Therapeutic treatment of dry skin

Preventive as well as therapeutic treatment to alleviate the symptoms of disorders characterized by cracking, flaking or scaling of the skin consisting of the topical application of a lotion, cream or ointment containing one or more of the .alpha.- or .beta.-hydroxy acids or .alpha.-keto acids and esters thereof, their amides and their ammonium salts is disclosed. The compounds include free acid, amide and/or ammonium salt forms of citric acid, glycolic acid, glucoronic acid, galacturonic acid, glucuronolactone, gluconolactone, .alpha.-hydroxybutyric acid, .alpha.-hydroxyisobutyric acid, lactic acid, malic acid, mandelic acid, mucic acid, pyruvic acid, methyl pyruvate, ethyl pyruvate, .beta.-phenyllactic acid, .beta.-phenylpyruvic acid, saccharic acid, tartaric acid, tartronic acid, and .beta.-hydroxybutyric acid. The therapeutic composition may include one or more of the compounds present in the total amount of from one to twenty percent. Topical application to affected areas has been found to achieve amelioration of the dry skin.

This invention relates to a treatment for skin disorders characterized by 
cracking, flaking or scaling of hands, feet or the body commonly known as 
"dry skin", and specifically to compounds which have been found to be 
effective when topically applied to prevent as well as heal the skin 
lesions associated with these conditions in humans. 
Severe "dry skin" conditions known as ichthyosis are hereditary disorders. 
The term ichthyosis alludes to a fish scale-like appearance of the human 
skin. Ichthyosis, characterized by a "dry skin" appearance, is usually 
detected during the early years of childhood. Small, fine scales with a 
"pasted-on" appearance are found most prominently on the trunk and upper 
extremities. Larger, more adherent scales are present on the legs. Only a 
small number of the population are affected by this hereditary disorder. 
In contrast to ichthyosis, mild to moderate "dry skin" conditions are quite 
common among the population. These common "dry skin" conditions are 
specially pronounced during the fall and winter seasons, when 
environmental humidity is comparatively low. They are characterized by 
fissures, chaps, cracks or flakes of the skin on hands, face, neck and 
legs. 
Conventional treatments for all kinds of dry skin conditions primarily 
involve the topical application of oils or oil preparations, and hydrating 
emollients. In addition, ointments containing salicylic acid, urea, 
glycerol, propylene glycol, sorbitol or vitamin A have been used. Prior 
treatments, however, have not been universally successful, and have, in 
many cases, been unable to promote healing to cause a complete remission 
of the symptoms. Because the mechanisms involved in causing dry skin are 
not known, treatment has usually resulted in a temporary remission or 
healing of the flaky or scaly lesions. 
We have now discovered that "dry skin" conditions may be successfully 
prevented or treated with the acid, amide or ammonium salt of .alpha.- or 
.beta.-hydroxyacids or .alpha.-keto acids and esters thereof. The 
compounds of the present invention include citric acid, glycolic acid, 
glucuronic acid, galacturonic acid, glucuronolactone, gluconolactone, 
.alpha.-hydroxybutyric acid, .alpha.-hydroxyisobutyric acid, lactic acid, 
malic acid, mandelic acid, mucic acid, pyruvic acid, methylpyruvate, ethyl 
pyruvate, .alpha.-phenylactic acid, .alpha.-phenylpyruvic acid, saccharic 
acid, tartaric acid, tartronic acid, and .alpha.-hydroxybutyric acid. 
Generally, the amide may be formed from acid anhydride or lactone and 
ammonia or any organic primary or secondary amine. The ammonium salt may 
be formed directly from acid and an organic primary, secondary or tertiary 
amine. 
Preferred organic primary amines include any alkylamines such as 
methylamine and ethylamine; ethanolamines such as monoethanolamine and 
monoisopropanolamine; and diamines such as ethylenediamine and 
1,2-diaminopropane. 
Preferred organic secondary amines include dialkylamines such as 
dimethylamine and diethylamine; diethanolamine and diisopropanolamine; 
N-methylethanolamine and N-ethylethanolamine. 
Preferred organic tertiary amines include trialkylamines such as 
trimethylamine and triethylamine; triethanolamine; N-methyldiethanolamine 
and triisopropanolamine. 
It has been established through tests on humans having "dry skin" 
conditions that topical application of a lotion, cream or ointment 
containing from 1 to 20 percent of at least one acid, the ester or the 
amide or the ammonium salt of the present invention and preferably from 2 
to 10 percent thereof, is therapeutically effective, when applied on a 
daily basis, to cause, within about one to two weeks, a return of the 
affected areas to a normal skin condition. If two or more acids, amides or 
ammonium salts are used in a composition of the invention, the total 
concentration of the compounds is preferred not to exceed 10 percent by 
weight of the composition. It has also been found in humans having 
frequent occurrence of cracking or flaking skin that topical application 
of the aforementioned composition of the present invention is effective, 
when applied on a daily basis, in preventing development of dry skin 
lesions. 
Accordingly, it is the object of this invention to provide a cosmetic 
composition containing at least one of the acids, the amides and/or the 
ammonium salts, which when topically applied will reliably prevent the 
development of dry skin conditions. 
It is another object of this invention to provide a medicinal composition 
containing at least one of the acids, the amides and/or the ammonium salts 
which when topically applied will substantially alleviate the symptoms of 
dry skin. 
It is still another object to provide a method for treating dry skin with a 
nonirritant and nontoxic lotion, cream or ointment of the present 
invention. 
It is still another object to provide a safe and efficient method for 
treating the symptoms of dry skin through regular topical application of a 
medicinal composition which will promote healing within about one to two 
weeks. 
It is still another object of this invention to provide a method for 
formulating a cosmetic as well as medicinal composition in lotion, cream 
or ointment which when topically applied at least daily to skin areas 
prone to lesions of cracking, flaking or scaling will prevent the 
development of dry skin or result in a restoration of normal healthy skin 
condition.

PREATION OF THE THERAPEUTIC COMPOSITIONS 
Previously, in treatment of extremely dry skin conditions such as 
ichthyosis, .alpha.- or .beta.-hydroxyacids or .alpha.-ketoacids were 
prepared in a composition containing 5 to 10 percent by weight of the 
compounds in a cream or ointment. The pH of the composition was about 2 or 
less. In treatment of common dry skin conditions according to this 
invention we found that the above composition with low pH could cause some 
skin irritation (redness and sensation of burning) on some of the 
sensitive subjects. It was therefore desirable to develop compositions 
which were therapeutically effective but not irritative. 
Most inorganic alkalis, forming inorganic salts with .alpha.- or 
.beta.-hydroxyacids or .alpha.-ketoacids that do not readily penetrate 
human skin, cannot be used to neutralize these acids. It has previously 
been discovered that certain organic bases, and ammonium hydroxide, may be 
successfully used to raise the pH of the compositions containing .alpha.- 
or .beta.-hydroxy acids or .alpha.-ketoacids without compromising the 
therapeutic efficaciousness of the active ingredients. Under such 
conditions the active ingredients are in the form of amide or ammonium 
salt. The organic bases may include any organic amine of primary, 
secondary or tertiary family. The organic primary amines may include any 
alkylamines such as methylamine and ethylamine; and ethanolamines such as 
monoethanolamine and monoisopropanolamine; any diamines such as 
ethylenediamine and 1,2-diaminopropane. The organic secondary amines may 
include dialkylamines such as dimethylamine and diethylamine; 
diethanolamine and diisopropanolamine; N-methylethanolamine and 
N-ethylethanolamine. The organic tertiary amines may include 
trialkylamines such as trimethylamine and triethylamine; triethanolamine; 
N-methyldiethanolamine and triisopropanolamine. 
The .alpha. and .beta.-hydroxyacids, .alpha.-ketoacids and the esters of 
the present invention include citric acid, glycolic acid, glucuronic acid, 
galacturonic acid, glucuronolactone, gluconolactone, 
.alpha.-hydroxybutyric acid, .alpha.-hydroxyisobutyric acid, lactic acid, 
malic acid, mandelic acid, mucic acid, pyruyic acid, methyl pyruvate, 
ethyl pyruvate, .beta.-phenyllactic acid, .beta.-phenylpyruvic acid, 
saccharic acid, tartaric acid, tartronic acid and .beta.-hydroxybutyric 
acid. 
Generally, a nonirritating composition of this invention should have a pH 
of the lotion, cream or ointment between 3.5 and 7.5. 
To prepare an amide or an ammonium salt of the present invention the 
lactone or the hydroxyacid or the ketoacid is allowed to react at room 
temperature with ammonium hydroxide or an organic amine in aqueous or 
alcoholic aqueous solution. Generally, the amide or ammonium salt thus 
formed needs no isolation procedure and may be directly incorporated into 
the therapeutic composition. 
The initial concentration of .alpha. or .beta.-hydroxyacid or 
.alpha.-ketoacid may range from 1 to 20 percent by weight of the total 
composition. The preferred concentration range, however, is from 2 to 10 
percent. 
Ordinary distilled water may be used as a solvent in the preparation of the 
composition. The concentration of the solvent may range from 5 to 30 
percent by volume of the total composition. 
In a variety of methods for formulating a composition of the present 
invention two or more than two different amides or ammonium salts may be 
utilized in the composition. 
The prophylactic as well as therapeutic composition may be prepared in a 
form of lotion, cream or ointment. In these instances, cosmetically 
acceptable ingredients are incorporated into the formulation, and lotions, 
creams or ointments are readily prepared. 
The following are illustrative examples of formulations of compositions 
according to this invention. Although the examples utilize only selected 
formulations useful according to this invention, it should be understood 
that the following examples are illustrative and not limited. Therefore, 
any of the aforementioned acids, esters and amines may be substituted 
according to the teachings of this invention in the following 
formulations. 
EXAMPLE 1 
Glycolic acid, 5 grams was dissolved in 10 ml water and ethanolamine, 3 ml 
was added to partially neutralize the acidity of the solution. This 
solution was admixed with 82 grams of water-nonwashable lotion prepared 
from mineral oil, cottonseed oil, isopropyl palmitate and water with a 
surfactant such as sorbitan sesquioleate. The ingredients of said lotion 
are present in 15:15:5:60:5 parts by weight, respectively. The lotion thus 
prepared is stored in a plastic squeeze bottle having a nozzle attached 
thereto. 
EXAMPLE 2 
Lactic acid, USP grade 5 ml was dissolved in 10 ml of water and 
triethanolamine, 5 ml was added to neutralize partially the acidity of the 
solution. This solution was admixed with 80 grams of water-nonwashable 
lotion prepared from mineral oil, cottonseed oil and water with a 
surfactant such as sorbitan sesquioleate. The ingredients of said lotion 
are present in 30:15:50:5 parts by weight respectively. 
EXAMPLE 3 
Part A: 
Polyoxyethylene (20) sorbitan monooleate (hereinafter Tween 80): 5 gm 
Cetyl alcohol: 20 gm 
Part B: 
Water: 45 ml 
Propylene glycol: 10 ml 
Glycolic acid: 10 gm 
Ethanolamine: 7 ml 
Heat Part A to 75.degree. C and heat Part B to 75.degree. C. Add Part B 
slowly to Part A with agitation. Continue agitation until the mixture is 
congealed. The water-washable cream thus prepared has a pH of 4.7. 
EXAMPLE 4 
Part A: 
Tween 80: 5 gm 
Cetyl alcohol: 22 gm 
Part B: 
Water: 55 ml 
Propylene glycol: 10 ml 
Lactic acid: 5 ml 
Ethanolamine: 2 ml 
Heat Part A to 75.degree. C and heat Part B to 75.degree. C. Add Part B 
slowly to Part A with agitation. Continue agitation until the mixture is 
congealed. The water-washable cream thus prepared has a pH of 4.5. 
EXAMPLE 5 
Part A: 
Tween 80: 5 gm 
Cetyl alcohol: 15 gm 
Stearyl alcohol: 5 gm 
Part B: 
Water: 60 ml 
Propylene glycol: 5 ml 
Citric acid: 2 gm 
Lactic acid: 2 ml 
Glycolic acid: 2 gm 
Ethanolamine: 3 ml 
Heat both Part A and Part B to 75.degree. C. Add Part B slowly to Part A 
with agitation. Continue agitation until the mixture is congealed. The 
water-washable cream containing three active ingredients has a pH of 4.4. 
EXAMPLE 6 
Glycolic acid, 7 grams was dissolved in 10 ml of ice water and 
ethanolamine, 5 ml was added to neutralize partially the acidity of the 
solution. This solution was admixed with 78 grams of water-nonwashable 
ointment prepared from petrolatum, mineral oil, spermaceti and water with 
a surfactant such as sorbitan sesquioleate. The ingredients of said 
ointment are present in 10:10:6:68:6 parts by weight, respectively. 
EXAMPLE 7 
Lactic acid, USP grade 5 ml was dissolved in 10 ml of ice water and 
triethanolamine, 4 ml was added to neutralize partially the acidity of the 
solution. This solution was admixed with 81 grams of water-nonwashable 
ointment prepared from petrolatum, mineral oil, isopropyl myristate, 
spermaceti and water with a surfactant such as sorbitan sesquioleate. The 
ingredients of said ointment are present in 10:10:10:6:58:6 parts by 
weight, respectively. 
EXAMPLE 8 
.alpha.-Hydroxyisobutyric acid, 5 grams and sorbitol 2 grams were dissolved 
in 8 ml of water. This solution was admixed with 85 grams of 
water-nonwashable ointment prepared from petrolatum, mineral oil, 
spermaceti and water with a surfactant such as sorbitan sesquioleate. The 
ingredients of said ointment are present in 10:10:6:68:6 parts by weight, 
respectively. 
EXAMPLE 9 
Pyruvic acid 2 ml, glycolic acid 2 grams, citric acid 2 grams, and lactic 
acid 2 ml were dissolved in 12 ml of water. This solution was admixed with 
commercially available USP grade hydrophilic ointment (80 grams) to a 
uniform consistency. A water-washable ointment thus prepared contained 
four active ingredients. 
TEST RESULTS 
(A) Severe Dry Skin 
Ten patients with severe dry skin conditions such as ichthyosis were 
instructed first to wet the body by taking a shower and then apply a thin 
film of the compositions formulated according to Examples 4, 7 or 9 on 
left side of the body. Other commercially available preparations such as 
vegetable oil or petrolatum were applied on right side of the body. Twice 
daily topical application was continued for several weeks. In all the 
patients tested the left side of the body became less flaky and felt 
smoother than the right side after about a week of topical treatment. The 
rough and flaky lesions on the left side of the body were substantially 
clear after ten days of treatment. The left side of the body devoid of any 
cracking, flaking or scaling usually reached an improved state comparable 
to normal appearing skin within two to three weeks after initial 
treatment. Very little or no substantial improvement was seen on the right 
side of the body, which had been treated with vegetable oil or petrolatum 
alone. Therefore after three weeks the patients were instructed to apply 
the composition of the present invention on the right side of the body. 
Again, the skin on the right side of the body became normal appearing 
within two to three weeks. 
Once a normal appearing skin was restored, it remained improved for from 
several weeks to several months, varying from patient to patient, without 
further application of the ointment. It was, however, necessary to 
continue the application of the ointment in order to maintain the skin 
free from recurrence of the overt disease. 
(B) Common Dry Skin 
Human subjects with mild to moderate degrees of dry skin conditions, as 
evidenced by dry, cracking or flaking of the skin, were instructed to 
apply topically the lotion, cream or ointment of the present invention 
formulated according to Examples 1 through 8 on the affected skin areas. 
Twice daily topical application was continued for a few weeks. In all the 
twenty-three human subjects tested the feeling of the skin dryness 
disappeared after three to four days of topical treatment. In twenty-one 
human subjects tested the rough and cracked skin usually became less 
pronounced within a week time. Generally the skin appeared normal and felt 
smooth after about two weeks of topical treatment. 
In contrast to the severe dry skin disease the common dry skin conditions 
once restored to normal appearing skin remained improved for some time 
until causes of dry skin, such as low humidity, cold weather, detergents, 
soaps, chemicals, etc., recurred. On continued use it was also found that 
twice daily topical application of a composition of the present invention 
prevented the development of new dry skin lesions. 
The invention may be embodied in other specific forms without departing 
from the spirit or essential characteristics thereof. The present 
embodiment is, therefore, to be considered in all respects as illustrative 
and not restrictive, the scope of the invention being indicated by the 
appended claims rather than by the foregoing description, and all changes 
which come within the meaning and range of equivalency of the claims are, 
therefore, intended to be embraced therein.