WO1988007371A2

WO1988007371A2 - Prevention and treatment of the deleterious effects of exposing skin to the sun, and compositions therefor

Info

Publication number: WO1988007371A2
Application number: PCT/US1988/001036
Authority: WO
Inventors: Peter M. Ross; Leon H. Bradlow
Original assignee: The Rockefeller University
Priority date: 1987-03-25
Filing date: 1988-03-25
Publication date: 1988-10-06
Also published as: CA1316827C; EP0307468A1; AU1707788A; AU613370B2; WO1988007371A3

Abstract

Triamcinolone acetonide 21-ennoic acid methyl ester, other compounds affecting the arachidionic acid cascade and other known synthesis inhibitors, and topical and pharmaceutical compositions thereof are utilized in a method of treating ultraviolet radiation exposed skin to inhibit ultraviolet radiation suppresion of delayed hypersensitivity in the epidermis thereby reducing or obviating the carcinogenic effects of the sunburn. Formulations of the triamcionolone acetonide 21-ennoic acid methyl ester preferably contain about 0.005 to 1.0 percent by weight of the active ingredient.

Description

PREVENTION AND TREATMENT OF THE DELETERIOUS EFFECTS OF EXPOSING SKIN TO THE SUN, AND COMPOSITIONS THEREFOR

Skin cancer now ranks as the number one form of cancer in the United States today. The increase in the occurrence of skin cancer ranks second only to the increase of lung cancer in women.

Some forms of skin cancer, such as basal cell carcinoma and squamous cell carcinoma, can be attributed to chronic, year-round exposure to the ultraviolet radiation of the sun. Malignant melanoma, a dangerous form of skin cancer because of the speed with which it can spread through the body, is thought to stem from "severe episodic sunburn". This type of sunburn is described as a sunburn obtained intermittently with no base tan. It occurs when people go out and get burnt once or twice a year; and then repeat this pattern year after year. It is frequently found in people who live in cold climates and who vacation in midwinter in warmer regions. There is no gradual exposure to the sun. They go into the sun with zero exposure, so that the skin has no chance to protect itself, and end up wi th severe sunburn.

Until now, severe sunburn has been treated in much the same way as a first or second degree burn with lotions and creams to soothe the pain and antibiotics, if necessary, in the most severe cases. Individuals with chronic exposure to ultraviolet radiation from the sun may or may not treat themselves.

The exposure to ultraviolet light which causes the sunburn likewise induces other changes in the skin which are believed to predispose, or lead, an individual to skin cancer. Such exposure can cause tumor graft tolerance and suppress delayed hypersensitivity (DH) [Parrish, J.A., ed. "The Effect of Ultraviolet Radiation on the Immune System", Johnson and Johnson Baby Products Company.]. Ultraviolet irradiation of mouse skin causes tolerance to the placing of relatively immunogenic skin tumor grafts,

[Kripke, J. Nat. Cancer Inst. 57, pp. 211-215 (1976)].

The extent of suppression of delayed hypersensitivity (DH) by ultraviolet light has been used to quantify immunological tolerance caused by ultraviolet light,

[Noonan, Springer Semin, Immunopathol., 4, pp. 293-304

(1981) and Parrish, cited above]. Irradiated mouse skin secretes low molecular weight protein that stimulates suppressor T cells in the spleen [Swartz, J. Invest.

Dermatol. 83, pp. 305-307 (1984) and Schwartz et al., J. Invest. Dermatol., 87, pp. 289-291 (1986)]. Moreover, the cis isomer of urocanic acid is released from irradiated mouse skin, presumably a photoproduct of the trans isomer, normally present in the skin [De Fabo et al., J. Exp.

Med., 157, pp. 84-98 (1983)]. Ultraviolet photoproducts of purified urocanic acid also were able to suppress DH to herpes virus in mice [Ross et al., J. Invest. Dermatol., 87, pp. 630-633 (1986)], so there may be more than one inducer or more than one cutaneous step in this process. Neither the mechanism of action, nor the source of the active substance, has been identified with certainty. Also, it is not known what normal physiological function, if any, is served by the suppressor cells. These cells, however, prevent rejection of tumor tissue, thus allowing ultraviolet carcinogenesis [Fisher et al., Science, 216, pp. 1133-1134 (1981)].

It is obvious that ultraviolet radiation suppression of delayed hypersensitivity can prevent rejection of ultraviolet radiation exposed skin, at the risk of the long-term consequence of elevated skin tumor susceptibility. It would be advantageous to eliminate this effect in order to reduce or eliminate the possible long-term consequence of skin cancer in individuals who have sustained recent sun exposure. We have now discovered that the 21-oic acid methyl ester of triamcinol one acetonide (TAme), other compounds affecting the arachidonic acid cascade and other known synthesis inhibitors, and topical compositions thereof can be utilized to inhibit ultraviolet radiation suppression of delayed hypersensitivity in the epidermis of individuals exposed to ultraviolet radiation, thereby reducing or obviating the carcinogenic effects of ultraviolet radiation by administering topically to the affected area the compound or a composition thereof in an amount effective to inhibit the ultraviolet radiation suppression of delayed hypersensitivity without systemic effects.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of tr iamcinolone acetonide 21-oic acid methyl ester, compounds affecting the arachidonic acid cascade and other known synthesis inhibitors, and topical compositions thereof to reduce or obviate the carcinogenic effects of ultraviolet radiation.

More particularly, this invention provides a method of inhibiting ultraviolet radiation suppression of delayed hypersensitivity in the epidermis of individuals exposed to ultraviolet radiation utilizing tri amcinol one acetonide 21-oic acid methyl ester, compounds affecting the arachidonic acid cascade and other known synthesis inhibitors, and topical compositions thereof without systemic effects.

The glucocorticoid utilized in the present invention is the 21-oic acid methyl ester of triamcinolone acetonide. It can be conveniently prepared by the synthetic routes detailed in Gorsline et al., Endocrinology, 116, pp. 263-273 (1985). The active glucocorticoid, triamcinolone acetonide 21-oic acid methyl ester, can be utilized in the method of the present invention alone, or more conveniently, formulated into a topical composition suitable for dermatological use. Such formulations comprise the triamcinol one acetonide 21-oic acid methyl ester in a vehicle suitable for topical administration to the epidermis of an individual in need of therapy for exposure to ultraviolet radiation or sunburn.

Similarly, the compounds affecting the arachidonic acid cascade and the prostaglandin synthesis inhibitors that may be utilized herein include, but are not limited to, aspirin, ibuprofen, indomethacin, salicylic acid, phenyl butazone, sulf inpyrazon and sulindac. These compounds may be formulated into pharmaceutical compositions with known pharmaceutically acceptable carriers for therapeutic administration.

Such topical compositions as are useful with the glucocorticoid of the present invention are exemplified by ointments, creams, lotions, aerosols, gels or soaps.

These compositions will normally be based upon standard dermatological carriers which are pharmaceutically acceptable and cosmetically elegant, such as those selected from pharmaceutically acceptable polyalkylene glycols, isopropanol, gelatin, benzyl alcohol, gums, glycerol and petrolatum. Optionally, the compositions may contain preservatives, aerosol propellants, such as hydrocarbons, and coloring, thickening, suspending, dispersing, emulsifying, wetting, stabilizing and buffering agents. These formulations are envisioned to contain the triamcinolone acetonide 21-oic acid methyl ester or the other compounds of the present invention in an amount of from about 0.005 to 1.0% by weight, with a range of from about 0.01 to 0.2% by weight being preferable for topical application. The compositions of the present invention may be utilized to treat the epidermis of individuals who have been exposed to ultraviolet radiation in potentially carcinogenic quantities. The amount of such exposure may vary from individual to individual and it is envisioned that a physician or other treatment administrator will consider factors such as the individual's age, weight, complexion and degree of exposure in administering the proper dosage. Treatment is envisioned to be accomplished by applying the topical composition to completely cover the affected area. The dosage of the compounds is preferably in the range of 0.01 mg/m² to about 100 mg/m² skin surface area. The predicted frequency of application is once or twice daily, but this may of course be varied depending upon the particular individual involved.

Thus, the method of treatment utilizing the compounds of this invention to treat individuals exposed to ultraviolet radiation comprises administering one or more of the compounds or a topical composition thereof to an individual in need of such therapy in an amount sufficient to inhibit the ultraviolet radiation suppression of delayed hypersensitivity in the epidermis thereby reducing or obviating the carcinogenic effects of the ultraviolet radiation.

The unique properties of the active ingredient allow treatment of the epidermis exposed to ultraviolet radiation without concommitant systemic effects. Since these compounds act only upon the epidermis in this therapeutic context, they are uniquely suited to the method of treatment of the present invention.

Treatment of the epidermis of individuals suffering from ultraviolet radiation exposure (sunburn) the method of the present invention will inhibit the ultraviolet suppression of delayed hypersensitivity in the epidermis. Thus, for example, the adminstration of the triamcinol one acetonide 21-oic methyl ester will prevent the induction of suppressor T lymphocytes which lymphocytes are responsible for the prevention of rejection of tumor tissue. By prevention of such a response, the epidermis will thus continue in a normal fashion which would thus allow the rejection of tumor tissue and prevent the carcinogenic effects of the ultraviolet radiation exposure. The elicited response to treatment with the compounds of the present invention in the individual's epidermis will be rejection of the sunburned skin. This rejection will result in intense infiltration, hyperproliferation and purulent crusting in the epidermis of the individual. This is a manifestation of a normal immune system which is indicative of the fact that the ultraviolet radiation suppression of delayed hypersensitivity has been successfully blocked. Thus, the so-treated individual will have increased his chances of rejecting to neoplasm and thus reduce or obviate his chances of sustaining ultraviolet radiation carcinogenesis.

While not wishing to be absolutely bound by a scientific explanation, it appears that when applied to irradiated skin, TAme and the other compounds of the present invention prevent the UV suppression of delayed hypersensitivity at the site of irradiation. TAme may block all cell responses by poisoning cell machinery or by vasoconstriction. One would thus expect less change in irradiated, treated skin than in irradiated skin not treated with compound, and atrophy or other abnormalities in the epidermis of unirradiated, compound-treated animals.

However, as to TAme, it has been noted as having no discernible effect on unirradiated skin, but enhanced markedly neutrophilic infiltration and epidermal hyperplasia in UV-irradiated skin. Thus, TAme directly prevents an epidermal signal inducing ultraviolet radiation suppression of delayed hypersensitivity. The nature of this signal remains obscure. Possible sources include the Langerhans cell, whose functional properties appear to be altered substantially by glucocorticoids; the keratinocyte; or arachidonic acid metabolism to prostaglandin in the skin, of which the last appears to be confirmed to date. Other explanations are possible. While there is no evidence that a steroid applied after irradiation would influence photocatalyzed conversion of urocanic acid to a suppressing substance, possible effects on its release or subsequent metabolism cannot be excluded.

Cell surface antigen changes following ultraviolet radiation should lead to immune recognition of the epidermis as foreign, but ultraviolet radiation suppression of delayed hypersensitivity can prevent rejection of sunburned skin, at the risk of the long-term consequence of elevated skin tumor susceptability. The intense infiltration, hyperproliferation, and purulent crusting in the test ultraviolet radiation + TAme group may reveal the epidermal response to ultraviolet radiation damaged skin in the absence of normal immune suppression or else some ancillary effect of the steroid.

Since the infiltrate and hyperplasia were absent in the TAme only group, these were not caused by simple drug effects such as irritation. However, the response did not resemble microscopically either graft rejection or delayed hypersensitivity, in that mononuclear cels were not abundant. The polymorphonuclear infiltrate could be a response to cell breakdown products or to bacterial antigens. Conceivably, the neutrophils or irradiated epidermal cells secrete a growth factor. Gamma interferon secretion from macrophages or T-lymphocytes has been implicated in acanthotic changes during delayed hypersensitivity reactions, see Kaplan et al., Proc. Nat. Acad. Sci. USA, 83, pp 3469-3473 (1986). This data evidences acanthosis with little or no T-lymphocyte or macrophage infiltrate. In view of the above, as well as the observation that TAme at the site of application can prevent sensitization and also response to challenge in DH, it seems likely that several cutaneous mechanisms were affected by TAme, including the stimulation of helper T cells potentially responsive to UV-modified skin. It should be emphasized, however, that no glucocorticoid effects beyond the site of TAme application are detected, yet TAme abolished UV suppression of DH in unirradiated skin. The simplest explanation is that TAme prevents synthesis of a suppressor substance or its release from the irradiated skin to which TAme was applied.

The data as a whole indicate that TAme-treated epidermis was ineffective at provoking or suppressing cell-mediated immunity when untreated epidermis was effective. TAme did not cause direct toxicity nor did it affect sensitization or challenge at a distal site.

The following examples describe in detail the methods and compositions illustrative of the present invention. It will be apparent to those skilled in the art that many modifications, both of materials and methods, may be practiced without departing from the purpose and intent of this disciosure.

EXAMPLE I

Materials: Mice aged about 4 months are secured from the Rockefeller University colony established in December, 1983, from NIH Balb/CAnN stock. DN CB ( 1-chloro-2,4-dinitrobenzene) and TA ( triamcinoone acetonide) are purchased from Sigma; TAme (triamcinol one acetonide 21-oic methyl ester) is synthesized as described by Gorsline, Bradlow and Sherman [Endocrinology, 116, pp. 263-273 (1985)]. Irradiation: To handle the irradiation of mice in groups, holes 2 cm on a side are cut in a cardboard mask which is then set above a bank of two GEG15T8 high pressure Hg lamps emitting primarily at 254 nm. This lamp minimizs possible systemic effects of irradiation. 254 nm light penetrates the epidermis less deeply than sunlamp radiation, which is more commonly used to study UV supression of delayed hypersensitivity. Incident dose is 12 W/m² as measured by an acti nometrically calibrated Black Ray model J-225 shortwave UV monitor. Mice anesthetized with nembutal injected i.p., 2 mg/kg in 0.5 ml saline, are fastened gently to the mask with tape for the 30 - 40 minute exposure. The cumulative exposure, 6 J/cm² (total 24 J per mouse), is applied from below the mask to clipper-shaved skin on the lower abdomen.

Steroid treatment: Forty micrograms of TA or TAme, dissolved at a concentration of 0.2% in absolute USP ethanol, is spread over the UV-irradiated site and spread with a microliter pipette (Rainin Pipetman P-20); the same dosage being used for both compounds since they differ only by a methyl group. ( TA is used to compare results with a glucocorticoid having undesirable systemic effects).

DNCB Applications: Animals are shaved on the lower back to expose about 4 cm² skin. For experimental sensitization, 20 microliters of a 2% solution of DNCB in ethanol are applied to this shaved site. To ascertain the degree of delayed hypersensitivity; four days after the first sensitizing application, 5 microliters of DNCB freshly dissolved to 2% in ethanol are applied to the inner and outer aspects of each animal's left ear (total 200 micrograms). Ear thickness is measured just prior to this challenge and at 24 hour intervals thereafter with the aid of a dissecting microscope and a dial engineer's caliper. Histology: Abdominal skin, fixed in formalin, is embedded in paraffin; microtome sections is stained with hematoxylin-eosin.

Procedure: Male mice from a colony are caged in six groups. Three of the groups of mice are exposed to 4 kJ/m² 254 nm light; others are shaved but not irradiated. Immediately following ultraviolet exposure (day 0), mice are painted with steroid or with vehicle (ethanol) at the site of irradiation. This treatment is repeated 3 times at approximately 24 hour intervals, then discontinued. On day 5, the lower back of each animal is shaved to expose about 4 cm² skin. Animals to be sensitized are painted at this site with 1-chloro-2, 4-dinitrobenzene (DNCB) in ethanol, and this treatment is repeated 24 hours later (day 6). The test for delayed hypersensitivity response is maximal four days after the first sensitizing tratment (not shown). Day 9 is chosen to challenge for contact sensitivity by application to the left ear of 1-chloro-2,-4-dinitrobenzene in ethanol. Ear swelling is measurable on day 10, but it peaks on day 11, 48 hours following challenge.

The data for this experiment are summarized in Table I, where the average for each group of mice is shown as the ratio of left and right ear thicknesses. The average thickness of the left and right ears for most groups was 0.24 mm on day 9. The sensiti zation causes the 1-chloro-2,4-dinitrobenzene treated skin to thicken and become indurated. This response is most pronounced in the controls, the TAme only, and the ultraviolet radiation + TAme groups.

Following challenge, ears swell according to group. The swelling is accompanied by a mild erythema, and a visual estimate of the extent of the erythema and swelling correlates well with the caliper measurements: Ears of sensitized controls swell to about twice their normal thickness. Ears of unsensitized mice do not swell. The response measured here is therefore a consequence of delayed hypersensitivity rather than primary irritation, which, at higher 1-chloro-2,4-dinitrobenzene concentrations than those used here, also produces ear swelling. For instance, 1-chloro-2,4-dinitrobenzene irritation is measurable in the controls.

The ultraviolet suppression of sensitization is readily apparent when columns 3 and 4 of Table I are compared for the sensitized control and ultraviolet radiation only groups. Ultraviolet radiation on day 0 suppressed the swelling for all but one animal in which the response was delayed but about normal in magnitude. In sharp contrast, mice treated with TAme either following ultraviolet radiation or without ultraviolet radiation responded like the control mice, showing normal delayed hypersensitivity. This shows that treatment with TAme immediately following ultraviolet irradiation prevents ultraviolet radiation suppression of delayed hypersensitivity.

Mice that were treated with triamcinolone acetonide after ultraviolet radiation like those treated with triamcinolone acetonide alone on days 1-3, had ears 0.18 mm thick on day 9, about 0.06 mm thinner than those of other mice. When the right ear is taken as the baseline, the triamcinolone acetonide only group was strongly suppressed for delayed hypersensitivity. The UV + TA group exhibited a weak degree of delayed hypersensitivity comparable to that in the UV only group. Mice treated with triamcinolone acetonide 21-oic acid methyl ester but not with UV , on the other hand, exhibited normal delayed hypersensitivity. Triamcinolone acetonide gains access to the circulation and thus may act at a distance. In this experiment, triamcinolone acetonide could act at the spleen or at the skin to prevent delayed hypersensitivity. Testing for the effect of TAme on delayed hypersensitivity at the site of sensitization is as follows: On day 0, the shaved back skin of C57B1/K6S mice are painted with 1-chloro-2,4-dinitrobenzene; with TAme; or with both compounds. On day 6, the animals are tested for delayed hypersensitivity by application of 1-chloro-2,4-dinitrobenzene or of TAme + DNCB. The data obtained shows that TAme prevents delayed hypersensitivity when applied to the back at the time of sensitization and also prevents ear swelling when applied to the ear at the time of challenge.

Some animals of the experiment shown in Table I are killed on day 3 or 12 for histological examination of the UV-exposed portion of their abdominal skin. The evaluation is summarized in Table II. The skin of UV only mice on day 3 contained a diffuse dermal infiltrate, consisting of about 90% neutrophils and 10% monocytes and macrophages. The inflammatory changes were not accompanied by erythema and were in other ways characteristic of UV-exposed mouse skin [Photobiol. 37 , pp 623-631 (1983)]. The dermis of TAme-treated, UV-irradiated mice was infiltrated by polymorphonucl ear leukocytes. Macroscopically, there was induration and purulent crusting. The infiltrate persisted for at least 12 days in the TAme plus UV-treated mice, when it had subsided in the ultraviolet radiation only group. There was no apparent influx or mononuclear cells in the UV + TAme infiltrate, suggesting that the cellular immune system was unresponsive to the ultraviolet radiation damaged skin. The other striking histological finding in UV + TAme treated animals was the intense epidermal hyperplasia, accompanied by acanthosis and hyperkeratosis. In many places, the epidermal thickness exceeded 20 nucleated cells. Normal mouse belly skin is 1 - 3 nucleated cells thick. This prolonged, exaggerated response was not noted in the ultraviolet radiation only group, or in the triamcinolone acetonide 21-oic acid methyl ester only group, so it is the result of an interaction of the two treatments. The triamcinolone acetonide 21-oic acid methyl ester only group, in contrast, had a normal epidermis, accompanied by mild follicular hyperplasia.

Tabl e I

Group average ear thickness (hυndredths of a millimeter)

GROUP DAY left std right std 1/r 1-r

(test) (control)

Sensitized 9 24.2 1.3 24.4 1.4 0.99 -0.2 control 10 42.6 3.6 26.9 1.5 1.58 15.6

11 48.8 2.0 26.4 1.2 1.84 22.4

UV only 9 23.9 1.4 25 0.9 0.95 -1.0

10 32.0 1.3 28.2 1.5 1.13 3.83

11 37 2.0 30 1.7 1.23 7

TAme only 9 25.5 3.1 24.8 0.7 1.02 0.66

10 41.3 2.2 23o6 2.3 1.74 17.6

11 45.1 3.8 24.8 1.1 1.81 20.3

TA only 9 18.6 2.4 17.5 2.5 1.06 1.16

10 33.3 2 22.5 2 1.48 10.8

11 26.1 1.1 22.5 2.0 1.16 3.66

UV + TAme 9 24.7 1.3 24.5 1.2 1 e00 0.2

10 42.4 2.2 26.6 1.0 1.59 15.7

11 45.2 2.7 25 0.9 1.81 20.2

UV + TA 9 17.6 1.8 16.4 1.7 1.07 1.2

10 29.6 1.7 22.6 1.5 1.30 7

11 31.4 2.1 21.4 1.5 1.46 10

Unsensitl zed 9 25.4 0.8 25.8 2.3 0.98 -0.4 control 10 27.1 1.6 26.7 1.8 1.01 0.41

11 27.5 0.7 27.6 1.4 0.99 -0.0

TABLE II.

SUHMMARY OF HISTOLOGICAL DATA

DAY 3 DAY 12

S Tm Tta UV Tm TA TA Tm UV

+ + +

UV UV UV

INFLAMMATORY

CHANGES

Spongiosis +++ + ++

Infiltrate

Neutrophilic

Dermal ++ ++ ++

Epidermal ++ ++

Mononuclear + +

HYPERPLASTIC

CHANGES

Dermal +

Epidermal

Hyperkeratosis + + + + +++ +

Hypergranulosis + + ++ +

Acanthosis +++

ATROPHIC

CHANGES

Dermal ++

Epidermal ++

NECROSIS ++ ++ +

KEY

S = shaved control

Tm= triamcinolone acetonide 21-oic acid methyl ester TA = triamcinolone acetonide

UV = ultraviolet vadiation Example 2

Cream Formulation mg/g

Triamcinolone acetonide

21-oic acid methyl ester 0.5 Cetyl Esters Wax 20.0

Cetyl Stearyl Alcohol 100.0

Sorbitan Monostearate 25.0

P-olysorbitan 60 20.0

Cetyl Dodecanol 100.0 Propylene Glycol 100.0

Benzyl Alcohol 10.0 Purified Water To make 1g

Example 3

Cream Formulation mg/g

Triamcinolone acetonide

21-oic acid methyl ester 2.0

Stearic Acid 60.0

Propylene Glycol Monostearate 100.0

Isopropyl myristate 50.0 Propylene Glycol 100.0

Polyoxyethyl ene 20 Sorbitan Monopalmi tate 60.0

Methyl paraben 1.0

Butylparaben 4.0 Purified Water To make 1g

Example 4

Gel Formulation mg/g

Triamcinolone acetonide

21-oic acid methyl ester 1.0

Propylene Glycol 50.0 Hydroxylppropyl Cellulose 20.0 Alcohol To make 1g

Example 5

Gel Formulation mg/g

Triamcinolone acetonide

21-oic acid methyl ester 2.0 Propylene Glycol 350.0 Alcohol 350.0 Carbomer 940 20.0 Monoamylamine 2.0 Purified Water To make 1g

Example 6

Lotion Formulation mg/g

Triamincinolone acetonide 21-oic acid methyl ester 1.0 Ethyl Alcohol 400.0

Polyethylene Glycol 400 300.0 Hydroxypropyl Cellulose 5.0 Propylene Glycol To make 1g

This invention may be embodied in other forms or carried out in other ways without departing form the spirit or essential characteristics thereof. The present disclosure is therefore to be considered as in all respects illustrative and not restrictive, the scope of the invention being indicated by the appended Claims, and all changes which come within the meaning and range of equivalency are intended to be embraced therein.

INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(51) International Patent Classification 4 (11) International Publication Number: WO 88/ 073

A61K 31/58, 31/60, 31/19 A3 (43) International Publication Date : 6 October 1988 (06.10. A61K 31/405, 31/41

(21) International Application Number: PCT/US88/01036 (74) Agent: JACKSON, David, A.; Klauber & Jacks One University Plaza, Hackensack, NJ 07601 (US

(22) International Filing Date : 25 March 1988 (25.03.88)

(81) Designated States: AT (European patent), AU, BE (

(31) Priority Application Numbers: 030,764 ropean patent), CH (European patent), DE (Eu 161,542 pean patent), FR (European patent), GB (Europe patent), IT (European patent), JP, LU (European

(32) Priority Dates: 25 March 1987 (25.03.87) tent), NL (European patent), SE (European patent 29 February 1988 (29.02.88)

(33) Priority Country: US Published

With international search report

Before the expiration of the time limit for amending t

(71) Applicant: THE ROCKEFELLER UNIVERSITY [US/ claims and to be republished in the event of the receipt

US]; 1230 York Avenue, New York, NY 10021-6399 amendments. (US).

(88) Date of publication of the international search report:

(72) Inventors: ROSS, Peter, M. ; 500 East 63rd Street, New 1st December 1988 (01.12.8

York, NY 10021 (US). BRADLOW, Leon, H. ; 8625 Palo Alto St., Holliswood, NY 11423 (US).

(54) Title: PREVENTION AND TREATMENT OF THE DELETERIOUS EFFECTS OF EXPOSING SKIN TO TH SUN, AND COMPOSITIONS THEREFOR

(57) Abstract

Triamcinolone acetonide 21-ennoic acid methyl ester, other compounds affecting the arachidionic acid cascade a other known synthesis inhibitors, and topical and pharmaceutical compositions thereof are utilized in a method of treati ultraviolet radiation exposed skin to inhibit ultraviolet radiation suppresion of delayed hypersensitivity in the epiderm thereby reducing or obviating the carcinogenic effects of the sunburn. Formulations of the triamcionolone acetonide 2 ennoic acid methyl ester preferably contain about 0.005 to 1.0 percent by weight of the active ingredient.

FOR THE PURPOSES OF INFORMAHON ONLY

Codes used to identify States p arty to the PCT on the front pages ofpamphlets publishing international applications under the PCT.

AT Austria FR France ML Mali

AU Australia GA Gabon MR Mauritania

BB Barbados GB United Kingdom MW Malawi

BE Belgium HU Hungary NL Netherlands

BG Bulgaria IT Italy NO Norway

BJ Benin JP Japan RO Romania

BR Brazil KP Democratic People's Republic SD Sudan

CF Central African Republic ofKorea SE Sweden

CG Congo KR Republic ofKorea SN Senegal

CH Switzerland LI Liechtenstein SU Soviet Union

CM Cameroon LK Sri Lanka TD Chad

DE Germany, Federal Republic of LU Luxembourg TG Togo

DK Denmark MC Monaco US United States of America

FI Finland MG Madagascar

Claims

WHAT IS CLAIMED IS:

1. A method of treating individuals exposed to ultraviolet radiation to inhibit the ultraviolet radiation suppression of delayed hypersensitivity in the epidermis thereby reducing or obviating the carcinogenic effects of the ultraviolet radiation, which comprises administering topically to the affected area of an individual in need of such therapy an amount of triamcinolone acetonide 21-oic acid methyl ester effective to inhibit the ultraviolet radiation suppression of delayed hypersensitivity without systemic effect.

2. The method of Claim 1 where the amount of triamcinolone acetonide 21-oic acid methyl ester is from 0.01 mg/m² to 100 mg/m² skin surface area.

3. The method of Claim 1 where the triamcinolone acetonide 21-oic acid methyl ester is administered once daily.

4. A topical composition for the treatment of individuals exposed to ultraviolet radiation to inhibit the ultraviolet radiation suppression of delayed hypersensitivity in the epidermis thereby reducing or obviating the carcinogenic effects of the ultraviolet radiation, which comprises an amount of triamcinolone acetonide 21-oic acid methyl ester effective to inhibit the ultraviolet radiation suppression of delayed hypersensitivity in a pharmaceutically acceptable carrier.

5. A composition according to Claim 4 wherein the amount of triamcinolone acetonide 21-oic acid methyl ester is 0.005 to 1.0 percent by weight.

6. A composition according to Claim 4 wherein the amount of triamcinolone acetonide 21-oic acid methyl ester is 0.01 to 0..2 percent by weight.

7. A composition according to Claim 4 which is an ointment.

8. A composition according to Claim 4 which is a cream.

9. A composition according to Claim 4 which is a gel.

10. A composition according to Claim 4 which is a lotion.

11. A method of treating individuals exposed to ultraviolet radiation to inhibit the ultraviolet radiation suppression of delayed hypersensitivity in the epidermis thereby reducing or obviating the carcinogenic effects of the ultraviolet radiation, which comprises administering to an individual in need of such therapy an amount of a compound affecting the arachidonic acid cascade or prostaglandin synthesis effective to inhibit the ultraviolet radiation suppression of delayed hypersensitivity.

12. A method according to Claim 11 wherein the compound administered is selected from the group consisting of aspirin, ibuprofen, indomethacin, salicylic acid, phenyl butazone, sulfinpyrazon and sulindac.

13. A topical composition for the treatment of individuals exposed to ultraviolet radiation to inhibit the ultraviolet radiation suppression of delayed hypersensitivιty in the epidermis thereby reducing or obviating the carcinogenic effects of the ultraviolet radiation, which comprises an amount of a compound affecting the arachidonic acid cascade or prostaglandin synthesis effective to inhibit the ultraviolet radiation suppression of delayed hypersensitivity in a pharmaceutically acceptable carrier.

14. A composition according to Claim 13 wherein the compound administered is selected from the group consisting of aspirin, ibuprofen, indomethacin, salicylic acid, phenyl butazone, sulfinpyrazon and sulindac.

15. A method of treating individuals to inhibit the sensitization and elicitation phases in contact hypersensitivity which comprises administering to an individual in need of such therapy an amount of a compound affecting the arachidonic acid cascade or prostaglandin synthesis effective to inhibit the sensitization and elicitation phases in contact hypersensitivity.

16. A method according to Claim 15 wherein the compound administered is selected from the group consisting of aspirin, ibuprofen, indomethacin, salicylic acid, phenyl butazone, sulf inpyrazon and sulindac.

17. A method of treating individuals suffering from xeroderma pigmentosum which comprises administering to an individual in need of such therapy an amount of a compound affecting the arachidonic acid cascade or prostaglandin synthesis sufficient to inhibit the cellular response to the nascent tumor after exposure to UV radiation.

18. A method according to Claim 17 wherein the compound administered is selected from the group consisting of aspirin, ibuprofen, indomethacin, salicylic acid, phenyl butazone, sulfinpyrazon and sulindac.

19. Use of a compound for the preparation of a topical composition for the treatment of individuals exposed to ultraviolet radiation to inhibit the ultraviolet radiation suppression of delayed hypersensitivity in the epidermis thereby reducing or obviating the carcinogenic effects of the ultraviolet radiation, which compound comprises triamcinolone acetonide 21-oic acid methyl ester.

20. Use of a compound for the preparation of a topical composition for the treatment of individuals exposed to ultraviolet radiation to inhibit the ultraviolet radiation suppression of delayed hypersensitivity in the epidermis thereby reducing or obviating the carcinogenic effects of the ultraviolet radiation, which compound comprises a compound affecting the arachidonic acid cascade or prostaglandin synthesis.

21. Use according to Claim 20 wherein the compound is selected from the group consisting of aspirin, ibuprofen, indomethacin, salicylic acid, phenyl butazone, sulfinpyrazon and sulindac.