U.S. patent application number 11/525288 was filed with the patent office on 2007-03-22 for topical macqui berry formulation.
This patent application is currently assigned to Tracie Martyn International, LLC. Invention is credited to Marius Morariu.
Application Number | 20070065396 11/525288 |
Document ID | / |
Family ID | 37884391 |
Filed Date | 2007-03-22 |
United States Patent
Application |
20070065396 |
Kind Code |
A1 |
Morariu; Marius |
March 22, 2007 |
Topical macqui berry formulation
Abstract
The present invention provides a topical formulation and method
of use where the formulation comprises macqui berry or a macqui
berry extract containing anthocyanins having a very high oxygen
radical absorbance capacity (ORAC). The formulation provides the
macqui berry in a stabilized form which includes a glucuronide or
glycuronide, a photostabilizing agent, encapsulation, or light
-and/or air-blocking packaging.
Inventors: |
Morariu; Marius; (Brooklyn,
NY) |
Correspondence
Address: |
DARBY & DARBY P.C.
P. O. BOX 5257
NEW YORK
NY
10150-5257
US
|
Assignee: |
Tracie Martyn International,
LLC
|
Family ID: |
37884391 |
Appl. No.: |
11/525288 |
Filed: |
September 21, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60719530 |
Sep 21, 2005 |
|
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Current U.S.
Class: |
424/74 ;
424/777 |
Current CPC
Class: |
A61K 8/46 20130101; A23V
2002/00 20130101; A61K 9/0053 20130101; A61K 8/9794 20170801; A61Q
1/02 20130101; A61K 8/11 20130101; A61Q 19/00 20130101; A61K
2800/43 20130101; A61K 2800/52 20130101; A61K 8/602 20130101; A61K
36/185 20130101; A61K 2800/26 20130101; A61K 2800/522 20130101;
A61Q 19/08 20130101; A61K 9/127 20130101; A61K 45/06 20130101; A61K
2800/56 20130101; A61K 2800/524 20130101; A61K 8/14 20130101; A61Q
1/00 20130101; A61K 8/9789 20170801; A61K 2800/74 20130101; A61K
8/4913 20130101; A61K 8/44 20130101; A23L 2/52 20130101; C11C 5/002
20130101; A61K 36/185 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/074 ;
424/777 |
International
Class: |
A61K 36/185 20060101
A61K036/185; A61K 8/97 20060101 A61K008/97 |
Claims
1. A topical formulation comprising: macqui berry, a macqui berry
extract or a dermatologically acceptable salt thereof containing an
effective amount of one or more antioxidants, and a stabilizer.
2. The formulation of claim 1, wherein the stabilizer is a
glucuronide, a glycuronide, diethylhexyl syringylidene malonate, a
microencapsulation agent, or a light and/or air-blocking
packaging.
3. The formulation of claim 2, wherein the microencapsulation agent
is a liposome or a nanosome.
4. The formulation of claim 2, wherein the microencapsulation agent
is a biodegradable substance.
5. The formulation of claim 2, wherein the light-blocking packaging
blocks light between 450 nm and 750 nm.
6. The formulation claim 1, which comprises a macqui berry, macqui
berry extract, in an amount of from about 0.05 to 50% by weight,
based on the total weight of the formulation.
7. The formulation claim 6, which comprises a macqui berry, macqui
berry extract, in an amount from about 1.0 to 5.0% by weight, based
on the total weight of the formulation.
8. The formulation claim 1, further comprising an additional
agent.
9. The formulation of claim 9, hwerein the additional agent is an
antioxidant.
10. The formulation of claim 9, wherein the additional antioxidant
is an antioxidant endogenous to the human body.
11. The formulation claim 9, wherein the additional antioxidant is
selected from the group consisting of grape seed procyanidins,
tocopherols, tocotrienols, astaxanthin, lutein, lycopene,
phytofluene, phytoene, rubixanthin, beta-cryptoxanthin, zeaxanthin,
tumeric extract, bilberry anthocyanins, betacyanins, a purified
single anthocyanin or combination of selected purified individual
anthocyanins, black raspberry extract, blueberry anthocyanins, acai
extract, aronia extract, prune extract, pomegranate extract,
ellagic acid, honokiol, magnolol, silymarin, quercetin, naringenin,
rosmarinic acid, rosemary extract, saffron extract, clove essential
oil, wolfberry extract, noni fruit extract, phyllantus emblica
extract, camellia sinensis extract, epicatechin-gallate, Garcinia
mangostana extract, shikimic acid, montmorency cherry extract,
anthocyanin-containing extracts of red, blue, magenta, purple or
black flowers, whole coffee fruit extract, chlorogenic acid,
caffeic acid, ferulic acid, olive extract, and hydroxytyrosol.
12. The formulation of claim 11, wherein the formulation comprises
a metal chelating agent.
13. The formulation of claim 9, wherein the antioxidant is
formulated in a ratio with the macqui berry or macqui berry extract
wherein the ORAC value is optimized.
14. The formulation claim 9, wherein the additional antioxidant is
a betacyanin.
15. The formulation claim 1, further comprising an AGE inhibitor, a
collagen enhancing agent, a mitochondrial resuscitant, a sunscreen
agent, an anti-edemic agent, a glutathione or an inducers thereof,
a collagenase-inhibitor, an anti-inflammatory agent, a
phenylpropanoid glycoside, a depigmenting agent or agent addressing
hyperpigmentation, a skin-protective lipids, hyaluronic acid, an
alpha hydroxy acid, an agent useful for treating hormonal decline,
an anti-acne agent, an agent altering lipolytic activity, an
anti-cellulitic agent, an agent altering anti-capillary-fragility,
an anti-elastase agent, an anti-erythema agent, an agent that
raises cyclic AMP, or nicotinamide-adenine-dinucleotide.
16. The formulation claim 1, wherein the macqui berry or macqui
berry extract is formulated in a makeup.
17. The formulation claim 16, wherein the makeup is a foundation, a
cover cream, or an eye shadow.
18. The topical formulation of claim 1, wherein said formulation is
a dye for cosmetic composition.
19. The formulation of claim 9, wherein the antioxidants are
present in the same enantiomeric ratio as found for these
substances in their natural form.
20. A method of treating skin, said method comprising administering
a topical formulation comprising: macqui berry, a macqui berry
extract or a dermatologically acceptable salt thereof containing an
effective amount of one or more antioxidants, and a stabilizer.
21. The method of claim 20, wherein the stabilizer is a
glucuronide, a glycuronide, a diethylhexyl syringylidene malonate,
a microencapsulation agent, or a light and/or air-blocking
packaging.
22. The method of claim 21, wherein the microencapsulation agent is
a liposome or a nanosome.
23. The method of claim 21, wherein the light-blocking packaging
blocks light between 450 nm and 750 nm.
24. The method of claim 20, further comprising orally administering
macqui berry or macqui berry extract, wherein the oral macqui berry
or macqui berry extract is administered alone or with one or more
additional antioxidants or nutrients.
25. The method of claim 20, wherein the formulation is administered
in a makeup.
26. A formulation comprising: macqui berry, a macqui berry extract
or salt thereof containing an effective amount of one or more
antioxidants, and a stabilizer, wherein the formulation is
formulated for use in a beverage or in a candle.
Description
[0001] This application claims priority pursuant to 35 U.S.C.
.sctn.119 from Provisional Patent Application Ser. No. 60/719,530
filed Sep. 21, 2005, the entire disclosure of which is hereby
incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to the topical application of
compositions containing macqui berry or macqui berry extract in a
topical formulation for the prevention and/or treatment of damage
to skin, particularly skin damage resulting from chronoaging and
photoaging.
BACKGROUND OF THE INVENTION
[0003] Skin is subject to abuse by many extrinsic (environmental)
factors as well as intrinsic factors. A common extrinsic factor is
exposure to ultraviolet radiation. Whether extrinsic or intrinsic,
the abuse results in skin aging. Skin aging happens in two ways:
(1) through the natural aging process which dermatologists call
chronological aging (also known as chronoaging); and (2) through UV
rays in sunlight accelerating the aging process which
dermatologists call photoaging. Chronoaging results in thinning,
loss of elasticity and general degradation of skin. As the skin
naturally ages, there is a reduction in the cells and blood vessels
that supply the skin. There is also a flattening of the
dermal-epidermal junction which results in weaker mechanical
resistance. As a consequence, older persons are more susceptive to
blister formation in cases of mechanical traumas or disease
processes (Oikarinen et al., Photodermatal. Photoimmunol.
Photomed., 7:3-4 (1990)).
[0004] By contrast, photoaging, or premature aging, is a process in
which the skin changes in appearance as a result of repeated
exposure to sunlight. Typically, photoaging occurs in areas of
habitual exposure, such as the scalp, face, ears, neck, chest,
forearms and hands. The changes associated with photoaging include
elastosis, atrophy, wrinkling, vascular changes (diffuse erythema,
ecchymoses, and telangiectasias), pigmentary changes (lentigines,
freckles, and areas of hypo- and hyper-pigmentation), and the
development of seborrheic keratosis, actinic keratosis, comedones
and cysts.
[0005] Antioxidants are useful agents treating the skin from damage
caused by chronoaging and photoaging. The most useful antioxidants
are those that provide the highest capacity to absorb free
radicals. The oxygen radical absorbance capacity (ORAC) is a
measurement of this (Dreher F, Maibach H. Curr Probl Dermatol.
2001;29:157-64.) Anthocyanins are a type of antioxidants that
generally encompass a class of flavonoid compounds that are
naturally occurring, water-soluble compounds, responsible for the
red, purple, and blue colors of many fruits, vegetables, cereal
grains, and flowers. Most anthocyanins have a high ORAC rating
compared to other antioxidants and make them particularly useful
for their topical antioxidative properties. Additionally,
anthocyanins are collagenase inhibitors, which helps in the
prevention and reduction of wrinkles, increase in skin elasticity,
etc., which are caused by a reduction in skin collagen.
[0006] For ripe berries, a rich source of anthocyanin antioxidants,
there is generally a linear relationship between ORAC values and
anthocyanin content. High ORAC ratings are generally defined as
greater than 25 .mu.mole of Trolox equivalents (TE)/g. In most
fruits, ORAC values ranged from 7.8 to 33.7 .mu.mole TE/g of fresh
berries and the ORAC values of the leaves range from 69.7 to 182.2
.mu.mole TE/g (Wang S Y, Lin H S., J Agric Food Chem. 2000
February;48(2):140-6.). Comparatively, a fruit with an ORAC value
of 8 .mu.mol TE/g of fresh berries will have an ORAC value of about
35 .mu.mol TE/g of dried berries and an ORAC of 34 .mu.mol TE/g of
fresh berries corresponds with an ORAC of 162 .mu.mol TE/g dried
matter. Black raspberries have a very high ORAC of 77 .mu.mole TE/g
while boysenberries have an ORAC of 48 .mu.mole TE/g, and red
raspberries and blueberries have an ORAC of 24 and 23 .mu.mole
TE/g, respectively. (http://www.deckerfarm.com/antioxidants.html).
Acai is another fruit having a high ORAC content(167 ORAC units/g
according to Brunswick Laboratories). Other fruit having high ORAC
values include pomegranate (33.1 .mu.mole TE/g) and aronia berry
(62 .mu.mole TE/g) as well as whole coffee fruit extract (6250 ORAC
units per gram according to Brunswick Laboratories). The stage at
which the plant is harvested affects the ORAC value. Blackberries
have their highest ORAC values during the green stages, whereas red
raspberries have their highest ORAC values when ripe. The ORAC may
be obtained by using the method described by the U.S. Department of
Agriculture's Agricultural Research Service (Prior and Cao, 83(4)
J. AOAC INT. 950-6 (2000)). Additionally, testing for ORAC, H-ORAC,
N-ORAC, S-ORAC, and ORAC-E (high throughput ORAC for oil-in-water
emulsion) is available from Brunswick Laboratories
(www.brunswicklabs.com).
[0007] Anthocyanins have been formulated in topical form. For
example, U.S. Pat. Pub. 2004/0022818 provides a skin care
composition comprising fruit particles. Red and blue fruits, as
well as other fruits which contain anthocyanins are included in
this composition. Similarly, U.S. Pub. 2003/0161897 and U.S. Pat.
No. 6,361,786 providc a topIcal antimicrobial factor having fruit
juice (cranberry, Aronia berry, blackberry, grape or blueberry) and
polyvinylprolidinone. A topical oil-in-water emulsion containing a
surfactant/emulsifier and a lipid, which may be an
anthocyanin-containing berry extract, is provided by WO 98/05294.
U.S. Pat. No. 5,011,855 provides a cosmetic composition having
a-linolenic acid and an oil extracted from Ribes genus fruits.
[0008] However, there are problems associated with these and other
uses of antioxidants in a topical formulation. Particularly,
antioxidants are readily oxidized and lose their anti-oxidant
capacity. Additionally, some of the oxidation products of
antioxidants will have a deleterious effect; for example, vitamin C
oxidizes to dehydroascorbate which is known to lead to the
formation of advanced glycation endproducts (AGEs) and therefore
increase the signs of aging skin.
[0009] Therefore, a topical formulation containing an antioxidant
with a much higher ORAC and consequently greater anti-oxidant power
is needed in combination with a formulation that protects the
antioxidant from degradation and loss of the anti-oxidative power
to be used in treating and protecting the skin.
SUMMARY OF THE INVENTION
[0010] It is an object of the present invention to provide a
composition and method for treating and protecting the skin.
[0011] In accordance therewith, a method and composition is
provided for treating skin, comprising a topical composition
containing macqui berry in a stabilized form and the administration
of an effective amount of the topical composition to the skin.
[0012] In a preferred embodiment, the stabilized form of macqui
berry includes a macqui berry or macqui berry extract and a
glucuronide or glycuronide, or a dermatologically acceptable salt
thereof.
[0013] In another embodiment, the stabilized form of macqui berry
includes a macqui berry or macqui berry extract or a
dermatologically acceptable salt thereof, which has been
encapsulated or placed in light-blocking packaging.
[0014] Additional agents such as NADH, an antioxidant, an AGE
inhibitor, a collagen enhancing agent, a mitochondrial resuscitant,
a light reflecting agent or a sunscreen, an anti-edemic agent, a
glutathione or an inducer thereof, an anti-inflammatory agent, a
phenylpropanoid glycoside, a depigmenting agent or agent addressing
hyperpigmentation, a skin-protective lipid, hyaluronic acid, an
alpha hydroxy acid, an agent useful for treating hormonal decline,
an anti-acne agent, an agent altering lipolytic activity, an
anti-cellulitic agent, an agent altering anti-capillary-fragility,
an anti-elastase agent. an anti-erythema agent; or an agent that
raises cyclic AMP may additionally be incorporated into the macqui
berry composition.
[0015] In one embodiment, in addition to the administration of
topical composition containing macqui berry in a stabilized form to
the skin, macqui berry is also orally administered on its own or
together with other antioxidants and synergistic compounds
disclosed herein that are suitable for oral administration. This
increases the protective effect on the skin.
[0016] In yet another embodiment of the present invention, the
stabilized form of macqui berry is used in a cosmetic. Since the
macqui berry formulation is a natural dye as well as an
antioxidant, the formulation provides both color and antioxidation
activity to the cosmetic.
[0017] Other features, advantages, and embodiments of the invention
will be apparent to those skilled in the art from the following
description and appended claims.
DETAILED DESCRIPTION
[0018] The present invention provides a formulation and method of
use for treating skin and reducing the signs of aging. This
formulation comprises macqui berry or an extract of macqui berry in
a stabilized formulation.
I. Macqui Berry
[0019] Macqui berry (Aristotelia Chilensis) comes from a berry
plant indigenous to Chile and Argentina. The anthocyanin content in
the macqui berry is high. The juice has a total anthocyanin content
of 203 mg anthocyanin per 100 ml juice. The ORAC of macqui berry
206 .mu.mol TE/g (Cao, G, Prior, L. Agricultural Research, November
1996, p. 4-8 Brunswich Labs (2003)). This can be compared to other
anthocyanin-containing fruit with high or moderately high ORAC
values, as shown in Table 1. TABLE-US-00001 ORAC value Fruit
(.mu.mole TE/g) macqui berry 206 black raspberry 77 aronia berry 62
boysenberry 48 pomegranate 33 red raspbererry 24 blueberry 23
[0020] The macqui berry is particularly advantageous when used as a
whole berry or partially purified extract. The berry or extract may
be used as a liquid or juice, pulp, or in solid, dried form. Other
compounds within the macqui berry are also advantageous for use in
the topical formulation of the present mvention Macnuii berry
contains a number of anthocyanins including:
delfinidin-3-glucoarabinoside-5-glucoside; delfinidin
3,5-diglucoside; cyanidine-3-glucoarabinoside-5-glucoside;
cyanidine-3,5-diglucoside; delfinidin-3-glucoarabinoside;
delfinidin-5-glucoarabinoside; delfinidin-3-glucoside;
cyaniding-3-glucoarabinoside; and cyaniding-3-glucoside.
[0021] The macqui berry used in the present invention may also
contain only the fruit or the fruit in combination with other parts
of the plant, such as the leaves. Additional useful ingredients in
the macqui include quercetin in the fruit and alkaloids in the
leaves. These alkaloids are mostly indolic in nature and have
anti-tumoral and antimicrobial activities; they include makonin,
aristotelinone, aristoteline, aristotelone, aristotelinine,
aristone, and others. Other agents found in the fruit include
n-nonacosane, .beta.-sitoesterol, antraquinone, and several
triterpenes. The content of the macqui berry has been described by
"Patagonal.RTM. Natural Antioxidants" BDS Nutraceuticals and DKSH
Market Intelligence product brochure; Cesped, C. et al.,
Phytochemistry (1993) 34(3) 881-2; Cesped, C., et al,
Phytochemistry, (1990) 29(4)1354-5; Munoz, O. et al, (2001)
Medicinal plants in Chile: Chemistry and Pharmacognosis Editorial
Universitaria University of Chile 330; and Miranda-Rottmnann. E.,
et al., (2002) J. Agricul. Food Chem. 50, 7542-7. However, these
references do not provide a topical formulation that can be used
for the prevention and/or treatment of damaged skin.
[0022] Quercetin, found in the fruit of the macqui berry, is a
phenolic antioxidant. The pharmacological actions of phenolic
antioxidants are primarily due to free radical scavenging and metal
chelating properties. They also affect cell signaling pathways and
gene expression. The ORAC activity order flavonol aglycones
decreases in the order quercetin, myricetin and kaempferol
(Soobrattee, M A, et al., Mutat Res. 2005 Aug. 25). Quercetin has
been used topically for the treatment of symptomatic diabetic
peripheral neuropathy due to oxidative stress (Valensi P, J
Diabetes Complications. 2005 September-October; 19(5):247-53.)
Therefore, the presence of this ingredient in the berry is
beneficial for the topical formulation.
[0023] Alkaloids, including makonin, aristotelinone, aristoteline,
aristotelone, aristotelinine, aristone, have antimicrobial
properties and therefore can be used in a topical preparation
against acne vulgaris or to reduce the amount of preservatives
needed in the topical formulation. Their anti-tumor effect may
prove beneficial in preventing damage to skin from environmental
tumor-inducing pollutants.
[0024] N-nonacosane is an anti-mutagenic. This is an important
function in skincare as skin is exposed to pollutants and UV
radiation on a daily basis that enhance the occurrence of mutation
in the cells. Therefore, the combination of the anthocyanins and
n-nonasosane in the formulation of the present invention are
particularly advantageous in a topical formulation.
[0025] .beta.-sitosterol is anti-inflammatory (Lawrence Review of
Natural Products, 1995) anti-bacterial (Internat. J. Crude Drug
Res. 28(1,2,3,4): 1990, page 155), anti-androgenic (Malini, T. and
Vanithakumari, G. 1989, Journal of Ethnopharmacology, 28: 221-234,
1990), and an antioxidant, making it a valuable ingredient for
topical formulations for skin damage from aging, acne or
rosacea.
[0026] Antraquinone, and it derivatives are known to have
antibacterial properties. (Chen CH , Yao Xue Xue Bao 1964;
11(4):258-65). Therefore, the combination of this agent with the
anthocyanins is particularly advantageous due to the disinfectant
properties of the formulation.
[0027] Therefore, the interactions between the different
constituents of the macqui berry make it a novel, potent ingredient
for topical application to address skin aging.
[0028] The macqui berry may be used as a whole fruit, a fruit
juice, or an extract of the fruit with the optional addition of
extract from the leaves or stem of the plant. The extract may be
used in a liquid or solid form.
II. Stabilizer
[0029] Since macqui berry contains antioxidants having a high ORAC
ratio, it is relatively unstable over time, especially when exposed
to light and/or air. Therefore, the present invention provides a
formulation where the antioxidant from the macqui berry is
stabilized. Stabilizing agents include, for example, glucuronide,
glucuronide, microencapsulation, and light- and/or air-blocking
packaging. Other stabilizing agents such as diethylhexyl
syringylidene malonate may be used. In one embodiment of the
present invention, two or more different stabilizers are be
used.
Flavonoid Glucuronides and Glycuronides
[0030] Flavonoid glucuronides and flavonoid glycuronides are added
to the formulation of the current invention as a stabilizer for the
macqui berry. As used herein, the term "flavonoid glucuronide"
encompasses flavonoids that are attached to a glucuronic acid
(e.g., glucose having a carboxylic acid at the C6 position on the
sugar ring); the term also encompasses flavonoid glucosides, which
are flavonoids attached to glucose. Similarly, flavonoid
glycuronides are flavonoids attached to glycuronic acid, and
flavonoid glycosides, which are herein encompassed in the term
flavonoid glycuronides, are flavonoids attached to a glycose.
[0031] Exemplary flavonoid glucuronides include: luteolin
7-glucuronide; luteolin 3'-glucuronide; luteolin 7-diglucuronide;
luteolin 7-glucuronide-3'-ferulyglucoside; apigenin 7-glucuronide;
quercetin 3-(isoferulylglucuronide); 7-sulfatoglucuronides of
tricin and luteolin; 3-glucuronide-7-sulfate of kaempferol,
quercetin, or isorhamnetin; quercetin 3-glucuronide-3'-sulfate;
gossypetin 8-glucuronide-3-sulfate; rhamnetin
3'-glucuronide-3,5,4'-trisulfate; the 7-glucuronide and
8-glucuronide of 5,7,8-trihydroxyflavone (norwogonin),
5,7,2'-trihydroxyflavone 7-glucuronide; apigenin
7-rhamnosyl-(1->2)-galacturonide; apigenin 7-digalacturonide;
apigenin 7-galacturonyl glucoside; apigenin 7-sulfatoglucuronide;
5,6,7,2'-tetrahydroxyflavone 7-glucuronide;
5,7,2'-trihydroxy-8-methoxyflavone 7-glucuronide;
5,7-dihydroxy-8,2'-dimethoxyflavone 7-glucuronide; luteolin
7-galacturonide-4'-glucoside; 8-hydroxyluteolin 4'-methyl ether
8-glucuronide; tricetin 7,3'-diglucuronide; tricetin 3'-methyl
ether 7,5'-diglucuronide; apometzgerin 7-glucuronide; 8
hydroxytricetin 7-glucuronide; kaempferol
3-rhamnoside-7-galacturonide; kaempferol 3-glucoside-7-glucuronide;
eupafolin 3-glucuronide; herbacetin 3-glucuronide-8-glucoside;
quercetin 3-glucoside-7-glucuronide; quercetin
3-gentiobioside-7-glucuronide; quercetin 3-glucuronide-3'-sulfate;
tamarixetin 5-glucoside-7-glucuronide; quercetin 3',4'-dimethyl
ether 5-glucoside-7-glucuronide; gossypetin
3-glucoside-8-glucuronide; and gossypetin
3-glucuronide-8-glucoside.
[0032] Exemplary flavonoid glycuronides include 7-glycuronide
luteolin and 7-glycuronide apigenin.
[0033] A particularly useful flavonoid glucuronide is the
glucuronide derived from rosemary. Rosmarinic acid is a
naturally-occurring flavonoid isolated from various plants, such as
Rosmarinus officinalis (Ricerca Sci. 1958, 28, 2329), Melissa
officinalis (Arch. Pharm. 1960, 293, 1043), and Teucrium scorodonia
(Planta Med. 1965, 13: 3, 331). Rosmarinic acid may be obtained
from these and other plants by extraction, (see U.S. Pat. No.
5,908,650), and also may be obtained from plant cell cultures, such
as Coleus blumei (see Naturwissenschaften 1977, 64:11, 585; See
also Liu, G., et al., Biochem Pharmacol., 1992 43, 147-152.)
[0034] Flavonoid glucuronides and glycuronides have been found to
be useful in stabilizing, (e.g., reducing the rate of loss of
anthocyanin color, intensity, and aromaticity, due to pH, heat,
and/or light) anthocyanin-containing foods and beverages. See U.S.
Pat. No. 5,908,650. As well as protecting the color of the
anthocyanin and creating a color shift, flavonoid glucuronides and
glycuronides can increase the stability of the macqui berry topical
formulation, and allow for increased antioxidant activity both in
the initial formulation of the topical composition and over time.
This is particularly useful for topical formulations where the
compound will likely sit on a shelf for a period of time before use
in a water-based gel, serum, or oil-in-water emulsion.
[0035] Many of these glucuronides, such as rosmarinic acid, have
antioxidant properties as well as stabilization properties.
Therefore, the use of these glucuronides is advantageous in the
present invention because of the additional antioxidative effective
on the skin and underlying tissue of the composition. Rosmarinic
acid has an IC.sub.50 of 0.74 .mu.M.
[0036] The flavonoid glucuronide or glycuronide is incorporated in
the present composition in an amount effective to protect and
stabilize the anthocyanin. This amount will depend on the amount
and type of anthocyanin in the formulation; therefore, the ratio of
flavonoid glucuronide or glycuronide to the macqui berry
anthocyanins will vary to achieve effective stabilization of the
anthocyanins. It is contemplated that the weight of flavonoid
glucuronide used will be between 0.1% and 500% of the weight of
anthocyanin used in the formulation. Preferably, the weight of
flavonoid glucuronide or glycuronide is between about 0.2%-10% of
the weight of anthocyanins. In a more preferred embodiment, the
weight of flavonoid glucuronide or glycuronide is between about
0.5%-5% of the weight of anthocyanins.
[0037] In one embodiment of the present invention, the stabilizer
is a stabilizer such as those described in U.S. Pat. Pub.
2005/0244349, herein incorporated by reference. These compounds are
taught to be useful for stabilizing photosensitive poly-unsaturated
and/or aromatic compound such as antioxidants against degradation
from sun light, heat and air oxidation. The stabilizers include
dialkylbenzalmalonates, monoalkyl-monoacyl benzalmalonate, dialkyl
benzalmalon-amide and mono-alkyl-monoacyl benzalmalonamide
compounds, and are able to stabilize photo-sensitive ingredients
within the macqui berry formulation of the present invention. In
particular, a preferred stabilizer is diethylhexyl syringylidene
malonate.
Encapsulation
[0038] In one aspect of the present invention, the macqui berry
formulation is stabilized using encapsulation, or more preferably,
microencapsulation. Microencapsulation can protect the anthocyanin
from the oxidative effects of the surrounding environment and
increase the effectiveness as an anti-aging agent. Processes
conventionally used for microencapsulation may be employed, and may
comprise encapsulation by nanosomes, liposomes, or other vehicles
known in the art.
[0039] The microcapsules may be prepared, for example, by
coacervation techniques or by interfacial polymerization, for
example, hydroxymethylcellulose or gelatin-microcapsules and
poly(methylmethacrylate) microcapsules, respectively, in colloidal
drug delivery systems (for example, liposomes, albumin
microspheres, microemulsions, nano-particles and nanocapsules) or
in macroemulsions. (Remington's Pharmaceutical Sciences, A. Osol
ed., 16th ed. (1980)). Microencapsulation is particularly useful
for formulations containing DHLA, which is prone to degradation and
oxidation. In one preferred embodiment, the microencapsulating
agent is biodegradable, such as a carbohydrate, a naturally
occurring polymer, or lecithin.
[0040] One typical process is to dissolve the shell material in a
solvent (in the form of a colloidal or true solution) and to
disperse the core material in the resulting solution in the form of
solids or micro-droplets. This dispersion is divided into
micro-droplets and then heated using, for example, hot air. During
this process, the solvent evaporates and the shell material
re-precipitates in the form of solids and forms a shell around the
core material. This gives crude microcapsules, which can then be
subjected to the customary processing steps and incorporated into
the final formulations. This process utilizes the known phenomenon
of coacervation.
[0041] Another process of microencapsulation uses interface
polymerization to create the microcapsule shell. In this method,
precursors of the shell material, for example monomers, are
concentrated onto the core material, where they polymerize to give
the final shell film. Fat-coating processes also may be used.
[0042] The materials used for microencapsulation are selected from
conventional hydrophilic or hydrophobic substances or mixtures
thereof. Solids, in particular natural polymers, for example,
starch and other polysaccharides, are preferred. However, synthetic
polymers can also be used. Examples of shell materials are fats
and/or waxes, preferably those having a solidification temperature
of approximately 35.degree.-80.degree. C. and include mixtures of
cetyl palmitate and cetyl alcohol. Other compounds include
polysaccharides and their derivatives of natural or partially
synthetic origin, (e.g. cellulose derivatives); further, polymers
of .alpha.- and/or .beta.-hydroxycarboxylic acids, in particular
polymers of glycolic acid (polyglycolides), lactic acid
(polylactides), .alpha.-hydroxybutyric acid (polyhydroxybutyrate),
.alpha.-hydroxyvaleric acid (polyhydroxyvalerate) and/or their
copolymers, or mixtures of such polymers and/or copolymers.
[0043] Independently of the specific technique for preparing the
microcapsules, it is preferred to carry out the process at a
temperature which does not cause any of the components of the
formulation to decompose or lose their antioxidant activity.
[0044] Similarly, nanoencapsulation may be used. Nanoemulsions are
meta-stable oil-in-water emulsions having a globule size is less
than 150 nm. They can be stabilized with amphiphilic lipids.
Nanoemulsions are structurally distinct from microemulsions which
are thermodynamically stable dispersions comprising micelles of at
least one amphiphilic lipid swollen with oil and do not require
mechanical energy to be prepared. An advantage of using
nanoencapsulation is the reduced need for surfactants, which may
tend to lead to intolerance and entailing a sticky feel when
applied to the skin (see 6,562,356).
[0045] In one embodiment, the formulation is encapsulated in
cyclodextrin. Such process is performed, for instance, by Wacker
Fine Chemicals (www.wacker.com).
[0046] In another embodiment, the macqui berry formulation is
encapsulated with NADH, R-DHLA, ATP., Glutathione, and SOD in Nano
Spheres. Such process is perfor .ed, for instancc, by Salvona
Technologies. In another embodiment, biopolymer nanoemulsions from
Ivrea-Pak Tech are used to eliminate undesirable residue
("ghosting") commonly associated with porous particulate entrapment
formulations.
Packaging Material
[0047] The macqui berry formulation may be stabilized by placing
the formulation in a packaging that blocks the radiation that
causes oxidation of the berry components. Preferably, this package
will block light from 450-750 nm, the visible range, which is known
to damage most nutrients. The packaging material will preferably
have less than 1% transmittance, or more particularly less than
0.1% transmittance within the range from 450-750 nm. The packaging
should not contain polyvinyl chloride-containing polymers that
degrade organic molecules to carcinogenic compounds. Dark violet
packaging plastic or glass may be used in a particular embodiment.
(mironglass.com.) The packaging may be additionally air-less and
therefore prevent air from getting in contact with the formulation
once opened. Additionally the packaging may be nitrogen-flushed to
further protect the formulation.
III. Additional Agents
[0048] In addition to the macqui berry, the topical formulation in
many preferred embodiments of this invention contains at least one
or more additional active ingredients. A non-limiting list of such
ingredients is included herein.
Collagen or Elastin Enhancing Agents
[0049] The collagen or elastin enhancing agent may be administered
by applying the agent to the skin. Collagen enhancing agents such
as those described herein may also be added to the present
formulation. This increased collagen synthesis is an important
aspect of the present invention, as it provides additional benefit
to the skin and reduces the effects of aging. Agents having
`collagenic activities` include the anthocyanidins, ascorbic acid,
asiatic acid (such as from centella asiatica), aucubin,
proanthocyanidins, stabilized vitamin C, the amino acids 1-lysine,
1-proline and their derivatives (e.g., dipalmitoyl-hydroxy-proline,
hydroxyproline, homoproline, and natural raw materials containing
these such as apt (Ahnfeltia concinna) available from CIR)), and
copper peptides. Agents having `collagenase-inhibitor activities`
include the anthocyanidins, eicosapentaenoic acid,
proanthocyanidins such as grape seed proanthocyanins, procyanidins,
bovine cartilage extracts, and glycosaminoglycans from shark.
Agents having `collagen-sparing activities` include caffeic acid,
chlorogenic acid, cichoric acid, cynarin, and echinacoside. Each of
these may be used in addition to the ATP enhancement of the present
invention. Alternatively, collagen itself may be added to the
formulation, such as in the form of collagen peptides (e.g. active
collagen polypeptide available from Shanghai UChem Co. LTD.) or in
a form adapted for delivery to the skin so that the collagen will
penetrate into the skin (e.g., the form described in U.S. Pat. No.
6,759,056).
[0050] Other collagen inducing agents are growth factors, such as
EGF, FGF, TGF, TGF-.beta., HGH, NGF, KGF, IGF, HGF natural sources
containing growth factors such as colostrums (Pepha.RTM. Nutrix
from Centerchem), deer antler preparations and peptides designed to
increase the production of any of these growth factors (e.g.,
Syn.RTM.-col from Centerchem- TGF-.beta., Hericium Erinaceus and
Idebenone-NGF), or the production of collagen itself (e.g.,
Matrixyl300, Dermaxyl, and Calmosensine each from Sederma),
collagen peptides and synthetic collagen inducing peptides (e.g.,
pal-kttks). Collagen stimulating agents are those such as TGF-beta,
retinoic acid and retinol derivatives, botanical and other natural
extracts such as Vigna Aconitifolia seed extracts, g-ascorbate and
g-hcl.
[0051] Glucosamine, glucoseamine sulfate, glucosamine HCl,
glucosamine ascorbate, chondroitin sulfate and other glucosamine
salts and derivatives may be used in the formulation to induce
collagen. Manganese gluconate, a common source of manganese, may
also be included in the formulation. The enzyme MnSOD, a powerful
antioxidant that removes superoxide radicals, may also be used.
[0052] In one embodiment, carnosine is added to the formulation to
stimulate collagen formation. Carnosine is degraded by histidine
and carnosinase to form histamine and .beta.-alanine and thereby
stimulates the biosynthesis of nucleic acids and collagen (Nagai, K
et al., Surgery 1986, 100(5); 815-821). Carnosine is able to react
with carbonyl groups on glycated or oxidized proteins (i.e.,
camosinylation) and inhibit the glycoxidised proteins from
cross-linking with normal macromolecules and causing the signs of
aging (Hipkiss A R, et al., Mech Ageing Dev 2001 Sep
15;122(13):1431-45; Hobart et al. Life Sci. 75:1379-89). In one
embodiment, a silicon, or an ortho silica acid described in U.S.
Pat. No. 5,922,360, may be used. This ingredient may be used to
boost collagen production.
[0053] Carnosine, the dipeptide .beta.-alanyl-L-histidine, and its
related compounds such as anserine
(.beta.-alanyl-1-methyl-L-histidine) and homocarnosine
(.gamma.-amino-butyryl-L-histidine) as well as the closely related
compound carcinine(.beta.-alanyl-histamine) are preferred
antioxidants exhibiting strong and specific antioxidant properties
that may be added to the formulation of the present invention.
Carnosine is present in millimolar concentrations in tissues,
including skeletal muscle and brain, and is an anti-glycation agent
and a free radical scavenger as well as an antioxidant. Useful
carnosine include the dipeptide .beta.-alanyl-L-histidine,
D,L-carnosine, D-carnosine, L-carnosine, the derivatives anserine
and homocarnosine, as well as their salts, such as zinc carnosine,
copper camosine, and copper anserine (Hipkiss A R, Chana H, Biochem
Biophys Res Commun. 248(1):28-32, 1998; Hipkiss ARetal., Ann N Y
Acad Sci, 854:37-53, 1998).
[0054] When carnosine is chelated to zinc or copper ions, the
presence of the ions enhances carnosine activity as a superoxide
radical scavenger (Gulyaeva N.Y., Biochemistry 57 (7:2) 1051-4,
1987). Therefore, the addition of carnosine as an agent in the
present invention in chelated form provides for superoxide
scavenger activity as well as the anti-glycation and anti-oxidation
properties of carnosine. Carnosine has been administered at dosages
above 500 mg/kg body weight in animal studies and has been found to
be safe at these levels.
Anti-glycation Agents
[0055] Anti-glycation agents may be used in the present invention
both to protect the ATP enhancing agent and for the anti-glycation
affect that decreases the signs of aging in the skin. The
anti-glycation agent will protect the ATP enhancing agent by
removing free radicals that would inactivate the ATP enhancing
agent or counteract the glycation effect of the ATP enhancing
agent.
[0056] As used herein, the term "anti-glycation agent" means a
compound useful for preventing and/or reducing the glycation of
skin proteins, in particular of dermal proteins such as collagen.
The anti-glycation agent inhibits the formation of advanced
glycation end products (AGEs) and is also known as an AGE
inhibitor.
[0057] Examples of anti-glycation agents are plant extracts of the
Ericaceae family, such as an extract of blueberry (Vaccinium
angustifolium), ergothioneine and its derivatives; and
hydroxystilbenes and their derivatives, such as resveratrol and
3,3',5,5'-tetra-hydroxystilbene. Other exemplary inhibitors of AGE
formation include, but are not limited to, benfotiamine,
pyridoxamine, G-rutin (Nagasawa T., Mol Cell Biochem.
249(1-2):3-10, 2003); pyridoxal phosphate, aminoguanidine, a
aminoguanidine-pyridoxal adduct, green tea (Ouyang P. Di Yi Jun Yi
Da Xue Xue Bao 24(3): 247-51, 2004); extracts of Thymus vulgaris
(Morimitsu et al., Biosci Biotechnol Biochem 59(11):2018-21, 1995);
Ge-132(2-carboxyethyl germanium sequioxide) (Unakar et al., Exp.
Eye Res. 61(2): 155-64, 1995); curcumine (Sajithlal et al., Biochem
Pharmacol. 56(12):1607-14, 1998); extracts of Cratoxylum
cochinchinense (Tang, S Y et al., Free Radic. Biol. Med.
36(12):1575-87, 2004); extracts of Apocynum venetum Luobuma
(Yokozawa et al., Food Chem. Toxicol. 42(6):975-81, 2004);
carnosine; carnosinylated proteins (Hipkiss A R et al., Cell Mol
Life Sci. 57(5):747-53, 2000); extracts of Eugenia bicyclis (Okada
et al., Nat. Prod. 67(1):103-5, 2004); rutin (Kiho, T et al.,
Biosci. Biotechnol. Biochem. 68(1):200-5, 2004); amadoriase enzymes
from Aspergillus fungi (Monnier V M et al., Biochem. Soc. Trans
31:1349-53, 2003; U.S. Pat. No. 6,605,642); guanidine rich extracts
of Galega officinalis; and extracts of lycoperrsicon esculentum.
The AGE inhibitor as described herein may be incorporated in
amounts from about 0.001%-30% by weight. More preferably, the AGE
inhibitor is incorporated in amounts from about 0.1%-5% by weight,
based of the total weight of the preparation.
[0058] One preferred anti-glycation agent is carnosine. Carnosine,
discussed above for its collagen enhancing properties, is also
useful as an anti-glycation agent. Carnosine also promotes wound
healing (Roberts P R, et al., Nutrition 1998;14;266-9), protects
against radiation damage, is potentially a modulator of enzymatic
activities, and has been shown to be a chelator of heavy metals
(Quinn, P J et al., Mol. Aspcts Med. 1992; 13(5), 379-444; (Hipkiss
A R. Int J Biochem Cell Biol 1998;30:863-8). Carnosine reacts
strongly with aldehyde and keto groups of sugars by Amadori
reaction, and is also theorized to deplete certain glycolysis
intermediates. Therefore, a reduction of glycolysis intermediates
by carnosine depletes their energy supply. But the addition of
pyruvate reverses this effect. (Holliday R Br J Cancer. 1996 April;
73(8):966-7 1). Therefore, it is preferable to add camosine in a
formulation with an agent which also reduces the amount of pyruvate
available. Additionally, the reaction between carnosine and
aldehydes protects susceptible macromolecules. Therefore, carnosine
inhibits nonenzymic glycosylation and cross-linking of proteins
induced by reactive aldehydes (aldose and ketose sugars, certain
triose glycolytic intermediates and malondialdehyde (MDA), a lipid
peroxidation product). (Hipkiss A R, et al., Ann N Y Acad Sci. 1998
Nov 20;854:37-53).
[0059] An anti-glycation agent of interest is garcinol. Garcinol
occurs naturally in the latex exudate of the herb Garcinia
Cambogia, which is used as a weight loss supplement. Garcinol is a
moderate antioxidant, metal chelator, and free radical scavenger.
It also is a superoxide anion scavenger and has been shown to
suppress glycation in a bovine serum albumin/fructose system.
(Yamaguchi F. et al., J Agric Food Chem. 2000 February;48(2):
180-5). It has also been shown that the (-)-hydroxycitrate from
Garcinia fruits may aid endurance during post-absorptive aerobic
exercise by promoting gluconeogenesis. Garcinia is particularly
useful as an additional agent because the combination of garcinol
with carnitine and chromium will have anti-glycation properties and
promote gluconeogenesis (McCarty M F. Med Hypotheses. 1995
September;45(3):247-54).
[0060] Aglycal LS 8777, made by Laboratoires Serobiologique (Cognis
France), may also be included as an anti-glycation agent in the
formulation of the present invention. Aglycal LS 8777 is a
plant-based complex that retards the glycation of proteins. This
photo-complex aids in the long-term elasticity of the skin and
protects against the fragmentation of collagen
(www.laboratoires-serobiologiques.com)
[0061] Aldenine, made by Lipotec (Spain), is a complex of a
tripeptide and hydrolyzed wheat and soy proteins that boosts
Collagen III synthesis while protecting cells from photo damage.
Aldenine detoxifies the skin from harmful RCS (Reactive Carbonyl
Species).
[0062] Another anti-glycation agent, ANTIGLYSKIN.RTM. from Silab,
is rich in phenolic acids and glycopeptides from sunflower and
inhibits the protein glycation reaction and prevents the
glyco-oxidation.
[0063] Compounds obtained from Pterocarpus marsupium may also be
incorporated into the topical formulation. (-) Epicatechin, the
active ingredient in the Indian herb Pterocarpus marsupium Roxb,
can be obtained from the water extract of the bark and is
insulinogenic. (Ahmad F, et al., Acta Diabetol Lat. 1989
October-December;26(4):291-300). It has been found to decrease
hepatic and skeletal muscle glycogen (Grover J K, et al., Mol Cell
Biochem. 2002 December; 241(1-2):53-9). In addition, three
flavonoid antioxidants are also present in the heartwood; these
flavonoid are marsupsin, pterosupin, and liquiritigenin. The gum
tannic acid and a non-glucosidal tannin, kino tannic acid, and
Pterocarpus marsupium extracts have also been shown to have
anti-oxidant activity (Katiyar S K, et al., Photochem Photobiol.
1995 November;62(5):855-61) and a strong anti-glycation agent
(www.laboratoires-serobiologiques.com/LSvi/english/prod.sub.--2.html)).
[0064] N-Acetylcysteine is an N-acetylated cysteine which is a
thiol containing amino acid, also called
.alpha.-acetamido-.beta.-mercaptopropanoic acid, which is a
preferred additional component of the present invention. The
incorporation of N-acetylcysteine into the topical formulation will
improve the signs of aging of the skin. N- acetylcysteine is an
antioxidant and also has been indicated as protective against
pulmonary oxygen toxicity (Eur. Respir. J. 2: 116-126 (1989)). It
is also an anti-glycation agent. Preferred forms of N-acetyl
cysteine include: N-acetyl-L-cysteine, N- acetyl-L-cysteine amide,
N- acetyl-L-cysteine methyl ester, N- acetyl-L-cysteine ethyl
ester, N- acetyl-L-cysteine propyl ester, and N- acetyl-L-cysteine
isopropyl ester. See PCT US96/16534 which teaches topical
compositions containing N-acetylcysteine, and U.S. Pat. Pub.
2003/0229141 which discloses the topical use of N-acetyl cysteine
to alleviate or improve various cosmetic conditions and
dermatological disorders.
[0065] One preferred AGE inhibitor is benfotiamine and benfotiamine
derivatives such as S-Benzoylthiamine O-monophosphate. Benfotiamine
is the most potent of the allithiamines, a unique class of
thiamine-derived compounds present in trace quantities in roasted
crushed garlic and other vegetables from the Allium genus (such as
onions, shallots, and leeks). Benfotiamine's unique open-ringed
structure makes it able to pass directly through cell membranes,
readily crossing the intestinal wall and being taken straight into
the cell, and is absorbed by the body better than thiamine itself,
and levels of thiamine and thiamine pyrophosphate remain higher for
longer, thereby decreasing the formation of AGEs.
[0066] Another preferred anti-glycation agent is pyridoxamine.
Pyridoxamine (4-aminomethyl-5-hydroxy-6-methyl-3-pyridinemethanol),
and derivatives of pyridoxamine such as
4-aminomethyl-5-hydroxy-6-methyl-3-pyridinemethanol dihydrochloride
and 4-aminomethyl-5-hydroxy-6-methyl-3-pyridylmethyl phosphate, may
be incorporated in the ATP enhancing formulation of the present
invention. Pyridoxamine is a vitamin B6 derivative which is
water-soluble and nontoxic in rats and humans. It inhibits the
formation of AGEs from Amadori proteins and is classified as a
post-Amadori inhibitor (Khalifah et al. Biochem. Biophys. Res.
Comm. 199:257, p. 251-258). It is also believed that pyridoxamine
traps reactive dicarbonyl intermediates in AGE formation and may
also decrease oxidative stress, which subsequently decreases AGE
formation from reactive oxygen species (lacovella et al. SCJMM,
2004: 5, p.73-101). Pyridoxamine has also been shown to inhibit
advanced lipoxidation end products (ALES) (Onorato J M. et al., J.
Biol. Chem. 275(28):21177-84 (2000)). Decreasing ALEs formation is
accomplished by decreasing the concentration of an oxidiable
substrate such as glucose and blood lipids (Metz TO, et al., Arch
Biochem Biophys. 419(1):41-9 (2003)). It has been proposed that the
antioxidant properties of pyridoxamine be used for the inhibition
of ALE as well as AGE formation and development of complications of
diabetes and hyperlipidemia (Mene P, et al., Am J Cardiovasc Drugs.
3(5):315-20 (2003)). U.S. Pat. Nos. 6,750,209 and 6,740,668
demonstrate the difference in pyridoxamine and the other B6
vitamins as inhibitors of post-Amadori antigenic AGE formation. The
efficacy of inhibition of overall glycation of protein, in the
presence of high concentrations of sugar, was not predictive of the
ability to inhibit the post-Amadori steps of AGE formation where
free sugar is removed. Pyridoxamine has been shown to be the
strongest AGE inhibitor of the B vitamins. (Price, D. L., J. Biol.
Chem. 2001 Dec 28;276(52):48967-72).
[0067] The combination of benfotiamine and pyridoxamine for AGE
inhibition is also a preferred additional ingredient that may be
added to the formulation of the present invention. This combination
is discussed in U.S. Pat. Pub. 2006/0045896-A1, herein incorporated
by reference
[0068] AGE inhibitors that may be added to the formulation include
the enzymes, fructosyl lysine oxidase and fructose lysine
3-phosphokinase, which catalyze the deglycation reaction and
generate free amine groups. The biochemical properties of these
amadoriase enzymes and their role in protein deglycation are
described by Wu, X et al., Arch Biochem Biophys. 419(1):16-24
(2003). See also Takahasi, M. et al., J. Biol. Chem. 272, 3437-43
(1997). The amadoriase enzymes are particularly useful since they
have strong anti-glycation activity, and some of these compounds
are selective for collagen. This makes these enzymes particularly
useful as components in the topical formulation of the present
invention since they will preferentially act on collagen and
therefore inhibit the glycation of collagen and reduce the signs of
aging in the skin.
[0069] Another class of AGE inhibitors that may be used in the
formulation of the present invention is described by Rahbar et al.,
Molecular Cell Biology Research Commun. 3, 360-66 (2000). These
compounds are benzoic acid derivatives, aryl and heterocyclic
ureido compounds, and aryl and heterocyclic carboxamido phenoxy
isobutyric acids. They have been shown to be potent inhibitors of
glycation, and have been shown to inhibit the glycation of
collagen. The compounds described by Wu, Takahasi, or Rahbar may be
used in combination with the formulation described herein.
[0070] Other AGE inhibitors may be added to the formulation of the
present invention. Extracts of Paeonia suffruticosa have been shown
to be AGE inhibitors (Okano et al., at
www.creative-developments.co.uk/papers/Natural%20Ingredients%201998.html)-
. Additionally, AGE inhibitors have been isolated along with
compounds having antioxidant activity from Paeonia suffruticosa;
these compounds include the monoterpene glycoside,
.alpha.-benzoyloxypaeoniflorin, .beta.-benzoyloxypaeoniflorin,
paeonolide, paeoniflorin and mudanpioside H. (Ryu G., et al, Arch
Pharm Res. 2001 April;24(2):105-8). Another AGE inhibitor is from
extracts of Sanguisorba officinalis, which has been shown to reduce
chronic photodamage to the skin. (Tsukahara K., Biol Pharm Bull.
2001 September;24(9):998-1003). Pterocarpus marsupium has been
shown to be an anti-diabetic agent and strong antihyperglycemic
agent (Babu P S., J. Pharm Pharmacol. 2004
November;56(11):1435-42). C. Cochinchinense has been found to be a
particularly potent AGE inhibitor on proteins and also to strongly
inhibit hypochlorous acid-induced DNA damage. (Tang S Y, Free Radic
Biol Med. 2004 Jun 15; 36(12):1575-87).
[0071] There are other natural products that are AGE inhibitors,
which may be used in the present invention. The screening method
described by Matsuura, based on a fluorometric analysis, may be
used to determine the inhibitory index of the Maillard reaction and
AGE inhibition to determine compounds useful to include in the
formulation of the present invention. (Nobuyasu Matsuura et al. J.
Health Science 48(6) 520-526 (2002)).
ATP-enhancing or Encouraging Agents
[0072] Carnitine is a betaine that is an ATP-encouraging agent and
is required for the transport of long-chain fatty acids, ATP
production, and removal of excess short- and medium-chain fatty
acids. It is derived from the amino acid lysine. L-carnitine is the
only biologically active isomer; however, the derivative
acetyl-L-carnitine may also be used as the ATP enhancing agent.
Acetyl-L-carnitine enters cells and crosses the blood brain barrier
more effectively than L-carnitine (Kidd, P. M. 1999 Alt. Med. Rev.
4, 144-161).
[0073] Acetyl-L-camitine has a three pronged anti-aging effect by
being a mitochondrial energy boosting agent, helping to boost
acetyl-choline necessary for proper face muscle tone and being an
effective antioxidant. It is useful in the transport of long-chain
fatty acids into the mitochondrial matrix, transport of short- and
medium-chain fatty acids away from the mitochondrial matrix, and
regulation of energy metabolism through the modulation of acetyl
CoA:CoA ratios. For this regulation, the acetyl group of acetyl CoA
is transferred to L-carnitine by camitine acetyl-transferase (CAT),
freeing CoA to participate in the PDH reaction. The
acetyl-L-carnitine can then be removed from the mitochondria
(Arrigoni-Martelli E, et al., Drugs Exp Clin. Res. 2001;
27(1):27-49; Rebouche CJ. Camitine. In: Shils ME, et al. eds.
Nutrition in Health and Disease, 9th ed., Baltimore: Williams &
Wilkins; 1999:505-512). This increase of free CoA relative to
acetyl CoA enhances the activity of pyruvate dehydrogenase (PDH)
which catalyzes the conversion of pyruvate to acetyl CoA, a crucial
reaction in glucose metabolism
(Ipi.oregonstate.edu/infocenter/othernuts/carnitine/carnitinerefs.html#re-
f2). Propionyl-L-carnitine, which is not available in the US as an
oral supplement, cleaves into L-camitine and propionate, which is
useful as an intermediate during energy metabolism (Brass E.P., et
al., J. Am. Coll. Nutr. 1998; 17(3):207-215). Useful carnitines
include L-carnitine, acetyl-L-carnitine, propionyl-L-carnitine,
acetyl-L-carnitine arginate and dermatologically acceptable salts
thereof (e.g., acetyl-L-carnitine hydrochloride and
acetyl-L-carnitine arginate dihydrochloride). While meats, fish and
dairy provide the richest sources of L-carnitine, it can also be
found in tempeh (fermented soybeans), wheat, (0.1 mg/slice of
bread), asparagus (0.4 mg/cup), and avocados (2 mg/ea). Generally,
oral L-carnitine and acetyl-L-carnitine are available in doses from
500 mg to 2,000 mg/day (Hendler S S, Rorvik D R, eds. PDR for
Nutritional Supplements. Montvale: Medical Economics Company, Inc;
2001), and the topical carnitine may be provided in similar or
greater doses.
[0074] Coenzyme Q.sub.10 (CoQ10, ubiquinone) is an ATP-encouraging
agent that is useful in the present invention. CoQ10 is a naturally
occurring compound that is a strong antioxidant and has therapeutic
potential for a number of disorders, including congestive heart
failure, muscular distrophy, periodontal disease, correction of
drug-induced deficiencies, and immune diseases (AIDS, allergies).
The biological activity of CoQ10 is believed to be linked to its
ability to act as an antioxidant and free radical scavenger
protecting the integrity of cell membranes and offsetting the
inability of diseased cells to manufacture sufficient energy for
cellular repair, by stimulating mitochondrial respiration and
production of ATP. It has been shown to be effective in both
clinical and cosmetic applications. The solubility and
bioavailability of CoQ10 used in the present invention can be
enhanced bv the method described in U.S., Pat. No. 6,632,443. In
one embodiment, 10-300 mg CoQ10 is added to the formulation. In one
particular embodiment of the invention, CoQ10 is all-trans CoQ10,
as this form occurs naturally in human metabolism. This can
minimize the side effects and risks seen with the cis-form or
cis-trans mixture. Trans-CoQ10 is available from Kaneka Corp, Japan
as KANEKAQ10. This material is used in the nutraceutical industry
and is novel in its use for topical application. One particular
embodiment combines delta tocotrienols with all-trans Coq10 for
synergy, as delta tocotrienol is known to increase the endogenous
production of CoQ10.
[0075] Coenzyme A (CoA) is an important ATP enhancing agent. CoA is
a carrier of acetyl and acyl groups and is essential for numerous
biosynthetic, energy-yielding, and degradative metabolic pathways.
CoA is associated with the first step of the Krebs cycle, in which
an acetyl group is introduced into the cycle. Acetyl-CoA is the
common cellular currency for acetyl transfers and has been used in
the nutraceutical industry. CoA is derived from adenine, ribose,
and pantothenic acid. The CoA precursor, panthethine, which is a
vitamin of the B complex, may also be used as an ATP-enhancing
agent of the present invention. Panthethine is manufactured by
Daichi Fine Chemicals, Inc. as Pantesin LQ80.
Myocontracting Agents
[0076] In some embodiments, a myocontracting agent may be combined
with the macqui berry. Myocontracting agents include, but are not
limited to, choline and acetylcholinesterase inhibitors. Some
particular agents include huperzine, cerberin, eburnamonine,
guanidion, histamine, leonurine, monocrotaline, panaxin, plumbagin,
serotionin, solanine, solasonine, and theobromine.
Anti-edema Ingredients
[0077] Edema is defined as soft tissue swelling due to expansion of
the interstitial volume. Agents that reduce edema are also useful
as agents in the topical formulation of the present invention.
Proanthocyanidins which affect blood vessels have been reported in
double-blind research to reduce the duration of edema after
face-lift surgery (Baroch et al. Ann Chir Polast Esthet 29:393-5
(1984)).
Lipolytic Ingredients
[0078] Lipolytic agents may also be applied as part of the topical
formulation of the present invention. Theophyline is an agent
useful as a lipolytic agent; it acts as both a localize diuretic
and a lipolytic agent. Quinolinic acid, a structural analogue of
nicotinic acid, inhibits phosphodiesterase activity in adipocytes
to increase AMP concentration and increase lipolytic intensity.
Other lipolytic ingredients useful in the topical formulation of
the present invention include cayenne, Coleus Forskohlii, banaba
extract, gugulsterone E & Z, bioprene, quinolinic acid,
3-n-butyl-phthalide, adenosine, ajoene, alginates, allicin, alliin,
amellin, bergapten, .beta.-ecdysone, bromelain, chebulinic-acid,
crocetin, cynarin, diallyl-disulfide, diallyl-sulfide,
diallyl-trisulfide, dipropyl-disulfide, forskolin,
ginsenoside-rb-2, imperatorin, inulin, nicotinic-acid, opc, opcs,
oxypeucedanin, phellopterin, polydatin, resveratrol,
s-allyl-cysteine-sulfoxide, s-methyl-l-cysteine-sulfoxide,
saikosaponin, wogonin, and xanthotoxin.
Cholinesterase Inhibitors and Acetyl-cholinesterase Inhibitors
[0079] Cholinesterase (ChE) and acetyl-cholinesterase inhibitors
(AChE) are partially useful as a component in the topical
formulation of the present invention because of their ability to
augment the restoring of a youthful tone to the skin.
[0080] The ChE inhibitor is preferably obtained from a plant
source. Preferred ChE inhibitors include, for example: (+)-carvone,
demissine, 1-carvone, solanidine, 1,8-cineole, ephedrine,
limonene-oxide, solanine, actinidine, eseramine, lycorine,
solasodine, allicin, eseridine, palmatine, thymol,
.alpha.-chaconine, fenchone, physostigmine, vasicinol,
.beta.-2-chaconine, galanthamine, pulegone, bufotenine,
huperzine-a, sanguinarine, d-carvone, huperzine-b, selagine,
demissidine, ibogaine, and serotonin,.
[0081] AChE inhibitors are preferrably obtained from a plant
source. Some preferred AChE inhibitors are: (+)-menthol,
berberastine, huperzine-a, menthone, (+)-piperitenone-oxide,
berberine, isomenthol, p-cymene, (+)-pulegone, carvone,
isomenthone, piperitenone, 1,8-cineole, chelerythrine, isopulegol,
pulegone, akuammicine, d-carvone, 1-carvone, sanguinarine,
akuammidine, d-limonene, 1-limonene, terpinen-4-ol,
alpha-terpinene, elemol, 1-menthol, viridiflorol, (+)-menthol,
galanthamine, limonene, yohimbine, (+)-piperitenone-oxide,
gamma-terpinene, menthol, menthone,
[0082] Preferably, the cholinergic substance is obtained from a
plant source. Some preferred cholinergic substances are: arecoline,
choline, deoxypeganine, deoxyvasicinone, eseridine, galanthamine,
iridin, irigenin, lecithin, lithium, nicotine, nobiletin,
physostigmine, pilocarpine, pronuciferine, and yohimbine.
[0083] Huperzine, an alkaloid derived from the herb Huperzia
Serrata, is a preferred inhibitor of acetylcholinesterase (AchE)
used in the present invention. Huperzine is useful in the forms
huperzine A, huperzine B, 6-.beta.-hydroxy huperzine A, and
tautomers thereof. Transdermal application of huperzine has been
shown to improve memory and cognitive functions by adding huperzine
with a permeation enhancer to increase blood plasma levels of
huperzine. (U.S. Pat. Pub. 2004/020705). Similarly, huperzine can
be administered topically for the treatment of Alzheimer's disease
(U.S. Pat. No. 6,352,715) and cholinergic deficient disorders (WO
2004 080436). In a preferred embodiment, the huperzine-a in the
topical formulation is encapsulated in a liposome or nanosome.
[0084] Cytidine 5'-diphosphocoline, also known as citicoline or
CDP-choline, is a preferred AchE inhibitor. Citicoline, or a
stabilized form thereof (see U.S. Pat. Nos. 3,687,932 and
6,057,301), may be used.
[0085] Galanthamine is a reversibly acting cholinesterase inhibitor
and an acetyleholinesterase inhibitor; it is a tetracyclic alkaloid
which was initially isolated from galanthus nivalis. Galanthamine
has unique specific properties, for example, highly analgesic
effects comparable to those of morphine, and is not as toxic as
cholinesterase inhibitors such as physostigmine and neostigmine.
The principal use in humans has been the postoperative reversal of
neuromuscular blockade. It has also been administered in a number
of neuromuscular diseases, and has been shown to enhance activation
of motor nerve terminals stimulated electrically, to increase
ganglionic depolarization induced by acetylcholine, and to protect
against hexamethonium, indicating enhancement of the activity of
nicotinic receptors (U.S. Pat. No. 6,670,356). Galanthamine may be
isolated, for example, by the process described in U.S. Pat. Nos.
6,617,452 and 6,573,376, from either biological or synthetic
material.
Glutathione
[0086] Glutathione, reduced glutathione, glutathione peroxidase,
glutathione s-transferase or glutathione reductase may be
incorporated in the formulation of the present invention.
Additionally, synergistic intracellular glutathione inducers and
precursors of glutathione may be used. These include omithine,
.alpha.-ketoglutarate, 1-cystein, 1-glycine, 1-glutamatic acid,
glycyl-1-glytamine, n-acetyl-cystein, riboflavin, vigtamin B6,
parsley seed or seed extract, sylimarin, and cysteine whey
peptides. Other ingredients synergistic with glutathione or
glutathione precursors which may be added to the formulation
include selenium salts, amino acid chelates (including
methyl-1-selenocysteine, I-selenomethionine) and sacharomyces
selenium ferment, polyenylphosphatidylcholine, myristicin (which
may be isolated from parsley), dihydromyristicin, quercetin,
riboflavin, purselane extract, spinach extract,
N-acetyl-cysteine,n-acetyl-glutamine, n,ndimethylglycine,
anthocyanins, pycnogenol (pinus maritima) extract, grape seed
extract, turmeric extract, sylimarin ,tocopherols, r-lipoic acid,
cynara scolymus extract, Picrorhiza kurrooa extract, Tinospora
cordifolia extract, Phyllanthus niruri extract,Terminalia belerica
extract, Terminalia chebula extract, Phyllanthus emblica extract,
Boerhavia diffusa extract, Defensine(available from Silab),
Phyllanthus amarus extract, Hibiscus rosa sinensis extract,
gentisic acid, Tephrosia purpurea,Andrographis paniculata extract,
Occinum santum extract and cysteine peptides. Additionally,
SUNACTYL.RTM. LS 9610 and AFR.RTM. LS 4467/VEG (from Laboratoires
serobiologique) may be used.
[0087] Glutathione is a tripeptide consisting of the amino acids
glutamic acid, cysteine, and glycine. Glutathione is important for
the maintenance of the function of enzymes in cell metabolism. It
assists in the transport of amino acids across cell membranes. It
prevents oxidative alterations of catalytic and allosteric centers,
and upholds the optimum conformation of the enzymes for proper
functioning (see WO 89/00427). The formation of cataracts is also
associated with decreased levels of glutathione. It has been
suggested that NADPH production from D-glucose aids in glutathione
regeneration and protection from mitochondrial dysfunction thereby
provide a neuroprotective effect. (Delgado-Esteban M, et al., J
Neurochem. 2000 October;75(4):1618-24). U.S. Pat. No. 6,573,299
describes the addition of glutathione in a formulation containing a
hydroxy acid. Glutathione has also been shown to be an ACE
inhibitor (IC50=3.2 .mu.g/ml), anticytotoxic, antieczemic,
antihepatitic, a cancer-preventive, and useful treating heavy metal
poisoning. In this formulation, glutathione is particularly useful
as it is involved with preventing both oxidative damage and
detoxifying RCS (reactive carbonyl species). When skin is exposed
to UVB, endogenous is depleted and cannot perform its protective
role. Therefore, replenishing can be a crucial step towards
preventing photoaging. Furthermore, detoxify RCS such as
4-hydroxynonenal may form adducts with glutathiones and work with
the formulation of the invention to reduce the signs of ageing. The
combination of glutathione in a topical formulation therefore is
particularly useful.
[0088] Glutathione peroxidase catalyzes the reduction of
hydroperoxides, such as hydrogen peroxides, by reducing glutathione
and protecting the cell from oxidative damage. Most glutathione
peroxidase enzymes are tetramers having four identical subunits
containing selenocysteine in the active site which participates
directly in the two-electron reduction of the peroxide substrate.
Glutathione is used as an electron donor to regenerate the reduced
form of the selenocysteine (Forstrom, J. W., et al., Biochemistry
17, 2639-2644 (1978); Paglia, D. E., Valentine, W. N. J Lab Clin
Med 70, 158-169 (1967). Glutathione peroxidase can be added to a
topical formulation to protect the skin for oxidative damage.
[0089] Glutathione also affects melanin in the skin. Melanin, or
skin pigment, is produced by melanocytes. There are two common
types of melanin in hair, eumelanin, which is brown/black in color,
and phaeomelanin, which is red/yellow in color. Glutathione has
been implicated in the biogenesis of the melanin precursor
5-S-cysteinyldopa and the melanogenic activity of pigment cells.
Along with cysteine (which is used for glutathione biosynthesis),
glutathione will effect the melanin and therefore coloration of the
skin (Benathan M. et al., Cell Mol Biol (Noisy-le-grand). 1999
November;45(7):981-90). Further, glutathione-reductase plays an
important role in the regulation and control of the biosynthetic
activity of melanocytes. The differences in the glutathione and the
glutathione enzyme content in eumelanin and phaeomelanin
pigmentation in skin indicate that the increase of glutathione
reductase activity in the environment of the melanocytes may
stimulate the pigment cells to produce phaeomelanin instead of
eumelanin pigment (Benedetto J P et al., J Invest Dermatol. 1982
December;79(6):422-4). Skin with no active melanocytes shows
glutathione levels intermediate between those of eumelanin and
phaeomelanin. This is consistent with glutathione reductase
activity playing an important role in the regulation and control of
the biosynthetic activity of melanocytes. (Benedetto J P, et al.,
Invest Dermatol. 1981 November;77(5):402-5).
[0090] Glutathione also affects hyperpigmentation of the skin.
Hyperpigmentation, caused by inflammatory skin disorders such as
eczema, allergic contact dermatitis, and irritant contact
dermatitis acne, is often treated using sunscreen and an agent such
as a hydroquinone, tretinoin, azelaic acid, or kojic acid (Pathak M
A, Fitzpatrick T B, Nghiem P, Aghassi D S. Fitzpatrick T B, Editor.
Dermatology in General Medicine, 4th ed, New York: McGraw-Hill, pp
2742-60 (1993). Glutathione plays a key role in the depigmenting
and melanocytotoxic action of these agents, which act to decrease
intracellular glutathione by stimulating pheomelanin rather than
eumelanin, and thereby lighten hyperpigmentation of the skin.
(Alena F, et al., Invest Dermatol 104(5):792-7 (1995)). Therefore,
the use of the topical formulation of the current invention can be
used to treat hyperpigmentation as well as affect the signs of
aging.
Antioxidants
[0091] In particular, preferred embodiments, in addition to the
antioxidants present in the macqui berry, additional antioxidants
may be added to the topical formulation of the present invention.
Exemplary antioxidants include, but are not limited to, amino acids
(e.g. glycine, histidine, tyrosine, and tryptophan) and their
derivatives, imidazoles (e.g. urocanic acid) and their derivatives,
carotenoids (e.g. lutein, lycopene), carotenes (e.g.
.alpha.-carotene, .beta.-carotene, lycopene, canthaxantin,
cryptoxanthin, zeaxanthin and astaxanthin) and their derivatives,
chlorogenic acid and its derivatives, aurothioglucose,
propylthiouracil, thiotaurine and other thiols (e.g. thioredoxin,
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,
aminoethylcysteine, decarboxylated dimmer of aminoethylcysteine
ketimine, 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 .mu.moles/kg); also (metal)
chelating agents (e.g. .alpha.-hydroxy fatty, acids, palmitic acid,
phytic acid, lactoferrin, tannins, and curcumine), .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 A and derivatives (e.g. vitamin A
palmitate), the B vitamins and their derivatives, 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)
including zinc amino acid chelates(zinc-methionine, zinc
acetyl-methionate), selenium and its derivatives (e.g. selenium
methionine), stilbenes and their derivatives (e.g. stilbene oxide,
trans-stilbene oxide), proanthocyanidins, ascorbic acid,
particularly fat-soluble fatty acid esters of ascorbic acid (e.g.
ascorbyl palmitate and tetrahexydecyl ascorbate), quercetin and its
derivatives (e.g. quercetin glycoside or rutin), hesperidine,
sylimarin, sylibin, glabridin, superoxide dismutase and their
derivatives, catalase and its derivatives, carnosic acid and its
derivatives, apigenin and its derivatives, luteolin and its
derivatives, chlorogenic acid and its derivatives, caffeic acid and
its derivatives, ferrulic acid and its derivatives, resveratrol and
its derivatives, green tea polyphenols and its derivatives, matrix
metalloproteinase inhibitors (e.g. green tea polyphenols,
trans-retinoic acid, luteoline, quercetine, ursolic acid, shark
cartilage preparations, diterpenes and ursolic acid from
Siegesbeckia and Centaurium extracts, and a tocopherol), Coenzyme
Q10, glutathione and its derivatives, myristicin, changkil saponins
(from platycodon grandiflorium, which is also known as jie geng),
pomengranate, ellagic acid, honokiol (from magnolia officinalis),
magnolol (from magnolia officinalis), naringenin, clove essential
oil, martynosides, verbascosides, wolfberry (from lycium barbarum)
extracts, cascading antioxidants including but not limited to
carnosic acid, standardized extract of Phyllanthus emblica (trade
named Emblica), pinus maritima and pinus radiata bark extracts,
hydroxytyrosol (from olives), genistein, thiotaurine, antioxidants
from marine species (e.g., Bioplasma.RTM. and monostrama extract
from Secma), roxisomes (from AGI), crocetin, pine pollen extracts,
beta glucans and the suitable derivatives of the invention (salts,
esters, ethers, sugars, nucleotides, nucleosides, peptides and
lipids) of these said active ingredients.
[0092] Anthocyanins in addition to the anthocyanins in the macque
berry may be added to the formulation of the present invention.
These anthocyanins may be obtained from any portion of various
plant sources, such as the fruit, flower, stem, leaves, root, bark,
or seeds. One of skill in the art will understand that certain
portions of the plant may contain higher natural levels of
anthocyanins and, therefore, those portions are preferably used to
obtain the desired anthocyanins. Methods to determine whether and
which portions of a plant contain anthocyanins are known and not
discussed herein. The extraction and identification of various
anthocyanins are described, for example, in U.S. Pat. No.
6,818,234, U.S. Pat. No. 6,780,442, and U.S. Pat. No. 4,413,004.
Particularly preferred anthocyanins are derived from natural
sources having high anthocyanin content. Approximately 300
anthocyanins have been discovered in nature, and come from sources
including, but not limited to, acai berries, aronia berries,
apples, bilberries, black carrots, blueberries, cherries,
cranberries, eggplants, elderberries, grapes, purple carrots,
purple loosestrife, purple rice, radishes, raspberries, red
cabbage, redcurrants, red-fleshed potatoes, red raspberries, red
onions, species from the Rubus class (e.g, black raspberry,
blackberry, and youngberry), species from the Ribus class (e.g.,
black currant and gooseberry), sea buckthorn, wolfberry extract,
and strawberries.
[0093] Preferred anthocyanins that may be added to the formulation
of the present invention include anthocyanis found in the extracts
of red, blue, purple, magenta and black flowers. These flowers
include, but are not limited to purple dahlias, blue lotus, black
tulips, and black orchids. Therefore, in one preferred embodiment,
the formulation includes an extract of purple dahlia, an extract of
black tulip, an extract of black orchid, or a combination
thereof.
[0094] In one embodiment, an additional antioxidant included in the
formulations of the present invention is one or more betacyanin.
Betacyanins, like anthocyanins, may be obtained from natural
sources and are antioxidants. One betacyanin of interest is betanin
found in beets.
[0095] A lipoic acid is a preferred antioxidant for use in the
topical formulation of the present invention. Lipoic acid is
available in both the R and S forms. R-lipoic acid is a preferred
form. Furthermore a form of R-Lipoic acid is preferred that does
not readily polymerize such as R-lipoic nicotinate and certain
sodium salt preparations of R-lipoic acid. The lipoic acid of the
present invention also includes the reduced form, or dihydrolipoic
acid. In aqueous systems, both lipoic acid and DHLA show strong
antioxidant activity. Lipoic acid is also useful in treating
diseases associated with oxidative stress including liver
cirrhosis, atheroschlerosis, and polyneuritis of diabetes mellitus.
(Maitra, I., et al., Free Rad. Biol. Med. 18:823-829 (1995),
introduction). The antioxidative activity of lipoic acid is due, at
least in part, to its ability to prevent free radical damage to
cells and cell components. Free radical damage is most evident in
cellular membranes because of the density of the molecular
structure of the membranes. (R)-Lipoic acid has been shown to
reverse the age-related decline in oxygen consumption and increase
mitochondrial membrane potential. The age-related decline in
hepatocellular glutathione and ascorbic acid levels is reversed by
treatment with (R)-lipoic acid (as an oral supplement in rats)
(Hagen T M, et al., FASEB J. 1999 February;13(2):411-8).
[0096] Reduced R-lipoic acid, or R-dihydrolipoic acid (R-DHLA), may
be used instead of or in addition to R-lipoic acid. R-DHLA which is
formed in situ by the reduction of R-lipoic acid by NADH has more
antioxidant properties than lipoic acid. Both DHLA and lipoic acid
have metal-chelating capacity (LA chelates Fe.sup.2+ and Cu.sup.2+;
DHLA chelates Cd.sup.2+) and can scavenge reactive oxygen species.
However, only DHLA can regenerate endogenous antioxidants and
repair oxidative damage. DHLA can regenerate the endogenous
antioxidants vitamin E, vitamin C and glutathione as well as
provide peptide methionine sulfoxide reductase with reducing
equivalents. The reducing equivalents help in the repair of
oxidatively damaged proteins such as a-i antiprotease (Biewenga G
P., et al., Gen Pharmacol. 1997 September;29(3):315-31). DHLA is a
potent sulfhydryl reductant and has also been shown to act as a
strong direct chain-breaking antioxidant which may enhance the
antioxidant potency of other antioxidants such as ascorbate and
vitamin E (Kagan V E, et al., Biochem Pharmacol. 1992 Oct
20;44(8):1637-49).
[0097] Retinol and its derivates such as retinyl palmitate and
trans-retinoic acid as well as retinols stabilized in liposomes and
cyclodextrin preparations may be added to the present invention.
One retinol derivate of interest is tocopheryl-retinoate available
from Nikko Chemicals Co. LTD.
[0098] Other agents useful in the topical formulation of the
present invention include vitamin C and the vitamin C derivatives
including ascorbic acid, sodium ascorbate, and the fat soluble
esters tetrahexyldecyl ascorbate and ascorbyl palmitate, magnesium
ascorbyl phosphate, ascorbyl-glucoside, glucosamine ascorbate,
ascorbyl acetate, etc. Additionally, extracts from plants
containing a high amount of vitamin C, such as camu berry
(Myrciaria dubia), acerola, emblica officinalis, and bioflavonoids
from rose hip and citrus, may be used including watersoluble
bioflavonoids such as hesperidin methyl chalcone.
[0099] In one particularly preferred embodiment, the antioxidant is
superoxide dismutase (SOD) (and derivatives), catalase (and
derivatives), or a mixture thereof. In a particularly advantageous
embodiment, SOD is heterologous SOD (HSDs), described in U.S. Pat.
No. 6,426,068, which no longer, or practically no longer, exhibit
dismutase activity, but which have conserved their immuno-redox
activity, stimulate the production of endogenous SOD, as well as
the production of catalase and of glutathione peroxidase. In
another embodiment, the macqui berry formulation contains a SOD and
a lipid or protein such as ceramides, prolamines or polymer films
based on prolamines (see U.S. Pat. No. 6,045,809). According to
another advantageous embodiment of said use, said plant
heterologous SOD is in particular derived from melon. The preferred
ermbodiiiieit uses an encapsulated SOD.
[0100] Sesame (Sesamum indicum) or sesame lignan may also be added
to the present invention. Sesame and its lignans (the fibrous
compounds associated with the sesame) act as antioxidants, reduce
inflammation, normalize blood pressure, improve lipid levels, and
promote fat burning. Sesame has also been shown to aid in the
oxidation power or bioavailability of fish oil and conjugated
linoleic acid, to enhance the anti-inflammatory effects of
essential fatty acids, lower total cholesterol and low-density
lipoprotein (LDL), block oxidative damage implicated in
atherosclerosis, and reduce blood pressure. Sesame lignans can
dramatically increase tissue and serum levels of the vitamin E
fractions .alpha. tocopherol and .gamma. tocopherol, thereby
enhancing their protective properties. (Yamashita K, et al., J
Nutr. 1992;122(12):2440-6). Studies have shown that sesame can also
reduce inflammatory processes known to promote cancer, senescence,
and aging.
[0101] Sesame seed lignans significantly enhance vitamin E activity
and increase .alpha. tocopherol concentrations in the blood and
tissue of rats fed a diet containing .alpha. tocopherol and sesame
seed or its lignans (Yamashita K, et al., Lipids. 1995
December;30(11):1019-28). Additionally, they elevate gamma
tocopherol concentration by inhibiting an enzyme involved in
breaking down tocopherols and tocotrienols (Ikeda S, et al., J
Nutr. 2002 June;132(5):961-6).
[0102] Other preferred antioxidants which may be incorporated in
the formulations of the present invention include tocopherols (e.g.
d-.alpha.-tocopherol, d-.beta.-tocopherol, d-.gamma.-tocopherol,
d-.delta.-tocopherol), tocotrienols (e.g. d-.alpha.-tocotrienol,
d-.beta.-tocotrienol, d-.gamma.-tocotrienol,
d-.delta.-tocotrienol,) and vitamin E (.alpha.-tocopherol acetate).
These compounds added to the compounds of the present invention may
be isolated from natural sources, prepared by synthetic means, or
mixtures thereof. Tocotrienol-enriched vitamin E preparations may
be obtained by fractionating vitamin E preparations to remove a
portion of tocopherols and recover a preparation more highly
concentrated in tocotrienol. Useful tocotrienols are natural
products isolated from, for example, wheat germ oil, grain, or palm
oil using high performance liquid chromatography, or isolated by
alcohol extraction and/or molecular distillation from barley,
brewer's grain or oats. As used herein, the term "tocotrienols"
includes tocotrienol-rich-fractions obtained from these natural
products as well as the pure compounds. The increased glutathione
peroxidase activity protects the skin from oxidative damage
(Musalmah M, et al., Asia Pac J Clin Nutr. 2002;11 Suppl
7:S448-51).
[0103] Gamma tocopherol is one particularly advantageous E vitamin
since it is capable of quenching reactive nitrogen oxide species
such as peroxynitrite and nitrogen dioxide (Boje K M. Front Biosci.
2004 Feb 1;9:763-76). Gamma tocopherol and its water-soluble
metabolite, gamma-CEHC, have been shown to reduce inflammation by
inhibiting prostaglandin E2 (Jiang Q, et al., Proc Natl. Acad Sci
USA. 2000 Nov. 10;97(21):11494-9) and gamma tocopherol
administration correlates with a reduced risk from heart disease.
(Kushi L H, et al. N Engl J Med. 1996 Jun. 2;334(18):1156-62).
[0104] When a tocopherol or tocotrienol is added to the formulation
of the present invention, it is also preferable to add sesame oil
(or an extract thereof such as sesaminol, a sesame lignans) due to
the enhanced antioxidant effect of the combination (Ghafoorunissa,
Hemalatha S., et al., Mol Cell Biochem. 2004 July;
262(1-2):195-202; Yamashita K, et al., Lipids. 2002 April;
37(4):351-8). One preferred formulation contains d-.alpha.-,
d-.beta.-, d-.gamma.-, and d-.delta.-tocopherol, d-.alpha.-,
d-.beta.-, d-.gamma.-, and d-.delta.-tocotrienol in addition to the
sesame lignans. Gamma-tocopherol, followed by .delta. and .alpha.
tocopherol, has the highest content, with a reduced risk from heart
disease. (Kushi L H, et al. N Engl J Med 1996 Jun 2;
334(18):1156-62).
[0105] Vitamin A is a preferred addition to formulations of the
present invention because of the increased stability it can impart
to lipoic acids (Segall, A., J Cosmet Sci. 2004
September-October;55(5):449-61).
[0106] In addition, carotenoids, particularly the xanthophyll type,
are also preferred antioxidants that can be used in the practice of
the instant invention. The xanthopyll type carotenoids include
molecules such as lutein, canthaxantin, cryptoxanthin, zeaxanthin
and astaxanthin. Xanthophylls protect compounds such as vitamin A,
vitamin E and other carotenoids (Demmig-Adamas, B. Biochemica et
Biophsyica Acta, 1020:1-24 (1990)). Xanthophylls can be obtained
from a multitude of natural sources, or produced as described, for
example, in U.S. Pat. No. 5,916,791.
[0107] Flavan-3-ols are also preferred antioxidants that may be
used in the formulations of the present invention; they belong to a
class of nutrients known as the flavonoid family. Particularly
preferred flavan-3-ols include the procyanidin mixtures extracted
from grape (Vitis vinifera) seed. Proanthocyanidins play a role in
the stabilization of collagen and maintenance of elastin, two
critical proteins in connective tissue that support organs, joints,
blood vessels, and muscle (Mitcheva et al. Cell Mol Bio 39:443-8
(1993); Maffei et al. Arzneimittelforschung; 44:592-601 (1994)).
Other flavan-3-ols may also be added to the formulation. These
include catechin and epicatechin. Procyanidins are the dimers and
oligomers of catechin and epicatechin and their gallic acid esters,
and are widely distributed in the plant kingdom. Other flavonoids,
such as isoflavin .beta., quercetin, glabridin, red clover, and
others described in U.S. Pat. Nos. 5,686,082 and 5,686,367 may also
be included in the formulation.
[0108] Myristicin, or 3-methoxy,4,5-methylendioxy-allylbenzene, is
a non-amine precursor of 3-methoxy-4,5-methylenedioxyamphetamine
and may be incorporated in the formulation of the present
invention. It can be found in Myristica fragrens (Nutmeg) contains
approximately 4.0% myristicin and in parsley (Petroselinum crispum,
Petroselinum hartense, Petroselinum sativum), which also contains
apiol. Parsley has been traditionally used as a diuretic, for
colic, indigestion, and intestinal gas. Myristicin has been shown
to induce production of a detoxifying, antioxidant enzyme called
glutathione S-transferase, in mice (Ahmad H, et al., Biochem
Biophys Res Commun. 1997 Jul 30;236(3):825-8). Myristicin can cause
convulsions and nausea, and is toxic and hallucinogenic if taken in
large amounts. However, smaller doses of myristicin have
antioxidantive properties. An oral psychotropic dose of myristicin
is 400 mg (see Stein U et al., Forensic Sci Int. 2001 Apr.
15;118(1):87-90; Zheng G Q, et al., Carcinogenesis, 1992
October;13(10):1921-3). Parsley, a source of myristicin, may be
used in the topical formulation. However, the amount of parsley
extract must be limited due to the fact that parsley can cause
phototoxic reaction if there is a simultaneous exposure to
sunlight. The rash is caused by the psoralen furocoumarin found in
the oil extract of parsley, and is present in other plants as well
(celery, fennel, parsnips, limes, lemons, and figs) (see Lagey, K,
Burns 1995 November;21(7):542-3; Gruenwald J. PDR for Herbal
Medicine. 1st ed. Montvale, N J: Medical Economics; 1998:1023-1024;
Smith D M. Practitioner. 1985;229:673-675; Stransky L, Tsankov N.
ContactDermatitis. 1980;6:233-234). Therefore, an extract
containing myristicin and not furocoumarin may be used to provide
the antioxidative and protective effect of the myristicin but
without the phototoxic reaction when applied to the skin.
[0109] Ethylenediaminetetraacetate (EDTA) or other metal chelators
are preferred antioxidants that can be included in the formulation.
Plant tannins are also metal chelators that may also be included in
the formulation of the present invention. The chelating agent forms
a complex with metal ions, inactivating them, and preventing them
from affecting antioxidant activity. Other chelators, in addition
to those described above, include, but are not limited to,
dihydroxyethyl glycine, citric acid, tartaric acid, and mixtures
thereof.
[0110] In one preferred embodiment, a metal chelators is added to
the formulation which may or may not include an additional
antioxidant. The metal chelating agent is particulary advantageous
in that it further stabilizes the color and antioxidant property of
the macqui berry or macqui berry extract and the optional
additional antioxidant.
[0111] An additional antioxidant that may be used in the present
invention is a phenylpropanoid glycoside. Martynoside, a
particularly preferred phenylpropanoid glycoside, may be isolated
from a number of botanical sources such as: Clerodendron
trichotomum (apps1.niaid.nih.gov/struct_search/); the aerial
section of Scutellaria pontica (Ersoz , T, et al., Turkish J. Chem.
"Phenolic Compounds from Scutellaria pontica", which also provides
the isolation of other phenylalkyloid glycosides); transformed root
cultures of Catalpa ovata (Halina Wysokinska J, et al., Free Radic
Res. 2003 August;37(8):829-33); Pedicularis plicata (Liao, R. et
al., Phytotherapy Research 1999 13(7):621-623; which also provides
the isolation of verbascoside); Pedicularis (Wang et al., Sci China
C Life Sci (1996) 39(2):154-8; which also provides the isolation of
the phenylpropanoid glycosides: echinacoside, verbascoside,
leucosceptoside a, and pediculariosides a, m and n). Their
antioxidant scavenging activities are similar to those of the o-
dihydroxy group of phenylpropanoid glycosides (Wang et al., Biochem
Pharmacol (1996) 51(5):687-91). The addition of martynoside or
verbascoside as an ingredient in the formulation of the current
invention is particularly advantageous because these
phenylpropanoid glycosides have been shown to reduce fatigue in
muscle tissue. This allows for a relaxation and smoothing in the
overlying skin and reduces the signs of aging (Liao, R. et al.,
Phytotherapy Research 1999 13(7):621-623).
[0112] An additional antioxidant that may be used in the present
invention is coffee berry. Coffee berry is the fruit from a coffee
tree or shrub, and has an ORAC of 6250 .mu.mole TE/g. The coffee
berry is rich in polyphenols, and contains phenolic acids at a
concentration of 97 mg/100 g (Mattila, P. et al., J Agric Food
Chem. 2006, 54(19):7193-9). In one preferred embodiment, an extract
of the whole berry may be added as a additional antioxidant. In
other embodiments, extracts containing only part of the coffee
berry, with or without the seed, may be used.
[0113] Green coffee extracts may also be added to the formulation
of the present invention. Hydroxycinnamic acid derivatives
(3-caffeoylquinic acid (3-CQA), 4-caffeolyquinic acid (4-CQA),
5-caffeoylquinic acid (5-CQA), 5-feruloylquinic acid (5-FQA),
3,4-dicaffeoylquinic acid (3,4-diCQA), 3,5-dicaffeoylquinic acid
(3,5-diCQA), and 4,5-dicaffoylquinic acid (4,5-diCQA)) are found in
coffee berry seeds (i.e., green coffee beans). The diCQA
hydroxycinnamic acid derivatives have a strong free radical
scavenging activity while the other hydroxycinnamic acid derivates
also show superoxide anion radical scavenging activity (Iwai K, et
al., J Agric Food Chem. 2004 Jul 28;52(15):4893-8). U.S. Pat. No.
5,972,409 describes a method of obtaining soluble extract from
green coffee. The green coffe extract may be provided from either
the whole fruit or the seed. In another embodiment, caffeic acid
may be added to the formulation.
[0114] In a preferred embodiment, the antioxidant is an antioxidant
endogenous to the human body. These antioxidants include, but are
not limited to superoxide dimutates (SODs, such as Mn, Zn, or Cu
SODs), glutathione and the glutathione enzymes, NADH, lipoic acid
and the salts and metabolites thereof, NAC, thioredoxin, and the
tocopherols.
[0115] The amount of antioxidant in the formulation (added in
addition to the anthocyanin) is preferably from about 0.001 to
about 80% by weight, preferably from about 0.1 to about 5% by
weight, based on the total weight of the preparation.
[0116] In one embodiment, the additional antioxidant in the
formulation is added in a particular ratio compared to the
antioxidant in the macqui berry or macqui berry extract. The ratio
is determine to optimize (i.e., increase) the ORAC value of the
formulation containing the two or more antioxidants. This ratio is
determined through testing the ORAC values of compositions having
various ratios, and may be done by the methods as disclosed by
Brunswick laboratories (www.brunswicklabs.com). Assays such as
those described by D. Huang et al. in J. Agric. Food Chem. 2005,
53, 1841-1856 and D. Huang et al. in J. Agric. Food Chem. 2002, 50,
4437-4444 may be used to determine ORAC.
Matrix Metalloproease Inhibitors
[0117] Matrix metalloprotease (MMP) inhibitors may also be added to
the formulation of the present invention. Most MMPs are thiols or
hydroxyamates. Many MMPs are neutral zinc-dependent endopeptidases
that selectively catalyze the hydrolysis of polypeptide bonds; they
degrade and rebuild structural proteins in collagens and are
required for the healing of moist skin wounds (Agren M S. Arch
Dermatol Res. 1999 291(11):583-90). Increased concentrations of MMP
1 (collagenase 1, interstitial collagenase), 3, (stromelysin 1), 7
(matrilysin, pump), 9 (gelatinase b, 92kd gelatinase), and 12
(macrophage metalloelastase) have been found in sun-exposed skin.
Additionally, increased levels of MMP-1 have been found in smokers
(Lahmann C, et al., Lancet 2001, 357:935-936) MMP levels are also
known to rise in fibroblasts as a function of age, and oxidant
stress is believed to underlie changes associated with both
photoaging and natural aging (Varani J, et al., J Invest Dermatol.
2000 114(3):480-6). Therefore the addition of inhibitors of MMPs,
particularly MMP-1, 3, 7, 9, and 11 in the topical formulation of
the present invention, is contemplated. MMP inhibitors include the
tissue inhibitors of metalloproteinases (TIMPS) which are the
natural inhibitors of MMP activity (Gomez, D E. et al. (1997) Eur.
J. Cell Biol. 74:111.), and include compounds such as ilomastat
(www.chemicon.com/product).
Anti-Inflammatory Agents
[0118] The free radicals associated with aging skin will often also
induce inflammation in the skin and lack of skin immunity.
Therefore anti-inflammatory agents including NSAIDS, COX-2
inhibitors (e.g., nexrutine, ursolic acid, quercetin, curcumine,
and evodia extract) (Kang, S. S., et al., Nat. Prod. Sci., 1999,
5(2): 65-69) can be included in the formulation of the present
invention.
Mitochondrial Resuscitants
[0119] Mitochondrial resuscitants may also be added to the macqui
berry formulation. Mitochondrial decay in aging is a major driving
force behind the aging process (Ann N YAcad Sci. 2004
June;1019:406-11; Proc Natl Acad Sci USA. 1994 91:10771-8). The
mitochondria are the powerhouses of the cell responsible for
producing all cellular energy and convert carbohydrates and fatty
acids into ATP. ATP is necessary for the production of proteins,
which declines with aging (e.g., collagen and elastin).
[0120] Agents useful as mitochondrial resuscitants include, but are
not limited to, lipoic acid (Ames B., Ann. N.Y. Acad. Sci. 1033:
108-116 (2004), carnitine, COQ10, CoA, NADH, FADH, succinic acid,
creatine, D-ribose, 5-phosphoribosyl-1-pyrophosphate(PRPP),
Sepitonic M3 .RTM. (containing magnesium aspartate, zinc gluconate,
copper gluconate), pyruvate, phosphoglycolipids, gymnostemma
pentaphyllum, and cytochrome C. Additionally, agents including
phenylbutylnitrone (PBN) and other spintraps, such as the nitrone
or nitroso spin traps described in U.S. Pat. No. 5,723,502
(N-t-butyl-.alpha.-phenylnitrone,
3,5-dibromo-4-nitrosobenzenesulfonic acid, 5,5-dimethyl-1-pyrroline
N-oxide, 2-methyl-2-nitrosopropane, nitrosodisulfonic acid,
.alpha.-(4-pyridyl-l-oxide)-N-t-butylnitrone,
3,3,5,5-tetramethylpyrroline N-oxide, and
2,4,6-tri-t-butylnitrosobenzene) as well as hydroxylamines such as
N-tert-butyl hydroxylamine may be used. These agents are
antioxidants as well as mitochondrial resuscitants.
[0121] D-ribose is a naturally occurring five-carbon sugar found in
all living cells, and is a preferred mitochondrial resuscitant. It
is not an essential nutrient, since it can be made in the body from
other substances, such as glucose. ATP (adenosine triphosphate)
requires D-ribose, as do nucleotides, nucleotide coenzymes, and RNA
(ribonucleic acid). D-ribose, in the form of ribonucleoside
diphosphates, is converted to deoxyribonucleoside diphosphates,
precursor molecules for DNA. D-ribose in RNA and D-deoxyribose in
DNA. When D-ribose is added to the formulation, it is particularly
preferred to additionally include an AGE inhibitor to prevent the
potential glycating effect of d-ribose.
[0122] R-lipoic acid is implicated in mitochondrial energy
production and protection from free radicals. It has been shown to
maintain microsomal protein thiols, protect against hemolysis,
protect against neurological disorders, and protect against
ischemia/reperfusion injury. R, not S-lipoic acid is produced by
the body and decreases in concentration during the aging process
(Pick U., et al., Biochem Biophys Res Commun. 1995 Jan.
17;206(2):724-30). The formulation of the present invention
replenishes this vital substance as well as provides protection to
the skin cells. R-lipoic acid is incorporated in the formulation in
one preferred embodiment of the present invention.
[0123] Acetyl-L-carnitine has a three pronged anti-aging effect by
being a mitochondrial energy boosting agent, helping to boost
acetyl-choline necessary for proper face muscle tone and being an
effective antioxidant. It is useful in the transport of long-chain
fatty acids into the mitochondrial matrix, transport of short- and
medium-chain fatty acids away from the mitochondrial matrix, and
regulation of energy metabolism through the modulation of acetyl
CoA:CoA ratios. For this regulation, the acetyl group of acetyl CoA
is transferred to L-carnitine by carnitine acetyl-transferase
(CAT), freeing CoA to participate in the PDH reaction. The
acetyl-L-carnitine can then be removed from the mitochondria
(Arrigoni-Martelli E, et al., Drugs Exp Clin Res. 2001;27(1):27-49;
Rebouche C J. Carnitine. In: Shils M E, et al. eds. Nutrition in
Health and Disease. 9th ed. Baltimore: Williams & Wilkins;
1999:505-512). This increase of free CoA relative to acetyl CoA,
enhances the activity of pyruvate dehydrogenase (PDH) which
catalyzes the conversion of pyruvate to acetyl CoA, a crucial
reaction in glucose metabolism
(Ipi.oregonstate.edu/infocenter/othernuts/carnitine/carnitinerefs.html#re-
f2).
[0124] The macqui berry formulation may be combined with a
combination of a lipoic acid, a camitine, and a carnosine. The
usefulness of a combination having these three ingredients is
described in U.S. patent application Ser. No. 11/388,908, herein
incorporated by reference.
[0125] ATP, adenosine 5'-monophosphate (AMP), and their degradation
products may also be administered directly as agents in the topical
formulation of the present invention. U.S. Pat. No. 5,227,371
teaches the oral or topical administration of AMP, ATP or their
degradation products adenosine and inorganic phosphate to increase
ATP levels. Extracellular ATP has been shown to help regulate
vascular tone (Burnstock, G. and Kennedy, C Circul. Res. 1986, 58,
319-330), promote muscle contractions (Burnstock, G. Pharmacol.
Rev. 1972, 24, 509-581), and arresting tumor growth (U.S. Pat. No.
5,049,372). When ATP or other agents susceptible to degradation are
used, a stabilized form of the agent is preferred.
[0126] Transforming growth factor-beta (tgf-beta), a potent
fibrogenic cytokine has been shown to decreases intracellular
glutathione content, and increases collagen I mRNA content and
collagen protein production. The effect of glutatione depletion on
tgf-beta-stimulated collagen production may be mediated by
facilitating reactive oxygen species signaling. (Liu R M et al., Am
J Physiol Lung Cell Mol Physiol. 2004 286(1):1121-8.) It is
therefore contemplated to additional add tgf-beta to the
formulation of the present invention.
Depigmenting Agents
[0127] Depigmenting agents may be added as an additional agent in
the present invention. Depigmenting agents include tyrosinase
inhibitors such hydroquinone and its derivatives (e.g.,
hydroquinone monomethyl ether, hydroquinone monoethyl ether,
arbutin); soy and derivatives thereof, retinoids such as retinol;
Kojic acid and its derivatives (e.g., kojic dipalmitate);
transexamic acid; vitamins such as niacin, vitamin C and its
derivatives; azelaic acid; phytic acid, licorice; mulberry
extracts; extracts from rumex species such as rumex crispus
extract; chamomile extracts; green tea extracts; lactic acid, pearl
extract, Tricholoma matsutake extract, magnesium-asorbyl-phosphate,
edelweiss extract, sedum acre extract, arbutine, ergothione,
phyllantus emblica extract, .alpha.-MSH antagonists such as
Undecylenoyl phenylalanine, germanium, and GABA and songyi
mushroom. Bowman-Birk Inhibitors are described in U.S. Pat. No.
6,750,229 (e.g., inhibitors derived from the leguminosae,
solanaceae, gramineae or cucurbitaceae family). Dermalight.RTM. and
Clariskin3.RTM. from Silab are also depigmenting agents that can be
used. Kinetin (N6 furfuryladenine) is a 6-(R-amino)purine cytokinin
and is described in U.S. Pat. Nos. 5,602,139, 5,164,394, and
5,021,422. It has been shown to have anti-aging effects on the skin
of dogs as well as the depigmenting effects without adverse effects
(Kimura T, Doi K., Rejuvenation Res. 2004 Spring;7(1):32-9).
Skin-protective Lipids
[0128] Skin-protective lipids, such as ceramides, cerebrosides,
essential fatty acids and botanical or marine oils containing
these, calophyllum inophyllum squalene,squalane, botanical oils and
butters such as (shea butter, meadowsweet oil and coconut oil)
phospatidylserine, spingolipids and natural materials containing
them such as Conyza Canadensis, phospholipids and sulfatet sterols
available from Vincience may also be added to protect the skin. A
particular embodiment comprises a krill oil rich in Omega 3 PUFAs
(EPA and DHA) as well as in antioxidants such as vitamin A, E or
asthaxanthin. This lipid is particularly suitable for use in the
formulation of the present invention due to its multipronged
effects including antioxidant action (ORAC value of 378), energy
production function and anti-inflammatory action.
[0129] Nicotinamide-adenine-dinucleotide (NADH), in its reduced
form, is a coenzyme form of vitamin B3 (niacinamide), which occurs
in all living cells including human cells. Similarly,
nicotinamide-adenine-phosphate-dinucleotide (NADPH) is the
phosphoralated form of NADH, and as used herein, NADPH is included
in the term "NADH." NADH may be added to the formulations of the
present invention.
NADH
[0130] NADH stimulates the production of ATP (adenosine
triphosphate) during the regulation and release of stored energy.
Higher levels of NADH in the cell allow for the release of energy.
Because of this, the oral administration has been used to NADH
treat fatigue, chronic fatigue syndrome, and fibromyalgia. There is
also an indication that NADH may be useful in treating Alzheimer's
disease (U.S. Pat. No. 5,444,053), treating Parkinson's disease
(U.S. Pat. Nos. 4,970,200 and 5,019,561), depression, improving
memory and concentration, and enuurance.
[0131] The topical administration of NADH is described in U.S. Pat.
No. 5,952,312, which demonstrates that NADH is adsorbed by the skin
and stimulates enzymes essential in the production of energy. When
NADH is included in the topical formulation, an additional
stabilizer which inhibits oxidation of NADH may also be added. The
stabilizer is NaHCO.sub.3, ascorbic acid, sodium ascorbate,
tocopherols, tocopherol acetate, polyvinylpyrolidone, or a
combination thereof (U.S. Pat. No. 5,952,312).
[0132] The addition of NADH is useful in the formulation of the
present invention when lipoic acid or DHLA is incorporated in the
formulation because it allows for the conversion of R-lipoic acid
into the more active DHLA. As DHLA works to remove the signs of
aging in the skin, it is oxidized to the less effective R-lipoic
acid. NADH will then reduce the lipoic acid to form DHLA, which
then continues to remove the signs of aging. In formulations of the
present invention, the addition of NADH is also useful because DHLA
will be converted to lipoic acid upon contact with an oxidizing
species in the skin; the NADH then effectively converts the lipoic
acid back to DHLA. In one preferred embodiment, the topical
formulation of the present invention contains NADH (or NADPH) at a
concentration of 0.1%-10%, or more preferably 1%-5%.
Sunscreen Agents
[0133] In some embodiments, an additional active ingredients
included in the formulations of the present invention are compounds
having sunscreening action. Sunscreening agents include, but are
not limited to aminobenzoic acid, avobenzone, dioxybenzone,
homosalate, lisadimate, menthyl anthranilate, octocrylene, octyl
methoxycinnamate, octyl salicylate, oxybenzone, padimate o,
phenylbenzimidazole, roxadimate, sulisobenzone, titanium dioxide,
trolamine salicylate, zinc oxide, hammamelitannin, and combinations
thereof (see
www.nlm.nih.gov/medlineplus/druginfo/uspdi/202782.html). In one
particular embodiment, the sunscreen agent or agents are naturally
occurring substances such as zinc oxide, coffee oil, leuco-melanin,
date palm fruit melanin, and galanga extract (available from
symrise). Other substances that protect from uv damage that may be
used include such as sanguinaria extract krameria triandra root
extract (15% neolignans) metallothionein, 1,25-dihydroxyvitamin d3,
and thymidin dinucleotide. A preferred sun-protective extract is a
polypodium leucomotos extract. This compound may be incorporated in
the topical formulation or, alternatively, it may be provided as an
oral supplement in addition to the formulation of the present
invention for increased protection from UV damage (Middlekamp-hup
et al., J Am Acad Dermatol, 2004, 51(6) 910-918). One preferred
sunscreen agent is isoamyl-p-methoxycinnamate (from galanga,
available from symrise, GMBY & Co.); this compound provides an
spf of greater than 30 using only natural ingredients (botanicals,
antioxidants, coffe oil and microfine zinc oxide). Additional
sunscreen agents include allantoin, aloesin, apigenin,
caffeic-acid, chlorogenic-acid, ellagic-acid, esculetin, esculin,
ferulic-acid, fraxetin, fraxin, lawsone, p-aminobenzoic-acid, paba,
procyanidins, rutin, silymarin, squalene, and umbelliferone.
Anti-erythema Ingredient
[0134] By adding an anti-erythema ingredient to the formula, an
additional effect caused by the damaging UV radiation besides free
radical formation, is addressed. The reduction in redness
accomplished by applying the formulation of the present invention
is due to an incorporation of aesculin, colchicines, esculin,
glycyrrhetinic-acid, opc, opcs, procyanidin-a-2, procyanidins,
rutin, or silymarin into the formulation. Silymarin is a mixture of
at least 4 closely related flavonolignans, 60 to 70% of which is a
mixture of 2 diastereomers of silybin. It has been shown to
increase patient serum levels of glutathione and glutathione
peroxidase. It also works to increase superoxide dismutase (SOD)
activity of lymphocytes and erythrocytes, as well as the expression
of SOD in lymphocytes. Silymarin has been administered orally at a
dosage of 420 mg/day. (Wellington K, Jarvis B, BioDrugs.
2001;15(7):465-89).
Agents for Hormonal Decline
[0135] Hormonal decline is known to occur with aging; therefore a
class of substances replenishing and regulating these is useful in
combination with the macqui berry formulation of the present
invention. A non-exclusive list of agents useful for treating
hormonal decline is estriol, 7-keto-dhea, dhea, estrone, estradiol,
progesterone, pregnenolone, melatonin, soy isoflavons,
phytoestrogens (back cohosh, red clover, sage, etc.), chrysin,
diosgenin, vitex extract, diindolmethane, pueraria mirifica
(puresterol available from bio-botanica), .beta.-sitosterol,
.beta.-stigmasterol, betulin and derivatives thereof, conyza
canadensis essential oil, and maca extract standardized to
macamides.
Anti-acne Agents
[0136] Anti-acne agents may also be combined with the formulation
of the present invention. Since both free radicals and inflammation
are cofactors in acne, especially in adult skin, a combination with
one or more anti-acne ingredient may be used in the topical
formulation of the present invention. A non-limiting list of useful
anit-acne agents includes (-)-epigallocatechin,
(-)-epigallocatechin-gallate, .alpha.-pinene, .alpha.-terpineol,
anacardic-acid, azelaic-acid, baicalein, berberastine, berberine,
.beta.-carotene, camphor, caryophyllene, cryptotanshinone,
.delta.-cadinene, .gamma.-linolenic-acid, indole, linoleic-acid,
nerolidol, pufa, pufas, pyridoxine, resorcinol, selenium, sulfur,
terpinen-4-ol; thymol, tin, and zinc.
Anti-cellulitic Agents
[0137] Compounds having anti-cellulitic activities may be included
as an additional ingredient in the formulation of the present
invention. These compounds include, but are not limited to,
aesculin, bromelain, esculin, theobromine, and theophylline.
Additional anti-cellulitic compounds include caffeine,
di-indolmethane, anti-estrogenic botanicals, terminalia arjuna,
garcinia cambodgia, dihydromyricetin as found in Myriceline by
Provital, as well as a citrus aurantium extract (see U.S. Pat. No.
6,224,873). This compound does not cross the blood/ brain barrier
and has minimal impact on .alpha. 1,2 and .beta.1,2 receptors, and
is therefore safer then caffeine, and/or ephedra containing agents.
In one embodiment, no stimulants having a systemic effect if
absorbed into the bloodstream are incorporated into the
formulation.
Anti-edemic Agents
[0138] Compounds having an anti-edemic activity are useful in
combination with the formulation of the present invention. The
prevention of swelling and fluid retention in the skin present in
both face and body can be aided by combining an agent such as one
of the following to the compound of the present invention. These
compounds include, but are not limited to,
(e)-4-(3',4'-dimethoxyphenyl)-but-3-en-ol,
10-acetoxy-8-hydroxy-9-isobutyloxy-6-methoxythymol,
13',ii8-biapigenin, 4-vinyl-guaiacol, 7-methoxycoumarin, acetyl-
11-keto-.beta.-boswellic-acid, actinidoles, aescin, .alpha.-amyrin,
amentoflavone, anagyrine, anisodamine, anthocyanoside, arbutin,
aristolochic-acid, aromaticin, artemetin, ascorbic-acid,
asiaticoside, astringenin, aucubin, baicalein, baicalin,
bavachinin, berberastine, berberine, .beta.-aescin, .beta.-amyrin,
.beta.-boswellic-acid, .beta.-damascenone, .beta.-escin,
.beta.-sitosterol, betulinic-acid, boehmerol-acetate, boldine,
boswellic-acid, bradykininase, brazilin, bromelain, caffeic-acid,
caryophyllene, caryophyllene-oxide, catechin, cis-spiroether,
coniferyl-aldehyde, coumarin, crotaloburine, cryptolepine,
curcumin, damascenine, digitoxin, diosmin, ephedrine, ephedroxane,
escin, eugenol, eupahyssopin, faradiol, faradiol-monoester,
friedelan-3-.beta.-ol, gentianine, gentiopicroside, germacrone,
ginkgetin, ginsenoside-r-o, glucose, glycyrrhetic-acid,
glycyrrhetinic-acid, glycyrrhizin, gnaphaliin, hederagenin,
helenalin, humulone, isoferulic-acid, kawain, lanceolarin,
lapachol, lupeol, madecassoside, maslinic-acid, matricine, matrine,
oleanolic-acid, opc, opcs, oxoushinsunine, paeonol, papain
,papaverine, piperine, proanthocyanidins, procyanidin,
procyanidins, pseudoephedrine, quercitrin, resveratrol,
rosmarinic-acid, rutin, saikogenin, saikosaponin, sanguinarine,
sciadopitysin, scopoletin, serrapeptase, sinapaldehyde,
strophanthidin, syringaldehyde, taraxasterol, taraxasterol-acetate,
taspine, tylophorine, umbelliferone, ursolic-acid, and
withaferin-a.
Anticapillary-Fragility Agents
[0139] Compounds having `anticapillary-fragility` activity may also
be included as an additional ingredient. Capillary-fragility causes
telangiectasia and spider veins, which are preferably reduced or
removed from the skin by using an anticapillary-fragility agent.
Further, AGES and free radicals can cause damage to the fine
vessels and induce telangiectasia or spider veins; therefore this
class of agents is also useful. These agents include, but are not
limited to, aescin, aesculetin, aesculetol, aesculin, aesculoside,
diosmin, escin, esculetin, esculin, hederagenin, hesperidin,
hydroxyethylrutoside, hyperoside, inulicin, luteolol, maniflavone,
neoruscogenin, patulin, procyanidin-a-2, quercetol, quercetoside,
rhamnetol, ruscogenin, rutin, rutoside, and xanthorhamnoside.
Additionally, microcirculation decreases with age, especially
around the eyes. Therefore this class is also beneficial and
includes hydroxysuccinimide, chrysin(and other bilirubinolytic
substances such as gardenin, gardenoside, berberine) or ingredients
containing such substances eg Haloxyl from Sederma, Nattokinase,
and vitamin K in all its forms including menaquinone-7.
Anti-elastase Agents
[0140] Anti-elastase ingredients are also beneficial as additional
ingredients which enhance the formula's ability to firm the skin.
These agents include, but are not limited to, PROTEASYL.RTM. TP LS
8657 (from Laboratories Serobiologique), anthocyanins,
caffeic-acid, isoquercitrin, procyanidin-a-2, and quercetin. To
help target sagging of skin, these ingredients can be included that
improve adhesion of cells to the basement membrane and among
themselves by enhancing synthesis of laminin V and integrin alpha
6. One such ingredient is Serilesine from Lipotec.
Alpha Hydroxy Acids
[0141] Alpha hydroxy acids and .alpha.-hydroxy acid derivatives,
known for their exfoliating and resurfacing properties, may be
combined as an ingredient in the topical formulation of the present
invention in combination with a saccharide isomerate, green tea,
strontium chloride and/or a COX 2 inhibitor to prevent stinging. An
.alpha.-hydroxy acid is an organic compound containing at least one
hydroxy group and at least one carboxyl group, and wherein at least
one hydroxyl group is located on the .alpha.-carbon atom.
Typically, the compounds are organic acids having at least one
carboxylic acid group and at least one hydroxyl group on the
.alpha.-carbon atom, and may contain other functional groups
including additional hydroxyl and carboxylic acid moieties (e.g.,
glycolic acid, lactic acid).
Liposomes
[0142] A In a preferred embodiment, liposomes made by the process
described by AGI Dermatics (New York) may be used. These photosomes
and ultrasomes are useful in formulations used to target DNA repair
associated with photoaging and are described in U.S. Pat. NOS.
6,623,724 and 6,479,533. A marine-derived photolyase, a DNA-repair
enzyme from Anacystis nidulans plankton may be added to the
formulation. These enzymes, incorporated into a liposome (e.g.,
Photosome.RTM.), are adsorbed through the skin and repair
sun-damaged DNA. Redness and sunburn cell formation may also be
reduced or prevented by the addition of these enzymes.
Dermorelaxants
[0143] Dermorelaxants, which relax the muscles directly beneath the
skin, may also be incorporated into the formulation of the present
invention. These compounds relax the muscles and reduce wrinkles in
the skin. Dermorelaxants include compounds such as myoxinol from
cognis, boswellia extract and hexapeptides (available from
Lipotech, Spain) and may be incorporated into the formulation of
the present invention. Additional dermorelaxants include limonoids
such as those described in U.S. Pat. No. 6,866,856. Limonoids are
plant alkaloids of the Maliaecae family, such as toosendanin and
azadirachtin, that are useful for relaxing the facial expression
muscles.
Acetylcholine Precursor
[0144] An acetylcholine precursor may be added to the topical
formulation of the present invention. An acetylcholine recursor is
any precursor in the bio-synthetic pathway of acetylcholine, or
related pathways. These include co-factors and precursors of
acetylcholine, synthetic enzymes and precursors or enhancers of
acetyl production. Useful acetylcholine precursor compounds for the
invention include, but are not limited to, ethylaminoethanol,
methylaminoethanol, dimethylaminoethanol, isopropanolamine,
triethanolamine, isopropanoldimethylamine, ethylethanolamine,
2-butanolamine, choline, serine, the calcium salt of 2-aminoethanol
phosphate, the sodium salt of 2-aminoethanol phosphate, the
potassium salt of 2-aminoethanol phosphate, and mixtures thereof.
Many preferred embodiments employ methylaminoaminoethanol,
dimethylaminoethanol, ethylaminoethanol, the calcium salt of
2-aminoethanol phosphate, and/or triethanolamine; particularly
preferred is dimethylaminoethanol (DMAE) and/or the calcium salt of
2-aminoethanol phosphate.
Additional Agents
[0145] Another particularly preferred skin-protective agent is beta
glucan, which may be obtained from yeast, oat and mushroom species.
It is a free radical scavenger and stimulates nonspecific
immunity.
[0146] Hyaluronic acid, a component of connective tissue whose
function is to cushion and lubricate the tissue, as well as
hyaluronidase inhibitors such as extracts of Echinacea species, are
also useful as additional agents in the present formulation.
[0147] Forskholin and other agents useful in raising cyclic AMP are
also contemplated as ingredients in the present formulation.
[0148] Lion's mane is included in the formulation in one
embodiment. This medicinal mushroom (Hericium erinaceum) has been
used to treat dementia and contains at least two classes of
compounds, erinacines and hericenones, both which strongly
stimulate NGF synthesis (Kawagishi, H. et al., Townsend Letter for
Doctors and Patients, 4-2004).
[0149] The additional agents can be used in the formulation of the
present invention, or may be applied separately. The amount of
additional agent is dependent upon the activity of that particular
agent, and will vary depending upon the preferred formulation. In
most instances, each agent will be present in the formulation in an
amount from about 0.001 to about 30% by weight, preferably from
about 0.1 to about 5% by weight, based on the total weight of the
preparation.
[0150] In some embodiments, certain agents may be included in the
formulation in a homeopathically diluted form due to their
potential toxicity or irritating potential. Therefore, these agents
may be added at much lower concentrations. These agents would be
formulated according to strict homeopathic standards and, depending
on the substance, the effect may be the same or different from that
of the starting molecule.
[0151] Similalry, for highly active agents such as growth factors,
the amount of agent added to the formulation may be less than the
0.001% as described above. For these agents, the weight percent may
be from 0.00001%, or from 0.0001% and up.
[0152] Of the additional agents described herein, 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, or more additional agents may be added. The additional
agents may be combined with the topical formulation using any
combination that one of ordinary skill in the art would perceive to
combine. Two or more additional agents from one category (e.g., two
AGE inhibitors) may be added to the same formulation. Since the
combination of some of the additional agents may cause adverse
effects not outweighed by their positive benefit when topically
applied to the skin, care will be taken when making a topical
formulation. Data from the FDA, research publications and any other
known sources will be used to determine if there are known adverse
interactions between any of the ATP enhancing agents and additional
agents incorporated in the formulation. Combinations with
unacceptable adverse effects will not be used in the topical
formulations of the present invention.
IV. Topical Formulations
[0153] The formulations of the present invention may also comprise
dermatologically acceptable topical carriers. Dermatologically
acceptable carriers, also known as auxiliaries, are known in the
fields of dermatology, pharmacology, food technology and related
fields. In particular, the carriers listed in relevant Pharmacopeia
(e.g DAB Ph. Eur. BP NF), and other auxiliaries whose properties do
not impede physiological use when applied to the skin, may be
used.
[0154] Suitable carriers may be lubricants, wetting agents,
emulsifying and suspending agents, preservatives, anti-irritants,
emulsion stabilizers, film formers, gel formers, odor masking
agents, resins, hydrocolloids, solvents, solubilizers, neutralizing
agents, permeation accelerators, pigments, quaternary ammonium
compounds, refatting and superfatting agents, ointment, cream or
oil base materials, silicone derivatives, stabilizers, sterilizing
agents, propellants, drying agents, opacifiers, thickeners, waxes,
emollients, or white oils.
[0155] Only effective amounts of macqui berry or macqui berry
extract and other optional active ingredients are needed. Generally
topical application is accomplished in association with a carrier,
and particularly one in which the active ingredients are soluble
per se or are effectively solubilized (e.g., as an emulsion or
microemulsion). Where employed, the carrier is inert in the sense
of not bringing about a deactivation or oxidation of the compounds,
and in the sense of not bringing about any adverse effect on the
skin areas to which it is applied. In one preferred practice of the
invention, active ingredients are applied in admixture with a
dermatologically acceptable carrier or vehicle so as to facilitate
topical application and, in some cases, provide additional
therapeutic effects as might be brought about by, e.g.,
moisturizing of the affected skin areas. While the carrier for
dermatological formulations can consist of a relatively simple
solvent or dispersant such as water, it is generally preferred that
the carrier comprise a composition more conducive to topical
application, and particularly one which will form a film or layer
on the skin to which it is applied so as to localize the
application in areas that will be electrically stimulated and/or
aid in the percutaneous delivery of the active agent.
[0156] Many preparations of topical carriers are known in the art,
and include lotions containing oils and/or alcohols and emollients,
vegetable oils, hydrocarbon oils and waxes, silicone oils, animal
or marine fats or oils, glyceride derivatives, fatty acids or fatty
acid esters or alcohols or alcohol ethers, lecithin, lanolin and
derivatives, polyhydric alcohols or esters, wax esters, sterols,
phospholipids and the like, and generally also emulsifiers
(nonionic, cationic or anionic), although some of the emollients
inherently possess emuisifying properties. Tnese same general
ingredients can be formulated into a cream rather than a lotion, or
into gels, or into solid sticks by utilization of different
proportions of the ingredients and/or by inclusion of thickening
agents such as gums or other forms of hydrophilic colloids. They
may be formulated using conventional techniques known to those of
ordinary skill in the art.
[0157] Additional excipients commonly found in skin care
compositions such as, for example, emollients, skin conditioning
agents, emulsifying agents, humectants, preservatives,
antioxidants, perfumes, chelating agents, buffering agents, etc.
may be utilized provided that they are physically and chemically
compatible with other components of the formulation. Preservatives
include, but are not limited to, C.sub.1-C.sub.3 alkyl parabens and
phenoxyenthanol, typically present in an amount ranging from about
0.5% to about 2.0% by weight percent, based on the total
formulation. Emollients, typically present in amounts ranging from
about 0.01% to 5% of the total formulation include, but are not
limited to, fatty esters, fatty alcohols, mineral oils, polyether
siloxane copolymers, and mixtures thereof. Humectants, typically
present in amounts ranging from about 0.1% to about 5% by weight of
the total formulation include, but are not limited to, polyhydric
alcohols such as glycerol, polyalkylene glycols (e.g., butylene
glycol, propylene glycol, dipropylene glycol, polypropylene glycol,
and polyethylene glycol) and derivatives thereof, alkylene polyols
and their derivatives, sorbitol, hydroxy sorbitol, hexylene glycol,
1,3-dibutylene glycol, 1,2,6-hexanetriol, ethoxylated glycerol,
propoxylated glycerol, and mixtures thereof. Emulsifiers, typically
present in amounts from about 1% to about 10% by weight of the
formulation, include, but are not limited to, stearic acid, cetyl
alcohol, stearyl alcohol, steareth 2, steareth 20,
acrylates/C.sub.10-30 alkyl acrylate crosspolymers, and mixtures
thereof. Chelating agents, typically present in amounts ranging
from about 0.01% to about 2% by weight, include, but are not
limited to, ethylenediamine tetraacetic acid (EDTA) and derivatives
and salts thereof, dihydroxyethyl glycine, tartaric acid, and
mixtures thereof. Buffering agents may be added to provide the
formulation with a pH ranging from about 4.5 to about 8.5, more
preferably from about 5.5 to about 8.5, most preferably from about
6.5 to about 8.0. Typical buffering agents are chemically and
physically stable agents commonly found in cosmetics, and can
include compounds that are also adjunct ingredients such as citric
acid, malic acid, and glycolic acid buffers.
[0158] One particular embodiment comprises the use of novel
dispersions of hydrophobes to yield a surfactant-free formulation,
by subjecting the materials to high pressure, high shear
processing. Cold process formulations are also a preferred method
as they protect certain heat-sensitive sensitive agents in the
formulation; they can be obtained by using self-emulsifying
oleosomes such as Natrulon OSF available from Lonza. In one
embodiment, the formulation is processed using the carriers and
dry-water process of Aerosil.RTM. (Degussa), which is based on
fumed silica. (see
www1.sivento.com/wps3/portal/en/aerosil/industries/personal0.html).
[0159] According to the invention, the formulations are
administered topically in the form of a cream, gel, or liquid. The
topical administration provides the stabilized macqui berry
formulation directly to the skin, which is preferably provided with
the use of a dermatologically acceptable carrier. While the carrier
may consist of a relatively simple solvent or dispersant, such as
an oil, it is generally preferred that the carrier comprise a
material more conducive to topical application, and particularly
one which will form a film or layer on the skin to which it is
applied. This localizes the application and provides some
resistance to perspiration and/or aids in percutaneous delivery and
penetration of the active ingredients into lipid layers. Many such
compositions are known in the art, and can take the form of creams,
gels, ointments, hydrogels, pastes or plasters, and liquid dosage
forms, such as solutions, emulsions, in particular oil-in-water
emulsions, suspensions, for example lotions, etc., or even solid
sticks. Liposomes or microspheres may also be used.
[0160] In some embodiments, the topical formulation will be
administered using a device or method designed to more readily
break the skin barrier and provide the agents in the topical
formulation with a faster or more effective means through the
stratum corneum. These include, for example, oxygen nebulizers and
nanosomal mist in conjunction with iontophoresis. A spray or
nebulizer may be used to create the nanosomel mist. In one
embodiment, the micro-electronic cosmetic delivery mechanism
described as PowerCosmetics.TM. may be used for delivery of the
topical agent to the skin. This method is useful for delivering
ionizable compounds to the skin and aids the penetration of small
molecules through the stratum corneum. (www.powerpaper.com).
[0161] Only effective amounts of each of the components in the
topical formulation are needed to treat the signs of aging in skin.
Generally, an effective amount of the topical formulation is
applied to exposed or affected skin sites in association with a
carrier, and particularly one in which the active ingredients are
soluble per se or are effectively solubilized (e.g. as an emulsion
or microemulsion). The term "an effective amount" of a compound or
property means an amount effective in reducing the signs of aging
skin, such as wrinkles, pigmentary changes, elastosis, and atrophy.
The exact amount required will vary from case to case, depending on
recognized variables such as the compounds employed and the
individual subject treated. Thus, it is not possible to specify an
exact "effective amount." However, an appropriate effective amount
may be determined by one of ordinary skill in the art using only
routine experimentation.
[0162] Preferably, the formulation will contain 0.01 to 80% by
weight of the macqui berry or macqui berry extract. Desirably, it
will contain 0.1%-10.0% by weight, or more preferably 1-5% by
weight macqui berry or macqui berry extract. Carriers can be chosen
which will solubilize or disperse the active ingredients at such
concentrations as provided herein. One particularly efficacious
embodiment contains about 1-5% by weight anthocyanins and 1-3% by
weight flavonoid glucuronide in a liposomal carrier.
[0163] As used herein, the term "treatment of aging skin" means the
treatment of the symptoms of skin damage due to either chronoaging
or photoaging of the skin, which is characterized by wrinkles, loss
of elasticity, and hyper-pigmentation. The treatment is effective
to enhance the appearance and/or health of the skin. This includes,
for example, reducing oxidative damage in the skin.
[0164] The term "effective amount" of a compound or property as
provided herein means such an amount as is capable of performing
the function of the compound or property for which an effective
amount is expressed. As pointed out above, the exact amount
required will vary from case to case, depending on recognized
variables, such as the compounds employed and the processing
conditions observed. Thus, it is not possible to specify an exact
"effective amount." However, an appropriate effective amount may be
determined by one of ordinary skill in the art using only routine
experimentation.
[0165] As used herein, the phrase "formulated for use in a
beverage" means that the formulation containing the macqui berry or
macqui berry extract is combined with ingredients that are safe for
human consumption. Optionally, these ingredients may be to keep the
macqui berry or macqui berry extract in solution or to improve or
enhance the flavor or color.
[0166] As used herein, the phrase "formulated for use in a candle"
means that the formulation containing the macqui berry or macqui
berry extract contains ingredients to keep the formulation stable
within candle wax. The formulation may be adapted to keep the
formulation mixed within the candle wax to maintain a consistent
color, or it may provide optimal release of aromatics from the
macqui berry or additional source to provide a pleasing smell.
[0167] Following long-standing patent law convention, the terms "a"
and "an" mean "one or more" when used in this specification. Each
patent described herein is hereby incorporated by reference in its
entirety.
EXAMPLES
[0168] The following examples are included to demonstrate preferred
embodiments of the invention. It should be appreciated by those of
skill in the art that the techniques disclosed in the examples
which follow represent techniques discovered by the inventor to
function well in the practice of the invention, and thus can be
considered to constitute preferred modes for its practice. However,
those of skill in the art should, in light of the present
disclosure, appreciate that many changes can be made in the
specific embodiments which are disclosed and still obtain a like or
similar result without departing from the spirit and scope of the
invention.
Example 1
[0169] TABLE-US-00002 Ingredient % by weight macqui berry extract
3.0 luteolin 7-glucuronide 1.0 Carriers and Excipients 96.0
Example 2
[0170] TABLE-US-00003 Ingredient % by weight macqui berry juice 5.0
quercetin 3-(isoferulylglucuronide) 3.0 Carriers and Excipients
92.0
Example 3
[0171] TABLE-US-00004 Ingredient % by weight macqui berry extract
3.0 Glutathione 3.0 Carnosine 1.0 Carnitine 1.0 Carriers and
Excipients 92.0 The formulation is encapsulated in a polysaccharide
micro-capsule.
Example 4
[0172] TABLE-US-00005 Ingredient % by weight macqui berry extract
0.5% Bilberry extract 0.5% Rosmarinic 0.1% Glutathione 1.0% Green
tea polyphenols 1.0% Resveratrol 0.1% Phenyl-butyl-nitrone(PBN)
0.1% Boldine 0.5% EGF 0.5% Rutin 0.5% MMP inhibiting
glycosaminoglycans 1.0% Tocopherols 0.5% SOD 0.5% Carriers and
Excipients 93.2%
Example 5
[0173] TABLE-US-00006 Ingredient % by weight macqui berry extract
1.0% Rosmarinic 0.5% Retinol 1.0% alpha-hydroxy acids 3.0%
allantoin 2% 2.0% betaine 5% 5.0% Carriers and Excipients 87.5%
Example 6
[0174] TABLE-US-00007 Ingredient % by weight macqui berry 0.1%
Vigna aconitifolia seed extract 5% 5% Coffe fruit extract 0.1% 0.1%
Saffron extract 0.01% 0.01% Betacyanins 0.01% 0.01% R-lipoic sodium
salt 0.01% 0.01% Rosemary extract 0.1% 0.1% ATP 0.01% 0.01% EGF
0.01% 0.01% Carnosine 0.01% 0.01% Sodium phytate 0.05 0.05%
Carriers and Excipients 94.6%
[0175] Having described the invention with reference to particular
compositions, theories of effectiveness, and the like, it will be
apparent to those skilled in the art that it is not intended that
the invention be limited by such illustrative embodiments or
mechanisms, and that the modifications can be made without
departing from the scope or spirit of the invention, as defined by
the appended claims. It is intended that all modifications and
variations be included with the scope of the invention. The claims
are meant to cover the claimed components and steps in any sequence
that is effective to meet the objectives there intended, unless the
context specifically indicates the contrary.
* * * * *
References