Note: Descriptions are shown in the official language in which they were submitted.
1 -~2496~
COMPOSITIONSAND METHODS FOR RETARDING THE
EFFECTS OF AGING OF TFiE SRIN
Field of the Invention
This invention relates to methods of
using vitamin A acid to retard the effects of aging
of the skin and generally improve the quality of
the skin, particularly photo-aging of human facial
skin.
Backqround of the Invention
Caucasians who have had a good deal of
sun exposure in childhood will show the following
gro s cutaneous alterations in adult life:
:~ wrinkling, leatheriness, yellowing, looseness,
roughness, dryness, mottling (hyperpigmentation~
~: 15 and various premalignant growths (often
subclinical). These changes are most prominent in
light-skinned persons who burn easily and tan
poorly. The baleful effects of sunlight are
cumulatlve, increasing with time. Although the
anatomic degradation of the skin is most advanced
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1 324962
in the elderly, the destructive effects of
excessive sun exposure are already evident by the
second decade. Serious microscopic alterations of
the epidermis and dermis occur decades before these
become clinically visible. Wrinkling, yellowing,
leatheriness, loss of elasticity are very late
changes.
It i~ known to use vitamin A acid for the
treatment of acne as set forth in my U.S. Patent
No. 3,729,568. Other known uses of vitamin A acid
which were reviewed by Thomas and Doyle in Journal
of American Academy of Dermatoloay ~May, 1981) Vo-
lume 4, No. 5, include, in addition to acne
. treatment, treatment of senile comedones, n~vus
comedonicus, linear verrucous nevus, plantar warts,
p eudofolliculitis, keratoacanthoma, solar kera-
tosis of extremitieæ, callosities, keratosis
palmaris et plantaris, Darier's disease,
ichthyosis, psoriasis, acanthosis nigricans, lichen
planus, molluscum contagiosum, reactive perforating
collagenosis, melasma, corneal epithelial peeling,
geographic tongue, Fox-Fordyce disease, cutaneous
metastatic melanoma and keloids or hypertrophic
1 324~62
scars. Vitamin A acid derivatives (retinoids) are
known to have prophylactic and therapeutic effects
on great variety of tumors and are being
inGreasingly used as anti-tumor drugs.
In view of the foregoing, it is believed
that vitamin A acid influences ultrastructural and
proliferative properties of epidermal cells.
However, these prior art uses of vitamin A acid
have generally involved short term treatments in
which relatively large doses of the acid are
applied ~i.e sufficient to cause significant
irritation and often peeling) in order to obtain a
quick cure or treatment of the particular
condition, such as removal of comedones~ as opposed
to persistent tréatment of normal aging skin.
Brief SummarY of the Invention
The present invention relates to the use
of low strength vitamin A acid (retinoic acid),
known clinically as tretinoin, in moderating and
preventing the aging changes of the exposed areas
of the skin, especially the face. In particular,
the methods o~ the pre~ent invention retard the
1 324962
ef~ects of photo-aging of the skin including
impairment of the differentiation of epidermal
epithelial cells, loss of collagen fibersr abnormal
changes in the elastic fibers, and deterioration of
small blood vessels of the dermis of the skin.
The methods comprise applying topically to the
epidermis of the skin effecti~e amounts o~ vitamin
A acid in a program of maintenance therapy, whereby
epithelial growths are substantially reduced and
prevented and the skin substantially regains and
maintains its firmne~s, turgor and elasticity
during the ~herapy. Generally, the maintenanc~
therapy is begun in middle age when epithelial
growths and other aging changes begln to appear
clinically.
Accordiny to one aspect of thP present
invention, therefore, there is provided a composition
for topical application to the epidermis of the skin
for retarding and reversing the loss of collagen
fibers, abnormal changes in elastic fibers, the
deterioration of small blood vessels, and the formation
- o~ abnormal epithelial growths in sundamaged human
skin, comprising effective amounts of vitamin A acid
in a non-toxic, dermatologically acceptable vehicle,
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4a
said composition and amounts of vitamin A acid
being selected 50 as to provide a dose of vitamin A
acid which is insufficient to cause excessive
irritation.
The present invention also provides a
method for retarding and reversing the loss of
collagen fibers, abnormal changes in elastic
fibers, the deterioration o~ small blood vessels,
and the formation of abnormal epithelial growths
in sundamaged human skin, comprising applying
topically to the epidermis of the skin a
composition comprising effective amounts of
Vitamin A acid in a non-toxic, dermatologically
acceptable vehicle in a program of maintenance
therapy, whereby the skin substantially regains
and maintains its firmness, turgor and elasticity
during said therapy, said composition and amounts
of Vltamin A acid being selected so as to provide
a dose of Vitamin A acld which is insufficient to
cause excessive irritation.
- -- The vitamin A ~c~d may be applied to the
skin in any suitable non-toxic, dermatoloqically
acceptable vehicle, preferably a non-volatile,
e~ollient or lubricating vehicle, in an amount and
at a fre~uency which are insuffic~ent to cause
excassive irrita~ of the skin. Generally,
concentr~tions in the r~nge of about 0.005 to 0.05S
by weigh~ of the v~hicle are preferred.
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Detailed Description of the Preferred
Embodiments _ _
The purpose of this invention is to
moderate and retard the photo-aging changes in the
skin by topical application of tretinoin begin-
ning in middle age when such changes first become
evident clinically~ Certain of the anatomic altera-
tions can be corrected and at least partialy
reversed, accompanied by improvement in the
appearance of the skin.
~he invention accomplishes two goals.
First, a prophylactic effect in preventing
progression and worsening of the damage with the
pas~age of time. Secondly, various abnormalities
are corrected and modified to the extent that the
structure and function of the skin acquires the
: characteristics of younger skin.
Aqe Associated Structural Chanqes
Although many of the effects of the aging
of the human skin are the result of underlying
structural changes which build up over a period of
years and can only be detected his~ologically
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prior to middle age, these changes and effect~
begin to appear clinically about middle age, namely
between about 35 and 45 years of age, and become
more and more evident and pronounced thereafter.
The more apparent effects of aging have already
been re~erred to above, and each is aæsociated with
one or more underlying structural changes in the
skin. For example, blotchiness or mottling
(hyperpigmentation) is due to changes in the
melanocytes in the population of epidermal cells.
These pigment producing cells, which unlike the
keratinocytes remain at the base of the epidermis,
lose their normal regulation process with aging and
produce excess pigment which causes the ~lotc~iness
and mottling.
~owever, aside from such obvious cos~etic
changeæ in the skin, there are a number of other
changes which arejOmore important though less
apparent, including 108s of sensory acuity and
ability to heal wounds, decreased blood flow and
decrease in the thickneæs of the skin. Older
people have le88 sen~itivity to pain and a longer
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response time. Thus, pain due to ~rritation or
~njury is not felt as soon or to the same extent as
in young people with the result that superficially
minor but potentially serious injuries may be
suctained without the individual being aware of the
injury until serious damage has occurred.
The surface temperature of the skin in
older people is somewhat lower than the skin
temperature in younger people, so that they often
feel cold. This is due to a decrease in the blood
supply to the skin due to los of small blood
ve-csels and decreased proliferation of new
capillaries and mall blood vessels in the skin.
This is at least one of the causes of ~he 105C of
sensory'acuity and response to pain. Furthermore,
the decreased blood supply decreases the rate at
which irritants and toxins are cleared from ~he
skin tissue.
Still further, the skin of older people
i8 more ea~ily torn than that of younger people,
since both the epidermis and dermis become thinner
with ~ge. As a re~ult, there is les~ bulk to
protect underlying organs and ~herefore more rlsk
1 32496~
of serious injury. Moreover, when wounds or
injuries are sustained, healing of the wounds is
much slower in older people and may take as much as
twice as long to heal as in younger persons~
The underlying causes of the above ~ross
skin effects may be understood more readily from
the following discussion of the specific changes in
the epidermis and dermis as aginy progresses.
1. Epidermis
With increasing exposure of a human to
sun (photo-aging) and other environmental traumas,
cells divide at a slower rate (decreased capacity
to renew themselves). They show marked irregu-
larities ih size, shape and staining properties;
orderliness ~polarity) from below to abovè is
loæt. The thickness of the epidermis decreases
(atrophy). The horny layer which comprises the
barrier against water loss and penetration of
chemicals becomes abnormal due to the shedding
~e~foliation) of cells in large groups or clusters
instead of as individual cells, resulting in
roughness, scaling and dryness. There is loss of
1 324962
the orderly transfcrmation of living epithelial
cells into cornified dead cells which are shed at
the surface, that is~ differentiation is impaired.
Aberrant differentiation results in numerous foci
of abnormal epithelial growths or tumors, the
most frequent and important of which are actinic
keratoses. After many years these can transform
into frank skin cancers called basal cell and
s~uamous cell cancers. Pigment producing cells
(melanocytes) can also become altered forming flat,
dark growths (lentigo melanoma) which may progress
to malignant melanoma. ~he cells which make up
these premalignant growths are destroyed by topical
tretinoin~
2. ermis
The cells which make the fibers of the
dermis become smaller and sparser with increasing
age, usually in sundamaged facial skin. ~here is a
great loss of collagen fibers resulting in
looseness and easy stretchability of the skin;
elastic fibers become abnormal so that the skin
does not promptly snap back af~er being stretched.
1 324962
Since the fibrous componentæ comprise more than 90~ -
of the bulk of skin of which g5% is collagen, the
degradation of these fibers, especially collagen,
is mainly responsible for wrinkling, laxness and
loss of elasticity.
Small blood vessels become thin walled,
dilated and often ruptured. Vascular supply
thereby becomes compromised.
Beneficial Effects of Tretino~n in Accordance
With the Present Invention
(a) Increases Proliferative-activit-y-of
epidermal cells. This results in thickening of the
epidermis with correction of atrophy.l Cell renewal
is quickened so that cells divide at a rate typica~
of younger skin. Treatment with vitamin A acid in
accordanc~ with the invention can double the ~kin
thickne~s. ~he stimulation of cell growth also
results in faster wound healing. Experiments have
been performed wherein blisters have been raised
and cut of~ on skins of individuals of various
ages. ~ealing takes place in 2 or 3 weeks in young
p~ople, but t~ke~ much longer in older persons w~th
~; sun damaged skin.
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11
Application of tretinoin before raising the blister
results in healing twice as fast in the older sub-
jects.
(b) Corrects abnormalities of
differentiation. Vitamin A acid regulates and
controls the physiologic ~ehavior of epithelial
tissue, assuring its stability and integrity. It
corrects and normalizes abnormalities of
differentiation. In sundamaged skin, the numerous
foci of abnormal growths and segments of atypical,
abnorma? epidermis are corrected, reversed or
eliminated. Fewer growths appear and progression
to cancer is halted. Normalizing of the epidermis
results in a smoother, less dry and rough skin,
since cells are not only produced more rapidly but
exfoliation occurs by individual cells rather than
clusters or scales, thus improving the topography
of the skin. Moreover, hyperpigmentation resulting
in blotches and splotches is reduced by tretinoin
stopping excessive production of pigment by the
melanocytes, although it canno~ eliminate
depigmentation.
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12
(c) The metabolism of fibroblasts is
increased. Fibroblasts synthesize the fibers of
the dermis; new collagen is laid down,
strengthening the physical foundation of the skin.
Fibroblasts also make the ground substance which
exists between the fibers, allowing these to glide
past each other. The ground substance, known as
acid mucopolysaccharides, is also responsible for
the turgor and bounce of the skin. Tretinoin
stimulates the formation of new acid
mucopolysaccharides.
Accordingly vitamin A acid promotes the
formation of a more normal dermis. Because of this
activity, it has been found to promote and
accelerate the healing of wounds in compromised
tissue, of which regressed, aged dermis is an
example. Further, the production of a new collagen
layer not only repairs damaged skin but results in
; the effacement and preventiôn of fine wrinkles and lines.
(d) Vascularitv is increased. Tretinoin
stimulates blood flow and promotes the formation of
new vessels. Blood flow is greatly reduced in
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13
aged, sundamaged skin~ A bri~ker blood supply
improves the physiologic competence of the skin and
imparts a livelier, glowing appearance. Patients
often say their skin feels ~more aliven.
Several of the prior art treatments of
skin disease using vitamin A acid as referred to
above have claimed there is an increase in the
blood flow in the skin. However, the increased
blood flow from such short term treatments results
simply from vasodilation caused by the irritating
effects of high concentrations of vitamin A acid.
In contrast, the low sub-irritating concentrations
of vitamin A acid according to the present inven-
tion do not cause significant vasodilation, but it
has been found that over the long ~erm there is not
only a proliferation of new ~lood vessels, but also
an increase in lymphocytes and other blood cells.
As a result, there are more cells to fight infec-
tion, and the increased blood supply allows the
skin to clear irritants and toxins more quickly
from the akin.
Still further, treatment with vita~in A
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14
acid according to the present invention raises the
surface temperature of the skin by about 1/2 degree
centigrade due to the greater basodermal flow of
blood. The increased blood flow also increases
acuity to pain and irritation, and the skin becomes
more reactive to chemical insults. For example,
experiments with highly drying and irritating
cosmetics, soaps, perfumes, etc. have shown that
young people will experience severe irritation
- 10 within 3 or 4 days whereas it may take 2 to 3 weeksfor an older person to feel the same irritation.
The increased sensitivity of the skin treated with
vitamin A acid provides an early warning system to
older people so that too much damage is not done
before the pain or irritation is felt.
Tretinoin may be formulated in bland,
moisturizing bases, such as creams or oi~tments, in
the broad concentration range of about 0.0001~ to
0.05~, usually about 0.005~ to 0.025% and
preferably about 0.01% by weight of base, although
higher concentrations may be used for darker skins.
Other non-tsxic, dermatologically acceptable
vehicles or carriers in which tretinoin is 3table
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I 324962
~ill be evident to those of ordinary skill in the
art. In general, emollien~ or lubricating
vehicles, such as olea~inous substances, which help
hydrate the skin are preferred. Volatile vehicles
which dry or otherwise harm the skin, such as
alcohol and acqtone, should be avoided.
An ointment base (without water) is
preferred in the winter and in subjects with very
dry skin. Examples of suitable ointment bases are
petrolatum, petrolatum plus volatil~ silicones,
and lanolin~
In warm weather and often for younger
persons, emulsion (cream) bases, which are mixtures
of oils and water are preferred. Examples of
suitab.le cream bases are "Eucerin"*(Beiersdorf), cold
cream (USP), "Pw~x~e ~m~**(JohnSon & Johnson), and
hydrophilic ointment (USP).
~retinoin is a mild irritant and may
c~u~e rednesæ and scaling, which ~ay be accompanied
by some tenderness and tightness. These reactions
quickly disappear when ~he applications are
stopped. ~owever, even when applied exces~ively to
* Trade mark
** ~xade mark
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16
produce an intense dermatitisr the reaction fades
quickly leaving no permanent sequelae. Systemic
side reactions are unknown. Selection of an
appropriate emollient vehicle will more readily
allow the use of a highly effective but s~b-
irritating dose of the vitamin A acld.
The extent or length of treatment
according to the present invention may best be
described as persistent or indefinite. That is,
compared to the short term prior art treatments of
various conditions with vitamin A acid in which the
treatments are terminated as æoon a~ the condition
di~appears or subeides, the treatment ~ccording to
the present invention is intended to continue
indefinitely, otherwise the effects of aging will
~eappear after treatment is terminated. That is,
the treatments of the present invention may be
considered to be intervention therapy in
decelerating the photo-aging process. If the
intervention is stopped, there is regres8ion to the
origlnal state.
Usually, there i8 little point in
beginning the treatments of the present invention
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17
until middle age when the effects of photo-aging
begin to appear clinically~ The particular program
of maintenance therapy according to the present
invention will vary depending upon the individual
being treated. Generally, depending upon the age
and state of the skin when treatments begin, it has
been found that once a day applications of vitamin
A acid for up to 6 months may be necessary to
reduce and control the effects of aging which have
already occurred. Once a stabilized skin control
has been obtained, the frequency of application of
vitamin A acid may be reduced, for example to two
or three times a week, and in some cases only once.
a week for the rest of the person's life~ ~hat is,
once the aging process has been controlled, a
maintenance dose on the order of two applications
per week is generally sufficient to maintain tha~
~tate.
The invention will be iliustrated in more
- 20 detail by reference to the following specific, non-
limiting exa~ples:
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18
Experimental Exam~le 1
There has been applied 0.01~ to 0.025% by
weight concentrations of tretinoin in a base to the
faces of middle-aged and elderly women. At least
500 persons have used typical tretinoin
experimentally for periods ranging from three
months to five years. These women were studied as
follows:
About two hundred were inmates of the
Philadelphia Home for the Indigent at Riverview.
They ranged in age from 45 to 75. ~he creams or
ointments containing vitamin A acid (tretinoin~
were applied once daily before bedtime in an amount
sufficient to achieve a continuous sustaining film.
Clinical assessments were made once monthly. Bene-
ficial effects were obtained in about 80% after
about three months. Most of those who improved
continued to use tretinoin daily for one to two
years. Improvement was maximal at about six months
and persisted as long as the tretinoin was used.
Withdrawal of tretinoin resulted in a slow loss of
improvement with a return to the original state in
about four to five months. Maintenance therapy was
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19
required to prevent relapse.
The beneficial effects included
effacement of small wrinkles, smoother surface,
greater turgor, elimination of actinic keratoses,
elimination of senile comedones, less conspicuous
pores and less mottling (fading of pigmented
spots).
Experimental Exam~le 2
~istologic studies were conducted on
twenty six residents of Riverview as follows.
Tretinoln was applied to one side of the face once
daily as in Experimental Example 1 for four to six
months. The other side received the cream or
ointment base alone~.
Biopsies were taken from both sides at
the end of the study and processed for histol~gic
; ~ examination using a variety of histochemical
stains. The tretinoin treated side was easily
recognized in 24 of 26 subjects. The chief effects
of tretinoin, as demonstrated by the indicated
tis ue staining techniques, were:
a) Routine H & E stain: epidermis
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thicker, polarity restored, cells were regular
size and shape, loss of atypia, no epidermal
irregularities or pre-malignant growths, density of
fibroblasts increased, more vessels.
b) Fontanas stain for melanin:
dispersion of pigment granules and far less pigment
in epidermal cells.
c) Reticulin stain: increase in young
collagen fibers indica ing depositîon of new
collagen.
d) Orcein stain for elastin: moderate
removal of degenerated elastic tissue, allowing
intact fibers to be visualized more clearly.
e) Hale's stain for ground substance:
lS definite increase in acid mucopolysaccharides,
especially in deeper dermis.
Ex~erimental Example 3
There have been treated at least another
two hundred subjects in the aging skin clinic at
the ~ospital of the University of Pennsylvania.
These are middle-class white women, ages 35 to 60.
Tretinoin was applied as in Experimental Example 1
for at least six months.
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Beneficial efects were clinically
evident in about 80% of these persons. With this
more sophisticated group we took note of subjective
reactions as well. These women uniformly thought
that their skin was livelier, smoother, fresher,
and tighter. Again, we noted more turgor,
effacement of fine lines, less hyperpigmentation,
more youthful appearance, less roughness, less
wrinkling.
Experimental Example 4
About one hundred paid volunteers
recruited at Ivy Research Laboratories have been
studied in a variety of ways including biopsies,
physiologic tests, etc. The importance of this
series is that the tests were conducted according
to the double-blind format and hence were strictly
controlled. Tretinsin was applied once daily as in
Experimental Example 1 for six to ~welve months to
one side of the face; the other side received the
unmedicated vehicle. The applications were made
five days a week by a trained monitor who did not
know which of the two preparations contained the
1 32~962
22
active agent. The clinical observations were made
without knowledge of the drug treated side.
When the code was broken, some
improvement was noted in about 15% of cases treated
with the vehicle alone. Distinctly beneficial
effects were secured in about 85% on the tretinoin
treated side. ~istologic study in thirteen cases
confirmed the clinical results of restoration to, a
more normal pattern on the tretinoin side. The
epidermal and dermal changes were those de cribed
above.
Fluorescein injected into both sides was
removed in about half the time on the tretinoin
side. This indicates improved vascularity
reæulting in ~aster clearance of drugs from the
skin. Moreover, a series of clinical stimuli
indicate that tretinoin treated ækin is more
reactive, showing behaviors more typical of young
skin. It responds more rapidIy and inten~ely to
~::
irritant chemicals ~uch as croton oil and
dlmethylsulfoxide7 it blushes more readily after
appl~cation of nicotinate; blisters raised by
~ ammonium hydroxide heal more quickly (greater wound
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23
healing, a known effect of tretinoin~ and contact
allergic reactions ~poison ivy) also heal more
quickly.
From the foregoing, it will be seen that
the invention has the following advantages inter
alia:
A. Clinical
.
Effacement of fine wrinkles
Smoother surface
Lightens pigmented blotches
Skin has more turgor
Large pores less noticeable
Skin feels livelier
; B~ ~istoloqic
Thicker epidermis
~ormalizes atypia and pre-malignant
; changes.
Atrophy and dysplasia corrected.
Stimulates blood flow; new vessels
formed.
Stimulates fibroblasts with new
collagen formation.
Increases ground substance
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Melanin within keratinocyteæ is
decreased.
It will be recognized by those s~illed in
the art that changes may be made to the above-
described embodiments of the invention without
departing from the broad inventive concepts
.thereof. It is understood, therefore, that this
invention is not limited to the particular
embodiments disclosed, but it is intended to cover
all modifications which are within the scope and
spirit of the invention as defined by the appended
claims.
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