Note: Descriptions are shown in the official language in which they were submitted.
~34~6
This application is directed to the preparation
of ce~tain aminosalicylic acid derivatives and the derivatives
D so produced. Divisional application S. N. 3~/~ 7~ filed
~ ~'C Jo~ /9~o is directed to pharmaceutical preparations
containing other aminosalicylic acid derivatives.
This invention relates to a ~ethod for the use
of certain aminosalicylic acid derivatives and compositions con-
taining the same to achieve a sunburn preventative action. In
particular it is concerned with the ultra-violet screening acti-
vity of alkyl esters of aminosalicylic acid, said alkyl group being
1~3486
¦¦from ~ to 8 carbon atoms in cbain length; alkenyL est~rs of aminosalicylic aci~i
2 ¦said alkenyl group selected from the group consisting of vinyl, allyl, undecenyl
¦oleyl and linolenyl groups, and cyclic esters of aminosalicylic acid, said cyclic~
¦group being hexyl, phenyl and menthyl groups as ultra-violet screening agents. j
S IIS is also intended todescribe pharmaceutical compositions such as wax-sticks, I
6 ¦ointments, lotions and solutions containing the aforesaid compounds and the use~
7 ¦ of said pharmaceutical compounds in achieving a tanning action on the skin of
¦ humans and animals, but without accompanying solar burn.
9 ¦ It is well known that rays within the ultra-violet spectrum, hav-
¦ing a wave-length of from 2950 to 3850 Angstrom units, will result in a hyper~
Il ¦ pigmentation or tanning of human or animal skin through a stimulation of the
12 ¦ cells capable of producing melanin. Within this portion of the light spectrum
13 ¦ it has further been determined that the wave-length of between 2950 A. to
14 ¦ 3150 ~ are particularly potent in causing an erythematous skin reaction and
~5 ¦ this range in wave-length o' llght is generally referred to as the "burn range".
16 ¦ However, the light rays within the range of from 3300 A, to 3850 ~. are cap- ¦
17 able of causing a desirablc stimulation of the tissue melanin-producing system ¦
~8 to result in direct tanning of skin without accompanying erythema or burn.
1~ ¦ ~hus it has become acceptcd that a satisfactory sun scrcen compound must¦ effectively block ultra-violet light within the wave-length range of 2950 A. to
21 ¦ 3150 A. while transmitting the light rays beyond the 3150 A. wave-length.
22 ¦ Preferably, the filtering capacity of the ultra-violet screening agent should be
23 ¦ between 34O0 ~. and 3650 ~. so that tanning of the skin will be accon1plished
24 ¦ ~vithout the occurrc1lce of erythc-na and consequcnt pain and suffcring accom-
panying solar burn.
26 ¦ Io achieve this goal, literally hundreds of compounds have been
27 ¦ proposed as sun screen agents, cach described as cal~ab1e of ab~;orbin~ ultra-
28 ¦ violet li~ht vithin the "burn range ' but transrnittin~,l the ph~siologically clcsir-
29 ¦ able ancl cosmc~ically prcferre~1 tanning r2ys. '~or c~;alnnlc, such ~gcllts as
30 sli ~1atc corlpounds, Lo illclude, ;~cn7yl ~iallC~ t~ mnthyl s.~Licyl~te,
1~1348~ ~
¦ glyceryl mono salicylate; ben~,oic acid derivatives, to inclu~e ethyl, propyl an~
2 I butyl esters of para-ar~ino benzoic acid and even para-amino benzoic acid it-
3 ¦ self; pyrimidines, sulfonic acid compounds, natural products, such as umbil-
¦ liferone and a whole host of diverse synthetic chemical agents each designed to
S I produce a particular type screening effect within the tanning range of light.
¦ Virtually all of the compounds suggested have some limitation to restrict their
7 ¦ use. For example, the class of saliyclic acid derivatives as sun screen com-
B ¦ pounds are water-soluble derivatives which are readily removed by water.
9 ¦ ~he insoluble salicylate compounds dry to an undesirable solid on the skin to
10 ¦ form a porous, cracked film to reduce the effectiveness of the preparation as a
¦ sun screen. 'rhe benzoic acid esters exert a local anaesthetic effect as well as
12 I being strong sensitizing agents thereby being considered physiologically unde-
13 ¦ sirable. The more complex organic compounds, while effective for special
1~ ¦ purposes, have objectionable odors and may induce a photo-sensitivity which i
IS ¦ generally not reversible. Moreover, it is well kno~vn that many of the sun-
16 ¦ screen agents are capable of causing allergic reactions requiring that the sub-
17 ¦ jcct stop their use and seek another compound or else suffcr acute distress anc
18 ¦ disability of solar burn. It is for these rcasons that the search for new and
19 ¦ e~fective sun screen compounds continues and is of necessity despite the my-
20 riad of compounds discovered and allegecl to have these properties.
21 It was unexpectedly found that certain alkyl esters of amino-
22 salicylic acid, said alkyl group being from 1 to 18 carbon atoms in chain lengt~ ;
23 alkenly esters of aminosalicylic acid, said alkenyl group selected from the
24 group consistinL~ of vinyl, allyl, un(lecenyl, olcyl an~l linolenyl groups, and,
2s cycl;c csters of aminosL~ ylic aci(1, said cycli~ group l~eing ~le~tecl fro~n the
26 group consisting of cyclohexyl, phenyl and menthyl groups,have beneficial
27 ultra-violet scrcening properties to absorb li~ht r.~ s over thc wavc-lcngt1l of
2~ 1 2950 ~. to 3150 l~ hile transmittina rays over Lhe wave-lcngth beyond
the 3200 A. ran~e, therchy ,~crlrlitti1lg a desiral~lc tallllingT of the skin without
30 ¦ sola r burn. Morcover, thc op~ir~1al zbsorptior. .-nge of the zforcsaid ar~1ino
3 _
1~134~36
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.
Throughout this specification, the nomenclature relating to
aminosalicylic acid is based on the carbon atom to which the carboxylic acid
group is attached as being the 1 position with the hydroxyl group in the
2 position. The nomenclature meta~aminosalicylic acid refers to the
compound 5-aminosalicylic acid.
p-Aminosalicylic acid is a well kno~m compound having a wide
therapeutic use as a tuberculostatic agent and is capable of forming metallic
salts and esters which are similarly employed in tuberculoses therapy. The
phenyl ester of para-aminosalicylic acid is described in U.S. Patent No.
2,604,488 (issued July 22, 1952).
The esters of aminosalicylic acid may be prepared by the reduc-
tion of the corresponding nitrosalicylic acid ester, dissolved in ethyl acetate,
using Raney nickel as a catalyst and hydrogen under pressure. The resultant
yield of the respective aminosalicylic acid ester is excellent and the respec-
tive compounds are obtained as oils or white crystalline substances and may
be purified by distillation under reduced pressure or crystallization. The
respective esters of aminosalicylic acid are insoluble in water but soluble
in alcohols acetone, benzene, chloroform and vegetable oils.
~ len an alkyl or alkenyl ester of aminosa]icylic acid is desired
then these may be prepared from either the alkyl-ortho-meta (5-) or para-
nitro-salicylate, said alkyl or alkenyl group may range from 1 to 18 carbon
atoms in chain length. The resultant alkyl aminosalicylate, wherein said
alkyl group has from 1 to 18 carbon atoms in chain length may be purified by
distillation in vacuum (below 2 mm. Hg. pressure) or by crystallization.
Those esters wherein the alkyl or a]kenyl group is between 1 to
6 carbon atoms in chain length are oi]y or waxy in character and distill over
the temperature range of below 180 C at 2 mm. Hg. Those esters in which
said alkyl group is from 6 to 18 carbon atoms in chain length are obtained as
-- 4 --
,~
~13486
solids, crystallized fro~ alcohol-water solution. The solid aminosalicylate
esters are white crystalline or waxy substances, insoluble in water but soluble
in the usual fatty solvents and alcohol.
- 4a -
.
1~1348~; 'I
The alkyl and alkenyl aminosalicylic acid ester compounds de-
2 scribed above were fous d to possess unique ultra-violet screening properties
by the well known spectroscopic method for determining the ultra-violet absorb~
~' ing capacity of the compound. A standard reference to this method is "Organic¦
Chemistry" by H. Gillnan, Volume III, p. lZ7, et. seq., John Wiley and Sorls,
6 1 New York, (1953). In the evaluation of tlle ultra-violet absorption capacity of
7 ¦ the compounds, the wave-length of the band of the ma~imusn absorption is the8 ¦ important factor in determining whether a compound is suitable as an ultra-
9 ~iolet screening substance. A useful means of expressing .he degree of light
o absorption is the absorption co-efficient. The ultra-violet absorption selec-
tions are determined spectropho ~meterically utilizing the conventional ultra-
~2 ¦ violet spectrometer and an appropriate solution of the compound to be tested.
l3 ¦ The absorption co-efficient at the wave-lengtll of maximum absorption designa-j
I,,s I ted as a ma.Y is an expression of the wave-length of maximum absorption and is
15 ¦ c~lculated from the following formula relationship:
16 ¦ a = ~ ~clog rO
17 ¦ wherein a is the absorption co-efficient
13 ¦ b is the thickness of the spectrophotonletric cell in centimeters
19 c is the concentration in grams per liter
T is the ~rrsount of light passing through solution
21 To is t's~e amount of liaht passing througll the solvent only
2t in the same cell.
23 When this test was applicd to thc aforesaicl compounds, it was
2~ ouncl that t}lC ultra-violct rays of the ~vave-length flolll 2'J~() ~. to 3200 ~.,
2s wllich have been sho-vn to cause solar burning, evidenced by erythema, pain26 and skin edenla, were effectively absorbeci or blocked, ~vhile those ultra-violet
27 ~ light rays within thc ~vavc-lcngt}l of bet~Yeen 3300 AC'. and 3800 ~. (establishc-
28 l cause a desirable ancl l~cnelicial tanrincr of the ski~ vcrc pcrmittcd to pass.
i9 l I~.~Ioreover, a prefcrred rangc of ultra-violc~t filtraLios~ occurccl betwccn lhe
;ave-lcllgt}l o 3-'6() /~. assd 3~00 ~"., t}~ercby selcctivcly filtcrisl~ thc t slni
5_
'11 1~1348~;
I . I
I rays from the solar burning rays in the ultra-violet spectrum. It was found
¦ that the aforesaid ne~ compounds had an absorbance ranC~e of bet~veen 0. 6 and
3 1 1 for the noxious ultra-violet burning rays ~.ithin the wave-length of from
¦ 2850 A. to 3150 A., whereas there was virtually no absorbance of the ultra-
¦ violet rays in the wave-lengt~l between 3460 A. to 3800 A.
6 ¦ Compositions comprising the sun screen compounds described
'~ I above, may be prepared in the form of solutions, lotior.s, crearns, ointments,
¦ wax-sticks. Solutions may be packaged as an aerosol spray for convenience
9 1 of application. Whatever the dosage form selected, the concentration of the
10 ¦ respective sun screen substance is from 0. 5 percent to 25 percent by weight.
11 ¦ 'rhe compositions ~vill be found to be stable and possess certain unique, advan-
12 ¦ tageous and desirabl.~ properties in pre~enting sunburn and causing a tanning
13 ¦ of the skin in humans and animals.
I ~en it is desired to effectively screen the ultra-violet light to
¦ achieve a tanning action without solar burning, then the aforesaid preparaticns
26 ¦ are applied to the skin prior to exposure tG ultra-violct light in a therapeuti-
17 ¦ cally sufficient quantity to provide a uniform coating. Both water-soluble ancl
18 ¦ water-inso]ublc carriers rllay bc ernployccl, clepending upon the incliviclual prc-
19 ¦ ference.
20 ¦ While it is known that tllc free acid, para-amino salicylic acicl
21 ¦ and its metal salts cause skin irritation and der~nal cruptions, such allergic
Z2 ¦ and skin irritant actions are notably absent for the above dcscribed alkyl and
23 alkenyl aminosalicylic a(-id cstcrs and tht new cornpou~ds arc singt1larl~/ free
~4 1 fron~ any of thc aforcsai(l no:ci(~lls s!~in l-C;~ ctions associ.ltcd witll p-arninoiali
2s ¦ cylic acid and its metal sall;s. It ~vas lurt~ler found ~hat when the above des- i
26 ¦ cribed compounds and cornpositiol1s containing the sarneJ were applieù to sun-
27 1 h~lrnecl skin or sl;in cxposcd to an excess al-llount of ultra-violct irracliation,
23 that a sootlling, c1~ aliYe cftcct occllrrc(l ~ith a collsc~lucnt ral)i(l C~i5appCal--
29 ! arl~oflocail)aiil tt;~ erlcssln(lscns itiVIt,~. ~~nllsti~ aC~iOllOtt]~; fc~rcslil
~o rcs[~cctiv. ac.iv~ (:on-ll,clu~ ds a;l(l co~ c)sitioils COn'~ il'' thc .'janl~ tcn-lc~.
~ - t~ _
l l
1~134S~ ¦
~beyond the ultra-vioiet screening effect to one of causing a healing action on
2 ¦ sunburnecl skin as well as the skin exhibiting the efects of eYcess ultra-~iolet
¦ radiation. Ihe mechanism for this unexpected desirable dermal effcct may be
4 ¦ postulated to occur by a topical analgesic and anaesthetic action. When it is
5 ¦ desired to counteract the erythema, pain, tenderness and other loc~l topica
6 dermal reactions to sunburn or excess ultra-violet irradiation, then the afore-
7 said active compounds and compositions containing the same, are applied to th
¦affected skin site from l to 6 times daily. An imrnediate cooling, soothing lo-9 1 cal response will be observed and pain and tenderness will be promptly elimi-
¦ nated. The erythema ~ill blanche within a reasonable period of tinle and be re~
Il ¦ placed by conventional tanning.
12 ¦ The following examples illustrate the scope of the present inven13 ¦ tion but it is not intended to limit the invention thereby.
14
5 r EX~MPLE
~6 ~ ~ In a suitable vessel containing l gm. mol of ~-a~lino alicyli-~
17 I acid is added l gm. mol of phenol and 0. 5 mol of tetraphosphoric acid, The13 ~ mixture is stirred and auto-claved for one hour aIl;er which time it is poured
19 1 into water. The solid rnaterial is filtered, suspellded in acetone and ncutral-
20 ¦ ized with sodium hyclro.~ide to pll 6. Dilute amlnonia solution is added to pre-
21 ¦ cipitate phenyl-p-aminosalicylate which is separated by filtration and dried.
l p hen~J-~ I
22 1 The white crystalline po~vder is pllcnyl--1n--aminosalicylate, melting bet~ een
23 ¦ l58C and 163C.
24 ¦ In place of the m~-amil1osalic~ylic acicl dcscribecl ~ove, therc
25 may be substituted an equimolar q.lantity of ortho-alninosalicylic acid. ~he
26 ~ remainder of the steps beit~ the same and the r esultant colnpound is the re-
27 spcctive phc-~nyl-ortho-~n~ osalicylate.
28
30 1
1~ ~ 7 ~
1'~ 1348~
EXAMPLE 2
One-tenth mol of methyl-5-nitrosalicylate is dissolved in
250 ml. of ethyl acetate and 10 gms. of Raney nickel added. The mix-
ture is placed in a suitable container to permit pressure hydrogena-
tion and hydrogen gas is passed into the solution. When the gas
pressure reaches 10 pounds psi. at 80C., the mixture is agitated and
when the absorption of hydrogen has reached equilibrium, it is shaken
for four hours and cooled. The mixture is filtered and the formed
methyl-5-aminosalicylate is isolated by distillation and is obtained
as an oily compound which distills at 126C. at 2 mm. Hg. pressure.
EXAMPLE 3
In place of the methyl-5-nitrosalicylate of Example 2 there
may be substituted in equimolar portions, an appropriate alkyl-nitro-
salicylate ester selected from the group consisting of alkyl-ortho-
nitrosalicylate compounds wherein said alkyl group is from 1 to 18
carbon atoms in chain length, alkyl-5-nitrosalicylate compounds,
wherein said alkyl group is from 2 to 18 carbon atoms in chain length
and alkyl-p-nitrosalicylate wherein said alkyl group is from 1 to 18
carbon atoms in chain length. The remainder of the steps are the
same and the respective ortho, 5- or para-aminosalicylate alkyl ester
is obtained.
EXAMPLE 4
One-tenth mol of an alkali metal salt of para-aminosalicylic
acid as for example, sodium-p-aminosalicylate, potassium-p-amino-
salicylate or lithium-p-aminosalicylate, is dissolved in 300 ml. of
alcohol and to this is added exactly one-tenth mol of a menthyl halo-
gen salt as for example, menthyl chloride, menthyl bromide or menthyl
iodide. The mixture is stirred and 0.5 gms. of freshly precipitated
silver hydroxide is added as a catalyst. The mixture is warmed to
50C. for a period of at least two hours, cooled to room temperature
and filtered. The filtrate is set aside to crystallize in an ice-
chest and menthyl-para-aminosalicylate is obtained as a white
- 8 -
1~13~
crystalline substance melting at 187C. to 189C. The compound is
insoluble in water but soluble in alcohol, benzene and chloroform.
In place of the alkali metal-para-aminosalicylate salt de-
scribed above, there may be substituted in equivalent molar quan-
tities, an alkali metal-ortho-aminosalicylate or an alkali metal-5-
aminosalicylate. The remainder of the steps being the same and the
formed compound obtained is the respective menthyl-ortho-amino-
salicylate (mp. 201C. - 206C.) or menthyl-5-aminosalicylate (mp.
173C. - 178C.).
EXAMPLE 5
In place of the menthyl chloride described in Example 4,
there may be substituted equimolar quantities of cyclohexyl chloride,
cyclohexyl bromide or cyclohexyl iodide. The remainder of the steps
being the same and the resultant compound formed is the respective
cyclohexyl-para-aminosalicylate, cyclohexyl 5-aminosalicylate and cy-
clohexyl ortho-aminosalicylate.
EXAMPLE 6
The ultra-violet filtering capacity of the respective com-
pounds obtained from Example 1 through 5 above, was determined with
the Bec~man Spectrometer, in the following manner:
One-hundred mg. of the selected compound was dissolved in
100 ml. of ethanol and 10 ml. of this solution was diluted with water
to make 1 liter. The concentration of active compound in the diluted
solution is 0.001 percent, by weight. A one-centimeter spectrophoto-
metric cell is filled with the diluted solution of the selected ac-
tive compound containing 0.001 percent by weight of active compound
and the ultra-violet spectrum of the solution is determined. A sol-
vent control or blank solution is prepared by dissolving 10 ml. of
ethanol in 1 liter of distilled water and the ultra-violet spectrum
determined in the same manner for the blank or solvent control solu-
tion. The absorption coefficient
15 ~348~; 1
for the respective compound is calculated from the formula: I
2a = ~ ~c log ~T~ ,
wherein a is the absorption co-efficient
b is the thickness of the spectrophotometric cell in centimeters
c is the concentration in grams per liter
T is the amount of light passing throu~h solution
7 To is the amount of light passing tllroug'n the solvent onLy
8 in the same cell.
It will be seen that the ~reatcr the absorbance value for a parti-
~4 cular wave-length, the lcss light is transnlitted. Thus, a high absorbance
~1value for the wave-length range of from 2950 A. to 3150 A., the less ~ill bc
12 the tendency for sol2r burning, ~vhereas the converse effect is de.sircd for the
13bencficial tanning ~.vave-length ran,e of from 3~i60 A. to 3800 A,, and in par-
14¦ ticular thc range of 3460 ~. and 36S0 A., whercin a lo~l~ absorballcc is de-
15 ¦ sired. lhe ultra-violet absorption capacity for thc rcspective formed coln-
l6 pounds was found to be as follo~,vs:
17T~P,LE 1
18Filtcrin~ Capacity o~ Ccrtairl ~minosalicylic Acicl Estcrs
19~bsorbancc ~,orbance of
Compound Wavc-len~tll ranL~c Vave-lcngth rangc
(0. 001 % conc. ) 2950 A. -3150 ~. 34(~0 ^.. -~650 A.
21 mcthyl-p-aininosalicyl~te 0. <S0 - 0. 93 nil
2t ethyl-p-aminosalicylatc 0.81 - 0.93 nil
23 propyl-p-aminosalicylate 0. 81 - 0. 91 nil
2~ isoI)ropyl-~-anlinoc;cllicylate 0. &2 - 0. 92 nil
2s bu tyl -p-~minosalicylatc 0. 8~ 0 . 94 nil
26 isobutyl-p-arninosalicy]atc 0. 85 - 0. 91 nil
27 lanlyl-p-aminQsalicylate 0. 87 - 0. 97 nil
29 hc~;yl-I)-anli~o ali(~yl~.te (). &:3 - 0. 9Z nil
2~ scptyl-p-;~ninos;1Licylatc G. 81 - 0. Q,9 nil
3D o(:ty~ oc;~ Jl.^~t~;~ O, ~?,2 - ~ 5
1~ ,
1~13486
Absorbance of Absorbance of
Compound Wave-length range Wave-length range
(0.001% eone.) 2950 A. - 3150 A. 3460 A. - 3650 A.
nonyl-p-aminosalicylate 0.87 - 1.00 nil
cecyl-p-aminosalicylate 0.82 - 0.93 nil
lauryl-p-aminosalicylate 0.87 - 1.00 nil
myristyl-p-aminosalicylate 0.81 - 0.97 nil
cetyl-p-aminosalicylate 0.82 - 0.98 nil
stearyl-p-aminosalicylate 0.82 - 0.97 nil
phenyl-p-aminosalieylate O.9S - 1.00 nil
cyclohexyl-p-aminosalicylate 0.93 - 1.00 nil
menthyl-p-aminosalicylate 0.98 - 1.00 nil
methyl-5-aminosalicylate 0.81 - 0.92 nil
ethyl-5-aminosalicylate 0.78 - 0.91 nil
propyl-5-aminosalicylate 0.79 - 0.89 nil
isopropyl-5-aminosalicylate 0.84 - 0.91 nil
butyl-5-aminosalicylate 0.86 - 0.95 nil
isobutyl-5-aminosalicylate 0.83 - 0.92 nil
amyl-S-aminosalicylate 0.88 - 0.98 nil
hexyl-5-aminosalicylate 0.80 - 0.96 nil
septyl-5-aminosalicylate 0.83 - 0.94 nil
octyl-5-aminosalicylate 0.87 - 0.96 nil
nonyl-S-aminosalicylate 0.86 - 0.97 nil
decyl-S-aminosalieylate 0.85 - 0.94 nil
lauryl-5-aminosalicylate 0.85 - O.9S nil
myristyl-5-aminosalicylate 0.87 - 0.97 nil
cetyl-5-aminosalicylate 0.83 - 0.92 nil
stearyl-5-aminosalicylate 0.84 - 0.94 nil
phenyl-5-aminosalicylate 0.92 - 0.99 nil
cyclohexyl-5-aminosalicylate 0.87 - 0.91 nil
menthyl-S-aminosalicylate 0.96 - 1.00 nil
1~134~6
Absorbance ofAbsorbance of
Comp~und Wave-len~th range Wave-length range
2 (- 001o conc. ) 2950 ~c. 3150 A. 3~oO A. -3650 A
I __ .
3 Imethyl -o -amino salicylate 0. 8 3 - 0 . 91 nil
4 ¦ethyl-o-aminosalicylate 0. 81 - 0. 89nil
¦propyl-o-aminosalicylate 0. 84 - 0. 92nil
6 ¦isopropyl-o-aminosalicylate 0.83 - 0.91 nil
7 ¦bk"yl_o-amillosal cylate 0. 84 - 0. 92nil
¦isobutyl-o-aminosalicylate 0. 86 - 0. 94nil
9 ¦amyl-o_aminosalicylate ~. 84 - 0. 91nil
lo ¦hexyl-o-aminosalicylate 0. 83 - 0. 93nil
ll ¦ septyl-o-ar~inosalicylate 0.81 - 0.91 nil
t2 ¦ octyl-o-aminosalicylate 0. 80 - 0. 9~nil
13 ¦nonyi-o~aminosalicylatc 0. 84 - 0. 9~nil
1~ ¦ dccyl-o-aminosalicylate 0. 87 - 0.97 nil
lS ¦ la~yl-o-aminosalicylate 0. 83 - 0. 92nil
16 ¦ myristyl-o-aminosalicylate 0. 85 - 0. 94 nil
17 ¦ cetyl-o-aminosalicylatc 0. 83 - 0.9S nil
1~ ¦ stearyl-o-arninosalicylatc 0. 8~ - 0. 96 ril
19 ¦ ~ enyl-o-aminosalicyllte 0. 93 - ) . 00nil
¦ cyclohe.Yyl-o-alllinosalicrlate 0. 92 _ 0. 98 nil
2l ¦ menthyl-o-arllinosalicylate 1. 00 - 1. 00nil
I .............. . _ . .
12 1 It will be ob~ervcd that thc rcspectivc compounrls possess a high'
23 ¦ absorbance valu~ wit}lin the solar b-1rning wave-len~t}l of ultra-violct light ran~
L4 i ng froln 2950 ~. to 31 50 ~., ~.vl~ile permitti~ T tln( hcncficial tanllir.g rays to
2~ l l~ass virlually -~naffectccl. Thc r;~ e in absorptioll Ol t11C h~rn~fwl solar burni
26 ultra..violet rays was betweell 0. h and 0. 9 for arninosalicyiic acid and its salts
27 larld a rnore conlplcte filtcrin occurrcd with tile ab~iOrbaliCC approilchillg 1.,
~8 ~r thc arrlinosa1icyla~e ~s~ers. Lllc compo~ l e.ii~itcrl virtuall)~ no in'.err~lp-~
2~ ~tion ~f t]lC b-`ll',riCi~ a;lrli71~r l'~'yS ~ r tlle ~,~.lVC-lCll`Ttll b~ eer~ 00 f~ . ~lnd
o ~ 3 c~ 0 ~ ) r l~ v ~ t .~ 7. ~ i ; 11 t l ~ ~ r ~
l l~ '
,,1
~13486
¦ultra-violet screening agents. I
~ l I
3 ¦ EX~MPL~i 7
~ To a solution of 0 5 gm. mol of alkali metal para-aminosalicy-
S ~late salt, as for e~;alnple the respective sodium, potassium or lithiunl salts
6 ¦aissolved in S00 n~l. of ethanoi is addc~l 0. 5 ~rn. mol of undecenyl chloride.
7 ¦The mixture is stirred and warmed to about 60C. for at least four hours. The
8 ¦scparated sodium chloridc is filtcred ~nd the alcohol solution set aside to cry-
¦stalli~e. A white waxy solid is obtained which melts betweell 80C. and 85C. !
10 ¦and is undecenyl para-aminosalicylate.
Il ¦ In a similar marmer, eq-limolar concentrations of vinyl cllloride
12 ¦allyl chloride, oleyl c~iloricle, linolenyl chloride, vinyl bromide, allyl bromide,
~ undecenyl bromifle, o~eyl bromide, linolenyl bromide, vinyl iodide, allyl iodidc
~4 1 undeccnyl iodide, oleyl iodine or linolcnyl iodide may be used in place of tlle
15 ¦ undccen~/l chloride described above ancl the respectivc formed alkelyl p-æmino-'
16 ~ salicylate ester is obtaincd.
17 1 In place of the rrfctal-para-~lninosalicylatc salt clcscri~ecl abovc
~8D¦ thcre may be sul)stituted in equi~nolar proi~ortion3 a Inetal-met~-aminos~Llicy- j
19 ¦ latc salt or a Inetal-ortho-alninosalicylatf~ salt, said rnctal being so(lium, po-
20 ¦ tassium or litllilml or ammonium. The rernainder of thc steps being tlle same
21 ¦ and the rcspective forlned allcenyl nleta-arrlinf salicylate ester and alkanyl
22 ¦ ortho-aminosalicylatc cster dcscribcd above is obtained.
23 ¦ Wllc~n thf~ ultra-violet absolbarlcc is dctermincd for thc above
2~i ~ .kC~llyl f~st(~rs, fhc ~O~ ifl~ val~lcs lrf Of~ d
¦ TABLE 2
26 ¦ ~bsorb3ncc at thc Absor!~ancc at the
¦ Compound Wave-lcflgth ran~e~'.';~Vf.'-lf'l~ th r an~,f?,
27 1 (0.001,, CO~ .) 7.950 ~. --31~0 ,~. 3~ `. 3~,50 ~.
I .~
2~ ¦ vinyl-p-alniilo~ ylate 0. 9~ - 1. 00 nil
?', j al1~ minos.l!icyl~te 0. ~5 - 1. 0() nil
3~ ,uncl(~ccllyl -p -3.~ l o~ yl~ic (). (~ . 0~
Il
] .,
~13486
,. .
, Absorbance at the Absorbance at the
Compound Wave-length range Wave-length range
(0.001% conc.) 2950 A. - 3150 A. 3460 A. - 3650 A.
oleyl-p-aminosalicylate 0.97 - 1.00 nil
linolenyl-p-aminosalicylate 0.97 - 1.00 nil
vinyl-5-aminosalicylate 0.92 - 1.00 nil
- allyl-5-aminosalicylate 0.91 - 1.00 nil
undecenyl-5-aminosalicylate 0.95 - 1.00 nil
,. ,
~^ oleyl-5-aminosalicylate 0.95 - 1.00 nil
linolenyl-5-aminosalicylate 0.96 - 1.00 nil
vinyl-o-aminosalicylate 0.92 - 1.00 nil
allyl-o-aminosalicylate 0.93 - 1.00 nil
undecenyl-o-aminosalicylate 0.93 - 1.00 nil
oleyl-o-aminosalicylate 0.95 - 1.00 nil
linolenyl-o-aminosalicylate 0.96 - 1.00 nil
EXAMPLE 8
, When it is desired to utilize a solution of the appropriate
sun screen compound described in Examples 1 to 7 above, then either
an aqueousl alcoholic or oil solution may be used. Aqueous solutions
are prepared with water-solulable metallic salts of aminosaliclylic
acid as for example, the respective sodium, potassium, lithium, and
ammonium amonisalicylic acid salts. The appropriate quantity of the
selected compound is dissolved in 90 percent of the final desired
volume-of water with a concentration of active sun screen oompound of
from O.S percent to 25 percent by weight with a preferred concentra-
tion of from 3 percent to 10 percent by weight of sun screen com-
pound. The solution may be clarified by treating with charcoal and
filtering. It may be desired to adjust the pH to between pH 6 and pH
8. This may be readily accomplished through the use of sodium acid
phosphate or other suitable buffer agent. m e solution is then
brought to final volume and packaged into dosage form of suitable
size and shape.
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1~134~6
Alcoholic solutions are prepared in a similar manner and
such alcohols as ethanol, and isopropanol are preferred as the sol-
vent. It may be found desirable to dilute the alcohol solvent with
water thus forming a hydro-alcoholic solution, in which case the con-
centration of water may range from equal parts of water and alcohol
to 10 parts of water and 90 parts of alcohol.
Oil solutions may be prepared by dissolving the appropriate
alkyl, alkenyl or cyclic ester of ortho-aminosalicylic acid, 5-amino-
salicylic acid and para-aminosalicylic acid as described above or to
utilize ortho, 5 or para-aminosalicylic acid. The range in concen-
tration of either the selected aminosalicylic acid ester or the a-
minosalicylic acid as described above is from 0.5 percent to 25 per-
cent by weight, with a preferred concentration of from 3 percent to
10 percent by weight of sun screen compound.
To prepare an oil sun screen solution, then the appropriate
quantity of the selected cyclic, alkyl or alkenyl ester of amino-
salicyllc acid described above is dissolved in a suitable oily vehi-
cle, as for example, cotton-seed oil, poppy-seed oil, peanut oil,
corn oil and liquid petrolatum. Suitable anti-oxidants and other fat
preservatives as well as perfume agents may be added and the oil so-
lution is brought to proper volume. The finished oil sun screen so-
lution is filtered and packaged in unit containers of suitable size
and shape.
EXAMPLE 9
When it is desirable to prepare an ointment, then either an
oleagenous carrier as for example, petrolatum and hydrophylic or
lipophylic emulsion ointment bases and water-soluble ointment bases
may be used as vehicles. 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 orth above may be
~r - 15 -
~il3486
prepared as follows:
(a) Oleagenous Ointments
Phenyl para-aminosalicylate 10 grams
Petrolatum U.S.P. q.s. 100 grams
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. me preparation may be packaged either
in the molten state or in the solidified forn-, in unit
containers of suitable size and shape. Should it be pre-
ferred to add perfume agents then these are added just
prior to the solidification of the molten mass.
(b) Water-in-Oil Emulsion Base
Menthyl para-aminosalicylate 3 grams
Cholesterol 3 grams
Stearyl alcohol 3 grams
White wax 8 grams
White petrolatum, q.s. 100 grams
Melt the stearyl alcohol, white wax and about 70 grams of
the white petrolatum, on a steam bath. Add the chole-
sterol and stir until all have dissolved. In a separate
container melt about 3 grams of white petrolatum and to
this add the menthyl para-aminosalicylate, stir until
dissolved and add to the mi~ture of stearyl alcohol,
white wax and petrolatum. Mix well and bring to proper
weight (100 grams) with additional molten white ~etrola-
tum, remove from the heat and stir until congealed.
The resultant sun screen ointment may be utili~ed in the an-
hydrous 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 amount of water is added before the mixture congcals and
- ]6 -
~13486
the hydrated ointment homogenized. The amount of water to be in-
cluded in such preparations will vary with the desired degree of
hardness. A preferred range of hydration for such water-in-oil emul-
sion bases is from 10 percent to 30 percent by weight of water.
(c) Oil-in-Water Emulsion Base
-
Ethyl 5-aminosalicylate 25 grams
Cetyl alcohol 15 grams
White wax 1.5 grams
Propylene glycol 10 grams
Sodium lauryl sulfate 2 grams
Water, q.s. 100 grams
Melt the cetyl alcohol and white wax with half the weight
of propylene glycol, avoiding heating above 60C. 13 the
remainder of the propylene glycol add the ethyl-5-amino-
salicylate and stir until a homogenous mixture is ob-
tained. The propylene glycol solution of the selected
sun screen compound is added to the molten cetyl alcohol-
white wax mixture and stirred well. Dissolve the sodium
lauryl sulfate in about 45 grams of water with the aid of
heat, avoiding temperature above 60C. Slowly add the
oil phase to the water phase, with rapid stirring while
maintaining the heat. After about five minutes of rapid
stirring, bring to proper weight with additional warm
water and stir until congealed. The oil-in-water
emulsion sun screen ointment is then milled or homoge-
nized and packaged into sultable unit containers.
A sun screen vanishing cream may also be prepared by mixing
the selected active compound with a pharmaceutically acceptable
vanishing cream carrier. m us 0.5 percen~ by weight of cyclohexyl-
ortho-aminosalicylate is added to a sufficient ~uantity of cold cream
and the mixture levigated until a uniform preparation results.
1~134~
(d) Water-soluble Ointment Bases
A typical water-soluble sun screen ointment is as follows:
Selected aminosalicylate sun screen agent 100 grams
Polyethylene glycol-400 500 grams
Polyethylene glycol-4000 600 grams
Heat the two glycol ingredients (on a water bath) to
about 60C. remove from the heat and stir. Add the
selected active compound to the base before it har-
dens and stir to obtain a uniform mixture.
A firmer ointment preparation may be made by replac-
ing a portion of the polyethylene glycol-400 with
polyethylene glycol-4000. Between 5 percent and 25
percent of water may be incorporated into the base,
in which event approximately 10 percent of the weight
of polyethylene glycol-4000 utilized is replaced ~ith
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 com-
pound 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 fin-
ished 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 de-
scribed above there may be substituted any of the compounds described
above in a concentration of selected active sun screen compound rang-
ing from 0.5 percent to 25 percent by weight. Appropriate adjus~ment
in the amount of ointment base is made for the increased or decreased
concentration of active compound. The ointment base formulations de-
scribed above are only intended to illustrate the class of ointment
- 18 -
- 1~1348~i
compositions pharmaceutically acceptable 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
water-soluble ointment bases may be used interchangeably without af-
- fecting the sun screen properties of the resultant composition.
EXAMPLE 10
Lotions are liquid suspensions or dispersions intended for
external application 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 ho-
mo~3enizers are used to obtain a uniform dispersion. An example of
sun screen lotions comprising the aforesaid active sun screen com-
pound described above and a lotion-vehicle, is as follows:
Phenyl-para-aminosalicylate 5 grams
Glycerin 2 ml.
Hydrated microcrystalline cellulose2 grams
Carboxy methyl cellulose 2 grams
Rose-water q.s. 100 grams
The phenyl-aminosalicylate is mixed with glycerin,
hydrated microcrystalline cellulose and about 20 ml.
of rose-water to prepare a smooth paste. The carboxy
metal cellulose is separately added to 20 ml. of
rose-water and warmed until uniform dispersion
results and the whole is added to the paste prepared
earlier. The mixture is stirred rapidly while adding
sufficient rose-water to bring to final volume.
In place of ~le glycerin described above, there may be sub-
stituted any aqueous vehicle as for example, distilled water, a
hydro-alcoholic solution containing from 60 to 80 parts of water and
20 to 40 parts of alcohol, pharmaceutically accep~able aromatic water
or mixtures of these.
In place of the glycerin described above there may be added
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~13486
propylene glycol and/or a liquid polyethylene glycol having a
molecular weight of from 200 to 800 in either the same concentration
or in varying concentration of between 1 percent and 5 percent, by
weight.
EXAMPLE 11
Should it be desired to prepare a wax-stick sun screen prep-
aration then this may be prepared by combining the selected sun
screen compound as described in Examples 1 through 7 above in concen-
tration of from 0.5 percent to 25 percent by weight with a preferred
concentration of 3 percent to 10 percent by weight in a suitable wax-
base 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
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 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 sun screen wax-sticks are useful to protect the lips
and the eyelids against solar burning. It has the particular advan-
tage of permitting spot application to an area without spreading.
EXAMPLE 12
When it is desired to block the noxious solar burning rays
or to prevent ultra-violet burning~ then any of the compounds de-
scribed 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 to either sunlight or ultra-violet light. The ultra-violet
screen is applied in sufficient quantity to provide continuous skin
- 20 -
~13~8~i
surface film of at least 0.1 mm. thick with a preferred thickness of
said surface film being between 0.3 mm. and 0.5 mm. me presence of
the skin surface film containing the new sun screen filtering com-
pound will effectively protect the treated area against solar burning
while permitting the beneficial and desirable tanning ultra-violet
rays 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 reap-
plied whenever required.
After exposure of the skin of humans or animals which previ-
ously treated with the above described sun screen compounds or phar-
maceutical compositions containing the same to ultra-violet light or
solar irradiation a rapid tanning effect will be observed without in-
tervening solar burning and its consequent distress and injury. The
above described sun screen compounds and the pharmaceutical composi-
tions containing the same are non-irritating and non-sensitizing to
human and animal skin and will not cause skin eruptions.
EXAMPLE 13
When it is desired to soothe or allay the pain and distress
accompanying sunburn then suitable pharmaceutical compositions con-
taining any of the active ingredients described above may be applied
to the affected surface from 1 to 4 times daily. Although the phar-
maceutical compositions described above exert an equal beneficial ef-
fect to a sunburned area, ointments are a preferred dosage form to
cover the larger areas of body surface while the aqueous lotion is
preferred to treat a blistered area. After appropriate application
of the above described compositions to the affected skin surface area
of humans or animals, a prompt, soothing action results with relief
of pain, tenderness and local distress. The skin edema of the solar
burn is reduced and the erythema will blanche to be replaced by a
desired beneficial tanning.
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