U.S. patent application number 10/071345 was filed with the patent office on 2003-01-23 for additives enhancing topical applications of therapeutic agents.
This patent application is currently assigned to TriStrata, Inc.. Invention is credited to Scott, Eugene J. Van, Yu, Ruey J..
Application Number | 20030017130 10/071345 |
Document ID | / |
Family ID | 25483418 |
Filed Date | 2003-01-23 |
United States Patent
Application |
20030017130 |
Kind Code |
A1 |
Yu, Ruey J. ; et
al. |
January 23, 2003 |
Additives enhancing topical applications of therapeutic agents
Abstract
Preventive as well as therapeutic treatment to alleviate
cosmetic conditions and symptoms of dermatologic disorders with
amphoteric compositions containing alpha hydroxyacids, alpha
ketoacids, related compounds or polymeric forms of hydroxyacids is
disclosed. The cosmetic conditions and the dermatologic disorders
in which the amphoteric compositions and the polymeric compounds
may be useful include dry skin, dandruff, acne, keratoses,
psoriasis, eczema, pruritus, age spots, lentigines, melasinas,
wrinkles, warts, blemished skin, hyperpigmented skin,
kyperkeratotic skin, inflammatory dermatoses, skin changes
associated with aging, and skin requiring cleansers.
Inventors: |
Yu, Ruey J.; (Ambler,
PA) ; Scott, Eugene J. Van; (Abington, PA) |
Correspondence
Address: |
AKIN, GUMP, STRAUSS, HAUER & FELD, L.L.P.
ONE COMMERCE SQUARE, SUITE 2200
2005 MARKET STREET
PHILADELPHIA
PA
19103
US
|
Assignee: |
TriStrata, Inc.
|
Family ID: |
25483418 |
Appl. No.: |
10/071345 |
Filed: |
February 8, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10071345 |
Feb 8, 2002 |
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09774822 |
Jan 30, 2001 |
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09774822 |
Jan 30, 2001 |
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09510368 |
Feb 22, 2000 |
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09510368 |
Feb 22, 2000 |
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09222995 |
Dec 30, 1998 |
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09222995 |
Dec 30, 1998 |
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08926030 |
Sep 9, 1997 |
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5962526 |
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08926030 |
Sep 9, 1997 |
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08487684 |
Jun 7, 1995 |
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5691378 |
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08487684 |
Jun 7, 1995 |
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08179190 |
Jan 10, 1994 |
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5470880 |
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08179190 |
Jan 10, 1994 |
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08089101 |
Jul 12, 1993 |
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5389677 |
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08089101 |
Jul 12, 1993 |
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08008223 |
Jan 22, 1993 |
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5665776 |
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08008223 |
Jan 22, 1993 |
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07812858 |
Dec 23, 1991 |
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07812858 |
Dec 23, 1991 |
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07469738 |
Jan 19, 1990 |
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07469738 |
Jan 19, 1990 |
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06945680 |
Dec 23, 1986 |
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Current U.S.
Class: |
424/78.03 |
Current CPC
Class: |
A61Q 5/006 20130101;
A61Q 17/005 20130101; A61K 31/192 20130101; A61K 31/715 20130101;
A61K 31/405 20130101; A61Q 17/04 20130101; A61K 8/38 20130101; A61K
8/365 20130101; A61K 8/347 20130101; A61K 8/676 20130101; A61K
45/06 20130101; A61Q 19/08 20130101; A61K 8/42 20130101; A61K 31/40
20130101; A61K 8/671 20130101; A61K 31/195 20130101; A61K 47/183
20130101; A61K 31/70 20130101; A61K 8/63 20130101; A61Q 19/007
20130101; A61K 31/445 20130101; A61K 31/66 20130101; A61K 31/715
20130101; A61K 47/24 20130101; A61K 8/43 20130101; A61K 31/445
20130101; A61K 31/20 20130101; A61K 31/7048 20130101; A61K 31/191
20130101; A61K 8/60 20130101; A61K 47/12 20130101; Y10S 514/946
20130101; A61K 31/365 20130101; A61K 31/415 20130101; A61Q 5/02
20130101; A61K 31/70 20130101; A61K 31/194 20130101; A61Q 19/02
20130101; A61Q 17/00 20130101; A61K 8/375 20130101; A61K 31/202
20130101; A61K 31/40 20130101; A61Q 7/00 20130101; A61K 8/37
20130101; A61K 47/26 20130101; A61K 31/366 20130101; A61K 31/19
20130101; A61K 31/195 20130101; A61K 31/405 20130101; A61Q 19/00
20130101; A61K 8/4953 20130101; Y10S 514/947 20130101; A61K 8/494
20130101; A61K 9/0014 20130101; A61K 31/415 20130101; A61K 2300/00
20130101; A61K 8/4973 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 31/19 20130101; A61K 8/362 20130101;
A61K 31/66 20130101; A61Q 19/008 20130101; A61Q 19/10 20130101;
A61K 8/675 20130101 |
Class at
Publication: |
424/78.03 |
International
Class: |
A61K 031/74 |
Claims
We claim:
1. A topical skin treating composition comprising: a) an effective
amount of at least one hydroxycarboxylic acid, wherein the at least
one hydroxycarboxylic acid is present in the form of a free acid,
lactone, or salt, b) at least one agent selected from the group
consisting of retinoids, wherein the agent is present in
stereoisomeric or non-isomeric form, and c) a
cosmetically-acceptable vehicle.
2. The composition of claim 1, wherein the composition is present
in a formulation selected from the group consisting of a solution,
a cream, an ointment, and a lotion composition for topical
treatment or management of aging-related skin changes.
3. The composition of claim 2, wherein the at least one
hydroxycarboxylic acid is selected from the group consisting of
glycolic acid, lactic acid, citric acid, tartaric acid, malic acid,
methyllactic acid, mandelic acid, 4-hydroxymandelic acid, benzilic
acid, ribonic acid, ribonolactone, gluconic acid, gluconolactone,
galactonic acid, galactonolactone, glucoheptonic acid,
glucoheptonolactone, glucuronic acid, glucuronolactone, galacuronic
acid, galaturonolactone, glucaric acid, glucarolactone, galactaric
acid, and galactarolactone.
4. The composition of claim 2, wherein the composition is present
in a formulation selected from the group consisting of a solution,
a cream, an ointment, and a lotion composition for topical
treatment or management of aging-related skin changes.
5. The composition of claim 1, wherein the at least one agent is
selected from the group consisting of retinol, retinal, retinoic
acid, retinyl acetate, retinyl palmitate, methyl retinoate, ethyl
retinoate, propyl retinoate and isopropyl retinoate.
6. The composition of claim 1, wherein the at least one
hydroxycarboxylic acid is selected from the group consisting of
gluconolactone and glucarolactone, and the at least one agent is
selected from the group consisting of retinol, retinyl acetate,
retinyl pahnitate, retinal acid and retinoic acid.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 09/744,882, filed Feb. 1, 2001, which is in
turn a continuation of U.S. patent application Ser. No. 09/510,368,
filed Feb. 22, 2000, now abandoned; which in turn is a continuation
of U.S. patent application Ser. No. 09/222,995, filed Dec. 30,
1998, now U.S. Pat. No. 6,051,609; which is itself in turn a
continuation of U.S. patent application Ser. No. 08/926,030, filed
Sep. 9, 1997, now U.S. Pat. No. 5,962,526; which is in turn a
continuation of U.S. patent application Ser. No. 08/487,684, filed
Jun. 7, 1995, now U.S. Pat. No. 5,691,378; which itself is a
continuation of U.S. patent application Ser. No. 08/179,190, filed
Jan. 10, 1994, now U.S. Pat. No. 5,470,880, which itself is a
continuation of U.S. patent application Ser. No. 08/089,101, filed
Jul. 12, 1993, now U.S. Pat. No. 5,389,677; which itself is a
divisional of U.S. patent application Ser. No. 08/008,223, filed
Jan. 22, 1993, now U.S. Pat. No. 5,665,776; which itself is a
continuation of U.S. patent application Ser. No. 07/812,858, filed
Dec. 23, 1991, now abandoned; which itself is a continuation of
U.S. patent application Ser. No. 07/469,738, filed Jan. 1, 1990,
now abandoned; which itself is a continuation of U.S. Patent
Application No. 06/945,680, filed Dec. 23, 1986, now abandoned.
BACKGROUND OF THE INVENTION
[0002] This invention relates generally to therapeutic treatment as
well as to preventive measures for cosmetic conditions and
dermatologic disorders by topical administration of amphoteric
compositions or polymeric forms of alpha hydroxyacids, alpha
ketoacids and related compounds. We initially discovered that alpha
hydroxy or keto acids and their derivatives were effective in the
topical treatment of disease conditions such as dry skin,
ichthyosis, eczema, palmar and plantar hyperkeratoses, dandruff,
acne, and warts.
[0003] We have now discovered that amphoteric compositions and
polymeric forms of alpha hydroxyacids, alpha ketoacids, and related
compounds of topical administration are therapeutically effective
for various cosmetic conditions and dermatologic disorders.
[0004] In U.S. Pat. No. 3,879,537, entitled "Treatment of
Ichthyosiform Dermatoses," we described and claimed the use of
certain alpha hydroxyacids, alpha ketoacids, and related compounds
for topical treatment of fish scale-like ichthyotic conditions in
humans. In U.S. Pat. No. 3,920,835, entitled "Treatment of
Disturbed Keratinization," we described and claimed the use of
these alpha hydroxyacids, alpha ketoacids, and their derivatives
for topical treatment of dandruff, acne, and palmar and plantar
hyperkeratosis.
[0005] In U.S. Pat. No. 4,105,783, entitled "Treatment of Dry
Skin," we described and claimed the use of alpha hydroxyacids,
alpha ketoacids, and their derivatives for topical treatment of dry
skin. In U.S. Pat. No. 4,246,261, entitled "Additives Enhancing
Topical Corticosteroid Action," we disclosed that alpha
hydroxyacids, alpha ketoacids and their derivatives could greatly
enhance the therapeutic efficacy of corticosteroids in topical
treatment of psoriasis, eczema, seborrheic dermatitis, and other
inflammatory skin conditions.
[0006] In U.S. Pat. No. 4,363,815, entitled "Alpha Hydroxyacids,
Alpha Ketoacids and Their Use in Treating Skin Conditions," we
disclosed alpha hydroxyacids and alpha ketoacids related to or
originating from amino acids, whether or not found in proteins, for
effective in topical treatment of skin disorders associated with
disturbed keratinization or inflammation. These skin disorders
include dry skin, ichthyosis, palmar and plantar hyperkeratosis,
dandruff, Darier's disease, lichen simplex chronicus, keratoses,
acne, psoriasis, eczema, pruritus, warts, and herpes.
BRIEF SUMMARY OF THE INVENTION
[0007] There is no doubt that alpha hydroxyacids, alpha ketoacids,
and related compounds are therapeutically effective for topical
treatment of various cosmetic conditions and dermatologic disorders
including dry skin, acne, dandruff, keratoses, age spots, wrinkles,
and disturbed keratinization. However, the compositions containing
these acids may irritate human skin after repeated topical
applications, due to the lower pH levels of the formulations. The
irritation may range from a sensation of tingling, itching, and
burning to clinical signs of redness and peeling. Causes for such
irritation may arise from the following:
[0008] Upper layers of normal skin have a pH of 4.2 to 5.6, but the
compositions containing most alpha hydroxyacids or alpha ketoacids
have pH values of less than 3.0. For example, a topical formulation
containing 7.6% (1 M) glycolic acid has a pH of 1.9, as does a
composition containing 9% (1 M) lactic acid. These compositions of
lower pH values, on repeated topical applications, can cause a
drastic pH decrease in the stratum comeum of human skin, and
provoke disturbances in intercorneocyte bondings, resulting in
adverse skin reactions, especially in individuals with sensitive
skin.
[0009] Moreover, it remains difficult to formulate a lotion, cream,
or an ointment emulsion which contains a free acid form of the
alpha hydroxyacid, and which is a physically stable commercial
product for cosmetic or pharmaceutical use.
[0010] When a formulation containing an alpha hydroxyacid or alpha
ketoacid is reacted equimolarly or equinormally with a metallic
alkali, such as sodium hydroxide or potassium hydroxide, the
composition becomes therapeutically ineffective. The reasons for
such loss of therapeutic effects are believed to be as follows:
[0011] The intact skin of humans is a very effective barrier to
many natural and synthetic substances. Cosmetic and pharmaceutical
agents may be pharmacologically effective by oral or other
systematic administration, but many of them are much less or
totally ineffective on topical application to the skin. Topical
effectiveness of a pharmaceutical agent depends on two major
factors: (a) bioavailability of the active ingredient in the
topical preparation, and (b) percutaneous absorption, penetration,
and distribution of the active ingredient to the target site in the
skin. For example, a topical preparation containing 5% salicylic
acid is therapeutically effective as a keratolytic, but one
containing 5% sodium salicylate is not an effective product. The
reason for such difference is that salicylic acid is a bioavailable
form and can penetrate the stratum comeum, but sodium salicylate is
not, and therefore cannot penetrate the stratum corneum of the
skin.
[0012] In the case of alpha hydroxyacids, a topical preparation
containing 5% glycolic acid is therapeutically effective for dry
skin, but one containing 5% sodium glycolate is not effective. The
same is true in case of 5% lactic acid versus 5% sodium lactate.
The reason for such difference is that both glycolic acid and
lactic acid are bioavailable forms and can readily penetrate the
stratum comeum, but sodium glycolate and sodium lactate are not,
and therefore cannot penetrate the stratum comeum of the skin.
[0013] When a formulation containing an alpha hydroxyacid or alpha
ketoacid is reacted equimolarly or equinormally with ammonium
hydroxide or an organic base, the composition still shows some
therapeutic effects for certain cosmetic conditions, such as dry
skin; however, the composition has lost most of its potency for
other dermatologic disorders, such as wrinkles, keratoses, age
spots, and skin changes associated with aging.
[0014] It has now been discovered that amphoteric compositions
containing alpha hydroxyacids, alpha ketoacids, or related
compounds, and also the compositions containing dimeric or
polymeric forms of hydroxyacids, overcome the aforementioned
shortcomings and retain therapeutic efficacies for cosmetic
conditions and dermatologic disorders. The amphoteric composition
contains, in combination, an amphoteric or pseudoamphoteric
compound and at least one of the alpha hydroxyacids, alpha
ketoacids, or related compounds. Such amphoteric system has a
suitable pH, and can release the active form of an alpha
hydroxyacid or alpha ketoacid into the skin. The dimeric and
polymeric forms of alpha, beta, or other hydroxyacids in
non-aqueous compositions have a more desired pH than that of the
monomeric form of the hydroxyacids. The non-aqueous compositions
can be formulated and induced to release the active form of
hydroxyacids after the compositions have been topically applied to
the skin. The cosmetic conditions and dermatologic disorders in
humans and animals, in which the amphoteric compositions containing
the dimeric or polymeric forms of hydroxyacids may be useful,
include dry skin, dandruff, acne, keratoses, psoriasis, eczema,
pruritus, age spots, lentigines, melasmas, wrinkles, warts,
blemished skin, hyperpigmented skin, hyperkeratotic skin,
inflammatory dermatoses, skin changes associated with aging and as
skin cleansers.
DETAILED DESCRIPTION OF THE INVENTION
[0015] Amphoteric substances by definition should behave either as
an acid or a base, and can be an organic or an inorganic compound.
The molecule of an organic amphoteric compound should consist of at
least one basic and one acidic group. The basic groups include, for
example, amino, imino, and guanido groups. The acidic groups
include, for example, carboxylic, phosphoric, and sulfonic groups.
Some examples of organic amphoteric compounds are amino acids,
peptides, polypeptides, proteins, creatine, aminoaldonic acids,
aminouronic acids, lauryl aminopropylglycine, aminoaldaric acids,
neuraminic acid, desulfated heparin, deacetylated hyaluronic acid,
hyalobiuronic acid, chondrosine, and deacetylated chondroitin.
[0016] Inorganic amphoteric compounds are certain metallic oxides,
such as aluminum oxide and zinc oxide.
[0017] Pseudoamphoteric compounds are either structurally related
to true amphoteric compounds or are capable of inducing the same
function when they are incorporated into the compositions
containing alpha hydroxyacids or ketoacids. Some examples of
pseudoamphoteric compounds are creatinine, stearamidoethyl
diethylamine, stearamidoethyl diethanolamine, stearamidopropyl
dimethylamine, quaternary ammonium hydroxide, and quatemium
hydroxide.
[0018] The amphoteric composition of the instant invention
contains, in combination, an alpha hydroxyacid or alpha ketoacid
and an amphoteric or pseudoamphoteric compound. There are two
advantages of utilizing an amphoteric or the like compound in the
therapeutic composition containing an alpha hydroxy or ketoacid.
These are: (a) the overall pH of the composition is raised, so that
the composition becomes less or non-irritating to the skin, and (b)
some alpha hydroxy or ketoacid molecules react with the amphoteric
compound to form a quadruple ionic complex which acts as buffering
system to control the release of alpha hydroxy or ketoacid into the
skin, therefore eliminating skin irritation while retaining
therapeutic efficacies.
[0019] For example, 2-hydroxyethanoic acid (glycolic acid) 1 M
aqueous solution has a pH of 1.9. The pH of the composition changes
to 3.0, 3.2 when arginine 0.5 M and creatinine 0.5H respectively
are incorporated into the formulation. 2-Hydroxypropanoic acid
(lactic acid) 1 M aqueous solution has a pH of 1.9. The pH of the
composition changes to 3.1 and 6.9 when arginine 0.5 M and 1.0 M
respectively are incorporated into the formulation. 2-Methyl
2-hydroxypropanoic acid (methyllactic acid) 1 M aqueous solution
has a pH of 1.9. The pH of the compositions change to 3.3, 3.4, and
3.2 when 0.5 M each of arginine, creatinine, and 4-aminobutanoic
acid, respectively, are incorporated into the formulation.
2-Hydroxybutane-1,4-dioic acid (malic acid) 1 M aqueous solution
has pH 1.8, but the pH of the composition changes to 3.0 when
creatinine 0.5 M is incorporated into the formulation.
[0020] Ideally, an amphoteric compound should contain both anionic
and cationic groups or functional groups capable of behaving both
as an acid and a base. Although inorganic amphoteric compounds such
as aluminum oxide, aluminum hydroxide, and zinc oxide may be
utilized, organic amphoteric compounds have been found to be more
efficient in formulating therapeutic compositions of the instant
invention.
[0021] Organic amphoteric and pseudoamphoteric compounds may be
classified into three groups, namely (a) amino acid-type, (b)
imidazoline and lecithin amphoterics, and (C) pseudoamphoterics and
miscellaneous amphoterics.
[0022] (a) Amino Acid-Type Amphoterics.
[0023] Amphoteric compounds of amino acid-type include all the
amino acids, dipeptides, polypeptides, proteins, and the like,
which contain at least one of the basic groups such as amino,
imirio, guanido, imidazolino, and imidazolyl, and one of the acidic
groups such as carboxylic, sulfonic, sulfinic, and sulfate.
[0024] Glycine is a simple amphoteric compound that contains only
one amino group and one carboxylic group. Lysine contains two amino
groups and one carboxylic group. Aspartic acid contains one amino
group and two carboxylic groups. Arginine contains one amino group,
one guanido group, and one carboxylic group. Histidine contains one
amino group, one imidazolyl group, and one carboxylic group.
Taurine contains one amino group and one sulfonic group. Cysteine
sulfinic acid contains one amino group, one carboxylic group, and
one sulfinic group. The amino group of an amphoteric compound may
also be substituted, such as in betaine which is a glycine
N,N,N-trimethyl inner salt.
[0025] Glycylglycine is a simple dipeptide that contains one free
amino group and one free carboxylic group. Glycylhistidine is also
a dipeptide that contains one free amino group, one imidazolyl
group, and one free carboxylic group.
[0026] The representative amphoteric compounds of amino acid-type
may be listed as follows: glycine, alanine, valine, leucine,
isoleucine, serine, threonine, cysteine, cystine, methionine,
aspartic acid, asparagine, glutamic acid, glutamine, arginine,
lysine, 5-hydroxylysine, histidine, phenylalanine, tyrosine,
tryptophan, 3-hydroxyproline, 4-hydroxyproline, and proline.
[0027] The related amino acids include homocysteine; homocystine;
homoserine; ornithine; citrulline; creatine; 3-aminopropanoic acid;
theanine; 2-aminobutanoic acid; 4-aminobutanoic acid;
2-amino-2-methylpropanoic acid; 2-methyl-3-aminopropanoic acid;
2,6-diaminopimelic acid; 2-amino-3-phenylbutanoic acid;
phenylglycine; canavanine; canaline; 4-hydroxyarginine;
4-hydroxyornithine; homoarginine; 4-hydroxyhomoarginine;
.beta.-lysine; 2,4-diaminobutanoic acid; 2,3-diaminopropanoic acid;
2-methylserine; 3-phenylserine; and betaine.
[0028] Sulfur-containing amino acids include taurine,
cysteinesulfinic acid, methionine sulfoxide, and methionine
sulfone.
[0029] The halogen-containing amino acids include
3,5-diiodotyrosine, thyroxine and monoiodotyrosine. The amino-type
acids include pipecolic acid, 4-aminopipecolic acid and
4-methylproline.
[0030] The dipeptides include for example, glycylglycine, camosine,
anserine, ophidine, homocamosine, .beta.-alanyllysine,
.beta.-alanylarginine. The tripeptides include for example,
glutathione, ophthalmic acid, and norophthalmic acid. Short-chain
polypeptides of animal, plant, and bacterial origin containing up
to 100 amino acid residues include bradykinin and glucagon. The
preferred proteins include for example protamines, histones and
other lysine- and arginine-rich proteins.
[0031] (b) Imidazoline and Lecithin Amphoterics.
[0032] The amphoteric compounds of imidazoline derived type are
commercially synthesized from 2-substituted-2-imidazolines obtained
by reacting a fatty acid with an aminoethylethanolainine. These
amphoterics include cocoamphoglycine, cocoamphopropionate, and
cocoamphopropylsulfonate. The amphoteric compounds of lecithin and
related type include, for example, phosphatidyl ethanolamine,
phosphatidyl serine, and sphingomyelin.
[0033] (c) Pseudoamphoterics and Miscellaneous Amphoterics.
[0034] Many pseudoamphoteric compounds are chemically related or
derived from true amphoterics. For example, creatinine is derived
from creatine. Other pseudoamphoteric compounds may include fatty
amide amines, such as stearamidoethyl diethylamine, stearamidoethyl
diethanolamine, and stearamidopropyl dimethylamine. Other
pseudoamphoteric related compounds include quaternary ammonium
hydroxide and quatemium hydroxide.
[0035] In accordance with the present invention, the alpha
hydroxyacid, the alpha ketoacids, and the related compounds which
are incorporated into amphoteric or pseudoamphoteric compositions
for cosmetic conditions and dermatologic disorders may be
classified into three groups.
[0036] The first group is organic carboxylic acids in which one
hydroxyl group is attached to the alpha carbon of the acids. The
generic structure of such alpha hydroxyacids may be represented as
follows:
(R.sub.a)(R.sub.b)C(OH)COOH
[0037] where R.sub.a and R.sub.b are H, F, Cl, Br, alkyl, aralkyl
or aryl group of saturated or unsaturated, isomeric or
non-isomeric, straight or branched chain or cyclic form, having 1
to 25 carbon atoms, and in addition R.sub.a and R.sub.b may carry
OH, CHO, COOH and alkoxy group having 1 to 9 carbon atoms. The
alpha hydroxyacids may be present as a free acid or lactone form,
or in a salt form with an organic base or an inorganic alkali. The
alpha hydroxyacids may exist as stereoisomers as D, L, and DL forms
when R.sub.a and R.sub.b are not identical.
[0038] Typical alkyl, aralkyl and aryl groups for Ra and Rb include
methyl, ethyl, propyl, isopropyl, butyl, pentyl, octyl, lauryl,
stearyl, benzyl, phenyl, etc. The alpha hydroxyacids of the first
group may be divided into (1) alkyl alpha hydroxyacids, (2) aralkyl
and aryl alpha hydroxyacids, (3) polyhydroxy alpha hydroxyacids,
and (4) polycarboxylic alpha hydroxyacids. The following are
representative alpha hydroxyacids in each subgroup.
[0039] (1) Alkyl Alpha Hydroxyacids
[0040] 1. 2-Hydroxyethanoic acid (Glycolic acid, hydroxyacetic
acid)
[0041] (H) (H) C (OH) COOH
[0042] 2. 2-Hydroxypropanoic acid (Lactic acid)
[0043] (CH.sub.3) (H) C (OH) COOH
[0044] 3. 2-Methyl 2-hydroxypropanoic acid (Methyllactic acid)
[0045] (CH.sub.3) (CH.sub.3) C (OH) COOH
[0046] 4. 2-Hydroxybutanoic acid
[0047] (C.sub.2H.sub.5) (H) C (OH) COOH
[0048] 5. 2-Hydroxypentanoic acid
[0049] (C.sub.3H.sub.7) (H) C (OH) COOH
[0050] 6. 2-Hydroxyhexanoic acid
[0051] (C.sub.4H.sub.9) (H) C (OH) COOH
[0052] 7. 2-Hydroxyheptanoic acid
[0053] (C.sub.5H.sub.11) (H) C (OH) COOH
[0054] 8. 2-Hydroxyoctanoic acid
[0055] (C.sub.6H.sub.13) (H) C (OH) COOH
[0056] 9. 2-Hydroxynonanoic acid
[0057] (C.sub.7H.sub.15) (H) C (OH) COOH
[0058] 10. 2-Hydroxydecanoic acid
[0059] (C.sub.8H.sub.17) (H) C (OH) COOH
[0060] 11. 2-Hydroxyundecanoic acid
[0061] (C.sub.9N.sub.19) (H) C (OH) COOH
[0062] 12. 2-Hydroxydodecanoic acid (Alpha hydroxylauric acid)
[0063] (C.sub.10H.sub.21) (H) C (OH) COOH
[0064] 13. 2-Hydroxytetradecanoic acid (Alpha hydroxymyristic
acid)
[0065] (C.sub.12H.sub.25) (H) C (OH) COOH
[0066] 14. 2-Hydroxyhexadecanoic acid (Alpha hydroxypalmitic
acid)
[0067] (C.sub.14H.sub.29) (H) C (OH) COOH
[0068] 15. 2-Hydroxyoctadecanoic acid (Alpha hydroxystearic
acid)
[0069] (C.sub.16H.sub.34) (H) C (OH) COOH
[0070] 16. 2-Hydroxyeicosanoic acid (Alpha hydroxyarachidonic
acid)
[0071] (C.sub.18H.sub.37) (H) C (OH) COOH
[0072] (2) Aralkyl and Aryl Alpha Hydroxyacids
[0073] 1. 2-Phenyl 2-hydroxyethanoic acid (Mandelic acid)
[0074] (C.sub.6H.sub.5) (H) C (OH) COOH
[0075] 2. 2,2-Diphenyl 2-hydroxyethanoic acid (Benzilic acid)
[0076] (C.sub.6H.sub.5) (C.sub.6H.sub.5) C (OH) COOH
[0077] 3. 3-Phenyl 2-hydroxypropanoic acid (Phenyllactic acid)
[0078] (C.sub.6H.sub.5CH.sub.2) (H) C (OH) COOH
[0079] 4. 2-Phenyl 2-methyl 2-hydroxyethanoic acid (Atrolactic
acid)
[0080] (C.sub.6H.sub.5) (CH.sub.3) C (OH) COOH
[0081] 5. 2- (4'-Hydroxyphenyl) 2-hydroxyethanoic acid
(4-Hydroxymandelic acid)
[0082] (HO--C.sub.6H.sub.4) (H) C (OH) COOH
[0083] 6. 2- (4'-Chiorophenyl) 2-hydroxyethanoic acid
(4-Chloromandelic acid)
[0084] (Cl--C.sub.6H.sub.4) (H) C (OH) COOH
[0085] 7. 2-(3'-Hydroxy-4'-methoxyphenyl) 2-hydroxyethanoic acid
(3-Hydroxy-4-methoxymandelic acid)
[0086] (HO--, CH.sub.3O--C.sub.6H.sub.3) (H) C (OH) COOH
[0087] 8. 2- (4'-Hydroxy-3'-methoxyphenyl) 2-hydroxyethanoic acid
(4-Hydroxy-3-methoxymandelic acid)
[0088] (HO--, CH.sub.3O--C.sub.6H.sub.3) (H) C (OH) COOH
[0089] 9. 3-(2'-Hydroxyphenyl) 2-hydroxypropanoic acid
[3(2'-Hydroxyphenyl) lactic acid]
[0090] HO--C.sub.6H.sub.4--CH.sub.2(H) C (OH) COOH
[0091] 10. 3-(4'-Hydroxyphenyl) 2-hydroxypropanoic acid
[3-(4'-Hydroxyphenyl) lactic acid]
[0092] HO--C.sub.6H.sub.4--CH.sub.2 (H) C (OH) COOH
[0093] 11. 2-(3', 4'-Dihydroxyphenyl) 2-hydroxyethanoic acid
(3,4-Dihydroxymandelic acid)
[0094] HO--, HO--C.sub.6H.sub.3 (H) C (OH) COOH
[0095] (3) Polyhydroxy Alpha Hydroxyacids
[0096] 1. 2,3-Dihydroxypropanoic acid (Glyceric acid)
[0097] (HOCH.sub.2) (H) C (OH) COOH
[0098] 2. 2,3,4-Trihydroxybutanoic acid (Isomers; erythronic acid,
threonic acid)
[0099] HOCH.sub.2(HO) CH.sub.2 (H) C (OH) COOH
[0100] 3. 2,3,4,5-Tetrahydroxypentanoic acid (Isomers; ribonic
acid, arabinoic acid, xylonic acid, lyxonic acid)
[0101] HOCH.sub.2 (HO) CH.sub.2 (HO) CH.sub.2 (H) C (OH) COOH
[0102] 4. 2,3,4,5,6-Pentahydroxyhexanoic acid (Isomers: allonic
acid, altronic acid, gluconic acid, manrioic acid, gulonic acid,
idonic acid, galactonic acid, talonic acid)
[0103] HOCH.sub.2 (HO) CH.sub.2 (HO) CH.sub.2 (HO) CH.sub.2 (H) C
(OH) COOH
[0104] 5. 2,3,4,5,6,7-Hexahydroxyheptanoic acid (Isomers:
glucoheptonic acid, galactoheptonic acid etc.)
[0105] HOCH.sub.2 (HO) CH.sub.2 (HO) CH.sub.2 (HO) CH.sub.2 (HO)
CH.sub.2 (H) C (OH) COOH
[0106] (4) Polycarboxylic Alpha Hydroxyacids
[0107] 1. 2-Hydroxypropane-1,3-dioic acid (Tartronic acid)
[0108] HOOC (H) C (OH) COOH
[0109] 2. 2-Hydroxybutane-1,4-dioic acid (Malic acid)
[0110] HOOC CH.sub.2 (H) C (OH) COOH
[0111] 3. 2,3-Dihydroxybutane-1,4-dioic acid (Tartaric acid)
[0112] HOOC (HO) CH.sub.2 (H) C (OH) COOH
[0113] 4. 2-Hydroxy-2-carboxypentane-1,5-dioic acid (Citric
acid)
[0114] HOOC CH.sub.2 C (OH) (COOH) CH.sub.2 COOH
[0115] 5. 2,3,4,5-Tetrahydroxyhexane-1,6-dioic acid (Isomers;
saccharic acid, mucic acid etc.)
[0116] HOOC (CHOH).sub.4 COOH
[0117] (5) Lactone Forms
[0118] The typical lactone forms are gluconolactone,
galactonolactone, glucuronolactone, galacturonolactone,
gulonolactone, ribonolactone, saccharic acid lactone,
pantoyllactone, glucoheptonolactone, mannonolactone, and
galactoheptonolactone.
[0119] The second group of compounds which may be incorporated into
amphoteric or pseudoamphoteric compositions for cosmetic conditions
and dermatologic disorders, is organic carboxylic acids in which
the alpha carbon of the acids is in keto form. The generic
structure of such alpha ketoacids may be represented as
follows:
(R.sub.a)CO COO(R.sub.b)
[0120] wherein R.sub.a and R.sub.b are H, alkyl, aralkyl or aryl
group of saturated or unsaturated, isomeric or non-isomeric,
straight or branched chain or cyclic form, having 1 to 25 carbon
atoms, and in addition R.sub.a may carry F, Cl, Br, I, OH, CHO,
COOH and alkoxy group having 1 to 9 carbon atoms. The alpha
ketoacids may be present as a free acid or an ester form, or in a
salt form with an organic base or an inorganic alkali. The typical
alkyl, aralkyl and aryl groups for R.sub.a and R.sub.b include
methyl, ethyl, propyl, isopropyl, butyl, pentyl, octyl, lauryl,
stearyl, benzyl and phenyl, etc.
[0121] In contrast to alpha hydroxyacids, the ester form of alpha
ketoacids has been found to be therapeutically effective for
cosmetic and dermatologic conditions and disorders. For example,
while ethyl lactate has a minimal effect, ethyl pyruvate is
therapeutically very effective. Although the mechanism for such
difference is not known, we have speculated that the ester form of
an alpha ketoacid is chemically and/or biochemically very reactive,
and a free acid form of the alpha ketoacid is released in the skin
after the topical application.
[0122] The representative alpha ketoacids and their esters which
may be useful in amphoteric or pseudoamphoteric compositions for
cosmetic conditions and dermatologic disorders are listed
below:
[0123] 1. 2-Ketoethanoic acid (Glyoxylic acid)
[0124] (H) CO COOH
[0125] 2. Methyl 2-ketoethanoate
[0126] (H) CO COOCH.sub.3
[0127] 3. 2-Ketopropanoic acid (Pyruvic acid)
[0128] CH.sub.3 CO COOH
[0129] 4. Methyl 2-ketopropanoate (Methyl pyruvate)
[0130] CH.sub.3 CO COOCH.sub.3
[0131] 5. Ethyl 2-ketopropanoate (Ethyl pyruvate)
[0132] CH.sub.3 CO COOC.sub.2H.sub.5
[0133] 6. Propyl 2-ketopropanoate (Propyl pyruvate)
[0134] CH.sub.3 CO COOC.sub.3H.sub.7
[0135] 7. 2-Phenyl-2-ketoethanoic acid (Benzoylformic acid)
[0136] C.sub.6H.sub.5 CO COOH
[0137] 8. Methyl 2-phenyl-2-ketoethanoate (Methyl
benzoylformate)
[0138] C.sub.6H.sub.5 CO COOCH.sub.3
[0139] 9. Ethyl 2-phenyl-2-ketoethanoate (Ethyl benzoylformate)
[0140] C.sub.6H.sub.5 CO COOC.sub.2H.sub.5
[0141] 10. 3-Phenyl-2-ketopropanoic acid (Phenylpyruvic acid)
[0142] C.sub.6H.sub.5CH.sub.2 CO COOH
[0143] 11. Methyl 3-phenyl-2-ketopropanoate (Methyl
phenylpyruvate)
[0144] C.sub.6H.sub.5CH.sub.2 CO COOCH.sub.3
[0145] 12. Ethyl 3-phenyl-2-ketopropanoate (Ethyl
phenylpyruvate)
[0146] C.sub.6H.sub.5CH.sub.2 CO COOC.sub.2H.sub.5
[0147] 13. 2-Ketobutanoic acid
[0148] C.sub.2H.sub.5 CO COOH
[0149] 14. 2-Ketopentanoic acid
[0150] C.sub.3H.sub.7 CO COOH
[0151] 15. 2-Ketohexanoic acid
[0152] C.sub.4H.sub.9 CO COOH
[0153] 16. 2-Ketoheptanoic acid
[0154] C.sub.5H .sub.1 CO COOH
[0155] 17. 2-Ketooctanoic acid
[0156] C.sub.6H.sub.13 CO COOH
[0157] 18. 2-Ketododecanoic acid
[0158] C.sub.10H.sub.21 CO COOH
[0159] 19. Methyl 2-ketooctanoate
[0160] C.sub.6H.sub.13 CO COOCH.sub.3
[0161] The third group of compounds that may be incorporated into
amphoteric or pseudoamphoteric compositions for cosmetic and
dermatologic conditions and disorders, is chemically related to
alpha hydroxyacids or alpha ketoacids. The third group of compounds
include ascorbic acid, quirlic acid, isocitric acid, tropic acid,
trethocanic acid, 3-chlorolactic acid, cerebronic acid, citramalic
acid, agaricic acid, 2-hydroxynervonic acid, aleuritic acid and
pantoic acid.
[0162] II. Dimeric and Polymeric Forms of Hydroxyacids
[0163] When two or more molecules of hydroxycarboxylic acids,
either identical or non-identical compounds, are reacted chemically
to each other, dimeric or polymeric compounds will be formed. Such
dimeric and polymeric compounds may be classified into three
groups, namely (a) acyclic esters, (b) cyclic esters and (c)
miscellaneous dimers and polymers.
[0164] (a) Acyclic esters. The acyclic ester of a hydroxycarboxylic
acid may be a dimer or a polymer. The dimer is formed from two
molecules of a hydroxycarboxylic acid by reacting the carboxyl
group of one molecule with the hydroxy group of a second molecule.
For example, glycolyl glycollate is formed from two molecules of
glycolic acid by eliminating one mole of water molecule. Likewise,
lactyl lactate is formed from two molecules of lactic acid. When
two molecules of different hydroxycarboxylic acids are
intermolecularly reacted, a different dimer is formed. For example,
glycolyl lactate is formed by the reaction of the carboxyl group of
lactic acid with the hydroxy group of glycolic acid. The polymer is
formed in a similar manner but from more than two molecules of a
hydroxycarboxylic acid. For example, glycoly glycoly glycollate is
formed from three molecules of glycolic acid. Copolymer is formed
from two or more than two different kinds of hydroxycarboxylic
acids. For example, glycolyl lactyl glycollate is formed from two
molecules of glycolic acid and one molecule of lactic acid.
[0165] The acyclic ester of dimeric and polymeric hydroxycarboxylic
acids may be shown by the following chemical structure:
H(--O--C(R.sub.a)(R.sub.b)--CO--].sub.n OH
[0166] wherein R.sub.a or R.sub.b is a hydrogen atom, alkyl,
aralkyl araryl group of saturated or unsaturated, isomeric or
non-isomeric, straight or branched chain or cyclic form, having 1
to 25 carbon atoms, and n=1 or other integer up to 200. R.sub.a and
R.sub.b in monomer unit 2,3,4 and so on may be the same or the
different groups from that in monomer unit 1. For example, R.sub.a
or R.sub.b is a hydrogen atom in monomer unit 1, and R.sub.a is
CH.sub.3 and R.sub.b is a hydrogen atom in monomer unit 2 when n=2
is a dimer called lactyl glycollate, because the first monomer is
glycollate unit and the second-monomer is lactic acid unit. The
hydrogen atom in Ra and Rb may be substituted by a halogen atom or
a radical such as a lower alkyl, aralkyl, aryl or alkoxy of
saturated or unsaturated, isomeric or non-isomeric, straight or
branched chain or cyclic form, having 1 to 9 carbon atoms. The
dimer and polymer of a hydroxycarboxylic acid may be present as a
free acid, ester or salt form with organic base or inorganic
alkali.
[0167] The typical alkyl, aralkyl and aryl groups for R.sub.a and
R.sub.b include methyl, ethyl, propyl, isopropyl, butyl, benzyl and
phenyl. Representative acyclic esters of hydroxycarboxylic acids
which may be useful for cosmetic conditions and dermatologic
disorders are listed below:
[0168] 1. Glycolyl glycollate (Glycolic acid glycollate)
[0169] R.sub.a, R.sub.b.dbd.H in units 1 & 2, n=2
[0170] 2. Lactyl lactate (Lactic acid lactate)
[0171] R.sub.a.dbd.CH.sub.3 and R.sub.b.dbd.H in units 1 & 2,
n=2
[0172] 3. Mandelyl mandellate
[0173] R.sub.a.dbd.C.sub.6H.sub.5 and R.sub.b.dbd.H in units 1
& 2, n=2
[0174] 4. Atrolactyl atrolactate
[0175] R.sub.a.dbd.C.sub.6H.sub.5 and R.sub.b.dbd.CH.sub.3 in units
1 & 2, n=2
[0176] 5. Phenyllactyl phenyllactate
[0177] R.sub.a.dbd.C.sub.6H.sub.5CH.sub.2 and R.sub.b.dbd.H in
units 1 & 2, n=2
[0178] 6. Benzilyl benzillate
[0179] R.sub.a and R.sub.b.dbd.C.sub.6H.sub.5 in units 1 & 2,
n.dbd.2
[0180] 7. Glycolyl lactate
[0181] R.sub.a.dbd.CH.sub.3 in unit 1, R.sub.a.dbd.H in unit 2,
R.sub.b.dbd.H in units 1& 2, n=2
[0182] 8. Lactyl glycollate
[0183] R.sub.a.dbd.H in unit 1, R.sub.a.dbd.CH.sub.3 in unit 2,
R.sub.b.dbd.H in units 1 & 2, n=2
[0184] 9. Glycolyl glycolyl glycollate
[0185] R.sub.a, R.sub.b.dbd.H in units 1, 2 & 3, n=3
[0186] 10. Lactyl lactyl lactate
[0187] R.sub.a.dbd.CH.sub.3, R.sub.b.dbd.H in units 1, 2 & 3,
n=3
[0188] 11. Lactyl glycolyl lactate
[0189] R.sub.a.dbd.CH.sub.3 in units 1 & 3, R.sub.a.dbd.H in
unit 2, R.sub.b.dbd.H in units 1, 2 & 3, n=3
[0190] 12. Glycolyl glycolyl glycolyl glycollate
[0191] R.sub.a, R.sub.b.dbd.H in units 1, 2, 3 & 4, n=4
[0192] 13. Lactyl lactyl lactyl lactate
[0193] R.sub.a.dbd.CH.sub.3 and R.sub.b.dbd.H in units 1, 2, 3
& 4, n=4
[0194] 14. Glycolyl lactyl glycolyl lactyl glycollate
[0195] R.sub.a.dbd.H in units 1, 3 & 5 and R.sub.a.dbd.CH.sub.3
in units 2 & 4,
[0196] R.sub.b.dbd.H in units 1, 2, 3, 4 & 5, n=5
[0197] 15. Polyglycolic acid and polylactic acid
[0198] (b) Cyclic ester. The cyclic ester of a hydroxycarboxylic
acid may also be a dimer or polymer. The most common type, however,
is a dimer form. The cyclic dimer may be formed from an identical
monomer or from different monomers. For example, glycolide is
formed from two molecules of glycolic acid by removing two
molecules of water. Lactide is formed from two molecules of lactic
acid in the same manner. The cyclic ester of dimeric and polymeric
hydroxycarboxylic acids may be shown by the following chemical
structure:
[(--O--C(R.sub.a)(R.sub.b)--CO--].sub.n
[0199] wherein R.sub.a and R.sub.b.dbd.H, alkyl, aralkyl or aryl
group of saturated or unsaturated, isomeric or non-isomeric,
straight or branched chain or cyclic form, having 1 to 25 carbon
atoms, and n=1 or any integer, preferably 2. R.sub.a and R.sub.b in
units 1, 2, 3, and so on may be the same or the different
groups.
[0200] For example, in glycolide, R.sub.a and R.sub.b are hydrogen
atoms in both units 1 & 2, but in lactoglycolide R.sub.a is H
in unit 1, CH.sub.3 in unit 2, and R.sub.b is a hydrogen atom in
both units 1 & 2. The hydrogen atom in R.sub.a and/or R.sub.b
may be substituted by a halogen atom or a radical such as a lower
alkyl, aralkyl, aryl or alkoxy of saturated or unsaturated,
isomeric or non-isomeric, straight or branched chain or cyclic
form, having 1 to 9 carbon atoms.
[0201] The typical alkyl, aralkyl and aryl groups for R.sub.a and
R.sub.b include methyl, ethyl, propyl, isopropyl, butyl, benzyl,
and phenyl. Representative cyclic esters of hydroxycarboxylic acids
which may be useful for cosmetic conditions and dermatologic
disorders are listed below:
[0202] 1. Glycolide
[0203] R.sub.a and R.sub.b.dbd.H, n=2
[0204] 2. Lactide
[0205] R.sub.a.dbd.CH.sub.3 and R.sub.b.dbd.H in units 1 & 2,
n=2
[0206] 3. Mandelide
[0207] R.sub.a.dbd.C.sub.6H.sub.5 and R.sub.b.dbd.H in units 1
& 2, n=2
[0208] 4. Atrolactide
[0209] R.sub.a.dbd.C.sub.6H.sub.5 and R.sub.b.dbd.CH.sub.3 in units
1 & 2, n=2
[0210] 5. Phenyllactide
[0211] R.sub.a.dbd.C.sub.6H.sub.5 CH.sub.2 and R.sub.b.dbd.H in
units 1 & 2, n=2
[0212] 6. Benzilide
[0213] R.sub.a and R.sub.b.dbd.C.sub.6H.sub.5 in units 1 & 2,
n=2
[0214] 7. Methyllactide
[0215] R.sub.a and R.sub.b.dbd.CH.sub.3 in units 1 & 2, n=2
[0216] 8. Lactoglycolide
[0217] R.sub.a.dbd.H in unit 1 and R.sub.a.dbd.CH.sub.3 in unit
2
[0218] R.sub.b.dbd.H in units 1 & 2, n=2
[0219] 9. Glycolactide
[0220] R.sub.a.dbd.CH.sub.3 in unit 1 and R.sub.a.dbd.H in unit
2
[0221] R.sub.b.dbd.H in units 1 & 2, n=2
[0222] (c) Miscellaneous dimers and polymers. This group includes
all the dimeric and polymeric forms of hydroxycarboxylic acids,
which can not be represented by any one of the above two generic
structures, such as those formed from tropic acid, trethocanic
acid, and aleuritic acid. When a hydroxycarboxylic acid has more
than one hydroxy or carboxy group in the molecule, a complex
polymer may be formed. Such complex polymer may consist of acyclic,
as well as cyclic, structures.
[0223] The following hydroxycarboxylic acids have more than one
hydroxy group: glyceric acid, gluconic acid and gluconolactone,
galactonic acid and galactonolactone, glucuronic acid and
glucuronolactone, ribonic acid and ribonolactone, galacturonic acid
and galacturonolactone, ascorbic acid, gulonic acid and
gulonolactone, glucoheptonic acid and glucoheptonolactone. These
polyhydroxycarboxylic acids can form complex polymers with
themselves or with other simple monohydroxymonocarboxylic
acids.
[0224] The following hydroxycarboxylic acids have more than one
carboxyl group: malic acid, citric acid, citramalic acid, tartronic
acid, agaricic acid and isocitric acid. These
monohydroxypolycarboxylic acids can also form complex polymers with
themselves or with other simple hydroxycarboxylic acids.
[0225] The following hydroxycarboxylic acids have more than one
hydroxy group and more than one carboxyl group: tartaric acid,
mucic acid, and saccharic acid. These polyhydroxypolycarboxylic
acids can form even more complex polymers with themselves or with
other hydroxycarboxylic acids.
[0226] III. Combination Compositions
[0227] Any cosmetic and pharmaceutical agents may be incorporated
into amphoteric or pseudoamphoteric compositions, or into
compositions containing dimeric or polymeric forms of hydroxyacids
with or without amphoteric or pseudoamphoteric systems to enhance
therapeutic effects of those cosmetic and pharmaceutical agents to
improve cosmetic conditions or to alleviate the symptoms of
dermatologic disorder. Cosmetic and pharmaceutical agents include
those that improve or eradicate age spots, keratoses, and wrinkles;
analgesics; anesthetics; antiacne agents; antibacterial agents;
antiyeast agents; antifungal agents; antiviral agents; antidandruff
agents; antidermatitis agents; antipruritic agents; antiemetics;
antimotion sickness agents; antiinflammatory agents;
antihyperkeratolytic agents; antidryskin agents; antiperspirants;
antipsoriatic agents; antiseborrheic agents; hair conditioners and
hair treatment agents; antiaging and antiwrinkle agents;
antiasthmatic agents and bronchodilators; sunscreen agents;
antihistamine agents; skin lightening agents; depigmenting agents;
vitamins; corticosteroids; tanning agents; hormones; retinoids;
topical cardiovascular agents and other dermatological agents.
[0228] Some examples of cosmetic and pharmaceutical agents are
clotrimazole, ketoconazole, miconazole, griseofulvin, hydroxyzine,
diphenhydramine, pramoxine, lidocaine, procaine, mepivacaine,
monobenzone, erythromycin, tetracycline, clindamycin, meclocycline,
hydroquinone, minocycline, naproxen, ibuprofen, theophylline,
cromolyn, albuterol, retinoic acid, 13-cis retinoic acid,
hydrocortisone, hydrocortisone 21-acetate, hydrocortisone
17-valerate, hydrocortisone 17- butyrate, betamethasone valerate,
betamethasone dipropionate, triamcinolone acetonide, fluocinonide,
clobetasol propionate, benzoyl peroxide, crotamiton, propranolol,
promethazine, vitamin A palmitate, and vitamin E acetate.
[0229] IV. Specific Compositions for Skin Disorders
[0230] We have discovered that topical formulations or compositions
containing specific alpha hydroxyacids, alpha ketoacids, or related
compounds are therapeutically effective for certain skin disorders
without utilizing any amphoteric or pseudoamphoteric systems. The
alpha hydroxyacids and the related compounds include
2-hydroxyethanoic acid, 2-hydroxypropanoic acid, 2-methyl
2-hydroxypropanoic acid, 2-phenyl 2-hydroxyethanoic acid,
2,2-diphenyl 2-hydroxyethanoic acid, 2-phenyl 2-methyl
2-hydroxyethanoic acid, and 2-phenyl 3-hydroxypropanoic acid. The
alpha ketoacids and their esters include 2-ketopropanoic acid,
methyl 2-ketopropanoate, and ethyl 2-ketopropanoate. The mentioned
skin disorders include warts, keratoses, age spots, acne, nail
infections, wrinkles and aging related skin changes.
[0231] In general, the concentration of the alpha hydroxyacid, the
alpha ketoacid, or the related compound used in the composition is
a full strength to an intermediate strength, therefore dispensing
and the application of such compositions require special handling
and procedures.
[0232] If the alpha hydroxyacid, the alpha ketoacid, or the related
compound at full strength (usually 95-100%) is a liquid form at
room temperature, such as 2-hydroxypropanoic acid, 2-ketopropanoic
acid, methyl 2-ketopropanoate and ethyl 2-ketopropanoate, the
liquid compound with or without a gelling agent may be directly
dispensed as 0.5 to 1 ml aliquots in small vials.
[0233] If the alpha hydroxyacid, the alpha ketoacid or the related
compound at full strength is a solid form at room temperature, such
as 2-hydroxyethanoic acid, 2- methyl 2-hydroxypropanoic acid,
2-phenyl 2-hydroxyethanoic acid, 2,2-diphenyl 2-hydroxyethanoic
acid, and 2-phenyl 3-hydroxypropanoic acid, the solid compound is
first dissolved in a minimal amount of vehicle or vehicle system,
such as water, ethanol and/or propylene glycol, with or without a
gelling agent. For example, 2-hydroxyethanoic acid 70 g is
dissolved in water 30 g, and the 70% strength solution thus
obtained is dispensed as 0.5 to 1 ml aliquots in small vials. If a
gelling agent is desired, 0.5 to 3% of, for example, hydroxyethyl
cellulose, methyl cellulose, hydroxypropyl cellulose, or carbomer
may be incorporated into the above solution.
[0234] To prepare an intermediate strength (usually 20%-50%), the
alpha hydroxyacid, alpha ketoacid, or related compound either a
liquid or solid form at room temperature is first dissolved in a
vehicle or vehicle system such as water, acetone, ethanol,
propylene glycol and butane 1,3-diol. For example,
2-hydroxyethanoic acid or 2-ketopropanoic acid 30 g is dissolved in
ethanol 56 g and propylene glycol 14 g, and the 30% strength
solution thus obtained is dispensed as 7 to 14 ml aliquots in
dropper bottles.
[0235] For topical treatment of warts, keratoses, age spots, acne,
nail infections, wrinkles or aging related skin changes, patients
are advised to apply a small drop of the medication with a
toothpick or a fine brush, such as commonly-available artists'
camel hair brushes, to affected lesions only and not to surrounding
skin. Prescribed applications have been 1 to 6 times daily for
keratoses and ordinary warts of the hands, fingers, palms, and
soles. For age spots, acne, nail infections, wrinkles and
aging-related skin changes, topical applications have been 1 to 2
times daily.
[0236] Very often, frequency and duration of applications have been
modified according to clinical responses and reactions of the
lesions, and the patient or responsible family member is instructed
accordingly. For example, some clinical manifestations other than
pain have been used as a signal to interrupt application. These
manifestations include distinct blanching of the lesions or
distinct peripheral erythema.
[0237] Alternatively, an office procedure may be adapted when a
full strength of 2-ketopropanoic acid or 70% 2-hydroxyethanoic acid
is used for topical treatment of age spots, keratoses, acne, warts,
or facial wrinkles.
[0238] We have found that the above mentioned alpha hydroxyacids,
alpha ketoacids and related compounds are therapeutically effective
for topical treatments of warts, keratoses, age spots, acne, nail
infections, wrinkles and aging related skin changes.
[0239] Preparation of the Therapeutic Compositions
[0240] Amphoteric and pseudoamphoteric compositions of the instant
invention may be formulated as solution, gel, lotion, cream,
ointment, shampoo, spray, stick, powder, or other cosmetic and
pharmaceutical preparations.
[0241] To prepare an amphoteric or pseudoamphoteric composition in
solution form, at least one of the aforementioned amphoteric or
pseudoamphoteric compounds and at least one of the hydroxyacids or
the related compounds are dissolved in a solution which may consist
of ethanol, water, propylene glycol, acetone, or other
pharmaceutically acceptable vehicle. The concentration of the
amphoteric or pseudoamphoteric compound may range from 0.01 to 10,
the preferred concentration ranges from 0.1 to 3 M. The
concentration of hydroxyacids or the related compounds may range
from 0.02 to 12 M, the preferred concentration ranges from 0.2 to
5M.
[0242] In the preparation of an amphoteric or pseudoamphoteric
composition in lotion, cream or ointment form, at least one of the
amphoteric or pseudoamphoteric compounds and one of the
hydroxyacids or the related compounds are initially dissolved in a
solvent such as water, ethanol, and/or propylene glycol. The
solution thus prepared is then mixed in a conventional manner with
a commonly available cream or ointment base such as hydrophilic
ointment or petrolatum. The concentrations of amphoteric or
pseudoamphoteric compounds and hydroxyacids used in the
compositions are the same as described above.
[0243] Amphoteric and pseudoamphoteric compositions of the instant
invention may also be formulated in a gel form. A typical gel
composition of the instant invention utilizes at least one of the
amphoteric or pseudoamphoteric compounds and one of the
hydroxyacids or the related compounds. The selected compounds are
dissolved in a mixture of ethanol, water, and propylene glycol in a
volume ratio of 40:40:20, respectively. A gelling agent such as
methyl cellulose, ethyl cellulose, hydroxyethylcellulose,
hydroxypropylcellulose, hydroxypropylmethylcellulo- se, carbomer,
or ammoniated glycyrrhizinate is then added to the mixture with
agitation. The preferred concentration of the gelling agent may
range from 0.1 to 4 percent by weight of the total composition.
[0244] Since dimeric and polymeric forms of hydroxyacids are less
stable in the presence of water or the like vehicle, cosmetic and
pharmaceutical compositions should be prepared as anhydrous
formulations. Typical vehicles suitable for such formulations
include mineral oil, petrolatum, isopropyl myristate, isopropyl
palmitate, diisopropyl adipate, octyl palmitate, acetone, squalene,
squalane, silicone oils, vegetable oils, and the like. Therapeutic
compositions containing dimeric or polymeric forms of hydroxyacids
do not require any incorporation of an amphoteric or
pseudoamphoteric compound. The concentration of the dimeric or
polymeric form of a hydroxyacid used in the composition may range
from 0.1 to 100%, the preferred concentration ranges from 1 to 40%.
Therapeutic compositions may be formulated as an anhydrous
solution, a lotion, an ointment, a spray, a powder or the like.
[0245] To prepare a combination composition in a pharmaceutically
acceptable vehicle, a cosmetic or pharmaceutical agent is
incorporated into any one of the above compositions by dissolving
or mixing the agent into the formulation.
[0246] The following are illustrative examples of formulations and
compositions according to this invention. Although the examples
utilize only selected compounds and formulations, it should be
understood that the following examples are illustrative and not
limited, therefore, any of the aforementioned amphoteric or
pseudoamphoteric compounds, hydroxyacids, dimeric or polymeric
forms of hydroxyacids may be substituted according to the teachings
of this invention in the following examples.
EXAMPLE 1
[0247] An amphoteric composition containing 1 M 2-hydroxyethanoic
acid and 0.5 L-arginine in solution form for dandruff or dry skin
may be formulated as follows.
[0248] 2-Hydroxyethanoic acid (glycolic acid) 7.6 g is dissolved in
water 60 ml and propylene glycol 20 ml. L-arginine 8.7 g is added
to the solution, with stirring, until all the crystals are
dissolved. Ethanol is added to make a total volume of the solution
to 100 ml. The amphoteric composition thus formulated has pH 3.0.
An amphoteric composition formulated from 1 M 2-hydroxyethanoic
acid and 1 L-arginine has pH 6.3. The solution has pH 1.9, if no
amphoteric compound is incorporated.
EXAMPLE 2
[0249] An amphoteric composition containing 1 M 2-hydroxyethanoic
acid and 0.5 M L-lysine in a cream form for dry skin and other
dermatologic and cosmetic conditions may be formulated as
follows.
[0250] 2-Hydroxyethanoic acid 7.6 g and L-lysine 7.3 g are
dissolved in 30 ml of water, and the solution thus obtained is
mixed with sufficient amount of an oil-in-water emulsion to make a
total volume of 100 ml. The amphoteric composition thus formulated
has a pH of 3.3.
EXAMPLE 3
[0251] An amphoteric composition containing 12-hydroxyethanoic acid
and 0.5H 4-aminobutanoic acid in lotion form for cosmetic and
dermatologic conditions may be formulated as follows.
[0252] 2-Hydroxyethanoic acid 7.6 g and 4-aminobutanoic acid 5.2 g
are dissolved in water 30 ml, and the solution is mixed with 50 g
of an oil-in-water emulsion. The lotion thus obtained is made up to
100 ml in volume with more oil-in-water emulsion. The amphoteric
composition thus formulated has a pH 3 of 1.
EXAMPLE 4
[0253] A pseudoamphoteric composition containing 12-hydroxyethanoic
acid and 0.5 M creatinine in solution form for cosmetic conditions
and dermatologic disorders may be formulated as follows.
[0254] 2-Hydroxyethanoic acid 7.6 g is dissolved in water 70 ml and
propylene glycol 10 ml. Creatinine 5.7 g is added to the solution
with stirring until all the crystals are dissolved. More water is
added to make a total volume of the solution to 100 ml. The
pseudoamphoteric composition thus formulated has a pH of 3.2. The
composition has a pH of 4.0 when 1 M instead of 0.5 M creatinine is
incorporated into the formulation.
EXAMPLE 5
[0255] An amphoteric composition containing 1 M 2-hydroxyethanoic
acid and 0.5 M L-histidine in a cream form for dermatologic and
cosmetic conditions may be formulated as follows.
[0256] 2-Hydroxyethanoic acid 7.6 g and L-histidine 7.8 g are
dissolved in 25 ml of water, and the solution thus obtained is
mixed with sufficient amount of an oil-in-water emulsion to make a
total volume of 100 ml. The amphoteric composition thus formulated
has a pH of 3.2.
EXAMPLE 6
[0257] An amphoteric composition containing 0.5 M 2-hydroxyethanoic
acid and 0.5 M dipeptide of .beta.-alanyl-L-histadine for cosmetic
and dermatologic conditions may be formulated as follows.
[0258] 2-Hydroxyethanoic acid 3.8 g and L-camosine
(.beta.-alanyl-L-histid- ine) 11.3 g are dissolved in water 40 ml
and propylene glycol 20 ml. After all the crystals have been
dissolved sufficient amount of ethanol is added to make a total
volume of the solution to 100 ml. The amphoteric composition thus
formulated has a pH of 4.5.
EXAMPLE 7
[0259] An amphoteric composition containing 0.5 M 2-hydroxyethanoic
acid and 0.5 M cycloleucine for cosmetic and dermatologic
conditions may be formulated as follows.
[0260] 2-Hydroxyethanoic acid 3.8 g and
l-aminocyclopentane-1-carboxylic acid (cycloleucine) 6.5 g are
dissolved in water 40 ml and propylene glycol 20 ml. After all the
crystals have been dissolved a sufficient amount of ethanol is
added to make a total volume of the solution to 100 ml. The
amphoteric composition thus formulated has a pH of 3.2.
EXAMPLE 8
[0261] A pseudoamphoteric composition containing 0.5 M
2-hydroxyethanoic acid and 0.25 M 1,12-diaminododecane for cosmetic
and dermatologic conditions may be formulated as follows.
[0262] 2-Hydroxyethanoic acid 3.8 g and 1.12-diaminododecane 5 g
are dissolved in water 40 ml and propylene glycol 20 ml. After all
the crystals have been dissolved sufficient amount of ethanol is
added to make a total volume of the solution to 100 ml. The
pseudoamphoteric composition thus formulated has a pH of 4.2.
EXAMPLE 9
[0263] An amphoteric composition containing 0.5H 2-hydroxyethanoic
acid and 5% protamine for cosmetic and dermatologic conditions may
be formulated as follows.
[0264] 2-Hydroxyethanoic acid 3.8 g and protamine 5 g, isolated and
purified from salmon sperm, are dissolved in water 25 ml. The
solution thus obtained is mixed with sufficient amount of an
oil-in-water emulsion to make a total volume of 100 ml. The
amphoteric composition thus formulated has a pH of 3.2.
EXAMPLE 10
[0265] An amphoteric composition containing 1 M 2-hydroxypropanoic
acid and 0.5 M L-arginine in solution form for dandruff or dry skin
may be formulated as follows.
[0266] 2-Hydroxypropanoic acid (DL-lactic acid) USP grade 9.0 g is
dissolved in water 60 ml and propylene glycol 20 ml. L-arginine 8.7
g is added to the solution with stirring until all the crystals are
dissolved. Ethanol is added to make a total volume of the solution
to 100 ml. The amphoteric composition thus formulated has a pH of
3.1. An amphoteric composition formulated from 1 M
2-hydroxypropanoic acid and 1 M L-arginine has a pH of 6.9. The
solution has a pH of 1.9 if no amphoteric compound is
incorporated.
EXAMPLE 11
[0267] An amphoteric composition containing 1 M 2-hydroxypropanoic
acid and 0.5 M L-lysine in a cream form for dry skin and other
dermatologic and cosmetic conditions may be formulated as
follows.
[0268] 2-Hydroxypropanoic acid 9.0 g and L-lysine 7.3 g are
dissolved in 30 ml of water, and the solution thus obtained is
mixed with sufficient amount of an oil-in-water emulsion to make a
total volume of 100 ml. The amphoteric composition thus formulated
has a pH of 3.6. An amphoteric composition formulated from 1 M
2-hydroxypropanoic acid and 1 M L-lysine has a pH of 8.4
EXAMPLE 12
[0269] An amphoteric composition containing 1 M 2-hydroxypropanoic
acid and 0.5 M 4-aminobutanoic acid in lotion form for cosmetic and
dermatologic conditions may be formulated as follows.
[0270] 2-Hydroxypropanoic acid 9.0 g and 4-aminobutanoic acid 5.2 g
are dissolved in water 30 ml, and the solution is mixed with 50 g
of an oil-in-water emulsion. The lotion thus obtained is made up to
100 ml in volume with more oil-in-water emulsion. The amphoteric
composition thus formulated has a pH of 3.0.
EXAMPLE 13
[0271] pseudoamphoteric composition containing 1 M
2-hydroxypropanoic acid and 0.5 M creatinine in solution form for
cosmetic conditions and dermatologic disorders may be formulated as
follows.
[0272] 2-Hydroxypropanoic acid 9.0 g is dissolved in water 70 ml
and propylene glycol 10 ml. Creatinine 5.7 g is added to the
solution with stirring until all the crystals are dissolved. More
water is added to make a total volume of the solution to 100 ml.
The pseudoamphoteric composition thus formulated has a pH of 3.3.
The composition has a pH of 4.4 when 1 M instead of 0.5 M
creatinine is incorporated into the formulation.
EXAMPLE 14
[0273] An amphoteric composition containing 1 M 2-hydroxypropanoic
acid and 1 M L-histidine in a cream form for dermatologic and
cosmetic conditions may be formulated as follows.
[0274] 2-Hydroxypropanoic acid 9.0 g and L-histidine 15.5 g are
dissolved in 35 ml of water, and the solution thus obtained is
mixed with sufficient amount of an oil-in-water emulsion to make a
total volume of 100 ml. The amphoteric composition thus formulated
was a pH of 4.9.
EXAMPLE 15
[0275] An amphoteric composition containing 1 M 2-hydroxypropanoic
acid and 1 M dipeptide of Gly-Gly for cosmetic and dermatologic
conditions may be formulated as follows.
[0276] 2-Hydroxypropanoic acid 9.0 g and glycylglycine 13.2 g are
dissolved in water 40 ml and propylene glycol 20 ml. After all the
crystals have been dissolved, a sufficient amount of ethanol is
added to make a total volume of the solution to 100 ml. The
amphoteric composition thus formulated has a pH of 3.0.
EXAMPLE 16
[0277] An amphoteric composition containing 1 M
2-methyl-2-hydroxypropanoi- c acid and 0.5 M L-arginine in solution
form for dandruff or dry skin may be formulated as follows.
[0278] 2-Methyl-2-hydroxypropanoic acid (methyllactic acid) 10.4 g
is dissolved in water 60 ml and propylene glycol 20 ml. L-arginine
8.7 g is added to the solution with stirring until all the crystals
are dissolved. Ethanol is added to make a total volume of the
solution to 100 ml. The amphoteric composition thus formulated has
a pH of 3.3. An amphoteric composition formulated from 1 M
2-methyl-2-hydroxypropanoic acid and 1 M L-arginine has a pH of
6.5. The solution has a pH of 1.9 if no amphoteric compound is
incorporated.
EXAMPLE 17
[0279] An amphoteric composition containing 1 M
2-methyl-2-hydroxypropanoi- c acid and 0.5 M 4-aminobutanoic acid
in a cream form for dry skin and other dermatologic and cosmetic
conditions may be formulated as follows.
[0280] 2-Methyl-2-hydroxypropanoic acid 10.4 g and 4-aminobutanoic
acid 5.2 g are dissolved in 30 ml of water, and the solution thus
obtained is mixed with sufficient amount of an oil-in-water
emulsion to make a total volume of 100 ml. The amphoteric
composition thus formulated has a pH of 3.2.
EXAMPLE 18
[0281] An amphoteric composition containing 1 M
2-methyl-2-hydroxypropanoi- c acid and 1 M dipeptide of Gly-Gly in
lotion form for cosmetic and dermatologic conditions may be
formulated as follows.
[0282] 2-Methyl-2-hydroxypropanoic acid 10.4 g and glycylglycine
13.2 g are dissolved in water 30 ml, and the solution is mixed with
50 g of an oil-in-water emulsion. The lotion thus obtained is made
up to 100 ml in volume with more oil-in-water emulsion. The
amphoteric composition thus formulated has a pH of 3.0.
EXAMPLE 19
[0283] A pseudoamphoteric composition containing 1 M
2-methyl-2-hydroxypropanoic acid and 0.5 M creatinine in solution
form for cosmetic conditions and dermatologic disorders may be
formulated as follows.
[0284] 2-Methyl-2-hydroxypropanoic acid 10.4 g is dissolved in
water 70 ml and propylene glycol 10 ml. Creatinine 5.7 g is added
to the solution with stirring until all the crystals are dissolved.
More water is added to make a total volume of the solution to 100
ml. The pseudoamphoteric composition thus formulated has a pH of
3.4. The composition has a pH of 4.4 when 1 M instead of 0.5 M
creatinine is incorporated into the formulation.
EXAMPLE 20
[0285] An amphoteric composition containing 0.5 M
2-phenyl-2-hydroxyethano- ic acid and 0.5 M L-histidine in a cream
form for dermatologic and cosmetic conditions may be formulated as
follows.
[0286] 2-Phenyl 2-hydroxyethanoic acid (mandelic acid) 7.6 g and
L-histidine 7.8 g are dissolved in 25 ml of water, and the solution
thus obtained is mixed with sufficient amount of an oil-in-water
emulsion to make a total volume of 100 ml. The amphoteric
composition thus formulated has a pH of 5.0. The composition has a
pH of 2.2 if no amphoteric compound is incorporated.
EXAMPLE 21
[0287] An amphoteric composition containing 0.5 M
2-phenyl-2-hydroxyethano- ic acid and 0.5 M L-lysine for cosmetic
and dermatologic conditions may be formulated as follows.
[0288] 2-Phenyl 2-hydroxyethanoic acid 7.6 g and L-lysine 7.3 g are
dissolved in 25 ml of water. The solution thus obtained is mixed
with an oil-in-water emulsion to make a total volume of 100 ml. The
amphoteric composition thus formulated has a pH of 4.6.
EXAMPLE 22
[0289] A pseudoamphoteric composition containing 0.5 M 2-phenyl
2-hydroxyethanoic acid and 0.5 M creatinine for cosmetic and
dermatologic conditions may be formulated as follows.
[0290] 2-Phenyl 2-hydroxyethanoic acid 7.6 g and creatinine 5.7 g
are dissolved in 30 ml of water, and the solution thus obtained is
mixed with sufficient amount of an oil-in-water emulsion to make a
total volume of 100 ml. The amphoteric composition thus formulated
has a pH of 4.6.
EXAMPLE 23
[0291] An amphoteric composition containing 0.5 M 2-phenyl
2-hydroxyethanoic acid and 0.5 M L-citrulline for cosmetic and
dermatologic conditions may be formulated as follows.
[0292] 2-Phenyl 2-hydroxyethanoic acid 7.6 g and L-citrulline 8.8 g
are dissolved in water 30 ml, and the solution is mixed with 50 g
of an oil-in-water emulsion. The lotion thus obtained is made up to
100 ml in volume with more oil-in-water emulsion. The amphoteric
composition thus formulated has a pH of 3.0.
EXAMPLE 24
[0293] An amphoteric composition containing 1 M citric acid and 1 M
L-arginine for cosmetic conditions and dermatologic disorders may
be formulated as follows.
[0294] Citric acid 19.2 g is dissolved in water 50 ml and propylene
glycol 10 ml. L-Arginine 17.4 g is added to the solution with
stirring until all the crystals are dissolved. More water is added
to make a total volume of the solution to 100 ml. The amphoteric
composition thus formulated has a pH of 3.0. The composition has a
pH of 1.8 if no amphoteric compound is incorporated.
EXAMPLE 25
[0295] A pseudoamphoteric composition containing 1 M citric acid
and 1 M creatinine for dermatologic and cosmetic conditions may be
formulated as follows.
[0296] Citric acid 19.2 g and creatinine 11.3 g are dissolved in 40
ml of water, and the solution thus obtained is mixed with
sufficient amount of an oil-in-water emulsion to make a total
volume of 100 ml. The amphoteric composition thus formulated has a
pH of 3.7.
EXAMPLE 26
[0297] An amphoteric composition containing 1 M malic acid and 1 M
L-arginine for cosmetic and dermatologic conditions may be
formulated as follows.
[0298] 2-Hydroxybutanedioic acid (DL-malic acid) 13.4 g and
L-arginine 17.4 g are dissolved in water 40 ml and propylene glycol
20 ml. After all the crystals have been dissolved sufficient amount
of water is added to make a total volume of the solution to 100 ml.
The amphoteric composition thus formulated has a pH of 3.3. The
composition has a pH of 1.8 if no amphoteric compound is
incorporated.
EXAMPLE 27
[0299] A pseudoamphoteric composition containing 1 M malic acid and
0.5 M creatinine for cosmetic and dermatologic conditions may be
formulated as follows.
[0300] DL-malic acid 13.4 g and creatinine 5.7 g are dissolved in
water 40 ml and propylene glycol 20 ml. After all the crystals have
been dissolved sufficient amount of water is added to make a total
volume of the solution to 100 ml. The pseudoamphoteric composition
thus formulated has a pH of 3.0. The composition has a pH of 3.8
when 1 M creatinine, instead of 0.5 M creatinine, is incorporated
into the formulation.
EXAMPLE 28
[0301] An amphoteric composition containing 1 M tartaric acid and 1
M L-arginine for cosmetic and dermatologic conditions may be
formulated as follows.
[0302] 2,3-Dihydroxybutanedioic acid (DL-tartaric acid) 15.9 g and
L-arginine 17.4 g are dissolved in water 40 ml and propylene glycol
20 ml. After all the crystals have been dissolved sufficient amount
of water is added to make a total volume of the solution to 100 ml.
The amphoteric composition thus formulated has a pH of 3.0. The
composition has a pH of 1.7 if no amphoteric compound is
incorporated.
EXAMPLE 29
[0303] A pseudoamphoteric composition containing 1 M tartaric acid
and 1 M creatinine for cosmetic and dermatologic conditions may be
formulated as follows.
[0304] DL-Tartaric acid 15.0 g and creatinine 11.3 g are dissolved
in 35 ml of water. The solution thus obtained is mixed with
sufficient amount of an oil-in-water emulsion to make a total
volume of 100 ml. The pseudoamphoteric composition thus formulated
has a pH of 3.4.
EXAMPLE 30
[0305] An amphoteric composition containing 1 M gluconolactone and
0.5 M L-arginine for cosmetic and dermatologic conditions may be
formulated as follows.
[0306] Gluconolactone 17.8 g and L-arginine 8.7 g are dissolved in
water 60 ml and propylene glycol 10 ml. After all the crystals have
been dissolved sufficient water is added to make a total volume of
the solution to 100 ml. The amphoteric composition thus formulated
has a pH of 3.1. The composition has a pH of 5.9 when 1 M instead
of 0.5 M L-arginine is incorporated into the formulation. If no
amphoteric compound is incorporated, the pH of the composition is
1.8.
EXAMPLE 31
[0307] An amphoteric composition containing 1 M gluconolactone and
0.5 M 4-aminobutanoic acid for cosmetic and dermatologic conditions
may be formulated as follows.
[0308] Gluconolactone 17.8 g and 4-aminobutanoic acid 5.2 g are
dissolved in water 60 ml and propylene glycol 10 ml. After all the
crystals have been dissolved sufficient water is added to make a
total volume of the solution to 100 ml. The amphoteric composition
thus formulated has a pH of 3.2.
EXAMPLE 32
[0309] An amphoteric composition containing 1 M gluconolactone and
1 M dipeptide of Gly-Gly for cosmetic and dermatologic conditions
may be formulated as follows.
[0310] Gluconolactone 17.8 g and glycylglycine 13.2 g are dissolved
in water 50 ml and propylene glycol 5 ml. More water is added to
make a total volume of the solution to 100 ml. The amphoteric
composition thus formulated has a pH of 3.1.
EXAMPLE 33
[0311] A pseudoamphoteric composition containing 1 M gluconolactone
and 0.5 M creatinine for cosmetic conditions and dermatologic
disorders may be formulated as follows.
[0312] Gluconolactone 17.8 g and creatinine 5.7 g are dissolved in
water 60 ml and propylene glycol 10 ml. More water is added to make
a total volume of the solution to 100 ml. The pseudoamphoteric
composition thus formulated has a pH of 3.2. The composition has a
pH of 4.8 when 1 M creatinine, instead of 0.5 M creatinine, is
incorporated into the formulation.
EXAMPLE 34
[0313] A pseudoamphoteric composition containing 1 M pyruvic acid
and 1 M creatinine for dermatologic and cosmetic conditions may be
formulated as follows.
[0314] 2-Ketopropanoic acid (pyruvic acid) 8.8 g and creatinine
11.3 g are dissolved in water 25 ml. The solution thus obtained is
mixed with sufficient amount of an oil-in-water emulsion to make a
total volume of 100 ml. The amphoteric composition thus formulated
has a pH of 3.4.
EXAMPLE 35
[0315] An amphoteric composition containing 0.5 M benzilic acid and
0.5 M L-lysine for cosmetic and dermatologic conditions may be
formulated as follows.
[0316] 2,2-Diphenyl 2-hydroxyethanoic acid (benzilic acid) 11.4 g
and L-lysine 7.3 g are dissolved in water 40 ml and propylene
glycol 20 ml. After all the crystals have been dissolved, a
sufficient amount of ethanol is added to make a total volume of the
solution to 100 ml. The amphoteric composition thus formulated has
a pH of 4.9. The composition has a pH of 2.7 if no amphoteric
compound is incorporated.
EXAMPLE 36
[0317] An amphoteric composition containing 0.5 M benzilic acid and
0.5 M L-histidine for cosmetic and dermatologic conditions may be
formulated as follows.
[0318] Benzilic acid 11.4 g and L-histidine 7.8 g are dissolved in
water 40 ml and propylene glycol 20 ml. Ethyl cellulose 2 g is
added with stirring, and a sufficient amount of ethanol is added to
make a total volume of the gel to 100 ml. The amphoteric gel
composition thus formulated has a pH of 5.0.
EXAMPLE 37
[0319] A pseudoamphoteric composition containing 0.5 M benzilic
acid and 0.5 M creatinine for cosmetic and dermatologic conditions
may be formulated as follows.
[0320] Benzilic acid 11.4 g and creatinine 5.7 g are dissolved in
water 40 ml and propylene glycol 20 ml. Sufficient amount of
ethanol is added to make a total volume of the solution to 1100 ml.
The amphoteric composition thus formulated has pH 4.9.
EXAMPLE 38
[0321] A pseudoamphoteric composition containing in combination 0.5
M 2-hydroxyethanoic acid and 0.05% betamethasone dipropionate in a
cream form for dermatologic disorders may be formulated as
follows.
[0322] 2-Hydroxyethanoic acid 3.8 g and creatinine 5.7 g are
dissolved in 25 ml of water, and the solution thus obtained is
mixed with 50 g of an oil-in-water emulsion. Betamethasone
dipropionate 1% in ethanol solution 5 ml is added to the above
mixture. More oil-in-water emulsion is added to make a total volume
of 100 ml. The pseudoamphoteric composition thus formulated has a
pH of 4.2.
EXAMPLE 39
[0323] A pseudoamphoteric composition containing in combination 0.5
M 2-hydroxyethanoic acid and 0.05% clobetasol propionate in a cream
form for dermatologic disorders may be formulated as follows.
[0324] 2-Hydroxyethanoic acid 3.8 g and creatinine 5.7 g are
dissolved in 25 ml of water, and the solution thus obtained is
mixed with 50 g of an oil-in-water emulsion. Clobetasol propionate
1% in acetone solution 5 ml is added to the above mixture. More
oil-in-water emulsion is added to make a total volume of 100 ml.
The pseudoamphoteric composition thus formulated has a pH of
4.2.
EXAMPLE 40
[0325] A pseudoamphoteric composition containing in combination 0.5
M 2-hydroxyethanoic acid and 0.1% triamcinolone acetonide in a
cream form for dermatologic disorders may be formulated as
follows.
[0326] 2-Hydroxyethanoic acid 3.8 g and creatinine 5.7 g are
dissolved in 25 ml of water, and the solution thus obtained is
mixed with 50 g of an oil-in-water emulsion. Triamcinolone
acetonide 2% solution of acetone:ethanol (50:50), 5 ml is added to
the above mixture. More oil-in-water emulsion is added to make a
total volume of 100 ml. The pseudoamphoteric composition thus
formulated has a pH of 4.2.
EXAMPLE 41
[0327] A pseudoamphoteric composition containing in combination 0.5
M 2-hydroxyethanoic acid and 0.2% 5-fluorouracil in a cream form
for dermatologic disorders may be formulated as follows.
[0328] 2-Hydroxyethanoic acid 3.8 g and creatinine 5.7 g are
dissolved in 20 ml of water, and the solution thus obtained is
mixed with 50 g of an oil-in-water emulsion. 5-Fluorouracil 2%
solution of propylene glycol: water (95:5) 10 ml is added to the
above mixture. More oil-in-water emulsion is added to make a total
volume of 100 ml. The pseudoamphoteric composition thus formulated
has a pH of 4.1.
EXAMPLE 42
[0329] A pseudoamphoteric composition containing in combination 0.5
M 2-hydroxypropanoic acid and 0.05% betamethasone dipropionate in a
cream form for dermatologic disorders may be formulated as
follows.
[0330] 2-Hydroxypropanoic acid 4.5 g and creatinine 5.7 g are
dissolved in 25 ml of water, and the solution thus obtained is
mixed with 50 g of a oil-in-water emulsion. Betamethasone
dipropionate 1% in ethanol solution 5 ml is added to the above
mixture. More oil-in-water emulsion is added to make a total volume
of 100 ml. The pseudoamphoteric composition thus formulated has a
pH of 4.1.
EXAMPLE 43
[0331] A pseudoamphoteric composition containing in combination 0.5
M hydroxypropanoic acid and 0.05% clobetasol propionate in a cream
form for dermatologic disorders may be formulated as follows.
[0332] 2-Hydroxypropanoic acid 4.5 g and creatinine 5.7 g are
dissolved in 25 ml of water, and the solution thus obtained is
mixed with 50 g of an oil-in-water emulsion. Clobetasol propionate
1% in acetone solution 5 ml is added to the above mixture. More
oil-in-water emulsion is added to make a total volume of 100 ml.
The pseudoamphoteric composition thus formulated has a pH of
4.1.
EXAMPLE 44
[0333] A pseudoamphoteric composition containing in combination 0.5
M 2-hydroxypropanoic acid and 0.1% triamcinolone acetonide in a
cream form for dermatologic disorders may be formulated as
follows.
[0334] 2-Hydroxypropanoic acid 4.5 g and creatinine 5.7 g are
dissolved in 25 ml of water, and the solution thus obtained is
mixed with 50 g of an oil-in-water emulsion. Triamcinolone
acetonide 2% solution of acetone:ethanol (50:50) 5 ml is added to
the above mixture. More oil-in-water emulsion is added to make a
total volume of 100 ml. The pseudoamphoteric composition thus
formulated has a pH of 4.1.
EXAMPLE 45
[0335] A pseudoamphoteric composition containing in combination 0.5
M 2-hydroxypropanoic acid and 0.2% 5-fluorouracil in a cream form
for dermatologic disorders may be formulated as follows.
[0336] 2-Hydroxypropanoic acid 4.5 g and creatinine 5.7 g are
dissolved in 20 ml of water, and the solution thus obtained is
mixed with 50 g of an oil-in-water emulsion. 5-Fluorouracil 2%
solution of propylene glycol:water (95:5), 10 ml is added to the
above mixture. More oil-in-water emulsion is added to make a total
volume of 100 ml. The pseudoamphoteric composition thus formulated
has a pH of 4.1.
EXAMPLE 46
[0337] A pseudoamphoteric composition containing in combination 0.5
M 2-hydroxyethanoic acid and 2% clotrimazole in a cream form for
athletes' foot and other fungal infections may be formulated as
follows.
[0338] 2-Hydroxyethanoic acid 3.8 g, clotimazole 2 g and creatinine
5.7 g are dissolved in water 20 ml and propylene glycol 5 ml, and
the solution thus obtained is mixed with enough amount of an
oil-in-water emulsion to make a total volume of 100 ml. The
pseudoamphoteric composition thus formulated has a pH of 4.2.
EXAMPLE 47
[0339] A pseudoamphoteric composition 0.5 M 2-hydroxyethanoic acid
and 2% erythromycin in solution form for acne may be formulated as
follows.
[0340] 2-Hydroxyethanoic acid 3.8 g, erythromycin 2 g, and
creatinine 5.7 g are dissolved in water 25 ml, ethanol 40 ml, and
propylene glycol 15 ml. More water is then added to make a total
volume of 100 ml. The pseudoamphoteric composition thus formulated
has a pH of 4.2.
EXAMPLE 48
[0341] A pseudoamphoteric composition containing in combination 0.5
M 2-hydroxyethanoic acid and 1% ketoconazole in a cream form for
fungal infections may be formulated as follows.
[0342] 2-Hydroxyethanoic acid 3.8 g, ketoconazole 1 g and
creatinine 5.7 g are dissolved in 25 ml of water, and the solution
thus obtained is mixed with enough amount of an oil-in-water
emulsion to make a total volume of 100 ml. The pseudoamphoteric
composition thus formulated has a pH of 4.2.
EXAMPLE 49
[0343] A pseudoamphoteric composition containing in combination 0.5
M 2-hydroxypropanoic acid and 2% clotrimazole in a cream form for
fungal infections may be formulated as follows.
[0344] 2-Hydroxypropanoic acid 3.8 g, clotrimazole 2 g and
creatinine 5.7 g are dissolved in 25 ml of water, and the solution
thus obtained is mixed with enough amount of an oil-in-water
emulsion to make a total volume of 100 ml. The pseudoamphoteric
composition thus formulated has a pH of 4.1.
EXAMPLE 50
[0345] A pseudoamphoteric composition containing in combination 0.5
M 2-hydroxyethanoic acid and 2% tetracycline in a gel form for
dermatologic disorders may be formulated as follows.
[0346] 2-Hydroxyethanoic acid 3.8 g, tetracycline 2 g, creatinine
5.7 g, xanthan gum 0.2 g, carbomer-941 1 g, propylene glycol 5 ml,
ethanol 20 ml, and sufficient water are homogenized to make a total
volume of 100 ml. The pseudoamphoteric composition thus formulated
for acne and oily skin has a pH of 4.2.
EXAMPLE 51
[0347] An amphoteric composition containing 0.2 M aleuritic acid
and 0.1 M L-lysine in a solution form for cosmetic and dermatologic
conditions may be formulated as follows.
[0348] Aleuritic acid 6.1 g and L-lysine 1.5 g are dissolved in
sufficient amount of a solution of ethanol:propylene glycol 80:20
to make a total volume of 100 ml. The amphoteric composition thus
formulated has a pH of 6.4.
EXAMPLE 52
[0349] A typical composition containing a dimeric form of alpha
hydroxyacid in solution for acne or dandruff, and for use as a skin
cleanser may be formulated as follows.
[0350] Glycolide powder 1.0 g is dissolved in ethanol 89 ml and
propylene glycol 10 ml. The composition thus formulated has a pH of
4.0, and contains 1% active ingredient.
EXAMPLE 53
[0351] A typical composition containing a dimeric form of alpha
hydroxyacid in ointment for dry skin, psoriasis, eczema, pruritus,
wrinkles, and other skin changes associated with aging may be
formulated as follows.
[0352] Glycolide powder 2.0 g is mixed uniformly with petrolatum 66
g and mineral oil 32 g. The composition thus formulated contains 2%
active ingredient.
EXAMPLE 54
[0353] A typical composition containing a full strength or a high
concentration of an alpha hydroxyacid, alpha ketoacid, or closely
related compound for topical treatments of warts, keratoses, acne,
age spots, nail infections, wrinkles and aging-related skin changes
may be prepared as follows.
[0354] If the alpha hydroxyacid, alpha ketoacid, or closely related
compound at full strength is a liquid form at room temperature such
as 2-hydroxypropanoic acid, 2-ketopropanoic acid, methyl
2-ketopropanoate, and/or ethyl 2-ketopropanoate, the compound is
directly dispensed as 0.5 to 1 ml aliquots in small vials. If the
compound is a solid form at room temperature such as
2-hydroxyethanoic acid and 2-methyl 2-hydroxypropanoic acid, it is
first dissolved in minimal amount of an appropriate solvent or
solvent system such as water or ethanol and propylene glycol with
or without a gelling agent. For example, 2-hydroxyethanoic acid 70
g is dissolved in water 30 ml, and the 70% strength
2-hydroxyethanoic acid thus obtained is dispensed as 0.5 to 1 ml
aliquots in small vials. If a gelling agent is desired, methyl
cellulose or hydroxyethyl cellulose 1 g may be added to the above
solution.
EXAMPLE 55
[0355] A typical composition containing an intermediate strength of
an alpha hydroxyacid, alpha ketoacid, or closely related compound
for topical treatment of warts, keratoses, acne, nail infections,
age spots, wrinkles and aging related skin changes may be prepared
as follows.
[0356] 2-Hydroxyethanoic acid or 2-ketopropanoic acid 40 g is
dissolved in ethanol 54 g and propylene glycol 6 g, and the 40%
strength solution thus obtained is dispensed as 5 to 10 ml aliquots
in dropper bottles.
Test Results
[0357] In order to determine whether amphoteric and
pseudoamphoteric compositions of the instant invention were
therapeutically effective for various cosmetic conditions and
dermatologic disorders, a total of more than ninety volunteers and
patients participated in these studies. Some participating subjects
were given two preparations: an amphoteric or pseudoamphoteric
composition containing an alpha hydroxyacid or the related
compound, and a vehicle placebo. Others were given multiple
preparations containing a known pharmaceutical agents such as a
corticosteroid with or without incorporation of an amphoteric or
pseudoamphoteric composition consisting of an alpha hydroxyacid or
the related compound of the instant invention. The amphoteric and
pseudoamphoteric compositions were formulated according to the
Examples described in the previous section. The results of rests
conducted using these compositions are set forth below.
[0358] 1. Common Dry Skin.
[0359] Human subjects having ordinary dry skin or with moderate
degrees of dry skin as evidenced by dryness, flaking, and cracking
of the skin were instructed to apply topically the lotion, cream or
ointment containing an alpha hydroxyacid or the related compound in
amphoteric or pseudoamphoteric composition, to the affected area of
the skin. Topical application, two to three times daily, was
continued for two to four weeks.
[0360] In all the twenty-eight subjects tested, the feeling of the
skin dryness disappeared within a week of topical application. The
rough and cracked skin became less pronounced and the skin appeared
normal and felt smooth after several days of topical treatment. The
alpha hydroxyacid and the related compounds which have been found
to be therapeutically effective when incorporated into the
amphoteric or pseudoamphoteric compositions for dry skin are as
follows:
[0361] 2-hydroxyethanoic acid (glycolic acid), 2-hydroxypropanoic
acid (lactic acid), 2-methyl-2-hydroxypropanoic acid (methyllactic
acid), phenyl 2-hydroxyethanoic acid (mandelic acid), phenyl
2-methyl-2-hydroxyethanoic acid (atrolactic acid),
3-phenyl-2-hydroxypropanoic acid (phenyllactic acid), diphenyl
2-hydroxyethanoic acid (benzilic acid), gluconolactone, tartaric
acid, citric acid, saccharic acid, malic acid, tropic acid,
glucuronic acid, galacturonic acid, gluconic acid,
3-hydroxybutanoic acid, quinic acid, ribonolactone,
glucuronolactone, pyruvic acid, methyl pyruvate, ethyl pyruvate,
phenylpyruvic acid, benzoylformic acid, and methyl
benzoylformate.
[0362] The ordinary 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, excessive contact
pressure, detergents, soaps, solvents, chemicals, etc., again
caused recurrence of the dry skin condition. On continued use it
was also found that twice daily topical application of an
amphoteric or pseudoamphoteric composition containing an alpha
hydroxyacid or the related compound of the instant invention
prevented the development of new dry skin lesions.
[0363] 2. Severe Dry Skin.
[0364] In severe dry skin, the skin lesions are different from the
ordinary dry skin. A main cause of severe dry skin is inherited
genetic defects of the skin. The involved skin is hyperplastic,
fissured and has thick adherent scales. The degree of thickening is
such that lesions are palpably and visually elevated. The thickened
adherent scales cause the surface of involved skin to be markedly
rough and uneven. These two attributes of thickness and texture can
be quantified to allow objective measurement of degree of
improvement from topically applied test materials as follows:
1 Degree of Improvement None Mild Moderate Substantial Complete (0)
(1+) (2+) (3+) (4+) Thickness Highly Detectable Readily Barely
Normal elevated reduction apparent elevated thickness reduction
Texture Visibly Palpably Uneven Slightly Visibly and rough rough
but not uneven palpably rough smooth
[0365] By means of such parameters, degrees of change in lesions
can be numerically recorded and comparisons made of one treated
site to another.
[0366] In order to evaluate the amphoteric and pseudoamphoteric
compositions of the instant invention, a total of six patients
having severe dry skin conditions were treated with the
compositions containing an alpha hydroxyacid or the related
compound.
[0367] Tested areas were of a size convenient for topical
applications, i.e., circles of 5 cm in diameter were demarcated
with a plastic ring of that size inked on a stamp pad. The
medicinal lotions or creams were topically applied by the patient
in an amount sufficient to cover the treatment sites. Applications
were made three times daily and without occlusive dressings.
Applications were discontinued at any time when resolutions of the
lesion on the treatment area was clinically judged to be
complete.
[0368] The test results of amphoteric and pseudoamphoteric
compositions containing the following alpha hydroxyacids or the
related compounds on patients with severe dry skin are summarized
as follows:
[0369] 4+ Effectiveness: glycolic acid, lactic acid, methyllactic
acid, mandelic acid, tropic acid, atrolactic acid, and pyruvic
acid.
[0370] 3+ Effectiveness: benzilic acid, gluconolactone, malic acid,
tartaric acid, citric acid, saccharic acid, methyl pyruvate, ethyl
pyruvate, phenyllactic acid, phenylpyruvic acid, glucuronic acid,
and 3-hydroxybutanoic acid.
[0371] 2+ Effectiveness: mucic acid, ribonolactone,
2-hydroxydodecanoic acid, quinic acid, benzoylformic acid, and
methyl benzoylformate.
[0372] 3. Psoriasis.
[0373] The involved skin in psoriasis is hyperplastic (thickened),
erythematous (red or inflamed), and has thick adherent scales. The
degree of thickening is such that lesions are elevated up to 1 mm
above the surface of adjacent normal skin; erythema is usually an
intense red; the thickened adherent scales cause the surface of
involved skin to be markedly rough and uneven. These three
attributes of thickness, color, and texture can be quantified to
allow objective measurement of degree of improvement from topically
applied test materials as follows.
2 Degree of Improvement None Mild Moderate Substantial Complete (0)
(1+) (2+) (3+) (4+) Thickness Highly Detectable Readily Barely
Normal elevated Reduction apparent elevated thickness reduction
Texture Visibly Palpably Unevent Slightly Visibly and rough rough
but not uneven palpably rough smooth Color Intense Red Dark pink
Light pink Normal skin red color
[0374] By means of such parameters, degree of improvement in
psoriatic lesions can be numerically recorded and comparisons made
of one treated site to another.
[0375] Patients having psoriasis participated in this study.
Amphoteric and pseudoamphoteric compositions containing both an
alpha hydroxyacid or the related compound and a corticosteroid were
prepared according to the Examples. Compositions containing only a
corticosteroid were also prepared and included in the comparison
test. Test areas were kept to minimal size convenient for topical
application, i.e., circles of approximately 4 cm in diameter. The
medicinal compositions were topically applied by the patient in an
amount sufficient to cover the test site [usually about 0.1
milliliter]. More applications were made two to three times daily
and without occlusive dressings. Test periods usually lasted for
two to four weeks. The test results on patients having psoriasis
are summarized on the following table.
[0376] Topical Effects on Psoriasis of Antipsoriatic
Compositions
3 Compositions* Therapeutic Effectiveness Hydrocortisone 2.5% alone
1+ With lactic acid 2+ With glycolic acid 2+ With ethyl pyruvate 2+
With methyl pyruvate 2+ With benzilic acid 2+ With pyruvic acid 2+
With methyllactic acid 2+ Hydrocortisone 17-valerate 0.2% alone 2+
With lactic acid 3+ With glycolic acid 3+ With benzilic acid 3+
With ethyl pyruvate 3+ With methyl pyruvate 3+ With gluconolactone
3+ With pyruvic acid 3+ Betamethasone dipropionate 0.05% alone 3+
With lactic acid 4+ With glycolic acid 4+ With ethyl pyruvate 4+
With methyl pyruvate 4+ With mandelic acid 4+ With benzilic acid 4+
Clobetasol propionate 0.05% alone 3+ With lactic acid 4+ With
glycolic acid 4+ With ethyl pyruvate 4+ With methyl pyruvate 4+
With methyllactic acid 4+ With mandelic acid 4+ With tropic acid 4+
With benzilic acid 4+
[0377] Except the "alone" preparations, all others were amphoteric
or pseudoamphoteric compositions containing 0.2 to 2 M alpha
hydroxyacids or related compounds.
[0378] We have also found that an amphoteric or pseudoamphoteric
composition containing an alpha hydroxyacid or the related compound
in combination with an antimetabolite agent such as 5-fluorouracil
with or without additional incorporation of a corticosteroid is
therapeutically effective for topical treatment of psoriasis.
[0379] 4. Eczema.
[0380] In a topical treatment of eczema patients, hydrocortisone
alone at 2.5% or hydrocortisone 17-valerate alone at 0.2% would
achieve only 2+ improvement, and betamethasone dipropionate or
clobetasol propionate alone at 0.05% would achieve only a 3+
improvement on all the eczema patients tested. Test results of
amphoteric and pseudoamphoteric compositions containing both a
corticosteroid and one of the following alpha 15. hydroxyacids or
the related compounds are shown as follows:
[0381] 3+ Effectiveness: hydrocortisone 2.5% or hydrocortisone
17-valerate 0.2% plus lactic acid, glycolic acid, mandelic acid,
ethyl pyruvate, gluconolactone, benzilic acid or ribonolactone.
[0382] 4+ Effectiveness: betamethasone dipropionate or clobetasol
propionate 0.05% plus lactic acid, glycolic acid, mandelic acid,
ethyl pyruvate, methyl pyruvate, benzilic acid, gluconolactone,
citric acid, tartaric acid, or methyllactic acid.
[0383] 5. Oily Skin and Skin Cleansing.
[0384] Human subjects having oily skin or blemished skin, as well
as acne patients having extremely oily skin participated in this
study. Amphoteric and pseudoamphoteric compositions containing
alpha hydroxyacids or the related compounds were formulated in
solution or gel form.
[0385] Each participating subject received a solution or a gel
preparation containing an alpha hydroxyacid or a related compound
in an amphoteric or pseudoamphoteric composition. The participating
subjects were instructed to apply topically the solution or gel
medication on the affected areas of forehead or other part of the
face. Three times daily applications were continued for two to six
weeks.
[0386] The degree of improvement of oily skin, as well as the rate
of improvement of acne lesions, were clinically evaluated. Most
participants reported that oiliness of skin disappeared within one
to two weeks of topical administration, and the skin so treated
became smooth and soft. Many participating subjects preferred gel
preparations than the solution compositions. It was found that all
the participants showed substantial improvements of oily skin and
acne lesions by six weeks of topical administration of amphoteric
or pseudoamphoteric compositions containing alpha hydroxyacids or
the related compounds of the instant invention.
[0387] Those alpha hydroxyacids and the related compounds which
have been found to be therapeutically effective for oily skin and
as skin cleansers include: benzilic acid, glycolic acid, lactic
acid, methyllactic acid, mandelic acid, pyruvic acid, ethyl
pyruvate, methyl pyruvate, tropic acid, malic acid, gluconolactone,
3-hydroxybutanoic acid, glycolide and polyglycolic acid. As a skin
cleanser for oily skin or acne-prone skin, the amphoteric or
pseudoamphoteric composition containing an alpha hydroxyacid or the
related compounds may also be incorporated with other dermatologic
agents. For example, an amphoteric gel composition may consist of
both an alpha hydroxyacid and erythromycin or tetracycline.
[0388] 6. Acne.
[0389] Amphoteric and pseudoamphoteric compositions containing
alpha hydroxyacids or the related compounds of the instant
invention in a solution or gel form were provided to patients
having comedongenic and/or papulopustular lesions of acne. Each
participating patient was instructed to apply topically the
composition on the involved areas of the skin such as forehead,
face and chest. Three times daily administration was continued for
six to twelve weeks.
[0390] The degree and rate of improvement on acne lesions were
clinically evaluated. It was found that acne lesions consisting
mainly of comedones improved substantially after six to eight weeks
of topical administration with the amphoteric or the
pseudoamphoteric composition containing an alpha hydroxyacid or the
related compound. The time for complete clearing of comedongenic
acne treated with the amphoteric or pseudoamphoteric composition of
the instant invention varied from six to twelve weeks.
[0391] As a topical treatment for papulopustular and/or pustular
acne the amphoteric or pseudoamphoteric composition containing an
alpha hydroxyacid or the related compound may incorporate in
addition an antiacne agent. The antiacne agents include antibiotics
such as erythromycin tetracycline, clindamycin, meclocycline, and
minocycline, and retinoids such as retinoic acid. Such combination
compositions have been found to be therapeutically more effective
for topical treatment of severe acne. 7. Age Spots.
[0392] Many small and large discolored lesions, commonly called
"age spots" on the face and the back of the hands are benign
keratoses, if they are not variants of actinic keratoses. Very few
of such age spots are true lentigines, therefore alpha hydroxyacids
and the related compounds may be effective in eradicating most age
spots without concurrent use of skin bleaching agents such as
hydroquinone and monobenzone. However, additional beneficial
effects have been found when a skin bleaching agent such as
hydroquinone or monobenzone is also incorporated into the
compositions of the instant invention for age spots involving
pigmented lesions.
[0393] Amphoteric and pseudoamphoteric compositions containing
alpha hydroxyacids or the related compounds, with or without
incorporation of hydroquinone were provided to volunteer subjects
and patients having age spot keratoses, melasma, lentigines and/or
other pigmented lesions. Each participating subject received two
products, i.e., products with or without the addition of 2%
hydroquinone to the amphoteric or pseudoamphoteric composition
containing an alpha hydroxyacid or the related compound.
[0394] The volunteer subjects and patients were instructed to apply
topically one medication on one side of the body such as left side
of the face or on the back of the left hand, and the other
medication on the other side of the body such as on right side of
the face or on the back of the right hand. Specific instructions
were given to the participating subjects that the medications were
applied three times daily to the lesions of age spot keratoses,
melasmas, lentigines and/or other pigmented lesions. Clinical
photos were taken of participating subjects before the initiation
of the topical treatment and every four weeks during the course of
treatment.
[0395] At the end of four to eight weeks, improvement of age spot
keratoses was clinically discernible. After four to six months of
topical treatment, substantial improvement of age spot keratoses
occurred in the majority of subjects tested. Complete eradication
of age spot keratoses occurred after six to nine months of topical
administration with the amphoteric or pseudoamphoteric compositions
of the instant inventions.
[0396] Amphoteric or pseudoamphoteric compositions containing both
an alpha hydroxyacid or the related compound and hydroquinone were
judged to be more effective in eradicating pigmented age spots,
melasma, lentigines, and other pigmented lesions.
[0397] The alpha hydroxyacids and the related compounds which have
been found to be therapeutically effective for age spots with or
without combination with hydroquinone include glycolic acid, lactic
acid, methyllactic acid, mandelic acid, pyruvic acid, methyl
pyruvate, ethyl pyruvate, benzilic acid, gluconolactone, malic
acid, tartaric acid, citric acid, and tropic acid. For flat or
slightly elevated seborrheic keratoses on the face and/or the back
of the body, amphoteric or pseudoamphoteric compositions containing
higher concentrations of alpha hydroxyacids or the related
compounds have been found to be effective in eradicating such
lesions.
[0398] Actinic keratoses may be successfully treated with
amphoteric or pseudoamphoteric compositions containing alpha
hydroxyacids or the related compounds in combination with an
antimetabolite agent such as 5-fluorouracil.
[0399] 8. Warts.
[0400] Eradication of common warts by topical application of
amphoteric or pseudoamphoteric compositions requires higher than
usual concentrations of alpha hydroxyacids or the related compounds
in the formulations. The amphoteric or pseudoamphoteric
compositions were formulated as a liquid or light gel form, and
dispensed usually as 0.5 to 1 ml aliquots in small vials.
[0401] Topical applications were made discretely to wart lesions by
adult patients or by responsible adult family members. For ordinary
usual warts of hands, fingers, palms and soles topical applications
were made two to four times daily, and were continued for two to
six weeks. Generally, the overlying stratum comeum of the wart
lesion change in appearance after several weeks topical application
of the composition. In most cases, the wart lesion simply fell off.
The skin then healed normally without forming any scars.
[0402] We have also found that when a dermatologic agent such as
5-fluorouracil is incorporated into the amphoteric or
pseudoamphoteric compositions containing alpha hydroxyacids or the
related compounds, the medications have been very effective for
topical treatment of warts without using higher concentrations of
alpha hydroxyacids or the related compounds.
[0403] The alpha hydroxyacids and the related compounds which have
been found to be therapeutically effective for topical treatment of
warts with or without incorporation of 5-fluorouracil include
glycolic acid, lactic acid, pyruvic acid, ethyl pyruvate, methyl
pyruvate and mandelic acid.
[0404] Topical formulations and compositions containing specific
alpha hydroxyacids, alpha ketoacids or the related compounds at
full strengths or high to intermediate concentrations prepared
according to Examples 54 and 55, without utilizing amphoteric or
pseudoamphoteric systems, have also been tested for ordinary warts
of the hands, fingers, palms, and soles. Participating patients
have been advised to apply a small drop of the medication with a
toothpick or a fine brush to the center of a wart lesion only.
Prescribed applications have been three to six times daily, and are
continued until the patient feels pain.
[0405] For the more rough-surfaced wart, the duration of
application has been as short as one or a few days. For lesions
with more compact, less permeable stratum comeum, the time until
which the patient experiences pain has been longer. Frequency and
duration of applications have been modified according to other
clinical responses and reactions of lesions, and the patient or
responsible family member is instructed accordingly.
[0406] For example, some clinical manifestations other than pain
have also been used as a signal to interrupt application. These
manifestations have included distinct blanching of the lesions or
distinct peripheral erythema. Very often, discomfort is the usual
signal of clinical reactions.
[0407] Generally, the overlying stratum comeum of the wart lesions
became loose, and the whole wart lesion simply fell off. The skin
then healed normally without forming any scars.
[0408] 9. Athlete's Foot and Nail Infections.
[0409] Amphoteric and pseudoamphoteric compositions containing both
an antifungal agent and one of the alpha hydroxyacids or the
related compounds were provided to patients having frequent
recurrence of fungal infections involving the foot. The antifungal
agents include clotrimazole, miconazole, ketoconazole, and
griseofulvin. When both feet, but not toenails were involved in the
infection, the patients were instructed to apply topically the
compositions of the instant invention on the left foot, and a
brand-name antifungal product on the right foot. Three times daily
applications were continued for one to four weeks. The degree and
rate of improvement on skin lesions were clinically evaluated, and
comparison was made one side of the body against the other. It was
found that the skin lesions improved much faster with the
amphoteric or pseudoamphoteric compositions containing both the
antifungal agent and the alpha hydroxyacid or the related compound.
The alpha hydroxyacids or the related compounds seemed to enhance
the efficacies of the antifungal agents, and also to eliminate the
discomfort such as itching, tingling, burning and irritation due to
fungal infections. When toenails were not involved, the infected
skin generally healed within one to two weeks from topical
application of the amphoteric or pseudoamphoteric composition
containing both an antifungal agent and an alpha hydroxyacid or the
related compound.
[0410] Fungal infections of the nails are very difficult to treat,
because antifungal products to date are not therapeutically
effective for topical treatment of nails. One of the reasons is
that most antifungal drugs have not been formulated as bioavailable
forms in the commercial products. When toenails were involved in
the infections, patients were provided with amphoteric or
pseudoamphoteric compositions containing in combination an
antifungal agent and an alpha hydroxyacid or an alpha ketoacid at
higher concentrations ranging from 20% to 99%, dispensed as 1 to 2
ml aliquots in small vials. The patients were instructed to
topically apply the compositions discretely to the infected nail
surface by means of a fine artists' paint brush. The technique was
the same as for conventional application of nail polish, that is
careful avoidance of contact with lateral nail folds or any
periungual skin. Once or twice daily applications were continued
for two to eight weeks.
[0411] As mentioned above, brand-name antifungal products are
usually not effective against fungus infections within or
underneath the nail; however, it was found that the amphoteric or
pseudoamphoteric compositions containing an antifungal agent and an
alpha hydroxyacid or alpha ketoacid were therapeutically effective
in eradicating fungal infections of the nails. Such treatment may
cause in some instances the treated nail plate to become loose and
eventually fell off from the nail bed. This happened quite
naturally without any feeling of pain or bleeding, and the skin
lesion healed quickly with normal growth of a new nail.
[0412] 10. Wrinkles.
[0413] Wrinkles of skin may be due to natural aging and/or sun
damage. Most fine wrinkles on the face are due to natural or innate
aging, while coarse wrinkles on the face are the consequence of
actinic or sun damage. Although the real mechanism of wrinkles
formation in the skin is still unknown, it has been shown that
visible fine wrinkles are due to diminution in the number and
diameter of elastic fibers in the papillary dermis, and also due to
atrophy of dermis as well as reduction in subcutaneous adipose
tissue. Histopathology and electron microscopy studies indicate
that coarse wrinkles are due to excessive deposition of abnormal
elastic materials in the upper dermis and thickening of the skin.
At present there are no commercial products that have been found to
be therapeutically effective for topical eradication of wrinkles,
although retinoic acid (tretinoin) has been shown to be beneficial
for sun damaged skin.
[0414] In order to determine whether the amphoteric or
pseudoamphoteric composition containing the alpha hydroxyacids,
alpha ketoacids or the related compounds are therapeutically
effective for wrinkles, patients and volunteer subjects
participated in this study. The participants were instructed to
apply the formulations of the instant invention twice daily on
areas of facial wrinkles for four to twelve months. All
participants were told to avoid sun exposure, and to use sunscreen
products if exposure to sunlight was unavoidable.
[0415] Photographs of each side of the face for each participant
were taken at the beginning of the study and repeated at one to
three-month intervals. The participants were asked not to wear any
facial make-up at the time of each office visit. Standardized
photographic conditions were used including the use of same lot of
photographic film, the same light source at two feet from the face,
aimed at a locus on the frontal aspect of each cheek. Each time
photographs were taken with camera aimed perpendicular to the
cheek. At the end of study twenty two participants had been entered
into the study for at least four months. Clinical evaluations and
review of photographs have revealed substantial reductions in
facial wrinkles of the temporal region and cheek area on at least
one side of the face in eighteen cases. Degree of improvement and
reduction in wrinkles has been evaluated and determined to be mild
to moderate in six participants but very substantial in twelve
participants.
[0416] The alpha hydroxyacids, alpha ketoacids, and other related
compounds including their lactone forms which may be incorporated
into the amphoteric and pseudoamphoteric compositions for cosmetic
conditions and dermatologic disorders such as dry skin, acne, age
spots, keratoses, warts, and skin wrinkles or in combination with
other dermatologic agents to enhance therapeutic effects include
the following:
[0417] (1) Alkyl Alpha Hydroxyacids.
[0418] 2-Hydroxyethanoic acid (glycolic acid), 2-Hydroxypropanoic
acid (lactic acid), 2-Methyl 2-hydroxypropanoic acid (methyllactic
acid), 2-Hydroxybutanoic acid, 2-Hydroxypentanoic acid,
2-Hydroxyhexanoic acid, 2-Hydroxyheptanoic acid, 2-Hydroxyoctanoic
acid, 2-Hydroxynonanoic acid, 2-Hydroxydecanoic acid,
2-Hydroxyundecanoic acid, 2-Hydroxydodecanoic acid (alpha
hydroxylauric acid), 2-Hydroxytetradecanoic acid (alpha
hydroxymyristic acid), 2-Hydroxyhexadecanoic acid (alpha
hydroxypalmitic acid), 2-Hydroxyoctadecanoic acid (alpha
hydroxystearic acid), 2-Hydroxyeicosanoic acid (alpha
hydroxyarachidonic acid).
[0419] (2) Aralkyl and Aryl Alpha Hydroxyacids.
[0420] 2-Phenyl 2-hydroxyethanoic acid (mandelic acid);
2,2-Diphenyl 2-hydroxyethanoic acid (benzilic acid); 3-Phenyl
2-hydroxypropanoic acid (phenyllactic acid); 2-Phenyl 2-methyl
2-hydroxyethanoic acid (atrolactic acid); 2-(4'-Hydroxyphenyl)
2-hydroxyethanoic acid; 2-(4'-Clorophenyl) 2-hydroxyethanoic acid;
2-(3'-Hydroxy-4'-methoxyphenyl) 2-hydroxyethanoic acid;
2-(4'-Hydroxy-3'-methoxyphenyl) 2-hydroxyethanoic acid;
3-(2'-Hydroxyphenyl) 2-hydroxypropanoic acid; 3-(4'-Hydroxyphenyl)
2-hydroxypropanoic acid; 2-(3', 4'-Dihydroxyphenyl)
2-hydroxyethanoic acid.
[0421] (3) Polyhydroxy Alpha Hydroxyacids.
[0422] 2,3-Dihydroxypropanoic acid (glyceric acid);
2,3,4-Trihydroxybutanoic acid (Isomers: erythronic acid, threonic
acid); 2,3,4,5-Tetrahydroxypentanoic acid (Isomers: ribonic acid,
arabinoic acid, xylonic acid, lyxonic acid);
2,3,4,5,6-Pentahydroxyhexanoic acid (Isomers: aldonic acid,
altronic acid, gluconic acid, mannoic acid, gulonic acid, idonic
acid, galactonic acid, talonic acid);
2,3,4,5,6,7-Hexahydroxyheptanoic acid (Isomers: glucoheptonic acid,
galactoheptonic acid, etc.).
[0423] (4) Polycarboxylic Alpha Hydroxyacids.
[0424] 2-Hydroxypropane-1,3-dioic acid (tartronic acid);
2-Hydroxybutane-1,4-dioic acid (malic acid);
2,3-Dihydroxybutane-1,4-dioi- c acid (tartaric acid);
2-Hydroxy-2-carboxypentane-1,5-dioic acid (citric acid);
2,3,4,5-Tetrahydroxyhexane-1,6-dioic acid (Isomers: saccharic acid,
mucic acid, etc.)
[0425] (5) Alpha Hydroxyacid Related Compounds
[0426] Ascorbic acid, quinic acid, isocitric acid, tropic acid,
3-chlorolactic acid, trethocanic acid, cerebronic acid, citramalic
acid, agaricic acid, 2-hydroxynervonic acid, and aleuritic
acid.
[0427] (6) Alpha Ketoacids and Related Compounds.
[0428] 2-Ketoethanoic acid (glyoxylic acid); Methyl
2-ketoethanoate; 2-Ketopropanoic acid (pyruvic acid); Methyl
2-ketopropanoate (methyl pyruvate); Ethyl, 2-ketopropanoate (ethyl
pyruvate); Propyl 2-ketopropanoate (propyl pyruvate);
2-Phenyl-2-ketoethanoic acid (benzoylformic acid); Methyl
2-phenyl-2-ketoethanoate (methyl benzoylformate); Ethyl
2-phenyl-2-ketoethanoate (ethyl benzoylformate);
3-Phenyl-2-ketopropanoic acid (phenylpyruvic acid); Methyl
3-phenyl-2-ketopropanoate (ethyl phenylpyruvate); 2-Ketobutanoic
acid; 2-Ketopentanoic acid; 2-Ketohexanoic acid; 2-Ketoheptanoic
acid; 2-Ketooctanoic acid; 2-Ketododecanoic acid; Methyl
2-ketooctanoate.
[0429] The amphoteric and pseudoamphoteric compounds that may be
incorporated into the compositions of the instant invention for
cosmetic and dermatologic conditions include amino acids, peptides,
polypeptides, proteins, and like compounds such as creatinine and
creatine.
[0430] The dimeric and polymeric forms of alpha hydroxyacids and
the related compounds which may be incorporated into the
compositions of the instant invention include acyclic esters and
cyclic esters; for example, glycolyl glycollate, lactyl lactate,
glycolide, lactide, polyglycolic acid, and polylactic acid.
[0431] The invention may be embodied in other specific forms
without departing from the spirit or essential characteristics
thereof. The present embodiments are therefore to be considered in
all respects as illustrative and not restrictive, the scope of the
invention being indicated by the appended claims and all changes
which come within the meaning and equivalency of the claims are
therefore intended to be embraced therein.
[0432] It will be appreciated by those skilled in the art that
changes could be made to the embodiments described above without
departing from the broad inventive concept thereof. It is
understood, therefore, that this invention is not limited to the
particular embodiments disclosed, but it is intended to cover
modifications within the spirit and scope of the present invention
as defined by the appended claims.
* * * * *