CA1338840E - Compositions and Methods for Retarding the Effects of Aging of the Skin - Google Patents

Abstract

Various effects of aging of skin due to impairment of differentiation of epidermal epithelial cells and loss of collagen fibers, abnormal changes in elastic fibers and deterioration of small blood vessels in the dermis of the skin are retarded by applying topically to the epidermis in a maintenance therapy program 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 amounts insufficient to cause excessive irritation.

Description

COMPOSITIONS AND METHODS FOR RETARDING THE

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 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 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, 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.

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 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 (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 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~

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~

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~

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:

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.

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 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 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 1 ~38840 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.

Claims (10)

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 according to claim 1 wherein said vehicle is an emollient vehicle.

4. The use of a composition comprising effective amounts of vitamin A acid in a non-toxic, dermatologically acceptable vehicle 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; wherein said use is 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 vitamin A acid being selected so as to provide a dose of vitamin A acid which is insufficient to cause excessive irritation.

5. 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.

6. 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.

7. Use according to claim 4 or 5 wherein said non-toxic, dermatologically acceptable vehicle is an emollient vehicle.

8. Use according to claim 4 or 5 wherein said skin is human facial skin.

9. Use according to claim 4 or 5 wherein said use commences in middle age of the subject to whose skin the vitamin A acid is applied.

10. Use according to claim 4 or 5 wherein the concentration of vitamin A acid in said vehicle is about 0.0002 to 0.025 weight percent of the vehicle.