Note: Descriptions are shown in the official language in which they were submitted.
- 1340120
Thls ls a dlvlslonal applicatlon of appllcatlon No.
549,964 flled October 22, 1987.
The lnvention of the parent appllcatlon relates
generally to method and composltlon contalnlng hydroxyacld or
related compound for enhanclng therapeutlc effects of cosmetlc
or pharmaceutlcal agent. As wlll be subsequently descrlbed ln
detall, we lnltlally dlscovered that alpha hydroxy or keto
aclds and thelr derlvatlves were effectlve ln the toplcal
treatment of dlsease condltlons such as dry skln, lchthyosls,
eczema, palmar and plantar hyperkeratoses, dandruff, acne and
warts.
We have now dlscovered that hydroxyaclds or related
compounds whereln lncorporated lnto a therapeutlc composltlon
can substantlally enhance toplcal effects of cosmetlc and
pharmaceutlcal agents.
The lnventlon of thls appllcatlon relates to use of
a therapeutlcally or prophylactlcally effectlve amount of a
toplcally appllcable therapeutlc or prophylactlc composltlon
comprlslng at least one hydroxycarboxyllc acld as a free acld
or salt form and a pharmaceutlcally or cosmetlcally acceptable
vehlcle ln treatment of flne or coarse wrlnkles, or skln
changes assoclated wlth aglng selected from flne llnes, skln
llnes, deepenlng of skln llnes, thlnnlng of skln, plgmented
age spots and leslons, coarse skln, rough skln, blemlshes,
blotches, xerosls, ltchlng skln, loss of skln elastlclty and
recollablllty, and old-looklng skln.
~'
' p
J
- 1~4~120
The lnventlon of further dlvlslonal appllcatlon
617,036 relates to a prophylactlc and therapeutlc composltlon
effectlve agalnst acne and for olly skln and as skln cleanser
comprlsing an effectlve amount of benzlllc acld ln a
pharmaceutlcally acceptable vehlcle for toplcal appllcatlon to
skln of human or anlmal body.
In our prlor U.S. Patent No. 3,879,537 entltled
"Treatment of Ichthyoslform Dermatoses", we descrlbed and
clalmed the use of certaln alpha hydroxy aclds, alpha keto
aclds and related compounds for toplcal treatment of flsh-
scale llke lchthyotlc condltlons ln humans. In our U.S.
Patent No. 3,920,835 entltled "Treatment of Dlsturbed
Keratlnlzatlon", we descrlbed and clalmed the use of these
certaln alpha hydroxy aclds, alpha keto aclds and thelr
derlvatlves for toplcal treatment of dandruff, acne, and
palmar and plantar hyperkeratosls.
In our prlor U.S. Patent No. 4,105,783 entltled
"Treatment of Dry Skln", we descrlbed and clalmed the use of
alpha hydroxy aclds, alpha keto aclds and thelr derivatlves
for toplcal treatment of dry skln. In our recent U.S. Patent
No. 4,246,261 entltled "Addltlves Enhanclng Toplcal
Cortlcosterold Actlon", we descrlbed and clalmed that alpha
hydroxy aclds, alpha keto aclds and thelr derlvatlves, ln
small amounts could greatly enhance the therapeutlc efflcacy
of cortlcosterolds ln toplcal treatment of psorlasls, eczema,
seborrhelc dermatltls and other lnflammatory skln condltlons.
la
~L~
134nl2~
In our more recent U.S. Patent No. 4,363,815 entitled nAlpha
Hydroxy acids, Alpha Keto acids and Their Use in Treating Skin
Conditions: we described and claimed that alpha hydroxy acids and
alpha keto acids related to or originating from amino acids,
whether or not found in proteins, were 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 and possibly warts and herpes.
In our most recent U.S. Patent No. 4,518,789 entitled
~Phenyl Alpha-Acyloxyacetamide Derivatives and Their Therapeutic
Use~ we described and claimed that phenyl alpha acyloxyacetamide
derivatives in topical or systemic administration were useful and
effective for pruritus, atopic dermatitis, eczema, psoriasis,
acne, dry skin, dandruff, malodors of integumental areas, various
aches, pains and discomforts of skin, joints and other body parts
in humans and domestic animals.
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
systemic 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 ma;or
factors a) Percutaneous absorption and penetration b)
Bioavailability of the penetrated ph~rmaceutical agent to the
target site in the skin. To be therapeutically effective as a
topical agent a pharmaceutical drug must penetrate the stratum
corneum into the epidermal layers, distributed and bioavailable
13~ 12~J
to the target sites for pharmacologic action. Many pharma-
cologic agents can readily penetrate the skin but they are not
bioavailable to the target sites in the skin, therefore
therapeutic effect is minimal and ineffective.
It has now been discovered that hydroxyacids and
related compounds including those described or not described in
our previous patents and additional compounds can substantially
enhance the therapeutic efficacy of cosmetic and pharmaceutical
agents in topical treatment of cosmetic conditions, dermatologic
disorders or other afflictions. The topical treatment means
topical application to the skin of humans and animals other than
through a mucous membrane (such as rectal or nasal application)
and a pour-on composition (that is often applied to animals)
is excluded. Cosmetic and pharmaceutical agents may include
any chemical substances natural or synthetic, intended for
topical application to the skin or its appendages in human and
animals. Some examples of cosmetic and pharmaceutical agents
include age spots and keratoses removing agents, analgesics,
anesthetics, antiacne agents, antibacterials, antiyeast agents,
antifungal agents, antiviral agents, antiburn agents, anti-
dandruff agents, antidermatitis agents, antipruritic agents,
antiperspirants, antiinflammatory agents, antihyperkeratolytlc
agents, antidryskin agents, antipsoriatic agents, antiseborrheic,
agents, astringents, softeners, emollient agents, coal tar,
bath oils, sulfur, rinse conditioners, foot care agents,
fungicides, hair growth promoters, hair removers, keratolytic
agents, moisturizer agents, powder, shampoos, skin bleaches,
skin protectants, soaps, cleansers, antiaging agents, sunscreen
agents, wart removers, wet dressings, vitamins, tanning agents,
topical antihistamin agents, hormones, vasodilators, retinoids,
1~0 12~
bronchial dilators, topical cardiovascular agents and other
dermatologicals. Further excluded from the invention of the
parent application is a combination of lactic acid as the
hydroxyacid and nicardipine hydrochloride as the cosmetic or
pharmaceutical agent.
In this invention among preferred active compounds
useful in therapeutic compositions for preventing or treating
undesirable skin conditions and disorders by topical application
to the skin as described above are:
citramalic acid, diphenyl 2-hydroxyacetic acid (benzilic
acid), 2-phenyl 3-hydroxypropanoic acid (tropic acid), aleuritic
acid, ribonic acid, ribonoloactone, 2,3,4-trihydroxybutanoic acid,
2,3,4,5-tetrahydroxypentanoic acid, 2,3,4,5,6-pentahydroxyhexanoic
acid, 2-hydroxylauric acid, 2,3,4,5,6,7-hexahydroxyheptanoic acid,
4-hydroxymandelic acid, 4-chloromandelic acid, 2-hydroxy-3-methyl-
butanoic acid, 2-hydroxy-4-methylpentanoic acid, 3-hydroxy-4-
methoxymandelic acid, 4-hydroxy-3-methoxymandelic acid, 3-(3-
hydroxyphenyl) lactic acid, 3-(4-hydroxyphenyl) lactic acid,
hexahydromandelic acid, 3-hydroxy-3-methylpentanoic acid,
1-hydroxy-1-cyclopropane carboxylic acid, 4-hydroxybutanoic acid,
2-hydroxyhexanoic acid, 5-hydroxylauric acid, 12-hydroxylauric
acid, 10-hydroxydecanoic acid, 16-hydroxyhexadecanoic acid,
4-hydroxydecanoic acid, 5-hydroxydecanoic acid, and 4-hydroxy-
2,2-diphenylbutanoic acid as a free acid or salt form.
3a
1~5~i~3
-- A
1~ The c..hs~ai..~ compounds of the instant invention are
hydroxycarboxylic acids and related compounds. There are three
group~ of ~uch hydroxyacids. The first is hydroxymonocarboxylic
acids having the following chemical structure:
Rl (CR20H)m(CH2)n COOH
wherein
Rl, R2 -H, alkyl, aralkyl or aryl group of saturated or
un~aturated, ~traight or branched chain or cyclic form, having 1
to 25 carbon atom~.
m-l, 2, 3, 4, 5, 6, 7, 8 or 9
n-0 or a numerical number up to 23
When n=0 and m=l or more, the hydroxymonocarboxylic acid is also
called aldonic acid. The name comes from a carbohydrate, aldose,
which may be oxidized to aldonic acid by the oxidation of the
aldehyde group in aldose to the carboyxlic group.
The hydroxymonocarboxylic acid may be present as a free
acid, lactone, or salt form. The lactone form could be either
inter or intramolecular lactone, however, most common one~ are
intramolecular lactones with a ring structure formed by
elimination of one or more water molecules between a hydroxy
group and the carboxylic group. Since the hydroxymonocarboxylic
acid~ are organic in nature, they may form a salt or a complex
with an inorganic or organic base ~uch as ammonium hydroxide,
sodium or potas~ium hydroxide, or triethanolamine.
The hydroxymonocarboxylic acld and its related compounds may
also exist a~ stereoisomers such as D, L, and DL forms.
1 ~ ~ O 1 2 3
._
The typical alkyl, aralkyl and aryl groups for R1 and R2
include methyl, ethyl, propyl, i~opropyl, benzyl and phenyl. The
hydrogen atoms of the Rl and R2 and (CH2)n may be substituted by
a nonfunctional element such as F, Cl, Br, I, S or a radical such
a~ a lower alkyl or alkoxy, ~aturated or unsaturated, having 1 to
9 carbon atom~. Representative hydroxymonocarboxylic acids are
li~ted below: -
1. 2-Hydroxyacetic acid (Glycolic acid)
Rl=H, R2-H, m=l, n=O
2. 2-Hydroxypropanoic acid (Lactic acid)
Rl~CH3, R2=H, m=l, n=o
3. 2-Methyl 2-hydroxypropanoic acid (Methyllactic acid)
1 CH3~ R2=CH3, m=l, n=o
4. 2-Hydroxybutanoic acid
Rl-C2H5~ R2=H, m=l, n=o
5. Phenyl 2-hydroxyacetic acid (Mandelic acid)
1 6H5, R2 H, m 1, n o
6. Phenyl 2-methyl 2-hydroxyacetic acid (Atrolactic acid)
1 C6Hs~ R2 CH3, m~l, n=o
7. 3-Phenyl 2-hydroxypropanoic acid (Phenyllactic acid)
Rl C6H5, R2-H, m~l, n-l
8. 2,3-Dihydroxypropanoic acid (Glyceric acid)
Rl-H, R2-H, m-2, n-O
9. 2, 3, 4-TrihydL~xy~Lanoic acid
Rl H, R2-H, m-3, n~o
10. 2, 3, 4, S-Tetrahyd~oxy~entanoic acid
Rl-H, R2-H,m-4, n~O
11. 2, 3, 4, S, 6-Pentahydroxyhenxanoic acid
Rl-H, R2-H, m~S, n-O
i 3 ~ 2 3
-
12. 2-Hydroxydodecanoic acid (alpha hydroxylauric acid)
Rl CloH21~ R2=H, m=l, n=o
13. 2, 3, 4, S, 6, 7-Hexahydroxyheptanoic acid
Rl-H, R2-H, m=6, n=o
14. Diphenyl 2-hydroxyacetic acid (benzilic acid)
1 C6H5' R2=C6H5~ m=l, n=o
15. 4-Hydroxymandelic acid
Rl-C6H4(OH), R2=H, m=l, n=o
16. 4-Chloromandelic acid
Rl~C6H4(Cl), R2=H, m-l, n=o
17. 3-Hydroxybutanoic acid
Rl~CH3, R2~H, m-l, n~l
18. 4-Hyd-oxybutanoic acid
Rl-H, R2-H, m=a, n~2
19. 2-Hyd~oxyh~xanoic acid
1 C4Hg, R2 H, m 1, n 0
20. 5-Hydroxydodecanoic acid
Rl'C7Hls~ R2~H, m-l, n-3
21. la-Hydroxydodecanoic acid - --
Rl-H, R2-H, m~l, n~l0
22. 10-Hyd~G~yd~-noic acid
Rl-H, R2-H, ~--1, n-8
23. 16-Hydroxyhexadecanoic acid
Rl H, R2-H, m-l, n-14
24. 2-Hydroxy-3-methylbutanoic acid
Rl-C3H7, R2~H, m-l, n-o
25. 2-hyd~o~y-4-methylpentanoic acid
Rl-C4Hg, R2-H, m~l, n-o
26. 3-Hydroxy-4-methoxymandelic acid
) 1 2 3
Rl-C6H3 (OH) (OCH3), R22H, m=l, n=o
27. 4-Hydroxy-3-methoxymandelic acid
Rl=C6H3 (OH) (OCH3), R2=H, m=l, n=o
28. 2-Hydroxy-2-methylbutanoic acid
Rl C2H5~ R2~CH3, m=l, n=o
29. 3-(2'Hydroxyphenyl) lactic acid
Rl=C6H4(0H) CH2, R2=H, m=l, n=o
30. 3-(4-Hydroxyphenyl) lactic acid
Rl=C6H4(0H) CH2, R2=H, m=l, n=O
31. Hexahydromandelic acid
1 C6Hll~ R2=H, m-l, n=o
32. 3-Hydroxy-3-methylpentanoic acid
1 C2Hs~ R2~CH3, m-l, n=l
33. 4-Hydroxydeeanoie aeid
1 C6H13~ R2SH, m-l, n=2
34. 5-Hydroxydeeanoie aeid
Rl CsHll~ R2eH, m=l, n=3
35. Aleuritie aeid
Rl-C6H12(0H), R2-H, m-2, n=7
The linear laetie aeid polymer is an intermoleeular lactone
formed by elimination of one water moleeule between the hydroxy
group of one moleeule of laetie aeid and the earboxylie group of
a seeond moleeule of laetie aeid. The common linear lactic acid
polymer may eontain 3 laetie aeid units.
Ribonie aeid i~ one of the stereoisomers of 2, 3, 4, 5-
tetrahydroxypentanoic aeid, and the corresponding lactone is
ribonolaetone. Glueonie aeid, galactonie acid, gulonic acid and
mannonic aeid are typical 2, 3, 4, 5, 6-pentahydroxyhexanoic
134~ 12i~
-
acids and thelr co~esponding lactone~ are gluconolactone,
galactonolactone, gulonolactone and mannonolactone respectively.
The related compounds of hydroxymonocarboxylic acids are
ketomonocarboxylic acids which are formed from the former by a
oxidation reaction or in vivo by a dehydrogenase enzyme. For
example, 2-ketopropanoic acid (pyruvic acid) and
2-hydroxypropanoic acld (lactic acid) are converted to each other
in vivo by the enzyme, lactate dehydrogenase. Although pure
pyruvic acid (liquid form) can be kept in a refrigerator for an
extended period of time a ~_ ,osition containing pyruvic acid for
topical use is not very stable at an elevated temperature.
Therefore, for practical purposes pyruvic acid esters are used
instead.
The ~e~eaentatlve esters are methyl pyruvate, ethyl
pyruvate, propyl pyruvate and isopropyl pyruvate. Other
repre~entative ketomonocarboxylic acids and their esters are
phenyl pyruvic acid and its ester~ such as methyl phenyl
pyruvate, ethyl phenyl pyruvate and propyl phenyl pyruvate;
formyl formic acid ~2-ketoacetic acid) and its esters such as
methyl, ethyl and propyl formyl formate: benzoyl formic acid and
its esters such as methyl, ethyl and propyl benzoyl formate;
4-hydloxyb~l~zoyl~ormic acid and its esters: 4-hydroxyphenyl-
pyruvic acid and its esters: 2-hydroxyphenylpyruvic acid and its
esters.
Many hydroxy or ketomonocarboxylic acids are structurally
related to amino acids either naturall-y occurring in proteins or
not. For example alanine and pyruvlc acid are interconverted to
each other in vlvo by an enzyme alanine dehydrogenase or alanine
ketoglutarate transaminase. As mentioned earlier pyruvic acid
13~0120
and lactic acid are interconverted to each other in vivo by the
enzyme lactate dehydrogenase. Therefore, alanine, pyruvic acid
and lactic acid are chemically related in that the amino group of
alanine may be converted to the keto group of pyruvic acid or the
hydroxy group of lactic acid. The same relationships may apply
to formyl for~ic acid and glycolic acid to glycine; hydroxpyruvic
acid and glyceric acid to serine: phenyl pyruvic acid and
phenyl lactic acid to phenylalanine; 2-keto- and 2-hydroxy-4
(methylthio) butanoic acids to methionine.
The second kind of hydroxyacid is hydroxydicarboxylic acid
having the following chemical ~tructure:
( fH2 ) nCOOH
(CHOH)mCOOH
wherein
m-l, 2, 3, 4, 5, 6, 7, 8 or 9
n~O or a numerical number up to 23
The hydroxydicarboxylic acid may al~o be present as a free
acid, lactone or salt form. The lactone form could be either
inter or intramolecular lactone. However, the common lactone is
an intramolecular lactone with a ring ~tructure formed by
eliminatlon of one or more water molecule between a hydroxy group
and one of the carboxylic ytou~s. Since the hydroxydicarboxylic
acid i8 organic in nature, it may form a salt or a complex with
an inorganic or organic base such a~ ammonium hydroxide. sodium
or pota~sium hydroxide, or triethanolamine.
The hydroxydicarboxylic acid and its related compounds may
al~o exi~t a~ stereoi~omer~ ~uch as D, L, DL and meso forms.
13401~i~
The hydrogen atom attached to the carbon atom may be
.cub~tituted by a nonfunctional element such as F, Cl, Br, I, S or
a radical such a~ a lower alkyl or alkoxy of saturated or
unsaturated, having 1 to 9 carbon atoms.
When n=O and m=l or more, the hydroxydicarboxylic acid is
also called aDdaric acid. The name comes from the carbohydrate,
and the common ones are saccharic acid and galactaric acid.
~epresentative hydroxydicarboxylic acid~ are listed below:
1. 2-Hydroxypropanedioic acid (Tartronic acid)
m-l, n=o
2. 2-Hyd~Gxy~utanedioic acid (Malic acid)
m-l, n-l
3. Erythrarlc acid and Threaric acid (Tartaric acid)
m-2, n~O
4. Arablraric acid, Ribaric acid, Xylaric acid and Lyxaric
acid
m-3, n-O
5. Glucaric acid (saccharic acid), Galactaric acid (Mucic
acid), Mannaric acid, Gularic acid, Allaric acid,
Altraric acid, Idaric acid and Talaric acid
m-4, n~O
Commercially available saccharolactone (D-saccharic acid 1,
4-lactone) is an intramolecular lactone formed by elimination of
one water molecule between the hydroxy group at position 4 and
the carboxylic group at position 1.
The third type of hydroxyacid is a miscellaneous group of
compoul.do which i~ not readily represented by the above generic
structure of either the first type or the second type. Included
in the third type of hydroxyacids are th~ following:
-- 10 --
- 1340123
Hydroxycarboxylic acid of
R (OH)m (COOH)n
Wherein m,n = 1,2,3,4,5,6,7,8,or 9
R=H, alkyl, aralkyl or aryl group of saturated or
unsaturated, straight or branched chain or cyclic form, having 1
to 25 carbon ~toms,
citric acid, isocitric acid, citramalic acid, agaricic acid
(n-hexadecylcitric acid), quinic acid, uronic acids including
glucuronic acid, glucuronolactone, galacturonic-acid,
galacturonolactone, hydroxypyruvic acid, hydroxypyruvic acid
phosphate, ascorbic acid, dihydroascorbic acid, dihydroxytartaric
acid, 2-hydroxy-2-methylbutanoic acid, 1-hydroxy-1-cyclopropane
carboxylic acid, 2-hydroxyhexanedial, 5-hydroxylysine,
3-hydroxy-2-aminopentanoic acid, tropic acid, 4-hydroxy-2,
2-diphenylbutanoic acid, 3-hydroxy-3-methylglutaric acid, and
4-hydroxy-3-pentenoic acid.
The third type of hydroxyacid may also be present a~ a free
acid, lactone or salt form. The lactone form could be either an
inter or intramolecular lactone, however, mo~t common are
intramolecular lactones with a ring structure. Commonly known
glucuronolactone is a r-lactone i.e. 1,4-lactone of
intramolecular typo.
The hydroxyacid of the third type may also exist as
stereoisomers such as D, L, DL and meso forms. The hydrogen atom
attached to the carbon atom may be substitùted by a nonfunctional
element such a~ P, Cl, Br, I, S or a radical such as a lower
alkyl or alkoxy of saturated or unsaturated, having 1 to 9 carbon
atom~.
-- 11 --
~3413 l~D
Any hydroxyacid and related compound of the above three
kinds may be used a~ an additive in a combination composition to
enhance the percutaneous penetration or the therapeutic efficacy
of co~metic and pharmaceutical agents. The cosmetic and
pharmaceutical agents may include but not limited to: age spots
and keratoses ~emoving agents, vitamins, aloe~, retinoids, sun
screens; tanning, depigmenting and shampooing agents;
antiperspirant~, antiyeasts, antifungal, antibacterial and
antiviral agent~; topical bronchial dilators; topical
cardiovascular agents; kerato~es, age spots and wrinkles removal
agents, hair growth promoting agents and other dermatological
agents.
Hydroxyacids and related compounds may also be used alone in
the prophylactic and therapeutic treatment of cosmetic conditions
or dermatologic disorders characterized by disturbed
keratinization, aging, lipid metabolism or inflammation. The
repre~entative hydroxyacids are listed below:
citramalic acid, tropic acid, benzilic acid, ribonic acid
and ribonolactone, gulonic acid and gulonolactone, 2,3,4-
trihydroxybutanoic acid, 2,3,4,5-tetrahydroxypentanoic acid,
2,3,4,5,6-pentahydroxyhexanoic acid, 2-hydroxylauric acid,
2,3,4,5,6,7-hexahydroxyheptanoic acid, aleuritic acid, 4-
hydroxymandelic acid, 4-chloromandelic acid, 2-hydroxy-3-
methylbutanoic acid, 2-hydroxy-4-methylpentanoic acid, 3-
hydroxy-3-methylbutanoic acid, 2-hydroxy-4-methylpentanoic acid,
3-hydroxy-4-methoxymandelic acid, 4-hydroxy-3-methoxymandelic
acld, 3-(2-hyd~xy~hcnyl) lactlc acid, 3-(4-hydroxyphenyl) lactic
acid, hexahydromandelic acid, 3-hydroxy-3-methylpentanoic acid,
l-hydroxy-l-cyclopropane carboxylic acid, 4-hydroxybutanoic acid,
- 12 -
13'~123
2-hydroxyhexanoic acid, 5-hydroxylauric acid, 12-hydroxylauric
acid, 10-hydroxydecanoic acid, 16-hydroxyhexadecanoic acid, 4-
hydroxydecanoic acid, 5-hydroxydecanoic acid, and 4-hydroxy-2,
2-diphenylbutanoic acid.
Preparation of the Therapeutic Compositions
To prepare a therapeutic composition in solution form at
least one of the aforementioned enhancing compounds of
hydroxyacids and a cosmetic or pharmaceutical agent are dissolved
in a solution which may consist of ethanol, water, propylene
glycol, acetone or other pharmaceutically acceptable vehicles.
The concentration of hydroxyacids may range from 0.01 to 99
percent by weight of the total composition. The concentration of
the cosmetic or pharmaceutical agent ranges from 0.01 to 40
percent by weight of the total composition.
In the preparation of a therapeutic compo~ition in cream or
ointment form at lea~t one of hydroxyacids and one of cosmetic or
pharmaceutic agents are initially dissolved in a solvent such as
water, ethanol, acetone, propylene glycol or poly~orbate 80. the
solution thus prepared is then mixed in a conventlonal manner
with commonly available cream or ointment base such as
hydrophilic ointment or petrolatum. The concentrations of
hydroxyacid~, cosmetic and pharmaceutical agents may range from
0.01 to 99 percent by weight of the total composition.
Therapeutic compositions of the instant invention may also
be formulated in gel, lotion, shampoo, spray, stick or powder.
typical gel compo~ition of the in~tant invention utilizes at
least one of hydroxyacids and one of cosmetic or pharmaceutical
aqents di~olved in a mixture of ethanol, water and propylene
glycol in a volume ratio of 40:40:20, respectively. A gelling
1 34$~
agcnt ~uch a~ hydroxyethylc-llulo~-, hydroxypropylcellulo~-,
hydroxypropylmethylc-llulo-- or am~onlat-d glycyrrhlzlnat- 1-
then add-d to the mlxture with agltation Tho preferred
concentratlon of the golling agent ~-y rang- fron 0 1 to 4
porcent by woight of the total conpo-ltion
Th- followlng are illu~trativo ~xaapl-~ of
formulation- and compo~ition~ accorting to th- lnventlon of the
parent and divi~ional applicatlons Althouqh th- examplo~
utillzo only ~-l-cted co~pound~ and formulatlonc, lt should bo
under~tood that th- followlng ~xa~plo- ar- illu~trativo and not
limltativo Th-r-foro, any of tho afor-nention-d hydroxyacids,
cosmetic and pharmaceutlcal ag-nts ~ay b- ~ub~titutod according
to th- t-aching~ of thi~ invontlon in th- following examples
Exanpl- 1
A prophylactic and th-rapeutlc co~po~ltlon in
~olution for- for ag- ~pot~ and for koratoc-~ ~ay b- propared
as follo~-
Mall¢ acid 1 gra~, gluconolacton- 19 gra-s and citric
acid 0 5 gr-m ar- di~olv-d in a ~lxtur- of othanol 30 ml,
wat-r 42 ml and glyc-rin 5 ~1 80diu~ bl~ulfit- 0 5 g and
hydroquinon- 2 gran~ aro add-d with ~tirring untll a cl-ar
~olutlon 1~ obtained Tho hydroxyacid-, nallc acid,
gluconolacton- and citric acid hav- be-n add-d a) a-
antloxldant- to h-lp ~tablllz- th- hydroqulnono in the
compo~ition b) to ~nhance th- p-n-tration and tho ~f~lcacy of
hydroquinon- c) to nor~allz- th- di~turb-d koratlnlzation in
ag- ~pota and k-rato~
~h- composition thu~ fornulat-d contain~ 2%
hydroqulnon-, 1% malic acid, 19% gluconolaaton-, 0 5~ citrlc
acid, and ha- pH 3 3
. 13~0.121~
Exa~ple 2
A therapeutlc compo~ltlon ln ~olutlon for~ for age
~pot- and for ~-rato~eo ~ay be formulated ~~ follow~
l~a
13 ~ 2 ~3
Alpha hydroxyi~obutyric acid (Methyllactic acid) 20 grams
and citric acid 2 grams are dissolved in a mixture of ethanol 49
ml, water 20 ml and propylene glycol 7 ml. Sodium bisulfite 0.5
g and hydroquinone 2 grams are added with stirring until a clear
solution is obtained. The co ~osition thus formulated contains
2% hydroguindne, 2% citric acid, 20% methyllactic acid, and has
pH 3.6.
Example 3
A prophylactic and therapeutic composition ~ontaining
minoxidil and lactic acid for hair growth and for prevention of
hair 1088 on the scalp may be formulated a~ follows.
Minoxidil 2 grams and lactic acid 3 ml are di~solved in a
mixture of ethanol 80 ml and propylene glycol 15 ml with stirring
until a clear solution iB obtained. The composition thus
formulated contain~ 2% minoxidil, 3% lactic acid, and has pH 4.7.
The lactic acid ha~ been added to help minoxidil di~solved into
solution, to enhance the penetration and the efficacy of
minoxidil for hair growth.
Example 4
A prophylactic and therapeutic composition in solution form
for hair growth on the scalp may be formulated as follows.
Minoxidil 2 grams and ethyl pyruvate 2 ml are dissolved in a
mixture o~ ethanol 80 ml and propylene glycol 16 ml. The
composition thus formulated contains 2~ minoxidil, Z% ethyl
p~vato, and has pH 5Ø The ketoacid ester, ethyl pyruvate has
been added to enhance the penetration-and the efficacy of
minoxidll for hair growth on the scalp.
1 2 3
Examplo 5
A therapeutic cv ,Gsition containing anthralin and
hydroxyacid for psoriasis may be formulated as follows.
Anthralin powder 0.5 gram and alpha hydroxyisobutyric acid 4
gram~ are dissolved in a mixture of ethanol 50 ml, acetone 30 ml
and diisopro ~ 1 adipate 16 ml with stirring until a clear
yellowish solution is obtained. The composition thus formulated
contains 0.5% anthralin, 4~ alpha hydroxyi~obutyric acid, and has
pH 4.2. The hydroxyacid ha~ been added to enhance the
penetration and the efficacy of anthralin for psoriasis.
Example 6
A therapeutic composition containing thionicotinamide and
hydroxyacid for psoriasis, keratoses and warts may be formulated
as follows.
Thionlcotinamide 2 grams and lactic acid 20 ml are dissolved
in a mixture of ethanol 40 ml, water 30 ml and propylene glycol 8
ml with stirring until a clear yellowish solution is obtained.
The composition thus formulated contains 2% thionicotinamide, 20%
lactic acid, and has pH 3.3. The lactic acid has been added to
enhance the penetration and the efficacy of thionicotinamide, and
also to normallze the disturbed keratinization in psoriasis,
keratoses and warts.
Example 7
A therapeutic composition containing 6-amlnonicotinamide and
hydroxyacid for psoriasis, kerato~es and warts may be formulated
a~ follows.
- 16 -
1~4~ i~3
~ 6-Aminonicotlnamide 1 gram and glycolic acid 19 grams are
dissolved in a mixture of ethanol 40 ml, water 32 ml and
propylene glycol 8 ml with stirring until a clear ~olution i5
obtained. The composition thus formulated contains 1~
6-aminonicotinamide, 19% glycolic acid, and has pH 3Ø The
glycolic acidlha~ been added to enhance the penetration and the
efficacy of 6-Aminonicotinamide, and also to normalize the
disturbed keratinization in psoriasis, keratose~ and warts.
Examplo 8
A therapeutic c~ ~Fition containing clotrimazole and
hydroxyacid for fungal infection may be formulated as follows.
Clotrimazole 1 gram and lactic acid 4 ml are dissolved in 4
ml of ethanol, and the solution thus obtained i~ mixed with 91
gram~ o~ hydrophilic ointment USP. The mixing i~ continued until
a uniform con~istency i~ obtained. The composition thus
formulated contains 1% clotrimazole, 4% lactic acid, and has p~
3.2. The lactic acid has been added to enhance the penetration
and the efficacy of clotrimazole for athlete's foot, and also to
~peed up healing and normalize the disturbed keratinization.
Example 9
A prophylactic and therapeutic composition containing
chlorhexidine and hyJLox~acid as general anti~eptics on ~kin, and
for prophylactio and therapeutic treatment of acne may be
formulated as follows. Chlorhexidine diacetato 1 gram and
benzilic acid S grams aro dissolved in a mixturo of ethanol 70
ml, water 10 ml and propyleno glycol 14 ml with ~tlrring until a
clear solution iJ obtained. The composition thu~ formulated
contains 1% chlorhexidine, 5% benzilic acid, and has pH 4.4.
- 17 -
13~-~0 120
~3enzilic acid has been added to enhance the antibacterial effect
of chlorhexidine, to eliminate the oiliness of the skin, and to
improve the acne lesions.
Example 10
A prophylactic and therapeutic composition containing
benzilic acidlas the only active ingredient for oily skin, acne,
skin cleansinq and skin malodor may be formulated as follows.
Benzilic acid 7 gram~ is dissolved in a mixture of ethanol
60 ml, water 20 ml and propylene glycol 13 ml with stirring until
a cle~r solution is obtained. The CG Fo6ition thus prepared
contains 7% benzilic acid, and has pH 3Ø
Example 11
A therapeutic composition containing tropic acid a~ the only
active ingredient for severe dry skin may be formulated as
follows.
Tropic acid 10 grams is dissolved in 20 ml of ethanol, and
the solution thus obtained is mixed with 70 grams of hydrophilic
ointment USP. The mixing is continued until a uniform
consistency is obtained. The c- ,o~ition thus formulated
contains 10% tropic acid as an active ingredient, and has pH 3.7.
Exampl- 12
A prophylactic and therapeutic composition containing
ribonolactone as the only active ingredient for oily skin, acne
and skin cleansing may be formulated as follows.
Ribonolactone 4 grams is dissolved in a mixture of ethanol
36 ml and water 60 ml with stirring until a clear solution i~
obtained. The composition thus prepared contains 4%
ribonolactone as an active in~redient, and has pH 3.8.
- 18 -
134~123
Example 13
A therapeutic composition containing hydrocortisone and
tropic acid for inflammatory and/or pruritic skin disorders may
be formulated as follows.
Hydrocortisone 0.5 gram and tropic acid 5 grams are
dis~olved inl10 ml of ethanol and 4 ml of acetone, and the
solution thus obtained is mixed with 80 grams of hydrophilic
ointment USP. The mixing is continued until a uniform
consistency is obtained. The composition thus formulated
contains 0.5% hydrocortisone and 5~ tropic acid as active
ingredients, and has pH 3.4. The tropic acid has been added to
enhance the penetration and the efficacy of hydrocortisone and
al~o to normalize the disturbed keratinization.
Example 14
A therapeutic composition containing triamcinolone acetonide
and benzilic acid for eczema, psoriasis and other inflammatory
and pruritic skin disorders may be formulated as follows.
Triamcinolone acetonide 0.1 gram and benzilic acid 5 grams
are dissolved in 10 ml of ethanol, and the solution thus obtained
i~ mixed with 85 gram~ of hydrophilic ointment USP. The mixing
i~ continued until a-uniform consistency i8 obtained. The
composition thus formulated contains 0.1% triamcinolone
acetonide, 5% benzilic acid, and has pH 3.4. The benzilic acid
has been added to enhance the penetration and the eff$cacy of
triamcinolone acetonide, and also to normalize the disturbed
keratinizatlon in eczema, psoriasis and other inflammatory skin
di~order~.
- l~4al20
Example 15
A prophylactic and therapeutic co ,osition containing
dipyridamole and lactic acid for hair growth and for prevention
of hair 1088 on the scalp may be formulated as follows.
Dipyridamole 2 gram~ and lactic acid 4 ml are dissolved in a
mixture of e~hanol 80 ml and propylene glycol 14 ml with stirring
until a clear yellowish solution is obtained. The composition
thus formulated contains 2~ dipyridamole, 4% lactic acid, and has
pH 4.4. The lactic acid has been added to help dipyridamole
dissolved into solution, to enhance the penetration and the
efficacy of dipyridamole for hair growth and for preventing hair
108~.
Example 16
A therapeutic composition containing clobetasol propionate
and agaricic acid for eczema, psoriasi~ and other inflammatory
and pruritic skin disorders may be formulated as follows.
Agaricic acid fine powder 2 grams and 98 grams of clobetasol
propionate cream are mixed until a uniform consistency is
obtained. the composition thus formulated contains approximately
0.05% clobetasol propionate, 2% agaricic acid, and has pH 4.3.
The agarlcic acid has been added to enhance the penetration and
the efficacy of clobetasol propionate, and also to normalize the
dlsturbed keratinization in eczema, psoriasis and other
inflammatory ~kin disorder~.
Example 17
A therapeutic composition containing betamethasone
diproplonate and benzilic acid for eczema, psoriasis, contact
dermatitis and other inflammatory and pruritic skin disorders may
be formulated as follows.
- 20 -
1 2 0
Benzillc acld powder 5 grams and 95 grams of betamethasone
diproplonate ointment are mixed untll a uniform consistency is
obtained. the c~ po~ltion thus formulated contains approximately
0.05~ betamethasone dipropionate and S~ benzilic acid. The
benzilic acid has been added to enhance the penetration and the
efficacy of betamethasone dipropionate, and also to normalize the
disturbed keratinization in eczema, p~oriasis and other
inflammatory skln disorders.
Example 18
A p~ophylactic and therapeutic composition containing aloe,
malic acid and gluconolactone for oily skin and acne may be
formulated as follows.
Aloe powder 200 fold 0.2 gram and ammoniated glycyrrhizinate
2 gram~ are mixed with water 61 ml and propylene glycol 2 ml.
The mlxture ls heated to 50-C until the aloe powder and the
ammoniated gly~yLrl.izinate are completely dissolved. Ethanol lo
ml is added to the solution followed by the addition of partially
neutralized malic acid stock solution 3 ml and gluconolactone
stock solution 22 ml wlth ~tlrring. The warm solution is poured
into container ~ar~ before cooling. The gel composition thus
formulated contains 40~ aloe, 1% malic acid, 9% gluconolactone,
and has pH 4Ø Malic acid and gluconolactone have been added to
enhance the skin softne~s and ~moothness by alo-, and also to
normalize any di~turbed keratinization of the skin.
Exampl- 19
A ~un screen composition containlng Octyl dimethyl PABA,
dioxybe.,zone and lactic acid may be formulated as follows. Octyl
dlmethyl PABA 5 gram~, diox~enzone 3 grams and lactic acid 2 ml
are dlssolved ln a mixture of ethanol 65 ml, water 10 ml and
- 21 -
13~120
.
propylene glycol 15 ml with ~tirring until a clear solution is
obtained. The cc osition thus formulated contain~ 5% octyl
dimethyl PABA, 3% dioxybenzone, 2% lactic acid, and has pH 3.6.
The lactic acid has been added to substantiate the absorption of
sunscreen agents, octyl dimethyl PABA and dioxybenzone, and to
enhance the s~n ~creen effect.
Example 20
A prophylactic and therapeutic composition containing
tetracycline and glycolic acid for oily ~kin and-acne may be
formulated as follow~.
Tetracycline 3 gram~ and glycolic acid S grams are dissolved
in a mlxture of ethanol 40 ml, water 40 ml and propylene glycol
12 ml with stirring until the tetracycline and glycolic acid are
completely dissolved. The CG ,osition thu~ formulated contains
3% tetracycline, S~ glycolic acid, and has pH 3.4. The glycolic
acid has been added to help tetracycline dissolved into the
solution, to enhance the penetration and the efficacy of
tetracycline, and to normalize the disturbed keratlnizatlon in
acne.
Example 21
A therapeutic composition containing griseofulvin and methyl
pyruvate for fungal infection of nail~ may be formulated at
follows .
Griseofulvin 1 gram and methyl ~Luvate 2 ml are dissolved
in a mixture of 2 py.~olidone 20 ml. PEG-400 47 ml and ethanol 30
ml with stirring until the griseofulvin is completely dissolved.
The composition thus formulated contain~ 1% griseofulvin, 2%
methyl p~L uvate, and has pH 4.4. The methyl ~yluvate has been
- 22 -
~13 1012~
added to help griseofulvin dis~olve into the solution, to enhance
the penetration and the efficacy of griseofulvin, and to
normalize the disturbed keratinization in nails.
Example 22
A therapeutic composition containing lidocaine and
atrolactic aclid for pruritic skin may be formulated as follows.
Lidocaine 2 grams and atrolactic acid hemihydrate 3 grams
are di~solved in a mixture of ethanol 40 ml, water 40 ml and
propylene glycol 15 ml with stirring until the lidocaine and
atrolactic acid are completely dissolved. The composition thus
formulated contains 2% lidocaine, 3% atrolactic acid, and has pH
4.6. The atrolactic acid has been added to help lidocaine
dissolved and stabilized in the solution and to enhance the
efficacy of lidocaine for pruritic skin.
Example 23
A ~o~hylactic and therapeutic composition containing
retinoic acid and ethyl pyruvate for oily skin and acne may be
formulated as follow~.
Retinoic acid, all-trans 0.1 gram and ethyl pyruvate 2 ml
are dissolvod in a mixture of ethanol 80 ml, water 10 ml and
propylene glycol 8 ml with stirring until a yellowlsh solution is
obtained. The compo~ition thus formulated contains 0.1% vitamin
A acid, 2~ ethyl p~.uv&te, and has pH 3.6. The ethyl pyruvate
has been added to enhance the penetration and the efficacy of
retinoic acid, and to normalize the disturbed ke~atinization in
acne.
.
1:~4~)120
"
Example 24
A prophylactic and therapeutic cu ~osition containing
erythromycin and aleuritic acid for oily skin and acne may be
formulated as follows.
Erythromycin 2 grams and aleuritic acid 2 grams are
dissolved in la mixture of ethanol 50 ml, water 40 ml and
propylene glycol 6 ml with stirring until a clear solution is
obtained. The cv osition thus formulated contain~ 2%
erythromycin, 2% aleuritic acid, and ha~ pH 5.7.~- The aleuritic
acid has been added to help erythromycin dissolve into the
solution, to enhance the penetration and the efficacy of
erythromycin, and to normalize the di~turbed keratinization in
acne.
Example 25
A therapeutic composition containing P-hydroxymandelic acid
for dry skin may be formulated a~ follow~.
P-Hydroxymandelic acid 10 grams is dis~olved in 20 ml of
ethanol, and the pinkish solution thus obtained is mixed with 70
grams of hydrophilic ointment USP with stirring until a uniform
con~istency i~ obtained. The composition thus formulated
contains 10~ P-hydroxymandelic acid as an active ingredient, and
has pH 3.2. P-Hydroxymandelic acid has been incorporated into
the composition to alleviate any scaly or flaky skin, and to
change the dry skin into normal smooth and soft skin.
~ xample 26
A therapeutic composition containing hydroquinone and lactic
acid in solution form for age spots, keratoses, melasmas,
lentigines and other pigmented skin spots may be formulated as
~ollows .
- 24 -
134~120
..
Lactic acid 10 ml, hydroquinone 4 grams and sodium
metabisulfite 0.6 gram are dissolved in a mixture of ethanol 70
ml, water 10 ml and propylene glycol 6 ml with stirring until a
clear solution is obtained. The co~position thus formulated
contains 4~ hydroquinone, 10% lactic acid, and has p~ 4Ø The
lactic acid has been added to help stabilize and enhance the
penetration and the efficacy of hydroquinone, and also to
normalize the disturbed keratinization in the skin lesions. The
composition thu~ formulated is packaged in felt pens for
controlled delivery to skin lesions.
Example 27
A therapeutic composition containing hydroquinone and
glycolic acid in solution form for age spots, keratoses,
melasmas, lentigines and other pigmented skin spots may be
formulated as follows.
Glycolic acid 8 grams, hydroquinone 5 grams and sodium
metabisulfite 0.5 gram are dissolved in a mixture of ethanol 70
ml, water 10 ml and propylene glycol 7 ml with stirring until a
clear solution is obtained. The c~ po~ition thus formulated
contains 5% hydroquinone, 8% glycolic acid, and has pH 3.9. The
glycolic acid ha~ been added to help stabilize and enhance the
penetration and the efficacy of hydroquinone, and also to
normalize the disturbed keratinization in the skin lesions. The
composition thus prepared is packaged in felt pen~ for controlled
delivery to skin leslons.
Example 28 --
A therapeutlc composition containing hydroquinone and
- 25 -
i~j, 4~)120
2-methyl 2-hydroxypropanoic acid in solution form for age spots,
keratoses, melasmas, lentigines and other pigmented skin spots
may be formulated as follows.
2-Methyl 2-hydroxypropanoic acid 12 grams, hydroquinone 4
grams and sodium bisulfite 0.3 gram are dissolved in a mixture of
ethanol 60 ml, water 20 ml and propylene glycol 4 ml with
stirring until a clear solution is obtained. The composition
thus formulated contains 4% hydroquinone, 12% 2-methyl
2-hydroxypropanoic acid, and ha~ pN 4Ø The composition
solution i~ packaged in felt pens for controlled delivery to skin
le~ion~. The 2-methyl 2-hydroxypropanoic acid has been added to
help stabilize and enhance the penetration and the efficacy of
hydroquinone, and also to normalize the disturbed keratinization
in the skin lesions.
Example 29
A composition containing hydroquinone alone in solution form
for age spot~ and keratoses studies may be formulated as follows.
Hydroquinone 5 grams and sodium metal bisulfite o.s gram are
dissolved in a mixture of ethanol 70 ml, water 15 ml and
propylene glycol 10 ml with stirring until a clear solution is
obtained. The compo~ition thus prepared contains 5~ hydroquinone
and ha~ pH 6Ø The composition solution is packaged in felt
pen~ for comparative studies; with or without hydroxyacids on age
spot~ and kerato~e~.
TEST RESULTS
In order to determine whether addition of a hydroxyacid in
the composition could enhance the therapeutic action of a
cosmetic or pharmaceutical agent a total of more than 55
- 26 -
1 2 ~
-- ,
volunt--r- and patl-nt- havlng dlt~-r-nt ~kln dl~ord~r~
partlalpat-d ln th-~- ~tudl-- Each partlclpating ~ub~ot wa~
glv-n two pr-paratlon~t l - wlth or wlthout th- addltlon of a
hydroxyaold ln th- th-rap~utia aompo~ltlon
Toplcal app11aatlon~ w-r- oarrl-d out ~lth-r by bl1at-ral or
tla1 admpari-on, In bllat-ral Oc ~rl~on the ~ub~-ct wa~
ln-truat-d to apply on- preparatlon on one ~ld- Or th- body and
th- oth-r on- on th- oth-r ~ld- ot th- body rOr p~orla~
~a~-ma, ~-v-r- dry ~kln, athl-to'~ rOot, ~ta , wh-r- both slde-
w-r- lnvolv-d, th- ~ub~-ct wa- ln~truat-d to apply two to three
tla-- dally on- a-dlaatlon on on- ~ld~ Or the body tor a perlod
ot up to ~-v-ral aonths of tlm- In th- pu1~- tr-atment for
p-orla~l~ or oth-r lntlammatory d~ a- th- ~odl¢ation waa
appli-d only on¢- every three dayo or twla~ a week Th-
a-dlaatlon wa- ~ ntlnu-d wh~n-ver a total ~ lon Or the
1-~lon- ocaurr-d prlor to th- t-~t p-riod o~ up to ~ev~ral
month-
For th- ~aalp or raa- lnvolv-m-nt ~uah a- ln dandrurr, olly
~kln, aan- and ~-borrh-la dermatltl~ th- ~ub~-ct wa~ lnstructed
to apply t~o to thr-- ti~- dally on- ~-dlaatlon on on- eid- Or
th- ~calp or th- ~ac- and th- oth-r aedlaatlon on th- other ~lde
o~ th- ~aalp or th- ~aae ~or a perlod ot up to 1~ w-ek~ o~ tlme
For ag- ~pota, ~-rato--~ or wart- th- a-dlaatlon wa- aontlnu~
~or up to ~ aonth- o~ tl~-
8-qu-ntla1 admlnl-tratlon- o~ ~-dlaatlon~ w-r- aarrl-d out
wh-n-v-r th- bllat-ral aomparl-on wa- dlttlau1t. For ~xampl- ln
prurltl~ aondltlon~ th~ ~ub~at w~- ln~tsuat-d to apply tour tlm~
dally or ~- ott-n aa n~ ry on- ~-dlaatlon on th- prurltlo
2 3
lesion~ for two days, then switched to the other medication on
the same lesions for another two days, thus to compare which
medication was more effective in relieving the itching.
1. Dry skin.
Human subject~ having ordinary dry skin or with moderate
degrees of d~y skin as evidenced by dry, flaking and cracking of
the skin were in~tructed to apply topically the lotion, cream or
ointment containing 3 to 7 percent of hydroxyacids of the instant
invention on the affected skin areas. Topical application, two
to three times daily, was continued for two to three weeks. In
all the nine sub~ects tested, the feeling of the skin dryness
disappeared within a week of topical application. The roug~ and
cracked ~kin became less pronounced and the skin appeared normal
and felt smooth after 10 days of topical treatment.
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
wa~ al~o found that twice daily topical application of a
composition containing one or more hydroxyacids of instant
invention prevented the development of new dry skin lesions.
In ~evere dry skin the skin lesions are different from the
above. The involved skin is hyperpla~tic, fissured and has thic~
adherent scales. The degree of thickening is such that lesions
are palpably and vi~ually elevated. The thickened adherent
~cale~ cause the surface of involved 6kin to be markedly rough
and uneven. The two attributes of thickness and texture can be
- 28 -
13~0120
quantified to allow ob~ective measurement of degree of
improvement from topically applied therapeutic test materials as
follows:
DEGREE OF IMPROV~ T
None Mild Moderate Substantial Complete
(O)(1+) (2~) (3+) (4+)
THICKNESS HighlyDetectable Readily Barely Normal
elevated reduction apparent elevated thickness
reduction
E Visibly Palpably Uneven but Slightly Visibly and rough rough not rough uneven palpably
smooth
By mean~ of ~uch parameters deg~e3 of change in lesions can
be numerically noted and comparisons made of one treated site to
another.
In order to evaluate the hydroxyacids and their related
com~ounds of the instant invention a total of ~ix patients with
severe dry ~kin condition~ or ichthyosis were treated with the
composition~ containing 7 to 15% of hydroxyaeids as described in
the ~xample~.
Treated areas were of a size eonvenient for topical
application~, i.e., eircles 5 cm in diameter demarcated with a
pla~tie ring of that size inked on a stamp pad. The medieinal
ereams or olntment~ were toplcally applled by the patlent in an
amount ~uffieient to eover the treatment sltes. Appllcations
were made three time daily and withou~ ocelusive dressings.
Applications were di~eontinued at any time when re601ution of the
le~ion on the treatment area was clinically ~udged to be
complete.
- 29 -
13'~12~
The test results on patients with severe dry skin are
~ummarized on the following table.
Topical Effectiveness of Hydroxyacids on Severe Dry Skin
Compound~ Number of Therapeutic
Patients Effectiveness
1. Tropic acid 4 4+
2. ~en2ilic acid 5 4+
3. Ribonolactone 3
4. 4-Hydroxymandelic acid 2 3+
5. 3-Chloro 4-hydroxymandelic acid 2 3+
6. 3,4-Dihyd~G~y ?ndelic acid 2 3+
2. P~oriasis
The involved skin in psoriasis is hyperplastic (thickened),
erythematous (red or inflamed), and has thick adherent scales.
the de~ce of thickening is such that lesions are elevated up to
1 mm above the surface of ad~acent normal skin; erythema is
usually an intense red: the thickened adherent scale~ cause the
~urface of involved skin to be markedly rough and uneven. These
three attributes of thickness, color and texture can be
quantified to allow ob~ective mea~urement of degree of
improvement from topically applied therapeutic test materials as
follow~.
- 30 -
1 2 ~
._
DEGREE OF IMPROVEMENT
None Mild Moderate Substantial Complete
( O) ( 1+) ( 2+) ( 3+) ( 4+)
Thlckness Hiqhly Detectable Readily Barely Normal
elevated reduction apparent elevated thickness
Texture Visibly Palpably Uneven but Slightly Visibly and
rough rough not rough uneven palpably smooth
Color Inten~e Red Dark PinX Light Normal skin
red pink color
By means of such parameters degree of improvements in
psoriatic le~ion~ can be numerically recorded and comparisons
made of one treated site to another. The treatment schedule was
quite different from the previously described in that the present
study was employing a ~Pulse Treatment. n Instead of several
time~ daily application the therapeutic composition of
antipsoriatic agent with or without a hydroxyacid in solution
form was topically applied to the involved skin only once in
every three days or twice a week. The test results on patients
having psoriasi~ are summarized on the following table.
- 31 -
, - 13~tl20
Topical Effects on Psoriasis of Antipsoriatic Agents
With or without Hydroxyacids
Compositions Number of Therapeutic
Patients Effectiveness
Thionicotinamide 3% alone 6 2+
with 10% Lactic acid 6 4+
with 5% Glycolic acid 4 4+
with 5t 2-methyl 2-hydroxypropanoic acid 3 4+
6-Aminonlcotinamide 15 alone 5 3+
with lOS Lactic acid 5 4+
with 10% Glycolic acid 4 4+
Betamethasone dipropionate o.os% ointment alone 5 3+
with 5% Benzilic acid 4 4+
with 5% Tropic acid 3 4+
with 5% 2-Methyl 2-Hydroxypropanoic acid 3 4+
Clobetasol propionate 0.05~ cream alone 4 Z+
with 5% Benzilic acid 3 3+
with 5% Tropic acid 2 3+
with 5~ 2-Methyl 2-hydroxypropanoic acid 3 3+
In a topical treatment of eczema patients, betamethasone
diproplonate or clobetasol propionate alone at 0.05% would
achieve only a 3+ improvement on all the eczema patients tested.
As shown by the table with the additional of 5% gluconolactone or
ribonolactone betamethasone dipropionate or clobetasol propionate
could attain a 4+ maximal clearing on all the eczema patients
to~ted.
- 32 -
i ~ 4C~ 12~
-
Topical Effects on Eczema of Corticosteroids
With and Without Hydroxyacid Lactone
Composition Number of Therapeutic
Patients Effectiveness
Betamethasone dipropionate 0.05~ alone 3 3
with 5% Gluconolactone 3 4+
with 5% Ribonolactone 2 4+
Clobetasol propionate 0.05~ alone 4 3+
with 5% Gluconolactone 4 4
with 5t Ribonolactone 3 4+
3. Age Spots, Wrinkles, Kerato~es and Pigmented Skin lesions.
Therapeutic compositions packaged in felt pens as described
in Examples were provided to 14 patients for treatment of age
spots, wrinkles, keratoses and other pigmented skin spots. Each
participating patient received two felt pens; i.e. with or
without the addition of hydroxyacid to the composition containing
hydroquinone. The patients were instructed to apply topically
ono medication on one side of the body such as on the back of the
left hand and th- other medication on the other side of the body
such as on the back of the right hand. Specific instructions
were given to the patients that the medications were applied
twice daily and discretely only to the skin lesions of age spots,
wrinkles, keratoses, melasmas, lentigines or other pigmented skin
spot~.
Within one to three weeks, improvement o~ age spot~ and
keratoses was clinically discernible. After one to three months
substantial eradication of age seots, wrinkles and keratoses
occurred in all the patients tested. Complete eradication of age
- 33 -
1 2 0
spots usually occurred within two to four months of topical
administration in most cases. Therapeutic compositions
containing higher concentrations of hydroxyacids (10 to 20%) and
hydroquinone (3 to 5%) were judged to be more efficient in
eradicating age spots, wrinkles and keratoses within shorter
periods of t~me. Without the addition of a hydroxyacid to the
composition of hydroquinone, eradication of age spots, wrinkles
or keratoses did not occur within four months of time.
It was also found that while compositions containing
hydroxyacid~ without hydroquinone were effective for eradication
of keratoses and wrinkles, the co ~,ositions were not efficient in
eradicating pigmented age spots, melasmas or lentigines within 4
months of time. In any case, with the addition of a hydroxyacid
to the composition containing hydroquinone, pigmented age spots,
melasmas, lentigines and other pigmented skin spots had been
substantially eradicated.
4. Acne.
Therapeutic compositions containing tetracycline,
erythromycin or chlorhexidine with or without the addition of a
hydroxyacid were provided to 9 patients having papulopustular or
pustular lesions of acne. Each participating patient received
two medications, with or without the addition of a hydroxyacid to
the composition containing an antibiotic. The patients were
instructed to apply topically one medication on one side of the
body such as ths left side forehead, face, back or chest, and the
other medication on the other side of the body such as right side
forehead, face, back or chest. Twic- daily administration was
continued for 4 to 12 weeks.
13~12~
The degree and rate of improvement on acne lesions were
clinically evaluated, and comparison was made between the two
sides; one side with and the other side without a hydroxyacid in
the compositions containing an antibiotic. It was found that the
degree and rate of improvement on acne lesions were substantially
better on the side treated with a combination composition
containing both the hydroxyacid and the antibiotic as compared to
that of the antibiotic alone. The time for complete clearing of
acne le~ions treated with a combination cc ~osition varied from 4
to 12 weeks of time, with an average time of 8 weeks, whereas
complete clearing with that of the antibiotic alone ranged from 8
weeks to 9 months, with an average of 4 months.
5. Preventing Hair Lo6s And For Hair Growth.
Prophylactic and therapeutic compositions containing
minoxidil or dipyridamole with or without a hydroxyacid or
related compound were provided to 6 human subjects having a
pLo~Le3sive 1088 of hair on the scalp. Each participating
sub~ect received two medications; i.e. with or without the
addition of a hydroxyacid to the composition containing minoxidil
or dipyridamolo. The sub~ects were instructed to apply topically
one medication on one side of the scalp and the other medication
on the other side of the ~calp. Twice daily topical applications
were continued for 2 to 6 months. Clinical evaluation ~hows that
the comblnation compositions containing minoxidil or dipyridamole
and a hydroxyacid or related compound were therapeutically more
efficient in preventing the hair loss and enhancing hair growth
on the scalp.
lX4û 120
-
Therapeutic compositions containing clotrimazole or
griseofulvin wlth or without the addition of a hydroxyacid were
provided to 6 patients having recurrent fungal infections of the
foot: i.e. athlete's foot with or without toe nail involvement.
Each participating patient received two medications with or
without the alddition of a hydroxyacid to the composition
containing clotrimazole or griseofulvin. The patients were
instructed to apply topically one medication on one side of the
body such as left foot, and the other medicatio~ on the other
side of the body such as right foot. Three time daily
applications were continued for one to two weeks. When nail
infections were involved the topical application was continued
for up to 4 months using the composition~ containing griseofulvin
with or without the addition of a hydroxyacid.
Ths 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 compositions containing both the
antifungal agent and the hydroxyacid. The presence of
hydroxyacid appeared to enhance the efficacy of the antifungal
agent, and also to eliminate the discomforts such as itching,
tingling, burning and heat due to the fungal infection.
Generally the iniected skin healed within a week from topical
application o~ the compositions containing an antifungal agent
and a hydroxyacid. When toe nails were involved in the fungal
inrectlon the complete healing and ~e~Lo~h of nails usually took
several month~ on continued topical application Or medications
containing grlseofulvin and a hydroxyacid.
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~ ~4'~120
".~ .
The hydroxyacids and related compound~ which may be useful
as dermatologic agents for various conditions and disorders
including age spots, keratoses, skin wrinkles etc. or as
additives to enhance therapeutic effects of other cosmetic or
pharmaceutical agents include 2-Hydroxyacetic acid;
2-hydroxypropanoic acid; 2-methyl 2-hydroxypropanoic acid;
2-hydroxybutanoic acid; phenyl 2-hydroxyacetic acid; phenyl
2-methyl 2-hydroxyacetic acid; 3-phenyl 2-hydroxyacetic acid;
2,3-dihyroxypropanoic acid; 2,3,4-trihydroxybutanoic acid;
2,3,4,5,6-pentahydroxyhexanoic acid; 2-hydroxydodecanoic acid;
2,3,4,5-tetrahydroxypentanoic acid; 2,3,4,5,6,7-
hexahydroxyheptanoic acid; diphenyl 2-hydroxyacetic acid;
4-hydroxymandelic acid; 4-chloromandelic acid; 3-hydroxybutanoic
acid: 4-hydroxybutanoic acid; 2-hydroxyhexanoic acid:
5-hydroxydodecanoic acid: 12-hydroxydodecanoic acid;
10-hydroxydecanoic acid; 16-hydroxyhexadecanoic acid;
2-hydroxy-3-methylbutanoic acid; 2-hydroxy-4-methylpentanoic
acid; 3-hydroxy-4-methoxymandelic acid; 4-hydroxy-3--
methoxymandelic acid; 2-hydroxy-2-methylbutanoic acid;
3-(2-hydroxphenyl) lactic acid; 3-(4-hydroxyphenyl) lactic acid;
hexahydromandelic acid: 3-hydroxy-3-methylpentanoic acid:
4-hydroxydecanoic acid: 5-hydroxydecanoic acid: aleuritic acid.
2-Hydroxypropanedioic acid: 2-hydroxybutanedioic acid;
erythraric acid: threaric acid arabiraric acid: ribaric acid;
xylaric acid: lyxaric acid glucaric acid: galactaric acid;
mannaric acid: gularic acid allaric acid altraric acid; idaric
acid: talaric acid: 2-hydroxy-2-methylbutanedioic acid.
- 37 -
1~0120
.
Citric acid, isocitric acid, agaricic acid, quinic acid,
glucuronic acid, glucuronolactone, galacturonic acid,
galacturonolactone, uronic acids, uronolactones, ascorbic acid,
dihydroascorbic acid, dihydroxytartaric acid, tropic acid,
ribonolactone, gluconolactone, galactonolactone, gulonolactone,
mannonolactonle, citramalic acid.
Pyruvic acid, hydroxypyruvic acid, hydroxypyruvic acid
phosphate, their esters: methyl pyruvate, ethyl pyruvate, propyl
pyruvate, isopropyl pyruvate; phenyl pyruvic acid, its esters:
methyl phenyl pyruvate, ethyl phenyl pyruvate, propyl phenyl
~ytu~ate; formyl formic acid; its esters; methyl formyl formate,
ethyl formyl formate, propyl formyl formate; benzoyl formic acid,
its esters; methyl benzoyl formate, ethyl benzoyl formate and
propyl benzoyl formate: 4-hydroxybenzoyl formic acid, its esters;
4-hydroxyphenyl pyruvic acid, its esters; 2-hydroxyphenyl pyruvic
acid and its esters.
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 Le_~e_~s as illustrative and not restrictive, the scope of
the invention being indicated by the appended claim~ and all
changes which come within the meaning and equivalency of the
claims are therefore intended to be embraced therein.
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