GB1581444A - Sunscreen compositions comprising aminosalicylic acids and esters - Google Patents

Description

PATENT SPECIFICATION 11 1 581 444

( 21) Application No 17533/79 ( 22) Filed 29 Mar 1977 ( 19)1 ( 62) Divided Out Of No 1581443 ( 44) Complete Specification Published 17 Dec 1980 ( 51) INT CL 3 A 61 K 7/44 U ( 52) Index at Acceptance A 5 B FE ( 72) Inventors: ALFRED HALPERN ERNEST J SASMOR ( 54) SUNSCREEN COMPOSITIONS COMPRISING AMINOSALICYLIC ACIDS AND ESTERS ( 71) We, MUNDIPHARMA A G a Swiss Corporation organised under the Laws of Switzerland, of St Alban-Vorstadt 94, Postfach, CH 4006, Basel, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following

statement: 5

This invention relates to compositions containing aminosalicyclic acid esters and to their use in achieving a sun-burn preventative action.

It is well known that rays within the ultra-violet spectrum having a wavelength of from 2950 to 3850 Angstrom units, will result in hyperpigmentation or tanning of human or animal skin through stimulation of the cells capable of producing melanin Within this 10 portion of the light spectrum it has further been determined that the wave-length of from 2950 A' to 3150 A' is particularly potent in causing an erythematous skin reaction and this wave-length range is generally referred to as the burn range" However, light rays within the range of from 3300 A O to 3850 A O are capable of causing a desirable stimulation of the tissue melanin-producing system, to result in direct tanning of skin without accompanying 15 erythema or burn It has thus become accepted that a satisfactory sun screen compound must effectively block ultra-violet light within the wave-length range of 2950 A O to 3150 A 0.

while transmitting light rays beyond the 3150 A O wave-length The filtering capacity of the ultra-violet screening agents should preferably be between 3460 A O and 3650 A O so that tanning of the skin will be accomplished without the occurrence of erythema and 20 consequent pain and suffering accompanying solar burn.

To achieve this goal literally hundreds of compounds have been proposed as sun screen agents, each described as capable of absorbing ultra-violet light within the "burn range" but transmitting the physiologically desirable and cosmetically preferred tanning rays Agents such as salicylate compounds for example benzyl salicylate; menthyl salicylate; glyceryl 25 mono salicylate: benzoic acid derivatives, for example ethyl propyl and butyl esters of para-amino benzoic acid itself: pvrimidines; sulfonic acid compounds; natural products.

such as umbilliferone and a whole range of diverse synthetic chemical agents each designed to produce a particular type screening effect within the tanning range of light have been proposed Virtually all of the compounds suggested have some limitation which restricts 30 their use For example the class of salicvlic acid derivatives as sun screen compounds are water-soluble derivatives which are readily removed by water The insoluble salicylate compounds dry to an undesirable solid on the skin to form a porous cracked film which reduces the effectiveness of the preparation as a sun screen The benzoic acid esters exert a local anaesthetic effect as well as being strong sensitizing agents and are thereby considered 35 to be physiologically undesirable The more complex organic compounds while effective for special purposes have objectionable odors and may induce a photosensitivity which is generally not reversible Moreover, it is well known that many of the sunscreen agents are capable of causing allergic reactions, requiring that the subject stop their use and seek another compound or else suffer acute distress and disability of solar burn It is for these 40 reasons that the search for new and effective sun screen compounds continues and is of necessity despite the myriad of compounds discovered and alleged to have these properties.

It has now unexpectedly been found that the C, to C,, alkyl esters: vinvl allyl.

undecenyl, oleyl and lhnolenyl esters and cyclohexyl phenyl and menthyl esters of aminosalicylic acid have beneficial ultra-violet screening properties to absorb light rays over 45 1 581 444 the wavelength of 295 ( O A to 3150 A , while transmitting rays over the wavelength beyond the 32 ( 00 A range thereby permitting desirable tanning of the skin without solar burn.

Moreover, the optimal absorption range of the aforesaid amino salicylic acid esters is such as to permit a maximal transmission over the wave-length between 3460 A and 3800 A thus preferably filtering the ultra-violet light to remove the burning rays 5 This invention therefore provides compositions other than simple solutions comprising a compound of any of the general formula H 2 NOH OH H 21 H O,,UH -10 COOR H 2 N COOR COOR (a) (b) NH 2 (C) 15 in which R represents hydrogen an alkyl group containing from 1 to 18 carbon atoms, a vinyl, allyl, undecenyl, oleyl or linolenyl group or a phenyl cyclohexyl or menthyl group, and a pharmaceutically acceptable carrier, for topical application 20 p-Aminosalicylic acid is a well known compound having a wide thereapeutic use as a tuberculostatic agent and is capable of forming metallic salts and esters which are similarly employed in tuberculosis therapy The phenyl ester of para-aminosalicylic acid is described in US Patent No 2604, 488 (issued July 22, 1952).

The compounds for use in the compositions of the present invention, include the novel 25 compounds described and claimed in our copending application No 13096/77 (Ser No.

Claims (14)

1581443) Claim I of our copending application reads in the following

terms: A compound of any of the general formulae H

2 N OH (a) 30 (a) COOR OH 35 (b) H 2 N COOR 40 OH (c) and COOR NH 2 45 NH 2 in which R represents an alkyl group containing from I to 18 carbon atoms: a vinyl, allyl, undecenyl.

olevl or linolenyl group, or a phenvl cvclohexyl or menthyl group provided that in the case 50 of formula (a) R does not represent all alkvl group containing I to 4 6 or 1 () carbon atoms.

a phenyl group or a cvclohexyl group anid in the case of formula (b), R does not represent an alkyl group containing I to 4 carbon atoms.

The alkvl and alkenivl aminosalicvlate acid ester compounds described above were found to possess unique ultraviolet screening properties by the well known spectroscopic method 55 for determining the ultra-violct absorbing capacity of the compounds A standard reference to this method is -Organic Chemistry" by H Gilman, Volume I,111 p 127 et seq John Wiley & sons New York ( 1953) In the evaluation of the ultra-violet aborption capacity of the compounds the wave-length of the balnd of the maximum absorption is the important factor in determining whether a I compound is suitable as an ultra-violet screening substance 60 A useful means of expressing the degree of light absorption is the absorption co-efficient.

The ultra-violet absorption selections are dctcrmined spectrophotometerically utilizing the conventional ultra-violet spectromneter a Cnd an appropriate solution of the compound to be tested The absorption co-efficient at the wave-length of maximum absorption designated as amax is an expression of the wave-leneth of maximumn absorption and is calculated from 65 Io St fl,IA,1 -,I1 Te

3 the following formula relationship:

I T a = log5 wherein a is the absorption co-efficient b is the thickness of the spectrophotometric cell in centimeters c is the concentration in grams per litre T is the amount of light passing through the solution and 10 To is the amount of light passing through the solvent only in the same cell.

When this test was applied to the aforesaid compounds it was found that the ultra-violet rays of the wave-length from 2950 A' to 3200 A O, which have been shown to cause solar burning, evidenced by erythema pain and skin edema, were effectively absorbed or 15 blocked, while those ultra-violet light rays within the wave-length 3300 A' and 38100 A', (established to cause a desirable and beneficial tanning of the skin) were permitted to pass.

Moreover, a preferred range of ultra-violet filtration occured between the wave-length of 3460 A' and 3800 A O, thereby selectively filtering the tanning rays from the solar burning rays in the ultra-violet spectrum It was found that the aforesaid new compounds had an 20 absorbance range of between O 6 and 1 for the noxious ultra-violet burning rays within the wave-length of from 2850 A O to 3150 A O, whereas there was virtually no absorbance of the ultra-violet rays in the wave-length between 3460 A O to 380)0 A 0.

Compositions comprising the sun screen compounds described above, may be prepared in the form of solutions, lotions, creams, ointments, wax sticks Solutions may be packaged 25 as an aerosol spray for convenience of application Whatever the dosage form selected, the concentration of the respective sun screen substance is from ( 1 5 percent to 25 percent by weight The compositions will be found to be stable and possess certain unique.

advantageous and desirable properties in preventing sunburn and causing a tanning of the skin in humans and animals 30 When it is desired to effectively screen the ultraviolet light to achieve a tanning action without solar burning, the the aforesaid preparations are applied to the skin prior to exposure to ultra-violet light in a therapeutically sufficient quantity to provide a uniform coating Both water-soluble and water-insoluble carriers may be employed, depending upon the individual preference 35 While it is known that the free acid, para-amino salicylic acid and its metal salts cause skin irritation and dermal eruptions, such allergic and skin irritant actions are notably absent for the above described alkvl and alkenvl aminosalicylic acid esters and the new compounds are singularly free from any of the aforesaid noxious skin reactions associated with p-amiinosalycvlic acid and its metal salts It was further found that when the above 40 described compounds and compositions containing the same, were applied to sun burned skin exposed to an excess amount of ultra-violet irradiation, that a soothing calmative effect occurred with a consequent rapid disappearance of local pain, tenderness and sensitivity Thus the action of the aforesaid respective active compounds and compositions containing the same is extended beyond the ultra-violet screening effect to one of causing a 45 healing action on sunburned skin as well as the skin exhibiting the effects of excess ultra-violet radiation The mechanism for this unexpected desirable dermal effect may be postulated to occur by a topical analgesic and anaesthetic action When it is desired to counteract the ervthema, pain, tenderness and other local topical dermal reactions to sunburn or excess ultra-violet irradiation, then the aforesaid active compounds and 50 compositions containing the same are applied to the affected skin site from 1 to 6 times daily An immediate cooling, soothing local response will be observed and pain and tenderness will be promptly eliminated The erythema will blanche within a reasonable period of time and be replaced by conventional tanning.

The invention w'ill now be further described with reference to the following examples, of 55 which Examples I to 7 are examples of the preparation and properties of the active ingredients for incorporation in the compositions of the present invention.

Example 1 In a suitable vessel containing I gim niol of meta-aminosailicylic acid is added 1 gm mol 60 of phenol and ( 1 5 mol of pyrophosphoric acid The mixture is stirred and auto-claved for one hour after which time it is poured into water The solid material is filtered, suspended in acetone and neutralized with sodium hydroxide to p H 6 Dilute ammonia solution is added to precipitated phenvl-m-aminosailicvlate which is separated by filtration and dried.

The white crystalline powder is phenvl-ni-aiminosilicylate melting between 1580 C and 65 s 1 JJ l

4 Q AA 101't 4 4 163 C.

In place of the meta-aminosalicylic acid described above, an equimolar quantity of ortho-aminosalicylic acid may be substituted The remainder of the steps are the same and the resultant compound is phenyl-ortho-aminosalicylate.

5 Example 2 One-tenth mol of menthyl-m-nitrosalicylate is dissolved in 250 ml of ethyl acetate and 1 ( O gms of Raney nickel added The mixture is placed in a suitable container to permit pressure hydrogenation and hydrogen gas is passed into the solution When the gas pressure reaches 10 pounds psi at 80 C, the mixture is agitated and when the absorption of hydrogen 10 has reached equilibrium, it is shaken for four hours and cooled The mixture is filtered and the menthyl-m-aminosalicylate formed is isolated by distillation and is obtained as an oily compound which distills at 126 C at 2 mm Hg Pressure.

Example 3 15 In place of the menthyl-m-nitrosalicylate of Example 2 may be substituted in equimolar portions, an appropriate alkyl nitrosalicylate ester selected from the group consisting of alkyl-ortho-nitrosalicylate compounds wherein said alkyl group is from I to 18 carbon atoms in chain length alkyl-meta-aminosalicylate compounds, wherein said alkyl group is from 1 to 18 carbon atoms in chain length and allyl-p-nitrosalicylate wherein said alkyl 20 group is from I to 18 carbon atoms in chain length The remainder of the steps are the same and the respective ortho, meta or para-amino-salicylate alkyl ester is obtained.

Example 4 One-tenth mol of an alkali metal salt of para-aminosalicylic acid as for example, 25 sodium-p-aminosalicylate potassium-p-aminosalicylate or lithium-paminosalicylate, is dissolved in 3 ( O () ml of alcohol and to this is added exactly onetenth mol of a menthyl halogen salt as for example menthvl chloride, menthyl bromide or menthvl iodide The mixture is stirred and ( O 5 gms otf fresh Iy precipitated silver hvdroxide is added as a catalyst.

The mixture is warmed to 50 ()C for a period of at least two hours, cooled to room 30 temperature and filtered The filtrate is set aside to crystallize in an ice-chest and menthyl-para-aminosalicylate is obtained as a white crystalline substance melting at 187 C.

to 189 C The compound is insoluble in water but soluble in alcohol, benzene and chloroform.

In place of the alkali metal-para-aminosalicvlate salt described above, there may be 35 substituted in equivalent molar quantities an alkali metal-orthoaminosalicylate or an alkali metal-meta-aminosalicvlate The remainder of the steps are the same and the formed compound obtained is the respective menthyl-ortho-aminosalicylate (mp 201 C 206 C) or menthvl-meta-aminosalicvlate (mp 173 (' 178 C).

40 Example 5 In place of the menthvl chloride described in Example 4, there may be substituted equimolar quantities of evclohexvl chloride cyclohexvl bromide or cyclohliexvl iodide The remainder of the steps are the same and the resultant compound formed is the respective cyclohexyl-para-amnino-salicylate cyclohexvl meta-aminosalicylate and cyclohexyl ortho 45 aminosalicylate.

A 1 CZO 1 AA A 1 581 444 Example

6 The ultra-violet filtering capacity of the respective compounds obtained from Examples 1 through 5 above, was determined with the Beckman (Registered Trade Mark) Spectrometer, in the following manner:

100 mg of the selected compound was dissolved in 100 ml of ethanol and 10 ml of this 5 solution was diluted with water to make I litre The concentration of active compound in the diluted solution is O 001 percent, by weight A one-centimeter spectrophotometeric cell is filled with the diluted solution of the selected active compound containing O 001 percent by weight of active compound and the ultra-violet spectrum of the solution is determined A solvent control or blank solution is prepared dissolving 10 ml of ethanol in I litre of 10 distilled water and the ultra-violet spectrum determined in the same manner for the blank or solvent control solution The absorption co-efficient for the respective compound is calculated from the formula:

I 1 T 15 a logbec To wherein a is the absorption co-efficient, b is the thickness of the spectrophotometeric cell in centimeters, 20 c is the concentration in grams per litre, T is the amount of light passing through the solution, and To is the amount of light passing through the solvent only in the same cell.

It will be seen that the greater the absorbance value for a particular wave-length, the less 25 light is transmitted Thus, a high absorbance value for the wave-length range of from 2950 A to 3150 A , the less will be the tendency for solar burning, whereas the converse effect is desired for the beneficial tanning wavelength range of 3460 and 3650 A wherein a low absorbance is desired The ultra-violet absorption capacity for the respective formed compounds was found to be as follows: 30 TABLE I Absorbance of Absorbance of Compound Wave-length range Wave-length range 35 ( 0.001 % conc) 2950 A -3150 A 3460 A -3650 A .

methyl-p-aminosalicylate ( O 80 O 93 nil ethyl-p-aminosailicylate O 81 O 93 nil propyl-p-aminosalicylaite ( 81 ( 91 nil 40 isopropyl-p-aminosalicylate t O 82 () 92 nil butyl-p-aminosalicvlate O ( 86 0 94 nil isobutyl-p-aminosalicylaite ( O 85 0) 91 nil amyl-p-aminosalicvlate () 87 O 97 nil hexyl-p-aminosalicylate O 83 0) 92 nil 45 septyl-p-aminosalicvlate () 81 () 89 nil octyl-p-aminosalicvlate 0) 82 () 95 nil nonyl-p-aminosalicylate ( O 87 1 00 nil decyl-p-aminosalicvlate O 82 ( O 93 nil lauryl-p-aminosalicylate O 87 1 00 nil 50 myristyl-p-aminosalicvylate O 81 ( O 97 nil cetyl-p-aminosalicylate O 82 () 98 nil stearyl-p-aminosalicylate 0) 82 ( O 97 nil 1 581 444 Absorbance of Absorbance of Compound Wave-length range Wave-length range ( 0.001 % conc) 2950 A -3150 A 3460 A -3650 A phenyl-p-aminosalicylate O 95 1 00 nil 5 cyclohexyl-p-aminosalicylate 0 93 1 00 nil menthyl-p-aminosalicylate O 98 1 00 nil methyl-m-aminosalicylate O 81 O 92 nil ethyl-m-aminosalicylate ( O 78 O 91 nil propyl-m-aminosalicylate O 79 O 89 nil 10 isopropyl-m-aminosalicylatc O 84)0 91 nil butyl-m-aminosalicylate 0 96 O 95 nil isobutyl-m-aminosalicylate O 83 O 92 nil amyl-m-aminosalicylate)88 O 98 nil hexyl-m-aminosalicylate O 80 ( O 96 nil 15 septyl-m-aminosalicylate O 83 0 94 nil octyl-m-aminosalicylate O 87 O 96 nil nonyl-m-aminosalicylate ( 86 O 97 nil decyl-m-aminosalicvlate ( O 85)0 94 nil lauryl-m-aminosalicylate 0) 85 0) 95 nil 20 myristvl-m-aminosalicylate 0) 87 O 97 nil cetyl-m-aminosalicylate () 83 O 92 nil stearyl-m-aminosalicylate ( O 84 0 94 nil phenyl-m-aminosalicylate ( O 92 O 99 nil cyclohexyl-m-aminosalicvyate ( 1 87 O 91 nil 25 menthyl-m-aminosalicylate ( O 96 1 O ( O nil methyl-o-aminosalicvlate O 83 O 91 nil ethyl-o-aminosalicy Il ate ( O 81( 1 89 nil propyl-o-aminosalicylatc ( O 84( O 92 nil isopropyl -oaminosalicylate ( O 83 O 91 nil 30 butyl-o-aminosalicvl ate () 84 ( O 92 nil isobutvl-o-aminosalicvlate O 86 0) 94 nil amyl-o-aminosalicvl aite O 84 () 91 nil hexyl-o-aminosalicvlate O 83 ( 1 93 nil septvl-o-aminosalicvlate O ( 81 O 91 nil 35 octyl-o-aminosalicy late ( O 80 (( O 94 nil nonyl-o-aminosalicv late O I 84 O 96 nil decyl-o-aminosalicx ylate ( O 87 ( O 97 nil laurvl-o-aminosalicv late ( O 83 O 92 nil myristyl-o-aminosalicvlate ( O 85 ( O 94 nil 40 cetyl-o-aminosalicv ite O 83 ( O 95 nil stearyl-o-aminosalicvlate ( O 84 O 96 nil phenyl-o-aminosalicylate ( O 93 1 ( 1)0 nil cyclohexvl-o-aminosalicvlate () 92 ( O 98 nil menthyl-o-aminosalicvlatc ( 1 O 1O ( nil 45 It will be observed that the respective compounds possess a high absorbance value within the solar burning wave-length of ultra-violet light ranging from 295 ( O A to 31501 A while permitting the beneficial tanning rays to pass virtually unaffected The range in absorption of the harmful solar burning ultra-violet rays was between ( O 6 and ( O) for aminosalicylic 50 acid and its salts, and a more complete filtering occurred with the absorbance approaching 1 ( 0, for the aminosalicvlatc esters The compounds exhibited virtually no interruption of the beneficial tanning rav S over the wave-length between 34 (( 00 A and 3800 (( A These absorbance values establish the new compounds to be effective ultraviolet screening agents 55 Example 7 To a solution of ( O 5 gin mol of alkali metal para-amtiinosalicylate salt, as for example the respective sodium potassium of lithium salts dissolved in 500 ( ml of ethanol is added ( O 5 gm mol of undecenvl chloride Thc mixture is stirred and warmed to about 6 ( 1 O 'C for at 60 least four hours The separated sodium chloridc is filtecred and the alcohol solution set aside to crystallize A white waxy solid is obtained which melts between 80 (' and 85 C and is undecenvl piara-aminllosaiclate.

In a similar mainner etuimiolar concentrations of vinyl chloride, allvl chloridce, oleyl chloride linolecnvl chloride, vinyl bromide, allyl bromide undecenyvl bromide, oleyl 65 7 1 581 444 7 bromide, linolenyl bromide, vinyl iodide, allyl iodide, undecenyl iodide, oleyl iodide or linolenyl iodide may be used in place of the undecenyl chloride described above and the respective formed alkenyl p-amino-salicylate ester is obtained.

In place of the metal-para-aminosalicylate salt described above there may be substituted in equimolar proportions a metal-meta-aminosalicylate salt or a metalortho 5 aminosalicylate salt, said metal being sodium, potassium or lithium or ammonium The remainder of the steps are the same and the respective formed alkenyl meta-aminosalicylate ester and alkenyl ortho-aminosalicylate ester described above is obtained.

When the ultra-violet absorbance is determined for the above alkenyl esters, the following values are obtained: 10 TABLE 2 Absorbance at the Absorbance at the Compound Wave-length range Wave-length range 15 ( 0.001 % conc) 2950 A -3150 A 3460 A -3651) A .

vinyl-p-aminosalicylate 0 94 1 00 nil allyl-p-aminosalivcylate O 95 1 00 nil undecenyl-p-aminosalicvlate 0) 95 1 00 nil 20 oleyl-p-aminosalicylate O 97 1 00 nil linolenyl-p-aminosalicylate O 97 1 00 nil vinyl-m-aminosalicylate 0 92 1 00 nil allyl-m-aminosalicylate O 91 1 00 nil undecenyl-m-aminosalicylate ( O 95 1 00 nil 25 oleyl-m-aminosalicylate O 95 1 00 nil linolenyl-m-aminosalicylate O 96 1 00 nil vinyl-o-aminosalicylatc O 92 1 00 nil allyl-o-aminosalicvlate O 93 1 00 () nil undecenyl-o-aminosalicvlatc O 93 1 00 nil 30 oleyl-o-aminosalicylate ( O 95 1 00 il linolenvl-o-aminosalicylate O 96 1 00 nil Example 8 35 When it is desired to utilize a solution of the appropriate sun screen compound described in Examples 1 to 6 above, then either an aqueous, alcoholic or oil solution may be used.

Aqueous solutions are prepared with waiter-soluble metallic salts of aminosalicylic acid as for example the respective acid salts The appropriate quantity ot the selected compound is dissolved in 9 ( O percent of the final desired volume of water with a concentration of active 40 sun screen compound of from () 5 percent to 25 percent by weight with a preferred concentration of from 3 percent to 110 percent by weight of sun screen compound The solution maybe clarified by treating with charcoal and filtering It may be desired to adjust the p H to Ib;etween pil 6 aind p H 8 This may be readily accomplished through the use of sodium acid phosphate or other suitable buffer agent The solution is then brought to final 45 volume and packaged into dosage form of suitable size and shape.

Alcoholic solutions are prepared in a similar manner and such alcohols as ethanols, and isopropanol are preferred as the solvent It may be found desirable to dilute the alcohol solvent with water thus forming a hvdro-alcoholic solution, in which case the concentration of water may range from equal parts of water and alcohol to 1 ( O parts of water and 9 ( O parts 50 of alcohol.

Oil solutions may be prepared bv dissolving the appropriate alkyl alkenyl or cyclic ester of ortho-aminosalicvlic acid meta-aminosalicylic acid and para-aminosalicvlic acid as described above, oir to utilize ortho meta or para aminosalicylic acid The range in concentration of either the selected aminosalicylic ester or the aminosalicylic acid as 55 described above is from ( O 5 percent to 25 percent by weight with a preferred concentration of from 3 percent to 1 ( O percent bv weight of sun screen compound.

To prepare an oil sun screen solution then the appropriate quantity of the selected cyclic, alkvl or alkenvl ester of aminosalicylic acid described above is dissolved in a suitable oily vehicle, as for example cotton-seed oil, poppy-seed oil, peanut oil, corn oil and liquid 60 petrolatum Suitable anti-oxidants and other fat preservatives as well as perfume agents may be added anda the oil solution is brought to proper volume The finished oil sun screen solution is filtered and packaged in unit containers of suitable size and shape.

1 581 444 Example 9 When it is desirable to prepare an ointment, then an oleagenous carrier such as for example, petrolatum or a hydrophylic or lipophylic emulsion ointment base, or a water-soluble ointment base may be used 5 Such ointment preparations contain from 0 5 percent to 25 percent by weight of the respective active sun screen compound described above with a preferred range in concentration of active sun screen compound of between 3 percent and 10 percent by weight Typical ointments of the types set forth above may be prepared as follows: 10 (a) Oleagenous Ointments Phenyl-para-aminosalicylate ester 10 grams Petrolatum U S P, q s 100 grams 15 Melt approximately 80 ( grams of the petrolatum, using care not to overheat The phenyl-para-aminosalicylate is added and stirred until dissolved, after which time the mixture is brought to final weight and allowed to cool to room temperature The preparation may be packaged either in the molten state or in the solidified form, in unit containers of suitable size and shape Should it be preferred to add perfume agents then 20 these are added just prior to the solidification of the molten mass.

(b) Water-in-Oil Emulsion Base Menthyl para-aminosalicylate 3 grams 25 Cholesterol 3 grams Stearvl alcohol 3 grams White wax 8 grams White petrolatum q s 1 ()1 grams 30 Melt the stearvl alcohol white wax and about 7 ( O grams of the white petrolatum, on a steam bath Add the cholesterol and stir until all have dissolved In a separate container melt about 3 grams of white petrolatum and to this add the menthyl paraaminosalicylate, stir until dissolved and add to the mixture of stearvl alcohol, white wax and petrolatum Mix well and bring to proper weight ( 1 (t 10 grams) with additional molten white petrolatum, 35 remove fronm the heat and stir until congealed.

The resultant sun screen ointment mav be utilized in the anhydrous form or mixed with water to form a water-in-oil emulsion base If it is desired to prepare the water in-oil base.

then the appropriate amliounlit of water is added before the mixture congeals and the hydrated ointment homogenized The amount of water to be included in such preparations 40 will vary with the desired degree of hardness A preferred range of hvydration for such water-in-oil emulsion bases is from 10) percent to 30) percent by weight of water.

(c) Oil-in-Water Lmalsion Base 45 Ethyl-meta-aminlosalicvlate 25 grame Cetyl alcohol 15 grams White wax 1 5 grains Propylene Glycol 10) grams Sodium laurvl sulfate 2 grams 50 Water, q s 1))} grams Melt the cetvl alcohol and white wax with half the weight of propylene glycol avoiding heating above 61) C' To the remainder of the propylene glycol add the ethyl-metaaminosalicvlate and stir until a hoimogenous mixture is obtained the propylene glycol 55 solution of the selected sun screen compound is added to the molten cetvl alcohol-white wax mixture and stirred well Dissolve the sodium laurvl sulfate in about 45 grams of water with the aid of heat avoiding temperature above 60 ()C Slowly add the oil phase to the water phase with rapid stirring while mailntaining L the heat After about five minutes of rapid stirring bring to proper W eight with additional warm water and stir until concealed 60 The oil-in-water iemulsion sun screen CCI ointment is then milled or homogenized and packaged into suitable unit containiers.

A sun screen vanishing cream nimav also be prepared by mixing the selected active compound with a pha-rmiaceutically acceptable vanishing cream carrier T Ihus 1 5 percent by weight of cvclohexvl-orthio-aiiinlosalicvlite is aldded to a sufficient quantity of cold cream 65 1 581 444 8.

1 581 444 and the mixture levigated until a uniform preparation results.

(d) Water-soluble ointment bases A typical water-soluble sun screen ointment is as follows: 5 Selected aminosalicylate sun screen agent 100 grams Polyethylene glycol-40 ()0 50 ( O grams Polyethylene glycol-4000 600 grams 10 Heat the two glycol ingredients (on a water bath) to about 60 C remove from the heat and stir Add the selective active compound to the base before it hardens and stir to obtain a uniform mixture.

A firmer ointment preparation may be made by replacing a portion of the polyethylene glycol-400 with polyethylene-glycol-4000 Between 5 percent and 25 percent of water may 15 be incorporated into the base, in which event approximately 10 percent of the weight of polyethylene glycol-4000 () utilized is replaced with an equal weight of stearyl alcohol.

It may be found desirable to utilize other polyethylene glycol compounds in preparing the base, as for example a polyethylene glycol compound having a molecular weight of between 200 and 800, in place of the polyethylene glycol-400 and a polyethylene glycol compound 20 having a molecular weight of between 1,000 and 6,000 in place of the polyethylene glycol-4000 Such modification of the formula will result in different degrees of ointment firmness for the finished preparation but will influence only its cosmetic properties and not its sun screen capacity.

In place of any of the active sun screen agents used as described above there may be 25 substituted any of the compounds described above in a concentration of selected active sun screen compound ranging from O 5 percent to 25 percent by weight Appropriate adjustment in the amount of ointment base is made for the increased or decreased concentration of active compound The ointment base formulations described above are only intended to illustrate the class of ointment compositions pharmaceutically acceptable 30 to prepare the new sun screen preparations and other ointment bases of the oleagenous type, water-in-oil emulsion bases, oil-in-water emulsion bases and watersoluble ointment bases may be used interchangeably without affecting the sun screen properties of the resultant composition.

35 Example 1 () Lotions are liquid suspensions or dispersons intended for external applications to the body and are prepared by triturating the ingredients to a smooth paste with a portion of the liquid phase and then adding the remainder of the liquid High speed mixers and homogenizers are used to obtain a uniform dispersion An example of sun screen lotions 40 comprising the aforesaid active sun screen compound described above and a lotion-vehicle.

is as follows:

Phenyl-para- laminosalic Vlate 5 cgirams Glycerin 2 grams 45 H;ydr'ated micr-oclrystailliine cellulose 2 grams Carboxw methyl cellulose 2 grams Rose-water q s 10)() rams The phenyl-aminosalicylate is mixed with glycerin, hydrated microcrystalline cellulose and 50 about 20 ml of rose-water to prepare a smooth paste The carboxy methyl cellulose is separately added to 20 i ml of rose-water and warmed until uniform dispersion results and the whole is added to the paste preparedl earlier The mixture is stirred rapidly while adding sufficient rose-water to bring to final volume.

In place of the glycerin described above there may be substituted any aqueous vehicle as 55 for example, distiled water a hydroalcoholic solution containing from 60 to 8 (I parts of water and 20 to 40 parts of alcohol, pharamaceutically acceptable aromatic water or mixtures of these.

In place of the glycerin described above there may be added propylene glycol and/or a liquid polyethylene glycol having a molcular weight of from 20 ()1) to 800 in either the same 60 concentration or a varying concentration of between I percent and 5 percenit by weight.

Example 11 Should it be desired to prepare a wax-stick sun screen preparation then this may be prepared by combining the selected sun screen compound as described in Examples I to 7 65 101580441 above in concentration of from O 5 percent to 25 percent by weight with a preferred concentration of 3 percent to 1 () percent by weight in a suitable waxbase which is then shaped into a rod and cut into desired size A suitable base for this purpose is as follows:

White-wax 3 parts 5 Spermaceti 3 parts Cetyl alcohol 3 parts White Petrolatum 5 parts Melt the ingredients on a water bath while stirring, and remove from heat The appropriate 10 quantity of the selected sun screen agent described above is then incorporated into the molten mixture and stirred and the whole poured into a suitable mold and allowed to congeal into sticks of proper size and shape.

Such screen wax-sticks are useful to protect the lips and the eyelids against solar burning.

It has the particular advantage of permitting spot application to an area without spreading 15 Example 12 When it is desired to block the noxious solar burning rays or to prevent ultra-violet burning, then any of the compounds described above or compositions containing the same, is applied to the skin surface of a human or an animal prior to exposure of the skin surface 20 to either sunlight or ultra-violet light The ultra-violet screen is applied in sufficient quantity to provide continuous skin surface film of at least O 1 mm thick with a preferred thicknessof said surface film being () 3 mm and)0 5 mm The pressure of the skin surface film containing the new sun screen filtering compound will effectively protect the treated area against solar burning while permitting the beneficial and desirable tanning ultra-violet rays 25 to pass through The frequency of application of the sun screen protective composition will depend upon its removal from the external surface by bathing or other means, and the preparation may be reapplied whenever required.

After exposure of the skin of humans or animals which have been previously treated with the above described sun screen compounds or pharma Iceutical compositions containing the 30 same to ultra-violet light or solar irradiation a rapid tanning effect will be observed without intervening solar burning and its consequent distress and injury The above described sun screen compounds and the pharmaceutical compositions containing the same nonirradiating and non-sensitizing to human and animal skin and will not cause skin eruptions.

35 Example 13 When it is desired to soothe or allay the pain and distress accompanying sunburn then suitable pharimaceutical co 1 mpositions containing any of the active ingredients described above may be applied to the affected surface from 1 to 4 times daily Although the pharmaceutical compositions described above exert an equal beneficial effect to a 40 sunburned area, ointments are a preferred dosage form to cover the larger areas of the body surface while the aqueous lotion is preferred to treat a blistered area Alter appropriate application of the above described composition to the affected skin surface area of humans andal animals, a prompt soothing action results with relief of pain, tenderness and local distress The skin edemlia of the solar burn is reduced and the erythema will blanch to be 45 replaced by a desired beneficial tan.

WHAT WE CLAIM IS:1 A composition for topical application other than a simple solution comprising a compound of any of the ceneral formulae:

H 2 N OH COOR (a) OH H 2 N COOR (b) 1 581 444 1 581 444 OH | COOR NH 2 (c) in which R represents hydrogen, an alkyl group containing from 1 to 18 carbon atoms; an vinyl, allyl, 10 undecenyl, oleyl or linolenyl group, or a phenyl, cyclohexyl or menthyl group, and a pharmaceutically acceptable carrier.

2 A composition as claimed in claim 1 which contains from O 5 to 25 % by weight of the compound of formula (a), (b) or (c).

3 A composition as claimed in claim 1 or claim 2 which contains phenylmeta 15 aminosalicylate or menthyl para-amino-salicylate.

4 A composition as claimed in any of claims 1 to 3 in which the carrier is a lotion vehicle.

A composition as claimed in any of claims 1 to 3 in which the carrier is an ointment base carrier 20 6 A composition as claimed in any of claims 1 to 3 in which the carrier is a solid wax-stick carrier.

7 A composition as claimed in any of claims 1 to 3 which the carrier is an aqueous, alcoholic or oil solution.

8 A composition as claimed in claim I substantially as herein described with reference 25 to the examples.

9 A process for the preparation of a composition as claimed in any of claims I to 8 which comprises mixing together the compound of formula (a) (b) or (c) and the pharmaceutically acceptable carrier.

10 A method of preventing solar burning in human or animal which comprises applying 30 to the skin of said human or animal a composition as claimed in any of claims I to 8 prior to exposing the skin to solar radiation.

11 A non-human animal which has been treated by a method as claimed in claim 10.

12 A method of treating an ultra-violet radiation dermal burn in a nonhuman animal comprising applying said ultra-violet burned area a composition as claimed in any of claims 35 1 to 8.

13 A method as claimed in claim 12 in which the composition is applied between one and six times daily.

14 A method as claimed in claim 13 substantially as herein described with reference to the Examples 40 ELKINGTON AND FIFE.

Chartered Patent Agents.

52-54 High Holborn, London W C 1 45 Agents for the Applicants.

Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon, Surrey, 1980.

Published by The Patent Office, 25 Southampton Buildings, London, WC 2 A l AY,from which copies may be obtained.

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