Topical composition and treatment of skin lesions therewith

Compositions and process employing guanidine compounds and peroxide compounds for treatment of acne and other skin lesions by topical application.

BACKGROUND OF THE INVENTION 
This invention relates to topical compositions comprising guanidine 
compounds and peroxide compounds and processes for the conjoint use of 
such compounds. More particularly, the invention relates to topical 
compositions for the treatment of skin lesions and methods for treating 
skin lesions whereby the irritation commonly produced by peroxide 
compounds is reduced. 
Acne and seborrhea are conditions of the human skin characterized by an 
excessive flow of sebum, or skin oil, from the sebaceous glands located in 
the pilosebaceous apparatus. Sebum reaches the skin surface through the 
duct of the hair follicle. The presence of excessive amounts of sebum in 
the duct and on the skin acts to block or stagnate the continuous flow of 
sebum from the follicular duct, thus producing a thickening and a 
solidification of the sebum to form a solid plug known as a comedone. When 
this process occurs, hyperkeratinization of the follicular opening is 
stimulated, thus completely closing the duct. The usual results are 
papules, pustules, or cysts, often contaminated with bacteria which cause 
secondary infections. Acne is particularly characterized by the presence 
of comedones, inflammatory papules, pustules, or cysts. The effect of acne 
ranges from slight skin irritation and pitting to disfiguring scars. 
Many topical therapeutic agents are employed in the treatment of acne and 
seborrhea to prevent the blocking of the follicular duct, to reopen the 
duct once it has become blocked, to act against the infecting bacteria or 
the thickened sebum, and to provide combinations of each of these actions. 
The horny outer layer of the skin (stratum corneum) is formed of dead 
cells composed largely of keratin. Therapeutic agents which act to prevent 
the blocking of the follicular duct by promoting the removal of sluffing 
off of excess keratin are known as keratolytic agents. Sulfur, resorcinol 
and salicylic acid have been used as keratolytic agents in the treatment 
of acne. 
For over sixty years, benzoyl peroxide has been used as a keratolytic agent 
in the topical treatment of skin lesions such as burns, varicose ulcers, 
sycosis vulgaris, seborrhea, and acne. Benzoyl peroxide, (C.sub.6 H.sub.5 
CO).sub.2 O.sub.2, is a colorless, odorless, tasteless, crystalline solid, 
stable at ordinary room temperatures; it is a powerful oxidizing agent, 
yet nontoxic to man. As noted, benzoyl peroxide has been used as a very 
effective keratolytic and antibacterial agent in the treatment of acne. 
While benzoyl peroxide is an effective topical agent for the treatment of 
skin lesions such as appear in acne or seborrhea, it has the undesirable 
side effect of being a contact irritant. Accordingly, some patients are 
denied the benefits of peroxide acne therapy because of the irritation 
problem. 
It has now been discovered that guanidine compounds used in conjunction 
with a peroxide compound will reduce the skin irritation caused by the 
peroxide compound. 
RELATED REFERENCES 
When used in the treatment of acne, benzoyl peroxide produces dryness, 
exfoliation, and a decrease in bacterial flora. The use of benzoyl 
peroxide in topical compositions for treating skin lesions such as burns, 
varicose ulcers, sycosis vulgaris, and acne has been known for some 60 
years. Levine, et al., Ohio State Med. J. 65, 492 (1969). 
Benzoyl peroxide formulations for the treatment of acne are disclosed in 
the following references: U.S. Pat. No. 3,535,422, Cox, et al., Oct. 20, 
1970; British Pat. Nos. 1,185,685, Fisher, Mar. 25, 1970; 1,163,044 
Stiefel Laboratories, Inc., Sept. 4, 1969; and 1,407,937 Stiefel 
Laboratories, Inc., Oct. 1, 1975. 
The use of benzoyl peroxide and benzoyl peroxide compositions for the 
treatment of skin lesions is well detailed in the technical literature, as 
is the irritation caused by benzoyl peroxide. The effectiveness of benzoyl 
peroxide and typical problems associated with its use, such as excessive 
drying, heavy scaling, edema, burning, peeling, redness, excessive 
erythema, allergic contact dermatitis, and sensitization reactions, are 
discussed in the following references: Brogden, et al., Drugs, 8, 417 
(1974); Poole, et al., Arch Derm. 102, 400 (1972); Eaglstein, arch. Derm. 
97, 527 (1968); Pace, Can. Med. Ass. J. 93, 252 (1965); Vasarinsh, Arch. 
Derm. 98, 183 (1968); Mysliborski, et al., AFP 15, 86, (1977); Hare, Br. 
J. Clin. Prac. 29, 63 (1975); Fulton, et al., Arch. Derm. 110, 83 (1974); 
and Wilkinson, et al., Can. Med. Ass. J. 95, 28 (1966). 
A reduction in, or control of, benzoyl peroxide irritation has been 
achieved by using certain gel formulations, or by temporarily suspending 
the topical application of the benzoyl peroxide compositions: Kuflik, et 
al., Cutis 17, 175 (1976); Liddell, Br. J. Clin. Prac. 28, 379 (1974); and 
Kirton, Br. J. Clin. Prac. 21, 127 (1967). 
The guanidine compounds used herein are well known; Condensed Chemical 
Dictionary, Van Nostrand Reinhold Co., 7th Ed., page 461 and The Extra 
Pharmacopeia, Martindale, 24th Ed., Vol. 1, page 1372. Various uses of 
inorganic guanidine salts are also known. For example, U.S. Pat. No. 
2,620,301, McLeod, Dec. 9, 1950, discloses the use of guanidine 
hydrochloride, carbonate, sulfate, and acetate in lubricant greases. 
Guanidine compounds are also known for use as antimicrobial agents and 
fungicides. French Pat. 1,218,170, Scanley, Dec. 14, 1959, discloses the 
use of alkyl guanidines and their salts as bactericides and fungicides in 
cutting oils. U.S. Pat. No. 3,312,589, Entley, et al., Apr. 4, 1967, 
discloses the use of n-dodecylguanidine acetate in a formulation as a 
fungicide; U.S. Pat. No. 3,628,941, Marks, Dec. 21, 1971, discloses the 
use of n-dodecylguanidine hydrochloride as an antimicrobial agent in 
cutting oils; U.S. Pat. No. 3,152,181, Shapiro, et al., Oct. 6, 1964, 
discloses the use of monobiguanide compounds as antimicrobial agents. U.S. 
Pat. No. 3,769,427, Hughes, et al., Oct. 30, 1973, discloses the use of 
aromatic guanidine compounds and their salts as vasoconstrictors. 
Attention is also drawn to the copending application of VanDuzee entitled 
"Skin Conditioning Compositions Containing Guanidine Inorganic Salts", 
Ser. No. 624,202, filed Oct. 20, 1975, which discloses the use of 
inorganic guanidine salts in cosmetic vehicles for moisturizing and 
conditioning skin and improving its flexibility. 
None of the foregoing references suggests the use of guanidine compounds 
with peroxides in the manner of the present invention. 
SUMMARY OF THE INVENTION 
The present invention encompasses compositions of matter comprising 
mixtures of guanidine compounds and peroxide compounds, especially in 
cosmetic vehicles, for the treatment of skin lesions. It has been 
discovered that guanidine compounds ameliorate the skin irritation effects 
of peroxide compounds. 
The use of peroxide compounds, especially benzoyl peroxide, for the 
treatment of acne and other skin lesions is well known. The use of 
guanidine compounds as fungicides and bactericides is also well known. The 
improvement provided by the present invention involves the conjoint use of 
these two types of compounds in the treatment of acne so that the peroxide 
can exert its healing effect while the guanidine compound exerts an 
assuasive effect so that the skin irritation often produced after 
prolonged topical use of the peroxide is reduced. 
The present invention also encompasses an improved method for treating skin 
lesions, especially acne lesions, by topically applying a safe and 
effective amount of peroxide compound to the afflicted situs in 
conjunction with a guanidine compound, whereby skin irritation caused by 
the peroxide compound is reduced.

DETAILED DESCRIPTION OF THE INVENTION 
The dermatological compositions herein comprise mixtures of 
toxicologically-acceptable peroxide compounds and 
toxicologically-acceptable guanidine compounds. These compositions are 
useful for the treatment of skin lesions, especially those of acne, with 
less skin irritation than normally occurs when only the peroxide compounds 
are used. 
The compositions herein comprise a safe and effective amount of a guanidine 
compound and a safe and effective amount of a peroxide compound, all as 
described more fully hereinafter. Said guanidine and peroxide compounds 
can be used as solutions or as suspensions in the form of small 
(preferably impalpable) particles, said particles being suspended in 
insoluble form in a compatible fluid carrier, especially water or a 
pharmaceutically and cosmetically acceptable carrier. 
By "safe and effective amount of a guanidine compound" herein is meant a 
sufficient amount of said guanidine compound to reduce skin inflammation, 
irritation, peeling, flaking, and other adverse effects resulting from the 
use of peroxide compounds, especially benzoyl peroxide. The amount of 
guanidine compound used will vary with the particular condition being 
treated, the severity of the condition, the duration of the treatment, the 
specific peroxide compound employed and its usage concentration, the 
severity of the reaction to the peroxide compound, and like factors within 
the specific knowledge and expertise of the patient or the attending 
physician. 
By "safe and effective amount of a peroxide compound" herein is meant a 
sufficient amount of said peroxide compound to alleviate skin lesions at a 
reasonable benefit/risk ratio attendant with any medical treatment. Within 
the scope of sound medical judgment, the amount of peroxide compound used 
will vary with the particular condition being treated, the severity of the 
condition, the duration of the treatment, the specific peroxide compound 
employed and its concentration, and like factors within the specific 
knowledge and expertise of the patient or the attending physician. 
By "toxicologically- or pharmaceutically-acceptable" herein is meant 
ingredients which are suitable for use in contact with the tissues of 
humans and lower animals without undue toxicity, irritation, allergic 
response, and the like, commensurate with a reasonable benefit/risk ratio. 
By the term "comprising" herein is meant that various other, compatible 
drugs and medicaments, as well as inert ingredients and cosmetic vehicles, 
can be conjointly employed in the compositions and processes of this 
invention, as long as the critical guanidine compounds and peroxide 
compounds are used in the manner disclosed. The term "comprising" thus 
encompasses and includes the more restrictive terms "consisting of" and 
"consisting essentially of" which characterize the use of the essential 
ingredients in the manner disclosed herein. 
By "applying topically" herein is meant directly laying on or spreading on 
epidermal tissue, especially outer skin. 
By "afflicted situs" herein is meant a localized area of inflammation or 
lesion, and the immediate surrounding area. 
By "skin lesion" herein is meant macules, patches, papules, plaques, 
nodules, comedones, burns, varicose and other skin ulcers, seborrhea, 
sycosis vulgaris, pustules, cysts, and similar afflictions treated 
medically by the application of peroxide compounds. 
By "acne" herein is meant common acne, acne vulgaris, in all forms 
including papular, pustular, or cystic. 
By "in conjunction with" herein is meant application of the guanidine 
compound either before, after, or at the same time as the application of 
the peroxide compound. 
By "treating" herein is meant the topical use of the compositions herein on 
an afflicted situs and the process of topically applying a guanidine 
compound in conjunction with a peroxide compound to an afflicted situs. 
By "particulate" herein is meant particles of the guanidine or peroxide 
compound within a size range below a diameter of about 0.1 mm. Particles 
below a diameter of about 0.05 mm are said to be "impalpable", inasmuch as 
they cannot be felt and recognized as particles on the skin of the average 
user and are preferred for use herein. 
The guanidine compounds and peroxide compounds critical to the practice of 
this invention are disclosed more fully hereinafter. Other ingredients 
which can be included in the compositions to provide aesthetic and 
cosmetic benefits and to facilitate use are also disclosed hereinafter. 
All percentages herein are by weight, unless otherwise specified. 
The guanidine compounds (a term which includes the biguanides) used herein 
are of the formula: 
##STR1## 
and organic or inorganic salts thereof; and the biguanides. 
##STR2## 
and organic or inorganic salts thereof, wherein each R group can be, for 
example, hydrogen, halogen, or organic substituents. Guanidine compounds 
comprise from about 1% to about 25% of the present compositions, 
preferably from 1% to 15%, and most preferably from 5% to 10%. 
By "inorganic guanidine compounds" herein is meant compounds of the above 
formulae wherein the R groups are hydrogen. Salts formed by reacting 
inorganic or organic acids and inorganic guanidine free bases are common 
inorganic guanidine compounds. Preferred inorganic guanidine compounds are 
inorganic guanidine salts such as guanidine hydrobromide, guanidine 
sulfate, guanidine bisulfite, guanidine carbonate, guanidine phosphate, 
and most preferably, guanidine hydrochloride. 
Organic guanidine compounds as used herein include guanidine compounds 
wherein any one or more of the R groups in the above formulae are organic 
substituents. Organic guanidine compounds may also be converted into salts 
by reacting the selected organic guanidine free base with an appropriate 
inorganic or organic acid. Preferred acids include hydrochloric, sulfuric, 
nitric, hydrobromic, hydroiodic, maleic, citric, acetic, tartaric, 
benzoic, propionic, and carbonic acids, all of which are well known for 
their formation of pharmaceutically acceptable salts. 
Alkyl guanidine compounds as used herein include guanidine compounds 
wherein R.sup.1, R.sup.2, R.sup.3, or R.sup.4 are alkyl groups having from 
one to eighteen carbon atoms, preferably from one to ten carbon atoms and 
most preferably are methyl guanidine, ethyl guanidine or n-dodecyl 
guanidine. Alkyl guanidines are typically produced by the reaction of a 
substituted or unsubstituted cyanamide with a primary or secondary amine 
hydrochloride, for example, cyanamide with methylamine hydrochloride to 
produce methyl guanidine hydrochloride. 
Aromatic guanidine compounds as used herein include compounds of formula 
(A) wherein one or more R groups are aryl substituents. Aromatic guanidine 
compounds are known compounds which are typically produced by the reaction 
of a substituted or unsubstituted cyanamide with an aryl amine 
hydrochloride, for example, cyanamide with aniline hydrochloride to 
produce phenyl guanidine hydrochloride. 
Biguanide compounds used herein include monobiguanide compounds of formula 
(B) wherein the R groups are hydrogen or organic substituents such as 
C.sub.1 -C.sub.20 alkyl, alkenyl, alkaryl, alkoxyalkyl, cycloalkyl, 
aralkyl, haloaralkyl, aryl, and haloaryl. 
Typical biguanide compounds are prepared by the aminolysis of 
bicyanodiamides, for example, dicyanoamide with methylamine hydrochloride 
to form methyl biguanide hydrochloride. Further details of the preparation 
of the guanidine compounds are found in the texts, OPEN CHAIN NITROGEN 
COMPOUNDS, Vol. I, Benjamin, 1965, and THE CHEMISTRY OF ORGANIC CYANOGEN 
COMPOUNDS, Reinhold, 1947. 
Other especially useful guanides are those disclosed in U.S. Pat. Nos. 
3,152,181 and 3,769,427 incorporated herein by reference. 
The term "peroxide compounds" as used herein encompasses compounds of the 
formula R.sub.1 --O--O--R.sub.2, where R.sub.1 and R.sub.2 are hydrogen or 
organic substituents. Preferred peroxide compounds include hydrogen 
peroxide and its salts and substituted or unsubstituted benzoyl peroxide, 
the most preferred compound being benzoyl peroxide. All such peroxides are 
items of commerce. Peroxide compounds comprise from about 1% to about 25% 
of the compositions, preferably from 1% to 15% and most preferably from 5% 
to 10%. 
In addition to the guanidine compounds and peroxide compounds, the 
compositions described herein can include any cosmetic vehicle which does 
not react with the guanidine compound or the peroxide compound. Typical 
compositions may include emollients such as hydrocarbon oils and waxes, 
lanolin and lanolin derivatives, silicone oils, triglyceride esters, fatty 
acids, fatty alcohols, alkyl and alkenyl esters of fatty acids, polyhydric 
alcohols and polyether derivatives, wax esters, and beeswax derivatives. 
Such emollients preferably comprise from 10% to 50% of the compositions. 
Emulsifiers of the nonionic, anionic, or cationic classes can also be used, 
and will usually comprise from 1% to 10% of the composition. Suitable 
emulsifiers include nonionic emulsifiers, such as fatty acid 
monoglycerides, fatty alcohols, polyethylene glycols, and propylene 
glycols, anionic emulsifiers, such as alkyl ethoxy ether sulfonates, 
ammonium alkyl sulfates, and fatty acid soaps, and cationic emulsifiers, 
such as quaternary ammonium, morpholinium and pyridinium compounds. When 
an emollient which has emulsifier properties is used, less additional 
emulsifier is necessary. 
Chelating agents such as EDTA, nitrilotriacetate, and gluconic, citric, and 
tartaric acids, preferably at a level of from 0.01% to 1% of the 
composition, are used to avoid the decomposition of the peroxide compound 
by metal ions. 
Optional components such as finely divided sulfur, USP grade, at a level of 
from 1% to 25% of the composition, thickening agents, such as methyl 
cellulose, cross-linked carboxyl polymethylene polymers, bentonite, gum 
tragacanth, gum kharaya, and polyethylene glycols, at a level of from 1% 
to 10% of the composition, and trace amounts of fragrance materials such 
as perfumes can also be used. The balance of the composition comprises 
water. 
The compositions are typically prepared by thoroughly blending all of the 
components together in admixture and milling, if necessary, to reduce all 
particles to impalpable size. The benzoyl peroxide should be of high 
purity, on the order of 97% to 100% pure, and in the form of a finely 
divided powder. The powder may be either wet or dry, but is preferably wet 
for ease of handling and safety. If wet benzoyl peroxide is used, it may 
be necessary to grind the crystals before admixture or to mill the 
composition after admixture and blending to reduce the crystals to 
impalpable size. Preferably, the milling or grinding operation is 
performed in the cold to prevent decomposition of the peroxide by 
localized friction. 
The following examples illustrate the present methods and compositions, but 
are not intended to be limitations thereof. The compositions are typically 
applied twice daily to acne lesions. The typical usage rate is about 0.001 
g/cm.sup.2 skin to about 0.5 g/cm.sup.2 skin, per application, but this 
can vary with the user, the severity of the affliction, and the 
concentrations of guanidine compound and peroxide compound in the 
particular composition being used. 
EXAMPLE I 
______________________________________ 
ANTI-IRRITANT COMPOSITION A 
______________________________________ 
Guanidine.HCl 5% 
Propylene glycol 14% 
PEG 400 6% 
Water Balance 
______________________________________ 
______________________________________ 
TREATMENT COMPOSITION B 
______________________________________ 
Benzoyl peroxide 5% 
Gum tragacanth 10% 
Water Balance 
______________________________________ 
Admix and thoroughly blend Compositions (A) and (B). Mill Composition (B) 
until all particles are impalpable. Apply Composition (B) to acne lesions 
at a rate of about 0.01 g/cm.sup.2 skin twice per day. Either immediately 
after or immediately before each application of (B), apply (A) at the same 
rate. 
Acne lesions treated in the foregoing manner over a two-week period are 
markedly improved with reduced incidence of irritation by the benzoyl 
peroxide. 
EXAMPLE II 
______________________________________ 
Ethyl guanidine 10% 
Benzoyl peroxide 10% 
Poloxyethylene lauryl ether 
6% 
Acidified colloidal magnesium 
aluminum silicate gel and water 
Balance 
______________________________________ 
Admix and carefully and thoroughly blend the component. As necessary, 
carefully mill the composition until all particles are impalpable. Apply 
0.05 g/cm.sup.2 skin twice a day to the acne lesions. 
EXAMPLE III 
______________________________________ 
N.sup.1 - (lauroxypropyl) biguanide 
15% 
Benzoyl peroxide 5% 
Ethyl stearate 17% 
Sorbitol 15% 
Water Balance 
______________________________________ 
Admix and carefully and thoroughly blend the components. As necessary, 
carefully mill the composition until all particles are impalpable. Apply 
twice daily at 0.5 g/cm.sup.2 skin twice a day to the acne lesions. 
EXAMPLE IV 
______________________________________ 
Phenyl guanidine hydrochloride 
5% 
Benzoyl peroxide 5% 
Methoxypolyethylene glycol 
10% 
Diethylene glycol 5% 
Bentonite 5% 
Water Balance 
______________________________________ 
Admix and blend the components. As necessary, mill carefully until all 
particles are impalpable. Apply topically to acne lesions twice a day at 
0.01 g/cm.sup.2 skin. 
EXAMPLE V 
______________________________________ 
Methyl guanidine carbonate 
5% 
Hydrogen peroxide 5% 
EDTA 0.5% 
Sulfur (colloidal) 2% 
Stearic acid 10% 
Water Balance 
______________________________________ 
Admix and blend the components. Apply topically to acne lesions twice a day 
at 0.05 g/cm.sup.2 skin. 
The compositions of Examples IV and V may also be used topically in the 
treatment of seborrhea at the same rate of application. 
Further examples include the composition of Example IV wherein the phenyl 
guanidine hydrochloride is replaced by alkoxypropyl biguanides as 
disclosed in U.S. Pat. No. 3,152,181, for example, N.sup.1 
-(lauroxypropyl), N.sup.5 -(dibenzyl)-biguanide; N.sup.1 
-(lauroxypropyl)-N.sup.5 -(methyl),N.sup.5 
-(2,4-dichlorobenzyl)-biguanide; and N.sup.1 -(lauroxypropyl),N.sup.5 
-(2,4-dichlorobenzyl)-biguanide. The phenyl guanidine hydrochloride of 
Example IV may also be replaced by aromatic guanidine compounds as 
disclosed in U.S. Pat. No. 3,769,427, for example, 
3'-chloro-4'-hydroxyphenylguanidine hydrochloride and 
3'-fluoro-4'-tolyguanidine nitrate. Still further examples include the 
composition of Example IV wherein the phenyl guanidine hydrochloride is 
replaced by N.sup.1 -dimethyl guanidine citrate; n-dodecyl guanidine 
carbonate; N.sup.1 -dibutylguanidine; N.sup.1 -amoxyguanidine 
hydrochloride; N.sup.1 -(1-hydroxyethyl) guanidine tartrate; and N.sup.1 
-dimethoxy guanidine. 
As can be seen from the foregoing, compositions of the present invention 
comprising a guanidine material and a peroxide, conveniently at a weight 
ratio in the range of about 10:1 to 1:10 and preferably about 1:1 to about 
2:1, provide excellent therapy for acne and like diseases.