Note: Descriptions are shown in the official language in which they were submitted.
1 338840
COMPOSITIONS AND METHODS FOR RETARDING THE
EFFECTS OF AGING 9F THE SKIN
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 the10 skin, particularly photo-aging of human facial skin.
Backaround of the InYentiorl
Caucasians who have had a good deal of sun exposure in
childhood will show the following gross cutaneous alterations in adult life:
15 wrinkling, leatheriness, yellowing, looseness, roughness, dryness, mottling
(hyperpigmentation).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 cumulative, increasing with time.
Although the anatomic degradation of the skin is most advanced
2 t ~38840
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 is 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 Academv of
Dermatoloqv (May, 1981) Volume 4, No. 5, include, in addition to acne treatment,10 I~dl~,e"L of senile comedones, nevus comedonicus, linear verrucous nevus,
plantar warts, pseudofolliculitis, keratoacanthoma, solar keratosis of extremities,
callosities, keratosis palmaris et plantaris, Darier's disease, ichthyosis, psoriasis,
acanthosis nigricans, lichen planus, molluscum contagiosum, reactive perforatingcollagenosis, melasma, corneal epithelial peeling, geographic tongue, Fox-Fordyce
15 disease, cutaneous metastatic melanoma and keloids or hypertrophic
1 338840
scars. Vitamin A acid derivatives ~retinoids) are known to havc prophylactic andtherapeutic effects on a great variety of tumors and are being increasingly used as
anti-tumor drugs.
In view of the foregoing, it is believed that vitamin A acid
5 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
10 to persistent treatment of normal aging skin.
Brief Summarv 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
15 particular, the methods of the present invention retard the
1 338840
effects of photo-aging of the skin including impairment of the differentiation of
epidermal epithelial cells, loss of collagen fibers, abnormal changes in the elastic
fibers, and detcrioration of small blood vessels of the dermis of the skin. The
methods comprise applying topically to the epidermis of the skin effective amounts
5 of vitamin A acid in a program of Illa~ nallce therapy, whereby epithelial growths
are suL,~Ld"Li~l!y reduced and prevented and the skin s~ Ld~Lially regains and
maintains its firmness, turgor and elasticity during the therapy. Generally, themaintenance therapy is begun in middle age when epithelial growths and other
aging changes begin to appear clinically.
According to one aspect of the present invention, therefore,
there is provided a composition for topical l" ' - Liu~ 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 of abnormal
epithelial growths in s~da~a~ed human skin, comprising effective amounts of
15 vitamin A acid in a non-toxic, dermatologically acceptable vehicle,
1 338840
4a
said composition and amounts of vitamin A acid being selected so as to provide adoes of vitamin A acid which is insufficient to cause excessive irritation.
The present invention also provides a method of retarding and
reversing the loss of collagen fibers, abnormal changes in elastic fibers, the
5 deterioration of small blood vessels, and the formation of abnormal epithelialgrowths in sundamaged human skin, comprising applying topically to the epidermisof 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 sul.~ "Li~lly regains and maintains its firmness, turgor and
10 elasticity during said therapy, said composition and amounts of Vitamin A acid
being selected so as to provide a dose of Vitamin A acid which is insufficient to
cause excessive irritation.
The vitamin A acid may be applied to the skin in any suitable
non-toxic, dermatologically acceptable vehicle, preferably a non-volatile, emollient
15 or lubricating vehicle, in an amount and at a frequency which are insufficient to
cause excessive irritation of the skin. Generally, concentrations in the range of
about 0.005 to 0.05% by weight of the vehicle are preferred.
1 338840
Detailed PesGriPtion 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 beginning inmiddle age when such changes first become evident clinically. Certain of the
5 anatomic alterations can be corrected and at least partialy reversed, a~,col"pd,l:cd
by improvement in the a,upealdllce of the skin.
The invention accol",ul;.,l-es two goals. First, a prophylactic
effect in preventing progression and worsening of the damage with the passage oftime. Secondly, various abnormalities are corrected and modified to the extent
10 that the structure and function of the skin acquires the characteristics of younger
skin .
A~e AssoGiated Structur~l Chanaes
Although many of the effects of the aging of the human skin
15 are the result of underlying structural changes which build up over a period of
years and can only be detected histologi~ally
~ ~8~a
prior to middle age, these changes and effects 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 referred to above, and each is ass~cic,l~d with one or more
5 underlying structural changes in the skin. For example, blu~cl, ~e~s 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 blotchiness and mottling.
However, aside from such obvious cosmetic changes in the
skin, there are a number of othor changes which are more important though less
apparent, including loss of sensory acuity and ability to heal wounds, decreasedbloc w and decrease in the thickness of the skin. Older people have less
~ensitivity to pain and a long~r
7 ~ 338840
response time. Thus, pain due to irritation or injury 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 sustained 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 coid. This is due to a decrease in the blood supply to the skin due to loss of
small blood vessels and de~ ased proliferation of new capillaries and small blood
vessels in the skin. This is at least one of the causes of the loss of sensory acuity
10 and response to pain. Furthermore, the dec,t:ased blood supply decreases the rate
at which irritants and toxins are cleared from the skin tissue.
Still further, the skin of older people is more easily torn than
that of younger people, since both the epidermis and dermis become thinner with
a~e. As a result, there is less bulk to protect underlying organs and therefore
15 more risk
1 338840
of serious injury. ~toreov~r, when wo~n~ls or
i~u~ies are sustained, healing of the vounds is
rlcch slower in ~lder people a~d m~y take as much as
tw~ce as long to heal as ln younger persons.
S The underlying csuses of the zboYe gross
- sk:n effec~s ;3~y be underseocd more readily from
.he following discussicr. of t~e sFec' fic caanges in
the epidermis and dermis ~s aging progresses.
1. ~Pi de r:; is
With increasing e~Fosure of a human to
sun Iphoto-aging) ~nd other enYironm~-atal traumas,
cells diYide at a slcwer rate ~decreased capacitY
to renew themselYes). They show marke~ irregu-
larities in 5iZ~, shape and staining p-operties;
1~ c,rderliness (polarity) from belo~ t~ dbove is
lost. The thickness of the ~pider:ni3 decreases
(atrophy). The horny layer vhich con:prises the
barrier ~gainst water loss aud penetration of
chemicals becomes abnor~al due to the shedding
(e~foliation) of cells .n large groups or clusters
instead of as indiYidual cells, resulting in
Lo .~ne3s, scaling and dry_ss. There is loss of
9 1 3388~0
the orderly transformation of living epithelial cells into cornified dead cells which
are shed at the surface, that is, dir~ idlion is impaired. Aberrant dirrt:,elllidlion
results in numerous foci of abnormal epithelial growths or tumors, the most
frequent and important of which are actinic keratoses. After many years these
5 can transform into frank skin cancers called basal cell and squamous cell cancers.
Pigment producing cells (melanocytes) can also become altered forming flat, darkgrowths (lenti00 melanoma) which may progress to malignant melanoma. The
cells which make up these pl~lll 'i~, Idlll growths are destroyed by topical
tretinoin .
2. Dermis
The cells which make the fibers of the dermis become smaller
and sparser with increasing age, usually in sundamaged facial skin. There is a
great loss of collagen fibers resulting in looseness and easy stretchability of the
15 skin; elastic fibers become abnormal so that the skin does not promptly snap back
after being stretched.
~ 3388~
Since the fibrous components comprise more than 90% of the bulk of skin of
which 95% is collagen, the deu,dd~lion of these fibers, especially colla~qen, ismainly responsible for wrinkling, laxness and loss of elasticity.
Small blood vessels become thin walled, dilated and often
5 ruptured. Vascu~ar supply thereby becomes corl",,u",i~ed.
Beneficial Effects of Tretinoin in Accordance With the Present Invention
(a) Increases Proliferative activitv of ePidermal cells. This
results in thickening of the epidermis with correction of atrophy. Cell renewal is
quickened so that cells divide at a rate typical of younger skin. Treatment with10 vitamin A acid in accordance with the invention can double the skin thickness.
The stimulation of cell growth also results in faster wound healing. Experimentshave been performed wherein blisters have been raised and cut off on skins of
individuals of various ages. Healing takes place in 2 to 3 weeks in young people,
but takes much longer in older persons with sun damaged skin.
11 1 3388~0
Application of tretinoin before raising the blister results in healing twice as fast in
the older subjects.
(b) Corrects abnormalities of di~ ,LidLion. Vitamin A acid
regulates and controls the physiologic behaviour of epithelial tissue, assuring its
5 stability and integrity. It corrects and normalizes abnormalities of di~ "LidLion.
In sundamaged skin, the numerous foci of abnormal growths and segments of
atypical, abnormal epidermis are corrected, reversed or: ' Il;lldL~d. 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
10 but exfoliation occurs by individual cells rather than clusters or scales, thus
improving the topography of the skin. Moreover, hy~.el,~.iy,~ ,ldLion resulting in
blotches and splotches is reduced by tretinoin stopping excessive production of
pigment by the melanocytes, although it cannot eliminate depiylllellLion.
~ 3388~0
12
(c) The metabolism of ~ bla~L~ is increased. riblubla~L~
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
5 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
10 acc~le,dlt: the healing of wounds in colll,u,ol"ised 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 prevention 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
13 1 338840
aged, sundamaged skin. A brisker blood supply improves the physiologic
competence of the skin and imparts a livelier, glowing appearance. Patients often
say their skin feels "more alive".
Several of the prior art ~l~dL~e~ of skin disease using vitamin
5 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
conce"L,dlions of vitamin A acid. In contrast, the low sub-irritating concentrations
of vitamin A acid according to the present invention do not cause significant
10 vasodilation, but is has been found that over the long term there is not only a
proliferation of new blood vessels, but also an increase in Iymphocytes and other
blood cells. As a result, there are more cells to fight infection, and the increased
blood supply allows the skin to clear irritants and toxins more quickly from theskin.
Still further, treatment with vitamin A
14 l 338840
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
5 drying and irritating cosmetics, soaps, perfumes, etc. have shown that young
people will experience severe irritation within 3 or 4 days whereas it may take 2 to
3 weeks for 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 ointments, in the broad concentration range of about 0.0001% to
0.05%, usually about 0.005% to 0.025,/o and preferably about 0.01% by weight
of base, although higher conc~LIc~Liol~:, may be used for darker skins. Other non-
toxic, dermatologically acceptable vehicles or carriers in which tretinoin is stable
~ 33~
1 5
will be evident to those of ordinary skill in the art. In general, emollient or
lubricating vehicles, such as oleaginous substances, which help hydrate the skinare preferred. Volatile vehicles which dry or otherwise harm the skin, such as
alcohol and acetone, should be avoided.
An ointment base Iwithout water) is preferred in the winter
and in subjects with very dry skin. Examples of suitable ointment bases are
petrolatum, petrolatum plus volatile 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
10 suitable cream bases are "Eucerin"*(Beiersdorf), cold cream (USP), "Purpose
Cream"**(Johnson & Johnson), and hydrophilic ointment (USP).
Tretinoin is a mild irritant and may cause redness and scaling,
which may be accompanied by some tenderness and tightness. These reactions
quickly disappear when the ~ Lions are stopped. However, even when
15 applied excessively to
* Trade mark
** Trade mark
1 }~88~
1 6
produce an intense dermatitis, the reaction fades quickly leaving no permanent
sequelae. Systemic side reactions are unknown. Selection of an a,uplOpli~l~
emollient vehicle will more readily allow the use of a highly effective but sub-irritating dose of the vitamin A acid.
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 ~ ol~.liLions with vitamin A acid in
which the l~ "e"L~ are L~ illdL~d as soon as the condition disappears or
subsides, the treatment according to the present invention is intended to continue
10 indefinitely, otherwise the effects of aging will reappear after treatment isterminated. That is, the L~ec,L~,,e,,L~ of the present invention may be considered to
be intervention therapy in decelerating the photo-aging process. If the intervention
is stopped, there is regression to the original state.
Usually, there is little point in beginning the treatments of the
15 present invention
1 ~8~
17
until middle age when the effects of photo-aging begin to appear clinically. Theparticular program of Illd;ll~ dl~Ce 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
5 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. That is, once the aging process has
10 been controlled, a Illa;lllt:l~dllCe dose on the order of two applications per week is
generally sufficient to maintain that state.
The invention will be illustrated in more detail by reference to
the following specific, nonlimiting examples:
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18
Ex,lJeli,,,t:,,Lc,l ExamPle 1
There has been applied 0.01% to 0.025% by weight
conce"L~dlions of tretinoin in a base to the faces of middle-aged and elderly
women. At least 500 persons have used typical tretinoin eXp~lilllt:llldlly for
5 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. The creams or
10 ointments containing Vitamin A acid (tretinoin) were applied once daily before
bedtime in an amount sufficient to achieve a continuous sustaining film. Clinical
a~ "~ L~ were made once monthly. Beneficial 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
15 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
19 l 338~0
required to prevent relapse.
The beneficial effects included ~rrdct:~,e~l of small wrinkles,
smoother surface, greater turgor,; ' IlilldLio,l of actinic keratoses, elimination of
senile comedones, less conspicuous pores and less mottling (fading of piylll~ d
5 spots).
ExDerimental ExamrJle 2
Histologic studies were conducted on twenty six residents of
Riverview as follows. Tretinoin was applied to one side of the face once daily as
10 in E~.elilll~"~dl 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 histologic examination using a variety of histochemical stains.
The tretinoin treated side was easily recognized in 24 of 26 subjects. The chief15 effects of tretinoin, as demonstrated by the indicated tissue staining techniques,
were:
a) Routine H & E stain: epidermis
1 33~8~0
thicker, polarity restored, cells were regular size and shape, loss of atypia, no
epidermal irregularities of pre-malignant growths, density of ribl~bla~l~ 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
indicating deposition of new collagen.
d) Orcein stain for elastin: moderate removal of
degenerated elastic tissue, allowing intact fibbers to be
visualized more clearly.
e) Hale's stain for ground substance: definite increase in
acid mucopolysaccharides, especially in deeper dermis.
ExPerimental ExamPle 3
There have been treated at least another two hundred subjects
15 in the aging skin clinic at the Hospital 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.
21 1 338840
Beneficial effects were clinically evident in about 80% of these
persons. With this more sopl,;~ d 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
5 hyp~",i~ ,e"Ldlion, more youthful d~J~Jedldl~Ce, less roughness, less wrinkling.
ExPerimental ExamDle 4
About one hundred paid volunteers recruited at Ivy Research
Laboratories have been studied in a variety of ways including biopsies, physiologic
10 tests, etc. The importance of this series is that the tests were conducted
according to the double-blind formal and hence were strictly controlled. Tretinoin
was applied once daily as in Ex~.e,i",~"Ldl Example 1 for six to twelve 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
15 which of the two pr~pa,dLions contained the
1 338840
22
active a0ent. 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 effects5 were secured in about 85% on the tretinoin treated side. Histologic study in
thirteen cases confirmed the clinica~ results of rcstoration to a more normal pattern
on the tretinoin side. The epidermal and dermal changes were those described
above.
Fluorescein injected into both sides was removed in about half
10 the time on the tretinoin side. This indicates improved vascularity resulting in
faster clearance of drugs from the skin. Moreover, a series of clinical stimuli
indicate that tretinoin treated skin is more reactive, showing behaviours more
typical of young skin. It responds more rapidly and intensely to irritant chemicals
such as croton oil and dimethylsulfoxide; it blushes more readily after 1,~, ' lion
15 of nicotinate; blisters raised by ammonium hydroxide heal more quickly Igreater
wound
1 338840
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
followiny advantages inter alia:
A. !~ -. -
Effacement of fine wrinkles
Smoother surface
Liyhtens piy~a~ d blotches
Skin has more turgor
Large pores less noticeable
Skin feels livelier
B. Histoloçlic
Thicker epidermis
Normalizes atypia and pre-malignant changes.
Atrophy and dysplasia corrected.
Stimulates blood flow; new vessels formed.
Stimulates riblubld~L!i with new collagen formation.
Increases ground substance
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24
Melanin within keratinocytes is decreased.
It will be recognized by those skilled 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,
5 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 theinvention as defined by the appended claims.
