CA1335651C - Method for the treatment or prevention of intrinsically aged skin with retinoids - Google Patents

Abstract

A method for the treatment or prevention of intrinsically aged skin by the topical administration of retinoids is described.

Description

~ -1- 1 335651 Title Q f the Invention METHOD FOR THE TREATMENT OR PREVENTION
OF INTRINSICALLY AGED SKIN
S WITH RETINOIDS

Baekqrot-n~ of the I~ventio~

10Fiel~ of the ~n~ention The present invention relates to a method for the treatment or prevention of intrinsieally ~ehronolog~eally) aged ~kin by the topical admini~tration of retinoids.

15De~er~ption of Prior Art Cutaneous aqing results from two distinct and independent processe~: intr~nsie aging an~ photoaging. Although tho ~kin chanqes that oeeur in intrin~ie aging may invol~e qenetieally programmed sene~eeneo mediated perhap~ by a~ yet unidentified endogenous faetor~, an under~tanding of the elinieal aiterations as well as ehanges in the estraeellular matri- and moleeular biology is beginninq to emerge. Clinieally, intrinsie aginq i~ eharaeterized by ha~ing a thin, atrophie dermis, reduetion in subeutaneous adipose tissue and by the presence of fine wrinkling. In addition, there appear~ an unblemishe~ suraee with some ~eepening of s~in surfaee markings an~ ~ome histopathologie and ultrastruetural alterations a~ well. Compared to young-skin, intrinsieally aged skin manifests it~ most pronouneed ehanges in the dermi~.
The ma~or ehanqe~ in the ela~tie tissue inelude an inerea~e in the number as well a~ thieknesa of fibers, 108s of vertieal fibers that insert into the basement membrane, an~ the presence of large irregular fibroblast~ eontaining estensive rouqh endoplasmie reticulum, eharaeteristie of elastogenesia.
'~

~ -2- 1 335651 . .

Conversly, photodamaged skin iJ characterized by coarse wrinkl~nq and furrowing and the skin appears loose, thickened and leathery. Photodamaged skin represents a state of mild chronic inflammation. Histologically, in photodamaged skin, there i~ e~cessive accumulation of elastotic material in the upper dermis, basophiliC
degeneration and homogenization of the collagen fibers accompanying the accumulation of glycosaminoglycan-proteoglycan comple~es. Also, there appears to be a loss of collasen bundles. Biochemically, thera is a decrease in mature ~insoluble) collagen with a concomitant increase in soluble collagen. Mature collagen may be degraded by the chronic inflammatory infiltrato produced by ultraviolet-B irradiation. However, in lS intrinsically aged skin, mature collagen i8 moro stable and resistant to enzymatic degradation, the bundles become larger forming disoriented rope-like structure~. Also, there is marked thickening or acanthosis in the epidermis as well as the dermis and sebaceous glands become greatly enlarged. Electronmicroscopic studies reveal that early changes in photodamaged skin consist of an increase and enlargement of the microfibrillar component of the elastic fibers. In more advanced stages, the elastic fibers are highly disorganized.
Concerning microcirculation, there is a loss of vascular area in both intrinsic and photoaged skin, with distinct differences between the two. Intrinsically-aged skin e~periences a uniform reduction in the vasculaturs with a progressive thinning of the vessel wall. The vessels are not dilated or deranged and havo an undisturbed superficial plesu~. In photoaged skin, the vasculaturo i~ almost totally missing in some areas of the dermis with the horizontal superficial ple~us almost completely destroyed, ~hile in other areas the vesse1s .

~ 1 335651 become dilated and tortuous and are seen on the surface of the skin as telangiectasias. In early photodamage, the vessel wall actually thickens and then progressively thins.
Thus, there are distinct differences between intrinsic aging and photoaging. Rligman, A. M. et al., "Cutaneous Aging: The Differences Between Intrinsic Aging and Photoaging," Journal of Cutaneous aging and Cosmetic Dermatology, Vol. 1, No. 1, pp. 5-12 (1988). These differences are summarized in Table 1.

TABLE

Feature Intrinsic aging Photoaging ~1in; ~Al appearance SmDoth, unblemished ~ rrA~e ~llAr, le~thPry Same ~PP~Pn;ng of skin ~lrrA~e with rfA~e markings blotches, yellowing Deep wrinkles Some loss of elasticity Sign;f;~Ant loss of elasticity Epidermis fflin and viable Marked a~nthos;~
C~ 11lAr atypia Elastic Tissue Increased, but almost Tremendbus increase, normal f~ J~ ~r ~Les into am~ hY.~ mass ~ollAgPn ~m~lf-s thick, ~i~nr;~nte~ f~arked decr~ase of a and fibers GAG~ PGs Slightly d~L~_sed Markedly increased R~t;~llAr dermis Th;nn~r Th;~k~n~, elastosis Fibrcblasts d~ ased, Fibroblæts increased, inactive h~ f~Live Mast cells de~L~ased, Mast cells mark~ly no inflammation increased, mLxed inflammatory infil-- trate P~r;llAry dermis No Grenz zone Solar elastosis with Grenz zone Micro~-~-lAtl-re Moderate loss Great loss, A~J~ r ~ 31 and t. ~1 An9i e~tatic 35 G~Gs glycosaninoglycans, PGs pL~Leoylycans Tretinoin, all trans retinoic acid, has been described ~ ~4~ 1 335651 as being e~fect~e in the treatment of photoagea skin (Weiss, J. J. et al., ~Topical Tretinoin Improves Photoaged Skin,~ Journal of the American Medical Association, Vol. 259, ~o. 4, pp. 527-532, (lg88). ~ittle is known, however, of the effectiveness of retinoids in the treatment or prQvention of intrinsically aged skin.

Vitamin-A acid has been suggested as being useful in the treatment of wrinkles, sun damaged and sagging s~in.
Saline, C., ~Adventures in the Skin Trade.~ Philadelphia Maga~ine, pp. 120-133 (1980). However, no method i~
described for the treatment of intrinsically aged skin by the topical administration of retinoids.

Summary of the Invention The present invention is directed to a method for the treatment or prevention of intrinsically ~chronologically) aged s~in by the topical administration of retinoids. The retinoi~s employed may be any natural and/or synthetic compound which po~sesses the biological activity of vitamin A.

Detailed Description of the Invention The invention relates to the use of retinoids for the treatment or prevention of intrinsically ~chronologically) aged skin.

Retinoids have been defined narrowly as comprisinq simply ~itamin A (ret,inol) and its derivatives, such as vitamin A aldehyde tretinal) and vitamin A acid (retinoic acid), which comprise so-called natural retinoids.
However, subsequent research has resulted in a much larger class of chemical compounds that sre deemed retinoids due to their biological similarity to vitamin A and its derivatives. Compounds useful in the ~res~nt invention ~ ~5~ 1 335651 include all natural and/or synthetic analog~ of v~tamin A
or retinol-lik~ compound~ wh~ch possess the biological acti~ity of vitamin ~ in th~ skin. These include:
regulation of epithelial cell differentiation of ketatinocyte~ ~n the epidermis; stimulation of new collagen synthesis in the dermi~, and production of new blood ~e~sels (angiogenesis). Accordingly, a~ used herein for purpose~ of the present invention, the term ~retinoid~
will ~e understood to include any of the foregoing compound~. Esample~ of suitable retinoid~ in the present in~ention are set forth in Table 2, although it will bo un~er~tood that the invention i~ not limited thereto.

Table 2 all-tran~-retinoic acid 13-ci~-retinoic acid .

(all-E)-9-(4-methosy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester (all-E)-9-(4-methosy-2,3,6-25trimethylphenyl-3,7-dimethyl-2,4,6,8-nonatetraenoic acid N-ethyl-9-(4-methosy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-2,4,6,8-~onatetraenamide (E,E)-9-(2,6-dichloro-4-methosy-3-methylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester Table 2 (continued) ~ -6- 1335651 7,8-didehydroretinoic acid (E,E)-4-~2-methyl-4-(2,6,6-trimethyl-1-cyclohesen-1-yl)-1,3-butadienyl]benzoie acid (E)-4-t4-methyl-6-(2,6,6-trimethyl-l-cyclohesen-l-yl)-1,3,5-hesa-trienyl]benzoic acid tall-E)-3~7-dimethyl-(3-thienyl) 2,4,6,8-nonatetraenoic acid (E,E,E)-3-methyl-7-(5,6,7,8-tetrahydro-lS 5,5,8,8-tetramethyl-2-naphthalenyl)-2,4,6-octatrienoic acid (E)-6-12-(2,6,6-trimethyl-1-cyclohesen-l-yl)ethenyl~-2-naphthalenecarbosylic acid (E,E,E)-7-(2,3-dihydro-1,1,3,3-tetra-methyl-lH-inden-5-yl)-3-methyl-2,4,6-octatrienoic acid (E)-4-t2-(2,3-dihydro-},1,3,3-tetramethyl-lH-inden-S-yl)-l-propenyl]benzoic acid (E)-4-t2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl-1-propenyl]benzoic acid (E)-4-[2-(5,6,7,8-tetrahydro-3-methyl-5,5,8,8-tetramethyl-2-naphthalenyl-1-propenyl]benzoic acid Table 2 (continued) ~ ~7~ 1 33565 1 (E)-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(1-methy}-2-phenylethenyl)naphthalene 56-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl)-2-naphthalenecarbosylic acid (E)-6-t2-(4-(ethylsulfonyl)phenyll-1-methylethenyll-1,2,3,4-tetrahydro-101,1,4,4-tetramethylnaphthalene 4-t(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoic acid 15(E) -2-(1,1,4,4-tetramethyl-1,2,3,4-tetra-hydronaphth-7-yl)-1-t4-tetrazol-5-yl)phenyll-1-propene (E) -4- E 2-(S,6,7,8-tetrahydro-7-hydro~y-205,5,8,8-tetramethyl-2-naphthalenyl)-l-propenyllbenzyl alcohol Included among the compounds which can be employed are the pharmaceutically acceptable addition salts and esters of the retinoids such as the palmitates etc. Also encompassed within the term ~retinoid~ are geometric and stereo~somers of the retinoids.

A pharmacological composition containing a retinoid a~
the active ingredient in intimate admisture with a pharmaceutical carrier can be prepared according to conventional pharmaceutical compounding techniques, such as, for esample, those known for topical application of all-trans-retinoid acid. The carrier may take a wide ~~ -8- 1 335651 variety of physical forms such as, for e~ample, creams, dressinqs, gels, lotion~, ointments or li~uids. The retinoid will be present ~n the composition in an amount from about 0.00001~ by weight to about 0.2% by weight, depending on the potency of the retinoid. A suitable topical retinoid preparation in a gel ~ehicle i~ Retin-A~, which contain~ 0.01~ to 0.1~ by weight of the activ~
ingredient, ~produced by Ortho Pharmaceutical Corporation).
The following esample describe~ the invention in greater particularity, and is intended to be a way of illustrating but not limiting the invention.

EXAMP~E 1 Lifetime Application of all-trans-Retinoic Acid to Albino Hairless Mice.

Materials an~ Metho~s Female Albino hairless mice (Skh-hairless-l), age 8-11 weeks, were treated topically, three times a week, for the remainder of their life span as follows:
Group 1. 0.025% all-trans-retinoic acid (100 ~1) 12 mice Group 2. Creaml~ehicle (100 ~1) 12 mice Group 3. Untreated 12 mice The mice were esamined monthly for skin changes and possible weight loss that might indicate a to~ic effect.
Toward the end of the study, mice were photographed to show the condition of the skin. A few mice were sacrificed at about 70, 80 and 90 weeks, with dorsal skin taken for histochemical evaluation. The remainder were allowed to live out their life span which ranged from 91-106 weeks and were biopsied when moribound, if possible. The histochemical stains were: ~&E for general histology, Luna's for elastic fibers, Yan Gieson's for collagen and Mowry' 8 for proteoglycans.

Res~llt~

A. To~icity 1. There was no difference in the weights of mice with~n the three groups.

2. There was no difference in mortality within the three groups.

3. At biopsy and necropsy there was no indication that the mice suffered any adverse or unusual effects.

Therefore: treatment with either all-trans-retinoic acid or vehicle over a lifetime produced no detectable tosic effects.

B. Clinical Observation~

Mice treated with all-trans-retinoic acid had thinner, pinker, more uniform skin than the controls. They more closely resembled far younger, untreated mice. Vehicle controls had thicker, yellower skin. Untreated controls had e~tremely thick, sagging, yellowed skin, typical of such aged mice (Figure 1).

~ -lo- 1335651 Figure 1. is a photograph which illustrates the results of lifetime application of vehicle or all-trans-retinoic acid to female albino hairles (Skh-l) mice. t Yehicle, tt - untreated, ttt -all-trans-retinoic acid. Mice were 91-106 weeks of age at photoqraph. All-trans-retinoic acid mice haa thinner, pinker, more uniform skin than controls or untreated mice. They resemble young mice. Vehicle control mice had thicker, yellow skin. Untreated mice had very thick, sagging, yellowed skin.

C. Histochemical Observations ~&E for General Histology (See Figures 2, 3 and 4) Figure 2. is a picture of a normal old mouse, at 80 weeks of age. H & E stain.

Figure 3 is a picture which illustrates cream vehicle mice at 85 weeks of age.

Figure 4 is a picture which illustrates mice treated with all-trans-retinoic acid. (~ifetime of treatment~.
Hyperplastic epidermis and strongly granular layer of appro~imately 4 cells. Cells are plump, cytologically normal and have abundant cytoplasm and an abundance of new blood vessel~. Sample wa~ taken from a mouse g5 weeks of age.
In all-trans-retinoic acid-treated specimens, the epidermis wa~ hyperplastic (about 8 cell layers) including a strongly granular layer of about 4 cell layers. The cell~ were plump, cytologically normal and had an abundant cytoplasm. Control specimens had the usual 2-4 compressed-looking cells. Blood ~e~sel~ were ~eadily seen in the all-trans-ret~noic acid group, unl~ke in the controls. Areas of new collagen were apparent by the parallel array of the bundles and the presence of numerou~
large fibroblasts. These regions were free of inflammation despite a mild inflammatory infiltrate in the mid-dermis. No repair areas were seen in the control~ and dermal inflammation was present but variable from specimen to spec~men.

r~lna~ Stain for ~lastic F~ber~
Thi~ stain confirmed the presence of new collagen in the sub-epi~ermal dermi~ of Retin-A~-treated mice. The~e areas, termed repair zones, are identified by elastic fiber~ at their lower border, having been displaced downward by the deposition of new collagen. Repair zones were intermittent acros~ the specimen, unlike in photodamaged skin where they are continuou~. In control~, no repair zones were found (Figure 2). In addition, mice treated with all-trans-retinoic acid appeared to have an 2S increase~ amount of new elastic fibers (Figure 4).

Van Gies~^s Stain fo~ Colla~pn Collagen in the repair zone~ stained mainly as normal, mature collagen.

MQwrY's Stain for GlYcosamino- an~ proteoqlycan~

There was little or no increase in dermal ~5 glycosaminogly~ans ~r proteoglycan~ in any of the groups escept for intermittent depo~its at the dermal-epidermal junction. These deposits are typically found in aging mice. Fewer ~eposits were found in the retinoid treated group.

EXAMP~E 2 Five, healthy white women, ages 7~ to 85 receive~
treatment or control~ on their upper lateral thigh once daily. One s~d~ recei~ed Purpose Cream~ (control), the other side ha~ Retin-A~ 0.05~ applied. The duration of the study is for one year.

Clinical results eight months into the study are as lS follows:

Some improvement on both sides was noted, but it was e~eedl~gly better on the Retin-A si~e. At tb- start of the esperlment the sk~n was wrinkled, rough, dry, loose, etc. With ~etin-A after S months the s~in was smooth, tighter, less wrinklea and firmer. Thero was som- initial irritation with Retin-A but the skin accommodated.

Skin biopsies were taken from another elderly female 6 months into the study.

A histoloqical e~amination of the Retin-A cream treated skin showed acanthosis, an increased granular layer, a compact horny layer~ less epidermal atypia and dysplasis, more dermal cells (fibroblasts and lymphocytes) with the morpholoqy of metabolic hyperactivity. On the control side, chanqes were slight.

Retin-A~ was clearly~shown to be efective against i~trinslc~l~y agod ski~ esght month~ into the study.

Claims (6)

1. A method for the treatment or prevention of intrinsically aged skin which comprises the topical administration of an effective amount of a retinoid in a pharmaceutically acceptable carrier.

2. The method of claim 1 wherein the retinoid is all trans retinoic acid.

3. The method of claim 1 wherein the retinoid is 13-cis-retinoic acid.

4. The method of claim 1 wherein the retinoid is retinol.

5. The method of claim 1 wherein the retinoid is selected from the group consisting of:

(E)-4-[4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3,5-hexa-trienyl]benzoic acid (E)-6-[2-(4-(ethylsulfonyl)phenyl]-1-methylethenyl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]benzoic acid and (E)-4-[2-(5,6,7,8-tetrahydro-7-hydroxy-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzyl alcohol

6. The method of claim 1 wherein the retinoid is present in an amount from about 0.00001% by weight to 0.2% by weight.