Note: Descriptions are shown in the official language in which they were submitted.
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R~oll~;ve Polymer NeLWO.LS and Methods of Their Use
Field of the Invention
The present invention relates to a polymer composition which exhibits a
5 reversible gelation in response to a change in temperature or other envir~nmPnr~l
stimlllllc More particularly, the present invention is directed to a v;s~ o ~iry;llg polymer
network that can be ~l~pcignpd to reversibly gel over a wide range of conrliti-~nc to
provide a composition having a controllable range of viccocitiPC~ making it useful in a
variety of pha~ l, cosmetic and industrial appli~ .ti(~nc
Ba~k~ u~ld of the Invention
A polymer network is a special type of polymer-polymer composition having
favorable interactions between the conctitllpnt polymers on a molecular level. Many
polymer networks of the prior art utilize covalent bonding between the conctit~lpnt
15 polymers to establish a permanent network structure. In ~ itinn to covalent bonding,
interactions which promote the formation of a polymer n~.wolL include coulombic
attraction in the case of poly~le~Llolyte network complexes, hydrogen bonding in the
case of polyether:poly(carboxyvinyl) complexes or Van der Waals attractions in case of
nonpolar polymers. In addition to these types of interactions, physical interactions,
20 such as Pnt~nglPmPnt, contribute to the interacting nature of these systems. Because of
the nature of these i~ . -;ons, interpolymer systems may possess unique synergistic
properties that none of the conctinlPnt polymers alone exhibit.
The capability of one component of a network to inflllPn~e one or more
components of a network during synthesis is known. As an example, a preformed
25 polymer may be used as a template in the polymerization of a second polymer. It has
been established that the rate of polymerization and the polymerization molecular
weight of poly(acrylic acid) is affected by the template polymer used for template
polymerization. Adachi et al. (Polymer J. 14(12):985-992 (1982)) report that
polymerization of acrylic acid in the presence of polyoxyethylene resulted in an30 interpolymer complex having a ladder-like structure in which each oxyethylene residue
forms a hydrogen bond with an acrylic acid residue.
The ability to form polymer:polymer complexes provides a stable composition
of two or more polymers. Thus, it is desirable to provide polymer network
compositions which possess all the properties of conctinlPnt polymers, but which have
35 h~lp~oved stability and compatibility over simple blends of the conctit~lpnt polymers. It
is also desirable to provide polymer network compositions in which a synergistic effect
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between the conctittl~nt polymers impart ~lu~Lies not possessed by the con~tit~ nt
polymers, either alone or in a simple blend.
Tanaka et al. (U.s. Patent No. 5,503,893) ~licrlc 5es a polymer network in whichthe interpolymer attractions are strong enough to permit a three-rlimPnci~nal polymer
5 network without the use of covalent crocclinking between the conctit~lPnt polymers.
The polymer composition of Tanaka is a gel which exhibits a volume change in
response to an external trigger.
Reversibly gelling solutions are known. Efforts have been directed to the
development of gelatinous drug delivery systems for topical applications and for10 ophth~lmir delivery to the eye. Such reversibly gelling systems are useful wherever it is
desirable to handle a m~r~ori~l in a fluid state, but p.lru.Luallce is preferably in a gelled
or more viscous state.
A known material with these properties is a thermosetting gel using poloxamers,
available co ..~l.ially as Pluronic0, which is described in U.S. Patent No. 4,188,373.
Adjusting the concentration of the polymer gives the desired liquid-gel tr~ncition
However, concentrations of the poloxamer of at least 15-20 % by weight are needed to
produce a composition which exhibits such a transition at commercially or
physiologically useful tempe.~ures. Also, sohltiQ~c cont~ining 15-20 % by weight of
responsive polymer are typically very viscous even under the lower viscosity state of
responsiveness, so that these solutions can not function under con~itinnc where low
viscosity, free-flowing characteristics are required prior to transition. In ~ ition~ these
polymer concentrations are so high that the material itself may cause unf;dvuldble
interactions during use.
Another known system which is liquid at room temperature, but forms a semi-
solid when warmed to about body temperature is formed from tetrafunctional blockpolymers of polyo~y~hylene and polyo2~y~.u~ylene condensed with ethylrnrrli~min.o,
commercially available as Tetronic0 poloxamers. These compositions are formed from
dppl-Ix;~ ly 10% to 50% by weight of the polyoxamer in an aqueous m~ m See,
U.S. Patent No. 5,252,318.
Joshi et al. in U.S. Patent No. 5,252,318 reports reversible gelling compositions
which are made up of physical blend of a pH-sensitive gelling polymer (such as a cross-
linked polyacrylic acid) and a temperature-s~L~;~ive gelling polymer (such as methyl
crlll1lose or block copolymers of PO1Y~LY~ hylene and polyuky~.u~ylene). In
compositions inrlll~iing methylrPlllllnse, 5- to 8-fold increases in viscosity are observed
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upon a ciml~lt~n~oous change in temperature and pH for very low methylcrlll.lose levels
(1-4% by weight). See, Figs. 1 and 2 of Joshi et al. In compositions inrlll-lingPluronic'19 and Tetronic0 poloxamers, commercially available forms of
polyu~y~Lhylene/polycl~y~Lo~7ylene block copolymer, commercially useful in~ l~d,es in
~ 5 viscosity (5- to 8-fold) upon a cimlllr~nrous change in te~p~l~Lure and pH are observed
only at much higher polymer levels (> 12% by weight). See, Figs. 3-6 of Joshi et al.
WO 95/24430 published September 14, 1995, describes graft and block
copolymers of component t~,.ne-d~Ul~, Se-la;~iv~, polymers and a pH se.~s;Li~ polymers.
The graft and/or block copolymers possess a lower critical solution temperature (LCS~
10 or cloud point between 20 ~C and 40 "C at a pH of 6.0-8Ø The LCST .~r~.. Ls the
te up~.~Lure at which the polymer phase separates from the solvent. This results in an
opaque or tr~nelllc. nt mixture or suspension. In medical applir ~tionC~ particularly
opthalmic applications, this undesirable.
Thus, the known systems which exhibit reversible gelation are limited in that
15 they require large solids content and/or in that the increase in viscosity are less than 10-
fold and/or exhibit a cloud point before viccocifir ~tion.
Su~u~ y of the Invention
It is an object of the present invention to provide polymer ncLwolL
20 compositions which are capable of reversible gelation or viccocifir~ti~7n, which have
improved visual clarity and which have i..~p.~ ;l stability over simple blends of the
conctit~lent polymers.
It is a further object of the invention to provide polymer network compositions
which exhibit gelation or viccocifir~rion at very low solids content.
It is another object of the present invention to provide polymer network
compositions which exhibit a synergistic effect between the conctit lrnt polymers to
impart properties not possessed by the conctimrnt polymers, either individually or in a
simple blend.
It is yet a further object of the invention to provide a method of making a
30 polymer network compositions in an simple, economic and efficient means of
production.
It is a further object of the present invention to provide a responsive polymer
network composition having improved flow and gelation characteristics as compared to
properties possessed by coll~ ional reversible gelation compositions.
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It is yet a further object of the invention to provide a polymer r...wc.lL
composition which is tl~lS~dUC.l~ or tr~nclllc.ont to light both before and after gelation.
It is yet a further object of the invention to provide new and useful devices,
articles and compositions incorporating the v;;,~us;fying polymer network composition
5 of the present invention, which take adVdllLdge of the reversible gelation pl.~p..Lies of
the polymer network composition.
It is yet another object of the present invention to provide reversibly gelling
polymer n.LwolLs which are composed of biocompatible polymers.
'rhe objects of the invention are achieved with a viscosifying polymer network
10 ~u~ ;ning an ~Ccori~ting component capable of ~,iCg~L--lg in response to an increase in
tC..l~.~dLulc;, and a solvophilic component which is linked to the associating component
in a solvent. The associating component may exhibit d~ ,.,Lion at a temperature
where no macrophase separation occurs. Both the ~cso~ ting and/or solvophilic
components may be oligomers or polymers.
As used herein, as ~Cso~i -ring component is an oligomer or polymer which will
respond to a temperature change to change its degree of association and/or
agglomeration. The 5timll1nc may be tC.llp~l~Lult~ and l~lrlition 7lly~ pH, ionic
con-fntration, solvent concentration, light, m~gntotic field, ~l~rtrir~l field, pl~_77Ul~:: or
other triggers commonly used to trigger a responsive gel n~t~-ri~l The aggrcgdLion is
20 most commonly in the form of micelle formation, however, plc~ ;p;L~Lion, labile
crocclinking or other factors may be contemplated as within the scope of the invention.
As used herein, the solvophilic component is an oligomer or polymer which is
linked to the associating component so that a copolymer network is formed. The
solvophilic component may be, but is not reguired to be, responsive in that it may also
25 exhibit a change in conform 7tio~ upon a change in environmental 5timnlllc The
interaction of the solvophilic and ~eSo~ ting components exhibits a synergistic effect,
which n~gnifi~oc the effect of the associating component in viscos;fying and/or gelling
the solution. It may also cause ag~ gdLion and/or mi~ ti~n to occur under
con-litionc which would show no appdlenL effect in the absence of the polymer
30 network. By "solvophilic", as that term is used herein, it is meant a component which
has an affinity for the solvent used in solvation of the polymer network.
In the absence of the solvophilic component, the associating component may or
may not show a change in viscosity in response to a change in t.~up.,~Lure. However,
if it does show a response in the absence of the solvophilic component, that response is
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qualitatively or 4~ .I.v~ly different. That is, the response is amplified or altered in
the presence of the solvophilic components.
The viscosifying polymer network is formed by solvation of the linked
associating and solvophilic components. Since a gel colllpl;ses a three~imt n~iQn~l
5 polymeric network conr~ining a solvent, the liquid component makcs up the responsive
visco~;fy;llg polymer network.
For cornmercial applications, the composition may of course include ~litinn~l
dPm~ontc~ such as are needed for the commercial purpose of the composition. These
additives may have no bPnefiei ll or detrimental effect on the polymer nctwork (i.e.,
10 inert additivcs) but have a bPn.ofi~i~l aspect for the particular commercial application or
formulation. These additives may have some detrimental effect to the polymer network
(i.e., colllproll.ising additivcs) but have a beneficial effector the particular commercial
application or formulation. As such, polymer networks may r~,plesc.l~ a col..prull~ise
between the requirements of the application or formulation and the requirements of the
15 polymer network.
The novel interaction between the con~tit~llont polymers in the responsive
visLL~,;fyil-g polymer network permits formation of gels at very low solids content.
Gelation and/or vicco~ifir~tion is observed in aqueous solutions having about 0.01 to 20
wt% of the associating component and about 0.01 to 20 wt% of the solvophilic
20 componcnt.
A typical reversibly gelling polymer network may advdll~ageou.ly be comprised
of less than about 4 wt% of total polymer solids of which less than about 2 wt% is the
associating component and less than about 2 wt% is the solvophilic component. The
balance is made of the aqueous-based solvent. An exemplary associating component is a
25 poloxamer having the forrnula (EO)(PO)(EO). An exemplary solvophilic componcnt is
sodium acrylate. The viscosifying polymer network is formed by poly.. ;~ l ;nn of
acrylic acid in the presence of the poloxamer followed by hydration and neutralization
of the polyacrylic acid. The viscosity of the gel increases at least ten-fold with an
increase in te~llp~. d~ure of about 5 ~ C.
By "gelation", as that term is used herein, it is meant a drastic increase in the
viscosity of the solution. Gelation is dependent on the initial viscosity of the solution,
but typically a viscosity increase in the range of 5- to 100-fold, and preferably 10- to 100-
fold, is observed in the present systems.
By "poloxamer", as that term is used herein, it is meant a polymeric or
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oligc,ll.c.;c structure having a general formula of (P~)l(P2)b(P~ where Pl and P2 l~l,wC.lL
two different poloxamer blocks. By way of example only, P, may be a poloxamer ofthe general formula (CHzCH2O)~, where a is in the range of 10-50 and P2 may be apoloxamer of the general formula, (CHRICHR2O)b, where Rl may be H or an alkyl
group, R2 may be an alkyl group, and where b is in the range of 50-70. Other possible
poloxamer combinations are contemplated within the scope of the invention.
Brief Description of the Drawin~
The invention is tescribed with reference to the Drawing, which is p~ d for
the purpose of illustration and is in no way int~nrlPr~ to be limiting, and in which:
Figure 1 is a graph of v;a~,Oa;Ly VS. tc.l.~.dLure for a 1 wt%, 2 wt% and 3 wt%
viscosifying polymer network aqueous composition of a triblock polnY~m.o./polyacrylic
acid (1:1) at pH 7.0 measured at a shear rate of 0.44 sec-l;
Figure 2 is a graph of v;a~,OS;Ly VS. pH for a 1 wt% viscc~a;rying polymer
network aqueous composition of a triblock poloxamer/polyacrylic acid (1:1) at pH 7.0
measured at a shear rate of 0.44 sec~l;
Figure 3 is a graph of v;SCO:~;Ly vs. t~llpc,dLule for a 2 wt% v;a~oa;rying polymer
network aqueous composition of a triblock poloxamer/polyacrylic acid (1:1) in sea water
at pH 7.0 lllea~ur~;l at a shear rate of 0.22 sec~l;
Figure 4 is a plot of endotherms for (a) 1 wt% Pluronic'~9 F127 and (b) 1 wt%
v;aCOa;rying polymer network aqueous composition of Pluronic0 F127/polyacrylic acid
(1:1);
Figure 5 is a plot of v;a~,OS;Ly VS. temperature for (a) a 1 wt% v;a~Oa;rylllg
polymer network aqueous composition of Pluronic'19 F127/polyacrylic acid (1:1) and (b)
a 1 wt% physical blend of Pluronic~9 F127/polyacrylic acid (1:1) at pH 7.0 measured at a
shear rate 0.22 sec~';
Figure 6 is a plot of viscosity vs. temperature for a 1 wt% viscosifying polymernetwork aqueous composition of Pluronic'19 F108/polyacrylic acid (1:1) at pH 7.0measured at a shear rate 2.64 sec~' with a SC4-18 spindle;
Figure 7 is a plot of endotherms for 1 wt% viscosifyirlg polymer network
composition of Pluronic'l9 F108/polyacrylic acid (1:1);
Figure 8 is a plot of viscosity vs. temperature for a 1 wt% v;aCOa;ryillg polymer
network aqueous composition of Pluronic0 F88/polyacrylic acid (1:1) at pH 7.0
measured at a shear rate 2.64 sec~l with a SC4-18 spindle;
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Figure 9 is a graph of the viscosity vs. temperature effec~ for a v;~OS;ry~lg
polymer network composition of 2 wt% Pluronic~l9 P104/polyacrylic acid (1:1) in
dPic)ni7Pd water at pH 7.0 measured at shear rate of 22 sec~l using a SC4-25 spindle;
Figure 10 is plot of viscosity vs. temperature for a ViSCOa;ryillg polymer network
composition of 2 wt% Pluronic~9 F123/polyacrylic acid (1:1) at pH 7.0 measured at a
shear rate of 22 sec-l using a SC4-25 spindle;
Figure 11 is a plot of viscosity vs. temperature for 1 wt% viscosifying polymer
network made of series of ltriblock copolymers and polyacrylic acid (1:1) in ~Pioni7P
water at a shear rate of 132 sec-l;
Figure 12 is plot of viscosity vs. temperature for a visco~ifying polymer n~wc.hcomposition of 2.5 wt% Pluronic0 F127/polyacrylic acid (1:1) pre~ d in (a) deionized
water and (b) 0.5M NaCl sol~lti~ln;
Figure 13 is plot of viscosity vs. temperature for a viscosifying polymer network
composition of 2 wt% Pluronic'l9 F127/poly(acrylic acid-c~methacrylic acid) (1:1) in
deionized water at a shear rate of 22 sec-l;
Figure 14 is plot of v;,cos;~y vs. temperature for a viscosifying polymer network
composition of 2.5 wt% Pluronic0 F88/polyacrylic acid (1:1) in deionized water and at
5000 psi;
Figure 15 is a plot of viscosity vs. temperature for a vis~o ,;fy;-lg polymer
network composition of a 2 wt% polyethyleneglycol mono(nonylphenylether)/
polyacrylic acid (1:1) at pH 7.0 at a shear rate of 2.64 sec-l;
Figure 16 is a plot showing the release of hemoglobin from a polymer network
.
composltlon ol the mventlon;
Figure 17 is a plot showing the release of ly~ozyme from a polymer network
composition of the invention;
Figure 18 is a plot showing the release of insulin from a polymer network
composition of the invention;
Figure 19 is a plot showing the release of timolol from (a) a control; (b) a 2 wt%
polymer network composition and (c) a 3 wt% responsive polymer network
composition of the invention;
Figure 20 is a plot of viscosity vs. temperature for a polymer network
composition (a) before and (b) after sterilization by autoclave;
Figure 21 is a plot of viscosity vs. temperature for a 5 wt% polymer network
prepared from polyacrylamide and Pluronic F127 (1:1) after St~nc~ing for 10 days;
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Figure 22 is plot of v;s~os;Ly vs. t~,l~..dLulc for a polymer network
composition of 5 wt% Pluronic0 F127/poly(acrylamide) (1:1) in deionized water at a
shear rate of 2 sec-l (a) after ctqn~ing one day and (b) after stqn~ing six days;
Figure 23 is plot of v;~os;~y vs. ~~up~.dLure for a polymer network
composition of 20 wt% Pluronic0 F127/poly(acrylamide) (1:1) in deionized water at a
shear rate of 0.066 sec~l after stqn~ing 12 days;
Figure 24 is a plot of v;:~.OS;Ly vs. ~-~u~e.dLure for an oil-free moi~ ;ng
formlllqtion prt~al'cd from (a) polymer network composition of the invention and (b) a
coll~,~t;onal oil-in-water forml.lqtion;
Figure 25 is a plot of (a) viscosity v. te.llpeldLu,c and (b) abosrobance v.
~~llp~.dLule for a 2 wt% viscosifying polymer network prepared from poly(acrylic acid)
and Pluronic0 F127 (1:1); and
Figure 26 is a plot of (a) viscosity v. temperature and (b) abosrobance v.
te u~ ldLulc for a 2 wt% v;s~os;fy;ng polymer network prepared from poly(acrylic acid)
and Pluronic'~9 L92 (1:1).
Detailed Deccription of the Invention
The present invention is directed to a novel reversibly gelling polymer network.The polymer n~w~lL advd,lL~,~ously cQntqinc less than about 20 wt% polymer solids,
20 and preferably less than about 4 wt% polymer solids and exhibits an at least five-fold
increase in v;~cos;Ly with an increase of temperature of about 5~C. The responsive
polymer network composition a~o~d;llg to the invention includes an associating
component and a solvophilic component. The tWO polymer phases are linked with one
another on a m~leclllqr level, typically through a direct covalent bond, although linkages
25 through atoms or other moieties is cont~mrlated. Exemplary concentrations of the
Con~ polymers, giving the widest range of v;scus;Ly changes, range from about 10
wt% to about 75 wt% for the qcco~i ~ting component and from about 90 wt% to about
25 wt% for the solvophilic polymer.
A v;:,co:~;ry;ng polymer network of the present invention is a special type of
30 polymer-polymer composition, in which the two or more polymer phases are covalently
linked, although other associating m.orhqnicmc, such as hydrogen bonding and van der
Waals force may also be present. The interacting nature of the two (or more) polymer
phases provide a stable miscible composition, i~ e~L;ve of the im micl~ihility of the
conctituPm polymers, and unique properties. Such stability and plope.Lies may be
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attributed to specific interactions of the conct~ f nt polymers.
The associating component undergoes a change in conformation in solution.
One type of ~Cco~i~ting component is a tC~llp.,~dLurC SC~lS;L;vt: agglcgd~;ng polymer. A
te up~, dLurC 3Clla;Livt: d~ ,gdLillg polymer undergoes conform~til n~l changes and
5 changes to the critical micelle concentration as a function of temperature. The polymer
will change from an open, non-aggregated form to a micellar, aggregated form with
changes in tC.llp~. dLul t:.
The solvophilic component may be a polymer which is capable of ionization
with a change in ionic strength of the solution. Changes in ionic strength may be
10 accomplished by a change in pH or by a change in salt concentration. Changes to the
ionic state of the polymer causes the polymer to experience dLLld~Live (coll~pcin~3 or
repulsive (expanding) forces. Ionization is not required, however, and the solvophilic
component may be neutral or uncharged.
The ~Cso~ ting component of the polymer network exhibits a reversible gelation
15 upon exposure to a change in te nE;~.dLure. The solvophilic component of the polymer
network may also exhibit a reversible gelation in response to one or more
enviro~.. l .l changes. The gelation may occur in response to an indirect
environm~ nt~l trigger, for ,example, light irr~ tion or electric field application which
generates an increase in temperature. Altc.lldLi~ly, gelation may be triggered by a
20 change in pH, ionic strength or solvent composition. Responsive polymer network gel
compositions which exhibit a reversible gelation at body tc..-p~.dLure (32-37-C) and/or
at physiological pH (ca. pH 7.0-7.5) are particularly preferred for certain medical and
pharm ~euti~l uses. Responsive polymer network compositions which exhibit a
reversible gelation at 70~C or above are particularly pr~r~ d for oil field applications.
Yet it is within the scope of the present invention for reversible gelation to occur at
much higher or lower te~p~.dLu.~s or pHs or in response to other stimuli.
In one embodimen~ of the invention, the polymer network exhibits flow
properties of a liquid at about room temperature, yet rapidly thicken into a gelconsistency of at least about five times greater, preferably at least about 10 times greater,
and even more preferably at least about 30 times and up to 100 times greater, viscosity
upon exposure to the particular envirorlm-ont~l trigger. The responsive polymer
network of the present invention exhibit gelation even at very low polymer
concentrations. For example, aqueous responsive polymer network compositions of
about 0.5 wt% responsive component and about 0.5 wt% il ni7ing polymer will gel
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when exposed to a critical l~upe~d~ulc or pH. The low polymer concentration in the
aqueous compositions of the present invention provide clear, colorless gels, both before
and after viccocifit~tion, making them pa~icularly well-suited for a variety of
applications. In ~ itinn~ very little residue is formed upon evaporation which may be
5 important in some applications, such as a~ ini~l . dL;on of ophth llmi~ drugs to the eyes
or in topically applied cocnnPti~c An aA~litinn~l alv~ age of the polymer network of
the invention is that it remains clear and tr mclllcPnt above and below the critical
t~llpL.dLure or pH.
The associating component of the present invention may be any polymer which
10 forms dggl~,d~es as a function of temperature. The associating component typically
possess regions, which are ~ .1L;eIVt:5 sub-components of hydrophilic and hydrophilic
character. The acsociating component may be linear or branched. As will be dppdl~lL
to one skilled in the art, a nonionic surfactant, due to its hydrophilic and hydrophilic
~L~d,L..-, may be suitable for use in the invention.
Suitable associating components include polo~u~. " such as block copolymers
of diL~.~L oxyalkylene units. At lea t one polyoxyalkylene unit should have
associating charartPrictirc and at least one polyoxyalkylene unit should have hydrophilic
J 1- ~ ;'I;rc A poloxamer of polyu~y~Lhylene and polyo~y~ro~ylene may be used ina p~ .led embodiment of the invention. Another suitable responsive component
20 inrhl~lP5 Pluronic'19 poloxamer (BASF) having the general formula (POE)l(POP)b(POE)c,
where POP is polyo~y~lu~ylene and l~l~..lL. the associating portion of the polymer
and POE is poly(~l~y~lylene and l~ S~.lL~ the hydrophilic portion of the polymer.
Pluronic~l9 (BASF~ triblock polymers are ~u~ ;ally available for ~ and c in the range
of about 16 to 48 and b ranging from about 54-62. Other P~Pmpl~ry polyoxyalkylene
25 polymers include alkyl poloxamers, which are a product of alcohol conrlPn~tioll
reactions with a terminal alkyl or arylalkyl group. The alkyl group should have
associating character, such as butyl, hexyl and the like. An alkyl poloxamer may have
the general formula R-(OCH2CH~)nOH, where R is a nonpolar pendant group such as
alkyl and arylalkyl and the like, and n is in the range of 5-1000. A pl~f~ d
30 alkylpoloxamer is polyethyleneglycol mono(nonylphenyl)ether. Still other exemplary
responsive components may include cellulosic, cPlllllnse ethers and guar gums which
possess hydrophobic and hydrophilic regions along the polymer backbone which permit
al;gl~gd~;on behavior. One or more associating components may be used in the
responsive polymer network composition of the present invention.
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Another type of solvophilic components is an ionizable polymer. These
materials typically are responsive to changes in pH and/or ionic strength. The icni7~hle
polymers of the present invention include linear, branched and/or crocclink~d polymers.
Of particular interest are carbol~yvhlyl polymers of monomers such as acrylic acid,
5 ll.eLLac.ylic acid, ethacrylic acid, phenyl acrylic acid, p~ntPnoir- acid and the like.
Polyacrylic acid is a pl~Lll~;l carboxyvinyl polymer. One or more poly(carbo~yvil,yl)
polymers may be used in the responsive polymer network compositions of the present
invention. Acrylamides or sllbstit~lted acrylamides are also preferred emborlimrntc
Copolymers, such as by way of example only, copolymers of acrylic acid and
10 methacrylic acid, are also contemplated. Naturally occurring polymers such as rhitoc~n
or hyaluronic acids are also possible as solvophilic polymers since they are capable of
forming an ionized network as polymers or copolymers of other solvophilic polymers.
As is clear from the description of the invention and from the Examples set
forth below, covalent cross-linking within an particular polymer component of the
15 responsive polymer network is not required in order to observe gelation at low solids
co..l ..I~, such as less than 20 wt% or preferably less than about 10 wt%, or more
preferably less than about 5 wt% or most preferably less than about 2.5 wt%. This is in
contrast to Joshi et al. ~U.s. Patent No. 5,252,318) which rlicrln5r5 the use of at least one
crocclinkr~l polymer in the formation of their reversibly viscosifying blends.
The reversibly gelling responsive polymer r.~Lwo.Ls compositions of the present
invention are highly stable and do not exhibit any phase separation upon ct~n~ing or
upon repeated cycling between a liquid and a gel state. Samples have stood at room
temperature for more than three months without any noticeable decomposition,
clouding, phase separation or degradation of gelation properties. This is in direct
contrast to polymer blends and aqueous mixed polymer solutions, where phase stability
and phase separation is a problem, particularly where the conctinl~tlt polymers are
immicrihle in one another.
The functioning of a component as the associating or solvophilic component
may be dependent upon the specific environmtont~l trigger being considered. For
30 ~ample, in the poly(acrylic acid)/EO/PO/EO system, when te~p~.~Lre is the erigger,
EO/PO/EO is the associating component, however at pH of 2-5, where the polymer is
completed protonated, the poly(acrylic acid) may be the associating component.
Exemplary of the drarnatic increase in viscosity and of the gelation of the
responsive polymer network aqueous compositions of the invention with a change in
CA 02230727 1997-12-10
W O 97/00275 PCTAUS96/~0376
t~l~.dLul~ are the aqueous responsive polymer network compositions shown in Fig. 1.
Fig. 1 is a graph of visco~;~y vs. t~llp~ld~ule for 1%, 2% and 3% aqueous responsive
polymer network compositions comprising a poloxamer of the general formula
(POP)(POE)(POP) and polyacrylic acid (1:1), which has been hydrated and neutralized.
The v;s. os;~y measurements were taken on a Brookfield V;~-JI.~ t' at a shear rate of
0.44 sec~l at pH 7Ø All solutions had an initial viscosity of about 1080 cP and
exhibited a dramatic increase in viscosity to gel point at about 35~C. Final viccociri~qc
were apE;l.~x;.~. ~Ply 33,000 cP, 100,000 cP and 155,000 cP for the 1 wt%, 2 wt% and 3
wt% compositions, l~ s~e~ ,ely. This l~ ,e.lL~ v;sco ,;-y increases of about 30-, 90- and
140-fold, lcs~e~ ,. ly.
Exemplary of the dramatic increase in viscosity and of the gelation of the
responsive polymer network aqueous compositions of the invention with a change in
pH are the aqueous responsive polymer network compositions shown in Fig. 2. Fig. 2
is a graph of viscosity vs. pH for a responsive polymer network composition ~ Ulllpl;~lllg
1 wt% poloxamer/polyacrylic acid (1:1), hydld-~l and ncu~l~l~d, taken on a Brookfield
viscometer at a shear rate of 0.11 sec~~ at 37 ~C. The solutions had an initial viscosity of
about 15 cP and ~-~rhihite~l a dramatic increase in viscosity to gel point at about pH 5Ø
Final viccociti~s was appro~im~t.oly 3000 cP, which represented a viscosity increase of
about 200-fold.
Another possible application of the observed vis~o:.;rymg phPn(~m~ncn is
illustrated in Fig. 3 where the v;sco~;ry;ng effect of temperature is shown in a 2 wt%
responsive polymer n~l wolk composition comprising a polcnram~r/polyacrylic acid in
sea water. Sea water is r~lcse.l~ed by a synthetic formlllation (NaCl, 23.84 g/l; CaClz,
0.93 g/l; MgCl26H2O, 10.76 g/l; Na2SO~, 4.29 g/l; NaHCO3, 0.205 g/l) in water. Aviscosifying effect is observed at telupc.d~ures higher than 70-C which is relevant for oil
field applications.
The responsive polymer network of the invention preferably is prepared by
initiation of polylllc~d~;on of one component, i.e., the solvophilic component, of the
polymer network in the presence of the fully formed second component, i.e., the
associating component. A general method of making the responsive polymer networkcompositions generally involves solubilization of the associating component in amonomer capable or a con~ntrated monomer solution of forming a solvophilic
component. The monomer is then polymerized to the solvophilic component.
Polymerization may be accomplished by addition of a polyl,le~;zd~;on initiator or by
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WO 97/00275 PCTrUS96/10376
irradiation terhniques. The initiator may be a free radical initiator, such as rh~-mir~l
free radical initiators and uv or gamma radiation initiators. During the polymerization,
the fully formed associating component is linked to or grafted onto the developing
polymer chain of the first solvophilic component. Alternatively, the t~rmin~l end of the
5 associating and/or the solvophilic component may contain a reactive moiety, which is
capable of reacting with and linking to the respective end of the compl~-mrnt~rypolymer component.
Copolymerizations may take place by proton abstraction from a secondary or
tertiary carbon upon free radical formation or ~-irradiation. The copolymerizations
10 proceeds vi~ the following scheme:
SCHEME 1
.
Imtlatlon:
R-R _ 2R-
or
CH3 C~3
~ ~ H20
~ OH
Polymerization:
R- + nA ~ AAAA~ AA
Graft propagation:
CII3 ~H3
l~A + I ~ ~
~ AAAAAA AA-
Cros~linkinE~:
~H3 ~H3
ICH3 CH3
AAAAAAA ~AAAA~A ~
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WO 97/00275 PCT~US96/10376
FcP~rtionc in Scheme 1 are PYPmplifiPrl by propylene oxide residue, but they areequally applicable to other alkylene oxides. Note that reaction (3) in presence of vinyl
monomers (typically, acrylic acid) leads to the grafting of growing poly(acrylic acid)
chain onto the polyether backbone with the possibility of crocclinking, resulting in the
5 dppcdl~ e of a "classical" three-dimensional gel structure. These gel structures may
form ag~;lCg~Lt:a, which scatter light even at very low concentrations far below gelation
t~lpcld~uies.
Due to the random nature of the proton abaLld~Lion process, the grafting of the
~cso~i~t~E~ component onto the ~;~owlng solvophilic chain is random. The degree of
10 grafting may be adjusted by 5plecti~n of the alkylene oxide (ease of free radical
formation) and the quantity and type of free radical initiation used.
Although not intPn-1Pd to be bound to a particular mode of operation, it is
believed that several factors contribute to this unique and previously unreported stability
of responsive polymer networks. The polyoxyalkylene chains such as those of
15 poloxamer polymers are known to be s~lbsr~nti~lly unfolded and free-flowing at
tempcld~ ea below a critical temperature of gelling. Above this temperature, thepolyoxyalkylene chains have been demonstrated to form zgglomPration5 due to the
temperature-dependent association of the associating component of the polymer. See,
Atwood et al. Intl. J. Phar~n. 26:25-333 (1985), herein incorporated by reference. The
20 polymer chains fold in on th~lae~ s due to associating interactions among associating
chain blocks.
The polymer morphology of the solvophilic polymer imparts stability to the
polymer network. The water-soluble solvophilic component illlplU~ the stability of
the polymer network in aqueous solution, and diacoul~cs phase separation. In
25 addition, linkage of the solvophilic and associating components increases the effective
size and molecular weight of the polymer network. This amplifies the d~;~,leg~;on effect
of the associating component.
Adachi et al., which is incorporated herein by reference, report that the
polymerization of acrylic acid in the presence of dilute polyu~y~hylene solution30 resulted in an interpolymer network having a ladder-like structure in which each
u~yc:thylene residue forms a hydrogen bond with an acrylic acid residue. Thus,
template-formed polyacrylic acids of this type may contribute to the bonding observed
in these new responsive polymer networks.
The properties of the responsive polymer network gel composition may be
CA 02230727 1997-12-10
W O 97/00275 PCTAJS96/10376
modified by varying the components and/or the microstructure of the polymer
network. For example, use of dir~ polyu~ d~ion initiators in the formation of the
concrinlpnt structural component of the responsive polymer network gel was found to
decrease the teLupc~d~ure for onset of viscosity by 5~C (see, Example 12). Also, different
5 responsive components have been found to exhibit d;r~~.~l- reversible gelation~UpC.d~ul~. For example, see Examples 18-19. In addition, solvation of a responsive
polymer network in a 0.5 M NaCl solution (as colupalc;l to distilled water) will result
in a 10~C decrease in the temperature of gelation. Thus, the ionic strength of the
aqueous solution may be used to modify the properties of the composition (see,
10 Example 8).
Examples of thermothirk.oning polymer systems are in the prior art; however,
these systems typically operate at much higher polymer concentrations, exhibit cloud
point transitions or require a complicated mnlrictep solution synthesis. These include
PEO-PPO-PEO block copolymers (Alexandritis, et al. Colloids Surf, 96:1 (1995))) and
15 other block- and graft-copolymers, such as PEO-PPO-PEO block copolymers-g-
polyacryliamide (de Vos, et al. Polymer, 3!S:2644 (1994)), and PEO-g-poly(acrylic acid)
(Hourdet, et al. Polymer, 35:2624 (1994); L'Allouret, et al. Colloid Polym. Sci., 273:1163
(1995)).
Thermoassociation is attributed to agglcgd~ion of the corresponding grafts or
20 blocks into relative associating microdomains which err~ ,ely crosslink adjacent
polymer chains. Thermodyn~mir~lly, a~ gd~ion results from a balance between
hydrogen bonding, ele~ ~ru .~d~ic interactions, and associating effects in aqueous systems.
Specific orientations of water that arise upon polymer dissolution lead to in~l.~illgly
unfavorable entropic (AS) contributions to the free energy of mixing as the temperature
25 is raised. This tendency ov~l~oLles the favorable enthalpy (~H) changes due to the
formation of hydlu~,~.l bonds between polymer and solvent. Let us imaging a polymer
chain that consists of different segm.ont~ (blocks), such that upon dissolution in, say,
water, not only segmrnt-sf gm. nt contacts exist, but also segment-solvent and solvent-
solvent contacts. The energy change (~G) per contact when we replace two segm.ont-
30 solvent contacts (El~) and form a segment-segm-ont (El,) and a solvent-solvent (E2z3
contact, is (Silverberg, A. Adv. Chem. Ser., 1989, 223, 1),
AG Ell + E22 - 2E~2.
The Flory-Huggins parameter (x) related to ~G as follows (FloryJ. Chem. Phys.l7:3o3
(1949),
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WO 97/00275 PCTAJS96/10376
X - constx(-~G/Kb~,
where Kb is the Rrllt~m~nn COIlaLdllL and T is absolute t~.lp~.d~ure Q;~). In the case of
good solubility, ~G < 0 and x < 1/2. Phase separation starts to occur when
x 2 1/2 [1/(1 + Nl/2)]
where N is the size of the polymer chain.
The strong segmPnt-segmPnt contacts (which are needed to form ~CsOri~ting
croc~link~) require negative Ell values that are large in absolute terms (because ~G must
be ncgdLiv~, see eqn.(l)). These large valucs, however, lead to a very large x > 1/2,
which in turn makes the polymer insoluble, resulting in conflirting l~luhc.ll~ s. Thus,
10 in order for a polymeric system to form a reversibly v;sco~;rymg gel, it is desirably a
copolymer. An ~csori~ting segmpnt that interacts very strongly with itself will form
temporary cros~link~, whereas the r~m~in~lrr of the chain composed of a soluble
sPgm. nt will permit the system to stay in the solution. This is in contrast to polymer
networks in which phase separation of the entire polymeric system occurs. Phase
15 separation can present itself as cloudiness at a temperature known as LCST.
However, in a polymeric chain where associating, self-agg.~gdLillg s~ogm~-nt is a
minor component and the solvophilic chain is very long, soluble d~ cgdLion occurs
prefereably over phase separation (i.e., pr~ripit~tirn or clouding). In such a system,
despite the large Ell due to the minor associating SPgmPnr El2 due to interactions
20 between water and large hydrophilic segment will overwhelm the Ell, thus r~-n~lrring x
< l/2. No cloudiness will be observed.
The above conrll~ion is supported by the observation of thermothirkPning
behavior of the two dirrcl~lL polymer networks systems. Pluronic F127, a triblock
copolymer with a minor hydrophobic component (MW of the poly(propylene oxide)
25 (hydrophobic) section of the block copolymer is 3600, weight pcrcc .Lage of ethylene
oxide in the copolymer is 70%, nominal total molecular weight is 12,600), exhibits no
cloudiness is observed while the system gels (Figs. 25(a) and (b)). In contrast, Pluornic
L-92, a triblock copolymer with a leld~ cly major hydrophobic component ~IW of the
poly(propylene oxide) section of the block copolymer is 2700, weight percentage of
30 ethylene oxide in the copolymer is only 20%, nominal total molecualr weight is 3650), a
very marked cloudiness is observed that is followed by gelation (Figs. 26(a) and (b)).
To further confirm the difference between ag~;l. ~dLion phPnr/m~n~ in relatively"hydrophilic" polymer networks based upon Pluronic'19 F127 and LCST in this system,
the following experiment was con.luct~i Absorbance of a suspension of viscosifying
16
CA 02230727 1997-12-10
WO 97/00275 PCT~US96/10376
polymer network (2 w% 1:1 Pluronic~19 127: poly(acrylic acid) in water, pH 7.0) at 500
nm was measured to be 0.0723 within the range of 3-80~ C. The ,u~pc.~s;on was then
placed in a vial, heated up in a microwave, gently opened up and its tC.llp~ laLure and
absorbance were immPfli-t.oly measured. Suhst~nti~l cloudiness was observed only when
the tclllpc~aLule PY- ee~lPd 100~ C. Absorbance of the suspension at 500 nm (T > 100~
C) was measured to be 0.1385. Upon cooling, the cloudiness quickly disd~pcd.~d. The
thermothi~kPning behavior of the suspension then was measured and the curve was
PccPnti~lly i~lPntir 11 to the one shown in Fig. 25(a). Thus gelation and LCST in this
system were observed to be dir~.~lL by ca. 70~ C.
It has been demonstrated that the viScOSiry;llg polymer networks of the present
invention demonstrate gelation at concentrations much lower than those needed for the
corresponding Pluronic system to gel. However, differential Sr~nning ~lQllmPtry (DSC)
measurements demonstrated that d~ cgiLLion phenomena ~Csori~t-ocl with
thermothi~kPnPing are thermodyn~rnir~lly i<lPnti~l in both systems.
It is generally accepted that, in low concentrations and teu~pc.aLuics of
poloxamer solutions, there exists and equilibrium between monomers, mi~llPs, andmicellar aggregates (Brown et al. J. Phys. Chem. 95:1850 (1991)). At low concentrations,
the a~pd.~.lL micellar radius increase with increasing temperature. As concentration
increases, agglc~ grow into asymmetic particles eventually resulting in a 5~li.1likP gel
that is ususally observed at de_ned t~ C~aLul~. The visco~.fyillg polymer network of
the present invention, however, does not require a cignific~nt formation of pol~ mPr
ag~ E,dLes before viccocific~tion occurs.
Consider what addition of a gel particle into a 5llcpPnci~n will do. For
simplicity, assume the liquid to be Newtonian (it is, in fact, non-Newtonian which
should show an even greater effect). When a gel particle is added to the solution, the
FinctPin equation can be written in the form (Ball, et al. J. Phys. Chem ~ iqr~ 9:99
(1980),
d~7 = const(~7d~),
where d~7 is the increment of viscosity on the addition of a small increment of phase
volume d~ to a suspension viscosity ~1.
When a gel particle is added to a suspension where polymer chains s~lbst~nti~llyoverlap, it will require more space than its volume d~s because of the packing riiffi~lltiP5
Accounting for the crowding effect yields,
CA 02230727 1997-12-10
WO 97/00275 PCTAJS96/10376
When ~ + l/K, the viscosity becomes infinite. Thus, only a few gel particles areneeded in the present viscosifying polymer network in order to cignifir~ntly vis~ O .;ry it
over a polnY~mrr solution, such a Pluronic, lacking such particles. This effect is
m~gnifirc~ by bridging gel particles with adjacent hydrophobic and hydrophilic
5 components of the polymer network.
Thermogelation has been observed in hydrophobe-mo~lifi~(i poly(n-
alkylacrylamides) (Schulz, Kaladas et al. ), polysaccharides aauregui et al. ), POP-POE
block copolymers (~l. Y~nr~ritic et al. ) and other systems. None of these systems,
however, shows useful pH-respon,l~.~ss in a wide range of tempe.~lu,~. Even graft
copolymers described by Hoffmann and Chen (WO 95/24430) exhibit a LCST and
therefore show a cloud point in connrctinn with viccocific ~tic n Such systems are
limited to dually responsive polymers which exhibit phase separation of the entire
system.
Fig. 4 shows endotherms of (a) 1% Pluronical' F127 and (b) 1% responsive
polymer r.~.w~"L (Pluronic'lD F127/polyacrylic acid 1:1) obtained using a MCS
Dir~,~lial Sr~nning Calorimetry System (Microcal, Inc.) by heating samples with the
rate of 15 centigrade/hour. Pluronic~9 F127 is a triblock polymer made up of ethylene
oxide tEO) and propylene oxide (PO) blocks and having the general formula
~O)(PO)(EO), where 70 wt% of the polymer is EO. Broad or sharp endothermic
peaks are seen at char~ rictir temperature of 29~C which coincides with the onset of
gelation in the responsive polymer n~LwolL composition (see, Fig. 1). The peaks are
measured to have enthalpy value of 1.26 cal/g. This enthalpy falls within the range
reported for Pluronic solutions (see, for inct~nrc~ Wanka et al, Colloid~;rul~:"~, Science,
1990, 268, 101, herein incorporated by reference).
The ~r~ ;oned thermal behavior of ~ccori:~ting polymer networks suggests
that the observed increase of viscosity at around 30 ~C is due to agg" gdLion ofpoloxamer molecules at this t~lpe~dLure which, because of covalent bonding (and
possibly hydrogen bonding and/or template formation) with polyacrylic acid or
polyacrylate molecules, serve as cross-links in viscous gel-like structures of illL~d~ -ive
polymer n~Lwo.L. Thus, nonionic surfactants should be well suited to the associating
polymer network compositions of the present invention because of their aggregate- and
micelle-forming capabilities in water.
A general method of making the responsive polymer network compositions of
the present invention comprises solubilization of the associating component in a
CA 02230727 l997-l2-lO
W O 97/00275 PCTAJS96/10376
monomer capable of rol...,ng a solvophilic component or formation of a melt of the
component materials. Solvophilic components suitable for use in the method are those
which exhibit expansion and con~ld~ion in response to a change in ionic strength. The
monomer is polymerized to the solvophilic component. Polym.ori7~tinn may be
5 accomplished by addition of a polymerization initiator or by irradiation techniques.
The initiator may be a free radical initiator, such as rhrmir~l free radical initiators and
uv or gamma radiation initiators. Conventional free radical initiators may be used
according to the invention, inrlll~ing, but in no way limited to a~mmonium persulfate,
benzoin ethyl ether, 1,2'-azobis(2,~dimethylprnt~nitrile) (Vazo 52) and
10 azobisisobu-ylon;Lr;le (AIBN). Initiation may also be accomrlic1..ocl using cationic or
ionic initiators. Many variations of this methods will be appdl~ to one skilled in the
art and are col,L~.llplated as within the scope of the inventiom For example, the
solvophilic component may be dissolved in a monomer/water mixture instead of pure
mc~ m.or. This may be particularly useful in inct~nrPc where the t~,llp~-dLur~ se-la;~iv~
aggrcgdLing monomer does not solubilize well in the monomer or in ;~ r~ ~ where the
monomer of the solvophilic component is a âolid. It may be desirable to remove
Um'ed,~ monomer from the resultant responsive polymer network. This may be
accomplished using collvc..L;onal techniques, such as, by way of example, dialysis.
Reverse phase polymerization may be used to prepare responsive polymer
network beads by dispersion of the solvophilic component/ionizable monomer mixture
in a nonpolar solvent such as heptane. The agglcgdLing polymer/monomer solution is
di~ ed with agitation in a nonpolar solvent, such as heptane or hexane, in order to
5llcpPn~ droplets of the solution. Polymerization of the monomer is initi:~tf'cl by
~u.~vcllL;onal means (i.e., addition of a initiator or irradiation) in order to polymerize
the monomer and form responsive polymer network beads. See, WO 96/02577 and
entitled "Useful Responsive Polymer Gel Beads" for further h~ dLion on the
pl~a dL;on of polymer gel beads, herein incorporated by l~f~.~.lce. Such a method may
be particularly desirable to provide a heat sink for the heat generated in the exothermic
polymerization reaction.
Those skilled in the art will appreciate that the polymer network compositions
of the present invention may be utilized for a wide variety of ph."...~
applications. To prepare an aqueous drug delivery system, according to the te-rhingc of
the present invention an effective amount of the desired ph~...~ ;r~l agent is
incorporated into the aqueous responsive polymer network composition of the present
19
CA 02230727 1997-12-10
WO 97l0027~ PCTrUS96/10376
invention. Preferably the selected compound is soluble in water which will readily lend
itself to a homogeneous dispersion through out the responsive polymer ncL~o.L
composition. It is also prcr~ d that the compound is nonreactive with the responsive
polymer network composition. For materials which are not soluble with the responsive
5 polymer network composition, it is also within the scope of the invention to disperse or
suspend powders throughout the responsive polymer network composition. It will also
be appreciated that many applications will require a sterile enviro~m-~nt It is
contemplated as within the scope of the invention that the aqueous responsive polymer
network compositions of the present invention may be pl~.u~d under sterile
10 conditions. An ?~lrlition~l feature of the interacting polymer gels of the invention is that
they may be pl.p~ d from conctitll~ont polymers that have known ~rcepte~
toxicological profiles. Thus, the interacting polymer gel may be prepared from
polymers which already have FDA-approval.
Exemplary drugs or thc.~..~Lics delivery systems which may be 3rlminict~red
15 using the aqueous responsive polymer network compositions of the invention include,
but are in no way limited to, mncocll therapies, such as esophageal, otic, rectal, buccal
oral, vaginal, and urological applications; topical therapies, such as wound care, skin care
and teat dips; and intravenous/sub~u~anevus therapies, such as hlLl'~ r~ intrabone
(e.g., joints), spinal and subcutaneous therapies, tissue suppl~ m~ nr~tinn, ~ h~ocinll
20 pl~Lion and p~.dl drug delivery. It will be dpp.~ d that the ionic nature of
the "structural component" component of the responsive polymer network provides an
adhesive interaction with mllroc~l tissue.
The biologically active compounds that may be loaded into the polymer
networks of the present invention are any s~lkst In~e having biological activity, in~hlrling
25 proteins, polypeptides, polynucleotides, nucleoproteins, polysaccharides, glycoproteins,
lipoproteins, and synthetic and biologically e.lg;lleCred analogs thereo~
Examples of biologically active compounds that might be utilized in a delivery
application of the invention include literally any hydrophilic or hydrophobic
biologically active compound. Preferably, though not necessarily, the drug is one that
30 has already been deemed safe and effective for use by the appl~p~iate gov~
agency or body. For example, drugs for human use listed by the FDA under 21 C.F.R.
330.5, 331 through 361; 440-460; drugs for veterinary use listed by the FDA under 21
C.F.R. 500-582, incorporated herein by reference, are all considered acceptable for use in
the present novel polymer networks.
CA 02230727 1997-12-10
W O 97/00275 PCT~US96/10376
Drugs that are not th~ .lscl~,~., liquid at body ttlllpc,dLulc can be incorporated
into polymers, particularly gels. Moreover, peptides and proteins which may normally
be lysed by tissue-activated enzymes such as peptidases, can be pa~ ly protected in gels
as well. See, Gehrke et al. Proceed. Intern. Syrtzp. Control. Rel. Bioact. Mater., 22:145
(1995)-
The term "biologically active compound" inrhlrlec pharmacologically active
sllhsrqnr.~c that produce a local or systemic effect in anim~lc~ plants, or viruses. The
term thus means any sllhstqnre intrn~ecl for use in the ~liqgnr,cic, cure, mitigqti~n,
treatment or pl~v~llLion of disease or in the rnhqnrPmrnt of desirable physical or mental
10 development and con-litirns in an animal, plant, or virus. The term "animal" used
herein is taken to mean n~qmm~lc, such as primates, inrl~ing hllmqnc, sheep, horses,
cattle, pigs, dogs, cats, rats, mice; birds; reptiles; fish; insects; arachnids; protists (e.g.
protozoa); and prokaryotic bacteria. The term "plant" means higher plants
(angiosperms, gymnosperms), fungi, and prokaryotic blue-green "algae" ( i.e.
15 cyanobacteria).
The phdL".~ ;rqlly active compound may be any 5nh5tqnre having biological
activity, inrl~lrling proteins, polypeptides, polynucleotides, nucleoproteins,
polysaccharides, gly~opluLeins, lipoproteins, and synthetic and biologically rnginrpred
analogs thereof. The term "protein" is art-l~ogm~ed and for purposes of this invention
20 also rnro~r-c~, peptides. The proteins or peptides may be any biologically active
protein or peptide, naturally oc~,ullh~g or synthetic.
Examples of proteins include antibodies, enzymes, steroids, growth hormone and
growth hormone-releasing hormone, gonadotropin-releasing hormone, and its agonist
and antagonist analogues, Som~tostqtin and its analogues, gonadotropins such as
25 lllt.oini7ing hormone and follicle-stimlll ting hormone, peptide-T, thyrocalcitonin,
pu;~LLyloid hormone, glucagon, ~opl~;n, oxytocin, angiotensin I and II, br~lyl~inin,
kqlli~lin, adrenocorticotropic hormone, thyroid 5timll1qting hormone, insulin, glucagon
and the UU"l~"OUS analogues and congeners of the foregoing molecules.
Classes of pha~ ..1 ;rqlly active compounds which can be loaded into
30 responsive polymer network compositions of the invention include, but are not limited
to, anti-AIDS sllbstqnres, anti-cancer sllhstqnc~c, antibiotics, immllno~pplc~ L~ (e.g.
cyclosporine) anti-viral snhstqnrloc~ enzyme inhibitors, neurotoxins, opioids, hypnotics,
qntihicrqmin~c, lubricants tranquilizers, anti-convulsants, muscle relaxants andanti-Parkinson sllhstqnres, anti-spasmodics and muscle contractants, miotics and anti-
CA 02230727 1997-12-lO
WO 97/00275 PCTrUS96/10376
dlolinergics, anti-gl Illcom~ compounds, anti-parasite and/or anti-protozoal compounds,
anti-hyp~ s;~,~, analgesics, anti-pyretics and anti-infl~mmqtQry agents such as
NSAIDs, local In~octhrtics~ oFhth llmirc, plO~ ~gl~llflinc~ anti-d.~r~.dll~, anti-psychotic
sllhst~nrrc, anti-emetics, imaging agents, specific targeting agents, n~ OIlA~ .a~
5 proteins, cell response modifiers, and vaccines.
A more complete listing of dasses of compounds suitable for loading into
polymers using the present methods may be found in the Pharm~7~ti~rhe Wirksto.~e(Von Klt~rm~nn et al. (eds) Stuttgart/New York, 1987, incorporated herein by reference).
Examples of particular phcu ...~ cu~ ;r~lly active 5nh5t~nre5 are presented below:
Anti-AIDS sllhct~nr~ c are 5~lh5t~nr~ c used to treat or prevent AutoimmllnP
Deficiency Syndrome (AIDS). Examples of such 5llh5t~nrec indude CD4,
3'-azido-3'-dco~yLLylllidine (AZl~, 9-(2-hydroxyethoxymethyl)-guanine acyclovirO,
phosphonoformic acid, 1-~ in~, peptide T, and 2',3' didc~ y~yLidine.
Anti-cancer s~lhst mrec are sllhcr~nrPc used to treat or prevent cancer. Examples
15 of such sllhst~nrec include methotrexate, cisplatin, plcdQisone, hydlo~y~lo~,c~Lerone,
med~o~y~lu~c~Lerone acetate, megestrol acetate, diethylstilbestrol, testosteronepropionate, fluu~ylll.~ .one, vinblastine, vincristine, vinfl~ocin~ daunorubicin,
doxorubicin, llydlo~yurea, procarbazine, aminogl~ltethimic3e, mechlor. Il~ r~
cyclophosphamide, melphalan, uracil mustard, chlorambucil, busulfan, ~.a~
20 lomllclinP, da~l,dzine (OTIC: dhll~llyl~llazenomidazolecarbo~r~mi~e)~ methotrexate,
fluorouracil, 5-fluolould~il, cytarabine, cytosine ar~hinr"ririP, mercaptopurine,
6-mercaptopurine, tnioguanine.
Antibiotics are art l~ogl~i~ed and are s~lhst~nr~s which inhibit the growth of or
kill microo~ ...c Antibiotics can be produced synthrtirllly or by microol~ ;c...c
25 Examples of antibiotics include pPnirillin, tetracycline, chloramphenicol, minocycline,
doxycydine, vanomycin, ba~ ld~ul, kdllduly~;ll, neollly~_;n, ge.l~lly~;n, erythromicin
and cephalosporins.
Anti-viral a~ents are sllhst~nr~c capable of destroying or ~ut)pl~;llg the
replication of viruses. Examples of anti-viral agents include a-methyl-P~
30 methylamine, l~-D-ribofuranosyl-l~2~4-triazole-3 carbn~mi~e,
9-[2-Lydlo~Ly-ethoxy]methylguanine,~ m~nt~n~mint, 5-iodo-2'-deoxyuridine,
trifluolo~hyulidine, interferon, and adenine arabinoside.
Fn7yme inhibitors are sllhst~nr. c which inhibit an enzymatic reaction.
Examples of enzyme inhibitors include edrophonium chloride, N-methylphysostigmin/~,
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nt oStigmin~- bromide, physostigmin~ sulfate, tacrine HCl, tacrine,l-hydroxy mqleqto,
iodotubercidin, p-bromu-~ Ll~ isole, 10-(alpha~iethylaminopropionyl)- phenothiazine
hydrochloride, ~ qlmi.lq701ium chloride, h-omi~holinium-3, 3,5-dinitrocatechol,
diacylglycerol kinase inhibitor I, diacylglycerol kinase in_ibitor II,
5 3-phenylpl~Jpd~;ylamine, N6-monomethyl-L-arginine acetate, carbidopa,
3-Lyd~ ybenzylhydrazine HC1, hydralazine HCI, clorgyline HCl, deprenyl HCl,L(-)-,
deprenyl HCl,D(+)-, hydroxylamine HCl, iproniazid phosph ~
6-MeO-tetrahydro-9H-pyrido-indole, niqlqmi~lP, pargyline HCl, quinacrine HCl,
semicarbazide HCl, tranylcypromine HCl, N,N-diethylq-min~othyl-2,2-diphenylvalerate
10 hydrochloride, 3-isobutyl-1-mc~hylx...~ e, papdv~;ne HCl, indomPth- inrl,
2-cyclooctyl-2-hyd~ol~y~Lhyla_ine hydrochloride, 2~3-dichloro-a-methylbenzyla-m--ine
(DCMB), 8,9-dichloro-2,3,4,5-tetrahydro-lH-2-be.~;~ e hydrochloride,
p-aminoglntethimide, p-aminogh~ltll.i...i~ tartrate,R(+)-, p-aminogltlt-othimi~etartrate,S(-)-, 3-iodotyrosine, alpha-melLyl~y.~,s;ne,L-, alpha-mc~hyl~y.osllle,D L-,
15 acetazolamide, dichlorph.on~mirle, 6-hydroxy-2-benzothi~7oleclllfon~mi~le~ and
allopurinol.
Neurotoxins are 5nh5t~nr~5 which have a toxic effect on the nervous system, e.g.nerve cells. Neurotoxins include adrenergic neu~ o~ulls, cholinergic neuloto~3s,dopalllin~l;;c neurotoxins, and other neul~ ~ns. Examples of adrenergic neurotoxins
20 include N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride. Examples of
dholinergic neurotoxins include acetylethylcholine mustard hydrochloride. Examples of
dop~i~ ;;c neurotoxins include 6-hydroxydopamine HBr,
1-methyl~(2-methylphenyl)-1,2,3,6- tetrahydro-pyridine hydrochloride,
1-methyl~phenyl-2,3- dihydropyridinium perchlorate, N-methyl4-phenyl-1,2,5,6-
25 tetrahydropyridine HCl, l-methyl~phenylpyridirlium iodide.
Opioids are sllhst Inr. ~ having opiate like effects that are not derived from
opium. Opioids include opioid agonists and opioid antagonists. Opioid agonists indude
codeine sulfate, fentanyl citrate, hydrocodone bitartrate, loperamide HCl, morphine
sulfate, noscapine, norcodeine, normorphine, thebaine. Opioid antagonists include
30 nor-binaltorphimine HCl, buprenorphine, chlornaltr~ mine 2HC1, funaltrexamione
HC1, nalbuphine HCl, nalorphine HCl, naloxone HCl, naloxonazine, naltrexone HCl,and naltrindole HCl.
Hypnotics are s~lhst~n~s which produce a hypnotic effect. Hypnotics include
pentobarbital sodium, phenobarbital, secobarbital, thiopental and ..lllL~ures, thereof,
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heterocyclic hypnotics, dioxopiprri~inrs~ glutarimides, diethyl isovaleramide,
a-bromoisovaleryl urea, urethanes and r~iclllf:~nt c
Amihict~min~s are 5llhst~nrec which competitively inhibit the effects of
hict~minf-c Examples include pyrilamine, chlorphenirarnine, tetrahydra~;oline, and the
5 like.
Lubricants are sllhstlnr~oc that increase the lubricity of the .,~vh~)ml~ent into
which they are delivered. Examples of biologically active lubricants include water and
saline.
Tranquilizers are sllhst~nr~c which provide a tranquilizing effect. Examples of
10 tranquilizers include chlorop.o..ld~me, prom~7inr, fluph~n7~inP, .~..~ e, deserpidine,
and meprobamate.
Anti-convulsants are sllhst~nrpc which have an effect of preventing, rednring~ or
~-limin~ting convulsions. Examples of such agents include primi~ic)nr~ phenytoin,
valproate, Chk and ethnsllYimirlr
Muscle l~ 'dll~ and anti-PalLnson agents are agents which relax muscles or
reduce or rlimin~tr :,yn-~c~ls associated with Pa.Lnson's disease. Examples of sudh
agents include mephenesin, methocarbomal, cydob. ~;~.illC hydrodlloride,
trihexylphenidyl hydrodlloride, levodopa/carbidopa, and biperiden.
Anti-sp Icm~rlifc and muscle cc~ rd. ~ are 5nbst~nr~oc capable of p~c~ mg or
20 relieving muscle spasms or co.-Lld~;ons. Examples of sudh agents include dLlvpine,
scopolarnine, oxyphrnrlnillm, and pd~d~ e.
Miotics and anti-cholinergics are compounds which cause brondhodilation.
Examples indude erhrrhiophate, pilocarpine, physostigminr salicylate,
dusoplu~ylnuoroph-~sph~te, epinephrine, nPostigminf, carbachol, mPthl~holine,
25 l: eth~nf rhol, and the like.
Anti-~l~llcom~ compounds include betaxalol, pilocarpine, timolol, timolol salts,and combinations of timolol, and/or its salts, with pilocarpine.
Anti-parasitic, -protozoal arld -fungals include ivermectin, pyrim.7tl~ lminf-,
trisulfapyrimi~linP, clindamycin, amphotericin B, nystatin, flucy-tosine, natamycin, and
30 micrn~7ole.
Anti-hypertensives are s~lbst~nrrs capable of counteracting high blood pressure.Examples of such sllhst~nrt~s include alpha-methyldopa and the pivaloylu~Ly.Lllyl ester of
alpha-methyldopa.
Analgesics are suhst~nrf c capable of preventing, reducing, or relieving pain.
24
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Examples of qnqlgPcirc include morphine sulfate, codeine sulfate, meperidine, and
nalorphine.
Anti-pyretics are sukstqnrpc capable of relieving or reducing fever and
anti-inflqmmqtory agents are sllhstqnres capable of counteracting or ~u~p~C~:~illg
inflqnnmqtinn Examples of such agents indude aspirin (salicylic acid), in~lc)mPth .~in,
sodium in~lomPth~in trihydrate, salicylamide, naproxen, colrhirinP, fenoprofen,
slllinr~ liflllnic~l~ diclofenac, indoprofen and sodium salicylamide.
Local ,q-npcth~tics are 5llhstqnrps which have an qnPcthPtic effect in a localized
region. Examples of such qnPsthptirc include procaine, lidocain, tetracaine and
dibucaine.
Ophthqlmirc indude rli~qgnostic agents such as sodium fluorescein, rose bengal,
mPthq~h~line, adrenaline, cocaine, and atropine. Ophrhqlmic surgical ad~ iv~j include
alpha-chymu~,y~sin and h~raluronidase.
Prostqelqn~linc are art ~u~;ni ed and are a class of naturally occurring
rhPmirqlly related, long-chain hydlo~y fatty acids that have a variety of biological
effects.
Anti-dep~c~ are sllhstqnrec capable of pl~ V~l ing or relieving depression.
Examples of anti-dep.essd.l~ include imipramine, allliL.;~yline, nortriptyline,
plu~;p~yline, des;p,dllline, amoxapine, doxepin, maprotiline, tranylcypromine,
phPnPl7inP, and isocarboxazide.
Anti-psychotic substqnrPc are substqnrPs which modify psychotic behavior.
Examples of such agents include phenothiq7in~c, buLy,uphenones and thi-~rqnthPnPc
Anti-emetics are substances which prevent or alleviate nausea or vomiting. An
example of such a substqnce inrhl<iPc dramqminP
Imaging agents are agents capable of imaging a desired site, e.g. tumor, in vivo.
Examples of imaging agents include sllhstqnrPs having a label which is detectable in vivo,
e.g. antibodies ~ttq~hP,I to fluorescent labels. The term antibody inrlurlPc whole
antibodies or fragments thereof.
Specific targeting agents include agents capable of delivering a therapeutic agent
to a desired site, e.g. tumor, and providing a therapeutic effect. Exarnples of targeting
agents include agents which can carry toxins or other agents which provide bPn~firiql
effects. The targeting agent can be an antibody linked to a toxin, e.g. ricin A or an
antibody linked to a drug.
Neu~ PrS are sllhstqnres which are released from a neuron on PYritqtinn
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and travel to either inhibit or excite a target cell. Examples of r.~ulu~ ...ittPrs indude
dopamine, serotonin, q-aminobutyric acid, norepinephrine, hict IminP, acetyldholine, and
epinephrine.
Cell response modifiers are dhemotactic factors such as platelet-derived growth
5 factor (l?DGF). Other chemotactic factors include neutrophil-activating protein,
monocyte rhPnnrJ .I l . d~ Ldll~ protein, macrophage-infl~ ol y protein, platelet factor,
platelet basic protein, and melanoma growth Stim~ ting activity; epidermal growth
factor, transforming growth factor (alpha), fibroblast growth factor, platelet-derived
endothelial cell growth factor, insulin-like growth factor, nerve growth factor, and bone
10 growth/cartilage-in~l.ring factor (alpha and beta), or other bone morphogenetic protein.
Other cell response modifiers are the interleukins, interleukin inhibitors or
intPrl~ llkin receptors, inr1~1-1ing interleukin 1 through interleukin 10; iI~t~lr~.uns,
inrhl~ing alpha, beta and gamma; hematopoietic factors, inrl~lrling e. ~LLopoietin,
granulocyte colony stimlll~ting factor, macrophage colony ctimnl:~ting factor and
15 granulocyte-macrophage colony stimlll7ting factor; tumor necrosis factors, inrl~lfling
alpha and beta; transforming growth factors (beta), inrhlrling beta-1, beta-2, beta-3,
inhibin, and activin; and bone morphogenetic proteins.
As those skilled in the art will ~pr~dLe, the foregoing list is PYrmrl~ry only.
Because the aqueous responsive polymer network composition of the present invention
20 is suited for application under a variety of physiological conditions, and in particular is
well-suited for tl~ csc~l applir~tirlnc a wide variety of pharm~re~ltir7l agents may be
incorporated into and ~~minicrPred from the responsive polymer network composition.
Other routes of delivery include, but are not limited to, opthalmic, otic, nasal,
buccal, sublingual, injectable, dermal, subdermal, oral, vaginal and rectal. These routes
25 benefit from the responsive polymer network being a system that has reverse
viccocifir~rion, bi~ lhPcinn, and Pmlllcifirltir~n propertes. In terms of opthalmic
delivery, the responsive polymer network composition may be used as a liquid vehicle at
ambient tclllpe.d~ule, and after ~ ini~lr.LLion to the eye, the responsive polymer
network would become viscous to f.~ilit~tP the delivery of actives or act as an adjuvant
30 for lubricity and hllm~ ncy. In terms of nasal delivery, the responsive polymer could
be delivered as a spray to the nasal cavity which would then viscosify in place, and
provide a film for coating the nasal mucosa. In terms of injectable delivery, the
responsive polymer network compositions may be used as an enteric coating for tablets
or as a suspension for delivery of active agents that benefit from PYt.onflerl release
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through viccocifir~tion in the g~L~ Pstin~l tract. In terms of vaginal and rectal
delivery, typical formulations exhibit viscosity decreases at body t~llp~,~Lure and exude
out of the vaginal or rectal cavity. The increase in viscosity at body te~ p~dLule that
the responsive polymer network exhibits will help to prevent leakage.
The responsive polymer network composition may be used in a variety of
applications where it is desired to change the viscosity of a liquid c,lv;lolllllent. The
responsive polymer network composition may be used to reversibly modify the
viscosity of an article, device or composition, by incorporating an aqueous responsive
polymer network composition co~ Jl;se;l of about 0.01 to 20 wt%, and preferably about
0.1 to 5 wt%, of ~Ccori~ting responsive component and about 0.01 to 20 wt%, and
preferably about 0.1 to 5 wt%, of a solvophilic component capable of expansion and
~o--Lra~Lion as a function of ionic strength into the article, device or composition. By
increasing temperature, the aqueous composition exhibits at least a five-fold increase in
vis~o,;Ly upon gelation, and by reducing te.llpe.~-ure~ the composition exhibits at least a
five-fold decrease in v;~.os;Ly upon liqllifir~tion
The four pl;lllaly characteristics of the materials introduced herein, which canbe exploited for commercial applications are:
1) Reversible viccosifir~tion above the transition temperature.
2) Reversible ~setting~ at temperatures above the transition temperature.
3) Controlled release of loaded molecules.
4) Conformation to physical environment upon viscocifir~tirln or formation of a
semi-solid m~tPri~l
Reversible Viccocifir~tion: The reversible viccocific~tinn of the responsive
polymer network family at elevated tempe.dL~Iles makes the materials ideal for am~gnirll(le of functions in several dir~ ,lL fields. One application would be in the
industrial and automotive use of oils and lubricants. Traditional lubricating products
tend to thin under high tel~lp~ldLul~ conditions, often to the point where they become
completely in~rr~ Live in reducing friction. An oil or lubricant which contained the
correct proportion of a reverse thermal gel, however, would be just as efre~Liv~ at high
t~lllpeldLures as at low temperatures, as the viscosifying effect of the responsive polymer
network would ~ ull-~ld-L the thinning of the other conctitllpntc of the lubricant as the
temperature rose above the responsive polymer network's transition temperature. The
same principle which makes the responsive polymer network's useful in this application
would also make them suitable as thirkPning agents in other commercial products such
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as paints and Co~t;n~c, liquid cleaners and polishers, as well as food products, ~ocperiqlly
microwave foods, at any t~lp~aLLllc above the transition. ~1 Ining products which are
intPnrle~l to act at high teLup~LdLllres, oven cleaners in particular, would especially
benefit from the addition of a reverse-thermal transition responsive polymer network, as
5 the viscosifying effect above the transition t~.upe-~Lure would act to thicken the
solution and keep the cleaner fixed and evenly spread over the oven surface during the
~lPqning process. Novel products could also be developed from this principle such as a
"liquid chewing gum~ which could be sold, stored, and introduced into the mouth as a
liquid, at which point it would viscosify and take on the p.op~. LLes of regular chewing
10 gum.
Another primarily inrlllctriql use of the "thirkPning~ of solutions contqining the
responsive polymer network is in emulsions. CU11~1L1Y PmlllcifiPr5 are often neg~Llvcly
effected by increased tP~-p~-dLul~. A simple example is the loss of volume and
"li~htnPss~ of whipped cream upon heating. An additive with reverse thermal
15 viccocifir~tic n p.up~Lies, however, would react in exactly the opposite way, increasing
its ability to emulsify as it gained three-&ensional structure upon heating above its
transition t~lUp~.~Lu.c. The ability to emulsify solutions at high temperatures would be
applicable in other solutions, inrl~lrling paints, co~tingc~ and waxes.
In the applications where the responsive component is a aulra~L~uL~ the
20 responsive polymer network will have the ability to act as a P1LU1.UY ~ mnlcifi~r without
any (or with very little) addition of traditional s--- r~ The responsive polymer
network will also act as a stabilizer for oil-soluble ingredients that would COll~ . ~1 ;c~nqlly
need to be solubilized by oils in formulation. The associating portion of the iU~.~L;llg
p~l~,~ldLillg network forms domqinc that act as reservoirs for such materials. These two
25 features of the material of the invention would enable it to be used as a base in a
cocmPti~ formulation that would be non-greasy due to lack of oils, such as petrolatum
and mineral oil.
The Pmlllcifir.ti~n abilities of the responsive polymer network would allow a
material to be m~intqinPd in a system for an in-lPfinirP period of time. The
30 .~mnlcifi~qtion could provide a barrier around the mqtPriql An example would be a
pigment or a dye in a mascara. The Pmlllcifi~ti~)n abilities of the responsive polymer
network could also provide a controlled rliffil~ion from the material upon activation.
Two examples would be the continuous release of a fragrance in a deodorant or cologne,
or the release of an active ingredient such as an antiperspirant.
28
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The responsive polymer network's ability to viscosify with increased
temperature could provide a semi-permeable or impermeable barrier. In a cocmpti~formulation, this feature would provide a protective barrier or allow for a slow diffusion
of other materials. The responsive polymer network may also become in. .ed~,.ngly rigid
5 with increasing te,~p~.dLule and thereby create rigidity in cocm~tirc
The responsive polymer network exhibits bioadhesive ch~d, 1. . ;~l ;rc, In
cocmPtit~ form~ tinnc, the responsive polymer network would adhere to the skin or
hair or hold other materials to the skin or hair.
'The reversible gels of the invention could also have a significant benefit in cases
10 where on wished to n Iint~in or establish a v;,~c, 7;Ly p-up~.Ly in a change from a cold
(e.g., refrigerated) to a heated environrnent. Two examples are dripless ice cream (where
the gel serves to add v;~,. o:,iLy to the ice cream as it melts) and a repair system for the
Alaska pipeline (where a joint might contain a liquid version of the gel which would
viscosify in the event of an oil leak to keep oil from leaking, the oil being at an elevated
15 te.ll~7~,dLule compared to the cold Alaskan environment).
The gel could also provide a dye to indicate that som~thing had been exposed to
too low a te...~eldLu.t:. Currently, there are products that are d.ocignf d to change color
and indicate when som~thing has been exposed to too high a temperature, but this dye
could indi~t~, for example, that a material that changes state, i.e., crystallinity, has been
20 frozen and therefore the change of state inr~ic~7tecl by the change of color would be
important.
The material can also be useful to help introduce a gel-like material into a space
where a semi-solid material would be difficult to introduce. For example, in capillary
electrophoresis, it would be useful to introduce the separations material in a liquid form
25 and then to gel it in situ, thereby greatly reducing the time required. As another
~ample, f~ tri~ and optical wires are often protected by gels, and the gel of the
present invention could help protect such wires by allowing field repair and coating in
difficult to reach areas.
Finally, the ability to form a highly viscous solution reversibly may be especially
30 useful in electrophoresis and other types of chromatography. The material could be
poured into columns or plates at low temperatures, warmed above the transition to
produce a matrix with separation capabilities, and then cooled after separation for easy
repl ~-omf-nt of cont~min ~tF-d material and l.~7Vcly of products.
Setting or Bindin~. The second property of the responsive polymer network's,
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the ability to sel up with increased t~ p~ld~ur~, can be viewed as an PYtPnCinn of the
viscosifying effect but has somewhat diL[..c.lL applications. In the food industry for
inct~nrP, this characteristic would be useful in the ...~....r;~ ~ -ring process. For example,
the fast setting of the responsive polymer network could be utilized in the m~mlf~ lre
5 of hard candies where it would be useful to have the product tahe on more ...a lageable
h~n~lling properties quickly, before the slower process of hardening by cooling sets in.
In formulations ~pluv~d by the proper regulatory agencies, the responsive polymer
network's could be introduced into the candy formlll~tion in ~p~upl;ate amounts to
cause the candy to harden enough to be moved along in the m~mlf~ ring process long
10 before the candy has cooled enough to become solid and non-tacky on its own. This
process might also introduce further desired properties in the end-product by mahing
the candy slower melting and longer lasting.
The same effect could also be introduced into ~rlition~l industrial applir~tioncwhere the responsive polymer network might serve in binding, extrusion, molding,15 cPmPnting~ and modified coating applications. An example of the use of the responsive
polymer ncLwo,h as a binding agent would be in ceramics. In this case, the binding
agent holds together the fine particles of the ceramic object until the firing process is
complete. The responsive polymer network is ideal for this application because it can
be easily applied as a solution and will hold the particles in place until the object is fully
20 fired, since it will begin to viscosify and bind particles as soon as the tc~p~.dLure is
slightly elevated and will continue to do so even at the high t~lpCldLulcs involved in
the firing process. The system can also serve as a thixatrope or a v;~ OSlLy modifying
agent below gellation temperature. In the same way, the responsive polymer network
solutions could be useful for sheet and fiber extrusion as well as molding processes, as
25 they would supply the cohesion which is nc~.d~y prior to the completion of curing.
In rPmPnting applications, the reverse thermal gelation would be useful in any instance
in which it would be desirable to have the cernent set up quichly. Exothermic
rP~tionC~ such as cement curing, would be particularly interesting because the heat
generated would cause a cignifir~nt thirkPning of the uncured cement. Thus, the correct
30 amount of responsive polymer network would help the cement to set even before the
curing process was complete. For co~tingc, the responsive polymer network solutions
could be used in modified setups where the coating material is mixed with the
responsive polymer network solution and applied to the surface to be coated. Thete --p~.dLure could then be elevated above the transition temperature, firmly but
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WO 97/00275 PCT~US96/10376
temporarily fixing the coating in place. The t~~ ,dLure could then be further elevated
to drive off the If .~.~hling water, leaving behind the smoothly coated material. Another
industrial application for the responsive polymer network f~mily is in a&esive
applications and pastes. In those incr~n~Pc where it is pl~f~.led that one have an
S adhesive which can be made to adhere and then easily reverse its properties, the
responsive polymer network's could be ideal c~n~ t~c A correctly forrn~ tP~
solution could be ~l~ocign~ with the needed degree of strength and adherence when the
responsive polymer network sets up above its transition te.llpe,d~ule. The ~h~ci~\n
could then be 1~ ;1 simply by reducing the te-lllp~.d-ure below the tr~ncition-
Controlled Release. The ability to provide controlled release of relatively small
molecules, previously f Y~min~cl in detail for personal care and phdl ..."' c~ ;r~l
applications, could also be applied to the agricultural and inrhlctri~l fields. For
example, a ~plant food" solution, applied to soil as a liquid at low temperature and
allowed to viscosify at ground tc.llp~.dLure, would provide prolonged release of15 nourishment to crops by .cignifi~ntly reducing runoff and isolating the nutrients aroundthe roots of the plants. In industrial applications, the same principle could be exploited
to provide a slow and continuous stream of any additive, slowing the rate of
introduction of the additive at elevated te up~,d~ul~. The release could be utilized in
coating systems, ~lf Ining systems, and ,,.~.,.r ~..ring processes in which it is desirable
20 to keep the additive in physical plo~ y to other materials involved in the process,
without allowing the total amount of additive to become involved in the system'sactivities at the time it is introduced. The controlled release of m t.ori~lc is also very
applicable to the food industries, where one could envision the use of controlled
diffusion from the material above its transition t~.llpe.~Lule to provide a ~on~L~l~ release
25 of flavors and fragrances in the mouth. Likewise, the ability of the highly viccocifif ~J
responsive polymer network to impede movement of large molecules could be utilized
to produce "enzyme factories" where the enzyme is immobilized by the rigid structure,
but substrate and product molecules are allowed to diffuse in and out of the matrix.
Collr(~ llldLion. The ability of the responsive polymer network's to conform to
30 any shape upon formation of the semi-solid state has applications in a variety of
conc lm~r products. The reversibly gelling polymer networks could be used in a variety
of footwear applications, such as in the insoles (factory or aftermarket), ankle collar,
tongue, etc. to give the wearer a custom fit and to enhance comfort and support. This
could be incorporated into almost any type of footwear in~h1~ling athletic shoes
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(walking, running, cross training, b3Ck~th ~ll, tennis, golf, cleated, etc.) casual or dress
shoes, slippers, sandals, hiking boots, work boots, ski boots, in line skates, ice skates,
etc.
These gels can also be used to provide ~ollrullllable fit and support in a variety
5 of different protective gear and sporting goods applications such as helmets
(footh~ll,h~ceb~ll, hockey, bicyde, motorcycle etc.), mouthpieces, h~ lge~r (boxing,
wrestling, etc.), sports gloves (baseball, boxing, hockey, lacrosse, etc), bike seats, masks
(hockey, catcher, lacrosse, etc.), shoulder pads, knee pads, shin pads, elbow pads, weight
belts, a~hletic supporters, goggles, saddles, hand grips (fitness equipment, tennis racquets,
10 baseball bats, etc.), sports clothing inrhl~ing w~u;LS, drysuits, padded g~ll,.-t~ (biking
shorts, etc.) and conrullllable g~lll.,.lL~.
Co~ullllable gels could be used in health care applications like orthopedic
devices, prosthetic appliances, denture plates, hearing aids, various braces (ankle, neck,
knee, etc.), conformable padding for ~LuL.lles, wh.q~l~h~irs, casting bqn~ ing, splints,
etc.
A variety of other cnnCllmtor and industrial uses are also possible for these
col~lll.able gels. These would include women's brassieres, eyeglass and sunglass nose
bridges and ear supports, seating and ful l~ult (chairs, beds, sofas, car seats, baby seats
etc.), hP~phnne5 (aviation, protective, studio, consumer audio), shoulder and hand rests
for telephones, keyboards, etc., conformable toys and models, teething rings, and
conformable park~ging for shipping.
Oil field Applications. The applir~tionc will include all those where an increase
in viscosity is alvdllLagc~ s. The applications also include those where a controllable
decrease in viscosity would also be advdllLag~ous, such as underbal~n~ed drilling.
The polymer system would allow good gas e.lL.ai.~ ent inside the well, which
would help n~int~in a homogeneous density and uniform p~ ule throughout the wcll.
While at the surface the decrease in viscosity would allow for good separation of the
gases and particulate (cuttings), allowing for a cleaner mud to be pul..ped back into the
hole. The polymer system would have the properties of ~nth~m gum while in the
30 well without the negative property of being a food source for microbial growth and
solid and gas entrainment at the surface. Also, the current fluids for underbalanced
drilling are quite thin. During periods of overbalanced pressure, the fluid loss and
formation damage can be quite severe because of the low viscosity of the fluid. With a
thicker fluid, the invasion would be much less because the increase in viscosity would
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slwo down the rate of forrnation penatration.
Removal of cllttin~c Viscosity is not a desirable trait of a drilling fluid while
being pumped into the well. The viscosity is desirable in the annulus of the hole to
remove cuttings from the well. The drilling fluid would be pumped into the well down
S the drill string. The drill string is usually cooler than the rest of the well, because it
cont~inc fluid that has recently been on the surface. The fluid would then leave the drill
string and heat up. The increased viscosity would carry the cuttings to the surface. The
current technology requires rigorous methods to then remove the cuttings from the
fluid. The responsive polymer llcLw~lk based drilling fluid would cool and the carrying
10 ca~awLy would decrease and simple settling could be employed. The behavior would
then be analogous to Xanthan gum, but in a synthetic material wherein the ~ lpc.dLule
could be modified. The responsive polymer network could also be used as a plug for
rlr~ning out the well. Drilling would cease and the responsive polymer network-based
fluid would be pulllped down and the increased viscosity would clean the hole of any
15 cuttingC Drilling with the regular fluid would then resume.
Filtration control fluid. During drilling the formation porosity could change
drastically causing whole mud to enter the formation. The responsive polymer network
could be pumped into the formation and as the heat from the formation warms the
invading fluid, the fluid would viscosify and tL~Lively stop the fluid from co..~ ing to
20 enter the formation. This could be permanent or a solution of high salinity could be
pumped down to remove the viscosifying property of the responsive polymer network.
Consolidation of sand formations. During offshore drilling, the well often
passes through areas of unconsolidated sands or shallow water flows. The responsive
polymer network could be pumped down and viscosify with the change in temperature.
25 The formation would then be stable enough to drill through. Cement could then be
poured to further stabilize the formation. This would not need to be reversible.Zonal shutoff tool. If during drilling, you wanted to temporarily seal a sectionof the well, the fluid could be pumped into place and the temperature would solidify the
material. This could latter be removed by cooling the section with water or by
30 pumping down a brine to remove the viscosifying property from the responsive
polymer network.
Other comrnercial applications. The responsive polymer network may have
additional benefits not described above. One would be the ability to provide a toy
which modified shape and then set to firm that shape. Another would be as a
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thermally-tllgg~.cd m~rh~nit~l device such as a sensor or valve. The ability of the
responsive polymer net vork gel to hold a hydrophobic material in the pr~ e of an
aqueous solution will also be useful in the plc~dlion of non-grea-cy ointn~pntc~ where it
is desired to reduce the amount of organic solvent. The reverse thermal gel could be
5 useful in a gel preform, as reverse of "lost wax" castings. In this case, the gel would
retain its shape as the object is formed and on cooling, it would turn to liquid and could
then be drained from the preform.
The possible appli~-~tinnc of such a reversibly gelling composition are numerousand include, by way of example only, as oil and lubricant additives, food additives,
10 emulsion additives, use in electrophoresis and chrom~t~.graphy, as adhesives and binding
agents, and as curing agents. They may be useful to provide initial green strength in a
liquid system while it is being cured or may be used to slow delivery of an additive at
high ~e.ll~eldLulc. The responsive polymer network composition may be used in shoes,
shoe liners, brassieres or other artides of rlothing~ or medical prosthetic devices to
15 provide conformation, fit and comfort. The responsive polymer network composition
may be useful in a condom as a coating which would in response to body ~C~ ,.dl.UlC
provide a degree of mPrh~ni~l stiffness to the condom-responsive polymer n~wolL
system. The re-cponsive polymer network composition may be used in thermo-
...~. I. ..~;r~l device, such as a sensor or valve. It may also be used as an in-situ plug
20 which gels at higher temperature and then releases at a lower tclllpc.dL~Ire. As an
example, the responsive polymer network composition would be useful as a temporary
block to the flow of urine. Then, for example, by lowering the temperature or byP~rreerling the holding strength of the plug, the flow of urine could be made to occur.
The thermally reversible gel could be useful for fire .o.~l ~;n...Pnt, such that it
25 would v;a~Oa;fy when a first started and keep burning liquid from spreading. Another
~oY Imple is a gel which is liquid in a fire extin~;uisl.~- and becomes a gel when it comes
in contact with a hot object. The gel composition of the invention may be useful as an
energy absorber at high temperatures where other systems break down. The gel may be
useful to open and close pores in clothing or other fabric articles in response to heat.
30 An example is a hot mitt, which is "breathable" at room temperature and would close
down when exposed to heat. The gel may be useful in ~el. l;~ical fluids system. The
gel retains its properties at supercritical conditions and could therefore provide a
m.orh~nicm for separating something in a supercritical system. For example, the gel is a
liquid at room t~lp~.d~llre, and is raised to supercritical conditions at which point a gel
34
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is formed. The p~ ule is then lowered but not to room tell,pe~Lure, so that the gel
retains whatever it surrounded.
The responsive polymer network complexes and aqueous gels of the present
invention may be understood with reference to the following examples, which are
5 provided for the purposes of illustration and which are in not way limiting of the
invention.
Example 1 This example describes the synthesis of a responsive polymer
network and an aqueous responsive polymer network solution prepdl.;l using a triblock
polymer of ethylene oxide and propylene oxide (Pluronic0 F27) and poly(acrylic acid).
10 This example also ~Lal~L.~ s the gelation and the physical pl.,p~ es of the resultant
responsive polymer network.
Synthesis. Block copolymer of propylene oxide (PO) and ethylene oxide Q~O)
having sandwich structure (EO)A(PO)B(EO)A (Pluronic F127 NF, Poloxamer 407 NF,
where ~F~ means Flakes, ~12" means 12X300-3600 - MW of the poly(propylene oxide)15 section of the block copolymer, ~7" ethylene oxide in the copolymer is 70 wt%, and
nnminql molecular weight is 12,600) from BASF (3.0 g) was dissolved in 3.0 g acrylic
acid (Aldrich). This r~pl.s&lL~ a s~bstqntiqlly 1:1 molar ratio of PluronicaD F127 and
polyacrylic acid. The solu~ion was deaerated by N2 bubbling for 0.5 h and following
addition of 100 ~1 of freshly pl~dL.;I saturated solution of qmm-)nillm persulfate
20 ~odak) in ~IPioni~cl water was kept at 70 ~C for 16 h resulting in a ~l~Sp~lL polymer.
Viscosity measurements. A known amount of the resultant polymer was
suspended in 100 ml deionized water into which NaOH was added. Following swelling
for 3 days while stirring, the pH of the resulting fine suspension was adjusted to 7.
Samples of 15 ml each were taken, and pH in each vial was adjusted to desired value by
addition of 1 M HCl or NaOH. Sarnples were then kept overnight and their viccocitit c
were measured at dir~.e.~L tc.~p~.dLures using Brookfield viccom. t-or using either an
SC~18 or an SC4-25 spindle.
A control experiment was done with a physical blend of Pluronic0 F127 and
polyacrylic acid (MW 450,000) available from Aldrich. Pluronic0 F127 and polyacrylic
acid were dissolved together in deionized water at 1 wt% total polymer concentration
and the resultant solution was adjusted to pH 7, stirred and kept in refrigerator. The
responsiveness of the responsive polymer network composition and the physical blend
to temperature and pH is illustrated in Figs. 1, 2 and 5. Figs. 1 and 2 clearly
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fl~rn~nctrate that the synthetic route outlined above resulted in a responsive polymer
ncLwolL polymeric system that is s~;Livc to pH and t~.llpe.dLulc of the environment.
Note that the liquid-gel transition is very sharp, OCcurl;~g over a very small Lcl~ dLure
change or ~pH. Fig. 5 is a viscosity vs. tcmp~rd~ure graph co...p~ g the gelling5 ell~d~L~ Lics of the responsive polymer network composition and the physical blend.
The blend pl~pal~d by physically mixing of the triblock EO/PO/EO polymer and
polyacrylic acid did not exhibit viscosifying effect either as a function of tclllpe~d~ure or
pH.
It was generally observed that 1-5 wt% responsive polymer n.Lwulk
compositions made of Pluronic'19 F127 and polyacrylic acid v;SCO:~;ry at twllp~dLu~ s of
around 30 ~C and higher if pH is ~lj..ct~d to 6 or higher. The gelling effect was
ûbserved in responsive polymer network compositions st~nr~ing 3 months or longer.
Repeated heating and cooling of responsive polymer n~LwulL compositions did not
cause deterioration of the responsive polymer network or the gelling effea. Solutions of
either Pluronic F127 or polyacrylic acid (1-5 w% in water, adjusted to pH 6 or higher)
or physical blends of the two lacked the gelling effects found for responsive polymer
network compositions.
Responsive polymer network structure. Solutions (1 wt% each) of responsive
polymer network composition, a polyacrylic acid (alone) polymerized without Pluronic~19
20 and Pluronic~D F127 (alone) were subjected to gel perm~ticln ~LrollldLography analysis
using triple detector system (light sr~ttl-ring, viscometer, and ~.Ld~Livc index d~cti~n~
Viscotek). The results of molecular weight d~. ..~in ~;o~ are outlined in Table 1.
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Table 1. Results of molecular weight determination of polyacrylic acid
in responsive polymer network, polyacrylic acid itself (PAA),
and Pluronic0 F127.
5 Parameter L)e~initionresponsivepolyacrylic Pluronic
polymer acid F127
network
complex
Number-average MW Mn LnjMj/Lni 212,200 782,000 12,100
Weight-average Mw Mw--~:n,Mj!/Ln;391,100 3,096,000 12,500
z-Average M~= LniMj'/LnjMj~775,600 14,620,000 12,900
Peak average deterrnined by ~W297,000 1,140,000
standards
Polydispersity M~/Mn 1.84 3.96 1.03
Radius o~ gyration rms distance ~rom mass 17.51 62.14 4.34
center
It can be seen from Table 1 that polyacrylic acid of the responsive polymer
network composition and polyacrylic acid synthPci7~ alone are sllhsr Inti~lly ~lirr~ L in
15 m(~lec~ r weights and polydispersity. The presence of the triblock (EO)(PO)(EO)
polymer and its interaction with the developing polyacrylic acid chains had a measurable
effect on the final responsive polymer network composition. Namely, polyacrylic acid
synrhPci7ed in presence of the triblock (EO)(PO)~O) polymer is of lower molecular
weight and is much more monodisperse than the polyacrylic acid p.~ d alone.
20 Pluronic0 was very monodisperse and it's molecular weight corresponded to the data
provided by the supplier. Thus, the responsive polymer ll~,LwOlk compositions of the
present invention are more than the sum of two individual polymers.
Further information on the structure of the responsive polymer network may be
gained using the Mark-Houwink equation. Analysis using Mark-Houwink equation
[~7]--K Mv~, (1)
where [~7] is intrinsic viscosity of (dilute) polymer solution, M~, is viscosity-average
molecular weight of the polymer, K and a are specific . Oll ~L~lL~, can reveal the status of
the polymeric chains. The v;~co~;Ly and molecular weight data obtained for PAA and
responsive polymer network are c~ . d in terms of equation (1), in double
30 log".. ;lh~ c coordinates so that the initial slope of the curves corresponds to the
pal';u~,L~,. a, which is a mea ure of branching of the polymeric chains. Results on
med:.u.~ent of a are coll~cted in Table 2.
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Table 2. Mark-Houwink parameter a and it's intc.~leLd~ion.
System a LlLc.~r~Lation
L)ilute polymer sollltinn in a ~0.5 Random coil
good solvent
Same ~ 1.8 Rigid rod
1 wt% polyacrylic acid0.477 (Log K=-l.990) Linear
1 wt% responsive polymer1.212 (LogK -6.646) Highly branched
network composition
1 wt% Pluronic~9 ~1270.S29 (Log K---2.907) Linear
ÇQ...r.~. ;con of a values suggests that polyacrylic acid prepared by itself and Pluronic'~9
F127 are linear, whereas the responsive polymer network composition is highly
branched (see diL[c.~.lccs in a and K). Because the preparation of the responsive
polymer l.~Lwc.lk composition uses preformed triblock polymer, it may be reasonably
~ccllml~d that the grafting of the triblock polymer onto the polyacrylic acid is the source
of the br~nching
Branching of polyacrylic acid in the responsive polymer network composition
can explain its stability (i.e. ability of responsive polymer network composition to
remain thermo-responsive in dilute scllltinnc for many months) and also may explain
the phenomena of viccocific-tinn at temperatures below the cloud point. Brançhedpolyacrylic acid mnlerlllPc interpenetrate and become ~ont~ngl~ocl with each other and
with the triblock (EO)(PO)(EO) polymer and tnereby forms a ~oll~Lldilled, stablestructure. Because of the branching nature of the responsive polymer network
composition and the degree of .ont~nglPm~nt which arises from the pl~pdldLion of the
interacting network, the conctitu~nt polymers ~ ;e )~e a much ~LIong~r degree ofinteraction than physically mixed polymers. These structures interact even more
strongly because of the tendency of responsive components, such as the triblock
(EO)(PO)(EO) polymers to form aggregates in solution.
Example 2 This example describes the synthesis of a responsive polymer
network and an aqueous responsive polymer network composition p.~aled using
Pluronica9 F108 and poly(acrylic acid). This example also characterizes the gelation and
the physical properties of the resultant responsive polymer network composition.Synthesis. Block copolymer of propylene oxide (PO) and ethylene oxide ~EO)
having sandwich structure (EO)A(PO)~(EO)A (Pluronic F108 NF, Poloxamer 338 NF,
where ~Fn means Flakes, ~10" means lOX300=3000 - MW of the poly(propylene oxide)section of the block copolymer, ~8" means that the weight percentage of ethylene oxide
in the copolymer is 80q~, and nnmin 1l molecular weight is 14,600, 3.0 g) was dissolved
38
,
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WO 97/00275 PCTrUS96/10376
in 3.0 g acrylic acid (Aldrich). The solution was prepared as described above for
Example 1.
Viscosity rr.e~ùlclllents. A known amount of the resultant polymer was
suspended in 100 ml ~inni7.ed water into whidl NaOH was added. Following swelling
for 3 days while stirring, the pH of the resulting fine suspension was adjusted to 7. The
responsive polymer network composition was studied as described in Example 1.
responsive polymer network compositions of 1 wt% Pluronic0 F108 and polyacrylic
acid (1:1) viccocifi~d at te~uEj~r~Lul~a of around 34 ~C and higher at pH 7, as illustrated
in the viscosity vs. temperature graph in Fig. 6. Repeated heating and cooling of the
responsive polymer network composition did not degrade the gelling effect. The liquid
to gel transition of 34~C correlates well with the observed ~ ;c ~llp~.~Lul~: of33.7 ~C of the endothermic peaks that are seen in the DSC endotherm (see Fig. 7~. The
peaks are measured to have enthalpy value of 1.504 caVg. This also corresponds dosely
to a similar endotherm observed for Pluronic0 F108 alone. The observed correlation
supports the con~lllcinn that it is the formation of the triblock (EO)(PO)~O) polymer
a~ g~Les that contribute to the gelation of the responsive polymer network
composltlons.
FY:~-nrle 3 This example describes the synthesis of a responsive polymer
network and an aqueous responsive polymer nc Lw~lk composition prepared using
Pluronic0F88 Prill and poly(acrylic acid). This example also ~llala~L~.~ the gelation
and the physical p.~p~.Lies of the resultant responsive polymer network composition.
Synthesis. Block copolymer of propylene oxide (PO) and ethylene oxide (EO)
having sandwich structure OEO)A(PO)B(EO)A (Pluronic F88 Prill, where ~F" means
Flakes, "8" means 8X300 2400 - MW of the poly(propylene oxide) section of the block
copolymer, "8" means 80 wt% ethylene oxide in the copolymer is 80%, and the nominal
m(~l~clll~r weight is 11,400, 3.0 g) was dissolved in 3.0 g acrylic acid (Aldrich). The
solution was prcp~Lc;l as described above for Example 1.
Viscosity me~ul~."ents. A responsive polymer network composition was
p.'~L cd and studied as described in Example 1. responsive polymer network
compositions of 1 wt% Pluronic0 F88 and polyacrylic acid (1:1) viccocifi.od at
temperatures of around 48 ~C and higher at pH 7, as is illustrated in the viscos;Ly vs.
temperature graph of Fig. 8. Repeated heating and cooling of responsive polymer
network suspensions was not observed to cause deterioration of the gelation effecl. This
measurement correlates well with the observed characteristic tc~lp~ldLure of 47 ~C of the
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WO 97/00275 PCTrUS96/10376
endothermic peaks that are seen in the DSC endotherm. The peaks are measured to
have enthalpy value of O.9 cal/g.
FY---,Ie 4 This Example is directed toward demonstrating that covalent cross-
linking of polyacrylic acid component of responsive polymer network may be used
without rletrimfntal effect to the ~ ons;vc polymer network gelation.
Pluronic0 F127 NF (3.0 g) and 7.5 mg of pentaerythritol triallyl ether
(crocclinking agent, Aldrich, tedh., 70%) were dissolved in 3.0 g acrylic acid (Aldridh).
The cros~linking agent was sl~ if nt to lightly crosslink the polyacrylic acid. The
solution was ded~.dL. d by N2 bubbling for 20 min and following addition of 50 ~1 of
freshly prepared 300 mg/ml solution of ammonium persulfate ~odak) in (~fioni7Pd
water was kept at 70 ~C for 2 h resulting in a strong whitish polymer. A sample of the
polymer obtained (2.0 g) was s~lcpfnrlf~l in 1OO ml ~lf~ioni7ed water into whidl 0.32 g
NaOH was added. Suspended responsive polymer network partides were allowed so
swell for 3 days under conctqnt stirring. The resulting fine suspension ~Yhihit.o~ very
high viscosity at T > 30 ~C and low viscosity at T < 30 ~C.
Exalnple 5 This example describes the synthesis of a responsive polymer
network and an aqueous responsive polymer network composition prepared using
Pluronic0 P104 and poly(acrylic acid). This example also ~ f c the gelation and
the physical p~up~.Lies of the resultant responsive polymer network composition.Block copolymer of propylene oxide (PO) and ethylene oxide (EO) having
sandwich structure (EO)A(PO)B(EO)~ (Pluronic P104, where ~P" means Paste, ~1O"
means 1OX300 3000 - MW of the poly(propylene oxide) section of the block
copolymer, ~4" means 40 wt% ethylene oxide in the copolymer and the nr~minq1
molecular weight is 5,900, 3.0 g) was dissolved in 3.0 g acrylic acid (Aldridh). The
solution was p~ as described above for Example 1. A responsive polymer
network composition was prepared and studied as described in Example 1. responsive
polymer network compositions of 2 wt% Pluronic0 P104 and polyacrylic acid (1:1)
vic~ocified at ttlup~.d~u~C of around 28 ~C ~nd higher at pH 7, as is illustrated in the
viscosity vs. ~e up~,d~ure graph of Fig. 9. Repeated heating and cooling of responsive
polymer network suspensions was not observed to cause deterioration of the gelation
effect.
FX~ 6 This example describes the synthesis of a responsive polymer
network and an aqueous responsive polymer network composition pr~fd using
Pluronic0 P123 and poly(acrylic acid). This example also charartfri7~c the gelation and
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W O 97/00275 PCTrUS96/10376
the physical pn~p~- Lies of the resultant responsive polymer network composition.
Block copolymer of propylene oxide (PO) and ethylene oxide (EO) having
sandwich structure (EO)A(PO)B(EO)A (Pluronic0 P123, where ~P} means Paste, ~12"
means 12X300 3600 - MW of the poly(propylene oxide) section of the block
5 copolymer, ~3" means 30 ~,vt% ethylene oxide in the copolymer and the n~min~l
molecular weight is 5,750, 3.0 g) was dissolved in 3.0 g acrylic acid (Aldrich). The
solution was pr~alcd as described above for Example 1. A responsive polymer
network composition was prepared and studied as described in Example 1. responsive
polymer network compositions of 2 wt% Pluronic0 P104 and polyacrylic acid (1:1)
10 viccocifi~fl at tempe.dL-n~s of around 25 ~C and higher at pH 7, as is illustrated in the
viscosity vs. temperature graph of Fig. 10. Repeated heating and cooling of responsive
polymer ne~wolk suspensions was not observed to cause deterioration of the gelation
effect.
Example 7 The following example ~lpmonctrates the effect of
15 hydrophilic/hydrophobic ratio on the gelling te llp~,ld~Ule. Responsive polymer
network compositions were pl~ ed from the following triblock copolymers shown inTable 3.
Table 3. Composition of triblock polymers inv~ostiget~l
20 poloxamer composition MW of l'O block wt% o~ l~:O block
(~:~)37(1~~)56(~ ~)37 3250 50
(I~'~)25(l~~)56(~ ~)2s 3250 40
(k~)l6(l~())56(~:~)l6 3250 30
Table 3 shows that in this series, the fraction of EO is reduced when the
molecular weight of the PO block is kept crlnct~nt, In a paper by Linse (Macromol.
26:4437-4449 (1993)), phase diagrams for these copolymers in water were r ~ tec~ and
it was shown that two-phase boundaries corresponding to the beginning of agg-~g~Lion
are almost lln~ff~t~ by the molecular mass, given a constant EO/PO ratio, whereas
these boundaries shifted to lower temperature as the EO content of the polymer is
reduced at constant mass. The strong dependence of the EO/PO ratio is a consequence
of the rliff~ring solubilities of EO and PO in water at the elevated temperatures. Thus
one would suppose that agg.eg;dL;on that causes viscocific~tinn in the responsive polymer
network composition should shift to lower temperature as EO fraction de~l~d~es.
41
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WO 97/00275 PCTAJS96/10376
The polo~r~m~r (3.0 g) was dissolved in 3.0 g acrylic acid. The s~.hltion was
deaerated by N2 bubbling for 20 min. and following addition of the 100 ~1 of freshly
p~al~ sdLuldL~d solution of ammonium persulfate in deionized water was kept at
70-C for 16 h resulting in a strong whitish polymer. A sample of the polymer obtained
5 (0.4 g) was suspended in 40 ml r~ <)rli7~d water into whidh NaOH was added.
Suspended responsive polymer network partides were allowed to dissolve under
COllaLdllt stirring. The resulting 1 wt% responsive polymer network solutions were
subjected to the viscosity lll~daulc~llent at shear rate of 132 or 13.2 sec~l using a SC4-18
spindle' It can be seen from Fig. 11 that, firstly, viscosity of the 1 wt% l~ponal~
10 polymer n~wo~L solutions before vic~ocifi~ati<~n (at 20-24-C) increases in the series
(EO)3~(PO)s6(E~)37 > (E~)2s(Po)s6(Eo)2s > ~EO)l6(1?O)56(EO)l6 and, secondly, thetc~u~e.dLule at whidh gelation shifts from about 45-C for (EO)37(PO)56(EO)37 to about
35 C for (EO)25(PO)56~O)25 and (EO)l6(PO)56(EO)l6. Both results are in ~ ont
agl~.... c,.L with the theory set forth in Linse.
FY~tnpl- 8 This example ~l~om~ .dtcs the ability to shift the te.u~.. d~ulc atwhidl a polymer network gel viccocifiloc by arlflitit~n of a salt into the aqueous solution.
The polymer network was pr~pdlcd as described in Example 1. The dry
polymer was placed into either deionized water or a 0.5 M NaCI solution. in
proportions to provide a 2.5 wt% solution. Viscosity profiles for the two aqueous
solutions were rl~ .od and are reported in Fig. 12. The ~dscos;Ly of a 2.5 wt%
solution in deionized water has a higher initial viscosity than that in a 0.5M NaCl
solution at 20~C. Further, the ~C~up~.dLulc at whidh gelation occurc shifts from about
35-C in water to about 30~C in the NaCl solution. Thus, a dhange in the ionic
strength of the aqueous gel composition alters its gelling properties.
F~Y~ple 9 This example describes the ~yllLhcs;s of a responsive polymer
network and an aqueous responsive polymer network composition prepared using
Pluronic"9 F127 and poly(acrylic acid) with a 75% reduction in ammonium persulfate
initiator, relative to Example 1.
Pluronic F127 NF grade from BASF (3.0~) was dissolved in 5 grams of Acrylic
Acid (Aldrich). The solution took approximately 30 minutes to solubilize. The
solution was dearated for 15 minutes and 25uL of a 0.1gramJ2mL ~mmorlil-m persulfate
(Kodak) in deionized water solution was added. The solution was heated in a bead bath
at 70~C for 20 minllt~s A white polymer is formed and is then removed from the
tube, cut into small pieces, and placed in a dish to dry overnight. A 3% by weight
42
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solution of dry polymer to c~PiQni7Pd water is prepared to allow the polymer to
soh~hili7~ To neutralize the solution d~pl~-X;~ y 0.3g of NaOH tFisher) is added to
the solution prior to solubilizing of the polymer. The polymer pieces solubilize at
neutral pH over a period of 48 - 72 hours. The viscosity of the sohltil~n increased at
5 37~C when tested using a Brookfield viscometer.
Example 10 This example describes the synthesis of a responsive polymer
network and an aqueous responsive polymer network composition prepared using
Pluronic0 F127 and poly(acrylic acid) with a 50% reduction in ammonium persulfate
initiator, as ~o,..pdl~d to example 1.
Pluronic F127 NF grade from BASF (3.0g) was dissolved in 5 grams of Acrylic
Acid (Aldrich). The solution took approximately 30 minutes to solubilize. The
soll~tinn was dearated for 15 minutes and 50uL of a 0.1grarn/2mL ammonium persulfate
(Kodak) in deionized water solution was added. The solution was heated in a bead bath
at 70~C for 20 minllt~s A white polymer is formed and is then removed from the
tube, cut into small pieces, and placed in a dish to dry overnight. A 3% by weight
solution of dry polymer to deionized water is prepared to allow the polymer to
50lnhili7e To neutralize the solution ~pro~llldLely 0.3g of NaOH tFisher) is added to
the solution prior to solubilizing of the polymer. The polymer pieces solubilize at
neutral pH over a period of 48 - 72 hours. The viscosity of the solution in~ledsed at
37~C when tested using a Brookfield V;~,O-~
Example 11 This example describes the synthesis of a responsive polymer
network and an aqueous responsive polymer network composition pre~d.~d using
Pluronic0 F127 and poly(acrylic acid) with Iwice the amount of ammonium persulfate
initiator, as ~oll~palcd to Example 1.
Pluronic F127 NF grade from BASF (3.0g) was dissolved in 5 grams of Acrylic
Acid (Aldrich). The solution took apprt ~rim -t.oly 30 minutes to sol~lhili7~. The
solution was dearated for 15 minutes and 100uL of a 0.1grarn/lmL ammonium
persulfate tKodak) in deionized water solution was added. The solution was heated in a
bead bath at 70~C for 20 min~t-~5 A white polymer is formed and is then removed
from the tube, cut into small pieces, and placed in a dish to dry overnight. A 3% by
weight solution of dry polymer to deionized water is prepared to allow the polymer to
solubilize. To neutralize the solution appro~rim -t.oly 0.3g of NaOH tFisher) is added to
the solution prior to solubilizing of the polymer. The polymer pieces solubilize at
neutral pH over a period of 48 - 72 hours. The viscosity of the solution increased at
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37~C when tested using a Brookfield viscometer.
FY~nlrl~P 12 This ~ample describes the synthesis of a .~SpOl~;Vc polymer
network and an aqueous responsive polymer network composition prepared using
Pluronic0 F127 and poly(acrylic acid) with AIBN as initiator.
Pluronic F127 NF grade from BASF (3.0g~) was dissolved in 5 grams of Acrylic
Acid (Aldrich). The solution took ~p~.~x;.n.lPly 30 minutes to 50lnhili7~P The
solution was dearated for 15 minutes and 50uL of a 0.1gram/lmL alpha,alpha'-
azoisobuLy.olllLl;le (Aldrich) in acetone was added. The solution was heated in a bead
bath at 70~C for 20 min~ltps A white polymer is formed and is then removed from the
tube, cut into small pieces, and placed in a dish to dry ~vcllligLL. A 3% by weight
solution of dry polymer to ~IPic.ni7ed water is prepared to allow the polymer tosnlllhili~P. To neutralize the solution approx;... ~ ly 0.3g of NaOH (Fisher) is added to
the solution prior to s.~hlbili7ing of the polymer. The polymer pieces solllhili7P at
neutral pH over a period of 48 - 72 hours. The v;~C~S;Ly of the solution increased at
15 40~C when tested using a Brookfield viccom~otpr~
Example13 This example describes the synthesis of a responsive polymer
network and an aqueous rcsponsive polymer network composition p.e~ using
Pluronic0 F127 and poly(acrylic acid) with Vazo 52 as initiator.
Pluronic F127 NF grade from BASF (3.0g) was dissolved in 5 grarns of Acrylic
20 Acid (Aldrich). The solution took app.~.ndL~ly 30 minutes to solubilize. The
solution was dearated for 15 minutes and 200uL of a 0.1gram lmL Vazo 52 (Dupont) in
acetone solntic n was added. The solution was heated in a bead bath at 70~C for 20
minllrPs A white polymer is formed and is then removed from the tube, cut into small
pieces, and placed in a dish to dry o~ ..igllL. A 3% by weight solution of dry polymer
to deionized water is pl.~dled to allow the polymer to solubilize. To neutralize the
solution ~p,.,x;.~IrtPly 0.3g of NaOH (Fisher) is added to the solution prior tosolubilizing of the polymer. The polymer pieces solubilize at neutral pH over a period
of 48 - 72 hours. The viscosity of the solution increased at 37~C when tested using a
Brookfield vi~comPter.
F,x~nrle 14 This example describes the synthesis of a responsive polymer
network and an aqueous responsive polymer network composition prepared using
Pluronic39 F127 and poly(acrylic acid) with 25% water added.
Pluronic F127 NF grade from BASF (2.25g) was dissolved in 3.75 grams of
Acrylic Acid (Aldrich) and 2g of deionized water. The sohltion took app..~.l.~L~ly 30
,
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rninutes to 50lllhili7e The solution was dearated for 15 minutes and 50uL of a
0.1gram~1mL ammonillm persulfate ~tKodak) in deionized water solution was added.The solution was heated in a bead bath at 70~C for 20 minlltpc A white polymer is
formed and is then removed from the tube, cut into small pieces, and placed in a dish to
5 dry overnight. A 3% by weight solution of dry polymer to deionized water is prepared
to allow the polymer to solubilize. To neutralize the solution approximately 0.3g of
NaOH (Fisher) is added to the solution prior to solubilizing of the polymer. Thepolymer pieces solubilize at neutral pH over a period of 48 - 72 hours. The viscosity of
the solution increased at 35~C when tested using a Brookfield vis. oll~
10Example 15 This example describes the synthesis of a responsive polymer
network and an aqueous responsive polymer network composition pre~d.ed using
Pluronic~l9 F127 and poly(acrylic acid) with 35% water added.
Pluronic F127 NF grade from BASF (1.95g) was dissolved in 3.25grams of
Acrylic Acid (Aldrich) and 2.8g of deionized water. The solution took approximately
1530 minutes to solllbili7P The solution was dearated for 15 minutes and 50uL of a
0.1gram/lmL ammonium persulfate (Kodak) in deionized water solution was added.
The solution was heated in a bead bath at 70~C for 20 mimlt~Pc A white polymer is
formed and is then removed from the tube, cut into small pieces, and placed in a dish to
dry overnight. A 3% by weight solution of dry polymer to deionized water is p~pdlcd
20 to allow the polymer to solubilize. To neutralize the solution appl. xi...-~. ly 0.3g of
NaOH (Fisher) is added to the solution prior to solubilizing of the polymer. Thepolymer pieces solubilize at neutral pH over a period of 48 - 72 hours. The viscosity of
the solution in~l~ced at 37~C when tested using a Brookfield viscometer.
Example 16 This example describes the synthesis of a responsive polymer
25 network and an aqueous responsive polymer network composition prepared using
Pluronic~ F127 and poly(acrylic acid) with 25% water added and a 50% reduction in
ammonium persulfate initiator, as colllpaled to F~mrlP 1.
Pluronic F127 NF grade from BASF (2.25g) was dissolved in 3.75 grams of
Acrylic Acid (Aldrich) and 2g of deionized water. The solution took ~ppl.~x;" .~Ply 30
30 minutes to solubilize. The solution was dearated for 15 minutes and 50uL of a0.1gram~1mT ammonium persulfate (Kodak) in deionized water solution was added.
The solution was heated in a bead bath at 70~C for 20 minlltPc A white polymer is
formed and is then removed from the tube, cut into small pieces, and placed in a dish to
dry overnight. A 3% by weight solution of dry polymer to deionized water is prepared
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to allow the polymer to solubilize. To neutralize the solution appro~rim~t~oly 0.3g of
NaOH (Fisher) is added to the solution prior to solubilizing of the polymer. Thepolymer pieces solubilize at neutral pH over a period of 48 - 72 hours. The viscosity of
the solution in~l~a3e;1 at 37~C when tested using a Brookfield v;S~u~ L~l.
FY~mrle 17 This example describes the synthesis of a responsive polymer
network and an aqueous responsive polymer network composition p.~p~ using
Pluronic0 Fl27/Pluronic0 F108 blend (1:1) and poly(acrylic acid).
Pluronic F127 NF grade from BASF (1.50g) and Pluronic F108 from BASF
(1.50g) was dissolved in 5 grams of Acr,vlic Acid (Aldrich). The solution took
approximately 30 minutes to solubilize. The solution was dearated for 15 minutes and
50uL of a 0.1gram~1mT ~mmnnillm persulfate (Kodak) in rl.oioni7Pd water solution was
added. The solution was heated in a bead bath at 70~C for 20 minllt~c A white
polymer is formed and is then removed from the tube, cut into small pieces, and placed
in a dish to dry overnight. A 3% by weight solution of dry polymer to deionized water
is p.~arc;l to allow the polymer to solllbili7e To neutralize the solution apprn~im t~ ly
0.3g of NaOH (Fisher) is added to the solution prior to solnbili7ing of the polymer.
The polymer pieces solubilize at neutral pH over a period of 48 - 72 hours. The
viscosity of the solution increased at 42~C when tested using a Brookfield viccol... I~or.
FY~n~rle 18 This example describes the synthesis of a responsive polymer
20 network and an aqueous responsive polymer network composition pl~dl~.d using
Pluronic0 F88 and poly(acrylic acid). This example illustrates the effect of theresponsive component on the gelation ~.llp~ld~ure of the composition.
Pluronic F88 from BASF (3.0g) was dissolved in 5 grams of Acrylic Acid
(Aldrich). The solution took appl~l..dLely 30 minutes to solubilize. The solution was
dearated for 15 minutes and 50uL of a 0.1gram/lmL ammonium persulfate (~odak) indeionized water solution was added. The solution was heated in a bead bath at 70~C for
20 minlltes A white polymer is formed and is then removed from the tube, cut into
small pieces, and placed in a dish to dry overnight. A 3% by weight solution of dry
polymer to cl~inni7t cl water is prepared to allow the polymer to solubilize. Toneutralize the solution applu~;llld~ely 0.3g of NaOH (Fisher) is added to the solution
prior to solllbili7ing of the polymer. The polymer pieces solubilize at neutral pH over a
period of 48 - 72 hours. The viscosity of the solution increased at 80~C when tested
using a Brookfield viscometer
Example 19 This example describes the synthesis of a responsive polymer
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network and an aqueous responsive polymer network composition p.~d.~d using
Pluronic'19 Fl27/Pluronic'l9 F88 blend (1:1) and poly(acrylic acid). This example
illustrates the effect of the responsive component on the gelation telllp~.dLu-e of the
composition.
Pluronic F127 NF gl~ade from BASF (1.50g~ and Pluronic F88 from BASF (1.50g)
was dissolved in S grams of Acrylic Acid (Aldrich). The solution took appro~im~t.oly
30 minutes to solubilize. The solution was dearated for 15 minutes and 50uL of a0.1gram/lmL ammonium persulfate (Kodak) in deionized water solution was added.
The sorution was heated in a bead bath at 70~C for 20 minl.t~c A white polymer is
formed and is then removed from the tube, cut into small pieces, and plaoed in a dish to
dry overnight. A 3% by weight solllti~m of dry polymer to deionized water is p.~cd
to allow the polymer to solubilize. To neutralize the solution approximately 0.3g of
NaOH (Fisher) is added to the solution prior to solubilizing of the polymer. Thepolymer pieces solubilize at neutral pH over a period of 48 - 72 hours. The viscosity of
the solution increased at 85~C when tested using a Brookfield viscometer.
ExaInple 20 This example describes the synthesis of a responsive polymer
network and an aqueous responsive polymer network composition pr~ t,aled using
Pluronica~' F127 and poly(acrylic acid) using suspension poly...., ;~ n.
Pluronic F127 NF grade from BASF (15.0g) was dissolved in 25 grams of acrylic
acid (Aldrich). The solution was dearated for 40 minutes while it solubilized and 250uL
of a 0.5gram/lmL ammonium persulfate (Kodak) in deionized water solution was
added. The continuous phase solvent, heptane, was added to a 500mL baffled reaction
vessel c~lu;pped with an R100 impeller blade. A surfactant Ganex V216 0.5 wt% was
added to the continUQus phase. The continuous phase was heated to 60~C while being
dearated for 75 minllt~c The polymer solution is then added to the reaction vessel
while stirring and allowed to react 2 hours. Then, 250 ~1 of APS solution is added and
stirring is continued for an additional 14 h. The heptane is .~ec~nt.orl from the white
polymer beads and the polymer is washed twice with an excess of hexane to removeresidual heptane on the surface of the beads. A 3% by weight solution of dry polymer
to deionized water is prepared to allow the polymer to solubilize. To neutralize the
solution approximately 0.3g of NaOH (Fisher) is added to the solution prior to
solllhili7ing of the polymer. The polymer pieces solubilize at neutral pH over a period
of 48 - 72 hours. The viscosity of the solution increased at 37~C when tested using a
Brookfield viscometer.
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F~ rle 21 This example describes the synthesis of a responsive polymer
network gel composition prepared using Pluronic~19 F127 and a copolymer of mc.La~l ylic
and acrylic acid.
Methacrylic acid (Aldrich, 0.2 g) and acrylic acid (Aldrich, 1.8 g) were mixed and
used to dissolve 2.0 g Pluronic~l9 FlZ7. The sQhltion was dearated for 0.5 h and,
following ~r~itinn of 100 ~l freshly ~ sd~uldLed solution of ~mm~ni~lm persulfate
in deionized water, was kept at 70~C for 16 h resulting in a ~dus~dlenL polymer. A
sample of the polymer was suspended in fl.oioni7~<1 water with added NaOH. Following
swelling for three day, pH was adjusted to 9Ø A 2 wt% composition viccocifiPd at
10 t~l~C.dLul~S of 40~C and higher. Viscosity vs. ~e?.ld~ure profile is shown in Fig. 13.
FY~nlrle 22 This example describes the synthesis of a responsive polymer
network and an aqueous responsive polymer network composition prepared using
Pluoronic'19 F127 and poly(acrylic acid) using suspension polym.,;z~ion.
261.4 g of a 50 wt% sodium hydroxide (Fisher) solution in ~leinl~i7~fl water wasadded to 4.2 kg acrylic acid (Aldrich ) kd. The s~lhlti~n was mixed to allow theresultant ple~ip~ to solubilize. 3.5 kg Pluronic F127 NF grade (BASF) was added to
the acrylic acid solution wiht agitation. The solution was deaerated for three (3) hours
while it solubilized. 39.0 L of the c~ ntinllous phase solvent (Norpar 12) was added to a
30 gallon stainless steel reaction vessel e~uipped with baffles and a heating/cooling
jacket. Two (2) A-200 impeller blades were mounted on the agitator shaft to provide
mixing. Ganex V-126 surfa~ w~s added to the continllous phase at 0.3 wt% (based
on total batch size). The continuous phase was deaerated for three (3) hours with
agitation. 26.7g benzoyl peroxide 75% (Akzo) was dissolved in 0.5 kg acrylic acid. This
initiator system was then added ot the PluoronicJacrylic acid monomer solution and
allowed to mix for 30 mimlte~ The monomer solution was ~la l,L.led to the reaction
vessel via a diaphragm pump. The reaction vessel agitator was set at 600 RPM, and the
entire contents of the vessel were deaerated for an additional one (1) hour. The reaction
vessel t~p~d~ure was ramped to reaction temE~wdLure using a tempered heating water
unit. The reaction was allowed to continue for 14 hours under a continuous nitrogen
sparge. At the completion of the reaction, the reactor contents were discharged into
clean containers. The bulk of the Norpar phase is ~lpc~nt~d from the polymer beads.
The r.om~ining slurry is vacuum filtered to remove residual Norpar. The filteredpolymer beads are then dried under vacuum for three (3) hours at 50 degrees centigrade.
Example 23 This ~ample describes the formation of gel beads of the invention.
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Pluoronic F88 from BASF (35.2) was dissolved in 42.1 grams of Acrylic Acid (Aldrich)
with 1.32 NaOH in 2.5 mL deionized water. The solution took d~pr.~x;... -~Fly 30minutes to solubilize. The solution was deaerated for 20 minutes and a 0.53 gram/5
gram benzoyl peroxide in acrylic acid solution was added. The continuous phase,
Norpar (Exxon), was added to a 500 ml baffled reaction vessel c~lui~pcd with a R100
impellar blade. Ganez V216 (0.2 wtYo) was added to the continuous phase. The
continllQus phase was then deaerated for 35 min~ltec The polymer solutionis thenadded to the reaction vessel with stirring. The vessel is heated to 70~ C and allowed to
react for 12 hours. The bulk of the Norpar is cler~ntFd from the white polymer beads
and the polymer is vacuum filtered and washed once with heptane. Then the beads are
vacuum oven dried for 3 hours at 50~ C. A 1 wt% solution is p..~alcd with
app~)x;.l~ lFly 300 mL of a 5N NaOH (Fisher) solution added to neutralize. This
solution shows reverse thermal viccocifi~ tion
FY ~nrle 24 Pluoronic F127 NF grade from BASF (140.8 g) was dissolved in
169.96 grams of acrylic acid (Aldrich) with 10.5 grams of a 50 wt% NaOH solution.
The solution was deaerated for 45 minutes while it solubilized and of a 1.1 gram/25.2
gram benzoyl peroxide in acrylic acid solution was added. The continllQus phase
solvent, Norpar (Exxon), was added to a 2000 ml water jacketed baffled reaction vessel
equipped with three A200 impellar blades. Ganez V216 (0.3 wt%) was added to the
20 continuous phase. The continuous phace was deaerated for 60 minlltFc The polymer
solution is then added to the reaction vecsel with stirring at a speed 650 rpm. The vecsel
is heated to 70~ C and the reaction continues for 12 hours. The bulk of the Norpar is
cler~nted from the white polymer beads and the polymer is vacuum filtered and rinsed
once with heptane. Then the beads are vacuum oven dried for 3 hours at 50~ C. A 1
25 wt% solution is prepared with appr--~rim~t~ly 300 mL of a 5N NaOH (Fisher) solution
added to neutralize. This solution shows reverse thermal viccocifir~ti- n
FY~nlrle 25 This example describes the synthesis of a responsive polymer
network gel composition prepared using Pluronic'l9 F88 and poly(acrylic acid). this
example clPmnnctrates gelation of the responsive polymer network under conditions
30 typically found in oil drillings.
A 3 wt% responsive polymer network gel was prepared from Pluronic F88 and
polyacrylic acid (1:1) according to the method described in Example 1. The viscosity
profile of the solution was determined at elevated pressures. Fig. 14 illu~LldL~s the
solution performance at 5000 psi. The responsive polymer network experiences an
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W O 97/0027S PCT~US96/10376
increase in viscosity at above 100-F and remains viscous under oil drilling conditions,
namely LC.llp..dLUlCs in the range of 150-200'F.
FY~mr1e 26 The aim of this Example is three-fold: ( i ) to demonstrate
responsive polymer network compositions using a responsive component other than
5 triblock polyoxyalkylene copolymers, (ii) to preserve useful plopc.Lies of responsive
polymer network, namely, ease of synthesis, viscos;fyil1g at body ~elu~..dL~lle,bio~lh~ n.~s, and entirely benign components, and (iii) to incorporate drug into the
responsive polymer network composition. For these purposes, nonylphenyl ether ofpolyethyl~egly~)l (Nonoxynol 9, drug name is Igepal C0-630) was chosen. This
10 remarkable compound is surface active, possesses cloud point at around 55 ~C and is
used as a spermicide and anti-HIV agent in vaginal appli~tinnc Synthesis and
properties of the resulted responsive polymer network are described below.
Synthesis. Igepal'CO-630 (Rhone-Poulenc) (3.0 g) was dissolved in 3.0 g acrylic
acid (Aldrich). The solution was d.de.d~ed by N2 bubbling for 30 min and following
~lition of 100 ~Ll of freshly p~aLcd 300 mg/ml solution of ~mm~-nillm persulfate(Kodak) in riPioni7pd water was kept at 70 ~C for 16 h resulting in a Ll~ dle-lL solid
polymer. A sample of the polymer obtained (2.0 g) was suspended in 100 ml ~Pinni7Pd
water into which 0.18 g NaOH was added. Sllcp~ n~iPd responsive polymer network
particles were allowed so swell for 1 day under consL;~l-L stirring. The pH of the
20 solution was adjusted to 7Ø
Viscosity measurement. Viscosity vs t~p..dLure effect for responsive polymer
network made of Non.~ n~ l 9 and polyacrylic acid (1:1) in dPioni7Pcl water (pH 7) is
presented in Fig. 15. The v;aCO~;~y is measured at shear rate of 2.64 sec~1 using a SC~18
spindle which allows a very sensiLiv~ d~ulc.,~ent. It can be seen that the responsive
25 polymer network starts to viscosify at about 30 ~C and the v;~ ;Ly approaches
m~rimnm at 55 ~C at which point d~gl~g.lLes are formed (cloudiness is developed) and
the v;s~,o~iLy drops precipitously.
Example 27 The following example is related to responsive polymer network
performance in drug release. Drug loading and kinetics of release of the protein30 hemoglobin from a responsive polymer network composition are pr~..lL.d
Synthesis. Pluronic F127 0 (3.0 g) was dissolved in 3.0 g acrylic acid. The
solution was deaerated by N~ bubbling for 0.5 h and following addition of 100 ~Ll of
freshly prepared saturated solution of ~mm~ninm persulfate (Kodak) in deionized water
was kept at 70 ~C for 16 h resulting in a transparent polymer. The resultant responsive
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polymer network obtained (5 g) was suspended in 95 ml deionized water into whichNaOH was added. The resulting suspension was allowed to swell for 7 days.
Hemo~lobin loadin~ and release. A 5 wt% responsive polymer network
composition (3 g) was allowed to swell for 16 h in 10 ml of 0.25 mg/ml solution of
human hemoglobin (Sigma) in deionized water adjusted to pH 8. The resulting mixture
was well shaken and placed into the feed chambers of customized vertical, static, Franz-
like diffusion cells made of Teflon. The feed and receiver chambers of the diffusion
cells were separated by mesh screens (#2063). The receiver chamber was continuously
stirred by a m~gn~ti~ bar. The cells were allowed to equilibrate to either 25 or 37~C (in
10 an oven). The feed and receiver phases concicte(l of 1 g of the hemoglobin-loaded
responsive polymer network and 6 ml of phosphate-buffered saline (pH 7.4),
respe~L;v~ly. In the control experiment, the feed phase was made of 1 g of 0.25 mg/ml
hemoglobin solution. After the feed solution had been loaded into the cell, the kinetic
time comml-nre~l Samples of the receiver phase was withdrawn from time to time and
their abso.l,~ce was measured spectrophotometrically at 400 nm. To r~ te
hemoglobin con~ntrations, corresponding calibration curves (absorbance in PBS versus
hemoglobin concentration) were generated. The results of the kinetic experiment are
presented in Fig. 16. It can be seen that the rate of hemoglobin release from responsive
polymer n~Lwo~L was substantially lowered at 37~C when cu..~p~l to that at 25~C,because of v;SCOS;Ly increase in responsive polymer network at elevated te.--p~d~ures
(see Fig. 1). The protein released from the responsive polymer network composition still
retained it's native structure, as was determined by comparison of uv-vis spectra of
release hemoglobin and natural hemoglobin.
Example28 Drug loading and kinetics of release of the protein ly:,o~yllle from
a responsive polymer network composition is reported. The responsive polymer
n~wolL composition was prepared as described in Example 19.
Lysozyme loadin~ and release. A 5 wt% responsive polymer network
composition (3 g) was allowed to swell for 16 h in 10 ml of 1 mg/ml solution of
chicken egg-white ly~ozy~le (Sigma) and 1.5 mg/ml sodium dodecyl sulfate (Aldrich) in
deionized water adjusted to pH 8.5. The resulting mixture was well shaken and placed
into the feed chambers of customized vertical, static, Franz-like diffusion cells made of
Teflon. The feed and receiver chambers of the diffusion cells were separated by mesh
screens (# 2063). The receiver chamber was continuously stirred by a m~gn~ti~ bar.
The cells were allowed to equilibrate to either 25 or 37 ~C (in an oven). The feed and
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receiver phases cQncic~ecl of 1 g of the ly~ozylnc loaded l~apO~;v~ polymer network and
6 ml of phosphate-buffered saline (pH 7.4)"c~e~ .1y. In the control exp.orim~ nt, the
feed phase was made of 1 g of 1 mg/ml ly~ozyllle solution. After the feed solution had
been loaded into the cell, the kinetic time comm~ nrecl Samples were withdrawn and
their absorbance measured spectrophotometrically at 280 nm. A calibration curve was
prepared for ly~ozyl~le concentration ranging from O mg/ml to 0.5 mg/ml in phosphate
burf~.~;l saline. The results of the kinetic ~periment are presented in Fig. 17. It can be
seen that the rate of ly~ozyllle release from the responsive polymer network
composition was sllhct Inri~lly lowered at 37~C when ~,Ulllpdl~,d to that at 25~C,
10 because of v;5~,0:.;Ly increase in responsive polymer n.LwulL at elevated tempe.dLu
(see Fig. 1).
In order to demonstrate the retention of the enzymatic activity of ly~o;~yllle,
the ly~oxyllle released from the responsive polymer network composition was assayed
using Micrococc~s Iy~o~i~ticus cells and ~,OlllpdlCd to that of original ly~ozyllle. The
15 ~2ylllatic activity of ly~o~yllle was the same, within the error of the assay (15%), as
that of the original ly~ozylnc. Control without ly~uzyllle in presence of sodium dodecyl
sulfate did not show any appreciable lysis of the cells.
F~n~rl~- 29 Drug loading and kinetics of release of insulin from a responsive
polymer network composition is reported. The responsive polymer network
composition was prepared as described in Example 19.
Insulin loadin~ and release. A 5 wt% responsive polymer network composition
(3 g) was allowed to swell for 16 h in 10 ml of 5 mg/ml solution of bovine Zn2 l -insulin
(Sigma) in ~i~oioni7ecl water adjusted to pH 7. The resulting mixture was well shaken
and placed into the feed chambers of ~u~,Lollu~.d vertical, static, Franz-like ~ ion
cells made of Teflon. The feed and receiver chambers of the diffusion cells wereS.p.Ud~ed by mesh screens (# 2063). The receiver chamber was continllously stirred by a
m~gnlotic bar. The cells were allowed to equilibrate to either 25 or 37~C (in an oven).
The feed and receiver phases consisted of 1 g of the insulin-loaded responsive polymer
network and 6 ml of phosphate-buffered saline (pH 7.4),lcspe~.L;vtly. In the control
~p.orimt nt, the feed phase was made of 1 g of 5 mg/ml insulin solution. After the feed
solution had been loaded into the cell, the tirning comm~on~e~l Samples were withdrawn
and their absorbance was measured spectrophotometrically at 280 nm. A calibration
curve was prepared for insulin ~oncc -LldLion ranging from O mg/ml to 1.25 mg/ml in
phosphate buffered saline. The results of the kinetic experiment are presented in Fig.
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WO 97/00275 PCTrUS96/10376
18. The rate of insulin release from responsive polymer network was s~lhct~nti Illy
lowered at 37 ~C when compared to that at 25 ~C, because of viscosity increase in
responsive polymer network at elevated tC .lp~.dLurcs (see Fig. 1).
F~ rle 30 Drug loading and kinetics of release of insulin from a responsive
~ 5 polymer network composition is reported. The responsive polymer network
composition was prepared as described in Example 19.
Solutions for release studies were pLCp~l'Cd as follows. A cim~ tPd tear solution
inrhlrling 3.35 g NaCl, 1.00 g NaHCO3, and 0.04g CaCl2. 2H20 was pl._~dLCd by
dissolving the salts in 500 ml total volume rlpic~ni7pd water. Solution A was p.~pdled by
dissolving 0.34 g Timolol in a 3% w/w solution of responsive polymer network in
cimlll ~tP~I tear solution to a total weight of 10.0 g. Solution B was prcpaLcd by
dissolving 0.34 g Timolol in cimlll~tPd tear solution to a total weight of 10.0 g.
Solution C was plcpdlcd by dissolving 0.34 g Timolol in a 2% w/w solution of
responsive polymer network lightly crocclinkPd with 25% crocclinkPr in cimlll~tP~ tear
solution to a total weight of 10.0 g.
Release study. A 250 ,uL aliquot of Solutions A, B, and C were plaoed in
shallow plastic pans with a total capa~;Ly of about 300 uL. A piece of screen (30 mesh)
was placed over the top of each pan and fixed in place. The same procedure was
repeated again for Solutions A and B so that samples could be run at 34 ~C and ambient
t~p~. dLure.
A 25.0 ml sample of the tear solution was placed in each of five small beakers.
Three of the beakers were left on the counter top, and two were placed in an incubator
set at 34.0 ~C to equilibrate for about 30 minrlt~pc Samples of Solutions A and B
imPn~l~Pfl for testing at 34 ~C were placed in the same inrllh3tor so that they too would
rise to the desired t~p~.dLure.
The samples of Solutions A, B, and C to be tested for timolol release at room
temperature were dropped into the three beakers on the counter top so that the open
mesh faced down. The warmed responsive polymer network samples were also placed
in their beakers in the same manner. A 150~1 sample was removed from each beakerevery thirty rninutes for the next 2 hours and replaced with the sarne volume of fresh
tear solution. Samples were analyzed by W at 295 nrn and ~o~paLed to a standard
curve to determine Timolol concentration. The results of the Timolol release study are
presented in Fig. 19.
Example 31 This example demonstrates the preparation of a sterile polymer
CA 02230727 1997-12-10
W O 97/00275 PCT~US96/10376
network aqueous composition and the stability of the composition to st~rili7~tion. The
polymer 11~1W~1k is pl~dl~d as described in Example 1, except that the composition is
p/l~,~drCd at 2 wt% Pluronic'19 F127/polyacrylic acid. After ~liccol~ltion of the 2 wt%
polymer network in water, the viscosity is measured. The composition then is
sterilized by autodaving at 121~C, 16 psi for 30 minllt.-C Viscosity is Ci~L .. ~in~c3 after
stiorili7~tio~ The corresponding curves for viscosity (a) before and (b) after sterilization
are shown in Fig. 20 and establish that minim~l dhange in the v;~ y profile of the
material has occurred with sterilization.
Fx~mrle 32 This example is p.~ ed to describe the formation of a neutral
10 responsive polymer network and to describe the formation of such a network from an
acrylamide monomer.
Three grams of acrylamide (99+%, Aldrich, mp 84-86-C) was thoroughly mixed
with three grams of Pluronic F127 NF and 50 mg benzoin ethyl ether (99%, Aldrich,
mp 59-61~C). The resulting homogc.lcous powder was placed into a pla tic vial with a
15 rubber septum and heated to up to 90~C at which point a homogeneous liquid was
obtained (by melting of the component materials). The resultant liquid was purged with
lugCll for 5 min. and then W-ilhlmin t. cl with a Light-Welder 3010 EC W
spot/wand lamp (spearal output 300-500 nm, ill~cn~;~y 6000 mW/cm2, Dymax Co,
Torrington, CT) for 60 min at 90-C. A white powder was re~o~ d and air dried
20 overnight.
A portion of the white polymer powder (1.25g) was suspended in ~i. ioni7~c~
water (23.75g) to form a 5 wt% polymer solution and was allowed to hydrate for 4 days
at room tc --p~.d~ure. The resulting suspension was homogenized and then stood for
another 6 days at room t~llp~.d~Ul~. The resultant opaque solution was pH 6.7 and
25 displayed a viccocificlti~m vs. t~ ~lp~.d~u~c curve as shown in Fig. 21. No hydrolysis of
the acrylamide mnietiec was observed as charaaerized by Fourier Transform IR
spearoscopy. While a very pronounced peak is observed at 1670 cm~l (-CO-NH2
vibration) in both freshly made response polymer networks and in networks which
were dried at 70~C, no peaks at 1720 cm-l (COOH dimers) are observed. This, along
30 with the essential neutral pH of the polymer is a good indication that the responsive
polymer network is not charged.
FY~mrlç 33 This example is presented to illustrate the p~.ro..~ance changes of
a polyacrylamide-based responsive polymer network with time.
Five grarns of acrylamide was thoroughly mixed with five grams Pluronic FlZ7
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WO 97/00275 PCTrUS96/10376
NF and 100 mg benzoin ethyl ether. The resulting homog~..eous powder was placed
into a plastic vial, sealed with a rubber septum, heated up to 100~C and cimlllt~n~Qusly
W~ <l by a spot~wand lamp for 60 minutes with a spectral output of 300-500
and an intensity of 6000 mW/cm2. The resulting homogeneous white powder was air
dried for 2 hours and ground; and a portion thereof (1.25 g) was dissolved in deionized
water (23.75 g~) to prepare a 5 wt% polymer solution. After one day, the solution
turned opaque at room t~--pel~-ure. Its viscosity vs. temperature pe~ ce was
determined after one day (Fig. 22(a)) and again after six days (Fig. 22(b)). Note that
curve 100 denotes cooling and curve 102 denotes heating performance of the polymer
network after one day. The curves differ cignifi~!~ntly
FY?n~rlc 34 This ~ample is presented to demonstrate an acrylamide-based
responsive polymer gel prepared with differeing proportions of responsive and structural
polymer components and to show performance under physiological cQn.liti~ns
Ten grams of acrylamide was thoroughly mixed with five grams Pluronic F127
NF and 100 mg of benzoin ethyl ether. The resulting homogeneous powder was placed
into a plastic vial, sealed with a rubber septum, heated up to 100~C and W-illllmin~ted
for 60 min with a spot/wand having a spectral output of 300-500 nm and an hl~ns;Ly of
600 mW/cm2 The resulting homogeneous white powder was air dried for 2 hours and
ground; and a portion (10 g) of the white powder was dissolved in a buffer solution
(23.75 g) comprising 7M urea (Aldrich, 99+%), 100 mM
tris(llyLo,~y~lethyl)~min. m~th~n~ (Fisher, A.S.C. ~lk llim~tric standard) and 120 mM
boric acid (CVS) to result in a 20 wt% sllcp~ncion~ The 5~Cp~n~inn was stored for 12
days at room temperature. The viscosity vs. te.llp~ld~ult curve is found in Fig. 23.
~ in~l and Cosmetic Formulations. Because of the surfactant nature of the
responsive component of the responsive polymer network composition coupled with the
gelation effect of the responsive polymer network composition, it is possible to prepare
a forml.l~tic.n which is 100% water-based, but which is lubricous and thick.
Formulations inrlllrling nonionic, anionic and cationic surf~rt~ntc (a) a
nonionic surfactant formulation: An O/W (oil-in-water) emulsion was made by
combining the following ingredients ~ltili7ing conventional mixing techniques:
CA 02230727 1997-12-10
WO 97/00275 PCT~US96/10376
1n~ .1L ~h W/W
10 % wt. 1:1 responsive polymer 20.0
network as prepared in Example 1
ls.lylng wax ~l 2.5
Mmeral Oil 5.0
' Polowax avaulable irom Croda
Into a vessel c~u;~ed with a high efficiency homogFni7rr, the formula amount of all
ingredients is added and allowed to mix to homogF~nriry. This formnl~tinn contains a noninnir
10 c~lrf~rt~nr and gives an emlllc;on that is fluid at room t. ~r ~ c but viscosifies above 32-C.
(b) a cationic surf~rtlnt f","".l~ n An O/W (oil-in-water) ~ . ..1<:rn was made by
c~ mhining the following ingredients utilizing conventional mixing techniques:
~ ;.. '' ' % w/w
10 Yo wt. 1:1 .~ona.v~ polymer 20.0
network as prepared in Example 1
. . .c nlllm Mrth~s~llt ~tr 2.5
(and) Cetearyl alcohol'
Mmeral C~il 5.0
1 Incroquat Behenyl IM~ avallable rom Croda
Into a vessel c~l.~ipped with a high efficieney hr~mogrni7Pr~ the formula amount of all
ingredients is added and allowed to mix to homogeneity. This formlll~tion contains a eationic
surf~rt~nr and gives an rmlllcit~n that is fluid at room t~.llp~ld~UlC but viscosifies above 32-C.
(c) an anionic surfactant forml-l~tion An O/W (oil-in-water) -mlllc;rn was made by
combining the following ingredients utilizing conventional mixing teehniques:
C ' t % W/W
lO % wt. 1:1 responsive polymer 20.0
network as prepared in Example 1
C;etearyl l'hosphate (and) Cetearyl Z.5
alcoholl
Mmeral C)ll 5.0
~ Crodalos CkS avallable ~rom Cro~a
Into a vessel e~u;~ed with a high effieieney homngrni7Fr, the formula amount of all
ingredients is added and allowed to mix to homogeneity. This formulation eontains a anionie
s--rf~rt~nt and gives an emulsion that is fluid at room t~lllp~ldLul~: but viscosifies above 32~C.
Vaginal MC~ LU1;~; An oil-free, hlhrirollc, vaginal moict-lri7rr is made by eombining
40 the following ingredients utilizing eonventional mixing teehniques:
56
CA 02230727 1997-12-10
WO 97/00275 PCT~US96/10376
ll~g.. ~ t % w/w
10 % wt. 1~ pol.:,.ve polymer20.0
network as prepared in Example 1
Cilycenn U~il' 5.0
lJl'G-2 Mynstyl l~'ther l'roplonatel 3.0
l>L-l'anthenol 0.5
C~ermaben' 11' 0.1
l~isodlum l~'L)'l'A 0.2
~;ltnc Acid 0.01
U~l' Puriiied water 71.19
I ~rodamol PMl' available lrom G3da
2 Germaben- II available from Sutton Laboratories
To one vessel, equipped with a Lightnin' Mixer with a 3 blade paddle prop, the full
15 amount of USP Purified Water is added. The water is then heated to 80~C and held for 20
minutes. The water is then cooled to 50~C, while m~int lining the t~ p~dLu~r~ with moderate
to vigorous mixing, the formula amount of Disodium EDTA, Citric Acid, DL-P~nthPn- l,
Glycerin, PPG-2 Myristyl Ether Propionate, and Germaben II is added. These n~qtPri~lc are
allowed to dissolve at 50~C. After ~iccolllti~ln, the vessel is then cooled to 20~C. To another
20 vessel, e~lu;~cd with a high efficiency homogPni7Pr, the formula amount of l~>ons;vt: polymer
network is added. The l~OllS;VC: polymer network vessel is then cooled to 4~C. After cooling,
while vigorously homogeni_ing, the contents of the first vessel is added to the second vessel, and
allowed to mix to hnm~7g~ nPiry.
The ~o.l.pG~;L;on displays a flowable creamy lotion appearance with PY~PllPnt
25 m~ Lur;,;ng, Pm~lliPnry~ spreadability and absorption char~ctpricti~c at room t~ pe~Lul~ and
after heating the form~ ti~n to 32~C, the cc,l..pG~;Lion thickens to a gel-like r~ .. y.
Formulation for Mana~ement of Bacterial Va~inosis: An oil-free, lubricous, bacterial
vaginosis treatment is made by combining the following ingredients utilizing conventional
mixing techniques:
ll~gre~l.. --L % w/w
10 % wt. 1:1 responslve polymer 20.0
network prepared as in Example 1
~lycerin USl' 5.0
Metromda70le 0.75
L)L-l'anthenol 0.5
C~ermaben~ 11~ 0.1
l~isodium ~Yl'A 0.2
C~ltnc Acld 0.01
U~;l' l'urihed Water 73.44
I C~ermaben' 11 available irom Sutto 1 Laboratones
.
To one vessel, equipped with a Lightnin' Mixer with a 3 blade paddle prop, the full
CA 02230727 1997-12-10
WO 97/00275 PCT~US96/10376
~mount of USP Purified Water is added. The water is then heated to 80~C and held for 20
minutes. The water is then cooled to 50~C, while ...~h~ldi~ the ~ d~ C, with mr~ r~tP
to vigorous mixing, the formula amount of Disodium EDTA, Citric Acid, DL-PdnthPnrl,
Glycerin, Metrcni~7r.1e and Germaben- II is added. These m~tPri~lc are allowed to dissolve at
5 50~C. After ~iics~ tion~ the vessel is then cooled to 20~C. To ;mother vessel, e~lu.~ed with a
high efficiency hrml~gPni7Pr~ the formula amount of I~Ou:~;ve polymer network is added. The
re~oL~lvc polymer network vessel is then cooled to 4~C. After cooling, while v;gu~uu~ly
ho...rb....,;ng, the contents of the first vessel is added to the second vessel, and allowed to mix
to hrmngPnPity.
The ~""p~ l ;nn displays a flowable jelly appearance with excellent spreadability and
absorption characteristics at room t~...l' dl~e~ and after heating the formlll~tion to 32~C, the
~ull~pos;Lion thickens to a gel-like cQnCictpnry.
F- rmnl~tion for M~n ~ 1 of Bacterial ('~ntli~i lcic An oil-free, lubricous, bacterial
r~n~ li cic ~lcdL~ .lL is made by comhining the following ingredients utilizing conventional
15 mixing tPrhni~lllPc.
Cd;~L % W/W
10 % wt. 1~ ol~-ve polymer 20.0
network prepared as in Example 1
Glycenn U~l' 5.0
M lronq7t-1e Nitrate2.0
L~L-l'anthenol 0.5
Germaben~ Il' 0.1
L~lsodlum kl~ lA 0.2
Gtrlc Acld 0.01
U~ 'urllled water 72.19
~ GPrm~hPn 1 1 av~lable ~rom Sutton t ~hordtr~Qes
To one vessel, e~lu;l,~ed with a Lightnin' Mixer with a 3 blade paddle prop, the full
30 amount of USP Purified Water is added. The water is then heated to 80~C and held for 20
minutes. The water is then cooled to 50~C, while m~int~ining the t.,llp..dLulc, with moderate
to vigorous mixing, the formula amount of Disodium EDTA, Citric Acid, DL-pdnthpnGlycerin, Mirrln~7r~1e Nitrate, and Germaben II is added. These materials are allowed to
dissolve at 50~C. After ~iccrbltinn, the vessel is then cooled to 20~C. To another vessel,
35 e~luiL~ d with a high efficiency homogenizer, the formula amount of l~on~;vc polymer
network is added. The l~ on~;ve polymer network vessel is then cooled to 4~C. After cooling,
while v;guluL~aly homogenizing, the contents of the first vessel is added to the second vessel, and
allowed to mix to hrmogPnPiry.
The co..-pr.~-l ;on displays a flowable jelly appearance with excellent spreadability and
40 absorption char~cTPrictirc at room T ~p ' dl ~-~ ~, and after heating the forml~lqtion to 32~C, the
CA 02230727 1997-12-10
W O 97/00275 PCTAUS96/10376
composition thickens to a gel-like ~-~ncictPn~y.
Acne M.o~licqtion: An oil-free, dear, anti-acne treatment is made by c~ mhining the
following ingredients utilizing collvc..L;onal mixing techniques:
- 5 III~.C;I~ L % w/w
10 9~ wt. 1:1 ~ Oll~lve polymer 20.0
network prepared as in Example 1
Glycerin U~l~ 5.0
Sal~cylic Acld 2.0
l~L-l~qnth-onr~l O 5
Germaben~ Ill 0.1
L)lsodlum kl~'l'A 0.2
U~l' Puniled Water 72.2
I Germaben~ 11 avallable ~rom Sutton Laboratones
To one vessel, equipped with a Lightnin' Mixer with a 3 blade paddle prop, the full
amount of USP Purified Water is added. The water is then heated to 80~C and held for 20
minutes. The water is then cooled to 50~C, while mqintqining the tC~up~dLulc~ with moderate
to vigorous mixing, the formula amount of Disodium EDTA, Citric Acid, DL-Pqnth.on~
20 Glycerin, Salicylic Acid, and Germaben II is added. These n~qr~riqlc are allowed to dissolve at
50~C. After ~liccohltion, the vessel is then cooled to 20~C. To another vessel, equipped with a
high efficiency h~-m~)gPni7Pr, the formula amount of l~ on:.;ve polymer network is added. The
l~pO~ ;ve polymer network vessel is then cooled to 4~C. After cooling, while V;gOI~ u~ly
homogeni7ing, the contents of the first vessel is added to the second vessel, and allowed to mix
25 to hr~m~g~-nrity.
The colllpo:.;L;on displays a flowable clear jelly appearance with P~ollPnt spreadability
and absorption characteristics at room te.llp~.dLule, and after heating the formlllqti~7n to 32~C,
the ~u...p~ n thickens to a gel-like .Ull,;.L~ y.
Topical Hormone Delivery Formulation: An oil-free, spreadable, topical h-~rmon~-
30 treatment using estradiol as ~he hormone is made by combining the following ingredientsutilizing conventional mixing te~hniqll~c
59
CA 02230727 1997-12-10
WO 97/00275 PCTAUS96/10376
~.~.~.. ~t % w/w
10 % wt. 1~ spollsl~,~ polymer 20.0
network prepared as in _xample 1
Glycerm U~l~ 5.0
5 ~'ctr~ ol 0.1
l~L-l'q nt hPn~l o 5
~;rrmqhPn~ Il~ 0.1
L)isodium kL~-l'A 0.2
TJ~l~l'ur~led water 74.1
' Grrn~qhrn~ 11 avallable ~rom Sutto l Laboratorles
' To one vessel, e~luiy~ed with a Lightnin' Mixer with a 3 blade paddle prop, the full
amount of USP Purified Water is added. The water is then heated to 80~C and held for 20
minutes. The water is then cooled to 50~C, while ~ nl:~in;llg the t~. p~. .t. .c, with mo-1Pt~qt~
15 to vigorous mixing, the formula amount of Disodium EDTA, DL-Pqnthrnr.1 Glycerin, Fctr_~linl
and Germaben- II is added. These mqtPriqlc are allowed to dissolve at 50~C. After riic5~ tir~n,
the vessel is then cooled to 20~C. To another vessel, e~lu;~d with a high efficiency
h~mogeni7rr, the formula amount of le~l cna;vc polymer network is added. The l~Olla;vc
polymer network vessd is then cooled to 4~C. After cooling, while vi~,uluualy homogeni7inE~
20 the contents of the first vessel is added to the second vessel, and allowed to mix to homogeneity.
The cul~lpua;~ion displays a flowable jeily d~dldn.c with excellent spreadability and
absorption .Ld d.L~ ics at room ~c.ll~.d~ulc, and after heating the f rml-lqtirn to 32~C, the
cu pos;~ion thickens to a gel-like cf~ y.
Topical Anti-Tnflq-mn~qtory Delivery Formlllqti~ln with Penetration FnhqnrPr: An oil-
25 free, spreadable, topical anti-i .n~ lo y treatment using in~lnmrthq~in as the anti-inflqmmqtory
and Azone as the prnPtr~Sir~n enhancer is made by comhininE the following ingredients utilizing
conventional mixing techniques:
Ingrcdient % w/w
30 10 % wt. 1:1 l'l~JOn:llVC polymer 20.0
network as prepared in Example 1
Glycerin U~ilJ 5.0
Inrlnmrthq~in 0.5
L~L-l'anthenol 0.5
35 GPrmqhrn~ 1l~ 0.1
L~isodlum ~L)'l A 0.2
USl~ Puntled water 73.7
' GPrrnqhPn~ llavallable ~rom Sutto 1 I qhQrqtoriP~
To one vessel, c~ui~ped with a Lightnin' Mixer with a 3 blade paddle prop, the full
amount of USP Purified Water is added. The water is then heated to 80~C and held for 20
minutes. The water is then cooled to 50~C, while mqinrqinin~ the tC.llp~.d~ul~ with moderate
CA 02230727 1997-12-lO
WO 97/0027S PCTAJS96/10376
to vigorous mixing, the formula amount of Disodium EDTA, DL-P~nthf n--l, Glycerin,
Tn~--mf rh ~in and Germaben II is added. These m~tf ri~lc are allowed to dissolve at 50~C. After
fliccolllti~n~ the vessel is then cooled to 20~C. To another vessel, e~u;~ped with a high efficiency
hnmog~ni7f r~ the formula amount of ~ .on~;v~ polymer network is added. The l~on.;vc
~ 5 polymer network vessel is then cooled to 4~C. After cooling, while V;l5v~vu ly homl~,gf.).,.. -g,
the contents of the first vessel is added to the second vessel, and allowed to mix to h~mogenf ity.
The cvlllpo:~;Lion displays a flowable jdly appearance with fY~fllfAnt spreadability and
absorption charact~ricti~c at room t~ pf ~ and after heating the fnrm~ ti~n to 32~C, the
~v~pvs;Lion thickens to a gel-like c~nCictf nry.
Topical Anti-Tnfl Imm~tl~ry Delivery Form~ ti-7n An oil-free, spreadable, topical anti-
infl lmm~tory treatment using hyd~vco~L;~one as the anti-infl~mm~tnry is made by comhinin" the
following ingredients utilizing conventional mixing techniques:
ln~.c.L~ % w/w
10 9~ wt. 1:1 responslve polymer 20.0
network as prepared in Example 1
Glycerin V~ 5 0
Hydrocortlsone 0.5
L)L-l'anthenol 0.5
C~ermaben~ 11' 0.1
L)isodium l~l~lA 0.2
U~ l'urilied water 73.7
I Ciermaben~ 1 l available irom Sutton Laboratori~
To one vessel, equipped with a Lightnin' Mixer with a 3 blade paddle prop, the full
amount of USP Purified Water is added. The water is then heated to 80~C and held for 20
minutes. The water is then cooled to 50~C, while m~int~ining the t~ p~.~Lulc, with moderate
to vigorous mixing, the formula amount of Disodium EDTA, DL-P~nth~ nol, Glycerin,
IIyl~v~vlL;,one and Germaben- II is added. These materials are allowed to dissolve at 50~C.
30 After ~iccr~llltion~ the vcssel is then cooled to 20~C. To another vessel, c~lu;~ped with a high
efficiency homogenizer, the formula amount of responsive polymer network is added. The
on:..ve polymer network vessel is then cooled to 4~C. After cooling, while v;~;u~vu~ly
h~mngeni7ing, the contents of the first vessel is added to the second vessel, and allowed to mix
to hom--genf ity.
35The .v..... pvs;Lion displays a flowable jelly appearance with f Y~f llf nt spreadability and
absorption characteristics at room t. ~r ~ . and after heating the formulation to 32~C, the
Cu---pvs;L;on thickens to a gel-like ~.-n~;~n .,~y,
Topical Anal~,esic Delivery Formulation with Penetration Fnh~n~f r: An oil-free,spreadable, topical analgesic treatment using Ibuprofen as the anti-infl~mm~tory and Azone as
40 the penetration f nh~nrf r is made by combining the following ingredients utilizing conventional
61
CA 02230727 1997-12-10
WO 97/00275 PCT~US96/10376
t rhn; rc
mD~mg c ~lu
~g.. d;c.~ % w/w
10 9~ wt. 1~ on~-vc polymer 20.0
network as prepared in Example 1
C;lycerm U~il' 5.0
Ibuprolen 0.5
L)L-l'anthenol 0.5
~ rrnqhrn~ lli 0.1
L)isodium kL~'A 0.2
Azone 5.0
U~l~ l'urliled Water 68.7
l Germaben~ 11 avallable lrom Sutto l Laboratones
To one vessel, e~lu;t,ped with a Lightnin' Mixer with a 3 blade paddle prop, the full
amount of USP Purified Water is added. The water is then heated to 80~C and held for 20
minutes. The water is then cooled to 50~C, while mqinrqining the ~ peldLu~c~ with moderate
to vigorous mixing, the formula amount of Disodium EDTA, DL-P-q-nthPnol, Glycerin, Azone,
Ibu~luL~ and Germaben- II is added. These n~qtPriqlc are allowed to dissolve at 50~C. After
20 rliccnluriotl~ the vessel is then cooled to 20~C. To another vessel, e~ Pcl with a high efficiency
hnmogeniqrr, the formula amount of l~ ~,Oll,;vc polymer net~,vork is added. The ~ OllS;VC
polymer network vessel is then cooled to 4~C. After cooling, while v;gvlu~ly hnmc~gPni7ing,
the contents of the first vessel is added to the second vessel, and allowed to mix to hnmogPnrity.
The ~o...rr ~:l ;nn displays a flowable jelly appearance with excellent spreadability and
25 absorption rhqrqcterictir~ at room ~.llp.ld~UlC, and after heating the forml~lqtion to 32~C, thc
composition thickens to a gel-like cnncistpnry.
Topical Hair Loss Treatment with Penetration Fnhqncrr: An oil-free, spreadable,
topical hair loss tlCa~lll.n~ using MinnYi~lil as the hair growth Stimlllqnt and A_one as the
penetration enhancer is made by combining the following in~ di..l~s utili_ing conventional
30 mixing techniques:
L % w/w
10 9~ wt. 1:1 l.~onslvc polymer 20.0
network as prepared in Example 1
C~lycerm U~l' 5.0
MinnYi<lll 1.0
l~L-l'anthenol 0.5
C~ermaben~ 11 l 0.1
l~isodlum ~L)'l'A 0.2
Azone 5.0
U~l' Purliied water 68.2
I ~ermaben~ 11 avallable lrom Sutto ~ Laboratorles
CA 02230727 1997-12-10
WO 97/00275 PCTrUS96/10376
To one vessel, e~lu;p~cd with a Lightnin' Mixer with a 3 blade paddle prop, the full
amount of USP Purified Water is added. The water is then heated to 80~C and held for 20
minutes. The water is then cooled to 50~C, while m~int lining the te~p~ .dLu.,, with m~ PratP
to vigorous mixing, the formula amount of Disodium EDTA, DL-P~nthPnol, Glycerin, Azone,
5 Min~Yi~il and GPrmqhPn- 11 is added. These materials are allowed to dissolve at 50~C. After
dissolution, the vessel is then cooled to 20~C. To another vessel, equipped with a high efficiency
homogPni7Pr, the formula amount of ~ OllS;ve polymer network is added. The .~on~lve
polymer network vessel is then cooled to 4~C. After cooling, while v;gu~u~ly h~ml,g. ~
the contents of the first vessel is added to the second vessel, and allowed to mix to h~lm~gPnPity.
10 The c~.. po~;l ;on displays a flowable jelly appearance with excellent spreadability and
absorption char~rtPrictirs at room t~ and after heating the form~ tion to 32~C, the
~vl~pos;L;oll thickens to a gel-like con~;:.L~,..y.
Topical Local AnPcthptic Delivery Formulation: An oil-free, spreadable, topical local
anPcthPti~ treatment using lic~o~ainP as the anti-inflamm~tory is made by ~t mhining the
15 following ingredients utilizing conventional mixing techniques:
lngredient % w/w
10 ~ wt. 1:1 responslve polymer 20.0
network (F127/AA)
20 Glycerm U~il' 5.0
illn~amP Hydrochlonde 225.0
-PanthPnfll O 5
~Prm ~ hPn ~ l l ~ 0.1
L)lsodlum ~'1 A 0.2
25 U~ilJ Purilied water 73.2
~ Germaben~ 1 l avallable ~rom Sutto I Laboratones
To one vessel, e~u;~lJcd with a Lightnin' Mixer with a 3 blade paddle prop, the full
amount of USP Purified Water is added. The water is then heated to 80~C and held for 20
minutes. The water is then cooled to 50~C, while maintaining the tc,l~p..dLu~t~ with moderate
30 to vigorous mixing, the formula amount of Disodium EDTA, DL-P~nthPnol, Glycerin, T ic~o~ainp
IIyLu~lloride and Germaben- II is added. These materials are allowed to dissolve at 50~C.
After dissolution, the vessel is then cooled to 20~C. To another vessel, c~lui~pcd with a high
efficiency homogenizer, the formula amount of responsive polymer network is added. The
Jon:,;ve polymer network vessel is then cooled to 4~C. After cooling, while v;gc~ u~ly
35 homf~gPni7ing, the contents of the first vessel is added to the second vessel, and allowed to mix
to homogeneity.
The ..Jl..po:,;Lion displays a flowable jelly appearance with excellent spreadability and
absorption characteristics at room temperature, and after heating the form-llqtic n to 32~C, the
composition thickens to a gel-like consistency.
Tnsomnia Treatment with Penetration T~.nh~nrPr: An oil-free, spreadable, topical hair
63
CA 02230727 1997-12-10
WO 97/00275 PCT~US96/10376
loss treatment using Melatonin as the sleep srim~ nr and Azone a~c the penetration enhancer is
made by cnmhining the following ingredients utilizing conventional mixing te~hniq~lPc
Illg~ .. L % W/W
10 % wt. 1:1 responsive polymer 20.0
network as prepared in E~cample 1
Cilycerm U~l' 5.0
MPI~r--nln 1.0
L)L-l~anthenol 0.5
~Prm~hPn~ 11~ 0.1
sodlum k~lA 0.2
Azone 5.0
U~l~ l'ur~led water 68.2
I Germaben~ ll avallable ~rom sutto 1 Laboratones
To one vessel, e~lu;~pcd with a T.ightnin' Mixer with a 3 blade paddle prop, thefull amount of USP Purified Water is added. The water is then heated to 80~C and held
for 20 minlltpc The water is then cooled to 50~C, while n~int~ining the t~.n~e.dLulc:,
with moderate to vigorous mixing, the formula amount of Disodium EDTA, DL-
20 Panthenol, Glycerin, Azone, Melatonin and Germaben- II is added. These m ItPri~lc are
allowed to dissolve at 50~C. After dissolution, the vessel is then cooled to 20~C. To
another vessel, equipped with a high efficiency homogenizer, the formula amount of
responsive polymer network is added. The responsive polymer network vessel is then
cooled to 4~C. After cooling, while vigorously homogPni7ing, the ~ ; of the first
25 vessel is added to the second vessel, and allowed to mix to homogeneity.
The composition displays a flowable jelly ~ped,dnce with PY~PllPnt spreadabilityand absorption characteristics at room ~..*e.dLure, and after heating the formulation to
32~C, the composition thickens to a gel-like consistency.
Formulation for M~ld~ lL of Decubitis Ulcers:
A gel wound dressing for decubitis ulcer treatment conr~ining a proteolytic
enzyme and antiseptic is made by combining the following ingredients lltili7ing
col~ ional mixing techniques:
64
CA 02230727 1997-12-10
W O 97/00275 PCTrUS96/10376
~.g,'~ % w/w
10% wt 1~ >ol~;v. polymer 20.0
network as prepared in Example 1
Glycerin USP 5.0
Sutilains 82000 USP Units/gram
Neo-l,y~in 0.75
DL-Panthenol 0.5
Germaben- II' 0.1
Disodium EDTA 0.2
Citric Acid 0.01
USP Puriiled Water qs
I Germaben~ Il available irom Sutton Laboratories
To one vessel, equipped with a T ightnin' Mixer with a 3 blade paddle prop, the
15 full amount of USP Purified Water is added. The water is then heated to 80~ C and
held for 20 minllt~s The water is then cooled to 50~ C, while m~int~ining the
temperature, with moderate to vigorous mixing, the formula amount of Disodium
EDTA, Citric Acid, DL-Panthenol, Glycerin, Neomycin, and Germaben' II is added.
These materials are allowed to dissolve at 50~ C. After dissolution, the vessel is then
20 cooled to 20~ C, and the Sutilains is added. To another vessel, e~luipped with a high
~-ffirien~y homogenizer, the formula amount of IPN is added. The IPN vessel is then
cooled to 4~ C. After cooling, while vigorously homogenizing, the contents of the first
vessel is added to the second vessel, and allowed to mix homogeneity.
The composition displays a flowable jelly appearance with ~Y~ nt spreadability
25 and absorption characteristics at room temperature, and after heating the formulation to
32~ C, the composition tl~ k~-nc to a gel-like CQncict~nry.
Oil-free Moisturizer: An oil-free, lubricous moisturizer is made by combing the
following ingredients ntili~ing conventional mixing techniques:
CA 02230727 1997-12-10
WO 97/00275 PCTAJS96/10376
I~g~c~e~L % w/w
10% wt 1~ on~ polymer 20.0
network as prepared in Example 1
Glycerin USP 5.0
S PPG-2 Myristyl Ether p.~ o""~l 3.0
DL-Panthenol 0.5
C.. l.,ab~ 0.1
Disodium EDTA 0.2
Citric Acid 0.01
USP Purified Water 71.19
I Croaamol PMl' available trom Croda
2 Germaben- II available from Sutton Labo~d~u,ie~
The above ingredients are added and processed as ~iPcrrihPd above for the vaginal
moisture. The composition displays a flowable creamy lotion appearance with ~ Pll~nr
Pmolli~n~y, s~,readability and absorption characteristics at room t~p~.dLure. After
heating the formnl~ti~ n to 26-C, the composition thirkPnc to a gel-like ~O~ If ~y.
The viscosity vs. ~~ ~e.d~u~e curve is shown in Fig. 24 and demon,LrdL~s that ?~lrliti~n
of adjuvdllL~ to the composition cignifi~-~ntly Pnh~lll'PC the responsive polymer network
m~Yimllm v;scos;Ly (~ 900,000 cps). The use of the responsive polymer network in the
formulation also imparts a urlique vicc-.cifi~lti~m effect after application to the skin,
which is not evident in typical commercial O/W emulsion formulations (See, Fig. 24).
66
