyl sulfates and ether
sulfates having
chain lengths of predominantly I2 and 14 carbon atoms, olefin sulfates having
chain lengths of
predominantly 14 and 16 carbon atoms, and paraffin sulfonates having chain
lengths of from 13
to 17 carbon atoms, and mixtures thereof. Especially preferred for use herein
is ammonium and
sodium lauryl sulfate, ammonium and sodium myristyl sulfate, ammonium and
sodium laureth-1
to laureth-4 sulfate, C 14-C 16 olefin sulfonates, C 13-C 17 paraffin
sulfonates, and mixtures
thereof.
Non-anionic surfactants of the group consisting of nonionic surfactants,
cationic
surfactants, amphoteric surfactants and mixtures thereof, have been found to
actually inhibit
residual effectiveness benefits. It is believed that these surfactants
interfere with the anionic
surfactant disruption of the lipid in the cell membrane. The ratio of the
amount of these non-
anionic surfactants to the amount of anionic surfactant should be less than
1:1, preferably less
than 1:2, and more preferably less than 1:4.
The leave-on antimicrobial compositions of the present invention preferably do
not
comprise hydrotropic sulfonates, particularly salts of terpenoids, or mono- or
binuclear aromatic
compounds such as sulfonates of camphor, toluene, xylene, cumene and
naphthene.
C. PROTON DONATING AGENT
The leave-on antimicrobial composition of the present invention comprise from
0.1% to
10%, preferably from 0.5% to 8%, more preferably from 1% to 5%, based on the
weight of the
leave-on composition, of a proton donating agent. By "proton donating agent"
it is meant any
acid compound or mixture thereof, which results in undissociated acid on the
skin after use.
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WO 98/55081 PCT/US98/10978
16
Proton donating agents can be organic acids, including polymeric acids,
mineral acids or
mixtures thereof.
Organic Acids
Proton donating agents which are organic acids which remain at least partially
undissociated in the neat composition. These organic proton donating agents
can be added
directly to the composition in the acid form or can be formed by adding the
conjugate base of
the desired acid and a sufficient amount of a separate acid strong enough to
form the
undissociated acid from the base.
Buffering Capacity
Preferred organic proton donating agents are selected and formulated based on
their buffer
capacity and pKa. Buffer capacity is defined as the amount of protons (weight
%) available in
the formulation at the product pH for those acid groups with pKa's less than
6Ø Buffer capacity
can be either calculated using pKa's, pH, and the concentrations of the acids
and conjugate
bases, ignoring any pKa greater than 6.0, or it can be determined
experimentally through a
simple acid-base titration using sodium hydroxide or potassium hydroxide using
an endpoint of
pH equals 6Ø
Preferred organic proton donating agents of the antibacterial composition
herein have a
buffer capacity of greater than 0.005%, more preferably greater than 0.01%,
even more
preferably greater than 0.02%, and most preferably greater than 0.04%.
Mineral Acids
Proton donating agents which are mineral acids will not remain undissociated
in the neat
composition . Despite this, it has been found that mineral acids can be
effective proton donating
agents for use herein. Without being limited by theory, it is believed that
the strong mineral
acid, acidify the carboxylic and phosphatidyl groups in proteins of the skin
cells, thereby
providing in-situ undissociated acid. These proton donating agents can only be
added directly to
the composition in the acid form.
It is critical to achieving the benefits of the invention that the
undissociated acid from the
proton donating agent (deposited or formed in-situ) remain on the skin in the
protonated form.
Therefore, the pH of the leave-on antimicrobial compositions of the present
invention must be
adjusted to a sufficiently low level in order to either form or deposit
substantial undissociated
acid on the skin. The pH of the compositions should be adjusted and preferably
buffered to
range from 3.0 to 6.0, preferably from 3.0 to 5.0 and more preferably from 3.5
to 4.5.
A non-exclusive list of examples of organic acids which can be used as the
proton
donating agent are adipic acid, tartaric acid, citric acid, malefic acid,
malic acid, succinic acid,
glycolic acid, glutaric acid, benzoic acid, malonic acid, salicylic acid,
gluconic acid, polymeric
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WO 98/55081 PCT/~JS98/10978
17
acids, their salts, and mixtures thereof. A non-exclusive list of examples of
mineral acid for use
herein are hydrochloric, phosphoric, sulfuric and mixtures thereof.
Polymeric acids are especially preferred acids for use herein from the
standpoint that
they cause less stinging to the skin than other acids. As used herein, the
term "polymeric acid"
refers to an acid with repeating units of carboxylic acid groups joined
together into one chain.
Suitable polymeric acids can include homopolymers, copolymers and terpolymers,
but must
contain at least 30 mole% carboxylic acid groups. Specific examples of
suitable polymeric acids
useful herein include poly(acrylic) acid and its copolymers, both ionic and
nonionic, (e.g.,
malefic-acrylic, sulfonic-acrylic, and styrene-acrylic copolymers), those
cross-linked
poly(acrylic) acids having a molecular weight of less than 250,000, preferably
less than 100,000
poly (a-hydroxy) acids, poly (methacrylic) acid, and naturally occurring
polymeric acids such
as carageenic acid, carboxy methyl cellulose, and alginic acid. Straight-chain
poly(acryiic) acids
are especially preferred for use herein.
Water
The leave-on antimicrobial compositions of the present invention comprise from
0% to
99.85%, preferably from 3% to 98%, more preferably from 5% to 97.5%, and most
preferably
from 38% to 95.99% water.
Leave-on antimicrobial compositions of the present invention, preferably have
an
apparent or neat viscosity of from 500 cps to 60,000 cps at 26.7°C,
preferably 5,000 to 30,000
cps. The term "viscosity" as used herein means the viscosity as measured by a
Brookfield
RVTDCP with a spindle CP-41 at 1 RPM for 3 minutes, unless otherwise
specified. The "neat"
viscosity is the viscosity of the undiluted liquid cleanser.
E. PREFERRED OPTIONAL INGREDIENTS
Mildness Enhancers
In order to achieve the mildness required of the present invention, optional
ingredients to
enhance the mildness to the skin can be added. These ingredients include
cationic and nonionic
polymers, co-surfactants, moisturizers and mixtures thereof. Polymers useful
herein include
polyethylene glycols, polypropylene glycols, hydrolyzed silk proteins,
hydrolyzed milk proteins,
hydrolyzed keratin proteins, guar hydroxypropyltrimonium chloride, polyquats,
silicone
polymers and mixtures thereof. When used, the mildness enhancing polymers
comprise from
0.1% to 1%, preferably from 0.2% to I.0%, and more preferably from 0.2% to
0.6%, by weight
of the leave-on antimicrobial composition, of the composition. Co-surfactants
useful herein
include nonionic surfactants such as the Genapol~ 24 series of ethoxylated
alcohols, POE(20)
sorbitan monooleate (Tween~ 80), polyethylene glycol cocoate and Pluronic~
propylene
oxide/ethylene oxide block polymers, and amphoteric surfactants such as alkyl
betaines, alkyl
sultaines, alkyl amphoacetates, alkyl amphodiacetates, alkyl amphopropionates,
and alkyl
CA 02291249 2002-05-07
Ig
amphodipropionates. When used, the mildness enhancing cosurfactants comprise
from 20% to
70%, preferably from 20% to 50%, by weight of the anionic surfactant, of the
leave-on
composition.
Another group of mildness enhancers are lipid skin moisturizing agents which
provide a
moisturizing benefit to the user of the leave-on composition when the
lipophilic skin
moisturizing agent is deposited to the use>'s skin. When used in the
antimicrobial leave-on
compositions herein, lipophilic skin moisturizing agents are used, they are
employed at a level
of 0.1% to 30%, preferably from 0.2% to 10%, most preferably from 0.5% to S%
by weight of
the composition.
In some cases, the lipophilic skin moisturizing agent can desirably be defined
in terms of
its solubility parameter, as defined by VauQhan in Cosmetics and Toiletries,
Vol. 103, p. 47-69,
October 1988. A lipophilic skin moisturizing agent having a Vaughan solubility
Parameter
(VSP) from 5 to 10, preferably from S.S to 9 is suitable for use in the leave-
on antimicrobial
compositions herein.
A wide variety of lipid type materials and mixtures of materials are suitable
for use in the
leavo-on antimicrobial compositions of the present invention. Preferably, the
lipophilic skin
conditioning. agent is selected from the group consisting of hydrocarbon oils
and waxes, .
silicones, fatty acid derivatives, cholesterol, cholesterol derivatives, di
and tri-glycerides,
vegetable oils, vegetable oil derivatives, liquid nondigestible oils such as
those described ~n U.S.
Patents 3,600,186 to Mattson; Issued August 17, 1971 and 4,00S,195 and
4,00S,196 to Jandacek
et al; both issued January 25, 1977, or blends
of liquid digestible or nondigestible oils with solid polyol polyesters such
as those described in
U.S. Patent 4,797,300 to Jandacek; issued January 10, 1989; U.S Patents
5,306,5 I 4, 5,306,516
and 5,306,5 I S to Letton; all issued Aprit 26, 1994,
and acetoglyceride esters, alkyl esters, alkenyl esters, lanolin and its
derivatives, milk
tri-gly~oaides, wax ~" bxswax derivatives, sterols, phospholipids and mixtures
thereof:
Fatty acids, fatty acid soaps and water soluble polyols are specifically
excluded from our
definition of a lipophilic skia moisturizing agent.
~yø~rbon oils and waxes: Some examples are petrolawm, mineral oil micro-
crystalline waxes, potyalkenes (e_g. hydrogenated and nonhydrogenated
polybutene and
polyd~cene~, parafFtns, caasin, ozokerite, polyethylene and perhydrosqualene.
Blends of
petrolatum and hydrogenated and nonhydrogenated high molecular weight
polybutenes wherein
the ratio of petrolatum to polybutene ranges from 90:10 to 40:60 are also
suitable for use as the
lipid skin mois~rrizing agent in the compositions herein.
Silicone Oils: Some examples are dimethicone copolyol, dimethylpolysiloxane,
diethylpolysiloxane, high molecular weight dimethicone, mixed Ci-C30 alkyl
polysiloxane,
CA 02291249 2002-05-07
19
phenyl dimethicone, dimethiconol, and mixtures thereof. More preferred are non-
volatile
silicones selected from dimethicone, dimethiconol, mixed C1-C30 alkyl
polysiloxane, and
mixtures thereof. Nonlimiting examples of silicones useful herein are
described in U.S. Patent
No. 5,011,681, to Ciotti et al., issued April 30, 1991r
Di and tri-glycerides: Some examples are castor oil, soy beanoil, derivatized
soybean oils
such as maleated soy bean oil, safflower oil, cotton seed oil, corn oil,
walnut oil, peanut oil,
olive oil, cod liver oil, almond oil, avocado oil, palm oil and sesame oil,
vegetable oils and
vegetable oil derivatives; coconut oil and derivatized coconut oil, cottonseed
oil and derivatized
cottonseed oil, jojoba oil, cocoa butter, and the like.
Acetoglyceride esters are used and an example is acetylated monoglycerides.
Lanolin and its derivatives are preferred and some examples are lanolin,
lanolin oil,
lanolin wax, lanolin alcohols, lanolin fatty acids, isopropyl ianolate,
acetylated lanolin,
acetylated lanolin alcohols, lanolin alcohol linoleate, lanolin alcohol
riconoleate.
It is most preferred when at least 75 % of the lipophilic skin conditioning
agent is
comprised of lipids selected from the group consisting: petrolatum, blends of
petrolatum and
high molecular weight polybutene, mineral oil, liquid nondigestible oils (e.g.
liquid cottonseed
sucrose octacsters) or blends of liquid digestible or nondigestible oils with
solid polyol
polyesters (e.g. sucrose octaesters prepared from C22 fatty acids) wherein the
ratio of liquid
digestible or nondigestible oil to solid polyol polyester ranges from 96:4 to
80:20, hydrogenated
or nonhydrogenated polybutene, micro-crystalline wax, polyalkene, paraffin,
cerasin, ozokerite,
polyethylene, perhydrosqualenc, dimethicooa, alkyl siloxane,
potymethylsiloxanc,
methytphenylpoiysiloxane, and ~aixtura thereof. When as blend of petrolatum
and other lipids
is used, tire ratio of petrotswm to the othe selected lipids (hydrogenated or
unhydrogenated
polybutene or palydecene or mineral oil) is preferably from 10:1 to 1:2, more
preferably from
5:1 to 1:1.
Stabilizes .
a lipophilic skin moisturizing ageat is employed as the mildness enhancer in
the
antimicrobial compositions herein, a stabilize may also be included at a level
ranging from
0.1% to 10~°, preferably fran O.1W to 8'k, more preferably from 0.1% to
5°/v by wtight of the
leave-on antimicrobial composition.
The stabilize is used to form a crystalline stabilizing network in the leave-
on
composition that prevents the lipophilic skin moisturizer agent droplets from
coalescing and
phase splitting in the product The network exhibits time dependent recovery of
viscosity after
shearing (e.g., thixotropy).
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WO 98/55081 PCT/US98/10978
The stabilizers used herein are not surfactants. The stabilizers provide
improved shelf and
stress stability. Some preferred hydroxyl-containing stabilizers include 12-
hydroxystearic acid,
9,10-dihydroxystearic acid, tri-9,10-dihydroxystearin and tri-12-
hydroxystearin (hydrogenated
castor oil is mostly tri-12-hydroxystearin). Tri-12-hydroxystearin is most
preferred for use in
the compositions herein. When these crystalline, hydroxyl-containing
stabilizers are utilized in
the leave-on compositions herein, they are typically present at from 0. I % to
10%, preferably
from 0.1 % to 8%, more preferably from 0.1 % to 5% of the leave-on
antimicrobial compositions.
The stabilizer is insoluble in water under ambient to near ambient conditions.
Alternatively, the stabilizer employed in the leave-on compositions herein can
comprise a
polymeric thickener. When polymeric thickeners as the stabilizer in the leave-
on compositions
herein, they are typically included in an amount ranging from 0.01% to 5%,
preferably from
0.3% to 3%, by weight of the composition. The polymeric thickener is
preferably an anionic,
nonionic, cationic or hydrophobically modifier polymer selected from the group
consisting of
cationic polysaccharides of the cationic guar gum class with molecular weights
of 1,000 to
3,000,000, anionic, cationic, and nonionic homopolymers derived from acrylic
and/or
methacrylic acid, anionic, cationic, and nonionic cellulose resins, cationic
copolymers of
dimethyldialkylammonium chloride, and acrylic acid, cationic homopolymers of
dimethylalkylammonium chloride, cationic polyalklene, and ethoxypolyalkylene
imines,
polyethylene glycol of molecular weight from 100,000 to 4,000,000, and
mixtures thereof.
Preferably, the polymer is selected from the group consisting of sodium
poiyacrylate, hydroxy
ethyl cellulose, cetyl hydroxy ethyl cellulose, and Polyquaternium 10.
Alternatively, the stabilizer employed in the leave-on compositions herein can
comprise
C10-C22 ethylene glycol fatty acid esters. C10-C22 ethylene glycol fatty acid
esters can also
desirably be employed in combination with the polymeric thickeners
hereinbefore described.
The ester is preferably a diester, more preferably a C 14-C I 8 diester, most
preferably ethylene
glycol distearate. When C10-C22 ethylene glycol fatty acid esters are utilized
as the stabilizer
in the leave-on compositions herein, they are typically present at from 3% to
10%, preferably
from 5% to 8%, more preferably from 6% to 8% of the leave-on compositions.
Another class of stabilizer which can be employed in the leave-on
antimicrobial
compositions of the present invention comprises dispersed amorphous silica
selected from the
group consisting of fumed silica and precipitated silica and mixtures thereof.
As used herein the
term "dispersed amorphous silica" refers to small, finely divided non-
crystalline silica having a
mean agglomerate particle size of less than 100 microns.
Fumed silica, which is also known as arced silica, is produced by the vapor
phase
hydrolysis of silicon tetrachloride in a hydrogen oxygen flame. It is believed
that the
combustion process creates silicone dioxide molecules which condense to form
particles. The
CA 02291249 2002-05-07
21
particles collide, attach and sinter together. The result of this process is a
three dimensional
branched chain aggregate. Once the aggregate cools below the fusion point of
silica, _which is
1710°C, further collisions result in mechanical entanglement of the
chains to form agglomerates.
Precipitated silicas and silica gels are generally made in aqueous solution.
See, Cabot Technical
Data Pamphlet TD-100 entitled "CAB-O-SILO Untreated Fumed Silica Properties
and
Functions", October 1993, and Cabot Technical Dat Pamphlet TD-104 entitled
"CAB-O-SILO
Fumed Silica in Cosmetic and Personal Care Products", March 1992.
The fumed silica preferably has a mean agglomerate particle size ranging from
0.1
microns to 100 microns, preferably from 1 micron to 50 microns, and more
preferably from 10
microns to 30 microns. The agglomerates arc composed of aggregates which have
a mean
particle size ranging from _0.01 microns to 15 microns, preferably from 0.05
microns to 10
microns, more preferably from 0.1 microns to 5 microns-and most preferably
from 0.2 microns
to 0.3 microns. The silica preferably has a surface area greater than SO sq.
m/gram, more
preferably greater than 130 sq. mJgram, most preferably greater than 180 sq.
mJgram.
When amorphous silicas are used as the stabilizer herein, they are typically
included in
the leave-on compositions at levels ranging from 0.1% to 10%, preferably from
0.25% to 8%,
more preferably from 0.5% to 5%.
A fourth class of stability which can be employed in the leave-on
antimicrobial
compositions of the present invention comprises dispersed smcctite clay
selected from the group
consisting of bentoaite and hectorite and mixtures thereof. Bentonite is a
colloidal aluminum
clay sulfate. See Merck Index, Eleventh Edition, 1989, entry 1062, p. 164,
Hectorite is a clay containing sodium, magnesium; lithium, silicon,
oxygen, hydrogen and flourine. See Merck Index, eleventh Edition, 1989, entry
4538, p. 729.
What smectite clay is anployed as the stabilizer in the leave-on composirions
of the
iavamion, it is typically included in amounts ranging from 0.1 % to~10%,
preferably from
0.25Yo to 8'/., more preferably from OS% to 5%.
Other known stabilizers, wch as fatty acids and fatty alcohols, can also be
anployed in
the compositions 6aria. Palmitic acid and lauric acid arc especially preferred
for use herein.
Other Optional InQredieats
The compositions of the present invention can comprise a wide range of
optional
ingredierns. 'i?te f,~'iFA International Cosmetic Instredient Dictionary Sixth
Edition, 1995,
describes a wide variety of nonlimiting
cosmetic and pharmaceutical iagrodients commonly used in the skin care
industry, which are
suitable for rue in the compositions of the present invention. Nonlimiting
examples of
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functional classes of ingredients are described at page 537 of this reference.
Examples of these
functional classes include: abrasives, anti-acne agents, anticaking agents,
antioxidants, binders,
biological additives, bulking agents, chelating agents, chemical additives,
colorants, cosmetic
astringents, cosmetic biocides, denaturants, drug astringents, emulsifiers,
external analgesics,
film fonmers, fragrance components, humectants, opacifying agents,
plasticizers, preservatives,
propellants, reducing agents, skin bleaching agents, skin-conditioning agents
(emollient,
humectants, miscellaneous, and occlusive), skin protectants, solvents, foam
boosters,
hydrotropes, solubilizing agents, suspending agents (nonsurfactant), sunscreen
agents,
ultraviolet light absorbers, and viscosity increasing agents (aqueous and
nonaqueous).
Examples of other functional classes of materials useful herein that are well
known to one of
ordinary skill in the art include solubilizing agents, sequestrants, and
keratolytics, and the like.
II. CHARACTERISTICS
The leave-on antimicrobial compositions herein, have the following
characteristics.
A. BACTERIAL EFFECTIVENESS
The rinse of antimicrobial cleansing compositions of the present invention
have one of
three characteristics of bacterial effectiveness.
Gram Negative Residual Effectiveness Index
The leave-on antimicrobial compositions of the present invention have a Gram
Negative
Residual Effectiveness Index of greater than about 0.3 (50% reduction),
preferably greater than
about 1.0 (90% reduction), and more preferably greater than about 2.0 (99%
reduction). The
Gram Negative Residual Effectiveness Index is measured by the In-Vivo Residual
Effectiveness
on Escherichia toll Test described hereinafter in the Analytical Methods
Section. The index
represents a difference in base ten logarithm values of bacterial
concentrations between a test
sample and a control. For example, an index of 0.3 represents a reduction in
log values of 0.3 (0
log = 0.3) which in turn represents a 50% reduction of bacteria counts.
Gram Positive Residual Effectiveness Index
The leave-on antimicrobial compositions of the present invention comprise a
Gram
Positive Residual Effectiveness Index of greater than 0.5 (68% reduction),
preferably greater
than 1.0 (90.0% reduction), more preferably greater than 2.0 (99% reduction),
and most
preferably greater than 2.3 (99.5% reduction). The Gram Positive Residual
Effectiveness Index
is measured by the In-Vivo Residual Effectiveness on Staphylococcus aureus
Test described
herein. The index represents a difference in base ten logarithm values of
bacterial
concentrations between a test sample and a placebo control. For example, an
index of 1.0
represents a reduction in log values of 1.0 (olog = 1.0) which in turn
represents a 90.0%
reduction of bacteria counts.
Immediate Germ Reduction Indexes
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The leave-on antimicrobial compositions provide improved immediate germ
reduction.
The degree of reduction can be measured after one-wash (application) of the In-
Vivo Health
Care Personal Handwash Test described herein. When measured after one wash the
leave-on
antimicrobial composition has One-wash Immediate Germ Reduction Index of
greater than
about 1.0 (90% reduction), preferably greater than about 1.5 (96.8%
reduction), more preferably
greater than about 2.0 (99% reduction), and most preferably greater than about
2.3 (99.5%
reduction). The index represents a difference in base ten logarithm values of
bacterial
concentrations between before and after washing. For example, an index of 1.0
represents a
reduction in log values of I.0 (olog = 1.0) which in turn represents a 90%
reduction of bacteria
counts.
B. MILDNESS -Mildness Index
The leave-on antimicrobial compositions of the present invention comprise a
Mildness
Index of greater than 0.3, preferably greater than 0.4, and more preferably
greater than 0.6. The
Mildness Index is measured by the Forearm Controlled Application Test (FCAT)
described
herein.
III. METHODS OF MANUFACTURE OF THE LEAVE-ON ANTIMICROBIAL
COMPOSITIONS
The Leave-on antimicrobial compositions of the present invention are made via
art
recognized techniques for the various forms of leave-on products.
IV. METHODS OF USING THE LEAVE-ON ANTIMICROBIAL COMPOSITION
The leave-on antimicrobial compositions of the present invention are useful
for
controlling the spread of Gram positive bacteria over time. Typically, a
suitable or effective
amount of the composition is applied to the area to be treated. Alternatively,
a suitable amount
of the cleansing composition can be applied via intermediate application to a
washcloth, sponge,
pad, cotton ball, puff or other application device. Generally, an effective
amount of product to
be used will depend upon the needs and usage habits of the individual. Typical
amounts of the
present compositions useful for cleansing range from 0.1 mg/cm2 to 10 mg/cm2,
preferably
from 0.6 mg/cm2 to 5 mg/cm2 skin area to be cleansed.
ANALYTICAL TEST METHODS
MICROTOX RESPONSE TEST
Reference: Microtox Manual: A Toxicity Testing_Handbook, 1992
Volume I IV; Microbics Corporation.
Equipment: Microtox M500 Toxicity Testing Unit; Microbics Corporation
Connected to computer for data acquisition and analysis according to above
reference.
Procedure:
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1. Preparation of Samule Stock Solution (Standard Concentration: I 000 nnm)
The stock solution of the test anionic surfactant sample is prepared and used
as a stock
solution from which all other dilutions are made. The standard "starting
concentration",
the highest concentration to be tested, is 500 ppm. (If a 500 ppm starting
concentration
fails to give a calculable result, e.g. an active surfactant kills all reagent
at all dilutions, the
starting concentration can be adjusted based on a known range of EC50 values
of
previously tested surfactants.) The stock solution is prepared at two times
the starting
concentration.
a) Add O.lg (or adjusted amount if required) of anionic surfactant, accounting
for
activity of raw material, to beaker.
b) Microtox Diiuent (2% NaCI, Microbics Corp.) is added to total 100g.
c) Stir solution to make sure of adequate mixing.
2. Reconstitution of Microtox Reagent and Preparation of Assay
a) Turn on test unit and allow reagent well temperature to equilibrate at
S.5°C and
incubator block and read well temperature to equilibrate at 15°C.
b) Place a clean cuvette (Microbics Corp.) in the reagent well, and fill with
I.0 ml of
Microtox Reconstitution Solution (distilled water, Microbics, Corp.). Allow to
cool for I S
m mutes.
c) Reconstitute standard vial of Microtox Acute Toxicity Reagent (Vibrio
fischerio,
Microbics Corp.) by quickly adding the 1.0 ml of the cooled reconstitution
solution to the
reagent vial.
d) Swirl solution in the reagent vial for 2-3 seconds then pour reconstituted
reagent
back into the cooled cuvette and return the vial to the reagent well. Allow to
stabilize for
15 minutes.
e) Place 8 cuvettes containing 500 p.1 of Microtox Diluent, as assay, into the
incubator
wells of the test unit. Let cool for 15 minutes.
3. Test Substance Dilution
Prepare 7 serial dilutions of the test substance from the sample stock
solution. The final
volume of all cuvettes must be 1.0 ml.
a) Place 8 empty cuvettes into a test tube rack.
b) Add 1.0 ml of Microtox Diluent solution to tubes 1-7.
c) Add 2.0 ml of the sample stock solution (1000 ppm) in cuvette 8.
d) Transfer 1.0 ml solution from cuvette 8 to cuvette 7 and mix cuvette 7.
e} Serially transfer 1.0 ml from the newly formed solution to the subsequent
cuvette (7
to 6, 6 to 5 etc.). Remove 1.0 ml of solution from cuvette 2 and discard.
Cuvette I is the
blank containing only Microtox Diluent. Place the cuvettes into the test unit
incubation
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wells keeping them in order of lowest to highest concentration. These cuvettes
should
correspond with the 8 cuvettes prepared in step 2 above. Allow to cool for 15
minutes.
4. Assay and Sample Bioluminescence Testing
a) Add 10 pl of reconstituted reagent to the 8 precooled cuvettes of assay
prepared in
step 2 above (containing 500 p.l of diluent). Allow 15 minutes for reagent to
stabilize.
b) Start Microtox Data Capture and Reporting Software (Microbics Corp.),
select
START TESTING, input file name and description, correct starting concentration
in ppm
(500 if standard concentration is used) and number of controls ( 1 ) and
dilutions (7). Time
1 should be selected as 5 minutes, time 2 is NONE. Press enter then the space
bar to begin
testing.
c) Place the assay cuvette containing reagent which corresponds to the test
blank into
the read well and press SET. After the cuvette has resurfaced press READ and
the value
will be captured by the computer.
d) Similarly read the remaining 7 cuvettes containing reagent when prompted by
the
computer by pressing the READ button with the correct cuvette in the READ
well.
e) After all 8 initial reading have been taken, transfer S00 pl of the diluted
test
substance into their corresponding cuvette containing the reagent. Mix by
vortexing or
swirling and return to the incubation wells. The computer will count for five
minutes and
prompt you to begin final readings.
f) Take final readings by placing the correct cuvette containing reagent and
diluted test
surfactant into the read well and pressing READ when prompted by the computer.
5. Data Analysis
The concentration of test substance, in ppm, that decreases the
bioluminescence of the
Microtox Acute Toxicity Reagent by 50% from the starting value (EC50 Value)
can be
calculated using the Run Statistics on Data File option of the Microtox
Software
(recommended) or by conducting a linear regression of the data (% reduction
vs. log of
concentration). % Reductions are calculated using the following formulas:
Final Reading of Reagent Blank - Con.ection Factor
Initial Reading of Reagent Blank
Final Reading of Reagent with Diluted Test Substapce
= Reduction FactorX
Initial Reading of Reagent with Diluted Test Substance
where x means at a corresponding concentration
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Correction Factor x - Reduction Factor
Reduction =
Correction Factor
The Microtox Index is the EC50 value in ppm.
IN VIVO RESIDUAL EFFECTIVENESS ON E.coli
References: Aly, R; Maibach, H.L; Aust, L.B.; Corbin, N.C.; Finkey, M.B. 1994.
1. In vivo effect of antimicrobial soap bars containing 1.5% and 0.8%
trichlorocarbanilide against two strains of pathogenic bacteria. J. Soc.
Cosmet.
Chem., 35, 351-355, 1981.
2. In vivo methods for testing topical antimicrobial agents. J. Soc. Cosmet.
Chem., 32,
317-323.
1. Test Design
Residual Antibacterial efficacy of liquid and bar soap antimicrobial products
are
quantified in the following method. Reductions are reported from a control,
non-
antibacterial placebo soap, without further treatment, used on one of the
subjects forearms.
By definition the antibacterial placebo will show no residual effectiveness in
the test.
2. Pre-Test Phase
Subjects are instructed not to use antibacterial products for 7 days prior to
testing.
Immediately before test, the subjects hands are examined for cuts/broken skin
that would
preclude them from participating.
3. Application Procedure for Leave-on Test Product
a) Wash both forearms with placebo soap one time to remove any contaminants or
transient bacteria. Rinse and dry forearms
b) Test monitor marks l Ocm x Scm treatment area on forearm.
c) Test monitor applies 0.5 m1 of test product over the treatment site rubbing
in for 10
seconds.
d) Arm is allowed to air dry and test sites are marked (~8.6 cm2 circle with
rubber
stamp).
e) Mark site with stamp on other forearm of subject for placebo product
evaluation.
4. Inoculation Procedure
a) E. coli inoculum (ATCC 10536, grown from lyophilized stock in Soybean-
casein
broth at 37C for 18-24 hrs) is adjusted to approximately 108 organisms/ml
(0.45
transmittance vs. TSB blank on specrophotometer).
b) Each test site is inoculated with 10 p,1 of E. coli. Inoculum is spread
with
inoculating loop into a ~3 cm2 circle and covered with a Hilltop Chamber
(Hilltop
Research Inc.).
c) This procedure is repeated for each test site on each forearm.
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5. Sampling Bacteria (Extraction Procedure)
- a) Prepare sampling solution of 0.04% KH2P04, 1.01 % Na2HP04, 0.1 % Triton X-
100, 1.5% Polysorbate 80, 0.3% Lecithin in water, adjusted to pH 7.8 with 1 N
HCI.
b) Exactly 60 minutes after inoculation, the Hilltop Chamber is removed from
the site
from which a sample is to be taken. A 8.6 cm2 sampling cup in placed over the
site
c) 5 ml of sampling solution is added to the cup.
d) Extract the bacteria by gently rubbing site with glass police man for 30
seconds.
e) Remove sampling solution with pipette and place in a sterile labeled test
tube.
f) Repeat extraction with 5 ml of sampling fluid. This entire extraction
procedure is
repeated for each site 60 minutes after inoculation.
6. Ouantifyin~ Bacteria
a) Prepare phosphate buffer solution of 0.117% Na2HP04, 0.022% NaH2P04, and
0.85% NaCI adjusted to pH 7.2-7.4 with 1 N HC1.
b) 1.1 ml of the sampling solution is aseptically removed from the tube, 0.1
ml of the
solution is spread plated onto trypticase-soy agar containing I.5% Polysorbate
80 .
Remaining 1 ml is placed into 9 m! of sterile phosphate buffer achieving a
1:10 dilution of
the sampling solution. This process is repeated 3 more times (each serial
dilution).
c) The plates are inverted and incubated for 24 hours at 35C.
d) Colonies formed on plates are then enumerated and results are calculated by
multiplying the counts by the dilution factor (original sample = 10, first
dilution = 100,
second dilution = 1000, etc.) and the final results are reported as the number
of colony
forming units per ml {CFU's/ml).
7. Index Calculation
Gram Negative Residual Efficacy Index =
logl0 (CFU's/ml of placebo site) - logl0 (CFU's/ml of test product site)
IN VIVD RESIDUAL EFFECTIVENESS ON Stavhylococcus aureus
References: Aly, R; Maibach, H.L; Aust, L.B.; Corbin, N.C.; Finkey, M.B. 1994.
1. In vivo effect of antimicrobial soap bars containing 1.5% and 0.8%
trichlorocarbanilide against two strains of pathogenic bacteria. J. Soc.
Cosmet.
Chem., 35, 351-355, 1981.
2. In vivo methods for testing topical antimicrobial agents. J. Soc. Cosmet.
Chem., 32,
317-323.
1. Test Desien
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Residual Antibacterial efficacy of liquid and bar soap antimicrobial products
are
quantified in the following method. Reductions are reported from a control,
non-
antibacterial placebo soap, without further treatment, used on one of the
subjects forearms.
By definition the antibacterial placebo will show no residual effectiveness in
the test.
2. Pre-Test Phase
Subjects are instructed not to use antibacterial products for 7 days prior to
testing.
Immediately before test, the subjects hands are examined for cuts/broken skin
that would
preclude them from participating.
3. Application Procedure for Leave-on Test Product
a) Wash both forearms with placebo soap one time to remove any contaminants or
transient bacteria. Rinse and dry forearms
b) Test monitor marks l Ocm x Scm treatment area on forearm.
c) Test monitor applies 0.5 ml of test product over the treatment site rubbing
in for 10
seconds.
d) Arm is allowed to air dry and test sites are marked (~8.6 cm2 circle with
rubber
stamp).
e) Mark site with stamp on other forearm of subject for placebo product
evaluation.
4. Inoculation Procedure
a) S. aureus inoculum (ATCC 27217, grown from lyophilized stock in Soybean-
casein broth at 37C for 18-24 hrs) is adjusted to approximately 108
organisms/m1 (0.45
transmittance vs. TSB blank on specrophotometer).
b) Each test site is inoculated with 10 ~1 of S. aureus. Inoculum is spread
with
inoculating loop into a ~3 cm2 circle and covered with a Hilltop Chamber
(Hilltop
Research Inc.).
c) This procedure is repeated for each test site on each forearm.
5. Sampling_Bacteria (Extraction Procedure)
a) Prepare sampling solution of 0.04% KH2P04, 1.0l J/o Na2HP04, 0.1 % Triton X-
100, 1.5% Polysorbate 80, 0.3% Lecithin in water, adjusted to pH 7.8 with 1 N
HCI.
b) Exactly 60 minutes after inoculation, the Hilltop Chamber is removed from
the site
from which a sample is to be taken. A 8.6 cm2 sampling cup in placed over the
site.
c) 5 ml of sampling solution is added to the cup.
d) Extract the bacteria by gently rubbing site with glass police man for 30
seconds.
e) Remove sampling solution with pipette and place in a sterile labeled test
tube.
f) Repeat extraction with 5 ml of sampling fluid. This entire extraction
procedure is
repeated for each site 60 minutes after inoculation.
6. QuantifyinQ Bacteria
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a) Prepare phosphate buffer solution of 0.117% Na2HP04, 0.022% NaH2P04, and
0.85% NaCI adjusted to pH 7.2-7.4 with I N HCI.
b) 1.1 ml of the sampling solution is aseptically removed from the tube, 0.1
ml of the
solution is spread plated onto trypticase-soy agar containing 1.5% Polysorbate
80 .
Remaining I ml is placed into 9 ml of sterile phosphate buffer achieving a
I:10 dilution of
the sampling solution. This process is repeated 3 more times (each serial
dilution).
c) The plates are inverted and incubated for 24 hours at 35C.
d) Colonies formed on plates are then enumerated and results are calculated by
multiplying the counts by the dilution factor (original sample = 10, first
dilution = 100,
second dilution = 1000, etc.) and the final results are reported as the number
of colony
forming units per ml (CFU's/ml).
7. Index Calculation
Gram Positive Residual Efficacy Index =
logl0 (CFU's/ml of placebo site) - logl0 (CFU's/ml of test product site)
IN VIVO HEALTH CARE PERSONAL HANDWASH TEST (HCPHWT)
Reference: Annual Book of ASTM Standards. Vol. I I .05; ASTM Designation: E
1174 - 94;
"Standard Test Method for Evaluation of Health Care Personnel Handwash
Formulation"
1. The test method used is identical to the method explained in this reference
with the
following changes/clarifications.
a. Testing on a subject was finished after the one wash extraction, when only
one-wash data was
desired. The test requires at least four subjects.
b. Historical Data was used as a control in this protocol. (i.e. a control
soap was not run in
every test)
c. Test Materials
O~r anism: Serratia marcescens ATCC 14756 (incubated 18-24 hrs. at 25C in
soybean
casein broth, adjusted to 108 organisms/ml by diluting to 0.45 transmittance
with a
spectrophotometer)
Dilution Fluid: phosphate buffer (0.1% Triton X-100, 00.3% Lecithin, I.5%
Tween 80)
adjusted to pH 7.2 with 1 N HCI
Agar: Soybean casein agar with I .5% polysorbate 80
d. Application Procedure
Laboratory technical places 2.0 ml of test leave-on composition in subject's
hand.
Subject then spreads composition on hands, rubbing for thirty (30) seconds,
covering palm,
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back of hand, fingers and web areas between fingers, cuticles, and nail beds.
Hands are not
dried.
e. Bacteria were enumerated by performing serial dilutions (1:10) of inoculum
or extracted
samples and spreading 0.1 ml of dilution on plates. Results are reported as
the log reduction
of bacteria from baseline.
One-wash Immediate Germ Reduction Index= Log (CFU's) in Baseline Extraction-
Log (CFU's) in Post-One Wash Extraction
Ten-wash Lnmediate Germ Reduction Index=Log (CFU's) in Baseline Extraction-
Log (CFU's) in Post-Ten Wash Extraction
e. Hands were decontamined by submersion in 70% ethanol for 15 sec. and then a
five
minute wash with control soap and water.
FOREARM CONTROLLED APPLICATION TEST fFCAT)
Reference: Ertel, K. D., et al.; "A Forearm Controlled Application Technique
for Estimating the
Relative Mildness of Personal Cleansing Products"; J. Soc. Cosmet. Chem. 46
(1995) 67-76.
The Forearm Controlled Application Test, or FCAT, is a comparative test which
discriminates differences in product mildness to the skin. A test product is
compared to a
standard soap based cleansing bar control.
Test Group Restrictions
Test groups of 20-30 subjects, 18 to 55 years of age, who regularly wash with
soap are
used. Potential subjects who {1) have an initial dryness grade of 3.0 or
higher on the forearms as
assessed during the initial examination, (2) have skin cancer, eczema, or
psoriasis on the
forearms, (3) are receiving injectable insulin, (4) are pregnant or lactating,
or (5) are receiving
treatment for skin problems or contact allergy are excluded. Subjects are to
avoid hot tubs,
swimming, and sun lamps, and to refrain from applying any soaps, cleansing
products, creams,
or gels to their forearms for the duration of the study. Subjects are to keep
water off their
forearms for at least two hours before the grading process. The studies are
executed using a
blinded, random product order format. Clinical assistant should verify the
correct treatment
sequence and document such before washing each subject.
Products are applied to the forearms a total of nine (9) times: two (2) times
each day on
the first four (4) days of the study and one ( 1 ) time on the final day.
Visits to the test facility for
washing must be spaced by a minimum of three (3) hours.
All clinical assistants must wear disposable gloves during wash procedure,
rinsing them
between treatments, and changing between subjects.
Control Product
The control product is a rolled bar soap containing:
56.1% Sodium Tallowate
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18.7% Sodium Cocoate
0.7% Sodium Chloride
24% Water
0.5% Minors (Perfume,
Impurities)
Product Application Procedure
Both test and control products are tested on the same arm. The following test
procedure is
used.
1. The subject wets the entire surface of his/her volar forearm with 95-
100°F tap water by
holding the arm briefly under running tap water.
2. A clinical assistant wets one-quarter sheet (approximately 8" x 6") of
Masslinn~ towel
with tap water, then squeezes the towel gently to remove excess water.
3. A clinical assistant applies the products to the arm, beginning with the
product designated
for the site nearest the elbow, using the appropriate procedure as follows:
Liquid Product
a. Dispense 0.10 cc of test product from a syringe into the center of the
appropriate
marked area.
b. Wet two finders of gloved (latex) hand under the running tap (index and
middle
fingers).
c. Move wetted fingers in a circular motion over the application site for 10
seconds to
lather product.
d. Lather remains on the application site for 90 seconds, then is rinsed off
with running
tap water for 15 seconds, taking care not to wash lather off the adjacent
sites. After
seconds of the rinse has expired, the Clinical Assistant will gently rub the
site
being rinsed with her two gloved fingers for the remaining 5 seconds of the
rinse..
Bar Product
a. Wet two finders of gloved (latex) hand under the running tap (index and
middle
fingers).
b. Wet bar by holding bar briefly under running tap water. Test bars must be
wet
under a running tap at the start of each day.
c. Rub wetted fingers in a circular motion, over the surface of the bar, for
15 seconds
to form lather on bar and fingers.
d. Rub the lathered fingers on the application site in a circular motion for
10 seconds
to lather product on the skin.
e. Lather remains on the application site for 90 seconds, then is rinsed off
with running
tap water for 15 seconds, taking care not to wash lather off the adjacent
sites. After
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seconds of the rinse has expired, the Clinical Assistant will gently rub the
site
being rinsed with her two gloved fingers for the remaining 5 seconds of the
rinse..
Wye Products
a. Fold wipe in half, crosswise, and gently rub the wipe in a curricular
motion within
the appropriate area.
b. Allow site to air dry for 90 seconds. Do not rinse site.
Leave-on Product
a. Dispense 0.10 cc of test product from a syringe into the center of the
appropriate
marked area.
b. Move gloved fingers in a circular motion over the application site for 10
seconds.
c. Allow site to air dry for 90 seconds. Do not rinse site.
4. While waiting for the 90 second residence time to expire, the above
procedure will be
repeated on the remaining application site on that arm, working down the arm
toward the
west.
5. Steps 1-4 are repeated on the appropriate test areas so two applications of
product are
made to test areas.
6. After all of the application areas have two applications of products, the
clinical assistant
gently pats the subject's arm dry with a disposable paper towel.
Evaluation
The skin on each treatment area is evaluated by an expert grader at baseline
and three
hours after the final study wash. The treatment areas are evaluated under
2.75x magnification
(model KFM-lA Luxo Illuminated Magnifying Lamp, Marshall Industries, Dayton,
OH) with
controlled lighting (General Electric Cool White, 22-watt, 8" Circuline
fluorescent bulb).
The skin is evaluated by an expert grader, for dryness and a rating is
assigned based on the
definitions set forth below.
Table 1
Forearm Grading Scale
Rating Skin Dryness
0 No dryness
1.0 Patches of slight powderiness and occasional patches of small scales may
be seen.
2.0 Generalized slight powderiness. Early cracking or occasional small lifting
scales
may be present.
3.0 Generalized moderate powderiness and/or heavy cracking and lifting scales.
4.0 Generalized heavy powderiness and/or heavy cracking and lifting scales.
S.0 Generalized high cracking and lifting scales. Eczematous change may be
present.
Powderiness may be present but not prominent. May see bleeding crack.
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6.0 Generalized severe cracking. Eczematous change may be present. Bleeding
cracks may be present. Scales large, may be beginning to disappear.
The FCAT generally produces only mild to moderate skin irritation; however, if
a treated
site reaches a rating of 5.0 or greater, at any time during the study,
treatment of all sites on that
subject should be discontinued.
Data
After all subjects have been evaluated at the end of the test, the following
values are
determined:
Rco = The average rating of control product area at baseline
Rc f= The average rating of control product area at test end
Rto = The average rating of test product area at baseline
Rt f= The average rating if test product area at test end.
There are many external conditions which could influence the FCAT, such as
relative
humidity and water softness. The test is valid only if sufficient response is
observed in the skin
to the control product. The control response must be greater than 1.0 (i.e.,
Rcf- Rco >_ 1.0) for
the test to be valid.
Given a valid test, the Mildness Index of the test product is the difference
in the skin
responses to two products.
Mildness Index = ( Rc f- Rco ) - ( Rtf- Rto )
CONSISTENCY (k) AND SHEAR INDEX (n) OF
THE LIPOPHILIC SKIN MOISTURIZING AGENT
The Carrimed CSL 100 Controlled Stress Rheometer is used to determine Shear
Index,
n, and Consistency, k, of the lipophilic skin moisturizing agent used herein.
The determination
is performed at 35°C with the 4 cm 2° cone measuring system
typically set with a 51 micron gap
and is performed via the programmed application of a shear stress (typically
from 0.06 dynes/sq.
cm to 5,000 dynes/sq. cm) over time. If this stress results in a deformation
of the sample, i.e.
strain of the measuring geometry of at least 10-4 rad/sec, then this rate of
strain is reported as a
shear rate. These data are used to create a viscosity a Vs. shear rate y' flow
curve for the
material. This flow curve can then be modeled in order to provide a
mathematical expression
that describes the material's behavior within specific limits of shear stress
and shear rate. These
results were fitted with the following well accepted power law model (see for
instance:
Chemical Engineering, by Coulson and Richardson, Pergamon, 1982 or Transport
Phenomena
by Bird, Stewart and Lightfoot, Wiley, 1960):
Viscosity, p, - k (y~)n-1
VISCOSITY OF THE LEAVE-ON ANTIMICROBIAL COMPOSITION
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The Wells-Brookfield Cone/Plate Model DV-II+ Viscometer is used to determine
the
viscosity of the leave-on antimicrobial compositions herein. The determination
is performed at
25°C with the 2.4 cm° cone (Spindle CP-41 ) measuring system
with a gap of 0.013 mm between
the two small pins on the respective cone and plate. The measurement is
performed by injecting
0.5 ml of the sample to be analyzed between the cone and plate and rotating
the cone at a set
speed of 1 rpm. The resistance to the rotation of the cone produces a torque
that is proportional
to the shear stress of the liquid sample. The amount of torque is read and
computed by the
viscometer into absolute centipoise units (mPa's) based on geometric constants
of the cone, the
rate of rotation, and the stress related torque.
EXAMPLES
The following examples further describe and demonstrate embodiments within the
scope
of the present invention. In the following examples, all ingredients are
listed at an active level.
The examples are given solely for the purpose of illustration and are not to
be construed as
limitations of the present invention, as many variations thereof are possible
without departing
from the spirit and scope of the invention.
Ingredients are identified by chemical or CTFA name.
Fifteen leave-on antimicrobial compositions are prepared according to the
tables below.
Component Ex. Ex. Ex. Ex. Ex.
1 Z 3 4 5
Mineral oil 1.00% 1.00% 1.00% 1.00% 0.00%
Propylene glycol 1.00% 1.00% 1.00% 1.00% 1.00%
Ammonium Lauryl Sulfate 0.60% 0.60% 0.60% 0.60% 0.60%
Citric Acid 4.00% 0.00% 0.00% 0.00% 0.00%
Sodium Citrate 3.30% 0.00% 2.00% 0.00% 0.00%
Succinic Acid 0.00% 4.00% 0.00% 0.00% 4.00%
Sodium Succinate 0.00% 3.30% 0.00% 0.00% 3.20%
Malic Acid 0.00% 0.00% 2.50% 0.00% 0.00%
Malonic Acid 0.00% 0.00% 0.00% 4.00% 0.00%
Sodium Malonate 0.00% 0.00% 0.00% 3.20% 0.00%
Steareth 20 0.55% 0.55% 0.55% 0.55% 0.00%
Steareth 2 0.45% 0.45% 0.45% 0.45% 0.00%
Triclosan~ 0.1 0.15% 0.1 0.15% 0.15%
S% S%
Miscellaneous 0.36% 0.36% 0.36% 0.36% 0.36%
Water q.s. q.s. q.s. q.s. q.s.
pH 4.0 4.5 3.9 3.9 3.9
Microtox of Anionic Surfactant1 1 1 1 1
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Head Group Size of AnionicSmall Small Small Small Small
Surfactant
Primary Chain Length of 12 12 12 12
Anionic
12
Surfactant
Component Ex.6 Ex.7 Ex.8 Ex.9 Ex.lO Ex.lOa
Mineral oil 0.00% 0.00% 1.00% 1.00% 1.00% 1.00%
Propylene glycol 1.00% 1.00% 1.00% I .00%1.00% 1.00%
Ammonium Lauryl 0.60% 0.60% 0.60% 0.60% 1.00% 0.60%
Sulfate
Citric Acid 0.00% 0.00% 2.50% 2.50% 4.00% 0.00%
Sodium Citrate 0.00% 3.70% 2.00% 2.00% 3.20% 0.00%
Succinic Acid 4.00% 0.00% 0.00% 0.00% 0.00% 0.00%
Sodium Succinate 3.00% 0.00% 0.00% 0.00% 0.00% 0.00%
Malic Acid 0.00% 4.00% 0.00% 0.00% 0.00% 0.00%
polyacrylic acid/sodium0.00% 0.00% 0.00% 0.00% 0.00% 2.5%
polyacrylate*
Steareth 20 0.55% 0.00% 0.55% 0.08% 0.28% 0.08%
Steareth 2 0.45% 0.00% 0.45% 0.07% 0.23% 0.07%
Oleth 20 0.00% 0.00% 0.00% 0.08% 0.28% 0.08%
Oleth 2 0.00% 0.00% 0.00% 0.07% 0.23% 0.07%
Triclosan~ 0.00% 0.50% 0.50% 0.15% 0.25% 0.15%
Thymol 1.00% 0.00% 0.00% 0.00% 0.00% 0.00%
Miscellaneous 0.36% 0.36% 0.36% 0.36% 0.36% 0.36%
Water q.s. q.s. q.s. q.s. q.s. q.s.
pH 3.2 S.0 3.9 3.9 3.9 3.8
Microtox of Anionic1 1
1 1 1 I
Surfactant
Head Group Size Small Small Small Small Small Small
of
Anionic Surfactant
Primary Chain Length12 12 12 12 12
of
12
Anionic Surfactant
Acumer 1020 sold by Rohm & Haas.
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Component Ex.ll Ex. Ex. Ex. Ex.lS
l2 l3 l4
Mineral oil 1.00% 1.00% 1.00% 1.00% 1.00%
Propylene glycol 1.00% 1.00% 1.00% 1.00% 1.00%
Ammonium Lauryl Sulfate0.00% 0.00% 0.00% 0.00% 0.60%
Ammonium Laureth Sulfate0.00% 5.00% 0.00% 0.00% 0.00%
Hostapur SAS 60 (SPS)1.00% 0.00% 0.00% 0.00% 0.00%
C14-C16 Sodium Alpha 0.00% 0.00% 2.00% 0.00% 0.00%
Olefin Sulfonate
Sodium Lauroyl Sarcosinate0.00% 0.00% 0.00% 1.00% 0.00%
Citric Acid O.OSS% 7.50% 0.00% 0.00% 0.00%
Sodium Citrate 0.00% 4.00% 2.00% 0.00% 0.00%
Succinic Acid 4.00% 0.00% 0.00% 0.00% 0.00%
Sodium Succinate 0.67% 0.00% 0.00% 0.00% 0.00%
Malic Acid 0.00% 0.00% 2.50% 0.00% 0.00%
Malonic Acid 0.00% 0.00% 0.00% 4.00% 0.00%
Sodium Malonate 0.00% 0.00% 0.00% 3.20% 0.00%
Salicylic Acid 0.00% 0.00% 0.00% 0.00% O.SO%
Steareth 20 O.SS% O.SS% O.SS% O.SS% O.SS%
Steareth 2 0.45% 0.45% 0.45% 0.45% 0.45%
Triclosan~ 0.15% 3.00% O.IS% 0.01% 0.15%
Cocamidopropyl Betaine0.00% 0.00% 0.00% 4.00% 0.00%
Polyquat 10 0.00% 0.00% 0.00% 0.40% 0.00%
Miscellaneous 0.36% 0.36% 0.36% 0.36% 0.36%
Water q.s. q.s. q.s. q.s. q.s.
pH 3-6 3-6 3-6 3-6 3-6
Microtox of Anionic ~a 150 20 <l50 1
Surfactant
Head Group Size of Small Large Small Large Small
Anionic
Surfactant
Primary Chain Length 15.5 12 14-16 12 12
of
Anionic Surfactant
The leave-on antimicrobial compositions shown ail have a Gram Negative
Residual
Effectiveness Index of greater than about 0.3, a Gram Positive Residual
Effectiveness Index of
greater than 0.5, have a One-wash Immediate Germ Reduction Index of greater
than about 1.0;
and a Mildness Index of greater than 0.3.
Procedure for Making Leave-on Antimicrobial Composition Examules
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When mineral oil is used, premix mineral oil, propylene glycol, active,
steareth 2 and 20,
oleth 2 and 20, and 50%, by weight of the oil, glycol, active, steareth and
oleth materials, water
to a premix vessel. Heat to 165°F ~ 10°F. Add additional 50%, by
weight of the oil, glycol,
active, steareth and oleth materials, of water to the premix tank.
Add all but S weight percent of remaining water to second mix tank. If
required, add
premix to the mix tank. Add surfactants to mix tank. Heat materials to
155°F ~10°F and mix
until dissolved. Cool to )ess than 100°F, add acid and antibacterial
active, if not in premix, and
perfumes. Mix until materials are dissolved. Adjust pH to target with required
buffer (NaOH or
buffer salt). Add remaining water to complete product.
