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Retin-A / Tretinoin from the mentor

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#1 Eva Victoria

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Posted 04 March 2008 - 05:46 PM

After the kindness of Time Traveller who posted a link to Dr Kligman's US Patent application, I thought to make a new post of it.
The reason is:
Those who want to have more info about Retin-A / Tretinoin will have a great opportunity to find it here.
Those who want to know more about the application of the drug and the expected results will have the possibilities to get answers to their questions.

Kligman, Albert M. (c/o Department of Dermatology, University of Pennsylvania,
Philadelphia, PA, 19104)
USPatent 1985

I claim:

1. A method 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 applying topically to the epidermis
of the skin a composition comprising effective amounts of vitamin A acid in an emollient
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 vitamin A acid being selected so as to provide a sub-irritating dose of vitamin A

2. A method according to claim 1 wherein said skin is human facial skin.


This invention relates to methods using vitamin A acid to retard the effects of aging of the
skin and generally improve the quality of the skin, particularly human facial skin.


Caucasians who have had a good deal of sun exposure in childhood will show the following
gross cutaneous alterations in adult life: 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 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. Pat. No.
3,729,568. Other known uses of vitamin A acid which were reviewed by Thomas and Doyle
in Journal of American Academy of Dermatology (May, 1981) Volume 4, No. 5, subsequent to
completion of the present invention, include, in addition to acne treatment, treatment 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 perforating collagenosis, melasma, corneal epithelial peeling,
geographic tongue, Fox-Fordyce disease, cutaneous metastatic melanoma and keloids or
hypertrophic scars. Vitamin A acid derivatives (retinoids) are known to have prophylactic and
therapeutic effects on a great variety of tumors and are being increasingly used as anti-tumor
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 treatment of normal aging skin.


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 of the present invention retard the
effects of normal aging of the skin due to impairment of the differentiation of epidermal
epithelial cells and due to loss of collagen fibers, 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 effective amounts of 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 firmness, turgor and elasticity during the
therapy. Generally, the maintenance therapy is begun in middle age when epithelial growths
and other aging changes being to appear clinically.
The vitamin A acid may be applied to the skin in any suitable non-toxic, dermatologically
acceptable vehicle, preferably a non-volatine, emollient or lubricating vehicle, in an amount
and at a frequency which are insufficient to cause excessive irration of the skin. Generally,
concentrations in the range of about 0.005 to 0.05% by weight of the vehicle are preferred.


The purpose of this invention is to moderate and retard the aging changes in the skin by
topical application of tretinoin beginning in middle age when aging changes first become
evident clinically. Certain of the anatomic alterations can be corrected and at least partially
reversed, accompanied by improvement in the appearance of the skin.
The invention accomplishes two goals. First, a prophylactic effect in preventing progression
and worsening of the damage with the passage 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.


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
histologically prior to middle age, these changes and effects being 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 associated 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 cause the blotchiness and mottling.
However, aside from such obvious cosmetic changes in the skin, there are a number of other
changes which are more important though less apparent, including loss of sensory acuity and
ability to heal wounds, decreased blood flow and decrease in the thickness of the skin. Older
people have less sensitivity to pain and a longer 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
superficialy minor but potentially serious injuries may be sustained without the individual
being aware of the injury until serious damage has occured.
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 loss of small blood vessels and decreased 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 and response to pain. Furthermore, the decreased 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 age. As a result, there is less bulk to
protect underlying organs and therefore more risk 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 gross skin effects may be understood more readily from
the following discussion of the specific changes in the epidermis and dermis as aging

1. Epidermis

With increasing age and exposure of a human to sun and other environmental traumas, cells
divide at a slower rate (decreased capacity to renew themselves). They show marked
irregularities in size, shape and staining properties; orderliness (polarity) from below to above
is lost. 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 (exfoliation) of cells in large group or clusters instead of as individual cells,
resulting in roughness, scaling and dryness. There is loss of the orderly transformation 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 squamous
cell cancers. Pigment producing cells (melanocytes) can also become altered forming flat,
dark growths (lentigo melanoma) which may progress to malignant melanoma. The cells
which make up these premalignant 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 skin; elastic fibers become abnormal so that the skin
does not promptly snap back after being stretched. Since the fibrous components comprise
more than 90% of the bulk of skin of which 95% 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.


(a) Increases proliferative activity 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 with vitamin A acid
in accordance with the invention can double the skin thickness. The stimulation of cell growth
also results in faster wound healing. Experiments have been performed wherein blisters have
been raised and cut off on skins of individuals of various ages. Healing takes place in 2 or 3
weeks in young people, but takes much longer in older persons. Application of tretinoin
before raising the blister results in healing twice as fast in the older subjects.

(b) Corrects abnormalities of differentiation
Vitamin A acid regulates and controls the physiologic behavior 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, abnormal
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 cannot eliminate

© 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 prevention of
fine wrinkles and lines.

(d) Vascularity 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 treatments 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 could result 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 invention do not cause significant
vasodilation, but it has been found that over the long term there is not only a proliferation of
new blood vessels, but also an increase in lymphocytes 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 the skin.
Still further, treatment with vitamin 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 within 3 or 4 days whereas it may take 2 or 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, moisterizing bases, such as creams or ointments,
usually in the concentration range of about 0.005% to 0.05% and preferably about 0.01% to
0.025% by weight of base, although higher concentrations may be used for darker skins.
Other non-toxic, dermatologically acceptable vehicles or carriers in which tretinoin is stable
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 skin are preferred. Volatile
vehicles which dry or otherwise harm the skin, such as alcohol and acetone, should be
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 volatile silicones, and
In warm weather and often for younger persons, emulsion (cream) bases, which are mixtures
of oils and water are preferred. Examples of suitable cream bases are Eucerin (Beiersdorf),
cold cream (USP), Purpose Cream (J & J), 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 applications are
stopped. However, even when applied excessively to produce an intense dermatitis, the
reaction fades quickly leaving no permanent sequellae. Systemic side reactions are unknown.
Selection of an appropriate 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
conditions with vitamin A acid in which the treatments are terminated as soon as the condition
disappears or subsides, the treatment according to the present invention is intended to
continue indefinitely, otherwise the effects of aging will reappear after treatment is
terminated. That is, the treatments of the present invention may be considered to be
intervention therapy in decelerating the 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 present invention until middle
age when the effects of aging begin to appear. 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. That is, once the aging process has been controlled, a maintenance dose on the
order of two applications per week is generally sufficient to maintain that state.

Clinical cases: read the whole study.

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