CA2012395A1

CA2012395A1 - Topical analgesic composition

Info

Publication number: CA2012395A1
Application number: CA002012395A
Authority: CA
Inventors: Jeffrey Wenig; Vincent Romeo
Original assignee: Individual
Current assignee: Marina Biotech Inc
Priority date: 1989-03-17
Filing date: 1990-03-16
Publication date: 1990-09-17
Also published as: JPH03504610A; WO1990011014A1; AU5341390A; EP0417245A1; EP0417245A4

Abstract

ABSTRACT OF
THE
DISCLOSURE

Flowable, aqueous, analgesic solutions containing substantially equimolar quantities of trolamine and salicylic acid together with a lower alkanol, a lower alkylene glycol and a lower alkyl ester of parahydroxybenzoic acid and water, and method for the preparation thereof.

Description

r-Trolamlne sali~ylat- ha~ long b-sn known a~ a topl~-l ~n~lge~lc for temporary ~Qll~f o~ mu~culo~kol~t-l ~ch-~ and paln-q ~peclally tho~e a~soci~ted wlth tra~n~, ~praln~, brulo-~ or ov~r-xcrtion, t ha~ alno b-on recomm-nd-d ~or ~empo~ary allovlation o~ arthritlc ~nd rh~umatlc paln oDp~cially ln th-h~nds and ~--t. It 18 ~peclally favor~d by atnlete~

Trolamine ~allcylAte 1~ a l:l complex formad by r-actlon o~
~qulmo~ar qu~ntitl~ of ~allcyllc acld ~nd trol~mlne (t~l-th~nol amln~ ho analgesic a~-nt 18 the ~allcyllc acld which fo~m~ tn JltU when th- Jalt cro~ th~ ~kln barrl-r, The prlnclpal da~ld-ratum of toplcal analge~lc~ 1~ r~pld p-n-tr~tlon of the ~ln barrler to th- r-glon of th~ paln. To thlJ cnd, a variety o~ toplcal cr-am-~ lotiono, ~02m~ and othar vl~cou~ oomposltlon~ hav- ~oon provid-d contalning a larg- numbe~
o~ omoli-nt-, suopon~lng agent~, eh-lating agents, ~t~ nlng ag-nt~, omulsirl~r6, olls, buf~-rln~ agent4 and oth-r component~
lnc~udlng, 80 call-d ol~agonou~ v-hlcle~ hav~ bo-n provlded, app~r~ntly in tho b-lle~ ~hat ~uch lngr~d~ont~ ~ro n0cos~ary ~or r-pld penotrEtlon o~ th- ~kin barr~-r.

Th~- vl~cou~ compo-ltion~ ar- o~ten di~flcult to apply and r~qulre xt~nslv~ "ru~blng ln". Thl~ may be burd~n~om~, -p-clally lf ~oth hands ar~ ~ff-cted, o~ lf th- aff-cted ar~a 1 h-rd to r-ach ~uch ~Q the ~r of th~ ~houlter ar-~.
Addltlo~ally~ the cr~am may 1~aY~ un-~ght~y raoldu~ on ths 4~1n or thoy may tain th~ clothl~g. Oft-n, -p~clally lf u~-d by nn athl-t~ ~urlng comp~tltlon thoy may ab~orb ~lr-~orn~ du~t and p-rtlcles and b-com~ n more unst~htly~ Mor-o w r, on~ or mor-of the compon-nt~ m~y b- allorg~nlc.

. .

20~3~5 .
Th~ a~t h~ long ~earch-d ~or compo~ltlon- whlch can b~
u~erully mploy~d whil~ avoiding th~ ~bove mentionod icultl~.

' .

It ha~ now b--n dl~cov-r-d that ~ ~eapito th- lndl~atlon~
from the ~rt, aqu-ou~ oolutlon~ con~inin~ t~ol~m~n- ~all~yla~e n--d ~ot contaln the larg- numbo~ of lngr-dl-~t~ pr~vlo~ly mployed, but th~t th~ anAl~o~lc may b~ promptly and e~ ien~ly d-llver~d to tho ~lt~ wh~ro it i3 naed6d ~rom ~ Garrlor baYe that contain~ only w~tor, ~ pr~a-r~ti~e, ~ low~r alkanol, ~nd A low mol-c~ wolght glycol. Th~ ~ctlv- l~gr~dlent w~ll r~pldly ~ -pon~trate th- ~ln barrl~r to prov~ a prompt ~oothlng analgeoic aetlon de~plt- tho absenc- o~ the oll~, ~mulsl~lar~ ~nd oth~r xcipient~ norm~lly employ-d with trolamln- ~-licylAt-.

~ h~ compo~itlon. o~ th- inYentlon ar- ~low~bl- ~ompo~ltlon~
wlth a vl~co~ty at dmbl-nt t~mper~ture whloh 1~ ~out th~t of w~ter, 1,~. ~bout 0.58 to 1.2 time~ th~ v~co~ity o~ water.
B~cau~e th-y are re~dlly flowable, 1.~., "llk- wat~r", tney may be ~a~lly And convonl-ntly ~ppll~d by a ~-ry brief rubblng. Th-y are r-~d~ly appll-~ ~om ea~lly d-~gn-d cont~l~er8 ~uch ~
~-rosol, bru~h or spongo ~ppllcator~. Tha volum- Or ~olutlon p-e~lng through tho Appllcator c~n be controll~ by ~ny o~
numbe~ o~ v~lve mean~ w-ll known to tho~ d in tno art, Some appllc~tor~ may ov-n ellminat- th- n-~d ~or touchlng th~
compo~ltlon~ of tho in~ent~on ~urtng ~ppllcat~on.

Tho ~ormatlo~ of th- trol~mine ~allcyl~t- ~omplsx ~3 ~n qulmolar r~ctlon. Acco~dlngly the compo~ltlon~ will ~ontaln ~ub~t~ntlally e~ulmol~r quantlt~a~ o~ the ~n~lg-~lc ~Cld and th- :~
b-Jo. ~t 1- pro~rre~ to omploy ~ ght molsr xc~o~, 4ay 1~ to Z01~39S
10~, o~ th~ ba9e to insur~ th~t all 4~ the acld will r4act an~
301ubillz~, The amount of trolamlne wlll vAry ~rom ~bout 5 to 12~, and of ~allcylic acid from about 3 to lO~ by w~i~ht bo~ed on tho total volum- o~ ~o oompo~tlon.

In thl- dl3closu~0 ond clolm~, all de~ined amount~ Aro tn p-rcont by w-ight ba~ad on tho total volume.

Tho alkonol dmployod in th~ oomposltlonJ will contaln two o~
~hree corbon atom~ ~nd b~ misclbl- wlth wat~r. Such alcohols hsve Low ~o~ling polnta and hlgh vapor p~e~sura. Th-y promo~e ropld ~vaporation of th~ carrier v~hiol- ot ~he compo~ltion. The amou~t o~ alcohol employed lo typlo~lly ~rom about 3 to 6~.

Th- pref~rr~d alkanol i~ l~opropyl alcohol. M~xtures of alcohol~ w~ich ~oy contoln eth~nol moy b~ ~m~loy~d.

Tho compoJltion- ol the inv~ntlon wSll al~o cont-in A
pre~orv~ttve. Th- pr~o~tly pr-~-rr-d pre~rv~tlv-~ arc low~r al~yl -ter~ of psrAhydroxyb-nzolc ocid, typlo~lly contalning up to thræe carbon atom~, Th~ ~mount of pr-~arvatlv~ normally employed will b~ ~rom about 0.1 to 0.5~, olthough wld- vorlation~
~re po~lble wlthout adverse re~ult~. The ~Jtar~ may be ~mploy-d lngly, but lt i~ pr-~rr~d to u~- a mlxture o~ m-thyl and propyl o~ter~ o~ p~rahydroxyben201c acl~ ~lnce tho mlxturo app~ar~ to ~e moro ctlve than lt~e~ e~t~r t~ken ~lono.

Propyleno glycol~ or mlxtures ther~o~ are UtlllZ-~ ~n the compo~ltlons o~ tho lnventlon ~- a ~olublll2~r for th~
pro~orvative ~y-t-m ln an amount of from ~out 2.5 to 6~. The compo~ltlon8 of thl~ invontlon are solution~. It i~ lmport~nt th~t ~11 of th- ~olid compon-~to dlJ~olv-~ A su~ficl-nt amount of glycol 1~ mployed to ln~ure ~uch ~olublllty, but too much - . ~ " j . . .

~ \

glycol m~y incr~a~ the vi~co~ty of the composltion and ~tlll decr~a~- the rata o~ evaporatlon rom ~he skln. ~h- pro~errod g~ycol 1~ 1,2-propan~ dlol.

~ g lndlcAted abov-, the c~mpon-nt~ Or the mlxtur~ mu~t rorm a oolutlon. It ha~ b--n dl~ov~r-d th~t th~ ~ethod o mlxlng i~
very lmport~nt to pr-v-nt pr~lplt~t~on o~ the ~olld compon-nt~.
In th~ pr-~orred procod~ro, th~ trol~mln- And ~allcyllo a~ld ~r-~dded ~t amb~-nt temp~r~ture to th~ ct-d quantlty of wat~r, which may be ~ll of th~ water employ~d ln th- compo~lt~on, and the mlxtur~ 18 allow-~ to stand untll complete ~olut~on 1~
e~f~ct~d. A socond mlxtura contalnlng th~ aelect~d quantltl~s of glycol and al~yl ~te~(~) o~ p~r~hydroxybenzolc acld, ~.q., mlxture o~ ~h- m~thyl and propyl estor 1~ ~-p~r~t~ly prep~r~d ~nd ~lowly adde~ to th- ~lr~t ~olutlon. I~ lt 1~ added too rapi~ly, lt wlll c~u3e preclpltation o~th- ~llcyl~c acid ~nd/or the alkyl o~ter o~ parahydroxyb-nzoic acid. Th~ glycollpreoe~vatlv-m$xtu~e may con~in ~omo o~ tho water of th- ~lnal compo~lt~on.
Th- select~d quantlty o~ alkanol 1~ th~n ~ddcd ~o ehe mlxtur-.

Th~ p~ o~ th~ composlt~on~ oS thl~ inventlon ar- preSerably a~ clo~c to n~utr~l a8 po4~1bl-, but a range oS 6 to 8, or evan ~llghtly wld~r c~n be to1crat-d.

It 1~ surprl~l~g to ob-~rve how qulckly the actlve ln~r-dlent penotr~tes th~ a~ln basrl~r ~rom th- ~olutlon~ o~ thls lnvention. Athl-t-~ hav~ b--n partlcul~rly ~-tl~led. ~h~y hdv~
ob~-rv-d rel~o~ ~rom musoular paln o~ the arm~ sn~ leg~ withln few mlnute4 a~t-r toplcal ppllcation.

The.~ollowlng ~ormulatlon~ A ~nd B axo repre~ntatlv~ o~ the ~n-lgo~lc compo~ltlon~ o~ the i~vontlon.
, 1 ' ' ' . ' . ' ' '' " ' ' '' '" ' ' ' "' ' ; ' . , ' ' ~ :

2 01~ 3 95 ~ w/v trol~mln- 99~ N.F. 5.76 ~allcylle ~ld U.S.P. 4~1 m~thyl parahydroxyb~201c aci~, N,F. 0.2 propyl p~rahydroxybenzoic acid, N.F, 0.1 propylane ~lycol U.S.P. 3.0 lsopropyl ~lcohol U.S.P. 3.0 wat~r U.S.P. ~3.13 qr~ms trolaml~e 9g~ N.F. 28. ~0 salleyllc ~ld U.~P. 2~05 methyl par~hydroxybenzole ~c~d, N.F. 1,00 propyl par~hydroxyben20~e ~cld~ N~F. 0.50 propylen~ glyeol U.~.P. 15.00 i~opropyl ~lcohol U.S.P. lS,00 wat~r U,S,P, ~1S.6S ~:.

For com~o~ltlon A, th- trolamlne, 50~ o~ th~ volume of wat~r ~nd thc ~llcjlic ael~ ~-ro ~tirro~ ~t room t-mporatur~ uns1l th- . :
~alleylic ~eid dl~-olv d. In ~ s~par~t- v~ l, th~
pr~J-rvatlve~ war- d~ol~d in propylo~e qlycol and th~
~olution ~d~ed ~lowly to th~ ~lr~t mlxtu~e wlth ~t~:rlng. ~hen ~:~
th~ addlt~on wa~ compl-t~, tho alcohol w~ ~dd~d ~ollowod by th- ::
b~l~ne- o~ tho w-t-r whlle contlnually Jtlrring. :

- 5 ~

20~239.~

CompoNltlon B tqa~ ~imil~rly prepar~d.

Claims

1. A flowable, analgesic, aqueous solution having a pH
of from about 6 to 8, a viscosity of from about 0.98 to 1.2 times that of water and containing, from, about 5 to 12% trolamine, about 3 to 10% salicylic acid, about 0.1 to 0.5% of a lower alkyl ester of parahydroxybenzoic acid, abut 2.5 to 5% of a propylene glycol or mixtures thereof, and about 3 to 6% of an alkanol containing two or three carbon atoms, the salicyclic acid and trolamine being present in substantially equimolar quantities.

2. A solution of claim 1 containing from 1% to 10%
molar excess of trolamine.

3. A solution of claim 1 or 2 wherein the alkyl group of the lower alkyl ester of parahydroxybenzoic acid contains up to three carbon atoms.

4. A solution of claim 1 or 2 wherein the propylene gylcol in 1,2-propane diol.

5. A solution of claim 1 or 2 containing a mixture of methyl and propyl esters of parahydroxybenzoic acid.

6. A solution of claim 1 or 2 containing a mixture of ethyl and isopropyl alcohol.

7. A solution of claim 1 or 2 containing a mixture of methyl and propyl parahydroxybenzoic acid together with, isopropyl alcohol, and 1,2-propane diol.

8. A method for the preparation of an aqueous solution of claim 1 dissolving the trolamine and salicylic acid in a portion of the total water of the solution which will dissolve all of the trolamine and salicylic acid to form a first mixture, separately forming a second mixture containing the lower alkyl ester of parahydroxybenzoic acid and the alkylene glycol;
combining the first and second mixtures at a rate which is insufficient to cause precipitation of any solid and thereafter adding the alkanol and any additional water necessary to form the said aqueous solution.

9. A method of claim 8 employing from 1% to 10% molar excess of trolamine.