U.S. patent number 3,678,156 [Application Number 05/048,655] was granted by the patent office on 1972-07-18 for compositions for topical application to animal tissue and method of enhancing penetration thereof.
This patent grant is currently assigned to The Proctor & Gamble Company. Invention is credited to Warren I. Lyness, Francis S. Kilmer MacMillan.
United States Patent |
3,678,156 |
MacMillan , et al. |
July 18, 1972 |
COMPOSITIONS FOR TOPICAL APPLICATION TO ANIMAL TISSUE AND METHOD OF
ENHANCING PENETRATION THEREOF
Abstract
Antiperspirant composition for topical application to animal
tissue comprising an astringent metal salt and from 0.1 to 10
percent by weight of a higher (C.sub.8 - C.sub.12) aliphatic
sulfoxide, said composition having enhanced penetration of the
antiperspirant through keratinized epiphelial tissue.
Inventors: |
MacMillan; Francis S. Kilmer
(Cincinnati, OH), Lyness; Warren I. (Cincinnati, OH) |
Assignee: |
The Proctor & Gamble
Company (Cincinnati, OH)
|
Family
ID: |
21955718 |
Appl.
No.: |
05/048,655 |
Filed: |
May 15, 1970 |
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
595437 |
Nov 18, 1966 |
3527864 |
|
|
|
344195 |
Feb 12, 1964 |
|
|
|
|
Current U.S.
Class: |
424/68; 424/59;
424/66; 514/169; 514/183; 514/291; 424/65; 424/685; 514/188 |
Current CPC
Class: |
A61K
47/20 (20130101); A61K 9/0014 (20130101); A61Q
15/00 (20130101); A61K 8/46 (20130101) |
Current International
Class: |
A61K
47/20 (20060101); A61k 007/00 (); A61k
027/10 () |
Field of
Search: |
;424/68,337 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Rose; Shep K.
Parent Case Text
This application is a division of application, Ser. No. 595,437,
now U. S. Pat. No. 3,527,864, which in turn is a
continuation-in-part of application, Ser. No. 344,195, filed Feb.
12, 1964, now abandoned.
Claims
What is claimed is:
1. An antiperspirant composition comprising from about 5 percent to
about 50 percent of an astringent metal salt and from about 0.1
percent to about 10 percent of an aliphatic sulfoxide of the
formula RSOR' wherein R is an alkyl, group containing from eight to
12 carbon atoms and R' is a low molecular weight alkyl or
hydroxy-substituted alkyl group, in a pharmaceutically acceptable
carrier.
2. The composition of claim 1 wherein the astringent metal salt is
aluminum chlorohydrate.
3. The composition of claim 1 wherein the aliphatic sulfoxide is
selected from the group consisting of octyl methyl sulfoxide, nonyl
methyl sulfoxide, decyl methyl sulfoxide, undecyl methyl sulfoxide,
dodecyl methyl sulfoxide, 2-hydroxydecyl methyl sulfoxide,
2-hydroxyundecyl methyl sulfoxide and 2-hydroxydodecyl methyl
sulfoxide.
Description
This invention relates to compositions for topical application to
animal (this term as used herein includes both humans and lower
animals) tissue and a method for enhancing the penetration of
various substances through such tissue. More particularly, it
relates to improved compositions for topical application and a
method for enhancing the penetration of pharmacologically active
substances through keratinized epithelial tissue.
The epidermal barrier to percutaneous absortition, i.e., the
stratum corneum, is a nearly impermeable heterogenous animal tissue
of which keratin is a major component. This tissue is found in
animal skin, tongue, gingiva, esophagus, and vagina.
A wide variety of pharmacologically active substances are desirably
applied topically to keratinized epithelial tissue for essentially
local effect. It is known that various surface-active compounds
improve the activity of such substances, apparently by enhancing
the penetration of same through skin. For example, British Pat. No.
940,279, published Oct. 30, 1963, discloses that the presence of a
surfactant in antiperspirant compositions based on anticholinergic
agents appears to increase antiperspirant activity by providing
more efficient absorption of the active agents at the site of
application. It has been found, however, that many surface-active
compounds enhance the permeability by actually damaging the barrier
tissue. Indeed, the degree of penetration enhancement appears in
some cases to be proportional to the extent of tissue damage. In
any event, only slight to moderate enhancement of penetration is
effected with the surface-active agents heretofore employed for
this purpose in the prior art.
Certain organic solvents also serve to enhance penetration of
substances through the epidermal barrier. For example,
dimethylsulfoxide (D.M.S.O.) and homologous low molecular weight
sulfoxides, when used in solvent concentrations, e.g., 50 percent
or more, will enhance penetration of various substances. However,
such compounds are systemically distributed in a very short time
and can cause undesirable symptoms.
The desirability of enhancing the localized effects of such
pharmacologically active substances as anesthetics, antimicrobial
and antibiotic substances without adverse effects on the skin and
with minimal general systemic involvement is readily apparent.
It is, therefore, an object of this invention to provide improved
compositions for topical application to keratinized epithelial
tissue and a method for enhancing the penetration of
pharmacologically active substances through such tissue.
It is a further object of this invention to provide a method of
enhancing the penetration of pharmacologically active substances
through keratinized epithelial tissue without damaging said tissue
or causing adverse systemic effects.
These and other objects are attained through a composition for
topical application to animal tissue comprising a safe and
effective amount of a pharmacologically active substance and from
about 0.1 percent to about 10 percent of an aliphatic sulfoxide of
the formula RSOR' wherein R is an alkyl, substituted alkyl, alkenyl
or hetero group containing from eight to 12 carbon atoms and R' is
a low molecular weight alkyl or hydroxy-substituted alkyl group, in
a pharmaceutically acceptable carrier.
By the term "pharmacologically active substance" as used herein is
meant any chemical element or compound suitable for topical
administration which induces any desired local transitory effect on
living structures contacted therewith (sometimes referred to
hereinafter as "penetrant"). Such substances include for example,
anticholinergics, antimicrobials, antibiotics, antihistamines,
local anesthetics, steroids, sunscreens, elemental sulfur and
various metal ions such as aluminum, iron and zinc.
The "enhanced penetration" effected through the use of sulfoxides
in accordance with this invention can be observed by measuring the
rate of diffusion of pharmacologically active substances through
guinea pig skin using the diffusion cell apparatus depicted in the
FIGURE as will be fully described hereinafter.
The sulfoxides which serve to enhance penetration in the
compositions of this invention as hereinbefore stated have the
formula RSOR' wherein R is a straight chain or branched chain
alkyl, alkenyl, substituted alkyl or hetero group containing from
eight to 12 carbon atoms and R' is a low molecular weight alkyl or
hydroxy-substituted group such as methyl, ethyl, propyl,
.beta.-hydroxyethyl, or hydroxy-isopropyl.
If R contains less than eight carbon atoms, substantially higher
concentrations than the 10 percent maximum concentration specified
herein must be employed to enhance penetration. For example, hexyl
methyl sulfoxide must be used at a concentration of about 30
percent or more to significantly enhance penetration. The lower
homologues must be used at solvent concentrations, e.g., 50 percent
or more to accomplish this purpose. At these concentrations these
lower sulfoxides (below C.sub.8 ) can produce undesired systemic
effects.
If R contains more than 12 carbon atoms the sulfoxide will not be
soluble enough to provide the desired degree of penetration
enhancement.
Substituted alkyl groups referred to in the foregoing definition of
R in the one case includes hydroxyalkyl, lower alkoxyalkyl (e.g.
methoxy) and ketoalkyl for example. Hetero groups include oxaalkyl,
thiaalkyl, and azaalkyl for example.
The preferred sulfoxides for the purposes of this invention are the
dialkyl sulfoxides wherein R is an alkyl or hydroxy-substituted
alkyl group containing from eight to 12 carbon atoms and R' is
methyl, ethyl or propyl. SO in the above general formula is a
representation of the sulfoxide group which is alternately
expressed as S.fwdarw.O, S = 0, or S - 0. Examples of R include
octyl, nonyl, decyl, undecyl, dodecyl, 3-decenyl, 2-dodecenyl,
3-undecenyl, 3-octenyl, 2-ketooctyl, 2-ketodecyl, 2-ketoundecyl,
2-ketododecyl, 2-hydroxyoctyl, 2-hydroxydecyl, 2-hydroxyundecyl,
2-hydroxydodecyl, 3-hydroxy-undecyl, 3-methoxyundecyl,
2-methoxydodecyl, 3,6-dioxadodecyl, 2-ethylhexyl, and branched
chain nonyl and dodecyl resulting from polymerization of three and
four moles of propylene respectively.
Especially preferred dialkyl sulfoxides for the purpose of this
invention are octyl methyl sulfoxide, nonyl methyl sulfoxide, decyl
methyl sulfoxide, undecyl methyl sulfoxide, dodecyl methyl
sulfoxide, 2-hydroxydecyl methyl sulfoxide, 2-hydroxyundecyl methyl
sulfoxide and 2-hydroxydodecyl methyl sulfoxide.
The sulfoxide compounds disclosed herein can be used singly or in
combination for the purpose of this invention. These compounds are
readily obtainable by well known methods, For example, most can be
prepared by the conventional method of first preparing the
corresponding thioether and then oxidizing to the sulfoxide. The
methods of carrying out these steps have recently been reviewed by
A. Schoberl and A. Wagner [Methoden Organischen Chemie
(Houben-Weyl), fourth Ed., Georg Thieme Verlog, Stuttgart, Vol. IX,
pp. 97-143, 211-218 (1955)]. Further methods for preparing
sulfoxide compounds are disclosed in U.S. Pat. No. 3,288,858;
3,288,859; and 3,288,860, granted Nov. 29, 1966.
The concentration of sulfoxide employed employed herein can range
from about 0.1 percent to about 10.0 percent by weight. If
concentrations less than about 0.1 percent are used the degree of
penetration enhancement attained, especially with the lower chain
length sulfoxides (e.g., octyl methyl sulfoxide), is not
appreciable. If concentrations greater than about 10.0 percent are
employed, solubility problems may be encountered with the higher
chain length sulfoxides (e.g., dodecyl isopropyl sulfoxide) and no
substantial improvement is seen. Preferably, the concentration of
sulfoxide will range from about 1 to 8 percent by weight of the
total composition.
The activity of the sulfoxides of this invention in enhancing skin
penetration was shown by measuring the diffusion of various
substances through guinea pig skin using the continuous flow
apparatus set forth in the FIGURE. This apparatus is constructed so
that an inner cylindrical chamber 1 can be mounted within a larger
outer cylindrical chamber 2 and sealed thereon with set screws 3
such that water of constant temperature can be introduced into the
space between said inner and outer cylindrical chambers, through
inlet 4 and flow around the inner cylindrical chamber 1 and out the
constant temperature water outlet 5. The test solution 8 is placed
in the inner chamber 1 in contact with a freshly sectioned piece of
guinea pig skin 9 affixed to the bottom of said inner chamber and
resting upon a stainless steel screen support 11 and sealed to base
chamber 13 with a neoprene ring 10. Ringer's solution as
hereinafter defined is introduced into the base chamber 13 through
an inlet 14 with a syringe infusion pump 6. A magnetic stirring bar
12 agitates the Ringer's solution in the base chamber 13 which is
in contact with the guinea pig skin 9. The effluent Ringer's
solution is collected at an outlet tube 15 and analyzed at
intervals for penetrants which have diffused through the guinea pig
skin from the test solution.
The diffusion cell allows for a precise rate of flow of a solution
under the skin (Krebs-Henseleit mammalian Ringer solution) and
subsequent collection of samples for any predetermined period of
time. The distinctive features of this method relative to other
methods described in the art are the very small volume of the
collecting chamber (to minimize dilution of the diffusate) and the
variable flow rate which allows collections of samples at intervals
commensurate with the specific activity of the penetrant system,
the rate of diffusion, and changes which occur in the diffusion
process.
Young adult guinea pigs were prepared by clipping the hair from
their abdomens. The abdominal skin was excised, the subcutaneous
fat was removed, and the skin placed in the diffusion cell. In
every experiment the abdominal skin was cut bilaterally and each
half used for one diffusion cell.
Diffusion studies were conducted with the diffusion cell of the
FIGURE by placing 1 ml. of various concentrations of the penetrant
in aqueous solution (at pH 7, unbuffered unless otherwise noted) on
the skin 9 after it was mounted on the inner chamber 1. The area of
skin exposed to the test solution 8 was 2.83 cm.sup.2. Penetration
was monitored by radiochemical analysis over a 20 hour period to
determine the shape of the diffusion curve and the steady state
rate of penetration. Liquid scintillation counting was employed
using the Packard Tricarb Scintillation Spectrometer, Model
4322.
Permeability constants were calculated by methods similar to those
employed by Treherne, J. E., Cutaneous Barriers, J. Invest. Derm.,
45:249, 1965, as follows:
In the steady state, the rate of diffusion is as follows:
dQ/dt = P = Co .times. A
(rate = permeability constant x concentration applied to the skin
(.mu. moles)
Q = the amount of material which has penetrated the skin (.mu.
moles)
P = the permeability constant (cm/min.)
Co = concentration applied to the skin (.mu. moles/cm.sup.3)
(The concentration in the base chamber 13 below the skin is
considered to be zero since new solution is constantly being flowed
over the surface.)
A = area of skin studied (cm.sup.2)
dQ/dt = rate of penetration (.mu. moles/min.) from the slope of the
accumulative curve which expresses the amount which has penetrated
with respect to time.
In Table 1 below, the permeability constants of a 0.369 percent
aqueous solution of nicotinic acid (a representative penetrant) in
the presence of varying concentrations of representative sulfoxides
are set forth. The permeability constant of nicotinic acid in
conjunction with the specified sulfoxides is divided by the average
permeability constant of a control solution of the same
concentration of nicotinic acid without sulfoxide (i.e. 1.23
.times. 10.sup..sup.-6 ), to obtain the approximate amplification
of penetration attributable to the sulfoxides.
TABLE 1
Permeability Approx. Am- Conc. % constant plification Sulfoxide by
weight cm/min. .times.10.sup.116 6 over control*
__________________________________________________________________________
Octyl methyl sulfoxide 5.0 5.0 4 Decyl methyl sulfoxide 1.0 31.4* *
25 Decyl methyl sulfoxide 2.0 63.0* 51 Decyl methyl sulfoxide 4.0
199.1* 161 Decyl methyl sulfoxide 5.0 225.0 183 Decyl methyl
sulfoxide 8.0 290.0 236 Dodecyl methyl sulfoxide 0.7 15.1 12
Dodecyl methyl sulfoxide 1.0 20.0 16 Dodecyl methyl sulfoxide 9.3
45.0 36
__________________________________________________________________________
As can be seen from the above table, the penetration of nicotinic
acid, a pharmacologically active substance (Vasodilator), through
guinea pig skin is substantially enhanced in the presence of the
various sulfoxides.
The concentration of nicotinic acid employed in compositions for
topical application should be sufficient to provide the desired
degree of vasodilation, preferably from about 0.01 percent to about
10 percent by weight.
Various other pharmacologically active substances were tested for
penetration of guinea pig skin in the above-described manner and
the values obtained are set forth in Table 2 below. The sulfoxide
employed in each case was decyl methyl sulfoxide in aqueous
solution at a concentration of 4.0 percent by weight.
TABLE 2
Permeability Approx. Am- Conc. % constant plification Penetrant by
Weight cm/min..times.10.sup.116 6 over control
__________________________________________________________________________
Glycine .225 80.3 28 Alanine .267 33.0 8 Lysine .438 289.0 11
Valine .351 20.0 7 Glutamine .438 8.0 267 Glutamic acid .441 1.4 3
Norleucine .393 218.0 109 Methionine .447 245.0 100
__________________________________________________________________________
It can be seen that the penetration through guinea pig skin of the
various amino acids tested is markedly enhanced by a representative
sulfoxide.
The enhancement of tissue penetration effected by the sulfoxides is
also observed with a variety of other pharmacologically active
substances as can be seen by permeability constant determinations
as described above or by measuring the degree of physiological
response of a given concentration of active substance with and
without a sulfoxide. Penetration of metal ions can also be
determined by staining sections of guinea pig skin which has been
treated with solutions of said ions, with and without sulfoxide and
microscopically examining the treated tissue or by X-ray
fluorescence to obtain a semiquantitative measure of the respective
degrees of penetration.
Normally, the stratum corneum is almost completely impervious to
metal ions. Such penetration may occur into the most superficial
layers from a simple aqueous solution but never exceeds the first
three layers. When sulfoxides are added to such solutions in
accordance with this invention, substantial concentrations of metal
ions can be detected throughout the entire stratum corneum. Tests
for metal ion penetration were undertaken in the following
manner;
Test solutions were applied under closed patches to either the
backs or abdomens of wax-depilitated guinea pigs 6 to 9 days after
depilitation. The patches were retained from 1-4 hours after which
the animals were sacrificed and skin biopsies taken. In some
instances the test solutions were swabbed on the back with cotton
and dried in a stream of air. In order to determine the duration
the metal was retained in the skin, animals were sacrificed over a
2 week period following either type of application. Zinc was
detected by a dithizone method on fresh cryostat cut sections. Iron
was visualized by Perl's Prussian blue method on neutral
formalin-fixed tissues. Aluminum was visualized by the aluminon
method. Semi-quantitative data on the amount of metal in the tissue
were obtained by analyzing separated epidermal sheets by X-ray
fluorescence.
Zinc acetate (50 mM) and ferric chloride (50 mM) were each
dissolved in 0.1 M decylmethyl sulfoxide and applied under a closed
patch for 4 hours. The X-ray fluorescence data are given in Table 3
below. These astringent salts are effective antiperspirants in
combination with the aforesaid sulfoxide in these compositions.
TABLE 3
Retention of Metal Salts
Day After Zinc Concentration, Iron Concentration Application
.mu.g/q Dry Epidermis .mu.g/g Dry Epidermis
__________________________________________________________________________
Control 80 70 (no application) 1 3200 2300 3 1400 500 7 430 100
__________________________________________________________________________
Compositions in accordance with this invention can be formulated
with a wide variety of dermatologically acceptable ingredients or
bases and in a number of physical forms. For example, such
compositions may be in liquid or cream form and may be either
aqueous emulsions or dispersions. Desirably, the active ingredients
are uniformly dispersed in a water dispersible, dermatologically
acceptable vehicle. Such a vehicle is non-toxic and is compatible
with animal tissue, and does not prevent absorption of the active
ingredients by these tissues. Such vehicles are well known in the
pharmaceutical and cosmetic fields and their choice is not critical
to the efficacy of the pharmacologically active substance and the
sulfoxide penetration enhancing agent as long as they are water
miscible. Examples of water dispersible dermatologically acceptable
vehicles are water; water-soluble alcohols (monohydric and
polyhydric alcohols -- particularly lower alcohols C.sub.1 -C.sub.8
-- e.g., ethanol, propanol, glycerol, sorbitol, 2-methoxyethanol,
diethyleneglycol, monomethyl or diethyl ether, ethylene glycol,
hexyleneglycol, mannitol, propylene glycol); polyethylene glycols
and methoxypolyoxyethylenes (carbowaxes having molecular weight
ranging from 200 to 20,000); glyceryl monolaurate, monopalmitate or
monostearate; polyoxyethylene glycerols; polyoxyethylene sorbitols;
and glucose. When alcohols or their derivatives are used, some
water is preferably included since such materials are usually
hydroscopic.
Although the vehicle is preferably water miscible as stated above,
petroleum based ointments and the like can also be used. For
example, such substances as mineral oil, petroleum jelly, stearoyl
diacetin, lanolin, paraffin and beeswax. Although they may tend to
slow absorption they can be used, especially if there is sufficient
water-dispersible vehicle present to provide a medium for
absorption by animal tissue. Emulsification of such substances also
provides a means for their use. Oil-in-water emulsions such as cold
cream bases can also be used.
An example of a cold cream contains: 13 percent stearic acid, 2
percent glyceryl monostearate, 5 percent olive oil, 0.5 percent
potassium hydroxide and 73.5 percent water.
Since the compositions of this invention are to be topically
applied to animal tissue, they should be formulated so that they
have a pH in aqueous solution of not less than about 3.5 nor more
than about 10.0. Irritation can be encountered at pH's lower than
about 3.5 and the stability of various ingredients can be adversely
affected at pH's higher than about 10.0.
The usual buffering materials can be used to adjust the pH to the
desired range. Examples of such buffers are: glycine, citric acid,
disodium hydrogen phosphate, potassium hydrogen tartrate, potassium
hydrogen pthalate, and sodium hydrogen succinate.
A preferred embodiment of this invention is an antiperspirant
composition containing a sulfoxide and an antiperspirant ingredient
uniformly dispersed in a dermatologically acceptable vehicle as
hereinbefore described. The antiperspirant ingredient of such
compositions can be an astringent salt such as the aluminum and
zirconium salts as disclosed in U.S. Pat. Nos. 2,814,585;
2,854,382; and 2,906,668. Such salts comprise in combination an
aqueous solution of a zirconium or hafnium salt of a strong
monobasic mineral acid and a basic aluminum compound. However, the
aluminum salts of strong acids, especially the chloride and
sulfate, are also useful. Aluminum chlorhydrate, for example, can
be used to advantage in the compositions of this invention.
It is has been found that safe and extremely effective
antiperspirant compositions based on various anticholinergic
compounds can also be prepared. Numerous operable anticholinergic
compounds are disclosed at length in British Pat. No. 940,279 and
by MacMillan et al. in J. Invest. Derm. 43:363 (1964) (both
incorporated herein by reference). Preferred anticholinergics for
the purpose of this invention are the scopolamine esters set forth
in the aforesaid publication. Especially preferred anticholinergic
compounds are the paraalkoxybenzoyl esters of scopolamine. These
compounds and a method for preparing same are disclosed by
MacMillan in copending U.S. Pat. application Ser. No. 379,023,
filed June 29, 1964.
The anticholinergic compounds of especial utility in the
compositions of this invention include the free base and acid salt
forms of a compound having the general formula: ##SPC1##
wherein C - R is selected from the group consisting of a straight
chain acyl group, a branched chain acyl group, an aromatic acyl
group and acyclic acyl group, containing from four to about 12
carbon atoms.
Specific examples of the C.sub.4 -C.sub.12 scopolamine esters that
are especially useful as active antiperspirants according to this
invention are:
trimethylacetyl scopolamine hydrochloride (pivaloyl scopolamine
hydrochloride)
2-ethylbutyryl scopolamine hydrobromide
2-ethyl-3-methylbutyryl scopolamine hydrobromide
n-butyryl scopolamine hydrobromide
n-valeryl-scopolamine hydrobromide
isovaleryl scopolamine hydrobromide
isopropylacetyl scopolamine hydrobromide
4-methylpentanoyl scopolamine hydrobromide
benzoyl scopolamine hydrobromide
2,4-dichlorobenzoyl scopolamine hydrobromide
cyclopentylpropionyl scopolamine hydrobromide
cyclohexylpropionyl scopolamine hydrobromide
naphthoyl scopolamine
n-hexanoyl scopolamine hydrobromide
n-heptanoyl scopolamine hydrobromide
n-octanoyl scopolamine hydrobromide
n-nonanoyl scopolamine hydrobromide
n-decanoyl scopolamine hydrobromide
The above mentioned C.sub.4 - C.sub.12 scopolamine esters can be
prepared by any convenient well known method. Especially good
preparative methods are described in U.S. Pat. No. 2,814,623.
Other less active anticholinergic compounds such as scopolammonium
N-methyl bromide, trimethyl acetyl scopolamine methyl bromide,
trimethylacetyl atropine hydrobromide, or benzoyl atropine
hydrobromide can also be used to advantage in the present
compositions due to the improved activity achieved by enhanced
penetration.
If astringent salts are used as the antiperspirant agent in the
compositions of this invention the concentration of this component
should range from about 5 percent to about 50 percent. Preferably
the concentrations of this pharmacologically active substance is
from about 10 percent to about 30 percent. In general substantially
greater antiperspirant effect is realized by a given concentration
of astringent salt in compositions in accordance with this
invention than is otherwise attainable.
If anticholinergic agents are used as the active ingredient in the
antiperspirant embodiments, this component comprises from about
0.001 percent to about 0.25 percent by weight. Preferably, this
pharmacologically active substance is used in concentrations
ranging from 0.005 to 0.2 percent.
The method used to test the effectiveness of the antiperspirant
compositions prepared according to this invention and other
compositions with which they were compared is the "forearm" method,
on human subjects.
The "forearm" test is primarily a qualitative test to determine
whether a given composition has antiperspirant activity. However,
with practice, grades can be readily given for visual results, as
described below, to evaluate effectiveness. Grades are assigned
from 0 (no antiperspirant effect) to 4 (complete perspiration
inhibition), and 4+ (complete perspiration inhibition spreading
beyond the treated area) with 3 being about 90 percent inhibition,
2 about 60 percent and 1 about 30 percent. In the "forearm" test, a
given area of the forearm is treated three times with the
composition to be tested over a period of 10 minutes, permitting
the composition to dry each time. After 4 or 5 hours, the arm is
washed and dried. A 11/2percent solution of iodine in ethanol is
then painted over the area and allowed to dry. A slurry of starch
and castor oil is then placed over the area and the subjects sits
in a room at 100.degree. F. for 5 to 15 minutes, depending on the
subject. Any perspiration emitted permits iodine to react with the
starch to give a visual indication (a blue-black color) of
perspiration. To determine the length of effectiveness, the test
can be repeated, with no re-application of the antiperspirant
composition, after 48, 72, and 96 hours or more.
EXAMPLE I
The following compounds were compared using the forearm method. The
anticholinergic compounds were in a 1 percent solution of the
dialkyl sulfoxide at a concentration of 0.025 or 0.05 percent
having a pH of approximately 4. The compounds were tested on the
same eight male subjects, each, at the end of 5, 24, and 48
hours.
Compound Average Grade (8 subjects) 5 Hrs. 24 Hrs. 48 Hrs.
__________________________________________________________________________
0.05% scopolamine hydrobromide in water 0.3 0.5 0.0 0.05%
scopolamine hydrobromide in 1% 2-hydroxyundecyl methyl sulfoxide
0.5 0.9 0.0 0.025% n-butyryl scopolamine hydrobromide in water 2.5
2.4 1.1 0.025% n-butyryl scopolamine hydrobromide in 1% 2-hydroxy-
undecyl methyl sulfoxide 3.5 4.0 + 2.0
__________________________________________________________________________
This comparison between representative scopolamine compounds with
and without 2-hydroxyundecyl methyl sulfoxide establishes improved
antiperspirant efficacy in the presence of the dialkyl sulfoxide.
None of the compositions tested damaged the skin of the test
subjects or caused systemic effects.
Antiperspirant embodiments of this invention are illustrated by the
several formulations noted above as well as by the following
example.
EXAMPLE II
Antiperspirant compositions having a pH of approximately 4 were
formulated by combining the following ingredients.
(A) n-butyryl scopolamine hydrobromide 0.025% 2-hydroxyundecyl
methyl sulfoxide 1,000% water 98.975% (B) n-butyryl scopolamine
hydrobromide 0.025% water 99.975 (C) n-butyryl scopolamine
hydrobromide 0.025% cetyl trimethylammonium bromide 1.000 water
98.975% (D) n-butyryl scopolamine hydrobromide 0.025% sodium
dodecylbenzene sulfonate 1.000% water 98.975%
The preceding compositions were tested for antiperspirant efficacy
by the previously described "forearm" method with the grading
readings on eight subjects taken 24 hours after application.
Composition A was prepared according to the present invention. That
is, it contained an anticholinergic scopolamine ester and as an
enhancing agent, a dialkyl sulfoxide within the range previously
described as being essential. This composition produced a 100
percent reduction in 24 hours, while Composition B containing only
the anticholinergic scopolamine ester in an aqueous solution
reduced perspiration by only 60 percent. Compositions C and D
containing a cationic and anionic surfactant respectively resulted
in no improvement whatsoever; specifically Composition C reduced
sweating by 55 percent and Composition D was even less effective
with a level of about 30 percent reduction in sweating.
Nonyl methyl sulfoxide, decyl methyl sulfoxide, undecyl methyl
sulfoxide or dodecyl methyl sulfoxide can be used instead of the
.beta.-hydroxyundecyl methyl sulfoxide in Composition A with
substantially equal results. Moreover, trimethylacetyl scopolamine
hydrochloride and benzoyl scopolamine hydrobromide can be used in
place of the n-butyryl scopolamine hydrobromide in the compositions
presented in this example. No skin damage or systemic effects were
observed in the test subjects.
An antiperspirant composition based on astringent salts is
formulated as follows:
EXAMPLE III
Percent by Weight Decyl methyl sulfoxide 5.0 Aluminum chlorhydrate
7.5 Zirconyl hydroxy chloride 4.6 Glycine 2.0 Glycerin 3.0 Titanium
dioxide 0.1 Glycerol monostearate 10.0 Spermaceti 2.0 Butyl
myristate 4.0 Behenic acid 5.0 Perfume 0.2 Dye, distilled water
Balance pH 4.5
when applied to human axillae, this composition substantially
reduces the volume of perspiration and is more effective in this
regard than a composition formulated as above but without decyl
methyl sulfoxide. Moreover the enhanced penetration of the
astringent salts is effected without damage to skin or systemic
distribution of these salts.
A variety of compositions for topical application to animal tissue
in accordance with this invention are set forth in the following
examples.
EXAMPLE IV
A topical local anesthetic is formulated as follows:
Percent By Weight Procaine Hydrochloride 6.0 Nonyl methyl sulfoxide
5.0 Water Balance pH 6.5
the above composition when applied to keratinized epithelial tissue
produces a local anesthetic effect shortly after application.
Nupercaine or pontocaine can be used in place of procaine in this
composition, at a 2 percent concentration with similar effect.
The concentration of this pharmacologically active substance can be
varied depending on the degree of anesthesia desired and the
relative activity of the anesthetic chosen. Ordinarily this
component will be used in a concentration of from 0.5 to 10
percent.
EXAMPLE V
A medicated face cream in accordance with this invention is
formulated as follows:
Percent By Weight Decyl methyl sulfoxide 4.5
3,5,4'-tribromosalicylanilide 2.0 Mineral Oil 33.6 Petrolatum 25.0
Stearyl Alcohol 25.0 Lanolin 2.0 Emulsifier 5.0 Ethylene Glycol 1.5
Distilled Water 0.5 Ti0.sub.2 0.7 Perfume 0.2
When applied to the face in accordance with ordinary practice, this
composition provides greater control over acne and various other
infections of the skin than a similar formulation without
sulfoxide.
The decyl methyl sulfoxide employed in this composition can be
replaced with octyl hydroxy-isopropyl sulfoxide, nonyl ethyl
sulfoxide, or dodecyl methyl sulfoxide with essentially equivalent
results. Similarly the penetration of a wide variety of
antibacterial agents is enhanced by the sulfoxides such that
3,5,4'-tribromosalicylanilide can be replaced by
bis(3,5,6-trichloro-2-hydroxyphenyl)methane,
bis(3,5-dichloro-2-hydroxyphenyl)sulfide,
3-trifluoromethyl-4,4'-dichloro-carbanilide, or mixtures thereof
with good results. A number of antibacterial agents are described
in U.S. Pat. No. 3,281,366, Judge et al.
Ordinarily the antibacterial component of compositions of this
invention is employed at concentrations ranging from about 0.1 to
10 percent, preferably 1 to 5 percent.
EXAMPLE VI
A suntan oil in accordance with this invention is prepared as
follows:
Percent By Weight Dodecyl methyl sulfoxide 1.0 2-ethyl hexyl
salicylate 5.0 Sesame Oil 40.0 Mineral Oil 50.0 Perfume, Color and
antioxidant Balance
The efficacy of the sunscreen 2-ethyl hexyl salicylate is enhanced
by virtue of the presence of the sulfoxide, as is seen when the
efficacy of a similarly formulated product without sulfoxide is
compared thereto.
Penetration of diverse sunscreens into the skin through conjoint
application with sulfoxides in accordance with this invention can
be demonstrated. Thus, 2-ethylhexyl salicylate employed in this
example can be replaced by dipropyleneglycol salicylate,
monoglyceryl p-aminobenzoate, digalloyl trioleate,
menthylanthranilate and mixtures of these sunscreens with improved
results.
EXAMPLE VII
An antibiotic mouthwash prepared in accordance with this invention
is formulated as follows:
Percent By Weight Nonyl methyl sulfoxide 0.2 Gramicidin .006
Spearmint Oil 0.05 Menthol .05 Cinnamon Oil .01 Coloring .001
Saccharin sodium 0.15 Ethyl Alcohol 25.0 Water Balance
The efficacy of the antibiotic component in the treatment of local
infection in the oral cavity is substantially improved by virtue of
the sulfoxide content of said composition.
The penetration of other antibiotic substances through gingival
tissue is also enhanced by sulfoxides. For example, penicillin,
aureomycin, or tetracycline can be used in place of gramicidin in
the above formulation to realize the benefits of this invention.
This composition should be diluted with three to four parts of
water before use.
EXAMPLE VIII
An antidandruff shampoo composition containing an antifungal agent
in conjunction with a sulfoxide as essential components is
formulated as follows:
Percent By Weight .beta.-hydroxyundecyl methyl sulfoxide 7.5 Zinc
2-pyridinethiol-1-oxide 2.0 Sodium coconut alkyl glyceryl ether
sulfonate (about 23% diglyceryl and the balance substantially
monoglyceryl). 25.0 Sodium tallow alkyl glyceryl ether sulfonate
(about 23% diglyceryl and the balance substantially monoglyceryl;
the tallow alkyls correspond to those of substantially saturated
tallow alcohols and contain approximately 2% C.sub.14, 32%
C.sub.16, and 66% C.sub.18). 3.0 Sodium chloride 6.7 Sodium sulfate
3.3 Sodium N-lauroyl sarcosinate 3.8 N-coconut acyl sarcosine 1.2
Diethanol amide of coconut fatty acids 2.0 Acetylated lanolin 1.0
Perfume 0.4 Color 0.04 Water Balance
This composition provides an effective means for treatment of
dandruff when used in the conventional manner. The activity of
other antidandruff agents can be improved by the presence of the
sulfoxide in this formulation. Thus, selenium disulfide or sulfur
can be used in place of zinc 2-pyridinethiol-1-oxide in this
example.
EXAMPLE IX
A typical steroid-containing composition embodying this invention
is formulated as follows:
Hydrocortisone acetate 9.0 g. Decyl methyl sulfoxide 10.0 g.
Methylparaben 0.25 g. Propylparaben 0.15 g. Propylene glycol 120.0
g. Stearyl alcohol 250.0 g. White petrolatum 250.0 g. Distilled
H.sub.2 0
when topically applied to keratinized epithelial tissue this
ointment provides greater penetration of hydrocortisone acetate
than can be achieved with the identical composition without the
sulfoxide.
EXAMPLE X
A composition identical to that set forth in Example IX is prepared
but replacing the hydrocortisone acetate with 21 g. of
methapyrilene hydrochloride, a typical antihistamine. This
composition is highly effective in treating allergic reactions.
The foregoing description of the invention has been presented
describing certain operable and preferred embodiments. It is not
intended that the invention should be so limited since variations
and modifications thereof will be obvious to those skilled in the
art, all of which are within the spirit and scope of this
invention. Further, the range of concentrations of the
pharmacologically active substances shown in the examples is not to
be construed as the operable range since the effective amount of
these substances will vary throughout a wide range and is
contingent on the activity of the substance per se and the nature
of the composition. In any case, the determination of amounts is
within the skill of the ordinary physician. The amount employed
will in all cases be the amount required to produce the desired
response safely. The concentration ranges specified herein for
various pharmacologically active substances reveal that this
component can comprise as little as 0.001 percent by weight and as
much as 50 percent by weight of the total composition. Percentages
referred to in the foregoing specification and the following claims
refer to weight percentages of the total composition unless
otherwise specified.
It should be noted that the compositions and method of this
invention find utility in veterinary medicine as well as in human
applications.
* * * * *