U.S. patent application number 10/091878 was filed with the patent office on 2003-09-11 for methods and devices for transdermal delivery of anti-aging compounds for treatment and prevention of facial or neck skin aging.
This patent application is currently assigned to Consumers Choice Systems, Inc.. Invention is credited to Kelley, Terry G..
Application Number | 20030167556 10/091878 |
Document ID | / |
Family ID | 27787759 |
Filed Date | 2003-09-11 |
United States Patent
Application |
20030167556 |
Kind Code |
A1 |
Kelley, Terry G. |
September 11, 2003 |
Methods and devices for transdermal delivery of anti-aging
compounds for treatment and prevention of facial or neck skin
aging
Abstract
Novel devices and methods are provided for preventing and
treating facial and neck skin aging in mammalian subjects. A
partial or complete facial or neck skin patch or mask includes a
flexible patch or mask body formed of a porous material that is
sized and dimensioned to conform to one or more contoured facial
and/or neck skin areas of the subject. Adhesive or other attachment
means connect the patch or mask body in contact with one or more
contoured facial and/or neck skin areas of the subject. At least
one anti-aging effective compounds, such as CoQ.sub.10, is applied
to or otherwise provided in chemical communication with an
undersurface of the patch or mask body to effectuate delivery of
the anti-aging compound to the contoured facial and/or neck skin
area, in an effective amount and for an extended period of time
effective to prevent or alleviate symptoms of skin aging in the
facial and/or neck skin area to which the patch or mask is
applied.
Inventors: |
Kelley, Terry G.; (Kirkland,
WA) |
Correspondence
Address: |
WOODCOCK WASHBURN LLP
ONE LIBERTY PLACE, 46TH FLOOR
1650 MARKET STREET
PHILADELPHIA
PA
19103
US
|
Assignee: |
Consumers Choice Systems,
Inc.
|
Family ID: |
27787759 |
Appl. No.: |
10/091878 |
Filed: |
March 5, 2002 |
Current U.S.
Class: |
2/206 |
Current CPC
Class: |
A61K 8/35 20130101; A45D
44/002 20130101; A61K 8/0208 20130101; A61Q 19/08 20130101 |
Class at
Publication: |
2/206 |
International
Class: |
A42B 001/18 |
Claims
I claim:
1. A facial or neck patch or mask for treatment of facial or neck
skin aging in a mammalian subject comprising: a flexible patch or
mask body formed of a porous material, said patch body sized and
dimensioned to conform to a facial or neck skin area of said
subject; attachment means connected to the patch or mask body for
securely, removably attaching the patch or mask in contact with one
or more contoured facial and/or neck skin areas of the subject; at
least one anti-aging effective compound provided in chemical
communication with an undersurface of the patch or mask body to
effectuate delivery of the anti-aging compound to the contoured
facial and/or neck skin area in an effective amount, and for an
effective period of time, to prevent or alleviate symptoms of skin
aging in the facial and/or neck skin area to which the patch or
mask is applied.
2. The facial or neck patch or mask of claim 1, wherein the
flexible patch or mask body is sized and dimensioned to conform to
one or more contoured facial and/or neck skin area(s) of the
subject selected from an orbital margin, nasal skin area, labial
margin, mandibular, maxillary, or temporal lateral facial skin
area, chin, jowl and/or neck skin area of the subject.
3. The facial or neck patch or mask of claim 1, wherein the facial
or neck patch or mask conforms and stretches in conjunction with
normal facial and neck skin movements as occur during jaw flexure,
head turning, and eye opening and closure.
4. The facial or neck patch or mask of claim 3, wherein the patch
or mask body is constructed for expansion and/or elastic flexure in
all directions planar to an undersurface of the patch or mask that
is applied to a facial or neck skin area to be treated.
5. The facial or neck patch or mask of claim 1, wherein the
attachment means is selected from: a tie, elastic or other manual
closure means that attaches to opposing lateral margins of the
patch or mask and encircles a head of the subject; one or more
mounting elements attached to opposing margins of the patch or mask
and adapted for engaging an ear or other securely engageable
anatomical feature of the subject's face; and/or adhesive gel,
strips, tape or other adhesive means connected to an undersurface
of the patch or mask or interposable between the undersurface of
the patch or mask and a skin surface area to be treated to provide
for adhesive attachment of the patch or mask thereto.
6. The facial or neck patch or mask of claim 1, comprising an
orbital patch or mask sized and dimensioned to conform to an
orbital margin of the subject for treatment of periorbital skin
aging in the subject.
7. The orbital patch or mask of claim 6, which conforms to one or
more portions of the orbital margin of the subject selected from a
supraorbital margin, infraorbital margin, lateral orbital and/or
medial orbital margin of the eye.
8. The orbital patch or mask of claim 6, wherein the patch or mask
comprises one or more separate or conjoined, countoured sections
individually shaped and dimensioned to conform to a selected
portion of the orbital margin.
9. The orbital patch or mask of claim 8, wherein said one or more
separate or conjoined, countoured sections are individually shaped
and dimensioned to conform to a portion of the orbital margin
selected from: a lenticular area of the supraorbital margin; a
lenticular area of the infraorbital margin; a medial orbital
margin; and a lateral orbital margin.
10. The orbital patch or mask of claim 8, wherein said one or more
separate or conjoined, countoured sections are conjoined in a
single patch or mask having a unitary body or by interconnecting
member(s) joining the individual sections in an anatomically
integrated array of sections.
11. The facial or neck patch or mask of claim 1, comprising a nasal
skin patch or mask sized and dimensioned to conform to a nasal skin
surface of the subject for treatment or prevention of nasal skin
aging in the subject.
12. The facial or neck patch or mask of claim 1, comprising a
labial skin patch or mask sized and dimensioned to conform to a
labial margin of the subject for treatment or prevention of
perilabial skin aging in the subject.
13. The facial or neck patch or mask of claim 1, comprising a neck
skin patch or mask sized and dimensioned to conform to a neck skin
surface of the subject for treatment or prevention of neck skin
aging in the subject.
14. The facial or neck patch or mask of claim 1, wherein the patch
or mask effectively and evenly delivers the anti aging effective
compound to a facial or neck skin surface to be treated in a
delayed release mode or formulation to provide extended, controlled
release of the anti-aging compound for a period of time effective
to prevent or reverse one or more symptoms of periorbital skin
aging in the subject.
15. The facial or neck patch or mask of claim 1, wherein the patch
or mask effectively delivers the anti aging effective compound to
achieve an effective concentration anti aging effective compound
over an extended period effective to reduce or prevent one or more
symptoms of facial and/or neck skin aging selected from: a)
Degeneration of the microvascular system; b) Flaccidity and
development of wrinkles due to a decrease in and/or crosslinking of
collagen, accumulation of glucosaminoglycans (base substance)
and/or solar elastosis (elastin clumping); c) Flattening of the
retial cones, associated with a reduction in thickness or area
between the dermis and epidermis through which substances are
exchanged for healthy metabolism of the epidermis; d) Restricted
regenerative turnover in the epidermis associated with defective
hornification, leading to drying out of the skin, roughness of the
skin, chapping of the skin and/or flaking; e) Defective regulation
of cell division (proliferation) and cell maturation
(differentiation) in the epidermis associated with cellular atypia,
atrophies, and loss of polarity; and/or f) Local hyper- and
hypopigmentation and/or abnormal pigmentation (age spots).
16. The facial or neck patch or mask of claim 1, wherein the patch
or mask body, or at least an undersurface portion thereof, serves
as a substrate or reservoir for receiving and retaining the
anti-aging effective compound.
17. The facial or neck patch or mask of claim 1, wherein the
anti-aging effective compound is absorbed, adsorbed, or otherwise
admixed with or invested in a material of the patch or mask body in
direct chemical communication between the patch or mask body and
the undersurface thereof through pores, fissures, perforations,
and/or other communication channels provided within the patch or
mask body or a layer thereof adjacent the undersurface.
18. The facial or neck patch or mask of claim 1, wherein the
attachment means comprises a bioadhesive material.
19. The facial or neck patch or mask of claim 1, wherein the
bioadhesive serves a dual purposes of mediating affixation of the
patch or mask to the facial or neck skin and providing a carrier or
delivery vehicle for incorporation and delivery of the anti-aging
effective compound(s).
20. The facial or neck patch or mask of claim 1, wherein the
anti-aging effective compound is an anti-oxidant.
21. The facial or neck patch or mask of claim 20, wherein the
anti-oxidant is Coenzyme Q.sub.10.
22. The facial or neck patch or mask of claim 1, wherein a
plurality of ant aging effective compounds are applied
simultaneously or coordinately with the patch or mask to yield
enhanced treatment or prophylaxis of skin aging in the subject.
23. The facial or neck patch or mask of claim 1, wherein the
anti-aging effective compound is selected from the group consisting
of: a ubiquinone; plastoquinone; vitamin A; vitamin B6; vitamin C;
vitamin D; vitamin E; glutathione; carnitine; arginine; taurine;
cysteine; methionine; superoxide dismutase; catalase; alpha lipoic
acid; dihydrolipoic acid; proanthocyanadins; and melatonin.
24. The facial or neck patch or mask of claim 1, which provides
controlled, time-release delivery of one or more anti-aging
effective compound(s) for a prolonged delivery time period selected
from: 1-4 hours; 4-8 hours; or more than 8 hours; to effectively
prevent or reverse one or more symptoms of facial skin aging in the
subject.
25. The facial or neck patch or mask of claim 1, comprising a
facial mask shaped and dimensioned to conform to multiple facial
skin areas.
26. The facial or neck patch or mask of claim 1, further comprising
a separate or integral, self-contained or externally charged
thermal element.
27. The facial or neck patch or mask of claim 26, wherein the
thermal element is a heating element to facilitate delivery and
activity of the anti-aging effective compound by increasing the
temperature at a target skin area.
28. The facial or neck patch or mask of claim 26, wherein the
thermal element is a thermal gel that can function as a heating
and/or cooling element.
29. The facial or neck patch or mask of claim 26, wherein the
thermal element is permanently or removably enclosed within a
pocket or cavity attached to or surrounded by the patch or mask
body.
30. The facial or neck patch or mask of claim 1, wherein the
anti-aging effective compound is formulated with a polymeric
delivery vehicle, hydrogel, or biodegradable polymer or matrix.
31. The facial or neck patch or mask of claim 1, wherein the patch
or mask body is comprised of a polymer or fiber material.
32. A method for treating facial and/or neck skin aging in a
mammalian subject comprising: applying a facial or neck patch or
mask to a facial and/or neck skin area(s) in the subject, wherein
the patch or mask comprises a flexible patch body formed of a
porous material sized and dimensioned to conform to one or more
contoured facial and/or neck skin area(s) of the subject; and
removably securing the patch or mask to the facial and/or neck skin
area(s) by attachment means connected to the patch body, wherein
the patch or mask delivers an anti-aging effective compound to the
facial skin and/or neck skin area(s) from an undersurface of the
patch or mask body after the patch or mask has been applied to
yield enhanced delivery and bioavailability of the anti-aging
compound to underlying facial and/or neck skin area(s) to
substantially prevent or alleviate one or more symptoms of facial
and/or neck skin aging therein.
Description
BACKGROUND OF THE INVENTION
[0001] Skin aging results from intrinsic and extrinsic processes.
The innate or intrinsic aging process of the skin, called
chronologic aging, is distinguished from changes resulting from
actinic damage, which is mainly due to UV light, called photoaging.
(Emerit, Free Radicals and Aging, Eds., I. Emerit & B. Chance,
1982, Birkhauser Verlag, Switzerland, incorporated herein by
reference). Both processes are superimposed on sun-exposed parts of
the body such as the hands and face.
[0002] Clinical morphological and biochemical characteristics of
intrinsic and actinic aging processes are distinct. Various
macroscopic and microscopic differences between the two processes
have been described. (Gilchrest et al., J. Invest. Dermatol. 80:
81-85, 1983; Kligman, Aging and the Skin, pp. 331-346, Eds. A. K.
Balin and A. M. Kligman, 1989, Raven Press, New York; Montagna et
al., J. Am. Acad. Dermatol. 21: 907-918, 1989, each incorporated
herein by reference). Macroscopically, intrinsic aging of the skin
results in fine wrinkling, thinning and laxity of the skin, while
photoaged skin displays a telangiectactic, leathery, dry, nodular
surface with deep wrinkles, accentuated skin furrows, sags and
bags. In addition, photoaged skin shows irregularities in
pigmentation, actinic keratoses, as well as a variety of benign or
premalignant growths. Microscopically, the dominant change in
photoaging of the skin is the hyperplasia of elastic tissue in the
dermis, which may lead to complete disorganization described as
solar elastosis. In contrast, intrinsic aging induces only a modest
increase in the number and thickness of the elastic fibers.
Collagen undergoes only minor changes in intrinsic aging, while
photoaging results in loss of collagen bundles, a decrease in
mature collagen and an increase in type III collagen. The ground
substance of the dermal matrix, which is composed of proteoglycans
and hyaluronic acid, increases greatly in photoaged skin, while in
protected skin the ground substance decreases with age.
[0003] Oxygen derived free radicals are generated in the skin from
various sources and by various mechanism. In addition the skin is
exposed to free radical generating environmental agents such as air
pollutants and solar radiation. It is generally believed that free
radicals are responsible for at least part of the degenerative
changes leading to cutaneous aging (Black, Photochem. Photobiol.
46: 213-221, 1987, incorporated herein by reference)
[0004] Hope for the successful treatment of intrinsic aging and
photoaging of skin depends in part on the identification of
therapeutic substances that can be effectively administered to
patients to mediate or enhance skin protection and/or healing. One
substance that has been reported as an effective agent against skin
aging is a coenzyme designated "CoEnzyme Q". CoEnzyme Q is also
known as ubiquinone on the basis that it occurs ubiquitously in
biological systems. CoEnzyme Q is a quinone derivative with a long
isoprenoid tail. The number of 5-carbon isoprene units in the
coenzyme is variable. The most common form in mammals contains 10
isoprene units (CoEnzyme Q10, or CoQ10), but other forms contain up
to 15 isoprene units (CoQ15). CoQ is the coenzyme for at least
three mitochondrial enzymes (Complexes I, II, and III) as well as
enzymes in other parts of the cell. These mitochondrial enzymes,
which function in the oxidative phosphorylation pathway, are
essential for the production of ATP, the energy source upon which
all cellular functions depend. The biosynthesis of CoQ is known to
be a multi-stage process requiring at least eight vitamins and
several trace elements.
[0005] CoQ10 has been reported to yield beneficial therapeutic
effects for many skin disorders, which effects may be attributed to
antioxidant or free radical quenching properties of the coenzyme.
Administration of CoQ10 reportedly reduces antioxidant damage to
tissues and improves the immunocompetence of treated cells. These
properties may be enhanced by administration of CoQ10 in
combination with other nonenzymatic and enzymatic antioxidants.
Based on a limited number of clinical trials, it has further been
reported that CoQ10 works most effectively in the presence of
certain vitamins and amino acids, including vitamins A, B6, C, D,
and E, glutathione, carnitine, arginine, taurine, cysteine and
methionine. Other ingredients may also significantly improve the
therapeutic efficacy of CoQ10, for example the enzymes superoxide
dismutase (SOD) and catalase, alpha-lipoic/dihydrolipoic acid, and
proanthocyanadins.
[0006] Previous attempts to transdermally deliver protective
substances such as CoQ10 and other anti-oxidants for therapeutic
treatment to the skin, particularly to areas of the neck and face
that are especially vulnerable to aging effects, have suffered from
a number of important and confounding deficiencies. One important
challenge that remains is to provide improved medication patches
that will continuously and evenly distribute medication to an
extended surface area of the facial and neck skin. Conventional
medication patches are also poorly adapted for comfortably and
effectively delivering medication to the skin of the face or neck
to treat facial or neck skin aging, particularly for an extended
time period of treatment. In particular, conventional medication
patches are not designed to conform to the contours and/or
movements of facial or neck skin areas. Related to these
deficiencies, conventional patches do not remain in effective
contact with the skin of the face or neck for an extended period of
time for controlled, extended release of medication from the patch
to the skin of the face or neck. Additional drawbacks of available
transdermal patch delivery devices and methods point to a need for
improved pharmaceutical formulations and methods for administering
protective substances, such as anti-oxidants, that are stable and
well tolerated and that provide enhanced delivery and
bioavailability to facial and neck skin areas.
SUMMARY OF THE INVENTION
[0007] The present invention fulfills the foregoing needs and
satisfies additional objects and advantages by providing novel,
effective devices, methods, and compositions for preventing and
treating facial and neck skin aging in a mammalian subject,
typically a human subject. In various alternative embodiments of
the invention a partial or complete facial or neck skin patch or
mask is provided that comprises a flexible patch or mask body
formed of a porous material. The patch or mask body is sized and
dimensioned to conform to one or more contoured facial and/or neck
skin areas of a subject to be treated for prevention or reversal of
skin aging. The patch or mask of the invention further comprises
attachment means connected to the patch or mask body for securely
attaching the patch or mask in contact with one or more contoured
facial and/or neck skin areas of the subject. One or more
anti-aging effective compound(s) is/are applied to, or otherwise
provided in chemical communication with, an undersurface of the
patch or mask body to effectuate delivery of the anti-aging
compound to the contoured facial and/or neck skin area in an
effective amount, and for an effective period of time, to prevent
or alleviate symptoms of skin aging in the facial and/or neck skin
area to which the patch or mask is applied.
[0008] In other embodiments, the invention provides a facial and/or
neck patch or mask for enhanced delivery of an anti-aging effective
compound to a facial and/or neck skin area of a mammalian subject
to treat or prevent skin aging in the subject. The facial and/or
neck patch or mask comprises a flexible patch or mask body formed
of a porous material. The patch or mask body is sized and
dimensioned to conform to one or more contoured facial and/or neck
skin area(s) of the subject, such as an orbital margin, nasal skin
area, labial margin, mandibular, maxillary, or temporal facial skin
area, chin, jowl and/or neck skin area of the subject. Flexibility
of the facial and neck patches and masks allows conformity and
stretching of the patch or mask in conjunction with normal facial
and neck skin movements, as occur during jaw flexure, head turning,
and eye opening and closure. Accordingly, the patch or mask body is
typically constructed for expansion and/or elastic flexure in all
directions planar to an undersurface of the patch or mask that is
applied to the facial or neck skin area to be treated. An
attachment means is connected to the patch body for securely
attaching the patch in contact with the facial and/or neck skin
area(s) to be treated. An anti-aging effective compound is provided
in contact with an undersurface of the patch body, which is adapted
for enhanced delivery and bioavailability of the anti-aging
compound to a facial and/or neck skin area to prevent or alleviate
symptoms of skin aging in the area(s) to which the patch or mask is
applied.
[0009] In further embodiments of the invention, a method for
treating facial and/or neck skin aging is provided that involves
applying a facial or neck patch or mask to a facial or neck skin
area in a mammalian subject. The patch or mask comprises a flexible
patch body formed of a porous material sized and dimensioned to
conform to one or more contoured facial and/or neck skin area(s) of
the subject, such as an orbital margin, nasal margin, labial
margin, or jowl skin area of the subject. The patch or mask is
applied to the subject facial and/or neck skin area(s) and
removably secured thereto by an attachment means connected to the
patch body for securely attaching the patch in contact with the
facial skin area(s) to be treated. The methods of the invention
further include delivering an anti-aging effective compound to the
facial skin and/or neck skin area(s) to be treated from an
undersurface of the patch or mask body after the patch or mask has
been applied, to yield enhanced delivery and bioavailability of the
anti-aging compound to the underlying facial and/or neck skin to
prevent or alleviate one or more symptoms of facial skin aging. In
more detailed aspects, the methods of the invention yield
controlled, time-release delivery of the anti-aging compound. In
other detailed aspects of the invention, a second anti-aging
effective compound is coordinately delivered with patch- or
mask-mediated administration of the first anti-aging effective
compound. Typically, the second anti-aging effective compound is
formulated in combination with the first anti-aging effective
compound and coordinately delivered via the facial patch or mask,
as described above. Alternatively, the second anti-aging effective
compound may be topically applied or otherwise coordinately
delivered to the facial and/or neck skin area to be treated before
or after application of the patch or mask.
[0010] In more detailed aspects of the invention, the facial patch
or mask comprises an orbital patch or mask for treatment of
periorbital skin aging in a mammalian subject. The orbital patch or
mask comprises a flexible patch or mask body formed of a porous
material, wherein the patch or mask body is sized and dimensioned
to conform to an orbital margin of the subject. An attachment means
is connected to the patch or mask body for securely attaching the
patch or mask in contact with the orbital margin of the subject. An
anti-aging effective compound is applied to or otherwise provided
in contact with an undersurface of the patch or mask body. The
undersurface of the patch or mask body is adapted for effective
delivery of the anti-aging compound to the orbital margin of the
subject for a period of time effective to prevent or alleviate
symptoms of periorbital skin aging.
[0011] In additional detailed aspects, an orbital patch or mask is
provided as above that conforms to one or more selected portions of
the orbital margin of the subject. Thus, the patch or mask may
conform to one or more areas of the orbital margin selected from
the supraorbital margin, infraorbital margin, lateral orbital
margin and/or medial orbital margin of the eye. In related aspects,
the orbital patch or mask may comprise one or more separate or
conjoined, countoured sections individually shaped and dimensioned
to conform to a selected portion of the orbital margin, for example
one or more sections conforming collectively or individually to a
lenticular area of the supraorbital margin, a lenticular area of
the infraorbital margin, a medial orbital margin, and/or a lateral
orbital margin. These sections may be provided as individual
patches, or the sections may be conjoined in a single patch or mask
having a unitary body or interconnecting member(s) joining the
individual sections in an anatomically integrated array of
sections.
[0012] The orbital patches and masks of the invention are flexible
and designed to conform closely to the skin of the orbital margin
of the subject, to effectively and evenly deliver an anti aging
effective compound to the periorbital skin area to be treated. In
related aspects, the anti-aging effective compound is provided in a
delayed release formulation to provided extended, controlled
release of the anti-aging compound for a period of time effective
to prevent or reverse one or more symptoms of periorbital skin
aging in the subject. The ocular patches of the invention are
typically constructed to ensure that the anti-aging effective
compound is delivered to the orbital margin while avoiding exposure
of the compound and other potentially irritating carriers and
materials to the mucus membrane of the eye.
[0013] In additional detailed embodiments, the invention provides a
nasal patch or mask for treatment or prevention of perinasal skin
aging in a mammalian subject. The nasal patch or mask comprises a
flexible patch or mask body formed of a porous material sized and
dimensioned to conform to a nasal skin surface or portion thereof
(e.g., a lateral nasal margin) of the subject. An attachment means
is connected to the patch or mask body for securely attaching the
patch or mask covering the nose or in contact with a nasal margin
of the subject. An anti-aging effective compound is applied to,
invested in, or otherwise provided in contact with an undersurface
of the patch or mask body. The undersurface is adapted for
effective delivery of the anti-aging compound to the nose or nasal
margin for a period of time effective to alleviate symptoms of
perinasal skin aging.
[0014] In other embodiments, the invention provides a labial patch
or mask for treatment or prevention of perilabial skin aging in a
mammalian subject. The labial patch or mask comprises a flexible
patch or mask body formed of a porous material sized and
dimensioned to conform to a labial margin of the subject. An
attachment means is connected to the patch or mask body for
securely attaching the patch or mask in contact with the labial
margin of the subject. An anti-aging effective compound is provided
in contact with an undersurface of the patch or mask body. The
undersurface is adapted for effective delivery of the anti-aging
compound to the labial margin for a period of time effective to
alleviate symptoms of labial skin aging.
[0015] In yet additional embodiments, the invention provides a neck
patch or mask for treatment or prevention of aging symptoms in the
skin of the neck and/or under the chin in a mammalian subject. The
neck patch or mask comprises a flexible patch or mask body formed
of a porous material. The patch or mask body is sized and
dimensioned to conform to one or more skin area(s) of the neck
and/or face, for example covering one or more of the sides of the
neck, the throat, and/or under the chin of the subject. An
attachment means is connected to the patch or mask body for
securely attaching the patch or mask in contact with the neck
and/or facial skin surface(s). An anti-aging effective compound is
provided in contact with an undersurface of the patch or mask body.
The undersurface is adapted for effective delivery of the
anti-aging compound to skin of the neck for a period of time
effective to alleviate symptoms of neck and/or facial skin
aging.
[0016] In more detailed aspects of the invention, the facial or
neck patch or mask comprises a flexible patch or mask body
comprising a self-supporting sheet, pad, or matrix of porous
material. The patch or mask body is often formed of a water
insoluble material, commonly a polymeric material, providing
suitable strength, integrity, and comfort for use as a facial
(e.g., ocular) patch or mask. Typically, the patch or mask body, or
at least an undersurface portion thereof, serves as a substrate or
reservoir for receiving and retaining the anti-aging effective
compound, which may be formulated in a variety of pharmaceutical
delivery vehicles or carriers. The anti-aging effective compound
may be applied directly to the undersurface of the patch or mask
body, or may be absorbed, adsorbed, or otherwise admixed with or
invested in the material of the patch body at the undersurface
and/or within the porous patch or mask body in communication with
the undersurface (e.g., by liquid or other direct chemical
communication between the body and the undersurface through pores,
fissures, perforations, or other communication channels provided
within the patch body or a layer thereof adjacent the
undersurface). In exemplary embodiments, the flexible patch body
comprises a natural or synthetic fiber or polymer such as cotton,
cellulose, nylon, polyester, or polyacetate polymer.
[0017] In additional detailed aspects of the invention, the
attachment means for attaching the facial patch or mask to the
facial skin area(s) to be treated comprises a bioadhesive material
such as a hydrogel. Optionally, the bioadhesive material is a
bioadhesive delivery vehicle that serves a dual purposes of
mediating affixation of the patch or mask to the facial skin
area(s) and providing a carrier or delivery vehicle for
incorporation and delivery of the anti-aging effective compound(s).
In other embodiments, the bioadhesive delivery vehicle is connected
to a periphery of the undersurface of the patch or mask body, for
example to the periphery of the undersurface of an ocular
patch.
[0018] In certain embodiments of the invention, the anti-aging
effective compound employed with the facial patch or mask comprises
an anti-oxidant compound. Exemplary anti-oxidants for use within
this aspect of the invention include anti-oxidant coenzymes, for
example "Coenzyme Q" coenzymes. Alternatively, anti-oxidants for
use within the invention are selected from vitamins, amino acids,
enzymes, and/or fatty acids. In additional embodiments, a second
anti-aging effective compound, for example a second anti-oxidant
compound, is delivered coordinately with patch- or mask-mediated
delivery of a first anti-oxidant compound. The second anti-aging
compound may be formulated in combination with the first anti-aging
compound and applied or otherwise provided in contact with the
undersurface of the patch or mask. Alternatively, the second
anti-aging compound may be administered, e.g., as a topical
formulation, to the facial skin area to be treated prior to or
subsequent to application and removal of the patch or mask. In
further detailed embodiments, the facial patch or mask provides
controlled, time-release delivery of one or more anti-aging
effective compound(s), typically for a prolonged time period of 1-4
hours, 4-8 hours, or more than 8 hours effective to prevent or
reverse one or more symptoms of facial skin aging in the
subject.
BRIEF DESCRIPTION OF DRAWINGS
[0019] FIG. 1 is a perspective view of a human female subject
wearing a variety of facial and neck patches and masks of the
invention.
[0020] FIG. 2 is a perspective view of a human female subject
showing various anatomical features that relate to novel
configurations of the facial and neck patches and masks of the
invention.
[0021] FIG. 3 is a perspective view of a human female subject
wearing alternate embodiments of facial masks of the invention.
[0022] FIG. 4 is a perspective view of a human female subject
wearing additional alternate embodiments of facial masks of the
invention.
[0023] FIG. 5 is an isometric view toward the undersurface of an
orbital patch of the invention having multiple drug delivery
sections.
[0024] FIG. 6 is an isometric view toward the undersurface of a
composite orbital patch of the invention having multiple drug
delivery sections.
[0025] FIG. 7 is a sectional view of an orbital mask of the
invention illustrating alternate features thereof.
[0026] FIG. 8 is a sectional view of a facial patch of the
invention illustrating alternate features thereof.
[0027] FIG. 9 is a sectional view of a facial patch of the
invention including a thermal element.
[0028] FIG. 10 is a sectional view of a facial patch of the
invention including a thermal element.
[0029] FIG. 11 is a sectional view of a facial patch of the
invention illustrating alternate features thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0030] As noted above, the invention provides a variety of novel
facial patches 10 and masks 12 for treating facial skin aging in
mammalian subjects, typically human subjects (FIG. 1). The facial
patch or mask comprises a flexible patch body 14 formed of a porous
material, wherein the patch or mask body is sized and dimensioned
to conform to one or more contoured facial surfaces of the subject,
for example an orbital margin, nasal skin surface, or labial
margin. The patch or mask includes attachment means 16 connected to
the patch or mask body for securely, removably attaching the patch
in contact with the facial surface to be treated. An anti-aging
effective compound is provided in contact with an undersurface 18
of the patch body that is in turn adapted for effective delivery of
the anti-aging compound to the facial skin surface when the patch
or mask is applied thereto.
[0031] In certain detailed aspects, the invention provides a facial
patch 10 or mask 12 or a neck skin patch or mask 146 for
prophylaxis and treatment of one or more symptoms of facial and/or
neck skin aging (e.g., photoaging oractinic aging, and
chronological aging), including symptoms selected from:
[0032] a) Degeneration of the microvascular system;
[0033] b) Flaccidity and development of wrinkles due to a decrease
in and/or crosslinking of collagen, accumulation of
glucosaminoglyeans (base substance) and/or solar elastosis (elastin
clumping);
[0034] c) Flattening of the retial cones, associated with a
reduction in thickness or area between the dermis and epidermis
through which substances are exchanged for healthy metabolism of
the epidermis;
[0035] d) Restricted regenerative turnover in the epidermis
associated with defective hornification, leading to drying out of
the skin, roughness of the skin, chapping of the skin and/or
flaking;
[0036] e) Defective regulation of cell division (proliferation) and
cell maturation (differentiation) in the epidermis associated with
cellular atypia, atrophies, and loss of polarity; and/or
[0037] f) Local hyper- and hypopigmentation and/or abnormal
pigmentation (age spots).
[0038] The invention thus provides novel facial patches 10 and
masks 12 for use in the prevention or treatment of one or more
symptoms of facial skin aging. The patch or mask body 14 is
typically comprised of a flexible, porous self-supporting material
that provides strength, comfort and integrity for use as a facial
skin patch. The patch body is shaped and dimensioned to conform to
a contoured skin surface of the face, and the mask body is shaped
and dimensioned to conform to a plurality of contoured skin
surfaces of the face. In exemplary embodiments, the patch or mask
body is formed of a water insoluble fiber or polymer. In additional
aspects, the patch or mask body provides a substrate or reservoir
for receiving and retaining an anti-aging effective compound, which
may be formulated in a variety of pharmaceutical or cosmetic
carriers or delivery vehicles, such as a polymeric delivery
vehicle. The anti-aging effective compound is applied to, admixed
with, invested in, or otherwise provided in contact with at least
the undersurface 18, or a portion thereof (e.g., a peripheral
portion of the undersurface) of the flexible patch or mask body, to
yield sustained transdermal delivery of the anti-aging effective
compound to the facial skin area to be treated.
[0039] In certain detailed embodiments of the invention, the
flexible patch 10 or mask 12 body 14 comprises a lightweight,
flexible strip, pad or a partial or complete mask of biologically
compatible material, for example a woven or nonwoven fiber or
polymer material, such as polyester, cotton, cellulose, or nylon
fibers. Exemplary materials include porous polymeric water
insoluble nonwoven fibrous fabrics. The fiber or polymer may be
complexed, cross-linked or bonded into a porous fabric or matrix,
for example by binding of individual fibers into a fabric using a
sizing resin. Suitable sizing materials for bonding fibers within
the patch or mask body include latex resins.
[0040] The flexible patch 10 or mask 12 body 14 is generally
nonirritating to human skin. If desired, the patch or mask body can
be coated on one or more surfaces with a release coating, such as a
silicone release coating as described in U.S. Pat. No. 4,696,854
which is incorporated herein by reference. A suitable release
coating in this context is a 100% solids electron beam curable
silicone such as Tego.RTM. (Silicone Resin Acrylates/RC-Series RC
705 and RC 726 by Goldschmidt Chemical Corporation, Hopewell,
Va).
[0041] In exemplary embodiments of the invention, the flexible
patch 10 or mask 12 body 14 comprises a stable, water insoluble
flexible material. For example, the body may be constructed of a
suitably thin (e.g., approximately 1 mm to 1 cm thick) strip, pad
or sheet of nonwoven fabric formed from one or more selected fibers
(e.g., cellulose fibers derived from wood pulp and/or polyester
fibers). When fibrous materials are used, the fibers may be
assembled loosely to form the patch or mask body and to maintain
porosity thereof. A unifying or sizing resin may be applied to hold
the fibers together. The sizing resin can comprise a nonirritating
resin such as a latex emulsion. One suitable resin emulsion
adhesive is Hycar.RTM. 26477 (B. F. Goodrich Co., Brecksville,
Ohio). Another suitable material for construction of the patch or
mask body is a nonwoven fabric comprising a wetlay cellulose and
polyester containing as a sizing resin an acrylic latex emulsion
(Dexter Corporation, Windsor Locks, Conn.)
[0042] Within additional embodiments of the invention, the flexible
patch 10 or mask 12 body 14 comprises a porous woven acetate
polymer cloth, sometimes known as "silk cloth."
[0043] Yet another suitable material for construction of the
flexible patch 10 or mask 12 body 14 is an open-cell plastic foam
strip, sheet, pad, or partial or complete mask. In exemplary
embodiments, the patch or mask body is formed of a low density
polyethylene or polyvinyl acetate resin. Alternatively, woven
cotton cloth, or synthetic cloths such as nylon, polyester,
polyacetate, and the like may be employed. When the flexible patch
or mask body is a woven cloth, no sizing resin is needed.
[0044] The flexible patch 10 or mask 12 body 14 is typically
pervious to air so that the patch or mask is non-occlusive to the
skin and allows moisture to pass from the treated skin surface
through the patch or mask body into the atmosphere. The moisture
vapor transmission rate (MVTR) of normal facial skin under various
conditions is typically from about 70 to about 150 g/m.sup.2/24 hr,
and the facial patch or mask of the present invention allows for
transmission of moisture vapor from the skin through the patch or
mask body at a rate of at least from about 35 to about 75
g/m.sup.2/24 hr, and more typically from about 70 to about 150
g/m.sup.2/24 hr or greater. Conventional medication-applying
patches that employ a rubber backing or other occlusive
construction materials adversely limit moisture evaporation from
the skin. By contrast, when non-occlusive materials are employed
within the patches and masks of the present invention, the patch or
mask will not substantially interfere with moisture evaporation
from the skin. This is important because the evaporation of
moisture from the skin helps the skin to act in its normal capacity
as a barrier to externally applied compounds that, if absorbed in
excessive amounts, can produce toxic reactions or skin irritation.
The invention thus enables the barrier function of the stratum
corneum to be maintained while providing for effective delivery of
the anti-aging compound(s) to the treated skin area(s).
[0045] The porosity of the flexible patch 10 or mask 12 body 14
also provides openings, pores, and/or channels 20 infiltrating at
least a portion of the patch or mask body adjacent the undersurface
18 thereof, wherein the openings, pores, and/or channels are
adapted for receiving and controllably releasing the anti-aging
effective compound(s). These openings, pores and/or channels
provide a reservoir for prolonged, controlled delivery of the
anti-aging effective compound(s) from the undersurface of the patch
or mask to the facial skin area to be treated. The openings, pores
and/or channels are in chemical communication with the undersurface
of the patch or mask body. For example, the anti-aging effective
compound can enter and/or leave the openings, pores and/or channels
via chemical communication facilitated by diffusion, capillary
transport, wicking, and/or decompression and compression transfer.
In this manner, the anti-aging effective compound can be initially
applied, loaded or infused within the openings, pores and/or
channels of the patch or mask body and subsequently released to the
undersurface in a controlled manner to yield efficient, optionally
time-release-controlled, delivery of the anti-aging effective
compound to the facial skin area(s) to be treated.
[0046] Various methods and carriers are provided within the
invention for applying the anti-aging effective compound(s) to the
undersurface 18 of the patch 10 or mask 12, and/or for loading or
infusing the anti-aging effective compound(s) within the openings,
pores and/or channels 20 of the patch body 14. For example,
application of the anti-aging effective compound onto the
undersurface of the patch or mask body can be achieved by simple,
known and optionally mechanized processes of aliquoting the
anti-aging effective compound (optionally combined in a
pharmaceutical or cosmetic carrier or delivery vehicle) onto the
undersurface in an appropriate (therapeutically or prophylactically
effective) concentration and amount to achieve an even distribution
of the compound over the portion(s) of the undersurface to be
coated. Alternatively, the anti-aging compound and optional carrier
can be imbued within at least a portion of a porous polymeric or
fibrous patch or mask body (e.g., a portion of the body adjacent
the undersurface, to a predetermined depth or thickness of the
body) facilitated by various know, methods, including surface
application coupled with diffusion, capillary transport, wicking,
and/or decompression absorption. In certain detailed embodiments,
the anti-aging compound is incorporated within at least a portion
of the patch or mask body during its manufacture, for example by
infusing a pressure-sensitive polymeric delivery vehicle containing
the anti-aging effective compound into a polymeric patch or mask
body by controlled manufacture methods (as disclosed, e.g., in U.S.
Pat. No. 6,096,334, incorporated herein by reference) to facilitate
penetration of the anti-aging compound and carrier into the patch
or mask body.
[0047] In related aspects of the invention, the anti-aging
effective compound is provided in a delayed release formulation to
provide extended, controlled release of the anti-aging compound to
yield delivery of the compound to a targeted facial skin area for
treatment for a period of time effective to prevent or reverse one
or more symptoms of facial skin aging in the subject.
[0048] In additional aspects, the anti-aging effective compounds
are formulated in a polymeric delivery vehicle or other
pharmaceutical or cosmetic carrier that allows penetration of the
anti-aging effective compound into a substantial portion of the
flexible patch or mask body. For example, the anti-aging effective
compound may be formulated and imbued, infiltrated, or otherwise
invested within the patch 10 or mask 12 body 14 to penetrate from
the undersurface 18 into openings, pores and/or channels 14 to at
least about one-fourth or one-half of a depth or thickness 22 of
the patch or mask body. More typically the anti-aging effective
compound is formulated and invested within the patch or mask body
10 to penetrate from the undersurface into openings, pores and/or
channels that infiltrate at least about one-half, three-quarters,
and up to the full depth or thickness of the patch body.
[0049] In certain detailed aspects of the invention, an orbital
facial patch 24 (FIG. 1) or orbital mask 26 (FIG. 3) is provided
for prevention or treatment of periorbital skin aging. The orbital
patch or mask anatomically conforms to, and provides for treatment
or prevention of skin aging in, all or part of an orbital margin 30
skin area, and optionally in the case of a mask to one or more
adjoining skin area(s). The orbital patch or mask comprises a
flexible patch or mask body 14 formed of a porous material, wherein
the patch or mask body is sized and dimensioned to conform to all
or part of an orbital marginal skin surface of the subject, and
optionally to one or more additional facial skin area(s), such as a
nasal skin area. An attachment means 16 is connected to the orbital
patch or mask body for securely attaching the patch or mask in
contact with all or part of the orbital margin 30 (FIG. 2) of the
subject. An anti-aging effective compound is applied to or
otherwise provided in contact with an undersurface of the patch or
mask body. The undersurface of the patch or mask body is adapted
for effective delivery of the anti-aging compound to all or part of
the orbital margin of the subject for a period of time effective to
prevent or alleviate symptoms of periorbital skin aging.
[0050] Various shapes and configurations of orbital facial patches
24 and masks 26 are provided, including patches and masks that
conform to the all or part of the orbital margin(s) 30 of one or
both eyes 32 of the subject, and optionally to one or more
additional facial skin area(s) (see, FIGS. 1-3). For example, as
shown in FIG. 1, a crescent shaped or lenticular supraorbital patch
34 is provided that conforms to a supraorbital margin 36 of the
eye, generally demarcated above a transverse plane bisecting the
eye and below the crescent-shaped eyebrow 38, optionally including
all or part of the upper eyelid 40. Often, the skin area of the
supraorbital margin that is covered by a supraorbital patch of the
invention is generally a lenticular (lens-shaped) area of skin that
excludes the most lateral and medial corners 42, 43 of the
supraorbital margin, and the patch is correspondingly shaped and
dimensioned, to prevent discomfort to the subject and/or creasing
of the patch in these spatially confined areas prone to muscular
contortion and/or skin folding. Orbital patches applied in this
configuration nonetheless effectively treat the entire supraorbital
skin by providing effective delivery to skin areas beyond the patch
margins.
[0051] In related embodiments, an infraorbital eye patch 44 is
provided that is shaped and dimensioned to substantially cover an
infraorbital margin 46 skin surface surrounding the eye 32 below a
horizontal plane bisecting the eyeball, optionally including all or
part of the lower eyelid 48 (FIGS. 1 and 2). As in the case of the
supraorbital patch 34, the infraorbital marginal skin area covered
by the infraorbital patch is often generally lenticular in shape
and excludes the most lateral and medial corners of the
infraorbital margin, and the patch is correspondingly lenticular
shaped and dimensioned.
[0052] In additional related embodiments, as exemplified in FIG. 1,
a lateral orbital patch 50 is provided that is shaped and
dimensioned to substantially cover a lateral orbital margin 52 of
the subject--the site where aging symptoms commonly referred to as
"crows feet" appear. As is also depicted in FIG. 1, a lateral
orbital patch may be generally circular, ovate, or fan-shaped to
substantially conform to the lateral orbital margin, comfortably
and without peripheral impingement of the patch against a
coordinately applied supraorbital patch 34 or infraorbital patch
44.
[0053] In further related embodiments, as exemplified in FIG. 1, a
medial orbital patch 56 is provided that is shaped and dimensioned
to substantially cover a medial orbital margin 58 of the subject.
The medial orbital patch may also be generally circular, ovate, or
fan-shaped to substantially conform to the medial orbital margin,
comfortably and without peripheral impingement of the patch against
a coordinately applied supraorbital patch 34 or infraorbital patch
44.
[0054] In other related embodiments, orbital patches 24 and masks
26 are provided that substantially conform to one, or to a
plurality of, selected portions of the orbital margin 30 of the
subject, up to and including an entire orbital marginal area, of
one or both orbital margins of the subject. In more detailed
aspects, the patch 24 or mask 36 may conform to one or more areas
of the orbital margin selected from the supraorbital margin 36,
infraorbital margin 46, lateral orbital margin 52, and/or medial
orbital margin 58 of one eye 32, or of both eyes.
[0055] In related aspects, the orbital patch 24 or mask 26 body 14
may comprise one or more separate or conjoined, contoured sections
individually shaped and dimensioned to conform to one or more
selected portions of one or both orbital margin(s) 30 of the
subject. For example, referring to FIGS. 2 and 4, the orbital patch
or mask may comprise one or more specially contoured and/or
constructed drug delivery sections of the body that conform,
collectively or individually, to all or part(s) of the surface(s)
of the supraorbital margin 34, the infraorbital margin 46, lateral
orbital margin 52, and/or medial orbital margin 58 of one or both
eye(s). Patches constructed in this manner can cover and
effectively deliver the anti-aging compound to any one or more of
these portions of the orbital margin, and may comprise one, two,
three, four or more sections, for example selected from a
supraorbital section 62, infraorbital section 64, lateral orbital
section 66 and/or medial orbital section 68. In other embodiments,
multiple sections of an orbital patch will each cover and deliver
medication to a plurality of skin portions of the orbital margin,
for example a supraorbital section 62 and lateral orbital section
66, or a infraorbital section 64 and medial orbital section 68.
[0056] Individual orbital patch 24 sections may be conjoined in a
single patch having a unitary body (e.g., as shown in FIGS. 4 and
5). Alternatively, the sections may be joined by interconnecting
member(s) 60 (e.g., as shown in FIG. 6) joining one or more
individual sections in an anatomically integrated array of
sections. The interconnecting member(s) can be constructed of the
same material as the patch sections that form the sectional patch
body, or they may be constructed of a different material, such as a
flexible or elastic strip, tape, or film. Interconnection of
multiple patch sections in this manner allows the subject to affix
one section to a first portion of the orbital margin 30 by
sectional attachment means (e.g., a bioadhesive gel in contact with
a sectional undersurface 18' of each section, allowing for
removable attachment of the sections individually to their
respective facial skin areas for application) and then affix a
second section to a second portion of the orbital margin in an easy
and positionally flexible manner. More specifically, the attachment
of the first section does not strictly constrain positioning and
attachment of the second section, because the interconnecting
member joining the first and second sections can be manually
deformed and/or stretched to provide for positional flexibility in
placing and affixing the second section, and so on for each
successive section to be attached. In this manner, attachment of
the sectional patch is facilitated, and the patch is rendered more
broadly applicable to different subjects having a range of
anatomical dimensions of their orbital skin areas. In addition,
flexibility of the interconnecting member(s) enhances comfort of
the patch by easing potential stress that might otherwise be
applied on the treated skin areas by a less flexible integration of
the patch sections. Nonetheless, when a unitary patch body is
provided with sectional members as described above, the anatomical
configuration and inherent flexibility of the patch body provides
for a suitable ease of anatomically direct attachment of the
sections without excessive discomfort.
[0057] As exemplified in FIG. 4, one illustrative sectional orbital
patch of the invention comprises multiple drug delivery sections of
the body selected from a supraorbital drug delivery section 62 an
infraorbital drug delivery section 64, a lateral drug delivery
section 66, and/or a medial drug delivery section 68. These
distinct sections may be formed of a separate layer and/or distinct
material from the primary patch body 14, or they may be integrally
formed as individually contoured portions of a unitary patch body.
The individual sections typically extend from the undersurface 18
of the patch body as contoured ridges or protrusions, as shown in
FIG. 5. In this example, the patch features anatomically contoured
ridges or protrusions comprising a supraorbital drug delivery
section 62 an infraorbital drug delivery section 64, a lateral drug
delivery section 66, and a medial drug delivery section 68. The
contoured ridges or protrusions provide a comfortable, anatomically
contoured shape to the patch, for example so that the undersurface
of the patch body in a central portion 70 of the body is raised
away from the orbital marginal skin surface(s) and does not impinge
forcefully against the eye 32 of the wearer. In addition, the
contoured ridges or protrusions typically serve an additional
purpose of providing discrete drug delivery sections or reservoirs
on, or within, the patch body that are adapted for effective,
site-specific delivery of the anti-aging compound to one or more
designated portions of the orbital margin 30--leaving sensitive
areas such as the eyeball and conjunctiva relatively free of
excessive exposure to the medication. In relation to these and
other embodiments, the medication may be applied to the
undersurfaces 18' of the drug delivery sections or infused or
otherwise invested the material comprising the sections, or
throughout the entire patch or mask body. In related aspects, the
orbital patches and masks of the invention are constructed to
ensure that the anti-aging effective compound is delivered to
selected portions of the orbital margin to be treated while
avoiding exposure of the mucus membranes of the eye and other
sensitive tissues to the compound and other potentially irritating
carriers and materials formulated therewith.
[0058] In other detailed embodiments of the invention a forehead
patch 72 or mask 72' is provided that anatomically conforms to, and
provides for treatment or prevention of skin aging in, all or part
of a forehead skin area 74, and optionally in the case of a mask to
one or more adjoining skin area(s), of a mammalian subject (see,
e.g., FIG. 1). The forehead patch or mask also comprises a flexible
patch or mask body 14 formed of a porous material sized and
dimensioned to conform to a forehead skin surface or portion
thereof of the subject. An attachment means is connected to the
forehead patch or mask body for securely attaching the patch
covering all or part of the forehead of the subject. An anti-aging
effective compound is applied to, invested in, or otherwise
provided in contact with an undersurface of the forehead patch or
mask body. The undersurface of the forehead patch or mask is
similarly adapted for effective delivery of the anti-aging compound
to a forehead skin surface for a period of time effective to
alleviate symptoms of forehead skin aging. As described above for
orbital patches 24 and masks 26, various portions of the forehead
skin can be covered and treated by a forehead patch or mask, and
the forehead patch or mask can be similarly constructed as a
unitary patch or mask or to comprise multiple forehead patch or
mask sections collectively arrayed and interconnected and adapted
for drug delivery to multiple portions of the forehead skin and/or
of other facial skin area(s). Thus, the forehead patch or mask can
comprise a unitary body or a plurality of sections that
individually or collectively cover any one or more portions of the
forehead skin. Optionally, a forehead patch or mask 72' can be
provided that conforms to all or part of the forehead skin and to
one or more adjoining skin areas, such as the temporal 114 lateral
facial skin area (see, e.g., FIG. 3).
[0059] In additional detailed embodiments of the invention a nasal
patch 80 or mask 80' is provided for treatment or prevention of
nasal skin aging in a mammalian subject (see, e.g., FIG. 1). The
nasal patch or mask anatomically conforms to, and provides for
treatment or prevention of skin aging in, all or part of the nasal
skin, and optionally in the case of a mask to one or more adjoining
skin area(s). The nasal patch or mask similarly comprises a
flexible patch or mask body 14 formed of a porous material sized
and dimensioned to conform to a nasal skin surface or portion
thereof (e.g., a lateral nasal margin 82) of the subject. An
attachment means is connected to the nasal patch or mask body for
securely attaching the patch covering the nose or in contact with a
nasal margin of the subject. An anti-aging effective compound is
applied to, invested in, or otherwise provided in contact with an
undersurface of the nasal patch or mask body. The undersurface of
the nasal patch or mask is similarly adapted for effective delivery
of the anti-aging compound to a nasal skin surface for a period of
time effective to alleviate symptoms of nasal skin aging. As
described above for orbital patches 24 and masks 26, various
portions of the nasal skin can be covered and treated by a nasal
patch or mask, and the nasal patch or mask can be similarly
constructed as a unitary patch or mask or to comprise multiple
nasal patch or mask sections collectively arrayed and
interconnected and adapted for drug delivery to multiple portions
of the nasal skin and/or of other facial skin area(s). Thus, for
example, as shown in FIG. 1, the nasal patch or mask can comprise a
unitary body or a plurality of sections that individually or
collectively cover any one or more portions of the nasal skin
selected from skin covering the root 84 of the nose, the dorsum 86
of the nose, the ala 88 of the nose, and/or the lateral margins 82
of the nose. Optionally, the nasal patch or mask can additionally
conform to an adjacent skin area such as one or more portion(s) of
the orbital margin 30, or a skin area extending laterally from the
ala of the nose between the cheek prominences of the face (e.g., as
depicted for a nasal mask 80' in FIG. 1).
[0060] In other embodiments, the invention provides a labial patch
90 or mask for treatment or prevention of perilabial skin aging in
a mammalian subject. The labial patch or mask anatomically conforms
to, and provides for treatment or prevention of skin aging in, all
or part of the perilabial skin, and optionally in the case of a
mask to one or more adjoining skin area(s). The labial or mask
patch comprises a flexible patch or mask body 14 formed of a porous
material sized and dimensioned to conform to a labial margin of the
subject. An attachment means 16 is connected to the patch or mask
body for securely attaching the patch or mask in contact with the
labial margin of the subject. An anti-aging effective compound is
provided in contact with an undersurface 18 of the patch or mask
body. The undersurface is adapted for effective delivery of the
anti-aging compound to the labial margin for a period of time
effective to alleviate symptoms of labial skin aging. The patch or
mask can cover and treat all of the labial margin circumscribing
the lips, or one or more selected portions of the labial margin,
such as the upper labial margin 92, including the philtrum and
philtral ridge (e.g., as provided by a supralabial patch 90 as
shown in FIG. 1), or the lower labial margin (e.g., as provided by
a sublabial patch conforming to a sublabial 94 area, or a lower
facial mask 96 as shown in FIG. 1 covering combined sublabial and
chin 98 areas of the facial skin). As described above for orbital
patches 24 and masks 26, various portions of the perilabial skin
can be covered and treated by a labial patch or mask, and the
labial patch or mask can be similarly constructed as a unitary
patch or mask or to comprise multiple labial patch or mask sections
collectively arrayed and interconnected and adapted for drug
delivery to multiple portions of the labial skin and/or of other
facial skin area(s). Thus, for example, as shown in FIG. 4, the
labial patch or mask can comprise a unitary body or a plurality of
sections (e.g., supralabial 100 and sublabial 102 drug delivery
sections) that individually or collectively conform to, and
effectively deliver the anti-aging compound to, any one or more
portions of the perilabial skin
[0061] In other embodiments, the invention provides a variety of
lateral facial patches and masks 106 that substantially conform to,
and effectively administer anti-aging compounds to, all or part of
one or more lateral facial skin areas, fore example lateral facial
skin areas selected from a mandibular 110, maxillary 112, and/or
temporal 114 lateral facial skin area. The mandibular facial skin
area generally circumscribes the lower jaw. The maxillary facial
skin area is between the upper and lower jaw and generally
corresponds to the cheek area. The temporal facial skin area is
between the upper jaw and hairline lateral to the orbital margin
30, and generally corresponds to the temple area. The various
lateral facial patches and masks of the invention individually
comprise a flexible patch or mask body 14 formed of a porous
material sized and dimensioned to conform to a lateral facial skin
area of the subject. An attachment means 16 is connected to the
patch or mask body for securely attaching the patch or mask in
contact with a lateral facial skin surface of the subject. An
anti-aging effective compound is provided in contact with an
undersurface 18 of the patch or mask body. The undersurface is
adapted for effective delivery of the anti-aging compound to one or
more lateral facial skin area(s) for a period of time effective to
alleviate symptoms of lateral facial skin aging. The patch or mask
can cover and treat all or part of one lateral facial skin, or all
or part of multiple lateral facial skin areas. As described above
for orbital patches 24 and masks 26, various portions of one or
more lateral facial skin areas can be covered and treated by a
lateral facial patch or mask. The lateral facial patch or mask can
likewise be constructed as a unitary patch or mask or to comprise
multiple lateral facial patch or mask sections collectively arrayed
and interconnected and adapted for drug delivery to multiple
portions of a single lateral facial skin area, of multiple facial
skin areas, and/or of other facial skin area(s). Thus, as
illustrated in FIG. 1, a lateral facial patch or mask 106 can
comprise a unitary body or a plurality of sections that are
collectively or individually sized and dimensioned to conform to
one or more lateral facial skin areas selected from mandibular 110,
maxillary 112, and/or temporal 114 lateral facial skin areas, and
to effectively deliver the anti-aging compound thereto. For
example, in the embodiment of the invention shown in FIG. 1, a
lateral facial mask 106 is provided which comprises a
tempero-maxillary-mandibular mask conforming to multiple lateral
facial skin areas (covering all or portions of the temporal,
maxillary, and mandibular facial skin areas) to treat or prevent
skin aging in these areas.
[0062] In further detailed embodiments of the invention, facial
masks 12 are provided that cover and deliver an anti-aging
effective compound to a plurality of facial skin areas (see, e.g.,
FIGS. 1 and 3). Various configurations of facial masks are
contemplated that anatomically conform to multiple facial skin
areas. For example, masks of the invention may conform to any two
or more facial skin areas selected from: i) an orbital marginal
area 30 (each (left and right) collectively including the
supraorbital margin 36, infraorbital margin 46, lateral orbital
margin 52, and medial orbital margin 58); ii) a nasal skin surface
area (collectively including the nasal root 84, dorsum 86, ala 88
and lateral nasal margins 82); iii) a perilabial skin surface area
(collectively including upper labial margin 92 and sublabial margin
94); iv) a forehead skin area 74; v) a chin skin area 98; vi) a
madibular lateral facial skin area 110; vii) a maxillary lateral
facial skin area 112; and viii) a temporal lateral facial skin area
114; and up to substantially the entire facial skin surface. As in
the case of facial patches 10, the areas of facial skin to which
the facial masks of the invention are directly attached (e.g., by
adhesive contact with the skin) typically exclude sensitive tissues
such as mucous membranes of the eyes, nose and mouth and are
generally sized and dimensioned so as not to make adhesive contact
with unshaven, hirsute facial skin areas such as the eyebrows. For
example, this can be achieved by including cut-outs or openings 120
in the patch or mask that are sized and dimensioned to leave
uncovered one or more sensitive or hirsute areas, for example the
mouth, eyes, nares, eyebrows, and sideburns. Alternatively, the
patch or mask may include specific attachment sections that form
adhesive and chemical contacts with only selected portions of the
facial skin and leave sensitive areas unaffected by adhesive
materials and chemicals (including the anti-aging compound and any
carriers and other potentially toxic or irritating agents
formulated therewith). These specific attachment sections typically
correspond to the discrete drug delivery sections of the patch or
mask, as described above. For example, an orbital patch 24 or mask
26 may comprise specific, drug delivery and attachment sections
selected from supraorbital 62, infraorbital 64, lateral orbital 66,
and medial orbital 68 sections (FIG. 4). A labial patch 90 or mask
can comprise specific, drug delivery and attachment sections
selected from supralabial 100 and infralabial 102 sections. These
sections will generally provide for anatomically conforming drug
delivery contacts with the target skin can, and may also be
modified (e.g., by coating each section with a biologically
compatible adhesive such as a hydrogel) to provide sectional
attachment means.
[0063] Exemplary facial masks 12 of the invention cover multiple
facial skin areas in a manner that allows a reasonable range of
movement between different muscular facial areas. For example, a
lower facial mask 96 is depicted in FIG. 1 that conforms to part of
the mandibular 110 facial skin area, and further conforms to the
chin 98 and sublabial 94 skin areas. This configuration of the
facial mask provides for freedom of movement between the lower,
mandibular and upper-medial maxillary portions of the face, as
occurs during normal facial movements such as yawning and
mastication. In another configuration, a lateral facial mask 106 is
sized and dimensioned to conform to multiple lateral facial skin
areas, for example to cover all or part of the mandibular 110,
maxillary 112, and/or temporal 114 lateral facial skin areas (see,
e.g., FIG. 1) to allow substantially unrestricted facial movements.
In yet another embodiment, a facial mask is provided that conforms
to both orbital margins to effectively deliver the anti-aging
compound thereto, for example as provided by the orbital mask 26
depicted in FIG. 3, that optionally also covers one or more nasal
skin area(s). A more discrete orbital mask is achieved by
connecting two orbital patches 24 with a nasal bridging element 130
(e.g., an elastic connecting strip) (see, e.g., FIGS. 4 and 7).
[0064] As noted above, the facial masks 12 of the invention can be
sized and dimensioned to cover and deliver an anti-aging effective
compound to any selected plurality of facial skin areas. Thus, a
mask of the invention may be shaped and sized to conform to any
combination of the facial areas disclosed herein, including any
combination of one or more: i) orbital marginal area(s) ii) nasal
skin area; iii) perilabial skin surface area; iv) forehead skin
area; v) chin skin area; vi) madibular lateral facial skin area;
vii) maxillary lateral facial skin area; and viii) temporal lateral
facial skin area. A specially configured mask to conform to or
treat any combination of these areas can be constructed based on
generally known facial anatomical characteristics in accordance
with the teachings herein. Partial facial masks can cover any two,
three, for or more discrete facial skin areas, for example a facial
mask that conforms to all or portions of both orbital margins (see,
e.g., FIGS. 3 and 4), to all or portions of both orbital margins
and a nasal skin area (see, e.g., FIG. 3), to all or portions of
the forehead and temporal skin areas (see, e.g., FIG. 3), to all or
portions of the temporal, maxillary, and mandibular facial skin
areas (see, e.g., FIGS. 1 and 3); or to perilabial and chin skin
areas (see, e.g., FIG. 1). More extensive facial masks are also
contemplated, such as a lower facial mask 140 (see, e.g., FIG. 4)
that conforms to three or more lower facial skin areas (e.g., to
three or more of the perilabial, chin, mandibular, maxillary, and
temporal skin areas). Full facial masks are also provided that
substantially conform to all facial skin areas.
[0065] In yet additional embodiments of the invention, a neck skin
patch or mask 146 is provided that is sized and dimensioned to
conform to one or more skin surface area(s) of the neck, for
example covering one or more sides 150 of the neck, throat skin
area 152, back of neck skin area 154, and/or jowl skin area 156 of
the neck under the chin 98 of the subject--and optionally to one or
more of the facial skin areas described above (see, e.g., FIGS. 1
and 4). The neck patch or mask comprises a flexible patch or mask
body 14 formed of a porous material. An attachment means 16 is
connected to the patch or mask body for securely attaching the
patch or mask in contact with the neck skin surface area(s). An
anti-aging effective compound is provided in contact with an
undersurface of the patch or mask body. The undersurface is adapted
for effective delivery of the ante aging compound to the skin
area(s) of the neck for a period of time effective to alleviate
symptoms of neck skin aging. Neck skin patches of the invention
cover all or part of a specific neck skin surface area (e.g., all
or part of the jowl, or throat, area). Neck skin masks of the
invention cover a plurality of specific neck skin surface area(s)
(e.g., all or part of the jowl and throat, or of the jowl, throat
and sides of the neck, etc.), and up to the entire skin surface of
the neck.
[0066] Anti-Aging Effective Compounds
[0067] The anti-aging effective compounds of the instant invention
may comprise a single compound or a mixture of compounds that are
individually or collectively effective to treat or prevent one or
more symptoms of facial aging when the compound or mixture is
delivered by a facial patch 10 or mask 12 applied for an effective
period to effectuate delivery and action of the anti-aging
compound(s) to a facial skin area. In alternative embodiments,
multiple anti-aging effective compounds are coordinately delivered
to the facial skin area, wherein at least one of the anti-aging
effective compounds is administered by application of the patch or
mask (e.g., with the compound(s) applied to the patch or mask
undersurface or invested in the patch body 14), and a second or
multiple additional anti-aging effective compounds is/are
co-administered before or after patch application (e.g., by topical
application before or after the patch or mask is applied). Thus, in
certain embodiments, a first anti-aging compound is administered to
the facial skin area to be treated by topical application, for
example of an anti-aging compound formulated in a paste, cream or
gel. Subsequently, a second anti-aging compound is administered
that is applied to the undersurface of a patch or mask or invested
in the body of the patch or mask. In related embodiments, a first
anti-aging compound is administered to the facial skin area to be
treated via application of a patch or mask, and a second anti-aging
compound is administered after removal of the patch or mask to the
same facial skin area by topical application.
[0068] Anti-aging compounds that are useful within the methods and
devices of the invention include a range of compounds that possess
antioxidant activity. Multiple antioxidants and other known
anti-aging compounds may be employed within the invention to
provide additive or synergistic anti-aging results, yielding
enhanced therapeutic and/or age-preventative effects. Antioxidant
compounds that can be applied with the patches 10 and masks 12 of
the invention, or coordinately administered therewith, include, but
are not limited to, various non-enymatic antioxidants such as
vitamins (for example, vitamin A (retinol palmitate), B.sub.6, C,
D, D3 (cholecalciferol), and E (tocopherol acetate). Also useful
are flavones, flavonoids, imidazoles, melatonin,
alpha-hydroxycarboxylic acids (for example malic acid, glycolic
acid, gluconic acid, salicylic acid and derivatives thereof),
ubiquinones (e.g., CoQ10-CoQ15), glutathione, alpha-lipoic
acid/DHLA, amino acids, proanthocyanadins, and various enzyme
antioxidants such as glutathione peroxidase, catalase and
superoxide dismutase. Any one or more of these anti aging effective
compounds can be administered simultaneously or coordinately with
application of a patch or mask of the invention, optionally
formulated in a carrier or delivery vehicle in a weight percentage
of the active compound in the formulation ranging from: 0.01 to
50%; 0.05 to 25%; 0.1 to 10%; 0.5 to 5%; or approximately 0.3%.
[0069] Within certain embodiments of the invention, one or more
anti-aging effective ubiquinones or plastiquinones are applied with
the patch 10 or mask 12 of the invention to alleviate one or more
symptoms of facial or neck skin aging. Also useful within these
methods and devices are pharmaceutically acceptable, active salts
and derivatives of ubiquinones and plastoquinones.
[0070] Ubiquinones function as electron transfer agents in
biological, mitochondrial oxidation and thus play an important role
in the energy metabolism of animal cells. Plastoquinones are
analogous compounds from the plant kingdom that play a role in
photosynthesis in the chloroplasts of plant cells. Plastoquinones
differ from ubiquinones in three substituents on the quinone ring,
wherein two methoxy groups in the ubiquinones are replaced by
methyl groups and one methyl group is replaced by a hydrogen atom
in corresponding plastoquinone structures.
[0071] Ubiquinones have been reported as antioxidants that protect
oxidation-sensitive substances against degradation induced by
oxygen free radicals. These compounds, (also referred to as
coenzymes Q.sub.n) include a group of substances that have n
isoprene units bonded in the form of a chain on their quinone ring
(Q.sub.0-Q.sub.10) The number of isoprene units in the side chain
of ubiquinones is designated by n variable in the common
nomenclature term "coenzymes Q-n", wherein n is an integer. Among
the useful ubiquinones for treating facial and neck skin aging
within the methods and devices of the invention are ubiquinones or
coenzymes Q-n, wherein n=from 0-12. The invention thus contemplates
use of the quinone parent substance of ubiquinone without isoprene
substituents. Often the selected anti-aging effective compound(s)
comprise(s) one or more ubiquinones wherein n=from 1-12, and
commonly wherein n=from 6 to 10. A sizable genus of useful
ubiquinones are available for use within the invention and known in
the art, as disclosed for example in "Rompp Chemie Lexikon"
[Rompp's Chemical Dictionary], Georg Thieme Verlag Stuttgart, N.Y.,
9th Edition, pages 4784-4785, and in The Merck Index, 11th Edition,
Merck & Co., Inc. Rahway, N.Y., USA, Abstr. 9751 (1989) (each
incorporated herein by reference). Exemplary ubiquinones for use
within the invention include coenzyme Q-6, Q-9 or Q-10. Other
examples of useful ubiquinones or derivatives thereof are
alkylubicuinones, in particular 6-alkylubiquinones with preferably
C.sub.1-C.sub.12-alkyl radicals. Within certain exemplary
embodiments of the invention one or more decylubiquinone(s), for
example 6-decylubiquinone, or
2,3-dimethoxy-5-methyl-6-decyl-1,4-benzoquinone, is/are selected as
the anti-aging effective compound(s).
[0072] The plastoquinones are closely related to the ubiquinones in
structure and are similarly referred to as isoprenoid quinines.
They likewise carry a side chain of isoprene units on the quinone
ring (see, e.g., "Rompp Chemie Lexikon" [Rompp's Chemical
Dictionary], Georg Thieme Verlag, Stuttgart, N.Y., 9th Edition,
page 3477, incorporated herein by reference). Plastoquinones for
use within the invention will typically possess from 0-12, often
from 1-10, and commonly from 6 to 10, isoprene units in the side
chain. Further examples of plastoquinones according to the
invention or derivatives thereof are alkyl-plastoquinones with
preferably C.sub.1-C.sub.12-alkyl radicals. Within certain
exemplary embodiments of the invention one or more
decylplastoquinone(s), for example 5- or 6-decylplastoquinone, or
2,3-dimethyl-5-decyl-1,4-benzoquin- one, is/are selected as the
anti-aging effective compound(s).
[0073] Within more detailed embodiments of the invention, one or
more uqiquinone(s) and/or plastoquinone(s) selected from coenzyme
Q-10, coenzyme Q-9, coenzyme Q-8, coenzyme Q-7, coenzyme Q-6, PQ-10
(i.e., plastoquinone with 10 isoprene units), PQ-9, PQ-8, PQ-7,
and/or PQ-6 is/are selected as the anti-aging effective
compound(s). The one or more ubiquinones or plastoquinones thus
selected (e.g., coenzyme Q-10) is/are applied to, or otherwise
invested in or provided in contact with, at least the undersurface
18 of the patch or mask body 14 for effective, controlled delivery
of the active agent(s) to a facial or neck skin area.
Alternatively, one or more ubiquinone(s) and/or plastoquinone(s)
may be coordinately topically applied before or after application
of a first anti-aging effective compound applied by a facial or
neck patch 10 or mask 12 of the invention.
[0074] In more detailed aspects, the anti-aging compound delivered
by the facial patch 10 or mask 12 or neck patch or mask 146 of the
invention is effective, alone or in combination with additional,
co-formulated or coordinately administered, anti-aging compound(s)
and/or other biologically active skin treatment agent(s), for
prophylaxis and/or treatment of one or more symptoms of facial skin
aging (e.g., photoaging or actinic aging, and chronological aging).
Each of the facial and neck patches and masks of the invention
operates to deliver an effective amount of one or more anti-aging
compound(s) over an effective time period of application of the
patch or mask to substantially reduce or prevent one or more
symptoms of facial and/or neck skin aging in the facial and/or neck
skin area(s) to which the patch or mask is applied, wherein
exemplary symptoms are selected from:
[0075] a) Degeneration of the microvascular system;
[0076] b) Flaccidity and development of wrinkles due to a decrease
in and/or crosslinking of collagen, accumulation of
glucosaminoglycans (base substance) and/or solar elastosis (elastin
clumping);
[0077] c) Flattening of the retial cones, associated with a
reduction in thickness or area between the dermis and epidermis
through which substances are exchanged for healthy metabolism of
the epidermis;
[0078] d) Restricted regenerative turnover in the epidermis
associated with defective hornification, leading to drying out of
the skin, roughness of the skin, chapping of the skin and/or
flaking;
[0079] e) Defective regulation of cell division (proliferation) and
cell maturation (differentiation) in the epidermis associated with
cellular atypia, atrophies, and loss of polarity; and/or
[0080] f) Local hyper- and hypopigmentation and/or abnormal
pigmentation (age spots).
[0081] For example, following single or repeated application(s) of
a facial patch 10 or mask 12 of the invention, substantial
reduction or prevention of facial skin aging is achieved as marked
by at least a 20% reduction, more typically a 30% reducion, often a
40-50% reduction, and as much as a 75%, 85%, 90%, 95%, or greater,
reduction in one or more of the foregoing symptoms of facial skin
aging. To demonstrate this efficacy, various morphologic and/or
physiologic indices associated with the foregoing aging symptoms
are routinely measured in suitable test and control subjects in
accordance with known procedures for assaying the efficacy of
anti-aging methods and formulations. A measureable reduction of
these indices correlated with aging in test subject skin areas to
which a facial patch or mask of the invention is applied (e.g., as
compared to values measured for control subjects in which a placebo
patch or mask lacking the anti-aging effective compound is applied)
will demonstrate the substantial reduction or prevention of the
facial skin aging symtom(s) as defined above. This unprecedented
efficacy can be demonstrated by a range of known morphological
assays and physiological assays for measuring, in comparable test
and control subjects, such skin aging characteristics as:
[0082] a) Morphological and/or physiological indices correlating
with degeneration of the microvascular system;
[0083] b) Morphological and/or physiological indices correlating
with flaccidity and development of wrinkles (including, but not
limited to, crosslinking of collagen, accumulation of
glucosaminoglycans, and/or elastin clumping);
[0084] c) Morphological and/or physiological indices correlating
with flattening of the retial cones (including, but not limited to,
reduction in thickness or area between the dermis and
epidermis);
[0085] d) Morphological and/or physiological indices correlating
with restricted regenerative turnover in the epidermis (including,
but not limited to, drying out of the skin, roughness of the skin,
chapping of the skin and/or flaking);
[0086] e) Morphological and/or physiological indices correlating
with defective regulation of cell division and/or maturation in the
epidermis (including, but not limited to, cellular atypia,
atrophies, and loss of polarity); and/or
[0087] f) Morphological and/or physiological indices correlating
with local hyper- and hypopigmentation and/or abnormal pigmentation
of the subject skin area(s).
[0088] Numerous suitable assays are contemplated for measuring
these indices and demonstrating the efficacy of the facial patches
10 and masks 12 and neck skin patches and masks 146 of the
invention. Suitable assays are well known and routinely practiced
in the art, as supplemented by the teachings herein. With the
application of these combined teachings, it can be readily
demonstrated that a single or repeat application of a facial or
neck patch or mask of the invention substantially reduces or
prevents one or more of the foregoing morphological and/or
physiological indices correlating with corresponding symptom(s) of
facial and/or neck skin aging at least 20%, more typically at least
30%, often at least 40-50%, and as much as a 75%, 85%, 90%, 95%, or
greater, compared with the corresponding value of the same
morphological and/or physiological indices measured in an
acceptable control model or system. Often, achievement of these
desired results requires prolonged application of the patch or mask
of the invention, for at least a single application period of 2-4
hours, more typically at least 4 hours, often for 4-8 hours, and
commonly for at least 8 hours.
[0089] To render the patch or mask functional for continued
delivery of the anti-aging effective compound for these prolonged
therapy periods, the anti-aging compound is formulated, and/or the
patch or mask body is constructed, so as to facilitate controlled,
prolonged release of the anti-aging effective compound for an
effective delivery period of 2-4 hours, more typically at least 4
hours, often for 4-8 hours, and commonly for at least 8 hours. Many
of the patches and masks provided herein are operable for prolonged
delivery of an overnight formulation of an anti-aging effective
compound, thereby achieving prolonged delivery of the active agent
with continuous anti-aging efficacy for periods of 7 hours or more,
up to 12 hours and even all day (16-24 hours), without unacceptable
adverse side effects such as excessive skin irritation,
dehydration, occlusion hydration (pruning), and the like.
[0090] This prolonged, controlled release capacity of the facial
and neck patches and masks of the invention can be routinely
demonstrated by known in vitro and in vivo assays, for example
assays as described below that measure skin concentration and
residence time for an anti-aging compound. In certain embodiments,
continued or "time-release" delivery is achieved at a substantially
consistent rate of delivery for the duration of the time release
period for which the patch or mask is applied to the skin, wherein
the concentration of the anti-aging compound(s) at the skin surface
remains substantially equivalent at an initial time point (e.g.,
one-half hour) after application of the patch or mask and at
subsequent time points (e.g., 2, 4, 6, 8 hours). However, in other
embodiments the rate of delivery declines after an initial time
point, but the patch or mask still delivers an anti-aging effective
concentration of the anti-aging compound(s) throughout the duration
of the specified time-release period.
[0091] Polymeric Delivery Vehicles and Methods
[0092] Within certain aspects of the invention, the anti-aging
effective compound(s), and, optionally, other biologically active
agent(s) and/or delivery-enhancing agents as described herein, are
incorporated within a biologically compatible carrier or delivery
vehicle, such as a polymeric carrier or delivery vehicle. In
exemplary embodiments, the carrier delivery vehicle comprises a
polymer that is non-toxic and nonirritating to the skin following
prolonged exposure thereto and is otherwise biologically compatible
for the uses disclosed herein. The polymeric carrier or delivery
vehicle functions as a carrier or base for the anti-aging effective
compound(s) and facilitates loading or containment of the
anti-aging compound onto the patch 10 or mask 12 undersurface 18 or
within all or a portion of the porous patch or mask body 14. In
addition, the delivery vehicle will optionally serve as a
controlled delivery vehicle to facilitate time-release delivery of
the anti-aging compound(s) to the facial or neck skin area(s) to be
treated.
[0093] Useful polymeric carriers within the methods and devices of
the invention include polymeric powders, gels, pastes, matrices and
microparticulate delivery vehicles, among other polymer forms. The
polymer can be of plant, animal, or synthetic origin. Often the
polymer is crosslinked. Additionally, in these polymeric delivery
systems the anti-aging effective compound(s) can be functionalized
in a manner where it can be covalently bound to the polymer for
enhanced loading, retention, stability delivery and/or
bioavailability of the active compound(s). In other embodiments,
the polymer is chemically modified with an inhibitor of enzymes or
other agents that may degrade or inactivate the anti-aging
effective compound(s) or other biologically active or delivery
enhancing agent(s). In certain formulations, the polymer is a
partially or completely water insoluble but water swellable
polymer, e.g, a hydrogel. Polymers useful in this aspect of the
invention are desirably water interactive and/or hydrophilic in
nature to absorb significant quantities of water, and they often
form hydrogels when placed in contact with water or aqueous media
for a period of time sufficient to reach equilibrium with water. In
more detailed embodiments, the polymer is a hydrogel which, when
placed in contact with excess water, absorbs at least two times its
weight of water at equilibrium when exposed to water at room
temperature (see, e.g., U.S. Pat. No. 6,004,583, incorporated
herein by reference).
[0094] Drug delivery systems based on biodegradable polymers are
particularly useful within the methods and devices of the invention
because such systems are typically broken down either by hydrolysis
or by enzymatic reaction into non-toxic molecules. These delivery
vehicles can therefore be employed effectively in conjunction with
a facial or neck patch or mask of the invention for long-term
release of anti-aging effective compounds. The rate of degradation
of biodegradable polymers in this regard can be controlled by
manipulating the composition of the biodegradable polymer matrix.
Exemplary biodegradable polymers for use within the invention
include, but are not limited to, poly(glycolic acid) (PGA),
poly-(lactic acid) (PLA), and poly(D,L-lactic-co-glycolic acid)
(PLGA), each of which produces degradation products having low
toxicity and excellent biocompatibility (Mehta et al, J. Control.
Rel. 29:375-384, 1994, incorporated herein by reference).
[0095] For prolonging the biological activity of anti-aging
effective compounds and other biologically active and
delivery-enhancing agents within the invention, the subject
compounds and agents may be incorporated into a polymeric matrix,
e.g., a polyorthoester, polyanhydride, or polyester matrix, to
yield sustained activity and release of the subject compounds and
agents (e.g., as determined by the degradation of the polymer
matrix). Exemplary polymeric matrices are described and
characterized in, e.g., Heller, Formulation and Delivery of
Proteins and Peptides, pp. 292-305, Cleland et al., Eds., ACS
Symposium Series 567, Washington DC, 1994; Tabata et al., Pharm.
Res. 10:487-496, 1993; and Cohen et al., Pharm. Res. 8:713-720,
1991 (each incorporated herein by reference). Useful polymeric
matrices for carrying and delivering anti-aging effective compounds
may be applied to, or incorporated within, the patch 10 or mask 12
body 14 during or after construction of the patch or mask body, and
they may in other embodiments form a primary or sole constituent of
the patch or mask body.
[0096] In additional aspects of the invention, polymeric carriers
and delivery vehicles are provided for use within the invention
that include derivatives and chemically or physically modified
versions of the foregoing types of polymers, in addition to other
naturally occurring or synthetic polymers, gums, resins, and other
agents. Also contemplated for use within the invention are blends
of these materials with each other, and with other polymers, so
long as the alterations, modifications or blending do not adversely
affect the desired properties, such as water absorption, hydrogel
formation, and/or chemical stability for useful application. In
more detailed aspects of the invention, polymers such as nylon,
acrylan and other normally hydrophobic synthetic polymers may be
modified by reaction to gain an additional useful function of water
swellability and/or an ability to form stable gels in aqueous
media.
[0097] Suitable polymers for use within the invention should
generally be stable alone and in combination with the selected
anti-aging effective compound(s) (e.g., Coenzyme Q10) and optional
additional biologically active agent(s) and/or delivery-enhancing
agent(s). Often, the polymers will form stable hydrogels in a range
of pH conditions from about pH 1 to about pH 10. More typically,
they are stable and form polymers under pH conditions ranging from
about 3 to 9, without additional protective coatings. However,
desired stability properties may be adapted to physiological
parameters characteristic of the targeted site of delivery (e.g., a
surface or basal layer of the facial or neck epidermis). Therefore,
in certain formulations higher or lower stabilities at a particular
pH and in a selected chemical or biological environment will be
more desirable.
[0098] Within additional embodiments of the invention, the
anti-aging effective compound(s) is/are formulated with one or more
absorption-promoting polymers that enhance absorption of the
anti-aging compound(s) from the patch undersurface 18 or body 14
into or across the facial or neck skin (e.g., to the basal cell
layer of the facial epidermis). These absorption-promoting polymers
may include any polymer that enhances facial skin absorption, for
example homo- and copolymers based on various combinations of the
following vinyl monomers: acrylic and methacrylic acids,
acrylamide, methacrylamide, hydroxyethylacrylate or methacrylate,
vinylpyrrolidones, as well as polyvinylalcohol and its co- and
terpolymers, polyvinylacetate, its co- and terpolymers with the
above listed monomers and 2-acrylamido-2-methyl-propanesulfonic
acid (AMPS.RTM.). Particularly useful are copolymers of the above
listed monomers with copolymerizable functional monomers such as
acryl or methacryl amide acrylate or methacrylate esters where the
ester groups are derived from straight or branched chain alkyl,
aryl having up to four aromatic rings which may contain alkyl
substituents of 1 to 6 carbons; steroidal, sulfates, phosphates or
cationic monomers such as N,N-dimethylaminoalkyl(meth)acrylamide,
dimethylaminoalkyl(meth)acrylate,
(meth)acryloxyalkyltrimethylammonium chloride,
(meth)acryloxyalkyldimethy- lbenzyl ammonium chloride.
[0099] Additional absorption-promoting polymers for use within the
invention are those classified as dextrans, dextrins, and from the
class of materials classified as natural gums and resins, or from
the class of natural polymers such as processed collagen, chitin,
chitosan, pullalan, zooglan, alginates and modified alginates such
as "Kelcoloid" (a polypropylene glycol modified alginate) gellan
gums such as "Kelocogel", Xanathan gums such as "Keltrol",
estastin, alpha hydroxy butyrate and its copolymers, hyaluronic
acid and its derivatives, polylactic and glycolic acids.
[0100] Yet another useful class of polymers applicable within the
instant invention are olefinically-unsaturated carboxylic acids
containing at least one activated carbon-to-carbon olefinic double
bond, and at least one carboxyl group; that is, an acid or
functional group readily converted to an acid containing an
olefinic double bond which readily functions in polymerization
because of its presence in the monomer molecule, either in the
alpha-beta position with respect to a carboxyl group, or as part of
a terminal methylene grouping. Olefinically-unsaturated acids of
this class include such materials as the acrylic acids typified by
acrylic acid itself, alpha-cyano acrylic acid, beta methylacrylic
acid (crotonic acid), alpha-phenyl acrylic acid, beta-acryloxy
propionic acid, cinnamic acid, p-chloro cinnamic acid,
1-carboxy-4-phenyl butadiene-1,3, itaconic acid, citraconic acid,
mesaconic acid, glutaconic acid, aconitic acid, maleic acid,
fumaric acid, and tricarboxy ethylene. As used herein, the term
"carboxylic acid" includes the polycarboxylic acids and those acid
anhydrides, such as maleic anhydride, wherein the anhydride group
is formed by the elimination of one molecule of water from two
carboxyl groups located on the same carboxylic acid molecule.
[0101] Representative acrylates useful as delivery vehicles and/or
absorption-promoting agents within the invention include methyl
acrylate, ethyl acrylate, propyl acrylate, isopropyl acrylate,
butyl acrylate, isobutyl acrylate, methyl methacrylate, methyl
ethacrylate, ethyl methacrylate, octyl acrylate, heptyl acrylate,
octyl methacrylate, isopropyl methacrylate, 2-ethylhexyl
methacrylate, nonyl acrylate, hexyl acrylate, n-hexyl methacrylate,
and the like. Higher alkyl acrylic esters are decyl acrylate,
isodecyl methacrylate, lauryl acrylate, stearyl acrylate, behenyl
acrylate and melissyl acrylate and methacrylate versions thereof.
Mixtures of two or three or more long chain acrylic esters may be
successfully polymerized with one of the carboxylic monomers. Other
comonomers include olefins, including alpha olefins, vinyl ethers,
vinyl esters, and mixtures thereof.
[0102] Other vinylidene monomers may also be used as delivery
vehicles and/or absorption-promoting agents within the methods and
compositions of the invention, including the acrylic nitriles.
Useful alpha, beta-olefinically unsaturated nitriles are preferably
monoolefinically unsaturated nitriles having from 3 to 10 carbon
atoms such as acrylonitrile, methacrylonitrile, and the like. Most
preferred are acrylonitrile and methacrylonitrile. Acrylic amides
containing from 3 to 35 carbon atoms including monoolefinically
unsaturated amides also may be used. Representative amides include
acrylamide, methacrylamide, N-t-butyl acrylamide, N-cyclohexyl
acrylamide, higher alkyl amides, where the alkyl group on the
nitrogen contains from 8 to 32 carbon atoms, acrylic amides
including N-alkylol amides of alpha, beta-olefinically unsaturated
carboxylic acids including those having from 4 to 10 carbon atoms
such as N-methylol acrylamide, N-propanol acrylamide, N-methylol
methacrylamide, N-methylol maleimide, N-methylol maleamic acid
esters, N-methylol-p-vinyl benzamide, and the like.
[0103] Yet additional useful delivery vehicles and/or
absorption-promoting materials are alpha-olefins containing from 2
to 18 carbon atoms, more preferably from 2 to 8 carbon atoms;
dienes containing from 4 to 10 carbon atoms; vinyl esters and allyl
esters such as vinyl acetate; vinyl aromatics such as styrene,
methyl styrene and chlorostyrene; vinyl and allyl ethers and
ketones such as vinyl methyl ether and methyl vinyl ketone;
chloroacrylates; cyanoalkyl acrylates such as alpha-cyanomethyl
acrylate, and the alpha-, beta-, and gamma-cyanopropyl acrylates;
alkoxyacrylates such as methoxy ethyl acrylate; haloacrylates as
chloroethyl acrylate; vinyl halides and vinyl chloride, vinylidene
chloride and the like; divinyls, diacrylates and other
polyfunctional monomers such as divinyl ether, diethylene glycol
diacrylate, ethylene glycol dimethacrylate,
methylene-bis-acrylamide, allylpentaerythritol, and the like; and
bis (beta-haloalkyl) alkenyl phosphonates such as
bis(beta-chloroethyl) vinyl phosphonate and the like as are known
to those skilled in the art. Copolymers wherein the carboxy
containing monomer is a minor constituent, and the other vinylidene
monomers present as major components are readily prepared in
accordance with the teachings known in the art and further
described herein.
[0104] In more detailed aspects of the invention, topical delivery
of the anti-aging effective compound is enhanced by retaining the
anti-aging effective compound(s) (e.g., Coenzyme Q10) and,
optionally, other biologically active and/or delivery enhancing
agents, in a slow-release or enzymatically or physiologically
protective carrier or vehicle, for example a hydrogel that shields
the active agent from the action of the degradative enzymes. In
certain embodiments, the anti-aging effective compound is bound by
chemical means to the carrier or vehicle, to which may also be
admixed or bound additional agents such as enzyme inhibitors, etc.
The anti-aging effective compound may alternately be immobilized
through sufficient physical entrapment within the carrier or
vehicle, e.g., a polymer matrix.
[0105] When hydrogels are employed as delivery vehicles and/or
absorption promoting agents within the invention, these may be
composed of synthetic copolymers from the group of acrylic and
methacrylic acids, acrylamide, methacrylamide, hydroxyethylacrylate
(HEA) or methacrylate (HEMA), and vinylpyrrolidones which are water
interactive and swellable. Specific illustrative examples of useful
polymers, for the delivery of anti-aging effective compounds are
the following types of polymers: (meth)acrylamide and 0.1 to 99 wt.
% (meth)acrylic acid; (meth)acrylamides and 0.1-75 wt %
(meth)acryloxyethyl trimethyammonium chloride; (meth)acrylamide and
0.1-75 wt % (meth)acrylamide; acrylic acid and 0.1-75 wt %
alkyl(meth)acrylates; (meth)acrylamide and 0.1-75 wt % AMPS.RTM.
(trademark of Lubrizol Corp.); (meth)acrylamide and 0 to 30 wt %
alkyl(meth)acrylamides and 0.1-75 wt % AMPS.RTM.; (meth)acrylamide
and 0.1-99 wt. % HEMA; (metb)acrylamide and 0.1 to 75 wt % HEMA and
0.1 to 99% (meth)acrylic acid; (meth)acrylic acid and 0.1-99 wt %
HEMA; 50 mole % vinyl ether and 50 mole % maleic anhydride;
(meth)acrylamide and 0.1 to 75 wt % (meth)acryloxyalky dimethyl
benzylammonium chloride; (meth)acrylamide and 0.1 to 99 wt % vinyl
pyrrolidone; (meth)acrylamide and 50 wt % vinyl pyrrolidone and
0.1-99.9 wt % (meth)acrylic acid; (meth)acrylic acid and 0.1 to 75
wt % AMPS.RTM. and 0.1-75 wt % alkyl(meth)acrylamide. In the above
examples, alkyl means C.sub.1 to C.sub.30, preferably C.sub.1 to
C.sub.22, linear and branched and C.sub.4 to C.sub.16 cyclic; where
(meth) is used, it means that the monomers with and without the
methyl group are included. Other useful hydrogel polymers are
swellable, but insoluble versions of poly(vinyl pyrrolidone)
starch, carboxymethyl cellulose and polyvinyl alcohol.
[0106] Additional polymeric hydrogel materials for use within the
invention include (poly) hydroxyalkyl (meth)acrylate: anionic and
cationic hydrogels: poly(electrolyte) complexes; poly(vinyl
alcohols) having a low acetate residual: a swellable mixture of
crosslinked agar and crosslinked carboxymethyl cellulose: a
swellable composition comprising methyl cellulose mixed with a
sparingly crosslinked agar; a water swellable copolymer produced by
a dispersion of finely divided copolymer of maleic anhydride with
styrene, ethylene, propylene, or isobutylene; a water swellable
polymer of N-vinyl lactams; swellable sodium salts of carboxymethyl
cellulose; and the like.
[0107] Other gelable, fluid imbibing and retaining polymers useful
for forming the hydrophilic hydrogel for topical delivery of
anti-aging effective compounds to facial and neck skin areas in
conjunction with application of a facial or neck patch or mask of
the invention include pectin; polysaccharides such as agar, acacia,
karaya, tragacenth, algins and guar and their crosslinked versions;
acrylic acid polymers, copolymers and salt derivatives,
polyacrylamides; water swellable indene maleic anhydride polymers;
starch graft copolymers; acrylate type polymers and copolymers with
water absorbability of about 2 to 400 times its original weight;
diesters of polyglucan; a mixture of crosslinked poly(vinyl
alcohol) and poly(N-vinyl-2-pyrrolidone);
polyoxybutylene-polyethylene block copolymer gels; carob gum;
polyester gels; poly urea gels; polyether gels; polyamide gels;
polyimide gels; polypeptide gels; polyamino acid gels; poly
cellulosic gels; crosslinked indene-maleic anhydride acrylate
polymers; and polysaccharides.
[0108] Synthetic hydrogel polymers for use within the invention may
be made by combining various monomers in selected ratios. The
hydrogel can be crosslinked and generally possesses the ability to
imbibe and absorb fluid and swell or expand to an enlarged
equilibrium state. The hydrogel typically swells or expands after
initial formulation (e.g., before or after application of the patch
to the facial or neck skin surface), absorbing about 2-5, 5-10,
10-50, up to 50-100 or more times fold its weight of water. The
optimum degree of swellability for a given hydrogel will be
determined for different anti aging effective compounds depending
upon such factors as molecular weight, size, solubility and
diffusion characteristics of the active agent carried by or
entrapped or encapsulated within the polymer, and the specific
spacing and cooperative chain motion associated with each
individual polymer.
[0109] Certain hydrophilic polymers useful within the invention are
water insoluble but water swellable. Such water swollen polymers
are typically referred to as hydrogels or gels. Such gels may be
conveniently produced from water soluble polymer by the process of
crosslinking the polymers by a suitable crosslinking agent.
However, stable hydrogels may also be formed from specific polymers
under defined conditions of pH, temperature and/or ionic
concentration, according to known methods in the art. Typically the
polymers are cross-linked, that is, cross-linked to the extent that
the polymers possess good hydrophilic properties, have improved
physical integrity (as compared to non cross-linked polymers of the
same or similar type) and exhibit improved ability to retain within
the gel network the anti-aging effective compound of interest and
optional additional compounds for coadministration therewith such
as an enzyme inhibitor, while retaining the ability to release the
active agent(s) at the appropriate location and time.
[0110] Generally hydrogel polymers for use within the invention are
crosslinked with a difunctional cross-linking in the amount of from
0.01 to 25 weight percent, based on the weight of the monomers
forming the copolymer, and more preferably from 0.1 to 20 weight
percent and more often from 0.1 to 15 weight percent of the
crosslinking agent. Another useful amount of a crosslinking agent
is 0.1 to 10 weight percent. Tri, tetra or higher multifunctional
crosslinking agents may also be employed. When such reagents are
utilized, lower amounts may be required to attain equivalent
crosslinking density, i.e., the degree of crosslinking, or network
properties that are sufficient to contain effectively the
anti-aging effective compound(s). The crosslinks can be covalent,
ionic or hydrogen bonds with the polymer possessing the ability to
swell in the presence of water containing fluids. Such crosslinkers
and crosslinking reactions are known to those skilled in the art
and in many cases are dependent upon the polymer system. Thus a
crosslinked network may be formed by free radical copolymerization
of unsaturated monomers.
[0111] Polymeric hydrogels may also be formed by crosslinking
preformed polymers by reacting functional groups found on the
polymers such as alcohols, acids, amines with such groups as
glyoxal, formaldehyde or glutaraldehyde, bis anhydrides and the
like. The polymers also may be cross-linked with any polyene, e.g.
decadiene or trivinyl cyclohexane; acrylamides, such as
N,N-methylene-bis (acrylamide); polyfunctional acrylates, such as
trimethylol propane triacrylate; or polyfunctional vinylidene
monomer containing at least 2 terminal CH.sub.2<groups,
including, for example, divinyl benzene, divinyl naphthlene, allyl
acrylates and the like. In certain embodiments, cross-linking
monomers for use in preparing the copolymers are polyalkenyl
polyethers having more than one alkenyl ether grouping per
molecule, which may optionally possess alkenyl groups in which an
olefinic double bond is present attached to a terminal methylene
grouping (e.g., made by the etherification of a polyhydric alcohol
containing at least 2 carbon atoms and at least 2 hydroxyl groups).
Compounds of this class may be produced by reacting an alkenyl
halide, such as allyl chloride or allyl bromide, with a strongly
alkaline aqueous solution of one or more polyhydric alcohols. The
product may be a complex mixture of polyethers with varying numbers
of ether groups. Efficiency of the polyether cross-linking agent
increases with the number of potentially polymerizable groups on
the molecule. Typically, polyethers containing an average of two or
more alkenyl ether groupings per molecule are used. Other useful
crosslinking monomers include for example, diallyl esters,
dimethallyl ethers, allyl or methallyl acrylates and acrylamides,
tetravinyl silane, polyalkenyl methanes, diacrylates, and
dimethacrylates, divinyl compounds such as divinyl benzene,
polyallyl phosphate, diallyloxy compounds and phosphite esters and
the like. Typical agents are allyl pentaerythritol, allyl sucrose,
trimethylolpropane triacrylate, 1,6-hexanediol diacrylate,
trimethylolpropane diallyl ether, pentaerythritol triacrylate,
tetramethylene dimethacrylate, ethylene diacrylate, ethylene
dimethacrylate, triethylene glycol dimethacrylate, and the like.
Allyl pentaerythritol, trimethylolpropane diallylether and allyl
sucrose provide suitable polymers. When the cross-linking agent is
present, the polymeric mixtures usually contain between about 0.01
to 20 weight percent, e.g., 1%, 5%, or 10% or more by weight of
cross-linking monomer based on the total of carboxylic acid
monomer, plus other monomers.
[0112] Polymers such as hydrogels useful within the invention may
incorporate functional linked agents such as glycosides chemically
incorporated into the polymer for enhancing topical bioavailability
of anti-aging effective compounds and other biologically active
agents formulated therewith. Examples of such glycosides are
glucosides, fructosides, galactosides, arabinosides, mannosides and
their alkyl substituted derivatives and natural glycosides such as
arbutin, phlorizin, amygdalin, digitonin, saponin, and indican.
There are several ways in which a typical glycoside may be bound to
a polymer. For example, the hydrogen of the hydroxyl groups of a
glycoside or other similar carbohydrate may be replaced by the
alkyl group from a hydrogel polymer to form an ether. Also, the
hydroxyl groups of the glycosides may be reacted to esterify the
carboxyl groups of a polymeric hydrogel to form polymeric esters in
situ. Another approach is to employ condensation of
acetobromoglucose with cholest-5-en-3beta-ol on a copolymer of
maleic acid. N-substituted polyacrylamides can be synthesized by
the reaction of activated polymers with omega-aminoalkylglycosides:
(1) (carbohydrate-spacer)(n)-polyacrylamide,
`pseudopolysaccharides`; (2) (carbohydrate
spacer)(n)-phosphatidylethanolamine(m)-polyacrylamide,
neoglycolipids, derivatives of phosphatidylethanolamine; (3)
(carbohydrate-spacer)(n)-biotin(m)-polyacrylamide. These
biotinylated derivatives may attach to lectins on target cell
surfaces to facilitate absorption of the anti-aging effective
compound, e.g., a polymer encapsulated protein or peptide.
[0113] Within more detailed aspects of the invention, anti-aging
effective compound (e.g., Coenzyme Q10), and, optionally,
additional, secondary active agents such as other antioxidant
compounds, protease inhibitor(s), etc., are modified and bound to a
polymeric carrier or matrix. For example, this may be accomplished
by chemically binding a Coenzyme Q10 active agent and other
optional agent(s) within a crosslinked polymer network. It is also
possible to chemically modify the polymer separately with an
interactive agent such as a glycosidal containing molecule. In
certain aspects, the anti aging effective compound(s) and optional
secondary active agent(s), may be functionalized, i.e., wherein an
appropriate reactive group is identified or is chemically added to
the active agent(s). For example, an ethylenic polymerizable group
may be added, and the functionalized active agent is then
copolymerized with monomers and a crosslinking agent using a
standard polymerization method such as solution polymerization
(usually in water), emulsion, suspension or dispersion
polymerization. Often, the functionalizing agent is provided with a
high enough concentration of functional or polymerizable groups to
insure that multiple sites on the active agent(s) are
functionalized.
[0114] After functionalization, the functionalized active agent(s)
is/are mixed with monomers and a crosslinking agent which comprise
the reagents from which the polymer of interest is formed.
Polymerization is then induced in this medium to create a polymer
containing the bound active agent(s). The polymer is then washed
with water or other appropriate solvents and otherwise purified to
remove trace unreacted impurities and, if necessary, ground or
broken up by physical means such as by stirring, forcing it through
a mesh, ultrasonication or other suitable means to a desired
particle size. The solvent, usually water, is then removed in such
a manner as to not denature or otherwise degrade the active
agent(s). One desired method is lyophilization (freeze drying) but
other methods are available and may be used (e.g., vacuum drying,
air drying, spray drying, etc.).
[0115] In additional aspects of the invention, the anti-aging
effective compound (e.g., Coenzyme Q10) and optional additional
anti-aging effective compounds and/or delivery-enhancing agents,
including anti-aging effective compounds (e.g., anti-oxidant
compounds), peptides, proteins, nucleosides, and other molecules
which are bioactivein vivo, are conjugation-stabilized by
covalently bonding one or more of the active or enhancing agent(s)
to a polymer incorporating as an integral part thereof both a
hydrophilic moiety, e.g., a linear polyalkylene glycol, and a
lipophilic moiety (see, e.g., U.S. Pat. No. 5,681,811, incorporated
herein by reference). In one aspect, a anti-aging effective
compound is covalently coupled with a polymer comprising (i) a
linear polyalkylene glycol moiety and (ii) a lipophilic moiety,
wherein the active agent, linear polyalkylene glycol moiety, and
the lipophilic moiety are conformationally arranged in relation to
one another such that the active therapeutic agent has an enhanced
in vivo resistance to enzymatic degradation (i.e., relative to its
stability under similar conditions in an unconjugated form devoid
of the polymer coupled thereto). In another aspect, the
conjugation-stabilized formulation has a three-dimensional
conformation comprising the anti-aging effective compound
covalently coupled with a polysorbate complex comprising (i) a
linear polyalkylene glycol moiety and (ii) a lipophilic moiety,
wherein the active agent, the linear polyalkylene glycol moiety and
the lipophilic moiety are conformationally arranged in relation to
one another such that (a) the lipophilic moiety is exteriorly
available in the three-dimensional conformation, and (b) the active
agent in the composition has an enhanced in vivo resistance to
enzymatic degradation.
[0116] In a further related aspect of the invention, a multiligand
conjugated complex is provided which comprises an anti-aging
effective compound (e.g., Coenzyme Q10) and/or other biologically
active or delivery-enhancing agent covalently coupled with a
triglyceride backbone moiety through a polyalkylene glycol spacer
group bonded at a carbon atom of the triglyceride backbone moiety,
and at least one fatty acid moiety covalently attached either
directly to a carbon atom of the triglyceride backbone moiety or
covalently joined through a polyalkylene glycol spacer moiety (see,
e.g., U.S. Pat. No. 5,681,811, incorporated herein by reference).
In such multiligand conjugated therapeutic agent complexes, the
alpha' and beta carbon atoms of the triglyceride bioactive moiety
may have fatty acid moieties attached by covalently bonding either
directly thereto, or indirectly covalently bonded thereto through
polyalkylene glycol spacer moieties. Alternatively, a fatty acid
moiety may be covalently attached either directly or through a
polyalkylene glycol spacer moiety to the alpha and alpha' carbons
of the triglyceride backbone moiety, with the bioactive therapeutic
agent being covalently coupled with the gamma-carbon of the
triglyceride backbone moiety, either being directly covalently
bonded thereto or indirectly bonded thereto through a polyalkylene
spacer moiety. It will be recognized that a wide variety of
structural, compositional, and conformational forms are possible
for the multiligand conjugated therapeutic agent complex comprising
the triglyceride backbone moiety, within the scope of the
invention. It is further noted that in such a multiligand
conjugated therapeutic agent complex, the anti-aging effective
compound(s) may advantageously be covalently coupled with the
triglyceride modified backbone moiety through alkyl spacer groups,
or alternatively other acceptable spacer groups, within the scope
of the invention. As used in such context, acceptability of the
spacer group refers to steric, compositional, and end use
application specific acceptability characteristics.
[0117] In yet additional aspects of the invention, a
conjugation-stabilized complex is provided which comprises a
polysorbate complex comprising a polysorbate moiety including a
triglyceride backbone having covalently coupled to alpha, alpha'
and beta carbon atoms thereof functionalizing groups including (i)
a fatty acid group; and (ii) a polyethylene glycol group having a
anti-aging effective compound or moiety covalently bonded thereto,
e.g., bonded to an appropriate functionality of the polyethylene
glycol group (see, e.g., U.S. Pat. No. 5,681,811, incorporated
herein by reference). Such covalent bonding may be either direct,
e.g., to a hydroxy terminal functionality of the polyethylene
glycol group, or alternatively, the covalent bonding may be
indirect, e.g., by reactively capping the hydroxy terminus of the
polyethylene glycol group with a terminal carboxy functionality
spacer group, so that the resulting capped polyethylene glycol
group has a terminal carboxy functionality to which the anti-aging
effective compound or other biologically active or
delivery-enhancing agent or moiety may be covalently bonded.
[0118] In yet additional aspects of the invention, a stable,
aqueously soluble, conjugation-stabilized complex is provided which
comprises an anti-aging effective compound (e.g., Coenzyme Q10)
and/or other biologically active or delivery-enhancing agent
covalently coupled to a physiologically compatible polyethylene
glycol (PEG) modified glycolipid moiety. In such complex, the
anti-aging effective compound may be covalently coupled to the
physiologically compatible PEG modified glycolipid moiety by a
labile covalent bond at a free amino acid group of the active
agent, wherein the labile covalent bond is scissionable in vivo by
biochemical hydrolysis and/or proteolysis. The physiologically
compatible PEG modified glycolipid moiety may advantageously
comprise a polysorbate polymer, e.g., a polysorbate polymer
comprising fatty acid ester groups selected from the group
consisting of monopalmitate, dipalmitate, monolaurate, dilaurate,
trilaurate, monoleate, dioleate, trioleate, monostearate,
distearate, and tristearate. In such complex, the physiologically
compatible PEG modified glycolipid moiety may suitably comprise a
polymer selected from the group consisting of polyethylene glycol
ethers of fatty acids, and polyethylene glycol esters of fatty
acids, wherein the fatty acids for example comprise a fatty acid
selected from the group consisting of lauric, palmitic, oleic, and
stearic acids.
[0119] In other detailed aspects of the invention, topical delivery
of an anti-aging effective compound (e.g., Coenzyme Q10) is
enhanced by combining or coordinately administering the anti-aging
compound (e.g., Coenzyme Q10) with a polypropylene-based or other
membrane penetration-enhancing polymer or copolymer (e.g., a
polypropylene glycol-(PPG)-PEG copolymer). A variety of such
polymers (e.g., polypropylene oxides, polypropylene glycols) are
known in the art and can provide for enhanced membrane permeation
of anti-aging effective compounds (see e.g., Vandorpe et al.,
Biomaterials 18: 1147-1152, 1997; Kajihara et al., Biosci.
Biotechnol. Biochem. 61: 197-199, 1997; Yeh et al., Pharm. Res. 13:
1693-1698, 1996; Rogers et al., J. Chromatogr. B. Biomed. Appl.
680: 231-236, 1996; Kronick, Pharmacol. Res. Commun. 10: 257-259,
1978, each incorporated herein by reference.)
[0120] Bioadhesive Delivery Vehicles and Methods
[0121] In additional aspects of the invention, the anti-aging
effective compound to be delivered by a facial skin patch 10 or
mask 12 of the invention are formulated or coordinately
administered with a nontoxic bioadhesive to enhance topical
delivery of the anti-aging effective compound. In certain
embodiments, safe and effective bioadhesive are formulated directly
with the anti-aging effective compound(s) and applied to the patch
or mask undersurface 18, or invested in the patch or mask body 14,
to enhance topical delivery of the anti-aging effective
compound(s). The bioadhesive delivery vehicle may serve a dual
purpose as a delivery vehicle and as an attachment means to mediate
removable attachment of the patch or mask to the facial or neck
skin area to be treated, to allow the patch or mask body to
securely, removably to conform to the subject skin area.
Alternatively, the bioadhesive may be applied to or invested in the
patch or mask body separate from the anti-aging effective
compound(s), to the same or different surface(s) or portions of the
patch or mask body to which the anti-aging effective compound(s)
is/are applied or invested.
[0122] Thus, in certain embodiments, the bioadhesive agent is
admixed with the anti-aging effective compound and layered onto the
undersurface 18 of the patch or mask body as an external
formulation coating 160 (see, e.g., FIG. 7). Alternatively, the
anti-aging effective compound can be initially applied (alone or
admixed with a different carrier or delivery vehicle) to the
undersurface separate from the bioadhesive agent as a first coating
layer 162, and then the bioadhesive agent is applied over this
coating as a second, adhesive coating layer 164. In other
alternative embodiments, the anti-aging effective compound can be
initially invested (alone or admixed with a different carrier or
delivery vehicle) into all or part of the patch or mask body 14 in
chemical communication with the undersurface thereof (e.g., by
absorbing, adsorbing, infusing, injecting, integrally molding,
encapsulating, etc., to invest the anti-aging compound in all or
part of the patch body) to separate from the bioadhesive agent as
an invested layer 170 or infiltrate, and then the bioadhesive agent
is applied or otherwise contacted with the undersurface to provide
a separate adhesive coating layer 172 (see, e.g., FIG. 8). When the
anti-aging effective compound(s) are invested in the patch or mask
body in this manner, they may be loaded as described above to
penetrate to a desired depth or width of the patch or mask body (as
depicted in FIG. 8). The depth of penetration 174 in this regard
allows for selective loading of the patch or mask body with a
predetermined amount of the anti-aging effective compound, and
further provides for additional control over the rate and duration
of delivery of the anti-aging effective compound. Often, the
anti-aging effective compound is loaded to penetrate one-fourth to
one-half or more of the total depth or thickness of the patch or
mask body 14, which may be directed across the entire body or at
one or more selected loading point(s) (typically where the patch or
mask contacts the facial or neck skin to be treated, for example at
one or more drug delivery section(s) such as a supraorbital 62,
infraorbital 64, lateral orbital 66 or medial orbital drug delivery
section, or at any other surface-contacting feature). In this
manner, the reservoir function of the patch or mask body can be
controlled and calibrated for controlled release and delivery of
the anti-aging compound, as well as to direct delivery to selected
target sites of the facial or neck skin, such as the orbital
marginal area 30 or portions thereof.
[0123] As also depicted in FIG. 8, the facial skin patch 10 or mask
12 of the invention may be packaged in any suitable enclosure,
preferably a sealed enclosure, and will often be provided with a
protective cover 175, such as a plastic sheet, tab, or tape applied
to the undersurface 18 of the patch or mask body, or covering the
external formulation coating 160, and/or the adhesive coating layer
164. The protective cover may be provided with an adhesive to
adhere in place or will alternatively adhere by removable bonding
to the adhesive coating layer, and protects the undersurface and
other portions of the patch or mask and the medicament from
contamination and/or leakage or transfer of the medicament and
other materials from the patch or mask. The protective cover may
completely envelop the patch or mask body, or may be applied at the
undersurface only, and is readily removed by tearing and/or peeling
of the cover away from the opposing patch or mask surface(s).
[0124] In further embodiments of the invention, the rate, duration
and/or location of delivery of the anti-aging effective compound
is/are additionally controlled by varying the construction of the
patch 10 or mask 12 body 14. For example, the fibrous or porous
composition or makeup of the patch or mask body can provide a
gradient of pore or channel size, density or orientation,
hydrophobicity, hydrophilicity, or other physicochemical
parameters, normal (i.e., generally perpendicular to) the patch or
mask undersurface 18 that selectively wicks, channels, expels, or
otherwise directs, delivery of the anti-aging compound toward the
undersurface 18 of the patch or mask body to come in contact with
the skin to be treated. For example, the patch or mask body may
feature a pore (e.g., open celled polymer cell) size gradient
between an outer patch or mask body surface 176 and the
undersurface, that serves to drive or transfer an anti-aging
compound deeply imbued within the patch or mask body in the
direction of the undersurface to facilitate controlled, prolonged
delivery of the anti-aging compound to the target skin surface.
[0125] The bioadhesive, whether admixed with the anti-aging
effective compound or applied as a separate layer, is permeable to
diffusion and other chemical transport of the anti-aging effective
compound to allow passage of the active compound through or from
the bioadhesive to the target skin surface to permit effective,
controlled delivery of the active compound as described above. In
yet additional embodiments, the bioadhesive agent may be applied to
selected portions of the patch or mask, for example to the
undersurfaces 18' of individual patch or mask sections (see, e.g.,
FIGS. 5 and 6), to a circumferential ridge 180 extending from a
peripheral undersurface 18" of an orbital patch 24 or orbital mask
26 body to conform (in a circular or oval shape) to an entire
orbital margin 30 of a subject (see, e.g., FIG. 7), or to any other
anatomically conforming surface feature (e.g., edge, margin, ridge,
protrusion, etc.) to direct adhesion of the patch to specific
facial or neck skin surface features for attachment.
[0126] Bioadhesive materials for use within the invention are
optionally effective as attachment means to removably affix the
patch 10 or mask 12 to a facial or neck skin area, with sufficient
integrity of adhesion to secure the patch for prolonged periods as
indicated above and in certain embodiments to resist dislodgement
of the patch when subjected to facial skin movements in the subject
skin area(s) to be treated. At the same time, the bioadhesive
provides a suitable level of adhesion to allow removal of the patch
or mask, typically without the aid of solvents, without
unacceptable discomfort to the subject. Various polymers, both
natural and synthetic ones, show acceptable binding to skin
surfaces under physiological conditions. The strength of this
interaction can readily be measured by mechanical peel or shear
tests. A variety of suitable test methods and instruments to serve
such purposes are known in the art (see, e.g., Gu et al., Crit.
Rev. Ther. Drug Carrier Syst. 5:21-67, 1988; Duchene et al., Drug
Dev. Ind. Pharm. 14:283-318, 1988, incorporated herein by
reference). When applied to a humid skin surface, many dry
materials will spontaneously adhere, at least slightly. After such
an initial contact, some hydrophilic materials start to attract
water by adsorption, swelling or capillary forces, and if this
water is absorbed from the underlying substrate or from the
polymer-tissue interface, the adhesion may be appropriate to
achieve the functions of the invention (see, e.g., Al-Dujaili et
al., Int. J. Pharm. 34:75-79, 1986; Marvola et al., J. Pharm. Sci.
72:1034-1036, 1983; Marvola et al., J. Pharm. Sci. 71:975-977,
1982; and Swisher et al., Int. J. Pharm. 22:219, 1984; Chen, et
al., Adhesion in Biological Systems, p. 172, Manly, Ed., Academic
Press, London, 1970, each incorporated herein by reference). Such
`adhesion by hydration` can be quite strong, but formulations
adapted to employ this mechanism must account for swelling which
continues as the dosage transforms into a hydrated skin. This is
projected for many hydrocolloids useful within the invention,
especially some cellulose-derivatives, which are generally
non-adhesive when applied in pre-hydrated state. Nevertheless,
bioadhesive drug delivery systems for topical administration are
effective within the invention when such materials are applied in
the form of a dry polymeric powder, microsphere, or film-type
delivery form.
[0127] Other polymers useful within the invention adhere to skin
surfaces not only when applied in dry, but also in fully hydrated
state, and in the presence of excess amounts of water. The
selection of a bioadhesive thus requires due consideration of the
conditions, physiological as well as physico-chemical, under which
the contact to the skin will be formed and maintained. In
particular, the amount of water or humidity usually present at the
intended site of adhesion, and the prevailing pH, are known to
largely affect the mucoadhesive binding strength of different
polymers.
[0128] Several polymeric bioadhesive drug delivery systems are
known in the art and useful within the methods and devices of the
invention (see, e.g., U.S. Pat. Nos. 3,972,995; 4,259,314;
4,680,323; 4,740,365; 4,573,996; 4,292,299; 4,715,369; 4,876,092;
4,855,142; 4,250,163; 4,226,848; 4,948,580; U.S. Pat. No. Reissue
33,093; and Robinson, 18 Proc. Intern. Symp. Control. Rel. Bioact.
Mater. 75 (1991), each incorporated herein by reference). The
potential of various bioadhesive polymers as a topical delivery
platform within the methods and devices of the invention can be
readily assessed by determining their ability to retain and release
a specific anti-aging effective compound, e.g., a therapeutic
anti-oxidant compound, as well as by their capacity to interact
with skin surfaces following incorporation of the active agent
therein. In addition, well known methods will be applied to
determine the biocompatibility of selected polymers with the tissue
at the site of topical administration. One aspect of polymer
biocompatibility is the potential effect for the polymer to induce
a cytokine response. In certain circumstances, implanted polymers
have been shown to induce the release of inflammatory cytokines
from adhering cells, such as monocytes and macrophages. Similar
potential adverse reactions of epidermal and associated cells in
contact with candidate bioadhesive polymers will be determined
using routine in vitro and in vivo assays to measure
biocompatibility of a selected polymer delivery platform.
[0129] Bioadhesion involves the attachment of a natural or
synthetic polymer to a biological substrate. It serves within the
methods and compositions of the invention as a practical method for
drug immobilization or localization at the skin surface, thereby
providing for enhanced absorption and better controlled drug
delivery, and optionally as attachment means to affix a patch 10 or
mask 12 of the invention to a target facial or neck skin area. The
use of bioadhesive polymers within the invention provides for
maintenance of a relatively constant effective drug concentration
at the target site for action for an extended time period. For
optimal performance, drug concentrations at the target site (e.g.,
a selected facial or neck skin surface or basal layer or associated
tissue or extracellular compartment)) should be maintained above
the effective concentration level for the drug and below a toxic or
otherwise excessive dosage level. Bioadhesive and other delivery
components within the methods and devices of the invention can
improve the effectiveness of a treatment by helping maintain the
drug concentration between effective and toxic levels, by
inhibiting dilution of the drug away from the delivery point, and
improving targeting and localization of the drug. In this context,
bioadhesion increases the intimacy and duration of contact between
a drug-containing polymer and the skin surface. The combined
effects of this enhanced, direct drug absorption, and the decrease
in excretion rate that results from reduced diffusion and improved
localization, significantly enhances bioavailability of the drug
and allows for a smaller dosage and less frequent
administration.
[0130] Exemplary bioadhesives for use within certain embodiments of
the invention include acrylic-based hydrogels, which are
well-suited for bioadhesion due to their flexibility and
nonabrasive characteristics in the partially swollen state to
reduce damage-causing attrition to the tissues in contact (Park et
al., J. Control. Release 2:47-57, 1985, incorporated herein by
reference). Furthermore, their high permeability in the swollen
state allows unreacted monomer, un-crosslinked polymer chains, and
the initiator to be washed out of the matrix after polymerization,
which is a desirable feature for bioadhesive materials for use
within the invention. Acrylic-based polymer devices exhibit very
high adhesive bond strength, as determined by various known methods
(Park et al., J. Control. Release 2:47-57, 1985; Park et al.,
Pharm. Res. 4:457-464, 1987; and Ch'ng et al., J. Pharm. Sci.
74:399-405, 1985, each incorporated herein by reference).
[0131] For controlled topical delivery of anti-aging effective
compounds, bioadhesive polymeric delivery vehicles may also
function in part to shield the anti-aging effective compound from
degradation or enzymatic breakdown, while at the same time
providing for enhanced penetration of the anti-oxidant compound
into or through the skin. In this context, bioadhesive polymers
have demonstrated considerable potential for enhancing topical drug
delivery. As an example, the bioavailability of 9-desglycinamide,
8-arginine vasopressin (DGAVP) intraduodenally administered to rats
together with a 1% (w/v) saline dispersion of the mucoadhesive
poly(acrylic acid) derivative polycarbophil, was 3-5-fold increased
compared to an aqueous solution of the peptide drug without this
polymer (Lehr et al., J. Pharm. Pharmacol. 44:402-407, 1992,
incorporated herein by reference). In this study, the drug was not
bound to or otherwise integrally associated with the mucoadhesive
polymer in the formulation, which would therefore not be expected
to yield enhanced peptide absorption via prolonged residence time
or intensified contact to the mucosal surface. Thus, certain
bioadhesive polymers for use within the invention will directly
enhance the permeability of the skin absorption barrier in part by
protecting the active agent, e.g., peptide or protein, from
enzymatic degradation.
[0132] Another useful bioadhesive agent within the methods and
devices of the invention is chitosan, as well as its analogs and
derivatives. Chitosan is a non-toxic, biocompatible and
biodegradable polymer that is widely used for pharmaceutical and
medical applications because of its favorable properties of low
toxicity and good biocompatibility (Yomota, Pharm. Tech. Japan
10:557-564, 1994, incorporated herein by reference). It is a
natural polyaminosaccharide prepared from chitin by N-deacetylation
with alkali. A wide variety of biomedical uses for chitosan have
been reported over the last two decades, based for example on its
reported wound healing, antimicrobial and hemostatic properties
(Kas, J. Microencapsulation 14:689-711, 1997, incorporated herein
by reference). Chitosan has also been used as a pharmaceutical
excipient in conventional dosage forms as well as in novel
applications involving bioadhesion and transmucosal drug transport
(Illum, Pharm. Res. 15:1326-1331, 1998; and Olsen et al., Chitin
and Chitosan-sources, Chemistry, Biochemistry, Physical Properties
and Applications, pp. 813-828, Skjak-Braek et al., Eds., Elsevier,
London, 1989, each incorporated herein by reference). Furthermore,
chitosan has been reported to promote absorption of small polar
molecules and peptide and protein drugs through nasal mucosa in
animal models and human volunteers (Illum et al., Pharm. Res.
11:1186-1189, 1994, incorporated herein by reference). Other
studies have shown an enhancing effect on penetration of compounds
across the intestinal mucosa and cultured Caco-2 cells (Schipper et
al., Pharm. res. 14:23-29, 1997; and Kotze et al., Int. J. Pharm.
159:243-253, 1997, each incorporated herein by reference). Chitosan
has also been proposed as a bioadhesive polymer for use in topical
drug delivery (Miyazaki et al., Biol. Pharm. Bull. 17:745-747,
1994; Ikinci et al., Advances in Chitin Science, Vol. 4, Peter et
al., Eds., University of Potsdam, in press; Senel, et al., Int. J.
Pharm. 193:197-203, 2000; Needleman, et al., J. Clin. Periodontol.
24:394-400, 1997, each incorporated herein by reference). Initial
studies showed that chitosan has an extended retention time on the
oral mucosa (Needleman et al., J. Clin. Periodontol. 25:74-82,
1998) and with its antimicrobial properties and biocompatibility is
an excellent candidate for the treatment of oral mucositis. More
recently, Senel et al., Biomaterials 21:2067-2071, 2000
(incorporated herein by reference) reported that chitosan provides
an effective gel carrier for delivery of the bioactive peptide,
transforming growth factor-.beta. (TGF-.beta.).
[0133] As used within the methods and compositions of the
invention, chitosan increases the retention of anti-aging effective
compounds at a topical site of application. This is thought to be
mediated in part by a positive charge characteristic of chitosan,
which may influence tissue permeability even after physical removal
of chitosan from the surface (Schipper et al., Pharm. Res.
14:23-29, 1997, incorporated herein by reference). Chitosan may
also increase the thermodynamic activity of other
absorption-promoting agents used in certain formulations of the
invention, resulting in enhanced penetration. Lastly, as chitosan
has been reported to disrupt lipid micelles in the intestine
(Muzzarelli et al., EUCHIS'99, Third International Conference of
the European Chitin Society, Abstract Book, ORAD-PS-059, Potsdam,
Germany, 1999), its absorption-promoting effects may be due in part
to its interference with the lipid organization in tissues.
[0134] As with other bioadhesive gels provided herein, the use of
chitosan can reduce the frequency of application and the amount of
anti-aging effective compound administered while yielding an
effective delivery amount or dose. This mode of administration can
also improve patient compliance and acceptance. The occlusion and
lubrication of chitosan and other bioadhesive gels is expected to
reduce any discomfort that may arise from inflammatory, allergic
and ulcerative conditions of the skin. In addition, chitosan acts
non-specifically on certain deleterious microorganisms, including
fungi (Knapczyk, Chitin World, pp. 504-511, Karnicki et al., Eds.,
Wirtschaftverlag NW, Germany, 1994, incorporated herein by
reference), and may also beneficially stimulate cell proliferation
and tissue organization by acting as an inductive primer to repair
and physiologically rebuild damaged tissue (Muzzarelli et al.
(Biomaterials 10:598-603, 1989, incorporated herein by
reference).
[0135] The foregoing bioadhesive agents are useful within the
methods and devices of the instant invention, which optionally
incorporate an effective amount and form of a bioadhesive agent to
prolong persistence or otherwise increase topical absorption of
anti-aging effective compounds. The bioadhesive agents may be
coordinately administered as adjunct compounds (i.e., separately
applied before or after application of the facial patch 10 or mask
12) or as additives to or carriers for the anti-aging effective
compound(s). In certain embodiments, the bioadhesive agent acts as
a `pharmaceutical glue` to provide attachment means for the patch
or mask, whereas in other embodiments adjunct delivery or
combinatorial formulation of the bioadhesive agent serves to
intensify contact of the anti-aging effective compound with the
skin, in some cases by increasing skin permeability to
significantly increase the drug concentration gradient measured at
a target site of delivery (e.g., the basal layer of the treated
skin). Yet additional bioadhesive agents for use within the
invention act as enzyme inhibitors to enhance the stability of
topically administered anti-aging effective compounds coordinately
or combinatorially applied with the bioadhesive agent.
[0136] Bioadhesive agents and other "delivery vehicles" and
carriers for use within the invention maintain a desired
concentration gradient of the anti-aging effective compound across
the skin to ensure penetration of even large molecules into or
through the skin. Typically, employment of bioadhesives and other
delivery or penetration-enhancing agents within the methods and
devices of the invention yields a two- to five-fold, often a five-
to ten-fold increase in permeability for anti-aging effective
compounds (e.g., anti-oxidant compounds), into or through the skin.
This enhancement of permeation often permits effective topical
delivery of anti-aging compounds to the basal portion of the
epidermis or even into the extracellular compartments or systemic
circulation underlying the skin.
[0137] This enhanced delivery provides for greatly improved
effectiveness of delivery of anti-aging effective compounds (e.g.,
anti-oxidant compounds). These results will depend in part on the
hydrophilicity of the compound, whereby greater penetration will be
achieved with hydrophilic species compared to water insoluble
compounds. In addition to these effects, employment of bioadhesives
and other delivery-enhancing agents to increase drug persistence at
the skin surface can provide a reservoir function for prolonged
drug delivery, whereby compounds not only penetrate across the skin
but also back-diffuse toward the skin surface once the material at
the surface is depleted.
[0138] In various embodiments, the methods and devices of the
instant invention optionally incorporate bioadhesive materials that
yield prolonged residence time at the skin surface or target site
of action of the anti-aging effective compound. Alternatively, the
bioadhesive material may otherwise facilitate topical absorption by
the skin of the anti-aging effective compound, e.g., by
facilitating localization of the active agent to a selected target
site of activity. In additional aspects, adjunct delivery or
combinatorial formulation of a bioadhesive agent within the methods
and devices of the invention intensify contact of the anti-aging
effective compound with the skin, in some instances including by
increasing skin permeability, (e.g., to effectively increase the
drug concentration gradient). In further alternate embodiments,
bioadhesives and other polymers disclosed herein serve to inhibit
proteolytic or other enzymes that might degrade the anti-aging
effective compound. For a review of different approaches to
bioadhesion that are useful within the methods and devices of the
invention, see, e.g., Lehr C. M., Eur J. Drug Metab.
Pharmacokinetics 21(2):139-148, 1996 (incorporated herein by
reference).
[0139] Liposomes and Micellar Delivery Vehicles
[0140] The methods and devices of the instant invention optionally
incorporate effective lipid or fatty acid based carriers,
processing agents, or delivery vehicles, to provide improved
formulations for topical delivery of anti-aging effective
compounds. For example, a variety of formulations and methods are
provided for topical delivery which comprise an anti-aging
effective compound, such as a anti-oxidant compound, admixed with
or encapsulated by, or coordinately administered with, a liposome,
mixed micellar carrier, or emulsion, to enhance chemical and
physical stability and increase the half life of the anti-aging
effective compound (e.g., by reducing susceptibility to enzymatic
degradation or chemical modification) upon topical delivery.
[0141] Within certain aspects of the invention, specialized
delivery systems for anti-aging effective compounds comprise small
lipid vesicles known as liposomes (see, e.g., Chonn et al., Curr.
Opin. Biotechnol. 6:698-708, 1995; Lasic, Trends Biotechnol.
16:307-321, 1998; and Gregoriadis, Trends Biotechnol. 13:527-537,
1995, each incorporated herein by reference). These are typically
made from natural, biodegradable, non-toxic, and non-immunogenic
lipid molecules, and can efficiently entrap or bind drug molecules,
including anti-aging effective compounds (e.g., anti-oxidant
compounds), proteins, or peptides, into, or onto, their membranes.
The attractiveness of liposomes as a delivery vehicle or carrier
for anti-aging effective compounds within the invention is
increased by the fact that the encapsulated anti-aging compounds
can remain in their preferred aqueous environment within the
vesicles, while the liposomal membrane protects them against
degradation and other destabilizing factors. Even though not all
liposome preparation methods known are feasible in the
encapsulation of anti-aging effective compounds (e.g., anti-oxidant
compounds) due to their specific physical and chemical properties,
several methods allow the encapsulation of these macromolecules
without substantial deactivation (see, e.g., Weiner, Immunomethods
4:201-209, 1994, incorporated herein by reference).
[0142] A variety of additional methods are available for preparing
liposomes for use within the invention (e.g., as described in Szoka
et al., Ann. Rev. Biophys. Bioeng. 9:467, 1980; and U.S. Pat. Nos.
4,235,871, 4,501,728, and 4,837,028, each incorporated herein by
reference). For use with liposome delivery, the anti-aging
effective compound is typically entrapped within the liposome, or
lipid vesicle, or is bound to the outside of the vesicle. Several
strategies have been devised to increase the effectiveness of
liposome mediated delivery by targeting liposomes to specific
tissues and specific cell types. Liposome formulations, including
those containing a cationic lipid, have been shown to be safe and
well tolerated in human patients (Treat et al., J. Natl. Cancer
Instit 82:1706-1710, 1990, incorporated herein by reference).
[0143] Like liposomes, unsaturated long chain fatty acids, which
also have enhancing activity for tissue absorption, can form closed
vesicles with bilayer-like structures (so called "ufasomes") to
provide a carrier or delivery vehicle for anti-aging effective
compounds. These can be formed, for example, using oleic acid to
entrap biologically active anti-oxidant compounds for topical
delivery within the invention.
[0144] Other delivery systems for use within the invention combine
the use of polymers and liposomes. Exemplifying this type of hybrid
delivery system, liposomes containing the model protein horseradish
peroxidase (HRP) have been effectively encapsulated inside the
natural polymer fibrin (Henschen et al., Blood Coagulation, pp.
171-241, Zwaal, et al., Eds., Elsevier, Amsterdam, 1986,
incorporated herein by reference). Because of its biocompatibility
and biodegradability, fibrin is a useful polymer matrix for drug
delivery systems in this context (see, e.g., Senderoff, et al., J.
Parenter. Sci. Technol. 45:2-6, 1991; and Jackson, Nat. Med
2:637-638, 1996, incorporated herein by reference). In addition,
release of anti-aging effective compounds from this delivery system
is controllable through the extent of covalent crosslinking and the
addition of antifibrinolytic agents to the fibrin polymer (Uchino
et al., Fibrinolysis 5:93-98, 1991, incorporated herein by
reference).
[0145] Additional delivery vehicles or carriers for use within the
invention include long and medium chain fatty acids, as well as
surfactant mixed micelles with fatty acids (see, e.g., Muranishi,
Crit. Rev. Ther. Drug Carrier Syst. 7:1-33, 1990, incorporated
herein by reference). Free fatty acids and their monoglycerides
which have polar groups attached have been demonstrated in the form
of mixed micelles to act on tissue barrier as penetration
enhancers. This discovery of barrier modifying function of free
fatty acids (carboxylic acids with a chain length varying from 12
to 20 carbon atoms) and their polar derivatives has stimulated
extensive research on the application of these agents as absorption
enhancers.
[0146] For use within the methods of the invention, long chain
fatty acids, especially fasogenic lipids (unsaturated fatty acids
and monoglycerides such as oleic acid, linoleic acid, linoleic
acid, monoolein, etc.) provide useful carriers to enhance topical
delivery of anti-aging effective compounds. Medium chain fatty
acids (C6 to C12) and monoglycerides have also been shown to have
enhancing activity in intestinal drug absorption and can be adapted
for use within the topical delivery methods and devices of the
invention. In addition, sodium salts of medium and long chain fatty
acids are effective delivery vehicles and absorption-enhancing
agents for topical delivery of anti-aging effective compounds
within the invention. Thus, fatty acids can be employed in soluble
forms of sodium salts or by the addition of non-toxic surfactants,
e.g., polyoxyethylated hydrogenated castor oil, sodium
taurocholate, etc. Mixed micelles of naturally occurring
unsaturated long chain fatty acids (oleic acid or linoleic acid)
and their monoglycerides with bile salts have been shown to exhibit
absorption-enhancing abilities in the intestinal mucosa (see, e.g.,
Muranishi, Pharm. Res. 2:108-118, 1985; and Crit. Rev. Ther. drug
carrier Syst. 7:1-33, 1990, each incorporated herein by reference).
Other fatty acid and mixed micellar preparations that are useful
within the invention include, but are not limited to, Na caprylate
(C8), Na caprate (C10), Na laurate (C12) or Na oleate (C18),
optionally combined with bile salts, such as glycocholate and
taurocholate.
[0147] Surface Active Agents and Methods
[0148] Within more detailed aspects of the invention, one or more
membrane penetration-enhancing agents may be employed within the
methods and devices of the invention to enhance topical delivery of
an anti-aging effective compound (e.g., an antioxidant such as
coenzyme Q10). Membrane penetration enhancing agents in this
context can be selected from: a surfactant; a bile salt; a
phospholipid additive; mixed micelle; liposome, or carrier; an
alcohol; an enamine; a long-chain amphipathic molecule; a small
hydrophobic penetration enhancer; sodium or a salicylic acid
derivative; a glycerol ester of acetoacetic acid; a clyclodextrin
or beta-cyclodextrin derivative; a medium-chain fatty acid; a
chelating agent; an amino acid or salt thereof; or any combination
of the foregoing membrane penetration enhancing agents.
[0149] Certain surface-active agents are readily incorporated
within the topical delivery formulations and methods of the
invention as topical absorption enhancing agents. These agents,
which may be coordinately administered or combinatorially
formulated with anti-aging effective compounds of the invention,
may be selected from a broad assemblage of known surfactants.
Surfactants, which generally fall into three classes: (1) nonionic
polyoxyethylene ethers; (2) bile salts such as sodium glycocholate
(SGC) and deoxycholate (DOC); and (3) derivatives of fusidic acid
such as sodium taurodihydrofusidate (STDHF). The mechanisms of
action of these various classes of surface active agents typically
include solubilization of the anti-aging effective compound. Within
exemplary embodiments of the invention, one or more surface active
agents is coordinately administered or combinatorially formulated
with an anti-aging compound, for example Coenzyme Q10, in an amount
effective to enhance skin absorption of the anti-aging effective
compound while not substantially adversely effecting the biological
activity of this or other active agent(s) nor causing substantial
adverse side effects (e.g., undesirable skin irritation). Exemplary
surface active agents within specific aspects of the invention
include, but are not limited to, non-ionic surfactants, such as
polysorbates (e.g., polysorbate 80), polyoxyethylene lauryl ether,
n-lauryl-.beta.-D-maltopyranoside (LM), cetyl ether, stearyl ether,
and nonylphenyl ether, and other surfactants, such as sodium lauryl
sulfate, sodium taurochloate, sodium cholate, sodium glycocholate,
L-carnitine, and saponin. Also included are different classes of
surfactants disclosed elsewhere herein, for example detergents
(e.g., Tween 80, Triton X-100) and fatty acid-surfactants (e.g.,
linoleic acid), which may be used alone or as mixed micellar
components. In more detailed aspects of the invention, laureth-9 is
employed as a surfactant within the methods and formulations of the
invention (see, e.g., Hirai et al., Intl. J. Pharmaceutics
1;173-184, 1981; G.B. Patent specification 1 527 605; and Salzman
et al., New Eng. J. Med., April, 1985, 1078-1084, each incorporated
herein by reference).
[0150] Formulations and Additives
[0151] The anti-aging effective compounds for use within the
methods and devices of the invention can be formulated in a variety
of suitable carriers and forms, including but not limited to
polymeric delivery vehicles, hydrogels, biodegradable polymers,
matrices, sprays, pastes, gels, ointments, suspensions, emulsions,
creams, lotions, unguents, solutions, suspensions, emulsions,
powders, and the like. Exemplary formulations include aqueous or
alcoholic solutions, aqueous suspensions, emulsions, ointments,
creams, oils, or powders.
[0152] Depending on the desired formulation, the anti-aging
compounds can be incorporated into pharmaceutical and/or cosmetic
bases for topical applications, which formulations may optionally
comprise as additional components, for example, oil components,
fats and waxes, emulsifiers, anionic, cationic, ampholytic,
zwitterionic and/or nonionic surfactants, lower mono- and
polyhydric alcohols, water, preservatives, buffer substances,
thickeners, fragrances, dyestuffs and opacifying agents. The active
substances according to the invention can also advantageously be
used in transdermal therapeutic systems, in particular cubic
systems.
[0153] Alternative formulations of the anti-aging effective
compound for application or incorporation to or within a facial
patch 10 or mask 12 of the invention may provide additional desired
effects in the skin, including such effects as smoothing,
lubricating, glossing, coloring and masking of the skin. In certain
embodiments, it may be further desired to add to the formulations
one or more substance(s) that modify cellular energy metabolism,
for example cellular energy transfer agents (such as creatine,
guanine, guanosine, adenine, adenosine, nicotine, nicotinamide or
riboflavin), coenzymes (for example pantothenic acid, panthenol,
lipoic acid or niacin), auxiliary factors (for example L-carnitine,
dolichol or uridine), substrates (for example hexoses, pentoses or
fatty acids) and intermediate metabolism products (for example
citric acid or pyruvate) and/or glutathione.
[0154] Yet additional methods and devices of the invention
advantageously incorporate substances that absorb UV radiation in
the UVA and/or in the UVB region and provide a sunscreen and/or
additional anti-oxidant effect. Examples of oil-soluble UVB
filtering agents that are useful within the invention include
3-benylidenecamphor derivatives, for example
3-(4-methylbenzylidene)camphor and 3-benzylidenecamphor. Examples
of useful water-soluble UVB filters include salts of
2-phenylbenzimidazole-5- -sulphonic acid, such as its sodium,
potassium or its triethanolammonium salt, and the sulphonic acid
itself. Useful UVA filters include derivatives of dibenzoylmethane,
for example 1-(4'-tert-butylphenyl)-3-(4-
'-methoxyphenyl)propane-1,3-dione and
1-phenyl-3-(4'-isopropylphenyl)propa- ne-1,3-dione.
[0155] In other embodiment, an abrasive substance may be included
within the methods and devices of the invention. The inclusion of
an abrasive substance promotes removal of dead or damaged
intervening tissue and makes the underlying tissue more accessible
to the therapeutic action of anti-aging compounds. Those of skill
in the art will recognize that many appropriate abrasive substances
are known and may be used in the practice of the instant invention.
Useful examples include, but are not limited to, ground fruit pits,
ground nut kernels, ground nut shells, grain hulls (from for
example wheat, bran, oats, rice, etc.), saw dust, aluminum oxide,
silica sand, pumice, plastic and acrylic grit, plastic flour, and
ground corn cobs.
[0156] Thermal Patches and Masks
[0157] In yet additional embodiments of the invention, the facial
patch 10 or mask 12 comprises a separate or integral,
self-contained or externally charged thermal element 190. The
thermal element can function as a heating element to facilitate
delivery and activity of the anti-aging effective compound by
increasing the temperature at a target skin area, thereby
increasing chemical kinetic factors as well as circulation in and
around the subject skin areas to be treated. This increases or
accelerates the extent or rate of therapeutic efficacy of the
facial patch or mask as described above, while increasing comfort
for the subject.
[0158] The thermal element 190 may be externally connected to the
patch or mask simply by placing the heating element in contact with
an outer surface 176 of the patch, but more typically by a thermal
element attachment means 200 that attaches the thermal element to
the patch or mask outer surface (see, e.g., FIG. 9). For example,
the thermal element can be permanently bonded to the patch or mask
outer surface by gluing, welding, stitching, or the like.
Alternatively, the thermal element can be removably attached by any
suitable closure/release device such as opposing hook and loop
(e.g., VELCRO.RTM.) material, snaps, ties, and the like. In certain
embodiments, the thermal element is removably attached to the patch
or mask to allow replacement or repeated charging of the thermal
element and subsequent reattachment of the thermal element to the
patch or mask.
[0159] In alternative embodiments, the thermal element 190 may be
integrally connected to the patch or mask body, for example by
enclosure of the thermal element within a pocket 202 defined within
the patch or mask body or other layer of the patch or mask (see,
e.g., FIGS. 10 and 11). The thermal element may thus be enclosed
within the patch or mask, permanently or removably. In the
embodiment shown in FIG. 10, the thermal element is removably
enclosed within a pocket enclosed within the patch body, which
pocket is accessible for removal of the thermal element for
replacement or recharging by way of a releasable closure 202 (e.g.,
a zippered or velcroed seam) of the pocket.
[0160] The shape of the thermal element 190 and the shape of the
pocket 202 when the thermal element is an integral element can
vary, e.g., from a square, rectangular, band, or circular shape.
Preferably, the thermal element and optional pocket is/are
anatomically shaped and dimensioned in approximately parallel shape
and dimension with anatomical features of the patch 10 or mask 12,
so that the thermal element substantially extends across all or
most of the skin area to be treated. This relationship is well
depicted in FIG. 11, wherein the heating element is contained in a
pocket 202 of an orbital patch 24 that is defined by a
circumferential ridge 180 extending from a peripheral undersurface
18" of the orbital patch body 14 to conform (in a circular or oval
shape) to an entire orbital margin 30 of a subject. Other thermal
elements will thus typically parallel the outline of an entire
patch or mask upper surface, or of one or more anatomically
configured patch or mask sections or surface ridges or protrusions
as described above.
[0161] With regard to selection of thermal elements 190, a variety
of useful self-contained or externally powered heating and/or
cooling elements are known in the art for use within the methods
and devices of the invention. For example, electrical heating and
cooling elements may be employed that use internal or external,
battery or central power sources. More preferable are less bulky,
self-contained heating or cooling elements, such as chemical and
thermal gel heating and/or cooling elements. Chemical heating
elements are available in a variety of compositions and forms, and
are typically activated for a single use. These chemical heating
elements are easily incorporated within the facial patches 10 and
masks 12 of the invention, and may be activated, for example by
exposing an exothermic chemical in a chemical heat pack to air.
[0162] In certain embodiments of the invention, a rechargeable
thermal gel is employed as the thermal element 190. Thermal gels
are well known in the art for their use in rechargeable heating
and/or cooling packs for prosthetic and therapeutic use. A thermal
gel efficiently stores and transmits heat in one mode of use, and
can be effectively cooled to absorb heat in an alternate mode of
use. Attachment or integration of a thermal gel thermal element
with the facial patches 10 and masks 12 of the invention is
therefore contemplated to serve dual or alternate purposes of
providing a rechargeable heat source for enhancing function of the
patch or mask as described above, and optionally a rechargeable
cooling source to alleviate facial swelling and/or pain in other
applications.
[0163] A thermal gel can be employed as a thermal element 190 for
use within the invention in a variety of ways. The gel can be
injected or otherwise incorporated in an integral pocket within the
patch 10 or mask 12 (e.g., orbital mask 26) body 14, as shown in
FIG. 11, provided the pocket is impervious to leakage of the gel.
Alternatively, a separate gel pack comprising a flexible bladder
220 enclosing a volume of thermal gel 222 (see, FIG. 10) may be
removably or permanently attached to the patch or mask or
incorporated in the patch or mask body as described above. A useful
construction in this regard employs a single layer bladder
constructed of flexible, durable material that is resistant to
heat, cold, and rupture. A lumen of the bladder is filled with and
sealably encloses a thermal gel adapted for repeated heating and
cooling. The bladder may be fabricated from a variety of materials
having suitable flexibility, strength and durability to provide a
supple, flexible feel when the gel pack is attached to or
incorporated within the patch or mask and the patch or mask is
applied to the facial skin area to be treated. Suitable materials
in this context include, for example, vinyl plastics, silicon
plastics (e.g, silastic materials used for breast implants), latex
or other like materials, provided the materials are heat stable
(e.g., upon heating in warm water or microwaving). It is
particularly preferred that the material used to construct the gel
pack bladder be expandable in order to allow for the escape of
steam from the lumen of the bladder to the outside (i.e., through
microscopic interstices in the bladder material) to prevent
explosion of the bladder in the event of overheating.
[0164] In one exemplary embodiment of the invention, the gel pack
bladder 220 is constructed of a vinyl or silicon plastic material
cut into upper and lower sheets each having a marginal outline
corresponding generally to, but slightly smaller than, a
circumferential margin of the pocket 202. The two bladder sheets
are annealed together, e.g., by gluing or heat sealing, along most
of the marginal outline of the gel pack, leaving a small filling
aperture between the two sheets for filling the bladder with gel.
Gel is then protruded through the filling opening into the lumen of
the bladder formed between the two sheets, and the bladder is
closed by heat sealing or otherwise annealing the two sheets
together at the site of the filling aperture.
[0165] The gel pack functions as a non-chemical, non-electrical and
non-fuel burning heating element which retains and transmits heat
energy or cold to the face of the wearer. Notably, the gel pack has
an adjustable heating capacity adapted to therapeutic and related
uses associated with a range of activities (including activities
undertaken in a warm or cold environment). Briefly, the temperature
and time period of heating or cooling of the gel pack dictates the
level and duration at which the gel pack transmits heat or cold to
the face of the wearer, whereby a broad spectrum of heating or
cooling levels and times can be selected by the user. The gel pack
is further adapted for fast, safe, and repeatable heating or
cooling, whereby the pack may be recharged repeatedly during
long-term use, for example to provide continued therapeutic benefit
during extended activities.
[0166] A variety of gels are known in the art which are
specifically adapted for their ability to be cooled and heated over
a wide range of temperatures and to maintain their physical
characteristics, e.g., chemical integrity and pliability, during
repeated heating and cooling. Many such gels are suitable for use
within the invention, while specific gel characteristics may be
selected for use within different embodiments of the invention.
Thus, gels having a higher maximum heating tolerance may be
selected for use with a monopiece face mask to alleviate symptoms
of facial skin aging by application of an anti-aging effect
compound. Alternatively, gels that maintain their physicochemical
properties at very low temperatures may be selected for specific
therapeutic uses, e.g., to reduce inflammation in a subject's
facial skin following surgery. In most cases, however, it is
generally desirable for safety purposes to select a gel having a
wide range of temperature tolerance, e.g., from about -20.degree.
C. to about 160.degree. C., to prevent decomposition of the gel or
rupture of the gel pack bladder from exposure to low or high
temperature extremes.
[0167] Preferred gels for use within the invention include gels
containing a water soluble humectant invested within a polymeric
matrix (e.g., polymers, copolymers, or terpolymers containing
monomer moieties, such as acrylic acid or acrylamide monomers).
Suitable humectants include glycerin, dimethyl sulfoxide (DMSO),
dimethyl formamide (DMF), among others. A preferred agent for the
polymeric matrix is a commercially available acrylic acid polymer
powder, e.g. Carbopol 940.RTM. (B. F. Goodrich Co.) Also included
within the gel is a suitable cross-linking agent, for example, N,N
methylene-bisacrylamide (MBA), N-methylolacrylamide, allyl
methacrylate, or ethylene glycol dimethacryllate). Other agents are
optionally included as well, such as, anti-freeze/boiling point
elevators (e.g., propylene glycol), absorbants (e.g.,
starch-acrylonitrile graft copolymers), agents to suppress
bacterial growth, and/or agents to enhance processibility or shelf
life. It will be appreciated by persons skilled in the art that the
consistency of the gel can be varied by selecting different
polymeric materials and by varying the ratio of the polymer agent
relative to the amount of humectant and/or cross-linking agent. To
produce a soft gel the ratio of humectant to polymer should be high
and/or a relatively low percentage of cross linking agent should be
used. A firmer gel is produced by decreasing the humectant relative
to polymer content and/or increasing the amount of cross-linking
agent.
EXAMPLE I
Transdermal Delivery of CoQ.sub.10to a Facial Skin Area
[0168] An exemplary orbital patch 24 for treatment of periorbital
skin aging is covered on an undersurface 18 of the patch or
invested within all or part of a porous body 14 of the patch with
an anti-aging effective compound, CoQ.sub.10, and the patch is
attached to an orbital marginal 30 skin surface area of a suitable
mammalian test subject. Within the present example, a porcine test
subject is selected to demonstrate effective delivery of the
CoQ.sub.10 compound into and/or across the test subject skin (e.g.,
past the stratum corneum which acts as an effective barrier to many
compounds when topically applied in the absence of the effective
patch delivery methods and formulations of the invention). Porcine
skin represents an accepted, reasonably correlative model to
evaluate skin penetration properties of the patches and anti-aging
compound formulations of the invention in other mammalian subjects,
including humans. Levels of CoQ.sub.10 in the skin following
application of the orbital patch are quantified by any of a variety
of methods, for example high performance liquid chromatography
(HPLC) of excised skin samples. (Lang et al., Anal. Biochem,
157:106-116, 1986; Giovannini, et al., Int. J. Tiss. Reac X(2)
103-105, 1988); Scalori, et al., Int. J. Tiss. Reac., XII(3)
149-154, 1990, each incorporated herein by reference). Within these
and related protocols, an orbital or other facial or neck skin
patch or mask of the invention applied for an extended period
(e.g., 2-4 hours, 4-8 hours, or approximately 7-8 hours) delivers
CoQ.sub.10 (optionally formulated within a polymeric, ethanol, or
other delivery vehicle or carrier) in a manner that achieves
penetration of the CoQ.sub.10 into the stratum corneum, with at
least 20%, often 30%-50% or more of the CoQ.sub.10 initially loaded
onto or within the patch or mask body penetrating into viable
(actively metabolic) layers of the epidermis, and in many
embodiments, into the basal skin layer and/or dermis.
EXAMPLE II
Maximal Skin Concentration and Residence Time of CoQ.sub.10 Applied
by Orbital Patch for Treatment of Periorbital Skin Aging in a
Mammalian Subject
[0169] An ocular patch containing CoQ.sub.10 at a concentration of
1% or 10% in a polymeric delivery vehicle is applied in accordance
with the above teachings for treatment of periorbital skin aging in
a mammalian subject. Maximum concentrations of CoQ.sub.10 in the
skin are measured in skin samples by means of high performance
liquid chromatography (HPLC) (see, e.g., Lang et al., 1986;
Giovannini, et al., 1988); Scalori, et al., 1990, each incorporated
herein by reference). An ocular patch partially or completely
imbued in the patch body with a formulation containing 1% or 10%
CoQ.sub.10 is applied to the periorbital margin of a mammalian
(e.g., porcine) subject to yield a maximum concentration of
CoQ.sub.10 after application of the patch (e.g., as measured 1-2
hour after application) in the underlying skin of the subject of at
least 1-5 .mu.g, and up to 5-15 .mu.g or greater of CoQ.sub.10 per
gram of skin as measured in a surface or basal layer of the skin.
Residence time of detectable concentrations of CoQ.sub.10 following
sustained application of the patch is at least 2-4, often 8 hours
or more hours. Time release formulations as disclosed above extend
residence time to at least 8 hours, up to 12 hours, 16 hours, 24
hours or longer.
EXAMPLE III
Facial Patch Delivery of CoQ.sub.10 Yields Antioxidant Effects in
Human Skin
[0170] Oxidative events in human skin in vivo following delivery of
CoQ.sub.10 via a facial patch or mask of the invention are
detected, for example, by means of ultra weak photon emission assay
[Sauermann et al., Oxidants & Antioxidants, Methods in
Enzymology, L. Packer, ed., Academic Press, 300: 419-428 (1999),
incorporated herein by reference]. In the basal state, cells emit
low levels of photons. When UVA irradiation is applied there is an
excited state with a large increase in the level of photons that
decay with time. The level of photons emitted is an indication of
the antioxidant status of the skin. If there is an increase in
antioxidants, the excitation is less and the level of photons
emitted will be reduced. The ultra weak photon emission (UPE) is
measured after UVA irradiation in two age groups: (1) aged 18-25
years, (2) aged 60-72 years. The level of UPE in the skin is
increased in the elderly group by approximately 33% indicating a
reduction in the level of antioxidants, thus demonstrating that the
level of antioxidants in the skin decreases with age.
[0171] To demonstrate that application of a facial patch or mask
for delivery of CoQ.sub.10 (e.g., in a polymeric delivery vehicle)
yields antioxidant effects in vivo, measurements are taken of the
UPE of 13 volunteers (mean age 49.+-.6 years) treated with a facial
patch or mask of the invention once or twice daily (for 2, 4, and 8
hours) for 7 days, for example using an orbital patch coated or
imbued with 0.3% CoQ.sub.10, or with a selected delivery vehicle
alone as a control. Following exposure to 50 mJ/cm.sup.2 UVA, the
peri-orbital skin sites treated with the orbital patch will exhibit
significantly lower levels (e.g., 20%, 30%, 40% reduced, and up to
50% reduced or lower levels) of UPE compaed to a corresponding
control level, indicating that the orbital patch containing
CoQ.sub.10 provides effective antioxidant activity in vivo to
protect the peri-orbital skin against oxidative effects of UVA.
EXAMPLE IV
Facial Patch Delivery of CoQ.sub.10 Reduces Symptoms of Photoaging,
Including Deep Wrinkles
[0172] A significant adverse symptom of photoaging is the presence
of deep wrinkles. To demonstrate the efficacy of a facial skin
patch of the invention delivering an anti-aging effective compound
(e.g., CoQ.sub.10 in a polymeric delivery vehicle) against
photoaging in vivo, an orbital or other facial skin area patch or
mask containing 0.3% CoQ.sub.10 or vehicle control is applied to 20
elderly volunteers, once daily (e.g., around the peri-orbital skin
of the eyes) for at least 2 hours each day and for test periods
ranging from one week to one, two, three, and up to six months. In
one exemplary protocol, an orbital patch containing CoQ.sub.10 in a
delivery vehicle or carrier as described above is applied to one
eye of a subject, and a control orbital patch containing a delivery
vehicle alone is applied around the other eye. Casts are then
prepared for quantitative microtopography [see, e.g., Hoppe, et
al., J. Soc. Cosmetic Chemists 36: 105-123 (1985), incorporated
herein by reference]. Photographs of the skin before treatment show
deep wrinkles, which are characteristic of photoaging, whereas fine
wrinkles are associated with chronological aging. Using
microtopography to measure a reduction in the depth of wrinkles in
aged skin, two important parameters can be calculated from the
microtopography. They are: R.sub.t which is the mean peak to valley
measurement of a defined unit distance, and R.sub.q which is the
integrated area of the peaks and troughs. These measurements
indicate the variation of the microtopography from a flat surface.
Following treatment with an ocular patch of the invention
delivering CoQ.sub.10, the depth of these deep wrinkles will be
significantly reduced (e.g., 20%, 30%, 40% reduced, and up to 50%
reduced or better). In certain examples, treatment with an orbital
patch containing 0.3% CoQ.sub.10 will results in at least a 25%
reduction in the mean peak to valley depth of the skin and at least
a 25% reduction in the R.sub.q value, compared to controls.
EXAMPLE V
Facial Patch Delivery of CoQ.sub.10 Reduces Senile Xerosis
[0173] Although the stratum corneum, the outermost layer of the
epidermis, is continuously sloughed off and replaced in healthy
individuals, it will display symptoms of aging in the underlying
living cells in older subjects. The area of corneocytes, which make
up the stratum corneum, is proportional to the time taken for the
keratinocyte to differentiate and move from the basal layer to the
stratum corneum. In aged skin, the time taken to move through the
epidermis increases, and corneocytes become larger. The surface can
develop fine lines and become dry and scaly (senile xerosis). As
aging progresses, the surface area of corneocytes increases, and
thus this value can be measured to determine the effectiveness of
an anti-aging treatment (i.e., to decrease the transit time and
corneocyte surface area). In the present example, treatment of
facial skin with a facial skin patch or mask of the invention
containing 0.3% CoQ.sub.10, once or twice daily for 7 days, will
yield a significant decrease in the corneocyte area over time
compared to treatment with a patch or mask coated or imbued with a
delivery vehicle or carrier alone.
[0174] Additional advantages and modifications of the invention
disclosed herein will be apparent to those persons skilled in the
art. Accordingly, the invention is not limited to the specific
details or illustrated examples described herein, except as
provided by the appended claims.
* * * * *