U.S. patent application number 15/018259 was filed with the patent office on 2016-06-02 for skin treatments containing carboxylic acid-substituted idebenone derivatives and methods of preparation and use thereof.
The applicant listed for this patent is Elizabeth Arden, Inc.. Invention is credited to Falko Diedrich, Joespeh C. DiNardo, James Alan Kerschen, Joseph A. Lewis, III, Birgit Neudecker, Andrew S. Thompson, Peter C. Wade, Eberhard Wieland.
Application Number | 20160151260 15/018259 |
Document ID | / |
Family ID | 42049330 |
Filed Date | 2016-06-02 |
United States Patent
Application |
20160151260 |
Kind Code |
A1 |
Diedrich; Falko ; et
al. |
June 2, 2016 |
Skin Treatments Containing Carboxylic Acid-Substituted Idebenone
Derivatives and Methods of Preparation and Use Thereof
Abstract
The present invention relates to novel carboxylic
acid-substituted idebenone derivatives, skin treatment compositions
containing these carboxylic acid-substituted derivatives, methods
of treating skin changes by topical application of these carboxylic
acid-substituted idebenone derivatives, and their methods of
synthesis. The carboxylic acid-substituted idebenone derivatives of
the present invention are unexpectedly effective in treating skin,
particularly with respect to skin tolerance. When included in a
topical composition, the carboxylic acid-substituted idebenone
derivatives of the present invention have an antioxidant effect
that is useful in treating a skin change.
Inventors: |
Diedrich; Falko; (Kaufungen,
DE) ; Neudecker; Birgit; (Fuldatat-Rothwestern,
DE) ; Wieland; Eberhard; (Goettingen, DE) ;
Lewis, III; Joseph A.; (Chesterfield, VA) ; DiNardo;
Joespeh C.; (Vesuvius, VA) ; Thompson; Andrew S.;
(Mountainside, NJ) ; Kerschen; James Alan;
(Somerset, NJ) ; Wade; Peter C.; (Somerset,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Elizabeth Arden, Inc. |
New York |
NY |
US |
|
|
Family ID: |
42049330 |
Appl. No.: |
15/018259 |
Filed: |
February 8, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13714136 |
Dec 13, 2012 |
9290436 |
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15018259 |
|
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|
|
13349651 |
Jan 13, 2012 |
8354550 |
|
|
13714136 |
|
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|
12574135 |
Oct 6, 2009 |
8173703 |
|
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13349651 |
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61103043 |
Oct 6, 2008 |
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Current U.S.
Class: |
514/458 ;
514/474; 514/548 |
Current CPC
Class: |
C07C 2601/16 20170501;
A61K 8/676 20130101; C07C 67/28 20130101; A61P 17/16 20180101; C07C
67/31 20130101; A61K 8/671 20130101; A61Q 90/00 20130101; C07C
67/14 20130101; C07C 67/08 20130101; A61P 17/02 20180101; A61Q
19/02 20130101; C07C 69/95 20130101; A61K 8/678 20130101; A61Q
19/004 20130101; A61K 8/375 20130101; A61K 8/37 20130101; A61Q
19/06 20130101; A61Q 19/08 20130101; A61Q 19/007 20130101; C07C
69/67 20130101; A61Q 17/04 20130101; A61Q 19/10 20130101; A61K
8/673 20130101; A61P 17/00 20180101; A61K 8/67 20130101; C07C 67/08
20130101; C07C 69/67 20130101; C07C 67/14 20130101; C07C 69/67
20130101; C07C 67/28 20130101; C07C 69/28 20130101; C07C 67/31
20130101; C07C 69/675 20130101 |
International
Class: |
A61K 8/37 20060101
A61K008/37; A61Q 19/08 20060101 A61Q019/08; A61K 8/67 20060101
A61K008/67 |
Claims
1.-6. (canceled)
7. A method of treating or preventing skin aging comprising
topically administering a composition comprising a therapeutically
effective amount of idebenone dipalmitoyl glycerate to a subject in
need thereof.
8. The method of claim 7, wherein the skin aging is caused by UV
damage.
9. The method of claim 7, wherein the skin aging comprises age
spots.
10. The method of claim 7, wherein the idebenone dipalmitoyl
glycerate is present in an amount of from 0.1 wt % to 2.0 wt %
based on the total weight of the composition.
11. The method of claim 7, wherein the idebenone dipalmitoyl
glycerate is present in an amount of about 0.5% based on the total
weight of the composition.
12. The method of claim 7, wherein the composition further
comprises one or more of vitamin A, a derivative of vitamin A,
vitamin B, a derivative of vitamin B, vitamin C, a derivative of
vitamin C, vitamin E and a derivative of vitamin E.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. Ser. No.
13/349,651, filed Jan. 13, 2012, which is pending, and which is a
divisional of U.S. Ser. No. 12/574,135, filed Oct. 6, 2009, now
U.S. Pat. No. 8,173,703, which claims the benefit of priority to
U.S. Provisional Patent Application No. 61/103,043 filed Oct. 6,
2008. Each of the aforementioned applications is hereby
incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to topical dermatological
compositions containing an effective amount of a carboxylic
acid-substituted idebenone derivative. In particular, the invention
relates to compositions that provide effective protection from
damaging oxidation processes in the skin leading to skin changes,
and also provide protection for the compositions themselves
(including, for example, the constituents of cosmetic compositions
containing these carboxylic acid-substituted idebenone derivatives)
from damaging oxidation processes. Furthermore, the carboxylic
acid-substituted idebenone derivatives of the present invention
show significant skin tolerance (i.e., non-irritation), support
vesicular breathing and cellular respiration, contribute to
stabilization of mitochondrial membranes, and promote the
regeneration and vitality of skin cells.
BACKGROUND
[0003] Skin is exposed to damage resulting from various sources,
including both environmental factors and biochemical processes.
Oxidative processes damage proteins, lipids, and other cellular
components necessary to maintain the health and appearance of skin,
resulting in skin changes, such as skin aging (e.g., age spots),
hyperpigmentation, UV damage, lines, wrinkles, uneven skin texture
(e.g., cellulitis), etc. Oxidative damage to the skin and its more
detailed causes are listed in Miyachi, Y: "Skin diseases associated
with oxidative injury," Fuchs J, Packer L (eds.), OXIDATIVE STRESS
IN DERMATOLOGY, Marcel Dekker, New York, pp. 323-331 (1993).
[0004] The damaging effects of the UV part of solar radiation on
the skin are generally known. While rays having a wavelength which
is less than 290 nm (the UVC range), are absorbed by the ozone
layer in the earth's atmosphere, rays in the range between 290 nm
and 320 nm (the UVB range), cause an erythema, simple sunburn or
even more or less severe burns. The narrower range around 308 nm is
given as a maximum for erythema activity of sunlight. For
protection against UVB radiation, numerous compounds are known, in
which they are derivatives of 3-benzylidene camphor, 4-aminobenzoic
acid, cinnamic acid, salicylic acid, benzophenone and also
2-phenylbenzimidazole. Also, for the range between about 320 nm and
about 400 nm (the UVA range) it is important to have filter
substances available, since its rats may cause reactions in
light-sensitive skin. It has been proven that UVA radiation leads
to damage of the elastic and collagenic fibres of the connective
tissue, which allows the skin to age prematurely, and that it is to
be regarded as a cause of numerous phototoxic and photoallergic
reactions. The damaging influence of UVB radiation may be amplified
by UVA radiation. It has also been proven that consumption of
lipophilic antioxidants, for example, alpha-tocopherol, is
triggered in the skin by UVA and UVB radiation (Thiele et al., J.
Invest. Dermatol. 100, p. 756 ff. (1998)).
[0005] Further, UV radiation is ionizing radiation. Hence, there is
the risk that ionic species are produced on UV exposure, which then
in turn are able to intervene oxidatively in the biochemical
processes.
[0006] For protection against the rays of the UVA range, certain
derivatives of dibenzoylmethane have therefore been used, the
photostability of which (Int. J. Cosm. Science 10, 53 (1988)) is
not provided to an adequate extent. UV radiation, however, may also
lead to photochemical reactions, wherein then the photochemical
reaction products intervene in the skin mechanism.
[0007] Predominantly such photochemical reaction products are free
radical compounds, for example hydroxyl radicals. Also, undefined
free radical photoproducts, which are produced in the skin itself,
may trigger uncontrolled side reactions due to their high
reactivity. Singlet oxygen, a non-free radical excited state of the
oxygen molecule, however, may occur in UV irradiation, short-lived
epoxides and many others. Singlet oxygen, for example, is
characterized with respect to the normally existing triplet oxygen
(free radical base state) by increased reactivity. Nevertheless,
excited, reactive (free radical) triplet states of the oxygen
molecule also exist. Furthermore, there is the occurrence of lipid
peroxidation products, such as hydroperoxides and aldehydes,
wherein first in turn free radical chain reactions may be triggered
and to which overall cytotoxic properties have to be ascribed
(Michiels and Ramacle, Toxicology, 66, 225 ff. (1990)). Lipid
peroxidation is an oxidative process that degrades lipids, wherein
free radicals steal electrons from the lipids in cell membranes,
causing oxidative stress and cell damage.
[0008] Light-sensitive skin includes the disorder photodermatoses
(photosensitive eruptions). Further designations for the
polymorphic light-dermatosis are PLD, PLE, Mallorca Acne and a
plurality of further designations, as are given in the literature
(e.g., A. Voelckel et al., Zentralblatt Hautund
Geschlechtskrankheiten (1989),156, p. 2).
[0009] Erythematous skin symptoms also occur as concomitant
symptoms in certain skin diseases or skin irregularities. For
example, the typical rash in the clinical picture of acne is
regularly reddened to a greater or lesser extent.
[0010] In order to prevent these reactions, additional antioxidants
and/or free radical absorbers/scavengers may be incorporated in
cosmetic or dermatological formulations. Antioxidants are
substances that scavenge free radicals and prevent oxidation
processes or prevent the auto-oxidation of fats containing
unsaturated compounds. Antioxidants used in the field of cosmetics
and pharmacy are, for example, alpha-tocopherol, in particular in
the form of alpha-tocopheryul acetate, sesamol, colic acid
derivatives, butylhydroxy anisole, butylhydroxy toluene, and
idebenone. Antioxidants are mainly used as protective substances
against the decay of the compositions containing them. However, it
is known that undesirable oxidation processes may also occur in the
human and animal skin. Such processes play a considerable part in
skin aging. Thus, antioxidants and/or free radical absorbers may
additionally be incorporated into cosmetic formulations to treat or
prevent damage caused by oxidative and degenerative biochemical
processes. It has been proposed to use vitamin E (U.S. Pat. Nos.
4,144,325 and 4,248,861), a substance having known anti-oxidative
action in sunscreen formulations, but even here the action achieved
remains far below that hoped for. Tocopherol (a vitamin E
antioxidant), for example, degrades to form pro-oxidative
products.
[0011] Idebenone
(6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone) has
been used previously to treat skin changes. For example, U.S. Pat.
No. 6,756,045, describes the use of idebenone as a topical
composition for treating skin changes.
SUMMARY OF THE INVENTION
[0012] The present invention relates to compounds of Formula I:
##STR00001##
[0013] wherein R.sup.1 is a C.sub.2-22 straight or branched sugar
acid, and wherein two or more hydroxy groups on the sugar acid are
each independently substituted with a C.sub.1-22 carboxylic
acid.
[0014] The present invention also relates to a method of preparing
a compound of general Formula I by coupling a corresponding di-,
tri-, or poly-carboxylic acid functionalized sugar acid to
idebenone. For example, a method of preparing idebenone dipalmitoyl
glycerate includes the steps of: subjecting benzyl acrylate to a
dihydroxylation reaction to form benzyl 2,3-dihydroxypropanoate;
reacting the benzyl 2,3-dihydroxypropanoate with palmitoyl chloride
to form 3-(benzyloxy)-3-oxopropane-1,2diyl dipalmitate; reacting
the 3-(benzyloxy)-3-oxopropane-1,2diyl dipalmitate with ethyl
acetate to form 2,3-bis(palmitoyloxy)propanoic acid; and reacting
the 2,3-bis(palmitoyloxy)propanoic acid with idebenone to form
idebenone dipalmitoyl glycerate.
[0015] The present invention also relates to a composition
comprising a compound of general Formula I and at least one
additive.
[0016] Further, the present invention relates to a method of
treating a skin change, comprising topically administering a
composition comprising a therapeutically effective amount of a
compound of general Formula I to a subject in need thereof.
DETAILED DESCRIPTION
[0017] The carboxylic acid-substituted idebenone derivatives of the
present invention are antioxidants and provide a significant
benefit in treating and preventing skin damage and unwanted skin
changes caused by oxidative and degenerative processes. The
inventors have surprisingly discovered that compositions prepared
with carboxylic acid-substituted idebenone derivatives of the
present invention provide a major improvement over comparable
compositions prepared with underivatized idebenone or with
underivatized idebenone substituted with a monocarboxylic acid.
Notably, neither underivatized idebenone nor underivatized
idebenone substituted with a monocarboxylic acid include a sugar
acid attached to idebenone, as in the compounds of the present
invention. Rather, the carboxylic acid-substituted idebenone
derivatives of the present invention are surprisingly and
significantly more effective in treating skin changes and show
significantly increased skin tolerance. Consequently, these
compounds provide a major advance and improvement in skin treatment
compositions.
[0018] For example, delivery of the active ingredient (idebenone)
is enhanced because the present carboxylic acid-substituted
idebenone derivatives increase skin permeability by virtue of the
presence of carboxylic acids (particularly di-, tri-, or poly-fatty
acids) that render the compound more soluble across the stratum
corneum lipid bi-layers of the skin that are composed of ceramides,
cholesterol, and essential fatty acids. Delivery of the active
ingredient is also enhanced because the present carboxylic
acid-substituted idebenone derivatives increase cell permeability,
which occurs because cell membranes are composed of fat soluble
lipids. Additionally, compositions prepared with the present
carboxylic acid-substituted idebenone derivatives are able to
provide a slow release therapy as the compound hydrolyzes in the
skin over time.
[0019] All of the foregoing advances associated with carboxylic
acid-substituted idebenone derivatives of the present invention
(i.e., reduced skin irritation, reduced inflammation, increased
skin permeability, increased cell permeability, and slow release
therapy) lead to improved skin conformity, and allow the skin
treatment compositions of the present invention to be used on more
skin types, more skin conditions, and on more areas of the body
than has been effectively feasible using comparable compositions
prepared with underivatized idebenone or underivatized idebenone
substituted with a monocarboxylic acid. Moreover, the carboxylic
acid-substituted idebenone derivatives of the present invention
have been found to be more hypo-allergenic and achieve improved
efficacy in treating skin damage (e.g., brown pigmentation) when
compared with underivatized idebenone or underivatized idebenone
substituted with a monocarboxylic acid.
[0020] The carboxylic acid-substituted idebenone derivatives of the
present invention may be prepared and used in topical compositions
for the treatment of skin changes. The compositions of the
invention may include other components or additives, such as
glycosaminoglycans and their salts, in particular hyaluronic acids
having a molecular weight of 1 to 1,000,000 and their salts, or
hyaluronidase inhibitors, such as inter-alpha-trypsin inhibitor.
The compositions of the invention can be used to treat or prevent a
wide variety of skin changes (e.g., erythematous), inflammatory,
allergic or autoimmune-reactive symptoms (e.g., dermatoses), skin
changes in light-sensitive skin (e.g., photodermatoses),
hyperpigmentation (e.g., age spots), and damaging effects of the UV
part of solar radiation on the skin.
[0021] The present invention comprises compounds of Formula I:
##STR00002##
[0022] wherein R.sup.1 is a C.sub.2-22 straight or branched sugar
acid, and wherein two or more hydroxy groups on the sugar acid are
each independently substituted with a C.sub.1-22 carboxylic acid.
Preferably, 2, 3, 4, or 5 hydroxy groups of the sugar acid are each
independently substituted with a C.sub.1-22 carboxylic acid.
Preferred compounds of the present invention may also include fewer
hydroxy groups substituted with longer chain carboxylic acids or
more hydroxy groups substituted with shorter chain carboxylic
acids.
[0023] Suitable carboxylic acids for use in the present invention
include monocarboxylic acids or polycarboxylic acids. The
carboxylic acids may be straight chained, saturated carboxylic
acids (e.g., formic acid, acetic acid, propionic acid, butyric
acid, valeric acid, caproic acid, enanthic acid, caprylic acid,
pelargonic acid, capric acid, lauric acid, palmitic acid, and
stearic acid) or short-chain unsaturated monocarboxylic acids
(e.g., acrylic acid).
[0024] Preferably, carboxylic acids of the present invention are
fatty acids (e.g., conjugate fatty acids, medium to long-chain
saturated and unsaturated monocarboxylic acids, such as
docosahexaenoic acid, and eicosapentaenoic acid). Carboxylic acids
for use in the present invention also include amino acids, keto
acids (e.g., pyruvic acid, acetoacetic acid), aromatic carboxylic
acids (e.g., benzoic acid, salicylic acid), dicarboxylic acids
(e.g., aldaric acid, oxalic acid, malonic acid, malic acid,
succinic acid, glutaric acid, adipic acid, maleic acid, fumaric
acid, phthalic acid, etc.), tricarboxylic acids (e.g., citric acid,
isocitric acid, aconitic acid, propane-1,2,3-tricarboxylic acid
(e.g., tricarballylic acid, carballylic acid)), alpha
hydroxycarboxylic acids (e.g., glycolic acid, lactic acid,
hydroxyacrylic acid, oxybutyric acid, glyceric acid, malic acid,
tartaric acid and citric acid), and hyaluronic acid.
[0025] "Sugar acid" is defined as a straight or branched, saturated
or unsaturated, substituted or unsubstituted C.sub.2-22 (preferably
C.sub.2-10, more preferably C.sub.2-5) alkyl group substituted with
two or more carboxyl groups wherein the hydroxy functional groups
of two or more carboxyl groups are each independently substituted
with a C.sub.1-22 carboxylic acid (preferably C.sub.14-20, more
preferably C.sub.15-18). "Branched" refers to one or more lower
alkyl groups such as methyl, ethyl, or propyl attached to a linear
alkyl chain. Preferably, 2, 3, 4, or 5 hydroxy groups on the sugar
acid are each independently substituted with a C.sub.1-22
carboxylic acid.
[0026] The inventors have found that compounds of the present
invention are surprisingly effective in treating skin changes
because they provide the added benefits of reduced skin irriation,
reduced inflammation, increased skin permeability, increased cell
permeability, and slow release therapy.
[0027] In a preferred embodiment, the compound of Formula I is
3-oxo-3-(9-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)monyloxy)propan-
e-1,2-diyl dipalmitate (idebenone dipalmitoyl glycerate), wherein
R.sup.1 is a C.sub.2 sugar acid wherein two hydroxy groups are each
independently substituted with a C.sub.16 carboxylic acid. The
structure of idebenone dipalmitoyl glycerate is shown below:
##STR00003##
[0028] In another embodiment, the present invention includes
topical compositions comprising carboxylic acid-substituted
idebenone derivatives (e.g., idebenone dipalmitoyl glycerate or
another compound of Formula I) and at least one additive. The
composition may be provided in a form selected from creams,
lotions, solutions, sera, anhydrous preparations, emulsions,
microemulsions, multiple emulsions, gels, solid sticks, ointments,
and aerosols. The at least one additive may be selected from
surfactants, cosmetic auxiliaries, pigments, UVA filters, UVB
filters, propellants, thickening agents, emulsifiers, solvents,
water, antioxidants, perfumes, dyestuffs, deodorants, antimicrobial
materials, back-fatting agents, complexing and sequestering agents,
pearlescent agents, plant extracts, vitamins, and combinations
thereof.
[0029] In another embodiment, the present invention relates to a
method of making carboxylic acid-substituted idebenone derivatives
of general Formula I. In general, compounds of the present
invention are made by syntheses that include a reaction well known
in the art as a Fischer esterification, by which a carboxylic acid
reacts with an alcohol to form an ester, as generically illustrated
below:
##STR00004##
[0030] For example, a compound of general Formula I (wherein
R.sup.1 is a C.sub.2-22 straight or branched sugar acid, and
wherein two or more hydroxy groups on the sugar acid are each
independently substituted with a C.sub.1-22 carboxylic acid) may be
made by coupling a di-, tri-, or poly-carboxylic acid
functionalized sugar acid to idebenone.
[0031] In one embodiment, compounds of the present invention may be
synthesized by the following reaction scheme:
##STR00005##
[0032] where R.sup.1 and R.sup.2 are as defined above.
[0033] For example, idebenone dipalmitoyl glycerate may be prepared
by a method comprising the steps of (a) subjecting benzyl acrylate
to a dihydroxylation reaction to form benzyl
2,3-dihydroxypropanoate; (b) reacting the benzyl
2,3-dihydroxypropanoate with palmitoyl chloride to form
3-(benzyloxy)-3-oxopropane-1,2diyl dipalmitate; (c) reacting the
3-(benzyloxy)-3-oxopropane-1,2diyl dipalmitate with ethyl acetate
to form 2,3-bis(palmitoyloxy)propanoic acid; and (d) reacting the
2,3-bis(palmitoyloxy)propanoic acid with idebenone to form
idebenone dipalmitoyl glycerate.
[0034] In yet another embodiment, the present invention relates to
a method of treating or preventing the worsening of a skin change
or (e.g., skin aging (e.g., age spots, wrinkling, fine lines),
hyperpigmentation (e.g., age spots), UV damage, erythematous,
cellulitis, inflammatory symptoms, photodamage, photoreactions,
etc.) comprising topically administering an effective amount of a
carboxylic acid-substituted idebenone derivative of the present
invention (e.g., idebenone dipalmitoyl glycerate) to a patient in
need thereof. Compositions of the present invention may be used to
reduce, if not completely prevent, damage to the skin caused by
oxidative influence, and cause a regenerating and vitalizing effect
on aging, stressed, or damaged skin by supporting vesicular
breathing, stabilization of mitochondrial membranes, and
antia-poptotic properties. These methods of treating a skin change
comprise topically administering a composition of the present
invention (containing a carboxylic acid-substituted idebenone
derivative, particularly of Formula I, and preferably idebenone
dipalmitoyl glycerate) to a subject in need thereof, wherein the
carboxylic acid-substituted idebenone derivative is present in a
therapeutically effective amount. These compositions may contain a
carboxylic acid-substituted idebenone derivative in a
therapeutically effective amount of 0.0001 wt % to 30 wt %,
preferably 0.05 wt % to 5 wt %, more preferably 0.1 wt % to 2.0 wt
%, based on the total weight of the composition. The skin change
may be selected from skin aging, hyperpigmentation, skin changes
caused by UV damage, and skin changes that comprise erythematous
symptoms.
[0035] The compounds of Formula I may be used in topical cosmetic
or dermatological compositions and act as antioxidants and free
radical absorbers/scavengers. These compounds provide better
prevention of damage to lipids, DNA, and proteins and also better
prevent skin aging and wrinkle formation. Examples of carboxylic
acid-substituted idebenone derivatives of Formula I include, but
are not limited to: idebenone dipalmitoyl glycerate, idebenone
dimyristoyl glycerate, idebenone dioleyl glycerate, idebenone
dilinoleyl glycerate, idebenone dieicosapentaenyl glycerate,
idebenone dierucyl glycerate, and other idebenone sugar acid
derivatives with two carboxylic acid substitutions, as well as
idebenone trimyristoyl trihydroxypropanoate, idebenone trioleyl
trihydroxypropanoate, idebenone trilinoleyl trihydroxypropanoate,
idebenone trieicosapentaenyl trihydroxypropanoate, and idebenone
trierucyl trihydroxypropanoate, and other idebenone sugar acid
derivatives with three carboxylic acid substitutions, etc.
[0036] Compositions comprising carboxylic acid-substituted
idebenone derivatives of the present invention protect the skin
against photo-reactions and prevent or treat inflammatory
reactions. It could not have been foreseen that topical application
of the carboxylic acid-substituted idebenone derivative compounds,
such as those that contain di-, tri-, or poly-fatty acids, would
result in significantly less skin irritation or inflammation than
similar compositions containing underivatized idebenone or
underivatized idebenone substituted with a monocarboxylic acid (see
Examples). This was a surprising result. The compositions of the
present invention also exhibit greater stability than other skin
care active ingredients, such as vitamin C and vitamin E. By
exhibiting significantly increased skin tolerance, the carboxylic
acid-substituted idebenone derivatives of the present invention are
surprisingly and significantly more effective in treating skin
changes than similar compositions containing underivatized
idebenone or underivatized idebenone substituted with a
monocarboxylic acid.
[0037] The compositions of the present invention may contain at
least one additive. Suitable additives include, but are not limited
to, surfactants, cosmetic auxiliaries, pigments, UVA filters, UVB
filters, propellants, thickening agents, emulsifiers, solvents
(e.g., alcoholic solvents), water, antioxidants, perfumes,
dyestuffs, deodorants, antimicrobial materials, back-fatting
agents, complexing and sequestering agents, pearlescent agents,
plant extracts, vitamins, active ingredients, and/or derivatives
and combinations thereof.
[0038] Pro-oxidative degradation products do not occur when using
carboxylic acid-substituted idebenone derivatives of Formula I. The
use of carboxylic acid-substituted idebenone derivatives as
antioxidants and their use for combating and/or prophylaxis of skin
aging caused by oxidative stress and inflammatory reactions are
within the scope of the present invention. The use of carboxylic
acid-substituted idebenone derivatives as antioxidants for the
stabilization of cosmetic or dermatological compositions, which
contain as additive either vitamin A and/or its derivatives (for
example, all-E-retinoic acid, 9-Z-retionois acid, 13-Z-retinoic
acid, retinal, retinal ester), vitamin B and/or its derivatives,
vitamin C and/or its derivatives and vitamin E and/or its
derivatives (for example, alpha-tocopherol acetate) individually or
in combination, is thus likewise within the scope of the present
invention. The stabilizing effect of the present invention relates
to both smell and color and in particular to the active ingredient
content of the composition.
[0039] Further, the use of carboxylic acid-substituted idebenone
derivatives as an agent for supporting vesicular breathing and
stabilization of mitochondrial membranes with additional
anti-apoptotic effect in skin cells and its use for the
regeneration and revitalization of aging, stressed or damaged skin,
is within the scope of the present invention.
[0040] The cosmetic or dermatological compositions of the invention
may be conventionally prepared and then used to provide treatment,
care, and cleansing of the skin, and as a make-up product in
decorative cosmetics. For administration, the carboxylic
acid-substituted idebenone derivatives of the invention may be
topically applied to the skin in cosmetic and dermatological
compositions of the invention in the manner conventional for
cosmetics.
[0041] Cosmetic and dermatological compositions of the invention
may exist in various forms. Hence, they may be, for example, a
solution, a serum, an anhydrous preparation, an emulsion or
microemulsion of the type water-in-oil (W/O) or of the type
oil-in-water (O/W), a multiple emulsion, for example of the type
water-in-oil-in-water (W/O/W), a gel, a solid stick, an ointment or
an aerosol. It is also advantageous to administer carboxylic
acid-substituted idebenone derivatives in encapsulated form, for
example in collagen matrices and other conventional encapsulation
materials, for example as cellulose encapsulations, in gelatin, wax
matrices or liposomally encapsulated.
[0042] It is also possible and advantageous within the scope of the
present invention to add carboxylic acid-substituted idebenone
derivatives to aqueous systems or surfactant compositions for
cleansing the skin.
[0043] The use of carboxylic acid-substituted idebenone derivatives
for the protection of the skin from oxidative stress is also
regarded as an advantageous embodiment of the present invention, in
particular the use of carboxylic acid-substituted idebenone
derivatives in washing formulations.
[0044] The cosmetic and dermatological compositions of the
invention may contain cosmetic auxiliaries, as are used
conventionally in such compositions, for example preservatives,
bactericides, perfumes, substances for preventing foaming,
dyestuffs, pigments which have a coloring effect, thickening
agents, surfactant substances, emulsifiers, softening, moisturizing
and/or moisture-retaining substances, fats, oils, waxes or other
conventional constituents of a cosmetic or dermatological
formulation, such as alcohols, polyols, polymers, foam stabilizers,
electrolytes, organic solvents or silicone derivatives.
[0045] In particular, carboxylic acid-substituted idebenone
derivatives may also be combined according to the invention with
other antioxidants and/or free radical absorbers. All antioxidants
which are suitable or conventional for cosmetic and/or
dermatological applications may be used according to the invention
as favorable antioxidants. The antioxidants are advantageously
selected from the group consisting of resveratrol, amino acids
(e.g., glycine, histidine, tyrosine, tryptophan) and their
derivatives, imidazoles (e.g., urocanic acid) and their
derivatives, peptides, such as D,L-carnosine, D-carnosine,
L-carnosine and their derivatives (e.g., anserine), carotinoids,
carotenes (e.g., alpha-carotene, beta-carotene, lycopene) and their
derivatives, chlorogenic acid and its derivatives, lipoic acid and
its derivatives (e.g., dihydrolipoic acid), aurothioglucose,
propylthiouracil and other thiols (e.g., thioredoxin, glutathione,
cysteine, cystine, cystamine and their glycosyl, N-acetyl, methyl,
ethyl, propyl, amyl, butyl and lauryl, palmitoyl, oleyl,
gamma-linoleyl, cholesteryl and glyceryl esters) and their salts,
dilauryl thiodipropionate, distearyl thiodipropionate,
thiodipropionic acid and their derivatives (esters, ethers,
peptides, lipids, nucleotides, nucleosides and salts) and
sulphoximine compounds (e.g., buthionine sulphoximines,
homocysteine sulphoximine, buthionine sulphones, pentathionine
sulphoximine, hexathionine sulphoximine, heptathionine
sulphoximine) in very low, acceptable doses (e.g., pmole to
moles/kg), also (metal) chelating agents (e.g., alpha-hydroxy fatty
acids, palmitic acid, phytic acid, lactoferrin), alpha-hydroxy
acids (e.g., citric acid, lactic acid, malic acid, mandelic acid),
humic acid, colic acid, colic extracts, bilirubin, biliverdin,
EDTA, EGTA and their derivatives, unsaturated fatty acids and their
derivatives (e.g., gamma-linolenic acid, linolic acid, oleic acid),
folic acid and their derivatives, ubiquinone and ubiquinol and
their derivatives, vitamin C and derivatives (e.g., ascorbyl
palmitate, Mg-ascorbyl phosphate, ascorbyl acetate), tocopherols
and derivatives (e.g., vitamin E acetate), vitamin A and
derivatives (e.g., vitamin A palmitate) and coniferyl benzoate of
benzoin resin, rutinic acid and their derivatives, butylhydroxy
toluene, butylhydroxy anisole, nordihydroguaiacic acid,
nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and
its derivatives, mannose and its derivatives, sesamol, sesamolin,
zinc and its derivatives (e.g., ZnO, ZnSO.sub.4), selenium and its
derivatives (e.g., selenium methionine), stilbenes and their
derivatives (e.g., stilbene oxide, trans-stilbene oxide,
resveratrol) and the suitable derivatives of the invention (salts,
esters, ethers, sugars, nucleotides, nucleosides, peptides and
lipids) of these said active ingredients.
[0046] The quantity of the aforementioned antioxidants (one or more
compounds) in the compositions may be 0.0001 wt % to 30 wt %,
preferably 0.05 wt % to 20 wt %, more preferably 1-10 a wt %, based
on the total weight of the composition.
[0047] Provided vitamin E, resveratrol, and/or their derivatives
represent the additional antioxidant(s), it is advantageous to
select their particular concentration from the range from 0.0001-20
wt %, based on the total weight of the composition.
[0048] Provided vitamin A or vitamin A derivatives or carotenes or
their derivatives represent the additional antioxidant(s), it is
advantageous to select their particular concentrations from the
range from 0.0001-10 wt %, based on the total weight of the
composition.
[0049] Emulsions according to the present invention are
advantageous and contain, for example the afore-mentioned fats,
oils, waxes and other adipoids, and water and an emulsifier, as is
used conventionally for such a type of formulation.
[0050] The lipid phase may advantageously be selected from the
following substance group: mineral oils, mineral waxes; oils, such
as triglycerides of capric or caprylic acid, also natural oils,
such as for example castor oil; fats, waxes and other natural and
synthetic adipoids, preferably esters of fatty acids with alcohols
of low C number, for example with isopropanol, propylene glycol or
glycerine, or esters of fatty alcohols with alkane acids of low C
number or with fatty acids; alkyl benzoates; silicone oils, such as
dimethylpolysiloxanes, diethylpolysiloxanes, diphenylpolysiloxanes
and mixtures thereof.
[0051] The oil phase of the emulsions, oleogels or hydrodispersions
or lipodispersions within the scope of the present invention is
advantageously selected from the group of esters of saturated
and/or unsaturated, branched and/or unbranched alkane carboxylic
acids of chain length from 3 to 30 C atoms and saturated and/or
unsaturated, branched and/or unbranched alcohols of chain length
from 3 to 30 C atoms, from the group of esters from aromatic
carboxylic acids and saturated and/or unsaturated, branched and/or
unbranched alcohols of chain length from 3 to 30 C atoms. Such
ester oils may then advantageously be selected from the group
isopropyl myristate, isopropyl palmitate, isopropyl stearate,
isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyloleate,
isooctyl stearate, isononyl stearate, isononyl isononanoate,
2-ethylhexyl palmitate, 2-ethylhexyl laurate, 2-hexyldecyl
stearate, 2-octyldodecyl palmitate, oleyl oleate, oleyl erucate,
erucyl oleate, erucyl erucate and synthetic, semi-synthetic, and
natural mixtures of such esters, for example jojoba oil.
[0052] Furthermore, the oil phase may advantageously be selected
from the group of branched and unbranched hydrocarbons and waxes,
silicone oils, dialkyl ethers, the group of saturated or
unsaturated, branched or unbranched alcohols, and fatty acid
triglycerides, namely the triglycerine esters of saturated and/or
unsaturated, branched and/or unbranched alkane carboxylic acids of
chain length from 8 to 24, in particular 12-18, C atoms. The fatty
acid triglycerides may advantageously be selected, for example from
the group of synthetic, semi-synthetic and natural oils, for
example olive oil, sunflower oil, soybean oil, peanut oil,
rape-seed oil, almond oil, palm oil, coconut oil, palm kernel oil
and the like.
[0053] Also any mixtures of such oil and wax components can be used
advantageously within the scope of the present invention. It may
also optionally be advantageous to use waxes, for example cetyl
palmitate, as the single lipid component of the oil phase.
[0054] The oil phase is advantageously selected from the group
2-ethylhexyl isostearate, octyl dodecanol, isotridecyl
isononanoate, isoeicosane, 2-ethylhexyl cocoate, C.sub.12-15 alkyl
benzoate, capryl-capric acid triglyceride, dicaprylyl ether.
[0055] Mixtures of C.sub.12-15 alkyl benzoate and 2-ethylhexyl
isostearate, mixtures of C.sub.12-15 alkyl benzoate and isotridecyl
isononanoate and mixtures of C.sub.12-15 alkyl benzoate,
2-ethylhexyl isostearate and isotridecyl isononanoate are
particularly advantageous.
[0056] Of the hydrocarbons, paraffin oil, squalane and squalene can
be used advantageously. within the scope of the present
invention.
[0057] The oil phase may advantageously also contain cyclic or
linear silicone oils or may consist completely of such oils, but
wherein it is preferable, apart from the silicone oil or the
silicone oils, to use an additional amount of other oil phase
components.
[0058] Cyclomethicone (octamethylcyclotetrasiloxane) is
advantageously employed as silicone oil to be used according to the
invention. However, other silicone oils should also advantageously
be used within the scope of the present invention, for example
hexamethylcyclotrisiloxane, polydimethylsiloxane,
poly(methylphenylsiloxane).
[0059] Mixtures of cyclomethicone and isotridecyl isononanoate, of
cyclomethicone and 2-ethylhexyl isostearate, are also particularly
advantageous.
[0060] The aqueous phase of the compositions of the invention may
optionally contain advantageously alcohols, diols or polyols of low
C number, and their ethers, preferably ethanol, isopropanol,
propylene glycol, glycerine, ethylene glycol, ethylene glycol
monoethyl or monobutyl ether, propylene glycol monomethyl,
monoethyl or monobutyl ether, diethylene glycol monomethyl or
monoethyl ether and analogous products, also alcohols of low C
number, for example ethanol, isopropanol, 1,2-propane diol,
glycerine and in particular one or more thickening agents, which
may advantageously be selected from the group silicon dioxide,
aluminum silicates, polysaccharides or their derivatives, for
example hyaluronic acid, xanthan gum, hydroxypropylmethylcellulose,
particularly advantageously from the group of polyacrylates, in
each case individually or in combination.
[0061] Mixtures of the above-mentioned solvents are used in
particular. For alcoholic solvents, water may be a further
constituent.
[0062] Gels according to the present invention conventionally
contain alcohols of low C number, for example ethanol, isopropanol,
1,2-propane diol, glycerine and water or an above-mentioned oil in
the presence of a thickening agent, which for oily-alcoholic gels
is preferably silicon dioxide or an aluminum silicate, for
aqueous-alcoholic or alcoholic gels is preferably a
polyacrylate.
[0063] The conventionally-known, highly volatile, liquefied
propellants, for example hydrocarbons (propane, butane, isobutane),
which may be used alone or mixed with one another, are suitable as
propellants for compositions which can be sprayed from aerosol
containers according to the present invention: Compressed air can
also advantageously be used.
[0064] Compositions according to the present invention may also
advantageously contain substances which absorb UV radiation in the
UVB range, wherein the total quantity of filter substances is, for
example 0.1 wt % to 30 wt %, preferably 0.5 to 10 wt %, more
preferably 1.0 to 6.0 wt %, based on the total weight of the
compositions, in order to provide cosmetic compositions which
protect the skin from the entire range of ultraviolet radiation.
They may also serve as sunscreen agents for the skin.
[0065] If the compositions according to the present invention
contain UVB filter substances, they may be oil-soluble or
water-soluble. According to the invention, advantageous oil-soluble
UVB filters are, for example: mineral oils, mineral waxes; oils,
such as triglycerides of capric or caprylic acid, also natural
oils, such as for example castor oil; fats, waxes and other natural
and synthetic adipoids, preferably esters of fatty acids with
alcohols of low C number, for example with isopropanol, propylene
glycol or glycerine, or esters of fatty alcohols with alkane acids
of low C number or with fatty acids; alkyl benzoates; silicone
oils, such as dimethylpolysiloxanes, diethylpolysiloxanes,
diphenylpolysiloxanes and mixtures thereof. 3-benzylidene camphor
derivatives, preferably 3-(4-methylbenzylidene) camphor,
3-benzylidene camphor; 4-aminobenzoic acid derivatives, preferably
(2-ethylhexyl) 4-(dimethylamino) benzoate, amyl 4-(dimethylamino)
benzoate; esters of cinnamic acid, preferably (2-ethylhexyl)
4-methoxycinnamate, isopentyl 4-methoxycinnamate; esters of
salicylic acid, preferably (2-ethylhexyl) salicylate,
(4-isopropyl-benzyl) salicylate, homomentyl salicylate, derivatives
of benzophenone, preferably 2-hydroxy-4-methoxybenzophenone,
2-hy-droxy-4-methoxy-4'methylbenzophenone,
2,2'-dihydroxy-4-methoxybenzophenone; esters of benzylidenemalonic
acid, preferably di(2-ethylhexyl) 4-methoxybenzylidenemalonate,
-2,4,6-trianilino(p-carbo-2'-ethyl-1'hexyloxy)-1,3,5-triazinc.
[0066] Advantageous water-soluble UVB filters are, for example:
salts of 2-phenylbenzimidazole-5-sulphonic acid, such as its
sodium, potassium or its triethanol-ammonium salt, and the
sulphonic acid itself; sulphonic acid derivatives of benzophenones,
preferably 2-hydroxy-4-methoxybenzophenone-5-sulphonic acid and
their salts; sulphonic acid derivatives of 3-benzylidene camphor,
such as for example 4-(2-oxo-3-bornylidene-methyl)benzene sulphonic
acid, 2-methyl-5-(2-oxo-3-bornylidene-methyl)sulphonic acid and
their salts as well as
1,4-di(2-oxo-10-sulpho-3-bornylidene-methyl)benzene and its salts
(the corresponding 10-sulphato compounds, for example the
corresponding sodium, potassium or triethanol; -ammonium salt),
also designated as
benzene-1,4-di(2-oxo-1-bornylidene-methyl)-10-sulphonic acid.
[0067] The list of the said UVB filters, which may be used in
combination with the active ingredient combinations of the present
invention, should not be limiting.
[0068] Also within the scope of the present invention is the use of
a combination of carboxylic acid-substituted idebenone derivatives
with at least one UVB filter as antioxidant or the use of a
combination of carboxylic acid-substituted idebenone derivatives
with at least one UVB filter as antioxidant in a cosmetic or
dermatological composition.
[0069] It may also be advantageous to combine carboxylic
acid-substituted idebenone derivatives with UVA filters, which
hitherto are conventionally present in cosmetic compositions. These
substances are preferably derivatives of dibenzoylmethane, in
particular
1-(4'tert.butylphenyl)-3-(4'-methoxyphenyl)propane-1,3-dione and
1-phenyl-3-(4'-isopropylphenyl)propane-1,3-dione. These
combinations or compositions which contain these combinations are
also an object of the invention. The quantities used for the UVB
combination may be used.
[0070] Also within the scope of the present invention is the use of
a combination of carboxylic acid-substituted idebenone derivatives
with at least one UVA filter as antioxidant or the use of a
combination of the active ingredient combinations of the invention
with at least one UVA filter as antioxidant in a cosmetic or
dermatological composition.
[0071] Also within the scope of the present invention is the use of
a combination of carboxylic acid-substituted idebenone derivatives
with at least one UVA filter and at least one UVB filter as
antioxidant or the use of a combination of carboxylic
acid-substituted idebenone derivatives with at least one UVA filter
and at least one UVB filter as antioxidant in a cosmetic or
dermatological composition.
[0072] Cosmetic and dermatological compositions having an effective
amount of carboxylic acid-substituted idebenone derivatives may
also contain inorganic pigments, which are used conventionally in
cosmetics to protect the skin from UV rays. They are oxides of
titanium, zinc, zirconium, silicon, manganese, cerium and mixtures
thereof, and modifications in which the oxides are the active
agents. They are particularly preferably pigments based on titanium
dioxide.
[0073] These combinations of UVA filters and pigment or
compositions containing this combination are also within the scope
of the present invention. The quantities mentioned for the above
combinations may be used.
[0074] Cosmetic compositions which are a skin-cleansing agent or
shampooing agent preferably contain at least one anionic, non-ionic
or amphoteric surfactant substance, or also mixtures of such
substances, carboxylic acid-substituted idebenone derivatives in
aqueous medium and auxiliaries, as are used conventionally
therefore. The surfactant substance or the mixtures of these
substances may be present in the shampooing agent in a
concentration between 1 wt % and 50 wt %.
[0075] These cosmetic or dermatological compositions may also be
aerosols having the auxiliaries conventionally used therefor.
[0076] Aqueous cosmetic cleansing agents of the invention or
low-water or anhydrous cleansing agent concentrates intended for
aqueous cleansing may contain anionic, nonionic and/or amphoteric
surfactants, for example traditional soaps, for example fatty acid
salts of sodium alkyl sulphates, alkyl ether sulphates, alkane and
alkyl benzene sulphonates sulphoacetates sulphobetaines
sarcosinates amidosulphobetaines sulphosuccinates sulphosuccinic
acid semi-esters alkyl ether carboxylates protein-fatty acid
condensates alkylbetaines and amidobetaines fatty acid alkanol
amides polyglycol ether derivatives.
[0077] Cosmetic compositions which are cosmetic cleansing
compositions for the skin, may be present in liquid or solid form.
In addition to carboxylic acid-substituted idebenone derivatives,
they preferably contain at least one anionic, non-ionic or
amphoteric surfactant substance or mixtures thereof, if required
one or more electrolytes and auxiliaries, as are used
conventionally therefor. The surfactant substance may be present in
the cleansing compositions in a concentration between 0.001 and
99.999 wt %, based on the total weight of the compositions.
[0078] Cosmetic compositions which are a shampooing agent, in
addition to a effective amount of carboxylic acid-substituted
idebenone derivatives, preferably contain an anionic, non-anionic
or amphoteric surfactant substance or mixture thereof, optionally
an electrolyte of the invention and auxiliaries, as are used
conventionally therefor. The surfactant substance may be present in
the shampooing agent in a concentration between 0.001 wt % and
99.999 wt %.
[0079] The compositions according to the present invention contain,
apart from the afore-mentioned surfactants, water and optionally
the additives which are conventional in cosmetics, for example
perfume, thickener, dyestuffs, deodorants, antimicrobial materials,
back-fatting agents, complexing and sequestering agents,
pearlescent agents, plant extracts, vitamins and/or their
derivatives, active ingredients and the like.
[0080] The present invention also includes a cosmetic process for
protecting the skin and the hair from oxidative or photooxidative
processes, which is characterized in that a cosmetic agent, which
contains an effective concentration of carboxylic acid-substituted
idebenone derivatives, is applied to the skin or hair in adequate
quantity.
[0081] Likewise, the present invention also includes a process for
protecting cosmetic or dermatological compositions from oxidation
or photo-oxidation, wherein these compositions, for example
compositions for treating and caring for the hair are, in
particular hair lacquers, shampooing agents, also make-up products,
such as for example nail varnishes, lipsticks, foundations, washing
and showering compositions, creams for treating or caring for skin
or other cosmetic compositions, the constituents of which may bring
with them stability problems due to oxidation or photo-oxidation on
storage, characterized in that the cosmetic compositions have an
effective amount of carboxylic acid-substituted idebenone
derivatives.
[0082] The quantity of carboxylic acid-substituted idebenone
derivatives in these compositions may be 0.0001-30 wt %, preferably
0.05-5 wt %, more preferably 0.1-2.0 wt %, based on the total
weight of the compositions.
[0083] Also within the scope of the present invention are processes
for producing the cosmetic agents of the invention, which is
characterized in that active ingredient combinations of the
invention are incorporated into cosmetic and dermatological
formulations in a manner known to one of skill in the art.
EXAMPLES
[0084] The use of these and other examples anywhere in the
specification is illustrative only, and in no way limits the scope
and meaning of the invention or of any exemplified form. Likewise,
the invention is not limited to any particular preferred
embodiments described herein. Indeed, modifications and variations
of the invention may be apparent to those skilled in the art upon
reading this specification, and can be made without departing from
its spirit and scope. The invention is therefore to be limited only
by the terms of the appended claims, along with the full scope of
equivalents to which the claims are entitled.
Example 1
Synthesis of Idebenone Dipalmitoyl Glycerate
[0085] This example provides a synthesis of
3-oxo-3-(9-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)monyloxy)propan-
e-1,2-diyl dipalmitate (Compound 5; idebenone dipalmitoyl
glycerate), which is representative of the carboxylic
acid-substituted idebenone derivatives of the present
invention.
##STR00006##
[0086] A starting material in the idebenone dipalmitoyl glycerate
synthesis is benzyl acrylate (Compound 1), which may be subjected
to various chemical reactions in order to form a crude diol oil
(Compound 2). This diol is then subjected to an acylation reaction
with palmitoyl chloride in the presence of various reagents (TEA,
4-DMAP, and CH.sub.2Cl.sub.2) in order to form a tri-ester,
Compound 3. This product is then reacted with ethyl acetate (AcOEt)
in the presence of various reagents (H.sub.2 and Pd--C (10%)) to
form an acid, Compound 4. Then, Compound 4 is combined with a
solvent (SOCl.sub.2/CH.sub.2Cl.sub.2) and reacted with idebenone in
the presence of various reagents (TEA, 4-DMAP, and
CH.sub.2Cl.sub.2) to form the end product, Compound 5 (idebenone
dipalmitoyl glycerate).
[0087] The dihydroxylation of benzyl acrylate (Compound 1) to form
Compound 2 may be performed in various ways. One method is to react
benzyl acrylate (1.0 mmol) with 0.4 mol % of potassium osmate
dihydrate, three equivalents of potassium ferricyanate (III), and
three equivalents of potassium carbonate in a 1:1 mixture of
t-butanol and water. (Angew. Chem. Int. Ed. Engl. 1996, 35,
448-451). Stir the reaction at room temperature for approximately
21 hours. It may be necessary to add more of the osmate catalyst to
drive the reaction to completion. After an aqueous workup, the
crude diol (Compound 2) is obtained in an almost quantitative
yield.
[0088] Another method for dihydroxylation of benzyl acrylate is to
use non-volatile potassium osmate dihydrate. (J Org. Chem. 1998,
6094). Benzyl acrylate (1.0 mmol) was reacted with 0.5 mol % of
potassium osmate dihydrate, 1.3 equivalents of N-methylmorpholine
N-oxide (NMO) in a 1:1:1 solvent mixture of
water:acetone:acetonitrile at room temperature. The reaction was
complete in 12 hours. After an aqueous workup, the crude diol
(Compound 2) was obtained as an oil in nearly quantitative yield.
The proton NMR indicated that the crude diol was .about.95% pure.
This crude oil became dark brown after standing overnight at room
temperature. Probably a small amount of residual osmate was present
in the crude diol and was responsible for the color change. The
work-up conditions may be modified to include a bisulfite wash
and/or a plug filtration to move any baseline impurities. If the
darkening cannot be eliminated, the crude diol (Compound 2) may be
taken directly on to the tri-ester (Compound 3) and purified at the
acid stage of Compound 4.
[0089] The crude oil was purified by column chromatography to
identify the diol (Compound 2). This compound did not ionize with
electrospray LC/MS. The proton NMR confirmed the desired product,
Compound 2, had been prepared.
Example 2
Compositions Containing Compounds of the Present Invention
[0090] Compositions containing carboxylic acid-substituted
idebenone derivatives of the present invention should preferably be
free of sensitizing agents (e.g., paraben). Suitable compositions
according to the present invention may be prepared with various
ingredients, as described below. The "CA-Sub Idebenone Derivative"
referenced in each composition in this example refers to a
carboxylic acid-substituted idebenone derivative of the present
invention, such as idebenone dipalmitoyl glycerate.
Facial Cleanser of the Present Invention Containing:
[0091] Aqua, Sodium Lauroyl Oat Amino-Acids, Sodium C12-16 Olefin
Sulfonate, Cocamidopropylamine Oxide, Sodium Lactate, PEG-6
Caprylic/Capric Glycerides, Sucrose Polysoyate, PEG-6 Lauramide,
Lactic Acid, CI 77891, Glycerin, Glycol Palmitate, Cetearyl
Alcohol, Ceteareth-33, CA-Sub Idebenone Derivative, Salicylic Acid,
Caprylic/Capric Triglyceride, Coco-Glucoside, Coconut Alcohol,
Cucumis Sativus Fruit Extract, PEG-120 Methyl Glucose Dioleate,
Hydroxyethylcellulose, Aluminum Hydroxide, Stearic Acid, Xanthan
Gum, Citric Acid, Disodium EDTA, and Phenoxyethanol.
Eye Serum of the Present Invention Containing:
[0092] Aqua, Sodium Lactate, Isopropyl Lauroyl Sarcosinate, PPG-3
Benzyl Ether Myristate, Algae Extract, CI-77891, Glycerin,
Palmitoyl Tripeptide-3, Glycerine, Lactic Acid, Decene/Butene
Copolymer, Caffeine, CA-Sub Idebenone Derivative, Retinol, Chondrus
Crispus, Phenyl Trimethicone, Cyclopentasiloxane, Phospholipids,
Dimethiconol, Xanthan Gum, Glucose, Aluminum Hydroxide, Hydrated
Silica, Alginic Acid, CI-77489, Silica, Sodium Polyacrylate, PVM/MA
Copolymer, Cetearyl Olivate, Sorbitan Olivate, C20-22 Alkyl
Phosphate, C20-22 Alcohols, Polysorbate 20, Acrylamide/Sodium
Acryloyldimethyl Taurate Copolymer, Isohexadecane, Polysorbate 80,
Hydroxyethylcellulose, Triethanolamine, Disodium EDTA, and
Phenoxyethanol.
Moisturizing Facial Cream of the Present Invention Containing:
[0093] Aqua, Sodium Lactate, Caprylic/Capric Triglyceride,
Bis-Hydroxyethoxypropyl Dimethicone, Glycerin, Isopropyl Lauroyl
Sarcosinate, Lactic Acid, Cetearyl Glucoside, Glycine Soja Protein,
Oxido Reductases, CA-Sub Idebenone Derivative, Retinol, Sodium
Hyaluronate, Sodium PCA, Urea, Trehalose, Chondrus Crispus,
Glucose, Isohexadecane, Polyquaternium-51, Sodium Polyacrylate,
PVM/MA Copolymer, Xanthan Gum, Cetearyl Olivate, Sorbitan Olivate,
Glyceryl Stearate, PEG-100 Stearate, Polysorbate 20,
Acrylamide/Sodium Acryloyldimethyl Taurate Copolymer, Polysorbate
80, Hydroxyethylcellulose, Magnesium Aluminum Silicate,
Steareth-100, CI-77891, Hydrogenated Glyceridic Oil, Disodium EDTA,
and Phenoxyethanol.
Treatment Peel of the Present Invention Containing:
[0094] Lactic Acid, Aqua, SD Alcohol 40-B, Ammonium Lactate,
Salicylic Acid, CA-Sub Idebenone Derivative, and
Hydroxyethylcellulose.
Alternative Composition (e.g., Cream) of the Present Invention
Containing:
[0095] Aqua, Glycerin, Cetyl Ricinoleate, Isohexadecane, Ceresin,
Glyceryl Stearate, Isopropyl Lauroyl Sarcosinate, Sericin,
Dimethicone, PEG-60 Hydrogenated Castor Oil, Stearath-2, Sodium
PCA, PEG-100 Stearate, CI-77891, CA-Sub Idebenone Derivative,
Cholesterol, Ceramide III, Linoleic Acid, Linolenic Acid,
Tocopherol, Panicum Miliaceum Extract, Glycosaminoglycans, BHT,
Propylene Glycol, Styrene Acrylates Copolymer, Hydrolyzed Corn
Starch, Ammonium Hydroxide, PEG-30 Dipolyhydroxystearate, Cetyl
Hydroxyethylcellulose, Xanthan Gum, Magnesium Aluminum Silicate,
Disodium EDTA, and Phenoxyethanol.
Alternative Composition (e.g., Cream) of the Present Invention
Containing:
[0096] Aqua, Sodium Lactate, Glycerin, Sucrose Cocoate, Lactic
Acid, Isohexadecane, Isopropyl Lauroyl Sarcosinate, Glyceryl
Stearate, PEG-100 Stearate, Sorbitan Stearate, Steareth-2,
CI-77891, Magnesium Aluminum Silicate, PEG-60 Hydrogenated Castor
Oil, Butylene Glycol, Methyl Dihydroxybenzoate, CA-Sub Idebenone
Derivative, Retinol, Tocopherol, Glycyrrhiza Glabra Root Extract,
Moms Alba Leaf Extract, Camellia Oleifera Leaf Extract, Vitis
Vinifera Extract, Magnesium Ascorbyl Phosphate, BHT, Bisabolol,
Allantoin Glycyrrhetinic Acid, Dimethicone, Polysorbate 20, PEG-30
Dipolyhydroxystearate, Xanthan Gum, Cetyl Hydroxyethylcellulose,
Disodium EDTA, Propylene Glycol, Styrene Acrylates Copolymer,
Hydrolyzed Corn Starch, Ammonium Hydroxide, and Phenoxyethanol.
Sun Protector of the Present Invention Containing:
[0097] Zinc Oxide, Octinoxate, Oxybenzone, Octisalate, Aqua,
Dicaprylyl Carbonate, PEG-20 Stearate, CA-Sub Idebenone Derivative,
Pentylene Glycol, Glyceryl Stearate, Laureth-23, Silica,
Bis-Hydroxyethoxypropyl Dimethicone, Cetearyl Alcohol,
Coco-Glucoside, Butyrospermum Parkii Extract, Phospholipids,
Cyclopentasiloxane, Cyclohexasiloxane, Butylene Glycol,
Caprylic/Capric Triglyceride, Ascorbyl Tetraisopalmitate,
Tocopherol, Carbomer, Sodium DNA, Cetyl Hydroxyethylcellulose,
Potassium Cetyl Phosphate, Hydrogenated Palm Glycerides,
Dimethoxydiphenylsilane/Triethoxycaprylylsilane Crosspolymer,
Xanthan Gum, Disodium EDTA, Diazolidinyl Urea, and Iodopropynyl
Butylcarbamate.
Environmental Protector of the Present Invention Containing:
[0098] Aqua, Glycerin, Dipropylene Glycol, Glyceryl Stearate,
PEG-100 Stearate, Stearyl Alcohol, Ceteareth-20, CA-Sub Idebenone
Derivative, Superoxide Dismutase, Cetyl Hydroxyethylcellulose,
Xanthan Gum, Disodium EDTA, and Phenoxyethanol.
Prophetic Composition (e.g., Body Cream) of the Present Invention
Containing at Least:
[0099] CA-Sub Idebenone Derivative, Resveratrol, Xanthin (e.g.,
Caffeine), AHA (Lactic Acid), and Stimulators of Collagen Synthesis
(as, e.g., Vitamin C and derivatives thereof).
Example 3
Maximization Test of Idebenone Dipalmitoyl Glycerate
[0100] A study was performed to evaluate the contact-sensitizing
potential of a topical Facial Cream containing idebenone
dipalmitoyl glycerate (Vehicle+1% idebenone dipalmitoyl glycerate)
using the Maximization Test. The test was a repeat insult patch
test wherein the test material was applied under an occlusive
dressing to the upper outer arm, volar forearm or back repeatedly
to the same site for five 48-hour induction periods, followed 10-14
days later by a single challenge to a naive skin site. The test
sample was coded Cream A and tested as supplied viz. neat. All test
materials were stored under ambient conditions in an inaccessible
location under the supervision of the investigator.
[0101] The test subjects were all healthy, adult volunteers over
the age of 18 years. None of the subjects had a medical or
dermatological illness and none were sensitive to sunlight or to
topical preparations and/or cosmetics. The criteria for exclusion
were: history of sun hypersensitivity and photosensitive
dermatoses; history of allergy or hypersensitivity to cosmetics,
toiletries or other dermatological products; history of recurrent
dermatological diseases, e.g., psoriasis, atopic eczema; pregnancy
or mothers who were breastfeeding; scars, moles or other blemishes
over the upper arm(s), volar forearm(s) or back which could have
interfered with the study; history of recurrent urticaria or hives;
subjects who were receiving systemic or topical drugs or
medications which could interfere with delayed immunologic
responses e.g., corticosteroids; history of allergies to the test
product or components in the test product; other conditions
considered by the investigator as sound reasons for
disqualification from enrollment into the study.
[0102] The patch was applied to the upper outer arm, volar forearm
or the back of each subject. The entire test was composed of two
distinct phases: an Induction phase and a Challenge phase.
[0103] Induction Phase:
[0104] Approximately 0.05 ml of aqueous SLS (0.25%) was applied to
a designated site under a 15 mm disc of Webril cotton cloth and the
patch was fastened to the skin with occlusive tape for a period of
24 hours. After 24 hours, the SLS patch was removed and 0.05 ml of
the test material was applied to the same site before the site was
again covered with occlusive tape (induction patch). The induction
patch was left in place for 48 hours (or for 72 hours when placed
over a weekend) after which it was removed and the site again
examined for irritation. If no irritation was present, a 0.25%
aqueous SLS patch was again reapplied to the same site for 24
hours, followed by reapplication of a fresh induction patch with
the test material to the same site. This sequence viz. 24 hour SLS
pre-treatment followed by 48 hours of test material application was
continued for a total of 5 induction exposures. If irritation
developed at any time-point during the induction phase as
previously outlined, the 24-hour SLS pre-treatment patch was
eliminated and only the test material was reapplied to the same
site after a 24-hour rest period during which no patch was applied.
The aim during this phase of the study was to maintain at least a
minimal degree of irritation in order to enhance penetration
through the corneum barrier.
[0105] Challenge Phase:
[0106] After a ten day rest period which follows the last induction
patch application, the subjects were challenged with a single
application of the test material to a new skin site on the opposite
arm, forearm or side of back in order to determine if sensitization
had developed. Pre-treatment with SLS was performed prior to
challenge. Approximately 0.05 ml of a 5.0% aqueous solution was
applied to a fresh skin site under a 15 mm disc of Webril cotton
and covered with occlusive tape. The SLS patch was left in place
for one hour. It was then removed and the test material was applied
to the same site. The challenge patch was then covered by occlusive
tape and left in place for 48 hours. After that period, the patch
was removed and the site graded 15-30 minutes later and again 24
hours later for any reaction.
[0107] Scoring Scale:
[0108] 0=not sensitized
[0109] 1=mild sensitization (viz. erythema and a little edema)
[0110] 2=moderate sensitization (erythema with infiltration,
raised, spreading beyond the borders of the patch, with or without
vesiculation)
[0111] 3=strong sensitization (large vesiculo-bullous
reaction).
[0112] Based on these findings, the number of subjects with
positive responses were tabulated for the test material. The test
system shown in Table I was used to classify the allergenic
potential of the test substance.
TABLE-US-00001 TABLE I Sensitization Rate Grade Classification
0-2/25 1 Weak 3-7/25 2 Mild 8-13/25 3 Moderate 14-20/25 4 Strong
21-25/25 5 Extreme
[0113] A total of 27 healthy, adult volunteers of both sexes who
satisfied the inclusion criteria were enrolled into this study.
There were 21 females and 6 males. Their ages ranged from 21 to 65
years. All 27 subjects completed the study. No adverse or
unexpected reactions were seen in any of the panelists during the
induction phase.
[0114] Results:
[0115] No instances of contact allergy were recorded in any of the
27 subjects at either 48 or 72 hours after the application of the
challenge patches. A successful compound is considered to be a
compound that elicits no reaction or response from a subject.
[0116] Conclusion:
[0117] Cream A containing idebenone dipalmitoyl glycerate does not
possess a detectable contact-sensitizing potential and hence is not
likely to cause contact sensitivity reactions under normal use
conditions.
[0118] Further, idebenone dipalmitoyl glycerate is representative
of the full genus of carboxylic acid-substituted idebenone
derivatives encompassed by general Formula I, any one of which (and
particularly those containing di-, tri-, or poly-fatty acid chains)
would be expected to exhibit analogous efficacy and skin tolerance
due, e.g., to their high molecular weight. For instance, idebenone
dimyristoyl glycerate, idebenone dioleyl glycerate, idebenone
dilinoleyl glycerate, idebenone dieicosapentaenyl glycerate,
idebenone dierucyl glycerate, idebenone trimyristoyl
trihydroxypropanoate, idebenone trioleyl trihydroxypropanoate,
idebenone trilinoleyl trihydroxypropanoate, idebenone
trieicosapentaenyl trihydroxypropanoate, and idebenone trierucyl
trihydroxypropanoate would all be expected to be highly effective
in treating skin changes and providing the added benefits of
reduced skin irriation, reduced inflammation, increased skin
permeability, increased cell permeability, and slow release
therapy. A key structural feature common to all carboxylic
acid-substituted idebenone derivatives of Formula I is the presence
of two or more carboxylic acids (particularly di-, tri-, or
poly-fatty acids) that render the compound more soluble across the
stratum corneum lipid bi-layers of the skin, enhance delivery of
the active ingredient by enhancing permeability of cell membranes,
and provide a slow release therapy as the compound hydrolyzes in
the skin.
Example 4
Clinical Evaluation of Idebenone Dipalmitoyl Glycerate
[0119] A six-week double-blind clinical evaluation was performed,
comparing a control vehicle to idebenone dipalmitoyl glycerate for
the treatment of red and brown pigmented skin. Approximately 36
women, ages 40-70 with moderate hyperpigmentation and reddening of
the skin were selected to participate in the study. Subjects were
randomly assigned to one of three groups. Group I received a
product with no idebenone active ingredient (vehicle), Group II
received the same vehicle with 0.5% Idebenone (Hydroxydecyl
Ubiquinone) added, and Group III received the same vehicle with
0.5% of Idebenone Dipalmitoyl Glycerate added. Subjects were
instructed to apply the product twice a day (morning and evening)
to the facial area for 6 weeks. Canfield VISIA-CR RBX images were
made at baseline and after 6 weeks use and analyzed. Digital and UV
photographs were also taken, standardizing distance and positioning
of the subjects, pre and post product application.
[0120] Based on the expert grading and review of the Canfield
VISIA-CR RBX images, 27%, 58%, and 58% of the subjects responded
with less redness in Group I, Group II, and Group III,
respectively. Similarly, 18%, 67%, 75% of the subjects responded
with a decrease in brown pigmentation in Group I, Group II, and
Group III, respectively. Thus, idebenone dipalmitoyl glycerate
achieved an overall improved effect as compared to underivatized
idebenone or underivatized idebenone substituted with a
monocarboxylic acid.
[0121] Idebenone dipalmitoyl glycerate, tested in Examples 3 and 4,
is representative of the full scope of carboxylic acid-substituted
idebenone derivatives encompassed by general Formula I. Analogous
results, particularly with respect to efficacy and skin tolerance
(e.g., not causing contact sensitivity in skin), would be expected
if other compounds of Formula I were tested using the same form
(i.e., a cream) or a different form (e.g., a lotion or ointment) as
that described in Examples 3 and 4.
Example 5
Comparative Clinical Sensitization Testing
[0122] Clinical sensitization testing was performed on two
idebenone esters having relatively low molecular weights (as
compared to the compounds of the present invention)--idebenone
linoleate ester and idebenone phosphate ester, the structures of
which are shown below:
##STR00007##
[0123] The same testing protocol described in Example 3 was used in
the comparative clinical sensitization tests in this example, but
on different panels of subjects.
[0124] In the idebenone linoleate ester test (Vehicle+1% idebenone
linoleate ester), 25 healthy, adult volunteers of both sexes who
satisfied the inclusion criteria were enrolled in the study. All of
the subjects completed this study. Results: One subject exhibited a
positive reaction--i.e., a recordable level of skin sensitization.
Sensitization in even one subject constitutes a failure. Hence,
compositions containing idebenone linoleate ester do not possess
the added benefits of reduced skin irriation and reduced
inflammation, as found in the carboxylic acid-substituted idebenone
derivatives of the present invention.
[0125] In the idebenone phosphate ester test (Vehicle+1% idebenone
phosphate ester), 29 healthy, adult volunteers of both sexes who
satisfied the inclusion criteria were enrolled in the study. There
were 23 females and 6 males, ranging in age from 19 to 65 years.
All of the subjects completed this study. Results: Four subjects
exhibited positive reactions i.e., a recordable level of skin
sensitization. Since sensitization in even one subject constitutes
a failure, compositions containing idebenone phosphate ester do not
possess the added benefits of reduced skin irriation and reduced
inflammation, as found in the carboxylic acid-substituted idebenone
derivatives of the present invention.
[0126] Conclusion:
[0127] The foregoing examples show that the carboxylic
acid-substituted idebenone derivatives of the present invention are
surprisingly effective compounds for treating skin changes with
increased skin tolerance. In particular, these examples and data
show that these carboxylic acid-substituted idebenone derivatives
have beneficial antioxidant properties and exhibit the particularly
advantageous property of increased skin tolerance.
[0128] All publications, patents, articles, and other references
cited and/or discussed in this specification are incorporated
herein by reference in their entirety and to the same extent as if
each reference was individually incorporated by reference.
* * * * *