Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
7~i~
'I`hi s :invenl,lo~l relates to lodine cont,aining polox~lmer-
gel composltlc)rls ur-lique1y adapted for use as topiccll germ-
icides, by virtue Or their ar-omalous liquef`ying when chilled
arld gelling when warmed. Ihe gels are prepared by co~bining
with an aqueous iodide-iodine solutiorl, preferably contain-
ing a comp~tible buff`ering agen-t, a polyoxyet;hylene-polyoxy-
propylene block polymer in which the polyoxypropylene hydro-
phobic block has a molecular weight of about 3500 to ~500,
and the molecular weight of -the polymer is abou-t 11,000-
12,000, in an amount to comprise about 20 to 30~ by weight
of the gel composition.
The gel composition may contain 0.25 to 2% of` elemental
iodine, and 0.25 -to 2% of iodide (I ), wi-th the I :I2 ratio
being in excess o~ 0.25:1; and a compa-tible bu~f`ering agent
such as sodium citrate, preferably comprising about 0.2 -to
1.0% of said composition.
_ ckground of the Invention
It has long been known that polyoxyethylene-polyoxy-
propylene block polymers of the general formula
H0(C2H40)X (C3H6o)y (C2H4 )x'
where y equals at leas-t 15 and (C2H40)x+x, equals 20 to 90%
of the total weigh-t of -the compound, show excellent iodine
complexing proper-ties, as disclosed in U.S. Patent 2,759,869
assigned to app]icant's assignee. In such pa-tent, however
the emphasis was on formulations in which the molecular
weigh-t of the polymers was relatively low, i.e., generally
within range of about 2500 to 8000. Polymers of -the general
-type are available commercially, being distributed under
the trademark "Pluronic".
- 2
I t has al~o ~)een kr~<>wn ~`or s(>rne time, as dis(l~ d ir
.S. I~ltent 3,028,29'~, assigrled to t;he app]iclntls ~Issigrlee~
thclt -the complexil-lg o~ .iodirle in aqueolls sollltion by vari-
OUS surfa(tarlts, e.g. polymeri(- materi~l1 inc1ud-ing "~'luro-
ni(sll, is grea-tly enhanced by inchldirlg in the composition
a source of iodide ion (I ) such as to provide arl I :I2
ratio in excess Or 0.25:1. Such en}-l~nced iodine complex-
ing is readily measured in terms of di.stribution coeffi-
cient, D.C., which depends on the equilibrium oi iodine
between an aqueous solution containing a complexing agent
and a norl-miscible solvent, heptane.
More recently in ~.S. Patent 3,740,421 assigned to BASF
Wyandotte Corporation, it has been disclosed -that polyoxy-
ethylene-polyoxypropylene block polymers of -the general
formula above mentioned, and having average molecular
weights in the range of about 4600 to 20,000 can bind water
as gel composi-tions useful in -the formulation of topically-
applicable cosme-tic and pharmaceutical compositions. The
amount of water bound in these gels varies with the molec-
- ular weight of the block polymer, and the proportion of
the polyoxypropylene (hydrophobic) and polyoxye-thylene
(hydrophilic)blocks therein. In general -the a.mount of
water will be in the range of lO~o to 60 or 70% of the gel,
although when the block polymer is of ver-y high molecular
weight, 16,000 to 20,000 -the amow~-t of bound water may be
as h:igh as about 80% of the gel composition. While the
patent lists a number of cosme-tic and pharmaceu-tical com-
ponents as compa-tible additions to -the gels, there is a
noticeable absence of any men-tioned prior art showing re-
lated block polymers of lower molecular weiglrt to be ex-
cellent iodine complexing agents.
~ ' .
'7~
I ~ ha~i r~oW ~ er~ cli sc c)vc~r ~ rl ~Ic~cc)rdanc ( Wi 1,1) t,~le pr c
sel~t inver-~tion, ~hat by prc)pcr selection oI` b]ocl< polymer~;
oL` thl~ t,ype bro(ldly disclosed in U.S. I'aterlt 3,7~0,42] it
is possible to prcp.lre 1odine containing gel composit,i,ons
which are extremel,y stab1e and uniquely suited for use as
olntmen-ts f`or topical germicidal purposes. Many oL the gel
systems disclosed in said patent are unsuited for this
purpose because of the limi,ted amount of wa-ter which is
bound, the inappropria-te consistency of the gel or -the dif-
ficulty in formulation due -to viscosity ol` the system in
the low temperature, non-gelled state.
The block polymers useful for our purpose are those
of intermediate molecular weight, about ll,000 to 12,000 in
which the polyoxypropylene hydrophobic has an average
molecular weigh-t of about 3500-4500 and the e-thylene oxide
blocks comprise about 60 to 80% of the weight of the poly-
mers. A block polymer fit-ting this description is commer-
cially available as "Pluronic F-l27".
Satisfactory iodine containing gels can be prepared us~
ing aslittle as 20 to 30 percent by weight of "Pluronic
F-127" wi-th 25% b~ing the preferred amoun-t. Ihis means
tha-t the gel is a predominantly aqueous system in which the
iodine, al-though strongly complexed by -the block polymer,
is available in the aqueous phase -to exer-t i-ts germicidal
action much as is the case with the known liquid "Pluronic"
-iodine compositions.
Furthermore, the "Pluronic F-127" a-t 25% by weigh-t con-
centration provides an ideal combination of fluid and gel
properties wi-th very low viscosity a-t reduced formulating
temperatures and a form retaining but easily spreadable
consis-tency at room -tempera-ture.
. a~ _
:~051.77~:i
A~ ointment~ for variouq topleal applic~t~on3D the new gel compositLon
will cont~ln ~bout OD25 to 2% by weigh~ of eleme~tal lod~nel and the iodine
¦comple~ing by the blook polymer i9 preferably enhanced by including in the com-
¦position a water soluble iod~de ln an amount to proYide about 0025 to 2% by
¦weight of iodide ion ~I), wlth the amo~nt of iodide ln a particul~r composl~
¦tion belng such 85 to assure ~n I-:I2 ratio in exce~s of 0.25:1.
¦ As the new gel ~ompositions sre ~rimarlly intended for application to
¦the skln ~t is preferable to include a small amount of compatible buffering
lagent to maintain an essentially ne~tral pH during periods of extended stora~e
¦by rounteracting the acidifylng effect of posslble form~tion of acid dur~ng
¦storage. While various buffering agents can be employed we prefer ~o use .
¦sodium citrate in ~he amount of about 002 to 1.07., ~nd suitably about 0,6% by
¦w~lght of the gel composition.
¦ In preparing the new gel composition it is preferable to first combine
¦the iodine~ iodlde~ and buffer lf present, with ~bout half the to$al amount of
¦block polymer and the bulk o~ the total waterO After this mlxing has been
completed the mlxture is cooled to about 40~50F and maintalned at thls
temperature durln~ the final mixing with the balance o the blvck polymer
This fin~l mixlng establishes the critioal gel-forming proportion of the block
polymer so that the composition gels as the temperature is allowed to rlse to
soom ~emperature. Care sho~ld be ~aken to hold the temperature irl the reduced
40-50F range until mixing ~s complete.aq an elevatlon, even to 60F, can so
¦ increase the vi.scosity a~ ~o interfere with proper mixing.
The resulting gel f 5 a re~ersible gel capable of belng repeatedly
l~quef~ed by co~llng ~nd retur~ed to gel form by heati~ s actcr 3i~nlflcant
~ 77~
ln b~lk h~ndl~ng~ p3ckaging an~ use~ The gel i9 ~table ~t temperatures sub-
_ st~tislly ~bove ro~m te~perature ~l~d the c~p~sle~n ~3 not ~d~ersely ~ffected
by free~lngc
The ne~ gel compo~i~ions of the presen~ ention ~nd their method of
preparati~n will be ~ore fully understood fro~ a consideration ~f the followl~
e~mplesl but it is to be under~ool~ that these e~a~ples are ~ven b~ way of
illustration and not of limitatlon~
Example
An iodine gel Dint~nent is prepared conta~ning, by wei~ht
. "Pluronic F 127"2500~.
Iodine 1.25
Svdium Iodide (U.S~P.) 0.60
cieric Acid ~U.S~PI~ 0.35
Sodium Hydroxide (4$~Be~ 0~43
Wa ter 7 2 . 37
. 1~OJ 0~.
The s~d~um iodide ls first dîssolved ln approxim~tely an equivalent
amount of water and the~ the elemental iodine is added and mixed until homo-
~eneous. In a separate vessel the citric acid is dissolved in the bulk of the
water and to this solution ls added approximately half the "Pluronic F^127"
with stirring until completely dissolved. To this is added the iodine
concentrate above mentioned and thP ~ixture is stirred until homoge~eous, Then
the ~odiam hydroxide ~46~Be) ls added and ~horoughly blended.
~ 7~
¦ At thi3 point the batch :15 cooled to 40~50F, the ~lanee of the
¦"Pluron$o P-127~' and ~-ater ~re added~ and the mi~ture stlrred ur~til ~11 the
¦"Pl~r~nic F 127" has dl3~01ve~ thereby complet~ the formulatlo~ The
product, poured intD suitable con~alners5 and all~wed to rise to room temper^
a~ureD ~et~ to 2 firm "rlng1ng" gelO The gel has a form retaining conJis~ency
penmlttin~ a container to be ln~erted and even shaken without any displaceme~t,
yet quantl~ies of gel can e~sily be removed by the flngers ~r implement, and
spread t~ a film ~f any deslred ~hickne-ss.
Testlng of this product for tltratable iodlne and pH stzbllity gives
the following resultsO . .
Available Iodi~e
I ~ ~
Initial 1.14 6~50
Overnight at 50C 1~09 5.90
1 week at 50C 1~02 S~35
2 weeks* a~ 50C 0,95 5.25
~equates to about ~o-years at ~oom ~empera~ureO
. The vlscosity chara~teristios of ~he gel are as foll~ws.
Tem~erature V1scosity ~ c~
10C 350 ~llquid)
15C 460 ~llquld)
18.5C ' 1,240 (liquid)
20C ~ery viscous (paste3
2305C 800,000 ~el3
26C 970~000 (gel)
..~..
1 ~5~7~ l
l Th~,d1~tribut1O~ ~oe~f1c1en~ ~.C~) or ~hi~ ~el at-15C (to fl~ldize ¦
¦the ~mp~sitlon) i~ ~ppr~ ately 600, whlch i.~ fln indic~Lion of ~e~y effectiYe
¦l~dine eomplexin~ by the blGck po1yaler~
¦ Example II
¦ ~ol1cwiDg ~h~ pr~cedure described tn E~ample I ~with the .sod1um
¦citrate bein~ formed in sltu)~ se~er~l~el compositions were prepared containing
¦d~fferi~g a~ounts of the block polymer and observed for physiea1 character1s
¦tics at 10C and 22C w1th results as 1ndicated in t~e fol1Owing t~b~la~ionO
~ sition
I ~
I ~e~ 1 2 ~ 4 5 6
~ _ ~,
¦Pluronic F-127 15.00% 18.007.2O~00/D~5~0~ 25~0070 30~00L
¦~lemental Iod~ne1.25% 1025% 1~10701~25% 1025%1~25%
¦W~I 0.607~ 0~6~k 0~6~7000607o 0063Z0960%
Na3Citraee (anhydrous~0.137O Do23% none 0~60% 0~20% 0~40%
Water to 10~L~/W 100%W~W 100% W~W 100% W~ 100%~/W 10Q%W/~
¦ Observation
I ~
Physica1 state @ 10C 1iquid liquidliqu1d llquid very
. liquld
Physlcal state @ 22C1iq~id liquid Y1iiSqCOUdS gel gel gel
On the basis of gelling tende.lcy i~ will be appsrent that compositions
1 ~nd 2 in ~he above tabulation are en~irely unsatiafactory, compositiorls 4 and
5 are satisfa~eory9 and composik1ons 3 ~nd S ~re borderline9 Composi~ion 3
which provides a v~scous liquid r~ther than n gel ~e 22DG, cou1d atill pr~vlde
8 desirnb1e praduct for top~c~l app1ieatio~l. Composition 6~ on-the other hand~
. ' o8,
~L~5~'77~i ~
prov~de~ an excellent gel ~t 22C bl.t i5 ~ery dlffic~lt t~ prepS~re due to the
high ~lSCD9~ty I~ the 1~ te~pe~ture, llquld st~te~
~a~ed on these result~ the optlm~m rdnge in the ~:oune of
"PltJronlc F~1?7" to gi~ good gel without formulating difflel3~tie~ is con-
sidered to be about ~2% to 2~7. by weight of the gel composltion~ .
Whlle compositlons 4 and 5 both provlde excellent gels, compo.sitio~ 5
¦ shows ~ pH drop to about pH 4 on ~ ~eeks stvra~e at 50C. Thus at the parv .
tlcular iodlne and iodlde leYels ~t is preferable to employ the slightly
higher b~ffer concentration as i~ compositio~ 4
Example IXI
Followin~ the procedure described ln E~a~ple I~ a number of iodine
~gels are prep~red having differi~g iodI~e and iodide c~ntent, as follo~s~
Composition
I Com~onent 1 Z 3
I . _ __ __ __
"Pluronic F- 121~' 25 o 00% 25~00~ 25~00%
~o~ 00~57~ 1~30% 2~07o
Sodiu~ Iodide 0030Z0 2~5% 2.35%
Sodium Citratc (anhydrous) 0 40~ 0 8C7o l~OO
Water to10070 lOQZ 100/.
These oompositions, which are typical of the variation in iodine con~
tent whlch may be deslred for Ysri~us tGplcal applic3t.ions~ all provide
excell~nt ~el~ with ~e l~dine stron~ly complexedA and exhibl~ing good pll
~ab~l~ty on storal~e~
1051776
Va~lous changes ~nd modific~ltions in the poloxamer-iodlne gel composl-
tls~ns hereln disclosQd may occur to those skllled in the ~rt~ and to the extent
that such changes and modific~tions are embrflced by the ~pp~nded cla~m~ it is
to be unde~stood that th2y constitute pa~t of the present invent~on.
ll -10-
