CA1324962C - Compositions and methods for retarding the effects of aging of the skin - Google Patents

Abstract

COMPOSITIONS AND METHODS FOR RETARDING THE
EFFECTS OF AGING OF THE SKIN
Abstract of the disclosure Various effects of photo-aging (sundamage) of the skin including impairment of the differentiation of epidermal epithelial cells, loss of collagen fibers, abnormal changes in the elastic fibers, and deterioration of small blood vessels in the dermis of the skin are retarded by applying topically to the epidermis of the skin in a program of maintenance therapy effective amounts of vitamin A acid (tretinoin) such that epithelial growths are substantially reduced and prevented, and the skin substantially regains and maintains its firmness, turgor and elasticity. Moreover, with persistent treatment dermal blood cells and vessels increase and the epidermis and dermis thicken, resulting in improved ability of the skin to sense, resist and recover from irritation or injury. Further, hyperpigmentation, lines and wrinkles due to aging are reduced and prevented. The treatment is particularly useful for human facial skin and preferably applied in an emollient vehicle in sub-irritating doses.

Description

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 , .

..

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 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, ~.~
i ~ ~ 1 32~962 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.

r 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 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 ~3, 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 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.

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.

.

, 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.

:

(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 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

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 , .

~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 ~ ' 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 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:

:, , 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 l 32~q62 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 .

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.

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 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 : .

~\

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 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.

~ ' ., .

Claims (9)

1. 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 of abnormal epithelial growths in sundamaged human skin, comprising effective amounts of vitamin A acid in a non-toxic, dermatologically acceptable vehicle, 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.

2. Composition according to claim 1 wherein the concentration of vitamin A acid in said vehicle is about 0.0001 to 0.025 weight percent of the vehicle.

3. A composition accoridng to claim 1 wherein said vehicle is an emollient vehicle.

4. The use of a composition according to claim 1 to retard and reverse the loss of collagen fibers, abnormal changes in elastic fibers, the deterioration of small blood vessels, and the formation of abnormal epithelial growths in sundamaged human skin.

5. The use of a composition according to claim 2 to retard and reverse the loss of collagen fibers, abnormal changes in elastic fibers, the deterioration of small blood vessels, and the formation of abnormal epithelial growths in sundamaged human skin.

6. Use according to claim 4 wherein said non-toxic, dermatologically acceptable vehicle is an emollient vehicle.

7. Use according to claim 4 wherein said skin is human facial skin.

8. Use according to claim 4 wherein said use commences in middle age of the subject to whose skin the vitamin A acid is applied.

9. Use according to claim 4 wherein the concentration of vitamin A acid in said vehicle is about 0.0002 to 0.025 weight percent of the vehicle.