U.S. patent application number 10/932097 was filed with the patent office on 2005-09-15 for anti-wrinkle agent.
This patent application is currently assigned to Koichi SHUDO, Tokyo, Japan. Invention is credited to Fujii, Seishiro, Shudo, Koichi.
Application Number | 20050202055 10/932097 |
Document ID | / |
Family ID | 34918444 |
Filed Date | 2005-09-15 |
United States Patent
Application |
20050202055 |
Kind Code |
A1 |
Shudo, Koichi ; et
al. |
September 15, 2005 |
Anti-wrinkle agent
Abstract
A medicament having an anti-wrinkle action, which comprises as
an active ingredient a retinoid having a fundamental structure of a
phenyl substituted carbamoyl benzoic acid or a phenyl substituted
carboxamide benzoic acid (for example,
4-(2,4-bistrimethylsilylphenylcarboxamide)benz- oic acid,
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbam-
oyl]benzoic acid, or the like).
Inventors: |
Shudo, Koichi; (Tokyo,
JP) ; Fujii, Seishiro; (Zama-shi, JP) |
Correspondence
Address: |
GREENBLUM & BERNSTEIN, P.L.C.
1950 ROLAND CLARKE PLACE
RESTON
VA
20191
US
|
Assignee: |
Koichi SHUDO, Tokyo, Japan
|
Family ID: |
34918444 |
Appl. No.: |
10/932097 |
Filed: |
September 2, 2004 |
Current U.S.
Class: |
424/401 ;
514/563; 514/63 |
Current CPC
Class: |
A61K 31/695 20130101;
A61K 31/195 20130101; A61P 43/00 20180101; A61P 17/00 20180101;
A61P 17/16 20180101; A61K 31/196 20130101 |
Class at
Publication: |
424/401 ;
514/563; 514/063 |
International
Class: |
A61K 031/695; A61K
031/195; A61K 007/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 11, 2004 |
JP |
2004-068454 |
Claims
1. A medicament having an anti-wrinkle action, which comprises as
an active ingredient a retinoid having a fundamental structure of a
phenyl substituted carbamoyl benzoic acid or a phenyl substituted
carboxamide benzoic acid.
2. The medicament according to claim 1, wherein the retinoid does
not substantially bind to a retinoic acid receptor (RAR) subtype
y.
3. The medicament according to claim 1, wherein the retinoid is
4-(2,4-bistrimethylsilyphenylcarboxamide)benzoic acid or 4-[(5,
6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)
carbamoyl]benzoic acid.
4. The medicament according to claim 2 wherein the retinoid is
4-(2,4-bistrimethylsilyphenylcarboxamide) benzoic acid or 4-[(5,
6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)
carbamoyl]benzoic acid.
Description
FIELD OF INVENTION
[0001] The present invention relates to an anti-wrinkle agent. More
specifically, the present invention relates to a medicament which
reduces wrinkles on skin.
BACKGROUND ART
[0002] Retinol or retinal has been known to be effective against
skin disorders such as wrinkles, warts, eczema, and dandruff
(European Published Unexamined Patent Application No. 301033, U.S.
Pat. No. 3,932,665, U.S. Pat. No. 4,934,114 and the like). Retinoic
acid has been known to reduce wrinkles (European Published
Unexamined Patent Application No. 379367, Drugs and Aging, 2, pp.
7-13, 1992). This substance has been used in the United States as a
medicament for a treatment of skin damaged from ray of sunlight. It
is reported that wrinkles caused by aging can be treated with
retinol, retinal, and retinoic acid (U.S. Published Unexamined
Patent Application No. 2001/53347). However, retinoic acid is
highly irritative to skin and induces flare or inflammatory
dermatitis. Therefore, development of an anti-wrinkle agent which
is low epispastic has been desired.
[0003] The term "retinoids" is a general name for compounds which
exert similar actions to those of retinoic acid or a part of the
actions by binding to receptors that are essential for expression
of the physiological actions of all-trans-retinoic acid or
9-cis-retinoic acid (three sub-types of each receptor are known to
exist). Among them, some compounds have almost the same level of
actions as that of retinoic acid or a higher level of actions.
However, a skin irritative action generally increases in proportion
to the level of the pharmacological actions (J. Med. Chem., 32, pp.
834-840, 1989). Moreover, 4-[(5,6,7,8-tetrahydro-5,5,-
8,8-tetramethyl-2-naphthalenyl) carbamoyl]benzoic acid, one of
typical retinoids, has been reported to be ineffective on
dermatopathy caused by rays of sunlight (WO96/30009).
DISCLOSURES OF THE INVENTION
[0004] An object of the present invention is to provide a
medicament which reduces wrinkles on skin. More specifically, the
object of the present invention is to provide a medicament which
has reduced irritation to skin and excellent anti-wrinkle
actions.
[0005] Through various studies on physiological actions of
retinoids, the inventors of the present invention found that a
particular class of retinoids have potent anti-wrinkle actions, and
further they have much reduced skin irritative action. The present
invention was achieved on the basis of these findings.
[0006] The present invention thus provides a medicament having an
anti-wrinkle action, which comprises as an active ingredient a
retinoid having a fundamental structure of a phenyl substituted
carbamoyl benzoic acid or a phenyl substituted carboxamide benzoic
acid. According to a preferred embodiment of the present invention,
provided are the aforementioned medicament wherein the retinoid
does not substantially bind to a retinoic acid receptor (RAR)
sub-type .gamma.; the aforementioned medicament wherein the
retinoid having the fundamental structure of a phenyl substituted
carbamoyl benzoic acid or a phenyl substituted carboxamide benzoic
acid is 4-(2,4-bistrimethylsilylphenylcar- boxamide)benzoic acid or
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naph-
thalenyl)carbamoyl]benzoic acid.
[0007] From another aspect, provided are a use of the retinoid
having a fundamental structure of a phenyl substituted carbamoyl
benzoic acid or a phenyl substituted carboxamide benzoic acid for
the manufacture of the aforementioned medicament; and a method for
reducing wrinkles on skin which comprises a step of applying to
skin the retinoid having a fundamental structure of a phenyl
substituted carbamoyl benzoic acid or a phenyl substituted
carboxamide benzoic acid.
[0008] The medicament of the present invention an excellent
anti-wrinkle action, and is characterized to have more reduced skin
irritative action than those of conventional medicaments such as
retinoic acid.
BRIEF EXPLANATION OF DRAWINGS
[0009] FIG. 1 shows results of cumulative skin irritancy test (50
ppm application) of a retinoid on guinea pig skin (changes with
date).
[0010] FIG. 2 shows results of cumulative skin irritancy test (50
ppm application) of a retinoid on guinea pig skin (the 9th day of
application).
[0011] FIG. 3 shows results of the horny layer turnover test.
[0012] FIG. 4 shows results of cumulative skin irritancy in the
horny layer turnover test.
[0013] FIG. 5 shows results of determination for RA and Am80 of
parameter KSD which correlates to the depth of skin grooves.
[0014] FIG. 6 shows degrees of skin thickening by RA and Am80.
BEST MODE FOR CARRYING OUT THE INVENTION
[0015] As an active ingredient of the medicament of the present
invention, a retinoid having a fundamental structure of a phenyl
substituted carbamoyl benzoic acid or a phenyl substituted
carboxamide benzoic acid can be used. Varieties of retinoids having
a fundamental structure of a phenyl substituted carbamoyl benzoic
acid or a phenyl substituted carboxamide benzoic acid are known.
The term "fundamental structure" means a main chemical structure to
which one or more of any kinds of substituents bind. Generally, the
phenyl group which substitutes on a carbamoyl group or a
carboxamide group preferably has one or more substituents. As such
substituents, for example, a lower alkyl group can be used (in the
specification, the term "lower" means about 1 to 6, preferably 1 to
4 carbon atoms). As the lower alkyl group, a linear or branched
alkyl group is preferred. More specifically, examples include
methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl
group, sec-butyl group, and tert-butyl group.
[0016] As the substituents of the aforementioned phenyl group,
examples include a lower alkoxy group such as methoxy group, a
halogen atom (as the halogen atom, any of fluorine, chlorine,
bromine, and iodine atom may be used), and a lower alkyl
substituted silyl group such as trimethyl silyl group. As the
phenyl group substituting on the carbamoyl group, for example, a
phenyl group substituted with 2 to 4 lower alkyl groups or a phenyl
group substituted with 1 to 2 tri-lower alkyl silyl groups is
preferred. A phenyl group substituted with 2 to 4 alkyl groups or a
phenyl group substituted with two trimethylsilyl groups is more
preferred.
[0017] When the two lower alkyl groups substituting on the
aforementioned phenyl group are in adjacent positions, the two
lower alkyl groups may combine to form one or two, preferably one,
5- or 6-membered ring together with the ring constituting carbon
atoms of the phenyl group to which the alkyl groups bind. The ring
thus formed may be saturated or unsaturated and may be substituted
with one or more lower alkyl groups such as methyl group and ethyl
group. The above formed ring may be substituted with preferably two
to four, more preferably two methyl groups. For example, two
adjacent lower alkyl groups substituting on the phenyl group may
preferably combine to form 5,6,7,8-tetrahydronaphthalene ring,
5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene ring or the
like.
[0018] In the specification, the term "retinoid" means a class of
compounds which exert similar actions to those of retinoic acid or
a part of the actions by binding to receptors essential for
expression of the physiological actions of all-trans-retinoic acid
or 9-cis-retinoic acid, and the term means the above compounds
having at least one or more retinoid-like actions such as cell
differentiation action, cell proliferation-promoting action, and a
life sustaining action. Weather or not a compound is a retinoid can
be easily judged by various methods described in M. Sporn et al.,
Retinoids, Academic Press, 1984. Retinoids generally have a
property of binding to a retinoic acid receptor (RAR). Preferably,
retinoids used as active ingredients of the medicaments of the
present invention are those binds to subtype .alpha. (RAR .alpha.)
and subtype .beta. (RAR .beta.) of the RAR, and does not
substantially bind to subtype .gamma. (RAR .gamma.). The bindings
to the retinoic acid receptor subtypes can be easily verified by a
method described in a publication (H. de The, and A. Dejean,
"Retinoids, 10 years on", Basel, Karger, pp. 2-9, 1991).
[0019] As a preferred retinoid, an example includes a compound
represented by the following general formula (I): 1
[0020] [wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5
each independently represents hydrogen atom, a lower alkyl group,
or a lower alkyl substituted silyl group, and when any two adjacent
groups of R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are lower
alkyl groups, the two groups may combine to form a 5- or 6-membered
ring together with the carbon atoms on the benzene ring to which
the groups bind (said 5- or 6-membered ring may have one or more
alkyl groups), and X represents --CONH-- or --NHCO--].
[0021] In the aforementioned general formula (I), as the lower
alkyl group represented by R.sup.1, R.sup.2, R.sup.3, R.sup.4, and
R.sup.5, a linear or branched alkyl group having 1 to 6, preferably
1 to 4, carbon atoms may be used. For example, methyl group, ethyl
group, n-propyl group, isopropyl group, n-butyl group, sec-butyl
group, or tert-butyl group may be used. On the aforementioned lower
alkyl group, one or more of any kinds of substituents may exist. As
the substituent, for example, hydroxy group, a lower alkoxy group,
and a halogen atom can be exemplified. As the lower alkyl
substituted-silyl group represented by R.sup.1, R.sup.2, R.sup.3,
R.sup.4, and R.sup.5, an example includes trimethylsilyl group.
[0022] Any two adjacent lower alkyl groups selected from the group
consisting of R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 may
combine to form one or two, preferably one, 5- or 6-membered ring
together with the carbon atoms on the benzene ring to which the
groups bind. The ring thus formed may be saturated, partially
saturated, or aromatic, and the ring may have one or more alkyl
group. As the alkyl group which may substitute on the ring, a
linear or branched alkyl group having 1 to 6, preferably 1 to 4,
carbon atoms may be used. For example, methyl group, ethyl group or
the like may be used, and the ring may be substituted with
preferably 2 to 4, more preferably 4, methyl groups. For example,
the benzene ring on which R.sup.2 and R.sup.3 substitute together
with R.sup.2 and R.sup.3 may preferably form
5,6,7,8-tetrahydronaphthalene ring,
5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene ring or the
like.
[0023] More specifically, as a retinoid having a fundamental
structure of a phenyl substituted carbamoyl benzoic acid or a
phenyl substituted carboxamide benzoic acid used as an active
ingredient of the medicament of the present invention, examples
include 4-(2,4-bistrimethylsilylphenyl- carboxamide)benzoic acid
(Am555s, J. Med. Chem., 33, pp. 1430-1437, 1990) and
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)
carbamoyl]benzoic acid (Am80, Hashimoto, Y., Cell struct. Funct.,
16, pp. 113-123, 1991; Hashimoto, Y., et al., Biochem. Biophys.
Res. Commun., 166, pp. 1300-1307, 1990). As the retinoid, a
substance in a salt form as well as a compound in a free form can
be used. A hydrate or a solvate of the free form or the salt may
also be used. Types of the salt are not particularly limited, and
for example, sodium salt or the like is preferred. When a retinoid
as an active ingredient of the medicament of the present invention
has one or more asymmetric carbon atoms depending on types of the
substituents, stereoisomers such as optical isomer and
diastereoisomer in a pure form, as well as any mixtures of the
stereoisomers, racemates or the like may be used as an active
ingredient of the medicament of the present invention.
[0024] The medicament of the present invention is effective as a
medicament used for reducing wrinkles on skin. Causes of wrinkles
are not particularly limited. Wrinkles caused by aging are
preferable targets of the medicament of the present invention. The
medicament of the present invention can apply to wrinkles caused by
dermatopathies due to rays of sunlight or drugs, juvenile
multi-wrinkle, and the like.
[0025] The routes of administration of the medicament of the
present invention are not particularly limited. The medicament can
be administered orally or parenterally. As the medicament of the
present invention, one or more of substances selected from the
group consisting of the aforementioned retinoids and salts thereof,
and hydrates thereof and solvates thereof. As the medicament of the
present invention, the aforementioned substance, per se, may be
administered. Preferably, the medicament can be administered as a
pharmaceutical composition for oral or parenteral administration
which can be prepared by a method well known to one of ordinary
skill in the art. As pharmaceutical compositions suitable for oral
administration, examples include tablets, capsules, powders, subtle
granules, granules, liquids, and syrups. As pharmaceutical
compositions suitable for parenteral administration, examples
include injections, suppositories, inhalant, eye drops, nasal
drops, ointments, creams, and patches. The medicament of the
present invention is preferably applied parenterally to skin or
mucous membrane as a pharmaceutical composition in a form of an
external preparation for topical administration. Types of
pharmaceutical compositions in a form of external preparations are
not particularly limited. For example, ointment, creams, lotions,
and solutions can be exemplified.
[0026] The aforementioned pharmaceutical composition can be
prepared by addition of physiologically and pharmacologically
acceptable additives. As physiologically and pharmacologically
acceptable additives, examples include excipients, disintegrants or
disintegration aids, binders, lubricants, coating agents, coloring
agents, diluting agents, base materials, dissolving agents or
dissolving aids, isotonizing agents, pH modifiers, stabilizers,
propellants, and adhesives. The pharmaceutical composition in a
form of an external preparation can be formulated by using
pharmaceutical additives generally used for external preparations
and by a method well known to one of ordinary skill in the art.
Types of the pharmaceutical additives are not particularly limited.
For example, water soluble or oily polymer base materials,
surfactants, pH modifiers, buffing agents, isotonizing agents,
preservatives, thickeners, organic solvents such as ethanol can be
exemplified. Further, amounts of the additives to be mixed are not
particularly limited. Suitable amounts can be chosen depending on a
type of formulation.
[0027] A dose of the medicament of the present invention is not
particularly limited. The dose may be suitably increased or
decreased depending on various factors which should generally be
taken into consideration, such as the body weight and age of a
patient, the type and condition of a disease, the administration
route, and the like. Generally, the medicament can be used in a
range of about 0.01 to 1,000 mg for oral administration per day for
an adult, and the aforementioned dose may suitably be increased or
decreased. A dose of the medicament in a form of an external
preparation is also not particularly limited. For example, the dose
is about 1 pg to 1 mg per day as a dose for topical administration.
The dose can be suitably increased or decreased depending on
conditions and the like.
EXAMPLES
[0028] The present invention will be explained more specifically
with reference to examples. However, the present invention is not
limited to the following examples.
Example 1
Skin Irritancy
[0029] Histological tests were conducted to study the irritancy of
a retinoid on guinea pig skin and correlation between an irritancy
threshold and a retinoid action threshold. Each of male guinea pigs
of approximately in a weight of 600 g was applied once every day
with 1, 5, 10, 50, or 100 ppm of retinoic acid (RA) or Am80
(4-[(5,6,7,8-tetrahydro--
5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid) as an
ethanol solution on the dorsal skin (5 days a week). As a control,
only the solvent (ethanol) was applied. The skin responses were
evaluated according to the following 5-step criteria, and average
values were calculated for each concentration of the drugs by using
results obtained from three of the guinea pigs.
[0030] 0: No skin response was observed.
[0031] 1: Slight erythema was observed.
[0032] 2: Obvious erythema was observed.
[0033] 3: Strong erythema or slight edema/crust was observed.
[0034] 4: Obvious edema/crust, or more severe changes was
observed.
[0035] The results are shown in FIG. 1. Comparison of RA and Am80
at the same concentration revealed that Am80 induces much weaker
skin response than retinoic acid and induces extremely slow skin
response. Further, concentration dependencies of cumulative skin
irritancy of RA and Am80 for the same application period were
compared. As a result, RA irritancy threshold was less than 5 ppm
and the irritancy was increased concentration dependently, whereas
Am80 of 10 ppm or less induced no skin responses during this period
(FIG. 2). Table 1 shows results of a comparison of histological
findings at the end of the application period. As compared with RA,
Am80 caused more slight skin thickening and inflammatory changes
even when applied at 10 times higher concentration.
1 TABLE 1 RA Am80 Concentration (ppm) 1 5 1 10 50 Skin Response -
.+-. - - .+-. Epidermis Skin thickening .+-. ++ - - + Cell
infiltration - .+-. - - - Edema (Intercellular) - + - - .+-. Edema
(Intracellular) .+-. + - - .+-. Dermis Cell infiltration - + - -
.+-. Vasodilation - + - - + Thinning of horny cell layer - + - -
.+-. Mucin staining - + - - .+-. (Increase in positive substances
between dermis upper layer and basal membrane) Application period
20 days 20 days
Example 2
Horny Layer Turnover Test
[0036] Actions on turnover of horny layer were evaluated by using
guinea pigs. Hartley albino male guinea pigs of approximately 750 g
in weight, whose hair was removed using depilatory wax three days
prior to the experiment, were applied occlusively with 5% Vaseline
ointment of dansylchloride for 24 hours using a patch test Finn
Chamber, and then the skin of the guinea pigs were wiped to remove
the ointment. A portable fluorometer was used for irradiation with
ultraviolet rays having maximum at around 338 nm, and the
fluorescent intensity of the dansylchloride was measured.
Simultaneously, fluorescent intensity of an area where
dansylchloride was not applied (blank value) was measured in the
same manner. After the measurement of the fluorescent intensities,
10 .mu.l/1 cm diameter of RA and Am80 at 50 ppm concentration were
applied once a day. During the measurement, skin irritancy was also
determined according to the criteria indicated in Example 1. The
results of the horny layer turnover test are shown in FIG. 3. It
was revealed that RA has strong accelerating action on the horny
cell layer turnover, whereas Am80 has almost no effect on the horny
cell layer turnover. Cumulative skin irritancy was simultaneously
evaluated according to the criteria in Example 1, and the results
were obtained as shown in FIG. 4.
Example 3
Planarization Action on Skin Surface Formation (Skin Groove)
[0037] Changes which appear on skin grooves after applications of
RA and Am80 (each at a concentration of 0.01% in ethanol) were
studied by using hairless mice (Skh-h41, 16 weeks old, female, 5
mice per group). The applications were conducted once a day, 5 days
a week, and for 30 days. As a control, only ethanol was applied. On
the next day of the day of last application, replicas of skin
surfaces were created by using a silicon resin, and various
parameters that represent features of the shape of the skin surface
were determined by using an apparatus for image analysis. As a
result, dermatography on the replicas were disappeared by the
repeated application of RA, and planarization changes of the
surfaces were observed. The same action was observed for Am80. The
image analysis parameter KSD (the dispersion of luminance
distribution in a 3.9 mm.times.3.9 mm pixel), which correlates to
the depth of skin grooves, was significantly decreased in the drug
applied group (FIG. 5). Further, the decrease in KSD correlated to
epidermal thickening. Both of Am80 and RA gave obvious changes
(FIG. 6).
Example 4
Actions of Fibroblast Cells on EGF-Dependent Growth
[0038] The growth of fibroblast cells, being suspended under a low
serum level, is dependent on growth factors, and the growth will
start by the addition of EGF. The acceleration effects of RA and
Am80 on the EGF-dependent growth were evaluated. RA gave the
maximum effect (40% promotion) at 10.sup.-6 M, and Am80 gave the
maximum effect (30% promotion) at 10.sup.-8M. The acceleration
effect of Am80 (10%) was also observed at 10.sup.-10 Ml.
Example 5
Actions on Human Keratinocyte Growth and Differentiation
[0039] Normal human keratinocyte obtained from human chest skin
(HK, Kurabo) was cultured, and the cells were added with RA or Am80
(0.01% in dimethyl sulfoxide) on the second day. The cells on the
second to 13.sup.th day after the addition of the agents were used
as samples. By using the amount of DNA as an index of HK growth,
and by using compositional ratio (K1/K16) of differentiated keratin
(k1; 68 kD) and proliferating keratin (K16; 48 kD) in one-dimension
SDS-PAGE as an index of differentiation, differentiation
suppression rate was determined as a value wherein the ratio of the
indexes of each sample and control applied only with a solvent was
subtracted from 1. Am80 has a similar cell growth suppression
action to that of RA. IC.sub.50 was 10.sup.-6 to 10.sup.-7 M for
RA, and 10.sup.-9 M for Am80. In addition, a cell differentiation
suppression action of Am80 is stronger than that of RA, and also
observed at a concentration as low as 10.sup.-8 to 10.sup.-10M, and
the suppression rates by Am80 were 1.3 to 1.7 times as compared to
that by RA.
[0040] The present disclosure relates to subject matter contained
in Japanese Patent Application No. 2004-068454, filed on Mar. 11,
2004, the contents of which are herein expressly incorporated by
reference in its entirety.
* * * * *