Composition for treating acne vulgaris

Procedure for treating acne vulgaris that uses salicylic acid and benzoyl peroxide either sequentially or simultaneously. Compositions for practicing each of these aspects of the invention are also described.

This invention relates to procedures for treating acne vulgaris that employ 
salicylic acid and benzoyl peroxide as active ingredients. It also 
concerns topical therapeutic compositions that are useful for this purpose 
and particularly stable compositions of this character. 
The pathology of acne vulgaris is believed to involve a number of factors; 
the first of which is the formation of comedones more commonly referred to 
as whiteheads (closed comedones) and blackheads (open comedones). These 
are solid horny masses that plug follicles and are associated with 
increased production of sebum. They are made up of tightly packed 
keratinized cells. These plugs are white (whiteheads) when originally 
formed but through continued growth and deposition of the normal pigment, 
pigment melanin becomes blackheads. 
As the comedo enlarges through continued accumulation of keratinized cells, 
pressure builds up within the follicles which eventually rupture, dumping 
the contents consisting of horny material, sebum and bacteria into the 
skin. This provokes inflammatory responses which take the form of pustules 
(pimples) when the rupture is small and cystic-nodules with complete 
rupture. 
One of the prior art modes for the treatment of acne vulgaris has been the 
application of a keratolytic agent for the purpose of drying and peeling 
the skin to remove the keratinous plugs. The agents used for this purpose 
include sulfur, resorcinol, resorcinol monoacetate and salicylic acid. 
Hexachlorophene has also frequently been added for its antibacterial 
effect. (See "Handbook of Non-Prescription Drugs", 1969 Edition pages 
118-121, published by the American Pharmaceutical Association, Washington, 
D.C. ). U.S. Pat. No. 3,530,217 also suggests that other antibacterial 
agents such as parachlorometaxylenol, tyrothricin, neomycin sulfate, 
benzalkonium chloride and Bithinonol may be used along with keratolytic 
agents such as sulfur, resorcinol, salicylic acid and benzoyl peroxide in 
the treatment of acne. 
It has now been found that benzoyl peroxide and salicylic acid when used 
together at certain specified levels, exhibit a therapeutic effect greater 
than either agent alone in treating acne. These materials may be used in 
combination with each other in the treatment of acne or may be employed in 
a regimen of treatment in which one is applied after the other. 
It is accordingly an object of this invention to provide procedures for the 
treatment of acne vulgaris that involve the use of salicylic acid and 
benzoyl peroxide at certain specified levels simultaneously (e.g. with 
both active ingredients in the same vehicle) or sequentially (e.g. with 
the active ingredients in separate vehicles). 
It is also an object of this invention to provide compositions or articles 
of manufacture carrying salicylic acid and benzoyl peroxide at certain 
specified levels that are especially useful in the treatment of acne 
vulgaris. 
It is still a further object of this invention to provide gel compositions 
which are chemically and physically stable (i.e. exhibit no degradation of 
active components or deterioration of the gel system) containing salicylic 
acid and benzoyl peroxide at certain specified levels that are useful in 
the treatment of acne vulgaris. 
Other and more detailed objects of this invention will be apparent from the 
following description and claims. 
Benzoyl peroxide is antimicrobial and suppresses the acne bacillus, 
Propionibacterium acnes, an organism which has an important causal role in 
acne vulgaris. Salicylic acid, on the other hand, is not just another 
keratolytic agent like resorcinol, phenol and other traditional agents 
which have been used to cause peeling. It belongs to a special class of 
comedolytic drugs which interfere with the formation of blackheads and 
whiteheads, horny masses which clog the follicles. Few keratolytic agents 
have this property, the other well-known one being vitamin A acid. Above 
and beyond the comedolytic effect, salicylic acid has other properties 
which add uniqueness to the present combination. It weakens the horny 
layer barrier, thereby increasing the permeability of skin to the benzoyl 
peroxide. As a result of its effect on the barrier, the tissue 
concentration of benzoyl peroxide is increased with a corresponding 
increase in efficacy. The combined therapeutic efficacy of benzoyl 
peroxide and salicyclic acid is considerably greater than the effect of 
each agent alone. 
Salicylic acid has been suggested for use in combination with tars or 
mercury compounds in the treatment of psoriasis to enhance the penetration 
of these drugs. However, there has been no suggestion in the prior art 
that this would increase the antibacterial effect of benzoyl peroxide in 
the treatment of acne vulgaris. 
It has been suggested in the prior art that the benzoyl peroxide is an 
effective keratolytic and antibacterial agent in the treatment of acne. In 
this connection, attention is directed to U.S. Pat. No. 3,535,422. This 
patent also suggests that the combination of precipitated sulfur and 
benzoyl peroxide produces greater keratolysis than either substance alone. 
Although sulfur is widely regarded as keratolytic and antimicrobial, it has 
repeatedly been found that it enhances neither the comedolytic nor 
antibacterial actions of benzoyl peroxide. It has been reported that it 
actually encourages the formation of comedones. In a like fashion, 5% 
resorcinol in association with benzoyl peroxide has also been evaluated 
and no enhancement of therapeutic activity was evident. 
The concentration of benzoyl peroxide and salicylic acid as employed in 
this invention is important. It has been found, for example, that 2.5% 
salicylic acid used in conjunction with 5% benzoyl peroxide was scarcely 
better than benzoyl peroxide alone in the treatment of acne vulgaris. On 
the other hand, 10% salicylic acid with 5% benzoyl peroxide caused 
excessive redness and peeling in about one third of subjects treated and 
therefore, is of little, if any, value in this connection. 
The level of salicylic acid, in accordance with this invention, will 
generally be in the range of from about 3% to about 7% by weight based on 
the total weight of the composition; whereas, benzoyl peroxide will 
ordinarily be employed at concentrations in the range of from about 3% to 
about 20% on the same basis. Optimum results are obtained when both the 
salicylic acid and the benzoyl peroxide are each used at a level of about 
5% by weight on the total weight of the composition. 
The active ingredients employed in this invention may be applied from a 
variety of vehicles. In a typical sequential treatment, the salicylic acid 
is applied, for example as a 5% solution in a hydroalcoholic vehicle (e.g. 
75% ethanol/25% water). This is followed by treatment with benzoyl 
peroxide applied, for example, as 5% benzoyl peroxide gel. In this 
procedure, the solution of salicylic acid applied to the acne lesions is 
permitted to dry on the skin and the 5% benzoyl peroxide gel is then 
immediately applied. 
In another form of this invention, the salicylic acid and the benzoyl 
peroxide are applied simultaneously in the same vehicle, e.g. as a gel 
vehicle. These gels will ordinarily be aqueous gels containing gelling or 
thickening agents. As examples of such gelling or thickening agents, 
mention may be made of such materials as Veegum (magnesium aluminum 
silicate), sodium CMC, hydroxypropyl cellulose (e.g. Klucel HF), 
hydroxyethyl cellulose (Natrosol 250 HHR), methyl cellulose (Methocel A 
4M); Carbopol 941 (neutralized with diisopropanolamine), etc. water 
dispersible starches (Nucol 4227) and mixtures thereof. The quantity of 
gelling or thickening agent that may be employed may vary somewhat. 
Ordinarily, it is comprised of about 0.1% to 5.0% by weight based on the 
total weight of the composition. 
Although gel products of varying degrees of stability and viscosity may be 
prepared using any of the gelling agents suggested above, it has been a 
problem to develop a gel product that has a commercially acceptable 
stability, consistency and viscosity. A number of gelling agents were 
tried in an effort to prepare a commercially acceptable product. One was 
rejected because there resulted a destruction of the gel consistency and a 
separation of the suspended active ingredients. Another was rejected 
because it gave a thick lumpy mass which could not be dispersed even after 
considerable mixing. Still another, although it initially gave a 
satisfactory product, after several hours the viscosity dropped 
precipitously and this could not be considered commercially acceptable. In 
other instances, while the gelling agent selected provided a stable gel, 
it did not give a product having a commercially acceptable viscosity or 
smoothness. 
Especially stable gel products of the present invention having the 
commercially requisite viscosity and texture are obtained by employing a 
mixture of a magnesium aluminum silicate (e.g. Veegum with methyl 
cellulose (methocel) as the gelling agent. Although the quantities of 
these agents may also vary somewhat in the preferred form of this 
invention, the magnesium aluminum silicate will preferably comprise from 
about 1.0 to 3.0% by weight based on the total weight of the composition; 
optimum results being obtained when the level of this material is at about 
2.0% by weight. With regard to the Methocel component of the gelling 
agent, this may also vary. Good results are obtained with levels of 
Methocel in the range of from about 1.0 to 3% by weight based on the total 
weight of the composition. The best results are obtained when the 
magnesium aluminum silicate is at a level of about 2% by weight and the 
methocel is at a level of about 1.25% by weight. In any event, the 
combined total of magnesium aluminum silicate and Methocel will preferably 
not exceed about 5% by weight based on the total weight of the 
composition. 
It has also been found that the texture, appearance as well as the chemical 
stability of the gel compositions of this invention, including those that 
contain both salicylic acid and benzoyl peroxide (e.g. see Example 2A 
below) may be enhanced by incorporating therein a "Cold Process Starch", 
i.e. a water soluble starch. Products of this character that are 
especially suited for the present purposes are sold under the tradename: 
NUCOL (e.g. NUCOL2 NUCOL 326 and particularly NUCOL 4227). These starch 
products may be present in the gel compositions of this invention in 
various quantities. However, generally it will be present in the range of 
from about 0.5% to about 2.0% by weight based on the total weight of the 
composition and preferably about 1.0%. 
In general, benzoyl peroxide is chemically stable in the freshly prepared 
gel compositions encompassed in the present invention. However, when 
benzoyl peroxide is combined with salicylic acid in a gel composition that 
also contains laureth-4, this seems to affect the shelf-life of the 
product insofar as benzoyl peroxide is concerned. Cold process starches 
(e.g. Nucol 4227) aid in enhancing the physical stability of products of 
this character (e.g. the composition of Example 2A) and may also play a 
role in enhancing their chemical stability. This is illustrated in the 
chemical stability study summarized below. In this study, the various 
products were stored for the number of months indicated in column 1 at 
room temperature; 35.degree. C. and 45.degree. C. unless otherwise 
specified. 
______________________________________ 
Benzoyl Peroxide Content 
% of Initial Assay 
Months Room Temperature 35.degree. C. 
45.degree. C. 
______________________________________ 
A. Benzoyl Peroxide 5% & Salicylic Acid 5% Gel (Example 2A) 
Zero 100.0 -- -- 
1 99.5 (100.4) 98.2 
2 -- 94.7 92.9 
4 (100.2).sup.2 (99.8) -- 
B. Benzoyl Peroxide 5% & Salicylic Acid 5% Gel (Example 2) 
Zero (100.0) -- -- 
1 -- (84.9).sup.1 
-- 
5 (77.0) -- -- 
C. Benzoyl Peroxide 5% Gel (Example 1, Composition B) 
Zero 100.0 -- -- 
1 -- 99.6 92.2 
2 100.9 97.5 85.9.sup.1 
3 99.2 96.7 -- 
______________________________________ 
.sup.1 Stability study discontinued at specified temperature since benzoy 
peroxide content &lt;90% 
.sup.2 ( ) values in parenthesis are for product in glass containers. All 
other values are for product in 11/2 oz. plastic tubes (white Hd P/E) 
Product A and C at room temperature exhibit no instability while Product B 
yields substantial (i.e. greater than 20%) loss in potency at 5 months. At 
elevated temperatures (35.degree. C. and 45.degree. C.) Product A yields 
good stability. Product B at 35.degree. C. exhibits very poor stability 
with over 15% loss of potency at 1 month. Product C yields some 
instability at 45.degree. C. while at 35.degree. C. the stability is 
relatively good. Overall, the stability of Product A is far superior to 
Product B while being similar to Product C. 
Salicylic acid and benzoyl peroxide are each sparingly soluble in water. As 
an optional feature, to facilitate the preparation of the aqueous gel 
composition and yield cleansing properties to the finished product, it is 
sometimes useful to employ a surface active agent. A variety of surface 
active agents may be employed for this purpose. Among these, mention may 
be made of such materials as laureth-4, sodium lauryl sulfate, dioctyl 
sodium sulfosuccinate, sodium laureth sulfate, sodium sulfoacetate. The 
quantity of surface active agent employed can also vary. Ordinarily, this 
will be in the range of from about 2.0% to 6.0% by weight based on the 
total weight of the composition. 
If a surface active agent is employed, laureth-4 is a typical choice. 
Laureth-4 is the CTFA name for the ethoxylated ether of lauryl alcohol 
having the formula CH.sub.3 (CH.sub.2).sub.10 CH.sub.2 (OCH.sub.2 
CH.sub.2).sub.n OH wherein n has an average value of 4. Laureth-4 may be 
used in the present composition in the range of from about 3.0% to 6.0% by 
weight based on the total weight of the composition. Optionally, this is 
present at a level of about 6.00% by weight. 
Another surface active agent which may be employed is dioctyl sodium 
sulfosuccinate, the CTFA name for the sodium salt of the diester of an 
octyl alcohol and sulfosuccinic acid which conforms to the formula: 
##STR1## 
Dioctyl sodium sulfosuccinate may be used in the present composition in the 
range from about 0.5% to 3.0% by weight based on the total weight of the 
composition. Optionally, this is present at a level of about 1.0% by 
weight. 
Another surface active agent which may be employed is sodium laureth 
sulfate, the CTFA name for the sodium salt of sulfated ethoxylated lauryl 
alcohol that conforms generally to the formula: CH.sub.3 (CH.sub.2).sub.10 
CH.sub.2 (OCH.sub.2 CH.sub.2).sub.n OSO.sub.3 Na wherein n averages 
between 1 and 4. 
Sodium laureth sulfate may be used in the present composition in the range 
from 3.0% to 6.0% by weight based on the total weight of the composition. 
Optionally, this is present at a level of about 4.0%. 
Another surface active agent which may be employed is sodium lauryl 
sulfoacetate, the CTFA name for the organic salt that conforms generally 
to the formula: 
EQU CH.sub.3 (CH.sub.2).sub.10 CH.sub.2 OSO.sub.2 CH.sub.2 COO.sup.- Na.sup.+ 
Sodium lauryl sulfoacetate may be used in the present composition in the 
range from about 1.0% to 3.0% by weight based on the total weight of the 
composition. Optionally, this is present at a level of about 2.0% by 
weight. 
However, under some circumstances, it is preferable to eliminate the 
surface active agent all together. Effective and stable gel preparations 
containing benzoyl peroxide and salicylic acid at the required levels have 
been prepared without using any surface active agent. 
Other ingredients commonly contained in aqueous gel compositions may also 
be contained in the compositions of this invention providing they do not 
effect the stability of the present composition. Typical among these are 
the metal sequestering or chelating agents such as disodium EDTA (i.e. 
disodium ethylenediamine tetraacetic acid) to prevent product 
discoloration due to salicylic acid and metals interaction. 
As indicated above, the procedures for treating acne in accordance with the 
present invention, involve a sequential or simultaneous application of the 
active ingredients. In both instances, the composition or compositions 
containing the actives are applied liberally twice a day until the lesions 
are cleared up. To control the condition, the composition are then applied 
in the same fashion; once a day as long as it is thought necessary.

The following Examples are given to further illustrate the present 
invention. It is to be understood, however, that the invention is not 
limited to these examples. 
EXAMPLE 1 
______________________________________ 
Composition A 
Solution % by Wt. 
______________________________________ 
Salicylic acid 5 
Ethanol 75 
Water to 100 
______________________________________ 
Composition B 
Aqueous Gel % by Wt. 
______________________________________ 
Benzoyl peroxide (actives) 
5.0 
Laureth-4 6.0 
Disodium EDTA 0.1 
*Carbopol 940 0.5 
Diisopropanolamine 0.6 
Water to 100.0 
______________________________________ 
*Carbopol 940 (Goodrich Chemical Co.) See also U.S. Pat. Nos. 3,133,865 
and 2,798,053 
The compositions of this Example i.e. Compositions A and B are intended for 
use in a sequential fashion. Each of the compositions is placed in its own 
dispensing container. For convenience of administration, one of each of 
these containers is packaged together in the same carton. 
EXAMPLE 2 
Aqueous Gel 
______________________________________ 
% by Wt. 
______________________________________ 
*Veegum K 2.00 
Methocel A 4M 1.25 
Disodium EDTA 0.10 
**Laureth-4 6.00 
Salicylic acid 5.00 
Benzoyl peroxide 
(approx. 70% active) 
7.79 
Water to 100.00 
______________________________________ 
*Magnesium aluminum silicate (Vanderbilt Chemical Co.) 
**CH.sub.3 (CH.sub.2).sub.10 CH.sub.2 (OCH.sub.2 CH.sub.2).sub.n OH 
wherein n has an average value of 4. 
The composition of this Example is used in accordance with the present 
invention to simultaneously apply the salicylic acid and benzoyl peroxide. 
EXAMPLE 2A 
Aqueous Gel 
______________________________________ 
% by Wt. 
______________________________________ 
Salicylic acid 5.00 
Benzoyl peroxide 
(approx. 70% active) 
7.14 
Veegum K 2.00 
*Methocel A 4M 1.25 
**Nucol 4227 1.00 
Disodium EDTA .10 
Water to 100.00 
______________________________________ 
*Methyl cellulose (Dow Chemical Co.) 
**Cold Process Starch (modified) (Staley Starch) 
The composition of this Example is also a convenient form for 
simultaneously applying salicylic acid and benzoyl peroxide. 
EXAMPLE 2B 
Aqueous Gel 
______________________________________ 
% by Wt. 
______________________________________ 
Salicylic acid 5.00 
Benzoyl peroxide 
(approx. 70% active) 
7.30 
Veegum K 3.00 
Methocel A 4M 0.50 
Disodium EDTA 0.10 
Water to 100.00 
______________________________________ 
This formulation afforded and acceptable but somewhat thin gel. 
EXAMPLE 2C 
Aqueous Gel 
______________________________________ 
% by Wt. 
______________________________________ 
Salicylic acid 5.00 
Benzoyl peroxide 
(approx. 70% active) 
7.30 
Veegum K 2.00 
Methocel A 4M 2.00 
Disodium EDTA 0.10 
Water to 100.00 
______________________________________ 
This formulation yielded a viscous off-white but elegant gel. 
EXAMPLE 2D 
Aqueous Gel 
______________________________________ 
% by Wt. 
______________________________________ 
Salicylic acid 5.00 
Benzoyl peroxide 
(approx. 70% active) 
7.30 
Methocel A 4M 4.00 
Disodium EDTA 0.10 
Water to 100.00 
______________________________________ 
This formulation produced a thick white elegant gel. 
EXAMPLE 2E 
Example 2D was repeated only 2% Methocel A 4M was employed in lieu of the 
4% utilized in said Example 2D. A less viscous but cosmetically acceptable 
semi-gel product was obtained. 
EXAMPLE 2F 
Aqueous Gel 
______________________________________ 
% by Wt. 
______________________________________ 
Salicylic acid 5.00 
Benzoyl peroxide 
(approx. 70% active) 
7.30 
Veegum K 8.00 
Nucol 4227 1.00 
Disodium EDTA 0.10 
Water to 100.00 
______________________________________ 
This formulation afforded a thick smooth elegant gel. 
EXAMPLE 2G 
Example 2F was repeated only 4% Veegum K was employed. An unacceptable gel 
exhibiting slight syneresis was produced. 
EXAMPLE 2H 
Aqueous Gel 
______________________________________ 
% by Wt. 
______________________________________ 
Salicylic acid 5.00 
Benzoyl peroxide 
(approx. 70% active) 
7.30 
Veegum K 6.00 
Disodium EDTA 0.10 
Water to 100.00 
______________________________________ 
This formulation afforded a gel product which exhibited slight syneresis. 
This indicates that the amount of Veegum K employed in the formulation is 
at the minimum level necessary to afford a satisfactory product when 
Veegum K is employed alone and not in conjunction with a cellulose 
derivative such as Methocel A 4M. 
As is seen from the previous examples, Veegum K can be utilized as the sole 
gelling and suspending agent to afford an elegant product, providing that 
it is employed in a concentration of about 6% to 10% by weight, preferably 
7% to 9% by weight and most preferably 8% by weight. 
It has been discovered that not all Montmorillonite clay suspending and 
gelling agents afford chemically and physically stable aqueous gels 
containing Benzoyl peroxide and Salicylic acid. As seen from the following 
Examples 2I and 2J, the use of 8% Bentonite alone (as in Example 2I) 
affords an unacceptable product. Further, the use of 4% and even 8% 
Hectorite as in Examples 2J and 2K results in a product which loses its 
viscosity upon the addition of the Salicylic acid. In contrast thereto, as 
is shown by Example 2F, 8% Veegum K affords an exceptionally elegant 
product. 
EXAMPLE 2I, J, and K 
______________________________________ 
% by Wt. 
I J K 
______________________________________ 
Salicylic acid 5.00 5.00 5.00 
Benzoyl peroxide 
(approx. 70% active) 
7.30 7.30 7.30 
Hectorite -- 8.00 4.00 
Bentonite, USP 8.00 -- -- 
Disodium EDTA 0.10 0.10 0.10 
Water to 100.00 100.00 100.00 
______________________________________ 
EXAMPLE 2L 
To further demonstrate that not all Montmorillonite earth suspending agents 
can be utilized to produce the desired chemically and physically stable 
gel formulations of the present invention, Example 2A was repeated only 
Bentonite USP was substituted for the Veegum K. The resultant product was 
not a gel, consequently, was considered unacceptable. 
EXAMPLE 2M 
Example 2A was repeated. 
(a) First: omitting the Cold Process Starch; 
(b) Second: omitting the Disodium EDTA; 
(c) Third: omitting both the Cold Process Starch and the Disodium EDTA; and 
(d) Fourth: omitting the Veegum K while increasing the Methocel A 4M from 
1.3% to 3.0%. 
In each case, a gel having satisfactory stability is produced. Gels (b) and 
(c) which did not contain a suitable sequestering agent showed 
discoloration, presumably, due to complex formation with salicylic acid. 
Although the Cold Process Starch is not an essential component, its 
presence is preferred as it affords a product having exceptional feel. Gel 
(d) demonstrates the Veegum K does not appear to be an indispensable 
component providing its absence is compensated for by suitable increase in 
the amount of Methocel A 4M or a like cellulose derivative. 
EXAMPLE 2N 
Example 2A was repeated only the amount of Veegum K was varied as follows: 
(a) 3% Veegum was employed; and 
(b) 1% Veegum was employed. 
Gel (a) though acceptable, was extremely viscous. Gel (b) was extremely 
thin though still a gel, indicating that the lower limit of Veegum K in 
Example 2A is about 1%. 
EXAMPLE 2O 
Example 2A was repeated only 1/2% Methocel A 4M was employed. The resultant 
product was not a gel and is considered unacceptable. 
EXAMPLE 2P 
The following Examples were carried out to ascertain whether cellulose 
derivatives other than Methocel A 4M could be employed in place of the 
Methocel A 4M in the preferred composition of Example 2A. 
(a) Example 2A was repeated only the Methocel A 4M was replaced with a like 
quantity of hydroxypropyl cellulose (Klucel HF-Hercules Chemical Co.). 
A highly unsatisfactory product resulted presumably due to incompatibility 
with the Salicylic acid. 
(b) Example 2A was repeated only the Methocel A 4M was replaced by: 
(i) a like quantity of hydroxypropyl methyl cellulose. (Methocel E 4M-Dow 
Chemical); 
(ii) by 2% hydroxypropyl methyl cellulose; 
(iii) by 3% hydroxypropyl methyl cellulose; and 
(iv) by 4% hydroxpropyl methyl cellulose. 
Gels (i)-(iv) were all acceptable thick smooth gels. 
It was noted that viscosity of the gel increases with increase in 
concentration of the Hydroxypropyl methyl cellulose. 
(c) Example 2A was repeated only the Veegum K was omitted and the Methocel 
A 4M was replaced by: 
(i) 3% hydroxypropyl methyl cellulose; 
(ii) 4% hydroxypropyl methyl cellulose; and 
(iii) 5% hydroxypropyl methyl cellulose. 
In each case an acceptable thick white gel was obtained. 
Confirming the finding that Veegum K can be omitted from preferred 
formulation 2A and relaced by a suitable quantity of either hydroxypropyl 
methyl cellulose or Methocel A 4M. 
EXAMPLE 2Q 
Example 2A was repeated only the Veegum K was omitted and the Methocel A 4M 
was replaced by: 
(i) 2% hydroxy ethyl cellulose (Natrosol 250-HHR Hercules Chemical Co.); 
and 
(ii) 4% hydroxy ethyl cellulose. 
In each case, (i) and (ii), a gel could not be produced. 
EXAMPLE 2R 
Aqueous Gel 
______________________________________ 
% by Wt. 
______________________________________ 
Salicylic acid 5.13 
Benzoyl Peroxide 
(72.37% active) 7.16 
Xanthan Gum 
(Keltrol - Kelco Co.) 
2.00 
Disodium EDTA 0.10 
Water to 100.00 
______________________________________ 
An acceptable smooth white gel was obtained. 
EXAMPLE 2S 
(i) Example 2R was repeated only 5% Xanthan Gum was employed. An acceptable 
viscous gel was obtained. 
(ii) Example 2R was repeated only the amount of Xanthan Gum was reduced to 
1% by weight and 1% by weight Veegum K was added. An acceptable gel was 
obtained. 
Xanthan and Veegum K may be employed as the thickening and suspending agent 
in the compositions of the present invention in a Xanthan to Veegum K 
ratio of respectively 2 to 3:1. 
Ideally from 1 to 3% by weight Xanthan is employed with from 1/2 to 1% by 
weight of Veegum K. 
EXAMPLE 2T 
Example 2A was repeated only in place of the Veegum K and Methocel A 4M one 
of the following thickening and suspending agents was employed: 
(i) 4% by wt. Polyethylene Oxide (having an average molecular weight of 
about 400,000-Polyox WSRN 3000-Union Carbide); 
(ii) 6% by wt. Polyethylene Oxide (Polyox WSRN 3000); 
(iii) 5% by wt. Polyethylene Oxide (having an average molecular weight of 
about 300,000-Poly WSRN-750-Union Carbide); 
(iv) 7% by wt. Polyethylene Oxide (Polyox WSRN-750); 
(v) 3% by wt. Polyethylene Oxide (having an average molecular weight of 
about 600,000-Polyox WSR-205-Union Carbide); 
(vi) 5% by wt. Polyethylene Oxide (Polyox WSR-205); 
(vii) 1% by wt. Pectin N.F. (Hercules); 
(viii) 3% by wt. Pectin N.F. 
(ix) 1% by wt. Polyacrylamide (e.g. Gelamide 250-American Cyanamide); 
(x) 3% by wt. Polyacrylamide; 
(xi) 1% by wt. of a 1:1 mixture of Hectorite and Hydroxyethyl cellulose 
(Bentone LT-National Lead); and 
(xii) 3% by wt. of a 1:1 mixture of Hectorite and Hydroxyethyl cellulose. 
All of formulations (i)-(xii) produced acceptable and stable gels. 
EXAMPLE 3 
Benzoyl Peroxide/Salicylic Acid Sequential Application in the Treatment of 
Acne Vulgaris 
Method: 
Three treatments were compared in three groups of 50 adolescents with 
moderate acne vulgaris. The subjects had numerous open and closed 
comedones with a variable quantity of papules and pustules. The agents 
were applied twice daily for 8 weeks; the effect of treatment was assessed 
globally according to a widely used conventional schema: 
poor =less than 25% improvement or worse 
fair=26% to 50% improvement 
good=51% to 75% improvement 
excellent=greater than 75% to clear 
The treatments were: (1) 5% salicylic acid in 75% aqueous ethanol 
(Composition A, Example 1); (2) 5% benzoyl peroxide gel (Composition B, 
Example 1); (3) 5% salicylic acid (Composition A, Example 1) followed 
immediately by 5% benzoyl peroxide gel (Composition B, Example 1). 
Results and Conclusions: 
The data are summarized in Table I below. 
Benzoyl peroxide alone was somewhat superior to salicylic acid alone. Both 
were moderately effective. The sequence of salicylic acid and benzoyl 
peroxide was clearly superior to either agent alone. The response was also 
swifter. The latter is important to maintain patient compliance. 
Papulo-pustules in particular regressed more rapidly with the combination. 
The drying effect was also greater and this was perceived as desirable in 
overcoming oiliness. 
All three treatments were well tolerated though temporary redness was more 
frequent with the combination. No subject dropped out of the study or 
thought the treatments too severe. 
TABLE I 
______________________________________ 
COMATIVE EFFICACY IN ACNE 
Excellent 
Good Fair Poor 
______________________________________ 
Salicylic acid 
3% 39% 44% 14% 
Benzoyl peroxide 
8% 46% 39% 7% 
Salicylic acid plus 
benzoyl peroxide 
14% 61% 23% 2% 
______________________________________ 
As pointed out previously, one of the features in the pathology of acne 
vulgaris is the formation of comedones. Any therapy that has a comedolytic 
effect should be beneficial in the treatment of this condition. The 
following Example demonstrates the comedolytic effect of a therapy that 
utilizes salicylic acid and benzoyl peroxide and further demonstrates that 
it is more effective for this purpose than the use of either alone. 
EXAMPLE 4 
Comedolytic Effect in Rabbit Ears 
Method: 
Comedones were induced in both external ear canals of albino rabbits by the 
daily application for two weeks of 5% crude coal tar ointment. 
The test agents were then applied once daily for two weeks to opposite 
sides. A group of five rabbits was used for each test. The tissue was 
biopsied and horizontally sectioned. The size of the comedones (follicular 
hyperkeratosis) was estimated under the microscope according to the 
following scale: 
0=none 
1=slight comedones 
2=moderate comedones 
3=large comedones 
The treatment groups were as follows: (1) 5% benzoyl peroxide gel 
(Composition B, Example 1) vs. 5% ethanolic salicylic acid (Composition A, 
Example 1) followed immediately by 5% benzoyl peroxide gel (Composition B, 
Example 1); (2) 5% ethanolic salicylic acid (Composition A, Example 1) vs. 
5% ethanolic salicylic acid (Composition A, Example 1) followed 
immediately by 5% benzoyl peroxide gel (Composition B, Example 1). 
Results: 
The results are summarized in Tables II and III below. In both comparisons, 
the comedones were unequivocally smaller on the combination side. It can 
be seen that salicylic acid alone is more comedolytic than benzoyl 
peroxide. 
TABLE II 
______________________________________ 
5% Benzoyl Peroxide 
vs. 
Sequential 5% Salicylic Acid and 
5% Benzoyl Peroxide 
Rabbit No. 5% Benzoyl Peroxide 
Combination 
______________________________________ 
1 2 1 
2 2 1 
3 1 0 
4 3 1 
5 2 0 
mean: 2.0 0.6 
______________________________________ 
TABLE III 
______________________________________ 
5% Salicylic Acid 
vs. 
Sequential 5% Salicylic Acid and 
5% Benzoyl Peroxide 
Rabbit No. 5% Salicylic Acid 
Combination 
______________________________________ 
1 1 0 
2 1 1 
3 2 1 
4 2 1 
5 1 0 
mean: 1.4 0.6 
______________________________________ 
As also indicated above, another feature of the pathology of acne vulgaris 
is the inflammation that results from the rupture of comedones. The acne 
bacillus, Propionibacterium acnes, plays an important causal role first in 
contributing to the formation of comedones and then by producing toxic 
products that cause their rupture. Any agent which reduces the level of 
these organisms within the follicles should have a beneficial effect in 
the treatment of acne. The following Example shows that the combination of 
salicylic acid and benzoyl peroxide greatly reduces the quantity of 
Propionibacterium acnes on the skin. Five percent benzoyl peroxide alone 
is a highly effective agent in reducing the density of Propionibacterium 
acnes, being more than 95% effective. It would hardly be expected that the 
combination of salicylic acid and benzoyl peroxide would be superior to 
benzoyl peroxide alone. The combination would have to be at least as 
effective as benzoyl peroxide alone in reducing Propionibacterium acnes. 
This is in fact the case as is demonstrated in Example 5 below (compare 
Tables IV and V). However, although benzoyl peroxide alone is equivalent 
to the combination as as antibacterial agent, this is only one aspect for 
measuring the effectiveness of these materials in the treatment of acne 
vulgaris. As already pointed out above by the least two other parameters, 
that are important in the treatment of acne vulgaris, the combination of 
salicylic acid and benzoyl peroxide were found to be superior to either 
salicylic acid or benzoyl peroxide alone. 
EXAMPLE 5 
Comparison of Anti-microbial Effect of 5% Benzoyl Peroxide alone and 5% 
Benzoyl Peroxide in Sequence with 5% Ethanolic Solution of Salicylic Acid 
Method: 
Two groups of ten healthy young adult black males were studied. These were 
selected because of facial characteristics associated with high levels of 
Propionibacterium acnes; namely, bright follicular fluorescence under the 
Woods light and excessive oiliness. 
The detergent scrub method was utilized to determine the density of 
Propionibacterium acnes on the cheeks. Samples were taken before and again 
after one and two weeks of treatment. 
The first group received 5% benzoyl peroxide gel (Composition B, Example 1) 
to the entire face twice daily for two weeks. In the second group, 5% 
salicylic acid solution (Composition A, Example 1) was applied twice 
daily, followed immediately each time with 5% benzoyl peroxide gel 
(Composition B, Example 1). 
It should be noted that a third group of ten subjects received 5% salicylic 
acid alone. There was no effect on the density of Propionibacterium acnes; 
hence the data are not given. 
TABLE IV 
______________________________________ 
5% Benzoyl Peroxide Gel 
Density of Propionibacterium Acnes 
(millions/cm.sup.2) 
Control Treatment 
Subject No. 
Pre-Treatment Week One Week Two 
______________________________________ 
1 6.5 5.3 3.9 
2 6.3 3.6 3.5 
3 4.4 2.2 2.0 
4 5.6 4.2 3.7 
5 6.2 2.7 3.0 
6 5.5 4.2 3.6 
7 7.0 4.9 4.5 
8 5.4 3.7 3.2 
9 7.1 4.3 4.0 
10 6.3 5.1 5.3 
mean: 6.03 4.02 3.67 
______________________________________ 
TABLE V 
______________________________________ 
Sequence of 5% Salicylic Acid 
and 5% Benzoyl Peroxide Gel 
Density of Propionibacterium Acnes 
(millions/cm.sup.2) 
Control Treatment 
Subject No. 
Pre-Treatment Week One Week Two 
______________________________________ 
1 5.5 4.1 3.2 
2 5.7 4.4 3.1 
3 5.5 2.5 2.8 
4 5.9 4.7 3.9 
5 5.2 3.7 3.0 
6 4.6 3.4 2.9 
7 6.1 4.2 3.2 
8 5.6 5.3 4.6 
9 6.5 2.3 2.5 
10 6.3 4.3 5.1 
mean: 5.69 3.89 3.43 
______________________________________ 
The following Example illustrates the utility of the simultaneous 
application of 5% salicylic acid and 5% benzoyl peroxide in an aqueous gel 
composition. In these tests, the antibacterial effect of this combination 
on Propionibacterium acnes was examined. 
EXAMPLE 6 
Method: 
The composition of Example 2A was applied twice daily for two weeks to the 
faces of ten healthy, young adult black males with oily skin. 
Propionibacterium acnes densities were determined before and again after 
one and two weeks of treatment. The results are summarized in Table VI. 
Results: 
These show that the reduction of Propionibacterium acnes with the 
combination was rather similar to that previously obtained with 
application of each agent in sequence. On the average, the 
Propionibacterium acnes population was reduced by 95% and more. The mixing 
of these two agents in one formulation does not result in loss of the 
desired effect although it takes somewhat longer to reach this effect. 
TABLE VI 
______________________________________ 
Combination of 5% Salicylic Acid 
and 5% Benzoyl Peroxide 
in a Gel Product 
(millions/cm.sup.2) 
Control Treatment 
Subject No. 
Pre-Treatment Week One Week Two 
______________________________________ 
1 6.3 4.8 4.6 
2 5.5 4.2 3.5 
3 4.8 3.8 3.2 
4 5.9 5.0 3.7 
5 7.0 4.6 3.6 
6 6.4 5.2 4.3 
7 5.2 4.1 2.4 
8 5.7 5.0 3.6 
9 6.1 4.3 2.5 
10 5.5 3.6 3.0 
mean: 5.8 4.5 3.4 
______________________________________