Note: Descriptions are shown in the official language in which they were submitted.
CA 02263411 1999-02-09
wo 98/06438 PCT/US97/13988
COMPOSITION FOR PHARMACEUTICAL APPLICATIONS
This application is a continuation-in-part application of copending apphcation
PCT/US96/10376 filed June 14, 1996, designating the United States, and entitled
"Responsive Polymer Networks and Methods of Their Use ', which is a continuation-
in-part application of copending application U.S.S.N. 08/S80,986 filed January 3,
1996, and entitled "Responsive Polymer Networks and Methods of Their Use", each of
which is incorpo-ated entirely by reference.
This application claims priority under 35 U.S.C. 119(e) to United States
Provisional Application 60/023,996, filed ~ugust 12, 1996, entitled "Drug Delivery
System", United States Provisional Application 60/025,974 filed September 16, 1996,
entitled "Modification of Rheological Properties of Reverse Thermoviscosifying Gels",
United States Provisional Application 60/028,183, filed October 15, 1996, entitled
"Shifts in Transition Temperature of Smart Hydrogel", United States Provisional
Application 60/030,798, filed November 14, 1996, entitled i Associative Thickeners
Based on Smart Hydrogel", United States Provisional Application 60/034,454, filed
~anuary 2, 1997, entitled "Responsive Polymer Networks and Methods of Their IJS~:
Thermal Stabilization", and United States Provisional Application 60/0,4,174, filed
January ~, 1997, entitled "Delivery of Peptides in Sheep, which are hereby
incorporated in its entiret,v by reference.
Field of the Invention
The present invention relates to pharmaceutic compositions useful in a variety
of pharmaceutical products and applications, and in particular, compositions useful
transmucosal applications, such as esophageal, otic, vaginak rectal, topical andophthalmic. More particularly, the present invention is directed to a pharmaceutic
composition for treating a disease or disorder comprising a polvmer network that can
be designed to reversibly gel over a wide range of conditions
CA 02263411 1999-02-09
Wo 98/06438 PCT/US97/13988
B~ck~round of the Invention
One of the major concerns in the delivery of drugs is the bioavailability of thedrug. Depending upon the nature of the drug and the route of delivery the
bioavailability may be very low due to, for example, the degradation of oral-delivered
drugs by hepato-gastrointestinal first-pass elimination or rapid clearance of the drug
from the site of application. The net result is that frequent dosing may be required
with higher than needed amounts of drug, which can lead to undesired side effects.
Thus, it is desired by the pharmaceutical industry to have ways of ~imini~tering drugs
such that their availability can be controlled in an even dosing manner, the amounts of
drugs can be kept as low as possible to minimi7e side effects, and dosing regime can
be kept to a minimum to provide greater convenience to the subject, thus promoting
greater compliance with appropriate dosin(J,.
Many instances are known in the pharrnaceutic industry where it is desired to
have certain properties of viscosity in order to facilitate the objectives noted above.
1~ Hydrogels, such as cellulosics, have been included as thickeners in pharrnaceutic
compositions. A hydrogel is a polymer network which absorbs a large quantity of
water without the polymer dissolving in water. The hydrophilic areas of the polymer
chain absorb water and forrn a gel region. The extent of gelation depends upon the
volurne of the solution which the gel region occupies.
Reversibly gelling solutions are known in which the solution viscosity increasesand decreases with an increase and decrease in temperature, respectively. Such
reversibly gelling systems are useful wherever it is desirable to handle a material in a
fluid state, but perforrnance is preferably in a gelled or more viscous state.
A known material with these properties is a therrnal setting gel using block
copolymer polyols, available commercially as Pluronic~) polyols (BASF,
Ludwigshafen, Gerrnany), which is described in U.S. Patent No. 4,188,373. Adjusting
the concentration of the polymer gives the desired liquid-gel transition. However,
concentrations of the polyol polymer of at least 18-20 % by weight are needed toproduce a composition which e~hibits such a transition at commercially or
physiologically useful temperatures. Also, solutions cont~ining 18-~0 % by weight of
CA 02263411 1999-02-09
W Og~l~6~8 PCTAUS97113988
responsive polymer are typically very viscous even in the "liquid" phase, so that these
solutions can not function under conditions where low viscosity, free-flowing isrequired prior to transition. In addition, these polymer concentrations are so high that
the material itself may cause unfavorable 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 polyoxyethylene and polyoxypropylene condensed with ethylene~ min~,
commercially available as Tetronic(~) polyols. These compositions are formed from
approximately 10% to 50% by weight of the polyol in an aqueous medium. 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 a physical blend of a pH-sensitive gelling polymer (such as a
cross-linked poly(acrylic acid) and a temperature-sensitive gelling polymer (such as
methyl cellulose or block copolymers of poly(ethyleneoxide) and
poly(propyleneoxide)). In compositions including methylcellulose, 5- to 8-fold
increases in viscosity are observed upon a simultaneous change in temperature and pH
for very low methylcellulose levels (1-4% by weight). See, Figs. 1 and 2 of Joshi et
al. In compositions including Pluronic~ and Tetronic~9 polyols, commercially
available forrns of poly(ethyleneoxide)/poly(propyleneoxide) block copolymers,
significant increases in viscosity (5- to 8-fold) upon a simultaneous change in
temperature and pH are observed only at much higher polymer levels. See, Figs. 3-6
of Joshi et al.
Hoffman et al. in WO 95/24430 disclose block and graft copolymers
comprising a pH-sensitive polymer component and a temperature-sensitive polymer
component. The block and graft copolymers are well-ordered and contain regularlyrepeating units of the pH-sensitive and temperature-sensitive polymer components.
The copolymers are described as having a lower critical solution temperature (LCST),
at which both solution-to-gel transition and precipitation phase transition occur. Thus,
the transition to a gel is accompanied by the clouding and opacification of the solution.
CA 02263411 1999-02-09
W 098106438 PCTAUS97/13988
Light tr~n~mis.~ion is reduced, which may be undesirable in many applications, where
the aesthetic characteristics of the composition are of some concern.
Thus, the known systems which e~hibit reversible gelation are limited in that
they require large solids content and/or in that the increase in viscosity less desired. In
5 addition, some known systems e~chibit an increase in viscosity which is accompanied
with the undesirable opacification of the composite.
Summarv of the Invention
It is an object of the present invention to provide a pharmaceutic composition
10 which includes a component capable of reversible gelation or viscosification.It is a further object of the invention to provide a pharmaceutic composition
which includes an component capable of gelation or viscosification at very low solids
content.
It is another object of the present invention to provide a pharmaceutic
15 composition which possesses improved flow and gelation characteristics as compared
to properties possessed by conventional reversible gelation compositions.
It is a further object of the invention to provide a polymer network compositionfor use in pharmaceutic compositions as a surfactant or emulsifier in the solubilization
of additives and, in particular, hydrophobic additives, and desirably to provide stable
20 emulsions at elevated temperatures.
It is a further object of the invention to provide a pharmaceutic composition
which possesses the a~plopliate thickness for sustained delivery and pharrnaceutic
effect with a minimum of solids content.
It is a further object of the invention to provide a polymer network for use in
25 pharmaceutic compositions as a suspension agent for otherwise insoluble additives.
It is yet another object of the present invention to provide reversibly gelling
polymer network compositions which are composed of biocompatible polymers.
These and other objects of the invention are achieved in a pharmaceutic
composition comprising a reversibly gelling polymeric network for the delivery of
30 drugs. New ways of delivering drugs at the right time, in a controlled manner, with
CA 02263411 1999-02-09
wo 98/06438 PCT/US97/13988
minim~l side effects, and greater efficacy per dose are continually sought by the drug
delivery and pharmaceutical industries. The reversibly gelling polymeric network of
this invention has the physico-chernical characteristics that make it a suitable drug
delivery vehicle for transmucosal delivery of conventional smal] chemical drugs as
S well as new macromolecul~r (e.g., peptides) drugs or therapeutic products
The reversibly gelling polymer network comprises a responsive polymer
component capable of aggregation in response to an environrnental stimulus. The
responsive polymer component is randomly bonded to a structural polymer component
which exhibits self-repulsive interactions over the use conditions of the pharmaceutical
composition. The repulsive forces cause the structural component to remain extended
and solvated in an aqueous medium. The reversibly gelling polymer network is
characterized in that it viscosifies in response to the environrnental stimulus. The
polymer network may also include some unbound or "free" responsive polymer or
other additives which contribute to or modify the characteristic properties of the
polymer composition.
In addition, the pharmaceutic composition includes a pharrnaceutic agent
selected to provide a preselected pharmaceutic effect. A pharmaceutic effect is one
which seeks to treat the source or symptom of a disease or physical disorder.
Pharmaceutics include those products subject to regulation under the FDA ph~rrn~ceutjc
guidelines, as well as consumer products.
By "gelation" or "viscosification" as those terms are used herein, it is meant adrastic increase in the viscosity of the polymer network solution. Gelation is
dependent on the initial viscosity of the solution, but typically a viscosity increase at
pH 7 and 1 wt% polymer concentration is in the range of preferably 2- to 100-fold,
and preferably 5- to 50-fold, and more preferably 10- to 20-fold for a polymer
net~,vork which is used in the preparation of the pharmaceutic compositions of the
invention. Such effects are observed in a simple polymer network solution and the
effect may be modified by the presence of other components in the pharmaceutic
composition.
CA 02263411 1999-02-09
Wo 98~ 8 PCT/US97/13988
By "reversibly gelling" as that term is used herein, it is meant that the process
of gelation takes place upon an increase in temperature rather than a decrease in
temperature. This is counter-intuitive, since solution viscosity typically decreases with
an increase in temperature.
By "use conditions" as that term is used herein it is meant all conditions to
which the composition is likely to be exposed during its use, including during
shipment and storage as well as during medical treatment.
The novel interaction between the constituent polymers components of the
reversibly gelling polymer network permits formation of gels at very low solids
content. Gelation and/or viscosification is observed in aqueous solutions having about
0.01 to 20 wt% of the responsive polymer component and about 0.01 to 20 wt% of the
structural polymer component. A typical reversibly gelling polymer network may be
comprised of about 0.01 wt% to about 10 wt%, preferably less than about 4 wt% oftotal polymer solids (e.g., responsive polymer and structural polymer), and morepreferably less than 1 wt% total polymer solids, while still exhibiting reverse thermal
viscosification. Of course, the total solids content of the composition, including
additives and the pharmaceutic agent, may be much higher. The viscosity of a 1 wt%
polymer network increases at least ten-fold with an increase in temperature of about
5~C at p~ 7. Viscosity increases may be even greater over a larger temperature range
at pH 7 and or hi her polymer network content.
The relative proportion of responsive polymer and structural polymer may vary
in the composition, dependent upon the desired properties of the pharmaceutic
composition. In one embodiment, the responsive polymer is present in a range of
about 1 to 20 wt% and the structural polymer is present in a range about of 99 to
80 wt%. In another embodiment, the responsive polymer component is present in a
range of about 21 to 40 wt% and the structural polymer component is present in arange of about 79 to 60 wt%. In another embodiment, the responsive polymer
component is present in a range of about 41 to 50 wt% and the structural polymercomponent is present in a range of about 59 to 50 wt%. In another embodiment, the
responsive polymer component is present in a rano,e of abou~ 51 to 60 ~t% and the
CA 02263411 1999-02-09
WO 98/06438 PCT/US97/13988
structural polymer component is present in a range of about 49 to 40 wt%. In yetanother embodiment, the responsive polymer component is present in a range of about
61 to 90 wt% and the structural polymer component is present in a range of about 39
to 20 wt%. In another embodiment, the responsive polymer component is present in a
range of about 81 to 99 wt% and the structural polymer component is present in arange of about l9 to I wt%.
The reversibly gelling polymer network described above may be included in a
pharrnaceutic composition as a delivery vehicle for a pharmaceutic agent. In addition,
the reversibly gelling polymer network may be included to improve the flow
characteristics, thickness and other properties of the composition. Additives also may
be included to modify the polymer network performance, such as to increase or
decrease the temperature of the liquid-to-gel transition and/or to increase or decrease
the viscosity of the responsive polymer composition.
In one aspect of the invention, the reversibly gelling polymer network is
incorporated into a pharmaceutic composition to impart thickening properties to the
composition at the use and/or application temperature. Such thickening properties
include enh~nced overall viscosity, as well as a desirable viscosity response with
temperature. The polymer network may be useful as a thickener in pH ranges whereother thickeners are not effective.
In another aspect of the invention, the reversibly gelling polymer network is
incorporated into a pharmaceutic composition to stabilize and solubilize hydrophobic
agents in the pharmaceutic composition. The reversibly gelling polymer network may
be included to increase emulsion stability. Many emulsions (a suspension of small
droplets or particles of a first material in a second material) lose viscosity upon
heating. As will be demonstrated herein, the reversibly gelling polymer network
retains its emulsifying properties even at elevated temperatures.
In addition, the reversibly gelling polymer network may be included in the
composition to impart emolliency to the composition. The composition may also act
as a film-forming agent after it has been applied to the skin or other mucosal
membrane. This film-forming agent may be used as a barrier to prevent water loss
-- , _ . . . .
CA 02263411 1999-02-09
W O 98/06438 PCTnUS97/13988
from the sl~in which contributes to the moisturization of the skin. The formed-film
could also provide protective coating ("band-aid") to protect the tissue againstenvironmentai challenge(s) or to provide a mechanical separation between to adjust
tissues (adhesion prevention).
Brief Description of the Drawina
The invention is described with reference to the Drawing, which is presented
for the purpose of illustration and is in no way intended to be limiting, and in which:
Figure 1 is a schematic illustration of the poloxamer:poly(acrylic acid) polymernetwork below and above the transition temperature illustrating the aggregation of the
hydrophobic poloxamer regions;
Figure 2 is a graph of viscosity vs. temperature for a I wt%, 2 wt% and 3 wt%
responsive polymer network aqueous composition of a poloxamer/poly(acrylic acid)(1:1) at pH 7.0 measured at a shear rate of 0.44 sec~';
Figure 3 is a graph of viscosity vs. temperature for a 1 wt% poloxamer:
poly(acrylic acid) polymer network composition demonstrating reversibility of the
viscosity response;
Figure 4 shows the viscosity response of a 2 wt% poloxarner:poly(acrylic acid)
polymer composition at various shear rates;
Figure 5 shows a viscosity response curve for a 2 wt% poloxamer: poly(acrylic
acid) polymer networlc composition prepared with nominal mixing and stirring andprepared using high shear homogenization (8000 rpm, 30 min);
Figure 6 is a graph of viscosity vs. temperature for a 1 wt% poloxamer:
poly(acrylic acid) polymer network composition at various pHs;
Figure 7 is a graph of viscosity vs. temperature for a 1 wt% poloxamer:
poly(acrylic acid) polymer network composition with and without addition of 0.25wt% KCI;
Figure 8 is a graph of viscosity vs. temperature for a I wt% poloxarner:
poly(acrylic acid) polymer network composition with and without addition of 0.5 wt%
acetamide MEA;
CA 02263411 1999-02-09
W O 98/06438 PCT~US97tl3988
Figure 9 is a graph of viscosity vs. temperature for a I wt% poloxamer:
poly(acrylic acid) polymer network composition without and with 5 wt%, 10 wt% and
20 wt% added ethanol, respectively;
Figure 10 is a graph of viscosity vs. temperature for a I wt% poloxamer:
5 poly(acrylic acid) polymer network composition without and with addition of 0.025
wt% Surfynol CTII;
Figure 11 is an illustration of a reversibly gelling polymer network used as an
emulsifier and stabilizer for a hydrophobic agent;
Figure 12A is a plot of equilibrium solubility of estradiol in aqueous (pH 7.0)
10 solutions of a reversibly gelling polymer network and Figure lOB a plot of the release
of estradiol from the polymeric composition as a function of concentration;
Figure 13A plot of equilibriurn solubility of progesterone in aqueous (pH 7.0)
solutions of a reversibly gelling polymer network and Figure 1 IB a plot of the release
of progesterone from the polymeric composition as a function of concentration;
Fioure 14 is a plot of viscosity vs. temperature for (a) a I wt% responsive
polymer net~vork aqueous composition of Pluronic~) F127 poloxarnerlpoly(acrylic acid)
(1:1) and (b) a I wt% physical blend of Pluronic(~) F127 poloxamer/poly(acrylic acid)
(1:1) at pH 7.0 measured at a shear rate 0.22 sec ';
Figure 15 is a plot of viscosity vs. temperature for a I wt% responsive polymer
network aqueous composition of Pluronicg) F88 poloxamer/poly(acrylic acid) (1:1) at
pH 7.0 measured at a shear rate 2.64 sec~';
Figure 16 is a graph of the viscosity vs. temperature effect for a responsive
polymer network composition of 2 wt% Pluronic~) P104 poloxamer/poly(acrylic acid)
(1:1) in deionized water at pH 7.0 measured at shear rate of 22 sec-';
Figure 17 is plot of viscosity vs. temperature for a responsive polymer network
composition of 2 wt% Pluronic~;) F123 poloxarner/poly(acrylic acid) (1:1) at pH 7.0
measured at a shear rate of 22 sec~';
Figure 18 is plot of viscosity vs. temperature for a responsive polymer network
composition of 2 wt% Pluronic~) F127/poly(acrylic acid-co-methacrylic acid) (1:1) in
deionized water at a shear rate of 22 sec-';
CA 02263411 1999-02-09
WO 98/06438 PCTrUS97/13988
Figure 19 is a plot of viscosity vs. temperature for I wt% made of series of
poloxamers and poly(acrylic acid) (1:1) in deionized water at a shear rate of 13~ sec-';
Figure 20 is a plot of viscosity vs. temperature for a responsive polymer
network composition of a 2 wt% polyethyleneglycol mono(nonylphenylether)/
S polyacrylic acid (1:1) at pH 7.0 at a shear rate of 2.64 sec ~;
Figure ~1 is a plot showing release of hemoglobin from a
poloxamer/poly(acrylic acid) polymer network of the invention;
Figure 22 is a plot showing the release of Iysozyme from the
poloxamer/poly(acrylic acid) polymer comple~c of the invention;
Figure 23 is a plot showing release of insulin from a poloxamer/poly(acrylic
acid) polymer network composition of the invention;
Figure 24 is a plot of viscosity vs. temperature for a polo~;amer/poly(acrylic
acid) polymer net~,vork composition (a) before and (b) after sterilization by autoclave;
Figure 25 is a plot of the effect of loading fluorescein on the onset of gelation
of responsive polymer network vs. total polymer concentration in responsive polymer
network solution (pH 7.0);
Figure 26 is a plot of the rate of progesterone release and macroscopic viscosity
vs. polymer concentration;
Figure 27 is a plot of the percentage of progesterone release vs. polymer
~0 concentration in responsive polymer network;
Figure 28 is a plot of fluorescein retention in rabbit eye vs. time for a I wt%
poloxamer:poly(acrylic acid) polymer network;
Figure 29 is a scinti raphic assessment of corneal residence time in human and
rabbit eyes, which compares residence time for a poloxamer:poly(acrylic acid)
~5 composition with that of cornmercially available materials;
Figure 30 is a plot of activity vs. time to determine retention time of a nasal
composition of the invention in the nasal passages;
Figure 3 I is a plot of serum concentration of luteinizing horrnone in sheep
a-lmini~tered nasally from a 5.5 wt% solution of a poloxamer:poly(acrylic acid)
polymeric network cont~inin~ 100 llg of a GnRH analog;
CA 02263411 1999-02-09
W O 98/06438 PCTAUS97/13988
Figure ,2 is a plot of activity vs. time to determine retention time of a nasal
composition of the invention in the esophageal passages;
Figure 33 is a plot of cumulative serum estradiol levels vs time following
vaginal deliverv of estrogens in sheep using a poloxamer:poly(acrylic acid) polymeric
5 delivery vehicle; and
Figure 34 is a plot of serum luteinizing hormone levels vs. time following
vaginal delivery of GrlRH and its analogs in sheep using a poloxamer:poly(acrylic
acid) polymeric delivery vehicle.
Detailed Description of the Invention
The present invention is directed to a pharmaceutic composition comprising a
novel responsive component:structural component polymer network. The polymer
network functions as an environmentally sensitive thickening agent, and in addition
possesses surfactant and emulsifying capabilities which may be beneficial to the15 pharmaceutic composition. The polymer network composition according to the
invention includes a responsive polymer component randomly covalently bonded to a
structural polymer component. The polymer network contains about 0.01-~0 wt% each
of responsive polymer and structural polymer. Exemplary polymer network
compositions range from about 1:10 to about 10:1 responsive polymer:structural
20 polymer. Polymer network gel compositions which exhibit a reversible gelation at
body temperature (25-40~C) and/or at physiological pH (ca. pH 3.0-9.0) and even in
basic enviromnents up to pH 13 (e.g., the gasto-intestinal environment) are particularly
preferred for pharmaceutic applications.
The compositions of the invention include a safe and effective amount of a
25 pharmaceutically active agent. "Safe and effective", as it is used herein, means an
amount high enough to significantly positively modify the condition to be treated or
the pharmaceutic effect to be obtained, but low enough to avoid serious side effects.
The responsive component is an oligomer or polymer which will respond to a
stimulus to change its degree of association and/or agglomeration. The stimulus may
30 be temperature, pH~ ionic concentration, solvent concentration. Iight. magnetic field,
CA 02263411 1999-02-09
W O 98/06438 PCTrUS97/13988
electrical field, pressure or other triggers comrnonly used to trigger a responsive gel
material. Temperature is a preferred environment~l trigger. The aggregation may be
in the form of micelle formation. precipitation. Iabile crosslinking or other factors.
The responsive component typically possesses regions of hydrophobic character,
e.g, poly(propyleneo~ide) blocks, and hydrophilic character, e.g., poly(ethyleneoxide)
blocks in order to facilitate aggregation. The responsive polymer may be linear or
branched. Suitable responsive components include polyoxyalkylene polymers, such as
block copolymers of different oxyalkylene units. At least one polyoxyalkylene unit
should have hydrophobic characteristics and at least one polyoxyalkylene unit should
l0 have hydrophilic characteristics. A block copolymer of polyoxyethylene and
polyoxypropylene may be used in a preferred embodiment of the invention. Anothersuitable responsive component includes polo~carners, which are triblock polyol
polymers having the general of a triad ABA block copolymer, (P~)~(P,)b(PI)D, ~vhere P,
= poly(ethyleneoxide) and P, = poly(propyleneoxide~ blocks, where a is in the range of
10-50 and uhere b is in the range of 50-70. Pluronic(g) (BASF) tribloc~ polymers are
commercially available for a in the range of 16 to 48 and b ranging from ~4-62.
Other exemplary polyoxyalkylene polymers include alkyl polyols. which are a
product of alcohol con~len~ation reactions with a terminal alkyl or arylalkyl group.
The alkyl group should have hydrophobic character, such as butyl, hexyl and the like.
20 An alkyl polyol may have the general formula R-(OCH~CH,)nOH, where R is a
nonpolar pendant group such as alkyl and arylalkyl and the like, and n is in the range
of ~-l000. A preferred alkylpolyol is polyethyleneglycol mono(nonylphenyl)ether.Still other exemplary responsive components may include cellulosic, cellulose ethers
and guar gums which possess hydrophobic and hydrophilic regions along the polymer
2~ backbone which perrnit aggregation behavior. One or more responsive components
may be used in the reversibly gelling polymer network composition of the present
inventlon.
The structural component is an oligomer or polymer which serves as a support
for the responsive polymer so that a multi-component polymer network is formed.
30 The structural component e:Yperiences self-repulsive interactions, that is. the structural
CA 02263411 1999-02-09
WO 98/06438 PCTrUS97/13988
polymer tends to repel rather than attract like structural polymer components. This
results in an extended structural polymer. The structural component exhibits such
repulsive interactions over the entire use conditions of the polymer network. Thus,
unlike the responsive component of the polymer network which exists in two different
states, e.g., a~gregated and non-aggregated, dependent upon its environment, thestructural component remains in a substantially extended over the entire use condition
of the composition.
Suitable structural components include ionizable polymers. Ionization provides
the repulsive self-interactions which characterize the structural polymer component.
The ionizable polymers of the present invention include linear, branched and/or
crosslinked polymers. Of particular interest are carboxyvinyl polymers of monomers
such as acrylic acid, methacrylic acid, ethacrylic acid, phenyl acrylic acid, pentenoic
acid and the like. Poly(acrylic acid) and its salts is a preferred carboxyvinyl polymer.
One or more poly(carboxyvinyl) polymers may be used in the responsive polymer
network compositions of the present invention. Copolymers, such as by way of
example only, copolymers of acrylic acid and methacrylic acid, are also contemplated.
Naturally occurring polymers such as chitosan or hyaluronic acids are also possible as
structural polymers since they are capable of forming an ionized network as polymers
or copolymers of other structural polymers.
Non-ionized polymers which contain both hydrophilic and hydrophobic groups
may be suitable structural polymers where they exhibit sufficient repulsive forces over
use conditions to In~int~in the polymer extended in solution. Suitable non-ionized
structural polymers include, acrylamides or substituted acrylamides.
The poly(acrylic acid) may be linear, branched and/or crosslinked. Poly(acrylic
acid) is capable of ionization with a change in pH of the solution. By ionization, as
that term is used with respect to poly(acrylic acid), it is meant the formation of the
conjugate base of the acrylic acid, namely acrylate. As used herein, poly(acrylic acid)
includes both ionized and non-ionized versions of the polymer. Changes in ionic
strength may be accomplished by a change in pH or by a change in salt concentration.
The viscosifying effect of the polymer network is partly a function of the ionization of
. . .
CA 02263411 1999-02-09
W O 98/06438 PCT~US97/13988
14
the poly(acrylic acid); however, reverse therrnal gelling may occur without ionization.
Changes to the ionic state of the polymer causes the polymer to e~cperience attractive
(collapsing) or repulsive (e~cpanding) forces. Wllere there is no need or desire for the
composition to be applied in a high viscosity state, it may be possible to prepare the
5 composition as non-ionized poly(acrylic acid). The body's natural buffering abiiity
will adjust the pH of the applied composition to ionize the poly(acrylic acid) and
thereby develop its characteristic viscosity.
The reversibly gelling responsive polymer networks compositions of the present
invention are highly stable and do not exhibit any phase separation upon standing or
10 upon repeated cycling between a liquid and a gel state. Samples were stored at 45 ~C
for more than three months without any noticeable decomposition, clouding, phaseseparation 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 constituent polymers are immiscible in
15 one another.
Without intending to be bound by any particular mech~nism or chemical
structure, it is believed that the structure of the polymer network involves a random
bonding of the responsive polymer component onto the backbone of an e~ctended, well
solvated structural polymer component. The combination of the structural polymer20 component and randomly bonded responsive polymer component gives the composition
its unique properties. Viscosity is a function of the molecular weight of the
solubilized polymer. Aggregation of the responsive polymer component increases the
effective molecular weight of the polymer network. The aggregation may be in theforrn of micelle formation, precipitation, labile cros.~linking or other factors. The
2~ repulsive forces of the structural polymer component keeps the polymer in an
extended, solvated state which prevents precipitation upon the effective increase in
molecular weight.
With reference to a particular reversibly gelling polymer network,
polo~amer:poly(acrylic acid), the observed thermal behavior of the reversibly gelling
30 polymer network suggests that the increase in viscosity is due to aggregation of the
CA 02263411 1999-02-09
W O 98/06438 PCTAUS97/13988
hydrophobic portion of the poloxamer at the transition temperature which, because of
bonding with the poly(acrylic acid) component, serve as temporary cross-links which
physically bridge adjacent chains of poly(acrylic acid) to provide a viscous gel-like
extended polymer structure. The aggregation process may be understood as occurring
5 as shown in Figure 1, in which a backbone 20 represent poly(acrylic acid), a thin band
24 represents the hydrophobic poly(propyleneoxide) region of the polo~camer and a
thick band 26 represents the hydrophilic poly(ethyleneoxide) region of the poloxamer.
Below the transition temperature, the polymer network is randomly arranged, as is
shown in Figure IA. At or above the transition temperature, the hydrophobic regions
10 24 associate to form aggregations or micelles 28, as is shown in Figure lB. The
association increases the effective molecular weight of the polymer network
composition with the corresponding increase in viscosity.
The reverse viscosification effect at low polymer concentrations provides clear,colorless gels which are particularly well-suited to pharmaceutic applications For
15 example, very little residue is formed upon dehydration which may be important in
some applications, such as in optically applied pharmaceutics. An additional
advantage of the polymer net~vork of the invention is that it remains clear and
translucent before and after the triggering environmental change. These characteristics
of the reversibly gelling polymer network make it well suited for use in pharmaceutic
20 compositions.
The practical advantage of this behavior of the composition is that the
formulation can be administered as a flowing liquid at ambient temperatures. Upon
contact with body tissues it viscosifies, thus ch~nging its flow properties, and more
importantly, its clearance from the site of application. Furthermore, for polymers in
25 general, the viscosity at ambient temperature is concentration dependent. As the
concentration is increased to achieve desired flow properties in contact with body
tissues, the viscosity at ambient temperatures also increases, making it more difficult to
lminister such compositions. The uniqueness of the polymeric network of this
invention also allows it to the administered easily at ambient temperatures as a flowing
CA 02263411 1999-02-09
W O 98/06438 PCTrUS97/13988
16
liquid at various concentrations; its gelled state is only realized once it has been placed
in contact with body tissues.
Thus, a composition may be prepared at low temperatures while the polymer
network is in a low viscosity state. Mixing of ingredients under low viscosity is
5 expected to be easier, thus simplifying the manufacturing process Yet, the resultant
mixture would be of increased viscosity at use temperatures. As a further advantage, a
pharmaceutic composition comprising reversibly gelling polymer networli may be
spread thinly to allow for even application, due to its low viscosity at room
temperature, but will thicken and "fill" the body contours upon warming up to body
10 surface temperature.
The reversibly gelling polymer network may also be included in a pharmaceutic
composition for use as a stabilizing, solubilizing or emulsifying agent for a
hydrophobic component of the pharrnaceutic formulation. Upon aggregation and/or
micelle formation in the responsive component, hydrophobic domains are created
15 which may be used to solubilize and control release of hydrophobic agents. Similar
micelle-based systems have been shown to protect trapped peptides and proteins
against enzymatic degradation from surface enzymes.
An example of the drarnatic increase in viscosity and of the gelation of the
reversibly gelling polymer network compositions of the invention is shown in Figure 2.
20 Figure 2 is a graph of viscosity vs. temperature for 1 wt%, 2 ~vt% and 3 wt% polymer
net~,vork compositions comprising 1:1 poloxamer:poly(acrylic acid), hydrated andneutralized. The viscosity measurements were taken on a Brookfield viscometer at a
shear rate of 0.44 sec-' 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. This is
25 not typical of all polymer network compositions since polymerization condition will
affect initial viscosity. Final viscosities were approximately 33,000 cP, 100,000 cP
and 155,000 cP for the I wt%, 2 ~vt% and 3 wt% compositions, respectively. This
represents viscosity increases of about 30-, 90- and 140-fold. respectively. This effect
is entirely reversible. Upon cooling, the composition regains its initial viscosity. This
30 is demonstrated in Figure 3, where a I wt% polo~camer:poly(acrylic acid) composition
CA 02263411 1999-02-09
W O 98/06438 PCTrUS97/13988
is warmed through the transition temperature up to 35 ~C (simple curve), cooled to
room temperature (24 ~C, ticked curve) and then warmed again to up above the
transition temperature (open bo:c curve). The viscosity response was virtually identical
in all three instances.
As would be expected with a non-Newtonian system, the solution viscosity
differs with different shear rates. Figure 4A shows the viscosity response of a 2 wt%
poloxamer:poly(acrylic acid) polymer composition at various shear rates. The
viscosity response is consistent up to 24 C; however, the final viscosity is reduced
with increasing shear rate. At low temperatures, the polymeric network behaves
approximately like a Newtonian liquid - very little she.~r thinnino is observed in the
available shear range. As the ttlllpel~ re and the viscosity increases, so does the
shear thinnino High temperature, high shear rate data can fitted with a power law
model, ~ ~x yn~l where T~ and y are the viscosity and the shear rate, respectively. The
4~ ~C date in Figure 4B yield the exponent n~0.9, which indicates extreme shear
thinningJ, since shear stress is almost independent of the shear rate.
However, unlike many prior art hydrogels, e.g., carbomers, the responsive
component: structural component polymer network composition does not permanentlyloose viscosity after being subjected to high shear conditions. The polymer network
composition remains unaffected by such shear conditions as homogenization. Figure 5
compares the viscosity response curve of a 2 wt% poloxamer:poly(acrylic acid)
polymer composition prepared with nominal mi~ing (simple line) and stirring with that
of a polymer composition of similar composition prepared using high shear
homogenization designated by a ticked line (8000 rpm, 30 min). No significant
decrease in viscosity is observed.
~he practical implication of this effect is that the polymeric net~vork compositions
can be delivered even at high temperatures if sufficiently high shear is available. In
specific pharmaceutical applications, such as ophthalmic compositions, the shearthinning behavior also allows for the composition to be spread across the precorneal
surface of the eye 2S a result of the shearing effect of the movement of the eyelids The
... . .
CA 02263411 1999-02-09
W O 98/06438 PCTAUS97/13988
18
composition may also be applied through a nozle that provides high shear to reduce
viscosity, yet the composition regains its viscosity after application to the treatment
area. This contrasts with conventional formulations which permanently lose viscosity
after being subjected to high shear.
S A number of factors influence the viscosity and transition temperature of the
composition. The more important factors include polymer concentration, pH and
presence and nature of additives.
The effect of pH on the viscosity of reversibly gelling polymer networks is
shown in Figure 6 for a I wt % poloxamer:poly(acrylic acid) polymer network.
10 Increasing pH from the starting pH has a lesser effect on the viscosity than decreasing
the pH. This may relate to the extent of ionization of the poly(acrylic acid)
component of the polymer network as discussed above which will affect the strength
of repulsive forces in the structural polymer. This may be clearly seen in Figure 6
when comparing the viscosity response at pH 5 and pH 11. Satisfactory viscosities
15 can be obtained at high pHs indicating the potential value of the revers;bly gelling
polymer network in applications such as in the intestinal tract.
The pharmaceutical composition may also include additives for influencing the
performance of the polymer network, such as the transition temperature and the
viscosity of the polymer composition above the transition temperature. The followinc
20 list is not intended to be exhaustive but rather illustrative of the broad variety of
additives which can be used.
These materials include solvents (e.g., 2-propanol, ethanol, acetone, 1,2-
pyrrolidinone, N-methylpyrrolidinone), salts (e.g., calcium chloride, sodium chloride,
potassium chloride, sodium or potassium phosphates, borate buffers, sodium citrate),
25 preservatives (benzalkonium chloride, phenoxyethanol, sodium
hydro~ymethylglycinate, ethylparaben, benzoyl alcohol, methylparaben, propylparaben,
butylparaben, Germaben II), humectant/moisturizers (acetamide MEA, lactimide MEA,
hydrolyzed collagen, mannitol, panthenol, glycerin), lubricants (hyaluronic acid,
mineral oil, PEG-60-lanolin, PPG-1~-PEG-50-lanolin, PPG-2 myristyl ether
30 propionate) and surfactants.
CA 02263411 1999-02-09
W 098/06438 PCT~US97/13988
19
Surfactants may be divided into three classes: cationic, anionic, and nonionics.An example of a cationic surfactant used is ricinoleamidopropyl ethyldimonium
ethosulfate (Lipoquat R). Anionic surfactants include sodium dodecyl sulfate and ether
sulfates such as Rhodapex C0-436. Nonionic surfactants include Surfynol CT-I 11,5 TG, polyoxyethylene sorbitan fatty acid esters such as Tween 65 and 80, sorbitan fatty
acid esters such as Span 65, alkylphenol ethoxylates such as Igepal CO-710 and 430,
dimethicone copolyols such as Dow Corning 190, 193, ~nd Silwet L7001.
The addition of polymers has been studied including xanthan gum, ceilulosics
such as hydroxyethylcellulose (HEC), carboxymethoxycellulose (CMC),
10 lauryldimonium hydroxypropyl oxyethyl cellulose (Crodacel QL),
hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC),
poly(acrylic acid), cyclodextrins, methyl acrylarnido propyl triammonium chloride
(MAPTAC), polyethylene oxide, polyvinylpyroliddone, polyvinyl alcohol, and
propylene oxide/ethylene oxide random copolymers. Poloxamers may also be used as15 additives. Examples include both the Pluronic(~ polyols having an (P,)~(P2)b(P,)~
structure such as Pluronic(~) F3B, L44, P65, F68, F~8, L92, P103, P104, P105, F108,
L122 and F127, as well as the reverse Pluronic~) R series (P,)~(P,)b(P~)a structure such
as Pluronic~ 17R2 and 25R8. Other miscellaneous materials include propyleneoxide,
urea, triethanolamine, alkylphenol ethoxylates (Iconol series), and linear alcohol
20 alkoxylates (Plurafac series).
Additives affect the viscosity of the compositions differently depending upon
the nature of the additive and its concentration. Some additives will affect the initial
or final viscosity, whereas others will affect the temperature range of the viscosity
response, or both.
2j Potassium chloride and acetamide MEA are two examples of additives which
decrease the final viscosity of the composition (see, Example 32). KCI (0.75%) added
to a 1 wt% reversibly gelling polymer composition reduces the viscositv by about 3000
cps. See, Figure 7. The humectant, acetamide MEA, lowers the viscosity of a I wt%
solution by approximately 1,500 cps (see, Figure ~).
.
CA 02263411 1999-02-09
W O 98/06438 rCTAUS97/13988
Glycerin, ethanol and dimethicone copolymer have been shown to affect the
temperature range over which the viscosity response occurs. Glycerin shifts the
transition temperature to a slightly lower range from an initial 24-34 ~C to about '74-
30 ~C, but does not affect the final viscosity (see, Example 28). The effect of ethanol
5 on the viscosity is different at different concentration levels. At i wt% and 10 wt%
added ethanol, the transition temperature is shifted to lower ranges, e.g., 24-29 ~C and
20-~9 ~C, respectively. At 20 wt% added ethanol, the composition not only e~chibits a
lowering of the transition temperature, but also a marked increase in initial and final
viscosity. See, Figure 9. Dimethicone copolymer (1 wt%) also changed the transition
10 temperature, but in this instance the transition temperature range was raised to 28-
41 ~C. Thus, proper selection of additives permits the formulator to adjust the
transition temperature to various ranges.
To further illustrate the scope of the changes that could be accomplished with
additives, the effect of adding the surfactant Surfynol CT11 to the polymeric network is
shown in Figure 10. In this e~ample, the addition of 0.25% of the surfactant to a 1%
polymer solution shifts the transition temperature downward.
These examples of the effects of formulation ingredients on the viscosity of thecomposition show that the polymeric network provides the forrnulator significantopportunities in creating compositions with different rheological properties by the
20 judicious choice of additives. Significantly, the low temperature properties of the
polymeric compositions are minim~lly affected by the additives while the properties of
the gelled or viscosified form of the compositions can show dramatic effects.
The reversible viscosification of the polymer network at elevated temperatures
makes the materials ideal for use as thickening agents in pharmaceutic and personal
25 care products at any temperature above the transition. Another use of the "thickening"
of solutions cont~ining the polymer network as a thickener supplement in emulsions.
Currently emulsifiers are often negatively effected by increased temperatures. An
additive with reverse thermal viscosification properties, however, would react in
e~cactly the opposite way, increasing its ability to emulsify as it ,ained three-
30 dimensional structure upon heating above its transition temperature.
CA 02263411 1999-02-09
W O 98/06438 PCTrUS97/13988
21
In the applications where the reversibly gelling polymer composition can act as
a surfactant, the polymer network will have the ability to act as a primary emulsifier
without any (or with very little) addition of traditional surfactant. The responsive
polymer network will also act as a stabilizer for oil-soluble ingredients that would
5 conventionally need to be solubilized by oils in formulation. The hydrophobic portion
of the polymer network (PPO) forms domains which act as reservoirs for an oil-
soluble or hydrophobic additive, such as a hydrophobic pharmaceutical agent, as is
illustrated in Figure 11. The increase in viscosity above the transition temperature
adds structure and yield value to the water phase and results in a highly stable10 emulsion for the hydrophobic additive.
The polymer network may be useful as a solubilization agent in pharmaceutic
applications. A self-assembling system comprising the reversibly gelling polymernetwork exhibits therrnogelation, pH sensitivitv, and the ability to solubilize
hydrophobic agents in aqueous media. When poloxarner is copolymerized with
15 poly(acrylic acid) (PAA) according to the invention, the resulting copolymer network
is bioadhesive and can be applied in a nurnber of therapies. The materials described in
this invention combine "reverse" thermoviscosification mucoadhesion, solubilization of
hydrophobic and difficult to manage moieties, easy formulation, and protection of
agents from degradation to provide a superior medium for pharmaceutic and personal
20 care products.
In addition to the unique rheological properties provided by the polymeric
network, the polymeric network is capable of solubilizing and releasing bioactive
materials. Solubilization is expected to occur as a result of dissolution in the bulk
aqueous phase or by incorporation of the solute in micelles created by the hydrophobic
25 domains of the polymeric network. Release of the drug would occur through diffusion
or network erosion mech~ni~mc.
Those skilled in the art will appreciate that the polymer network compositions
of the present invention may be utilized for a wide variety of pharmaceutic
applications. To prepare a pharmaceutic composilion, an effective amount of
30 pharrnaceutically active agent(s) which imparts the desirable pharrnaceutic effect is
CA 02263411 1999-02-09
WO 98/06438 PCTnUS97/13988
incorporated into the reversibly gelling polymer network composition of the present
invention. Preferably the selected a(Jent is water soluble, which will readily lend itself
to a homogeneous dispersion through out the reversibly gelling polymer network
composition; however, the polymer network has been demonstrated to si_nificantly5 solubilize or suspend hydrophilic agents in order to improve formulation homogeneitv
(see, Example 34). It is also preferred that the agent(s) is nonreactive with the
polymer network composition. For materials which are not water soluble, it is also
within the scope of the invention to disperse or suspend lipophilic material throughout
the polymer network composition.
A discussion of particular applications follows.
Esopha~eal and buccal applications. One indication for the use of this
polymeric network would be as a coating to protect tissue from external or internal
chemi~l challenges. For example, the polymeric network in the form of an
esophageal formulation could coat the esophagus and protect it from the effects of
acid, resulting from gastric reflux (GERD). Because of its ionic nature, the
neutralized, polyacrylic acid component of the polymeric network could neutralize a
certain amount of acid and prevent the acid from acting upon the tissue. In another
variation, the polymeric net~vork formulation could include acid absorbing substances,
such as, alllmin~lm oxide.
With the incorporation of bioactive materials, the polymeric network provides
a suitable vehicle for delivering drugs within the esophageal lining. As explained
above, its rheological and mucoadhesive properties are desirable attributes for
controlling and facilitating drug delivery.
Opthalmic applications. Most ophthalmic drugs are applied to the eye
topically to the precorneal area. The most cornmon dosage form is a liquid drop.Drug bioavailability is generally low because liquid forrnulations are quickly cleared
from the eye by tearing and blinking, resulting in the need for frequent dosing and
uneven drug delivery.
The polymeric network provides a new vehicle for achieving greater
bioavailability of topically ~lmini.ct~red ophthalmic drugs. Formulations cont~ining it
CA 02263411 1999-02-09
wo 98/06438 PCTlUSs7ll3988
can be applied as drops which viscosify or gel upon contact with eye. Since gelling
can be accomplished with low concentrations of the polymer, blurring can be
minimi7~d upon drop inctill~ion Low solid concentrations also help to minimize
crusting along the eyelid margins. See, Examples 35-37.
A particular advantage of the polymeric network is that, as a result of its
rheological properties, compositions cont~ining the polymer will evenly coat theprecorneal surface. This is in contrast to other ophth~lmic drug delivery vehicles
which may gel upon application to the eye but which form deposits of the for~nulation
that reside under one eyelid. The ability of the polymer to shear-thinning or toevenly spread over the precorneal surface is particularly advantageous in dry eye
formulations or in the treatment of infl~mm~tion and wound healing conditions.
The use of the polymeric network would be indicated for delivering bioactive
materials, such as, ~n~sth~tics, mydriatics and cycloplegics, antimicrobial agents
(antibacterial, antifungal, antiviral), anti-infl~mm~tory agents, agents for the treatment
of glaucoma, ocular decongestants, diagnostic agents, and wound healing agents.
Nasal apDlications. The use of the polymeric network is also indicated for the
delivery of drugs to the nasal cavity. Nasal drug delivery has been considered as an
alternative to parenteral routes of administration of drugs that demonstrate low oral
bioavailability. In order to increase the bioavailability of nasally ~minictered drugs,
efforts have ~een made to increase the residence time of forrnulations in the nasal
cavity. Nasal delivery of drugs can offer advantages over other methods of delivery,
including rapid systemic absorption, lower dosing, more rapid onset of desired
therapeutic effects, and improved pharmacokinetics. In addition, it provides an
alternative route for ~tiministering peptide drugs, which generally have low
~5 bioavailability via the oral route and are normally administered parenterally. See,
E~ample 40.
The rheological properties of the polymeric network are uniquely suited to
nasal delivery systems. Earlier results demonstrated that forrnulation variables can be
manipulated to significantly affect the higher temperature viscosity of the polymeric
net~vork. These same variables have only minim~l effects on the low temperature
., ~ , . .
CA 022634ll l999-02-09
W O 98/06438 PCTAUS97/13988
~4
viscosity. Therefore, formulations containing the polymeric network can be readily
sprayed at low temperature; the subsequent viscosification occurs only after
lmini.~Sràtion of the formulation and only at the site of application.
The polymeric network is also useful for delivering agents such as
decongestants, ~ntihi~t~mines, anti-osteoporosis agents, hormones, antineoplastic
agents, Parkinsonism drugs, etc.. The polymeric network is also indicated for the
application of vaccines, such as those against the influenza virus.
A further desirable outcome of the use of the polymeric network in the delivery
of nasal formulations is the prevention of roll back, or the loss of the formulation by
10 rapid flow to the posterior section of the nasal cavity and into the esophagus. In
addition to the negative effects on the delivery of the drug across the desired mucosal
tissue, roll can lead to unpleasant taste sensations associated with some drug
formulations. See, Example 41.
Veterinarv applications. The reversibly gelling polymer network of the
15 invention also may be useful in the treatment of not only human conditions but in
providing treatments for animal care. For veterinary products, the polymeric network
is indicated for the preparation of topical dermal products, such as antibacterials,
antifungals, antipruritics, and antiseborrheia, antiodor, and antiseptic/wound healing
preparations. Otic products would include ear cleaners with or without actives, such
20 as, antifungals. Ophthalmic products would include eye moisturizers or antimicrobial
preparations. The rheological, solubilizing, drug delivery, and chemical properties
provide the formulator of veterinary products the latitude to prepare compositions in a
variety of delivery forms and, more importantly, with regard to companion ~nim~
with a non-oily quality.
2~ Tablet ExciDients. It has been demonstrated that the polymeric network of the
invention can be processed by standard pharmaceutical processes, such as
Iyophilization and air drying. The reversible thermal viscosifying polymer network ma
be reconstituted with water, phosphate buffer or calcium chloride solution, without loss
or degradation of the rheological properties of the polymer. Thus, it is contemplated
30 that the polymer network of the invention may also be incorporated as excipients into
CA 022634ll l999-02-09
W O 98106438 PCT~US97/13988
tablets or granules for oral delivery. The polymer may be coated on an outer surface
of the tablet or may be introduced in powder form into the t~blet along with the active
agent and other ingredients. The poloxamer:poly(acrylic acid) polymer network may
be used to promote bioadhesion of the tablet and its contents with the mucosal lining
5 of the gastro-intestinal tract to extend transit time.
Injectibles. The polymeric network of the invention is well-suited for use in
injectable applications. A depot formulation may be prepared and administered at low
viscosity to a subdermal or intramuscular site, for example. The polymer will
viscosify and forrn a depot site, which will slowly release the active agent. The
10 reversible therrnally viscosifying polymer network, upon contact with body fluids
including blood or the like, undergoes gradual release of the dispersed drug for a
sustained or extended period (as compared to the release from an isotonic salinesolution). This can result in prolonged delivery (over, say 1 to 2,000 hours, preferably
2 to 800 hours) of effective arnounts (say, 0.0001 mg/kg/hour to 10 mg/kg/hour) of the
15 drug. This dosage forrn can be administered as is necessary depending on the subject
being treated, the severity of the affliction, the judgment of the prescribing physician,
and the like.
Alternatively, the polymeric network may be prepared at higher viscosities in
order to suspend micropheres or particles in the formulation. The formulation can
then take advantage of the shear thinning properties of the polymeric material. Thus,
during injection, the formulation is subjected to shear stresses which reduce viscosity
and allow an ordinarily viscous formulation to be introduced into the patient byinjection. Cessation of the strain results in reestablishing the high viscosity of the
formulation, so that the active agent may be slowly released therefrom.
The variety of different therapeutic agents which can be used in conjunction
with the copolymers of the invention is vast. In general, therapeutic agents which may
be a~mini~tered via the pharmaceutical compositions of the invention include, without
limitation: antiinfectives such as antibiotics and antiviral agents; analgesics and
analgesic combinations; anorexics; antihelmintics; antiarthritics; antiasthmatic agents;
CA 02263411 1999-02-09
W O 98~ PCT~US97/13988
26
anticonvulsants; antidepressants; antidiuretic agents; antidiarrh@als; antihistamines;
antiinfl~mm~tQry agents; antimigraine preparations; antin~ eants; antineoplastics;
antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics, antispasmodics;
anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations
including calcium channel blockers and beta-blockers such as pindolol and
antiarrhythrnics; antihypertensives; diuretics; vasodilators including general coronary,
peripheral and cerebral; central nervous system stimulants; cough and cold
preparations, including decongestants; hormones such as estradiol and other steroids,
including corticosteroids; hypnotics; immunosuppressives; muscle relaxants;
parasympatholytics; psychostimulants; sedatives; and tranquilizers; and naturally
derived or genetically engineered proteins, polysaccharides, glycoproteins, or
lipoproteins. Suitable pharmaceuticals for parenteral ~rlministration are well known as
is exemplified by the Handbook on Injectable Drugs, 6th edition, by Lawrence A.
Trissel, American Society of Hospital Pharmacists, Bethesda, Md., 1990 (hereby
incorporated by reference).
The polymeric nehvork is effective in extending the duration of contact of
preparations that have been applied to mucosal tissues. In providing a longer residence
time, the polymeric network provides a valuable tool for increasing drug delivery
across mucosal surfaces.
The polymeric network also may be used for products in which there is no
bioactive ingredient. The function of the polymeric network would be to provide, for
example, a protective or lubricating film to the surface of the tissue. For example,
the polymeric network could be the basic ingredient for a lubricating drop for the eye.
By its nature, that is, that of a hydrogel, it could provide a long lasting lubricious and
2~ moisturizing film to the eye of individuals suffering from dry eye conditions due to
pathological states or environmental stress. Other similar indications would be for
nasal or vaginal moisturizers.
It will also be appreciated that a sterile enviromnent may be required It is
contemplated as within the scope of the invention that the reversibly oellino polymer
CA 02263411 1999-02-09
W O 98/06438 PCTAUS97/13988
network compositions of the present invention may be prepared under sterile
conditions. See, Exarnple 16.
In the preparation of pharrnaceutical compositions, problems can be
encountered in the solubilization of hydrophobic bioactive materials. Because of its
hydrophobic moieties the polymeric network is capable of facilitation such dissolution,
even at the low concentrations which are used in forrnulating. To illustrate this
property, the solubility of hydrophobic materials, such as, estradiol and progesterone in
the polymeric network as a function of concentration of the polymeric system is shown
in the following two examples. See, E:Yample 34.
The solubility of the steroid hormones was measured by equilibration of excess
hormone in aqueous solutions with and without the polymeric network, followed bycentrifugation and filtration to remove the undissolved material. The concentrations of
the hormones was deterrnined spectrophotometrically at 240 nm (progesterone) or 280
nm (estradiol).
The solubility curves as a function of temperature for various concentrations ofthe polymeric network are shown in Figure 12A (estradiol~ and Figure 13A
(progesterone). The results show that increasing the concentration of the polymeric
network increased the solubility of the horrnones and that this solubility was greater at
higher temperatures.
The kinetics of the in vitro release of the hormones from the polymeric
network are shown in Figures 12B and 13B. These studies were perforrned using
thermostatted, vertical Franz cells. Spunbonded poly(propylene) microfilters (15-20
micron retention) were used to separate the feed and receiving chambers. The
receiving chamber consisted of 20% polyethylene glycol in water.
Figure 12B shows that the initial transport rate increases with decreasing
concentrations of the polymeric network. Figure 13B shows that this initial transport
rate also increases with a decrease in the temperature. Both of the these results are
related to the changes in the macroviscosity of the compositions.
These in vitro studies have shown the advantage of the polymeric network in
solubilizing and releasing hydrophobic bioactive materials. The usefulness of the
, . , . . _ .. . .. . .
CA 02263411 1999-02-09
W O 98/06438 rcTrusg7/l3988
28
polymeric network, however, is not limited to hydrophobic bioactive materials. This
property offers further advantages over other commonly used drug delivery vehicles.
Dissolution of more hydrophilic materials is expected, as demonstrated in iater
e:~arnples, by a mech~ni.~m of dissolution in the bulk aqueous component of the
5 formulations.
The poloxamer:poly(acrylic acid) polymer network has been evaluated under
Good Laboratory Practice (GLP) standard protocols known in the art for toxicity in
animal models and found to exhibit no toxic effects. The results of the toxicity study
are summarized in the following Table l. The non-toxicity of the polymer networkl O makes it an ideal candidate for use in pharmaceutic compositions.
Table 1. Toxici~y data for 6% polo~amer:poly(acrylic acid) solu~ion at pH 7.
Reaction testes mode of testing results
Skin sensitization guinea pig - topical not a sensitizer
eye irritation rabbit eye instiliation negative
primary dermal irritation rabbit - topical very slight edema (I on a
scale of 1-8)
acute dermal toxicity rat- single dose (2g/kg) no toxicity
acute oral toxicity rat - single dose (5g/kg) no toxicity
AMES test negative
Preparation of pharrnaceutic compositions may be accomplished with reference
to any of the pharrnaceutic formulation guidebooks and industry journals which are
available in the pharmaceutic industry. These references supply standard formulations
which may be modified by the addition or substitution of the reversible viscosifying
polymer network of the present invention into the formulation. Suitable guidebooks
~5 include Pharmaceutics and Toiletries ~ 7ine~ Voh 111 (March, 1996); Formularv:
Ideas for Personal Care; Croda, Inc, Parsippany, NJ (1993); and Pharmaceuticon:
Pharrnaceutic Formularv. BASF, which are hereby incorporated in their entirety by
reference.
CA 02263411 1999-02-09
wo 98/06438 PCT/US97/13988
29
The pharmaceutic composition may be in any forrn. Suitable forms will be
dependant, in part, of the intended mode and location of application. Opthalmic and
otic forrnulations are preferably administered in droplet or liquid form; nasal
formulations are preferable ~imir~ tered in droplet or spray forrn, or may be
5 administ~red as a powder (as a snuff); vaginal and rectal formulations are preferably
~lmini.st~red in the form of a cream, jelly or thick li~uid; veterinary forrnulations may
be adminictered as a cream, lotion, spray or mousse (for application to fur or exterior
surface); esophageal and buccalJoral cavity applications are preferably ~Amini~tered
from solution or as a powder; film forming applications or dermal applications may be
10 ~clmini.~tered as a lotions, crearns, sticks, roll-ons formulations or pad-applied
formulations.
Exemplary drugs or therapeutics delivery systems which may be ~-imini~tered
using the aqueous responsive polymer network compositions of the invention include,
but are in no way limited to, mucosal therapies, such as esophageal, otic, rectal,
15 buccal, oral, vaginal, and urological applications; topical therapies, such as wound
care, skin care and teat dips; and intravenous/subcutaneous therapies, such as
intramuscular, intrabone (e.g, joints), spinal and subcutaneous therapies, tissue
supplementation, adhesion prevention and parenteral drug delivery. In addition, filrther
applications include transdermal delivery and the forrnation of depots of drug
20 following injection. It will be appreciated that the ionic nature of the "structural
component" component of the responsive polymer network provides an adhesive
interaction with mucosal tissue.
Because the reversibly gelling polymer network composition of the present
invention is suited for application under a variety of physiological conditions, a wide
2~ variety of pharmaceutically active agents may be incorporated into and ~rlministered
from the polymer network composition. The pharmaceutic agent that mav be loaded
into the polymer networks of the present invention are any substance having biological
activity, including proteins, polypeptides, polynucleotides, nucleoproteins,
polysaccharides, glycoproteins, lipoproteins, and synthetic and biologicallv engineered
30 analogs thereof.
CA 02263411 1999-02-09
W 098/06438 PCT~US97/13988
Examples of suitable pharmaceutic agents 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
has already been deemed safe and effective for use by the appropriate governmental
S 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.
Drugs that are not themselves liquid at body temperature can be incorporated
10 into polymers, particularly gels. Moreover, peptides and proteins which may normally
be Iysed by tissue-activated enzymes such as peptidases, can be passively protected in
gels as well. See, Gehrke et al. Proceed. Inlern. Symp. Control. Rel. Bioact. Mater.,
22:145 (1995).
Ph~rm~cel-tic agents includes ph~rm~cologically active substances that produce
15 a local or systemic effect in ~nim~, plants, or viruses. The term thus means any
substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of
disease or in the enhancement of desirable physical or mental development and
conditions in an animal, plant, or virus. The term "animal" used herein is taken to
mean m~mm~l~, such as primates, including humans, sheep, horses, cattle, pigs, dogs,
20 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. cyanobacteria).
The ph~rm~reutically active compound may be any substance having biological
activity, including proteins, polypeptides, polynucleotides, nucleoproteins,
25 polysaccharides, glycoproteins, lipoproteins, and synthetic and biologically engineered
analogs thereof. The term "protein" is art-recognized and for purposes of this
invention also encompasses peptides. The proteins or peptides may be any biologically
active protein or peptide, naturally occurring or synthetic.
E~camples of proteins include antibodies, enzymes, steroids, growth hormone
30 and grov~h hormone-releasing hormone, gonadotropin-releasing hormone, and its
CA 02263411 1999-02-09
WO 95,'~ 8 PCT/US97/l3988
agonist and antagonist analogues, somatostatin and its analogues, gonadotropins such
as luteinizing hormone and follicle-stimulating hormone, peptide-T, thyrocalcitonin,
parathyroid hormone, glucagon, vasopressin, oxytocin, angiotensin I and II, bradykinin,
kallidin, adrenocorticotropic hormone, thyroid stimulating hormone, insulin, glucagon
5 and the numerous analogues and congeners of the foregoing molecules. The
pharrnaceutical agents may be selected from insulin, antigens selected from the group
consisting of MMR (mumps, measles and rubella) vaccine, typhoid vaccine, hepatitis A
vaccine, hepatitis B vaccine, herpes simplex virus, bacterial toxoids, cholera toxin
B-subunit, influenza vaccine virus, bordetela pertussis virus, vaccinia virus, adenovirus,
10 canary pox, polio vaccine virus, plasmodium falciparum, bacillus calmette geurin
(BCG), klebsiella pneumoniae, HIV envelop glycoproteins and cytokins and other
agents selected from the group consisting of bovine somatropine (sometimes referred
to as BST), estrogens, androgens, insulin growth factors (sometimes referred to as
IGF), interleukin-I, interleukin-II and cytokins~ Three such cytokins are
15 interferon-.beta., interferon-.gamma. and tuftsin.
Examples of bacterial toxoids are tetanus, diphtheria, pseudomonas A,
mycobacterium tuberculosis. Examples of HIV envelop glycoproteins are gp 120 andgp 160 for AIDS vaccines. E~arnples of anti-ulcer ~I2 receptor antagonists are
ranitidine, cimetidine and farnotidine, and other anti-ulcer drugs are on-pa~d~ide,
20 cesupride and misoprostol. An example of a hypoglycaemic agent is glizipide. Insulin
is used for the control of diabetes.
Classes of pharmaceutically active compounds which can be loaded into a
reversible thermal viscosifying polymer network composition include, but are notlimited to, anti-AIDS substances, anti-cancer substances, antibiotics,
25 imrnunosu~ ssa~ (e.g. cyclosporine) anti-viral substances, enzyme inhibitors,neurotoxins, opioids, hypnotics, ~ntihi~t~mines, lubricants tranquilizers,
anti-convulsants, muscle relaxants and anti-Parkinson substances, anti-spasmodics and
muscle contractants, miotics and anti-cholinergics, anti-glaucoma compounds, anti-
parasite and/or anti-protozoal compounds, anti-hypertensives, analgesics, anti-pyretics
30 and anti-infl~mm~tory agents such as NSAIDs, local anesthetics, ophthalmics,
CA 02263411 1999-02-09
W O 98/06438 PCT~US97/13g88
prost~ ntlinc, anti-depressants, anti-psychotic substances, anti-emetics, im~gin~
agents, specific targeting agents, neurotransmitters, proteins, cell response modifiers,
and vaccmes.
A more complete listing of classes of compounds suitable for loading into
S polymers using the present methods may be found in the Pharmazeutische Wirksto~e
(Von Kleemann et al. (eds) Stuttgart/New York, 1987, incorporated herein by
reference). A more complete list of suitable pharmaceutic agents can be found in WO
97/00275, which is hereby incorporated by reference.
Exemplary pharmaceutical agents considered to be particularly suitable for
10 incorporation into the pharrnaceutical composition of the invention with retention of
therapeutic effectiveness and other advantageous properties include but are not limited
to imidizoles, such as miconazole, econazole, terconazole, saperconazole, itraconazole,
metronidazole, fluconazole, ketoconazole, and clotrimazole, luteini7ing-hormone-releasing hormone (LHRH) and its analogues, nonoxynol-9, a GnRH agonist or
15 antagonist, natural or synthetic progestrin, such as selected progesterone, 17-
hydroxyprogeterone derivatives such as medroxyprogesterone acetate, and 19-
nortestosterone analogues such as norethindrone, natural or synthetic estrogens,conjugated estrogens, estradiol, estropipate, and ethinyl estradiol, bisphosphonates
including etidronate, alendronate, tiludronate, resedronate, clodronate, and pamidronate,
20 calcitonin, parathyroid hormones, carbonic anhydrase inhibitor such as felbamate and
dorzolamide, a mast cell stabilizer such as xesterbergsterol-A, lodoxarnine, andcromolyn, a prost~gl~ntlin inhibitor such as diclofenac and ketorolac, a steroid such as
prednisolone, dexamethasone, fluromethylone, rimexolone, and lotepednol, an
antihist~mine such as antazoline, pheniramine, and histimin~se, pilocarpine nitrate, a
25 beta-blocker such as levobunolol and timolol maleate, a sunscreen agent, an acne
medication such as salicylic acid, sulfur, resorcinol, resorcinol monoacetate, and
benzoyl peroxide, an anti-dandruff medication such as coal tar, pyrithione zinc,salicylic acid, selenium sulfide, and sulfur, a derrnatological agent such as bath oils,
emollients, hydrating agents, astrigents, antipruritics, protectants, keratin-softening
30 agents, and hydrocortisone, hydroquinone, or nicotine.
CA 02263411 1999-02-09
W 0 98/06438 PCTrUS97/13988
As will be understood by those skilled in the art, two or more pharmaceutical
agents may be combined for specific effects. The necessary amounts of active
ingredient can be determined by simple experimentation.
This material meets many of the requirements for an optimum transmucosal
5 delivery system for proteins, including peptides. Effective and efficient delivery
involves four primary elements: a method of holding an optimal quantity of peptides
against the mucosa for an extended period; a method of controlling the release of the
peptides in a desired pattern (e.g., burst, s~lct~ine(l, circadian, etc.), transferring the
peptides from the mucosal surface to the blood sera or other target, and maintenance
10 of activity of peptides. The measure of merit is the reliable achievement of a desired
pharmaceutical effect with minim~l wasted active material-for example, the
achievement and sll~t~ining of an effective level of active peptide in the blood stream
for a given time period with minim5l1 excess delivery and minim~l loss of activity
through inactivation or erosion.
The structural component and responsive component of the system can be
chosen for protein delivery. The structural component can be a mucoadhesive material
(acrylic acid). The structural component can be a material which erodes (acrylic acid)
or one that degrades (hyaluronic acid). The backbone can be crosslinked, can involve
comonomers, and can be of varying molecular weights or structures. These
modifications to the backbone directly effect retention of the Peptide-gel system,
patterns of release, and peptide activity.
In addition to the poloxamer:poly(acrylic acid) polymer network, additional
pharmaceutically acceptable carriers may be included in the composition, such as by
way of example only, emollients, surfactants, humectants, powders and other solvents.
2S Preservatives can be desirably inco~porated into the ph~ ceutic compositions
of the invention to protect against the growth of potentially harrnful microorg~ni~mc
Suitable preservatives include, but are not limited to, alkyl esters of para-
hydroxybenzoic acid, hydantoin derivatives, parabens, propioniate salts, triclosan
tricarbanilide, tea tree oil, alcohols, farnesol, farnesol acetate, hexachlorophene and
quaternary ammonium salts, such as benzolconjure, and a variety of zinc and
.. ...
CA 02263411 1999-02-09
wo 98/06438 PCT/USg7/13988
aluminum salts. Pharmaceutic chemists are farniliar with apl.lo~liate preservatives and
may selects that which provides the required product stability. Preservatives are
preferably employed in amounts ranging from about 0.0001% to 2% by ~veight of the
composlhon.
S Emollients can be desirably incorporated into the pharmaceutic compositions
of the invention to provide lubricity to the formulation. Suitable emollients may be in
the form of volatile and nonvolatile silicone oil, highly branched hydrocarbons and
synthetic esters. Amounts of emollients may be in the range of about 0.1-30 wt%, and
preferably about 1-20 wt%. A variety of oily emollients may be employed in the
compositions of this invention. These emollients may be selected from one or more of
the following classes: triglyceride esters; acetoglyceride esters; ethoxylated glycerides;
alkyl esters of fatty acids having 10 to 20 carbon atoms; alkenyl esters of fatty acids
having 10 to 20 carbon atoms; fatty acids having 10 to 20 carbon atoms; fatty alcohols
having 10 to 20 carbon atoms; fatty alcohol ethers, such as ethoxylated fatty alcohols
of 10 to 20 carbon atoms having att~hed thereto from l to 50 ethylene oxide groups
or 1 to 50 propylene oxide groups; ether-esters such as fatty acid esters of ethoxylated
fatty alcohols; lanolin and derivatives; polyhydric alcohol esters; wax esters; beeswax
derivatives; vegetable waxes including carnauba and candelilla waxes; phospholipids;
sterol including cholesterol and cholesterol fatty acid esters; and amides such as fatty
acid amides, ethoxylated fatty acid amides, solid fatty acid alkanolamides.
Humectants may be added to the composition to increase the effectiveness of
the emollient, to reduce scaling, to stimul~te removal of built-up scale and improve
skin feel. The amount of humectant may be in the range of about 0.5-30 wt% and
preferably between 1-15 wt%.
By way of example only, in the case of antibiotics and antimicrobials may be
included in the composition of the invention. Antimicrobial drugs preferred for
inclusion in compositions of the present invention include salts of ~-lactam drugs,
quinolone drugs, ciprofloxacin, norfloxacin, tetracycline, erythromycin, amikacin,
triclosan, doxycycline, capreomycin, chlorhexidine, chlortetracycline, oxytetracycline,
clindamycin. ethambutol, hexamidine isethionate, metronidazole, pentamidine,
CA 02263411 1999-02-09
W O 98/06438 PCTAUS97/13988
gentamicin, kanamycin, lineomycin, methacycline, methenamine, minocycline,
neomycin, netilmicin, paromomycin, streptomycin, tobramycin, miconazole and
amanfadine and the like.
A wide variety of acids, bases, buffers, and sequestrants can be utilized to
5 adjust and/or m~int~in the pH and ionic strength of the compositions useful in the
instant invention. Materials useful for adjusting and/or m~int~ining the pH and/or the
ionic strength include sodium carbonate, sodium hydroxide~ hydrochloric acid,
phosphoric acid, sulfuric acid, acetic acid, sodium acetate, sodium hydrogen phosphate,
sodium dihydrogen phosphate, citric acid, sodium citrate, sodium bicarbonate,
10 triethanolamine, EDTA, disodium EDTA, tetrasodium EDTA, and the like.
A general method of making the responsive polymer:structural polymer
network compositions of the present invention comprises solubilization of the
responsive polymer, e.g., poloxamer, in a monomer of the structural polymer, e.g.,
acrylic acid monomer, followed by polymerization of the monomer. Polymerization
15 may be accomplished by addition of a polymerization initiator or by irradiation
techniques. The initiator may be a free radical initiator, such as chemical free radical
initiators and uv or gamma radiation initiators. Conventional free radical initiators
may be used according to the invention, including, but in no way limited to
ammonium persulfate, benzoin ethyl ether, benzyl peroxide, 1,2'-azobis(2,4-
20 dimethylpentanitrile) (Vazo 52) and azobisisobutyronitrile (AIBN). Initiation may alsobe accomplished using cationic or ionic initiators. Many variations of this methods
will be apparent to one skilled in the art and are contemplated as within the scope of
the invention. For example, the poloxamer component may be dissolved in an acrylic
acid/water mixture instead of pure monomer. It may be desirable to remove unreacted
25 monomer and/or free poloxamer from the resultant polymer network. This may beaccomplished using conventional techniques, such as, by way of example, dialysis or
sohxlet extraction.
Without inte~ ing to be bound by a particular mech~ni~m or structure, the
following scheme represents a possible chemical mechanism for the formation of the
30 system here described. These mech~nicm~ are presented by way of explanation and
. .
CA 02263411 1999-02-09
W O98/06438 PCTnUS97/13988
36
are no way limiting of the invention. It is contemplated that these or other
mechanistic routes may in fact occur in the formation of the polymer network of the
present invention.
I. Initiation
RR--> 2R- (1)
R- ~ CH2=CHCOOH ---> RCH2CH-COOH (2)
II. Hvdrooen Abstraction
R- + -OCHRCH20- ---> RH + -OCR-CH20- (3)
R- + -CH2CH2COOH ---> RH + -CH2CH-COOH (4
III. Chain Transfer
-CH2CH-COOH + -OCH~CRH- ---> -CH2CH2COOH + -OCH2CR-- (5)
-OCH~CR-O- + -CH2CHCOOH ---> -OCH2CRHO- + -CH2rH-COOH (7)
IV. Propaaation
RCH2CH-COOH + CH~-CHCOOH --> RCH2CHCOOHCH2'~H-COOH (8)
V. Side Chain Branchina Off AA Backbone
-CH2CH-COOH- + CH,=CHCOOH --> -CH2CH(CH2CH-COOH)COOH (9)
VI. AA BranchinD off Poloxamer Backbone
-OCH2CR-O-+CH2=CHCOOH--> -OCH2CR(CH,CH-COOH)O- (10)
VII. Homoaenous Termination
2-CH2CH-COOH--> -CH2CHCOOHCHCOOHCH2- (11)
VIII. Heteroaenous Termination with bondino of Pluronic to PAA
-CH2CH-COOH + -OCH2C-RO- --> -CH2CH(-OCRCH2O-)COOH (12a)
The scheme for bonding of poloxamer to acrylic acid may involve initiation (eq
1), hydrogen abstraction from the propylene or ethylene moiety of the poloxamer (eq
25 3), and att~chment to acrylic acid via addition across the unsaturated bond (eq 10).
Propagation (eq 8) leads to the final PAA.
Alternatively, the mech~ni~m may proceed by initiation according to eqs. (1)
and (2), propagation to form PAA (eq.8), a chain transfer reaction to generate areactive poloxamer moiety (eq. 5), followed by addition of the reactive poloxamer
CA 02263411 1999-02-09
WO 98l06438 PCr/US97/13988
moiety to the unsaturated bond of acrylic acid (eq. 10) and subsequent propagation of
the PAA chain.
Thus the polymer network may include a plurality of poly(acrylic acid)) units
bonded to a single poloxamer unit or, alternatively, a plurality of poloxamer units
bound to a single PAA backbone. Combinations of these alternatives are also a
possibility.
Reverse phase polymerization may be used to prepare polymer network beads
by dispersion of the poloxamer and acrylic acid monomer mixture in a nonpolar
solvent such as hexane or heptane. The aggregating polymer/monomer solution is
dispersed with agitation in the nonpolar solvent in order to suspend droplets of the
solution. Polymerization of the monomer is initiated by conventional means (i.e.,
addition of a initiator or irradiation) in order to polymerize the monomer and form
responsive polymer network beads. See, U.S.S.N. 08/276,532 filed July 18, 1995 and
entitled "Useful Responsive Polymer Gel Beads" for further information on the
preparation of polymer gel beads, herein incorporated by reference. Such a method
may be particularly desirable to provide a heat sink for the heat generated in the
exothermic polymerization reaction.
The polymer network complexes and aqueous gelling solutions of the present
invention may be understood with reference to the following examples, which are
provided for the purposes of illustration and which are in no way limiting of the
invention.
Example I This example describes the synthesis of a polymer net~,vork and an
aqueous responsive polymer network solution prepared using a triblock polymer ofpoly(ethyleneoxide) and poly(propyleneoxide), Pluronic(~) F27 polyol, and poly(acrylic
acid). This example also characterizes the gelation and the physical properties of the
resultant polymer network.
Svnthesis. Block copolymer of poly(propyleneoxide) (PPO) and
poly(ethyleneoxide) (PEO) having triad ABA structure (PEO)A(PPO)B(PEO)A
(Pluronic~ F127 NF polyol, Poloxamer 407 NF polyol, where ';F" means Flakes, "12"
means 12X300=3600 - MW of the PPO section of the block copolymer, ' 7" PEO in
.
CA 02263411 1999-02-09
wo 98/06438 PCT/US97/13988
38
the copolymer is 70 wt%, and nominal molecular weight is 12,600) from BASF (3.0
g) was dissolved in 3.0 g acrylic acid (Aldrich). This represents a substantially 1:1
weight ratio of Pluronic(~) F127 polyol and poly(acrylic acid). The solution wasdeaerated by N~ bubbling for 0.5 h and following addition of 100 ml of freshly
5 prepared saturated solution of arnrnonium persulfate (Kodak) in deionized water was
kept at 70 ~C for 16 h resulting in a transparent polymer.
Viscositv measurements. A lcnown arnount 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
10 to 7. Samples of lS ml each were taken, and pH in each vial was adjusted to desired
value by addition of 1 M HCI or NaOH. Sarnples were then kept overnight and their
viscosities were measured at different temperatures using Brookfield viscometer using
either an SC4-18 or an SC4-25 spindle.
A control experiment was done with a physical blend of Pluronic(l~) F127 polyol
and poly(acrylic acid) (MW 450,000) available from Aldrich. Pluronic(~) F127 polyol
and poly(acrylic acid) were dissolved together in deionized water at 1 ~t% totalpolymer concentration and the resultant solution was adjusted to pH 7, stirred and kept
in refrigerator. The responsiveness of the polymer network composition and the
physical blend to temperature and pH is illustrated in Figures 2 and 6 which clearly
20 demonstrate that the synthetic route outlined above resulted in a polymer network
system that is sensitive to pH and temperature of the environment. Figure 14 is a
viscosity vs. temperature graph comparing the gelling characteristics of the responsive
polymer network composition (curve (a)) and the physical blend (curve (b)). The
blend prepared by physically mixing of the triblock PEO/PPO/PEO polymer and
25 poly(acrylic acid) did not exhibit viscosifying effect either as a function of temperature
or pH.
It was generally observed that 0.5-5 wt% polymer network compositions made
of Pluronic~) F127 polyol and poly(acrylic acid) viscosify at temperatures of around
30 ~C and higher if pH is adjusted to 6 or higher. The gelling effect was observed in
30 polymer network compositions standing 3 months or longer. Repeated heating and
CA 02263411 1999-02-09
W O 98/06438 PCTAUS97/13988
cooling of responsive polymer network compositions did not cause deterioration of the
polymer network or the gelling effect. Solutions of either Pluronic~ F127 polyol or
poly(acrylic acid) (1-5 w% in water, adjusted to pH 6 or higher) or physical blends of
the two lacked the reverse thermal gelling effects found for polymer network
compositions.
Example 2. This example describes a standard operating procedure for the
manufacture of the reversible gelling polymer network.
The procedure is based upon a 50 liter production. A NaOH solution was
prepared by dissolving 131.8 g NaOH pellets in 131.8 mL DI water (50% solution).The NaOH was allowed to dissolve completely. The NaOH solution will be used to
convert a percentage of the acrylic acid to sodium acrylate in situ. Acrylic acid
monomer ( 4 kg) is charged into a monomer feed tank and agitated at 250 rpm.
NaOH is added slowly. The precipitate formed as the acrylic acid is neutralized to
sodiurn acrylate is allowed to dissolve. Pluronic~) F127 (3.5 kg) is slowly added to
the monomer feed tank. Pluronic~) F127 is dissolved under continued agitation.
Norpar 12 (a refined C-12 alkane) is added to the reaction vessel (37 L). The mixture
is agitated at 100 rpm. Stabilizer solution of Ganex V-126 is prepared in 2L Norpar
12 and added to the reactor under agitation.
A reaction vessel was degassed using a nitrogen sparge introduced from the
bottom of reactor and was continued throughout the reaction. Initiator (13.63 g Lauryl
peroxide and 4.23 g Vazo 52 in 0.7 kg acrylic acid monomer) is introduced into the
monomer solution. The monomer solution was transferred to the reaction vessel.
Agitation was increased to 150 rpm. Nitrogen sparging continued for an additional 20
minutec and then heating began. Heating began at a rate of 0.5-1.0 ~C/min up to
75 ~C. The reaction began to exotherm at about 45-50 ~C and is allowed to continue
without cooling until a maximum is reached. It is then cooled to 75 ~C using forced
cooling. The reaction continued for 12 hours and was then cooled to 35 ~C. The
slurry was transferred into pails and the polymer beads were allowed to settle.
The slurry was filtered through Buchner Funnels with filter paper (11 ~Lm pore
size) until the bulk of the Norpar had been removed from the beads. The beads were
CA 02263411 1999-02-09
WO 98/06438 PCT/US97/13988
washed three times with heptane. The filtered beads were transferred to a Pyrex
drying tray and spread on the tray in a uniform layer. The beads were dried under
vacuum for 4 hours at 40-50 ~C. The dried beads were analyzed as follows.
Elemental analvsis. The elemental analysis was perforrned by Quantitative
S Technologies, Inc., Whitehouse, NJ using a Perkin Elmer 2400 CHN Elemental
Analyzer. Analysis provided C (52.49%), H (7.~0%), N (< 0.05%), the balance
assumed to be oxygen (39.96%).
Thermal Gravimetric Analvsis (TGA). The TGA method was performed by
Massachusetts Material Research, Inc., West Boylston, MA using a Dupont TGA
model 295. The assay was run using a temperature ramp from 30 to 500 ~C/min. Theresolution for the system was set to 4 (l.0 ~C/min for all slope changes). The data
was analyzed using the first derivative of the curve and using maxima and mtnim~ to
mark transitions. The moisture content was also calculated in this manner. The first
derivative yielded three maxima. The first transition (moisture) was 3.0% by weight,
the second transition was 14.0% by weight and the third was 67.02% by weight.
Residue (15.98% r~m;lined).
Molecular weioht determination bv oel permeation chromatooraphv (GPC).
The molecular weight was determined by GPC on a Hewlet Packard 1100 Liquid
Chromatography system with a Viscotech T60 Triple Detector system. Three Waters
Ultrahydrogel columns, 1000, 500 and 250 ~, were used for the separation. The
mobile phase was O.lM NaNO3 and 0.01M K~HPO, salt solution, pH adjusted with
phosphoric acid to a pH of 8.0 l 0.1. The flow rate for the separation was 0.9
mLlmin. The column temperature was maintained at 15 C. The injection volume for
the assay was 50 IlL. A PEO molecular weight standard of 23,000 Daltons was usedto align the detectors. The result for the assay were:
M": 341,700 Daltons
Mp: 1,607,000 Daltons
M~v: 2,996,000 Daltons
Free poloxarner determination bv GPC. The amount of free (unbound)
poloxamer in the polymer matrix was determined using the above GPC method and
CA 02263411 1999-02-09
W O 98/06438 PCTAUS97/13988
41
comparing the poloxamer peaks to that of a standard poloxamer solution. The typical
result is approximately 18-22% free poloxamer by weight.
The effect of both the bonded and non-bonded poloxarner on the gelation
properties of the responsive polymer network has been deterrnined by extraction of
the non-bonded poloxamer from the material. Such extraction studies have
established that the graft co-polymer alone exhibits the characteristic reverse thermal
gelation of the composition; however, the presence of non-bonded poloxamer
component modulates the gelation process. The non-bonded poloxamer component
can affect the temperature of transition (from liquid to gel) and the degree of
10 transition and assists in a more controlled and reproducible transition.
Bound poloxamer determination bv ethvlene oxide (EO) titration. The EO
titration was performed as follows. A 5 gm sample of the product polymer was
extracted in dichloroethane for three hours at reflux temperatures. The solid isremoved and dried under a vacuum for 12 hours at room temperature. The dry
lS material is then analyzed using ASTM method D 2959-95, "Standard Test Method for
Ethylene Oxide Content". The amount of EO in the sample is related to the arnount of
poloxamer bound to the polymer. The typical result is approximately 1 j % by weight
of EO.
The relative amount of free poloxamer may be varied dependent upon the
20 relative proportions of starting materials and the method of polymerization. Although
the residual solids presumably contain only poloxamer which is bonded to the
poly(acrylic acid), i.e., a graft co-polymer, the material still shows strong
viscosification when it is neutralized and dissolved in water. However, the
temperature of viscosification is increased substantially and the degree of
25 viscosification per gram of total solids is increased by removal of free poloxamer.
Thus, the free poloxamer plays a role in modifying the extent and temperature ofviscosification. The poloxamer undergoes conformational changes and changes to the
critical micelle concentration as a function of temperature. The poloxamer will
change from an open, non-aggregated form to a micellular, aggregated form with
30 changes in temperature.
. . _
CA 02263411 1999-02-09
wo 98/0643~ PCT/US97l13988
4~
Residual acrvlic monomer determination bv ~as chromato~raphv (GC). The
residual acrylic acid monomer was determined by GC analysis using a Hewlet Packard
GC 5890A, using a HP-FFDAP-TPA 10 m x 0.53 mm x l~Lm column. The sample
was extracted and run in methanol. Using an internal standard ratio, the sample was
5 compared to a one point calibration. The typical results for this assay were below 70
ppm acrylic acid monomer.
Residual Norpar solvent bv GC. The residual Norpar in the sample was
deterrnined by GC using the above method and comparing the Norpar peaks to that of
a standard. The typical results were below 1.5 wt%.
10UV-vis spectrum. Optical clarity data of UV-vis spectrophotometer was
obtained. A 1.0% solution in water was prepared and measured at 420 nm.
Transmittance (%) was typically greater than 90%.
Differential sc~nninP calorimetrv (DSC). The DSC was performed by
Massachusetts Material Research, Inc., West Boylston, MA using a temperature ramp
15from 30 to 350 ~C at 5 ~C/min. The resolution for the system was set to 4 (1.0~C/min
for all slope changes). The assay yielded one endothermic event at 26j ~C, typically
270 J/g.
Examples 3-9. This example describes the synthesis of a several reversible
therrnal gelling polymer network prepared using a variety of poloxarners and
20 poly(acrylic acid). The ~,elation and the physical properties of the resultant polymer
network compositions are reported in Table 2.
CA 02263411 1999-02-09
W O 98/06438 PCTnUS97/13988
T~ble2.
e~arnp',e poloxamerpoloxamer composition polox- trans. comments
amer: temp.
PAA
Pluronic~) F88 ~400 MW PPO; 80 wt% 1:1 48 C viscosity response
Prill polyol PEO; nominal MW curve shown in
11,400 ~igure 15
4 Pluronic(~ Fi27 ~600 MW PPO; 70 wt% 1:1 ~0 C pentaerythritol
NF polyol PEO; nominal MW 12,600 triallyl ether
crosslink agent
used
S Pluronic~) P104 3000 MW PPO; 40 wt% 1:1 28 C viscosity response
polyol PEO; nominal MW 5,900 cu~ve shown in
Figure 16
G Pluronic(~ Pl~, 3600 MW PPO; iO wt% 1:1 25 ~C viscosity response
polyol PEO; nominal MW 5,750 curve shown in
Figure 17
7 Pluronic~ as above 1:1.7 42 Cpolymer solid
F127/Pluronic~ . formed, dried;
F108 polyol resolubilized in
blend (1:1) solution
8 Pluronic~) F88 as above 1:1.~80 C polymer solid
pOIyOl forrned, dried;
resolubilized in
neutralizing
solution
9 Pluronic~) as above 1:1.7 85 Cpolymer solid
F1~7/Pluronic~ forrned, dried;
F88 polyol blend resolubilized in
(1: 1) neutralizing
solution
Example 10. This example describes the synthesis of a responsive polymer
network gel composition prepared using Pluronic~ F127 and a copolymer of
methacrylic and acrylic acid.
Metnacrylic acid (Aldrich, 0.2 g) and acrylic acid (Aldrich, 1.8 g) were mixed
and used to dissolve 2.0 g Pluronic~ F127. The solution was dearated for 0.5 h and,
following addition of 100 :I fresnly prepared saturated solution of ammonium
persulfate in deionized water, was kept at 70~C for 16 h resultin~J, in a transparent
CA 02263411 1999-02-09
W O 98/06438 PCTrUS97/13988
44
polymer. A sample of the polymer was suspended in deionized water with added
NaOH. Following swelling for three day, pH was adjusted to 9Ø A 2 wt%
composition viscosified at temperatures of 40~C and higher. Viscosity vs.
temperature profile is shown in Figure 18.
S Example l l. The following example demonstrates the effect of
hydrophilic/hydrophobic ratio on the gellin~ temperature. Polymer network
compositions were prepared from the following poloxamers shown in Table 3.
Table 3. Composition of poloxamers investigated.
triblock polyol polymer MW of PPO block wt% o~' PEO block
1 0 composition
P l 03 3250 50
(PEO)3,(PPO)56(PEo)37
P 1 04 3250 40
(PEO)~5(PPo)56(pEo)~5
1~ P105 3250 . 30
(PEO) ~6(PPo)s6(pEo) 16
Table 3 shows that in this series, the fraction of PEO is reduced when the
molecular weight of the PPO block is kept constant. Linse (Macromol. 26:4437-4449
(1993)) report phase diagrams for these copolymers in water were calculated and it
was shown that two-phase boundaries corresponding to the beginning of aggregation
are almost unaffected by the molecular mass, given a constant PEO/PPO ratio,
whereas these boundaries shifted to lower temperature as the PEO content of the
polymer is reduced at constant mass. The strong dependence of the PEO/PPO ratio is
a consequence of the differing solubilities of PEO and PPO in water at the elevated
temperatures. Thus one would suppose that aggregation that causes viscosification in
the responsive polymer network composition should shift to lower temperature as
PEO fraction decreases.
The poloxamer (3.0 g) was dissolved in 3.0 g acrylic acid. The solution was
deaerated by N2 bubbling for 20 min. and followinu addition of the 100 :1 of freshly
CA 02263411 1999-02-09
W O 98/06438 PCTAUS97/13988
prepared saturated 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 (0.4 g) was suspended in 40 ml deionized water into which NaOH was
added. Suspended responsive polymer network particles were allowed to dissolve
under constant stirring. The resulting 1 wt% polymer network soJutions were
subjected to the viscosity measurement at shear rate of 132 or 13.2 sec~' using a SC4-
18 spindle. It can be seen from Figure 19 that, firstly, viscosity of the 1 wt%
responsive polymer network solutions before viscosification (at 20-24~C) decreases in
the series (PEO)37(PPO)56(PEO)37(Fl03) > (PEO)2s(PPO)56(PEO)2~Fl04) >
(PEO),6(PPO)56(PEO),6(F105) and, secondly, the temperature at which gelation shifts
from about 45~C for (PEO)37(PPO)56(PEO)37 to about 35~C for
(PEO)25(PPO)56(PEO)~5 and (PEO)l6(PPO)56(PEO),6. Both results are in excellent
agreement with the theory set forth in Linse.
Example 12. The aim of this example is three-fold: ( i ) to demonstrate
responsive polymer network compositions using a responsive component other than
triblock polyoxyalkylene copolymers, (ii) to preserve useful properties of responsive
polymer network, namely, ease of synthesis, viscosifying at body temperature,
bioadhesiveness, and entirely benign components, and (iii) to incorporate drug into the
responsive polymer network composition. For these purposes, nonylphenyl ether ofpolyethyleneglycol (Nonoxynol 9, drug name is Igepal C0-630) was chosen. This
remarkable compound is surface active, possesses cloud point at around 55 ~C and is
used as a spermicide and anti-HIV agent in vaginal applications. Synthesis and
properties of the resulted responsive polymer network are described below.
Synthesis. IgepalX C0-630 (Rhone-Poulenc) (3.0 g) was dissolved in 3.0 g
acrylic acid (Aldrich). The solution was deaerated by N, bubbling for 30 min andfollowing addition of 100 Fl of freshly prepared 300 mg/ml solution of ammonium
persulfate (Kodak) in deionized water was kept at 70 ~C for 16 h resulting in a
ransparent solid polymer. A sample of the polymer obtained (2.0 g) was suspendedin 100 ml deionized water into which 0.18 g NaOH was added. Suspended
CA 022634ll l999-02-09
W O 98106438 PCTrUS97/13988
46
responsive polymer network particles were allowed so swell for 1 day under constant
stirring. The pH of the solution was adjusted to 7Ø
Viscositv measurement. Viscosity vs temperature effect for responsive polymer
network made of Nonoxanol 9 and polyacrylic acid (1:1) in deionized water ~pH 7) is
S presented in Figure 20. The viscosity is measured at shear rate of 2.64 sec-1 using a
SC4-18 spindle which allows a very sensitive measurement. It can be seen that the
responsive polymer network starts to viscosify at about 30~C and the viscosity
approaches maximum at 55~C at which point aggregates are formed (cloudiness is
developed) and the viscosity drops precipitously.
Example 13. The following example is related to release of an active agent
from a poloxamer:poly(acrylic acid) polymer network. Drlg loading and kinetics of
release of the protein hemoglobin from poloxamer:poly(acrylic acid) polymer network
is described.
SYnthesis. Pluronic~ F127 (3.0 g) was dissolved in 3.0 g acrylic acid. The
solution was deaerated by ~2 bubbling for 0.5 h and following addition of 100 Fl of
freshly prepared saturated solution of ammonium persulfate (Kodak) in deionized
water was kept at 70~C for 16 h resulting in a transparent polymer. The resultant
responsive polymer network obtained (5 g) was suspended in 95 ml deionized waterinto which NaOH was added. The resulting suspension was allowed to swell for 7
20 days.
Hemoglobin loading 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,
25 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 magnetic 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
hemoglobin-loaded responsive polymer network and 6 ml of phosphate-buffered saline
30 (pH 7.4), respectively. In the control experiment, the feed phase was made of 1 g of
CA 02263411 1999-02-09
Wo 98/06438 PCTIUS97/13988
47
0.25 mg/ml hemoglobin solution. After the feed solution had been loaded into thecell, the kinetic time commenced. Samples of the receiver phase was withdrawn from
time to time and their absorbance was measured spectrophotometrically at 400 mn.To calculate hemoglobin concentrations, corresponding calibration curves (absorbance
5 in PBS versus hemoglobin concentration) were generated. The results of the kinetic
experiment are presented in Figure 21. It can be seen that the rate of hemoglobin
release from the polymer network was substantially lowered at 37~C when comparedto that at 25~C, because of viscosity increase in the polymer network at elevated
temperatures (see Figure 2). The protein released from the polymer network
10 composition still retained its native structure, as was determined by comparison of uv-
vis spectra of release hemoglobin and natural hemoglobin.
Example 14. The following example is related to release of an active agent
from a poloxamer:poly(acrylic acid) polymer network. Drug loading and kinetics of
release of the protein Iysozyme from a polymer network is reported.
Lysozyme loading 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 lysozyme (Sigma) and 1.5 mg/ml sodium dodecyl sulfate (Aldrich)
in deionized water adjusted to pH 8.5. The resulting mixture was well shaken andplaced into the feed chambers of c~stomi7~d vertical, static, Franz-like diffusion cells
20 made of Teflon. The feed and receiver chambers of the diffusion cells were separated
by mesh screens (~f 2063). The receiver chamber was continuously stirred by a
magnetic 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 Iysozyme-loaded
responsive polymer network and 6 ml of phosphate-buffered saline (pH 7.4),
25 respectively. In the control experiment, the feed phase was made of 1 g of 1 mg/ml
lysozyme solution. After the feed solution had been loaded into the cell, the kinetic
time cornmenced. Samples were withdrawn and their absorbance measured
spectrophotometrically at 280 nm. A calibration curve was prepared for lysozyme
concentration ranging from 0 mg/ml to 0.5 mg/ml in phosphate buffered saline. The
30 results of the kinetic experiment are presented in Figure 22. It can be seen that the
CA 02263411 1999-02-09
Wo 98/06438 PCT/US97/13988
48
rate of lysozyme release from the responsive polymer network composition was
substantially lowered at 37~C when compared to that at 25~C, because of viscosity
increase in responsive polymer network at elevated temperatures (see Figure 2).
In order to demonstrate the retention of the enzymatic activity of lysozyme,
S the lysozyme released from the responsive polymer network composition was assayed
using Micrococcus lysodeikticus cells and compared to that of original lysozyme. The
enzymatic activity of lysozyme was the same, within the error of the assay (15%), as
that of the original lysozyme. Control without Iysozyme in presence of sodium
dodecyl sulfate did not show any appreciable lysis of the cells.
Example 15. The following example is related to release of an ac~ive agent
from a poloxamer:poly~acrylic acid) polymer network. Drug loading and kinetics of
release of insulin from a responsive polymer network composition is reported.
Insulin loading 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+-insulin (Sigma) in deionized water ad~usted to pH 7. 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 magnetic 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), respectively. In the control experiment, 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
timing comm~nred. Samples were withdrawn and their absorbance was measured
spectrophotometrically at 280 nrn. A calibration curve was prepared for insulin
concellt~dtion ranging from 0 mg/ml to 1.25 mg/ml in phosphate buffered saline. l he
results of the kinetic experiment are presented in Figure 23. The rate of insulin
release from responsive polymer network was substantially lowered at 37~C when
compared to that at 25~C, because of viscosity increase in responsive polymer
network at elevated temperatures (see Figure ~).
CA 02263411 1999-02-09
Wo 98/06438 Pcr/uss7ll3988
49
Example 16. This example demonstrates the preparation of a sterile reversibly
gelling polymer network aqueous composition and the stability of the composition to
sterilization. The polymer network is prepared as described in Example 1, except that
the composition is prepared at 2 wt% Pluronic~ P127 polyol/poly(acrylic acid). After
5 dissolution of the 2 wt% polymer network in water, the viscosity is measured. The
composition then is sterilized by autoclaving at 121~C, 16 psi for 30 minllt~s~
Viscosity is determined after sterilization. The corresponding curves for viscosity (a)
before and (b) after sterilization are shown in Figure 24 and establish that minim~l
change in the viscosity profile of the material has occurred with sterilization.Examples 17-32. These examples show additives which may be used to affect
the transition temperature overall viscosification of the polymer network composition.
A 1 wt% polymer network was prepared in deionized water at pH 7 in which
a variety of additives were included in the composition. The effect of the additive
was determined by generation of a Brookfleld viscosification curve. Results are
15 reported in Table 4.
CA 02263411 1999-02-09
W O 98/06438 PCTrUS97/13988
Table 4.
Example No. Additive (wt%) Effect of additive on:
transition temp. final viscosity
( C) (% change)
17 1,2-methyl I (1.8) N
pyrrolidone (5)
18 Rhodapex C0-436 I (1.6) N
(2)
19 Dow Corning 190 I (5) I (150)
(2)
isopropyl alcoholI (3.1) I (45)
(0.5)
21 Pluronic~ L122 (1) D (4.4) D (13)
22 Pluronic~ F88 (1) N I (41)
23 Tween 80 (0.5) N I (18)
24 Germaben'~9 II (1) D (9) I (100)
Iconol NP-6 (1) D (9) I (500)
26 Plurafac C-17 I (5.2) D (36)
(0.5)
27 Dow Corning 193I (4.1) D (12)
(0.75)
28 glycerin (5) D (2) N
29 UC 50-HB- N N
170/EO/PO
random copolymer
(0.5)
PVP K15 (1) N N
31 MAPTAC (1) N D (8)
32 potassium chloride N D (34)
(0.25)
20 = increase; D = decrease; and N = no change
CA 022634ll l999-02-09
W 0~8/OC138 PCT~US97/13988
Example 33. This example demonstrates the preparation of pharmaceutic
compositions of forrnulations tailored to particular applications.
(a) Formulations includin~ a nonionic surfactant formulation: An O/W (oil-in-
water) emulsion was made by combining the following ingredients ntili?ing
conventional mixing techniques:
Table 5.
lngredient % w/w
10 % wt. 1:1 responsive 20.0
polymer network as prepared
in Example 1
Emulsifying Wax NE' 2 . 5
Mineral Oil 5.0
' Polowax available from Croda
Into a vessel equipped with a high efficiency homogenizer, the formula amount
1~ of all ingredients is added, water is added to 100% w/w and allowed to mix tohomogeneity. This formulation contains a nonionic surfactant and gives an emulsion
that is fluid at room temperature but viscosifies above 32~C.
(b) Formulations includin~ a cationic surfactant formulation: An O/W (oil-in-
water) emulsion was made by combining the following ingredients lltili7ing
20 conventional mixing techniques:
Table 6.
Ingredient % w/w
10 % wt. 1:1 responsive 20.0
polymer network as prepared
in Example 1
Behentrimonium Methosulfate 2 . 5
(and) Cetearyl alcoholl
Mineral Oil 5 0
' Incroquat Behenyl TMS availa~le from Croda
Into a vessel equipped with a high efficiency homogenizer, the formula amount
of all ingredients is added and allowed to mix to homogeneity. This formulation
.
CA 02263411 1999-02-09
W O 98/06438 PCTrUS97/13988
contains a cationic surfactant and gives an emulsion that is fluid at room temperature
but viscosifies above 32~C.
(c) Formulations includina an anionic surfactant formulation: An O/W (oil-in-
water) emulsion was made by combining the following ingredien~s utilizing
5 conventional mixin~ techniques:
Table 7.
Lngreàient % w/w
10 % wt. 1:1 responsive 20.0-
polymer network as prepared
in Example 1
Cetearyl Phosphate (and) 2.5
Cetearyl alcohol'
Mineral Oil S.0
' Crodafos CES available from _roda
Into a vessel equipped with a high efficiency homogenizer, the formula amount
of all ingredients is added, water is added to 100% w/w and allowed to mix to
homo~eneity. This formulation contains a anionic surfactant and gives an emulsion
that is fluid at room temperature but viscosifies above 32~C.
(d) Va inal Moisturizer: An oil-free, lubricous, vaginal moisturizer is made
20 by combining the following ingredients lltili7in~ conventional mixing techniques:
Table 8.
Ingredient % w/w
10 % wt. 1:1 responsive 20.0
polymer network as prepared
in Example 1
Glycerin USP 5 o
PPG-2 Myristyl Ether 3.0
Propionate'
DL-Panthenol 0 5
3 0 Gerrnaben~ 0.1
Disodium EDTA 0.2
Cilric Acid 0.01
USP Puri~ied Water 71.19
' Crodamol PMP available ~rom Croda
2 Germaben~ II available from Sutton Laboratories
CA 02263411 1999-02-09
W O 98/0G438 PCT~US97/13988
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~Cand held for 20 minutes. The water is then cooled to SOCC, while m~int~ining thetemperahlre, with moderate to vigorous mixin~,, the forrnula amount of Disodium
5 EDTA, Citric Acid, DL-Panthenol, Glycerin, PPG-2 Myristyl Ether Propionate, and
Gerrnaben~ 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, equipped with a
high efficiency homogenizer, the formula amount of responsive polymer network isadded. The responsive polymer network vessel is then cooled to 4~C. After cooling,
10 while vigorously homogenizing, the contents of the first vessel is added to the second
vessel, and allowed to mix to homogeneity.
The composition displays a flowable creamy lotion appearance with e,~cellent
moisturizing, emolliency, spreadability and absorption characteristics at room
temperature, and after heating the formulation to 32~C, the composition thickens to a
15 gel-like consistency.
(e) Formulation for Mana~ement of Bacterial Va~inosis: An oil-free,
lubricous, bacterial vaginosis treatment is made by combining the following
ingredients ntili7inP conventional mixing techniques:
Table 9.
~ Ingredient % w/w
10 % wt. 1:1 responsive 20.0
polymer network prepared as
in Example 1
Glycerin USP 5 o
Metronidazole 0.75
DL-Panthenol 0 5
Gerrnaben~ II' 0.1
Disodium EDTA 0.2
Citric Acid 0.01
USP Puri~ied Water 73 44
' Germaben~II available ~rom Sutton Laboratories
. . ~ . .
CA 02263411 1999-02-09
W 098/06438 PCT~US97/13988
To one vessel, equipped with a Lioh[nin' Mixer wilh a 3 blade paddle prop,
the full amount of USP Purified Water is added. The water is then heated to 80~Cand held for 20 minutes. The water is then cooled to 50~C, while m~lint~inin. the
temperature, with moderate to vigorous mixing, the formula amount of Disodium
S EDTA, Citric Acid, DL-Panthenol, Glycerin, Metronidazole, and Gerrnaben~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, 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
10 vigorously homogenizing, the contents of the first vessel is added to the second
vessel, and allowed to mix to homogeneitv.
The composition displays a flowable jelly appearance with excellent
spreadability and absorption characteristics at room temperature, and after heating the
formulation to 3'~~C, the composition thickens to a gel-like consistency.
(f) Fo~nulation for Mana ement of Bacterial Candidiasis: An oil-free,
lubricous, bacterial candidiasis treatment is made by combining the following
ingredients l~tili7~n~ conventional mixing techniques:
Table 10.
Ingredient Yo wlw
10 % wt. 1:1 responsive 20.0
polymer network prepared as in
Example 1
Glycerin USP 5 . o
Miconazole Nitrate 2.0
DL-Panthenol 0.5
Germaben~ II' 0.1
Disodium EDTA 0.2
Citric Acid ().01
USP PuriIied Water 72.19
' Germaben~ II available ~rom Su-.ton Laboratories
To one vessel, equipped with a Lightnin' ~vIixer with a 3 blade paddle prop,
the full amount of USP Purif1ed Water is added. The water is then heated to 80~C
CA 02263411 1999-02-09
W 098/06438 PCT~US97/13988
and held for 20 minutes. The water is then cooled to 50~C, while m;lint~iniTIg the
temperature, with moderate to vigorous mixing, the formula amount of Disodium
EDTA, Citric Acid, DL-Panthenol, Glycerin, Miconazole Nitrate, and Germaben~ II
is added. These materials are allowed to dissolve at 50~C. After dissolution, the
S vessel is then cooled to 20~C. To another vessel, equipped with a high efficiency
homogenizer, the forrnula amount of responsive polymer network is added. The
responsive polymer network vessel is then cooled to 4~C. After cooling, while
vigorously homogenizing, the contents of the first vessel is added to the secondvessel, and allowed to mix to homogeneity.
The composition displays a flowable jelly appearance with excellent
spreadability and absorption characteristics at room temperature, and after heating the
formulation to 32~C, the composition thiclcens to a gel-like consistency.
( ) Topical Hormone Delivery Formulation: An oil-free, spreadable, topical
hormone treatment using estradiol as the hormone is made by combining the following~5 ingredients utilizing conventional mixing techniques:
Table 11.
Ingredient ~o wlw
10 % wt. 1:1 responsive 20.0
polymer network prepared as
in Example 1
Glycerin USP 5 .o
Estradiol 0. 1
DL-Panthenol o.5
Germaben~ II' 0.1
Disodium EDTA 0.2
USP Purified Water 74.1
' Germaben~ II available from Sutton Laboratories
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~C30 and held for 20 minutes. 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, DL-Panthenol, Glycerin, Estradiol and Germaben~ II is added. These
materials are allowed to dissolve at 50~C. After dissolution, the vessel is then cooled
CA 02263411 1999-02-09
W O 98/06438 PCTrUS97/13988
56
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 homogenizing,
the contents of the first vessel is added to the second vessel, and allowed to mix to
S homogeneity.
The composition displays a flowable jelly appearance with excellent
spreadability and absorption characteristics at room temperature, and afier heating the
forrnulation to 3~~C, the composition thickens to a gel-like consislency.
(h) Nasal Decon~estant Formulation: A r.on-drip nasal decongestant was made
lO by combining the following ingredients l-tili7inu conventional mixing techniques:
Table 12.
Lnoredient ~o wlw
5% wt. 1:1 responsive polymer network 12.()
as prepared in Example 1
15Polyvinyl Alcohol (7~-~2% Hydrolyzed)l 2.5
Triblock poloyol polymers o ~
Oxymetazoline Hydrochloride 0.05
Benzalkonium Chloride 0.015
USP Purified Water 85.435
20Airvol 603 is available from Air Products
To one vessel, equipped with a Caframo mixer with a three blade paddle prop,
the full amount of USP purified water was added. With moderate to vigorous mixing
the formula amount of Airvol 603, Oxymetazoline Hydrochloride, and Benzalkonium
Chloride was added. This malerial was allowed to mix until dissolved The forrnula
25 amount of responsive polymer was then added with moderate to vigorous mixing.(i) Opthalmic Formulation: A bioadhesive eye drop formulation is made by
combining the following ingredients .Itili7i~.g conventional mixing techniques:
Table 13.
Ingredient % ~;eight
3~USP Puri~ïed Waler 91.()2
Polaxamer 2.~
Mannitol 2.0
aclive ingredient 1.5
CA 02263411 1999-02-09
W O 98/06438 PCT~US97/13988
responsive polymer composition 1.2
Polyvinyl Alcohol (78-82% Hydrolyzed)l 0.5
Benzalkonium Chloride 0. 01
Sodium Citrate 0.4s
55N Sodium Hydroxide 0.82
Airvol 603 is available from Air Products.
To one vessel, equipped with a Caframo mixer with a three blade paddle prop,
the full amount of USP purified water was added With moderate to vigorous
10 mixing, the formula amount of Airvol 603, mannitol, active, and Benzalkonium
Chloride was added. This material was allowed to mix until dissolved. The formula
amount of sodium citrate was then added and allowed to dissolve. This was followed
by the addition of the formula amount of Pluronic~ F127. This was then allowed to
dissolve and the formula amount of responsive polymer composition was then added15with moderate to vigorous mixing.
(i) Otic Formulation:
Table 14.
Ingredient % w/w
5% wt. 1:1 responsive polymer network 10.0
20as prepared in Example l
~J~P PuriIïed Water gO.o
active 0.1 -l .0
To one vessel, equipped with a Caframo mixer with a three blade paddle prop,
25 the full amount of USP purifled water is added. Wilh moderate to vigorous mixing
the formula amount of active is added. This material is allowed to mix until well
dispersed. The formula amount of responsive polymer network is then added with
moderate to vigorous mixing.
CA 02263411 1999-02-09
W 0~8/0~8 PCT~US97/13988
58
(k) Veterinarv SPrav Formulation:
Tab1e 1~.
Ingredient % w/w
5 % wt. l: l responsive polymer network 20.0
5as prepared in Example 1
USP Purified Water 90 0
glycerin 5 o
Hydrocortisone o 5
Exam~le 34. Solubilization studies of model hvdrophobic pharmaceutical
a(Jents in the poloxamer: polyfacrvlic acid) polvmer network: estradiol and
Pro~esterone. This exarnple is presented to demonstrate the solubilization and
delivery of a hydrophobic bioactive material in the polymeric network. Progesterone
and estradiol were used as the hydrophobic agents.
Acrylic acid (99%), fluorescein (98%), ~-estradiol (98%), and progesterone
(98%) were all obtained from Aldrich and used as received. Pluronic~ F127 ~F wasobtained from BASF. Poly(oxyethylene-b-oxypropylene-b-oxyethylene)-g-poly(acrylic
acid) copolymers (responsive polymer network ) were synthesized by free-radical
polymerization of acrylic acid in the presence of poloxamer as described above. The
20 polymer network copolymers discussed here were composed of about l:1 ratio ofPAA to poloxamer. The rheological properties of polymer network were assessed
using LVDV-II+ and RVDV-II+ Brookfield viscometers. The microscopic light
scattering of 21 nm poly(styrene) latex particles in deionized water and l w%
reversibly gelling polymer network was measured using He-Ne laser as described
25 previously (See, Matsuo, E.S., Orkisz, M., Sun, S.-T., Li, Y., Tanaka, T.,
Macromolecules, 1994, 27, 6791). The solubility of fluorescein and hormones in
aqueous solutions was measured by the equilibration of excess solubilizate with the
corresponding solution following removal of undissolved species by centrifugation and
filtration. Hydrophobic agents were assayed spectrophotometrically at 240
30 (progesterone) or 280 nrn (estradiol), or by using 70/30 w/w H,SO~/MeOH
(Tsilifonis-Chafetz reagent). In vitro horrnone release studies were conducted using
CA 02263411 1999-02-09
W O 98/06438 PCT~US97/13988
59
thermostatted, vertical Franz cells. Spunbonded polypropylene microfilters (micron
retention, 15-20) were used as a membrane separating feed and receiver phases inFranz cells. The responsive polymer network, water, ethanol, and 20% PEG in water
were observed to wet the membrane. The receiver solutions consisted of 20 w% PEG5 in water (pH 7) and were stirred by magnetic bars. The feed phases composed ofresponsive polymer network were loaded with either estradiol or progesterone. Each
hormone was dissolved in ethanol and the resulting solution was added into the
responsive polymer network.
Equilibrium solubility vs. temperature plots for estradiol and progesterone
(partition coefficient octanol/water (P) 7200 and 5888, respectively, in aqueoussolutions of Pluronic~ F127 polyol and responsive polymer network are presented in
Figures 12 and 13. It can be seen that increasing temperature and concentration (C) of
polymers in the solution raises the amount of the hormone dissolved. In Figure 12A,
vertical lines represent critical micellar temperatures (CMT) for corresponding
Pluronic F127 polyol solutions. It is interesting to note that the slope of the
solubility-temperature plots increased as temperature reached CMT, indicating that
solubilization in the Pluronic solutions was predominantly due to the formation of
micelles. Similar trend was observed in the reversibly gelling polymer network
solutions. The S values in 5% aqueous solutions of branched PAA did not exceed 15
and 40 ~g/mL at 60 ~C for estradiol and progesterone, respectively. The solubility
values found for reversibly gelling polymer network were the same as S in parentPluronic solutions of equivalent concentrations. Therefore, it may be suggested that
solubilization behaviors of the reversibly gelling polymer network are governed by the
properties of the poloxamer incorporated into it. A detailed analysis of
therrnodynamic data may be found in co-pending application U.S.S.N. 60/034,805,
filed January 2, 1997, which is hereby incorporated by reference.
Solubilization was found to be spontaneous at all temperatures, and the
solubilization was endothermic, similar to the solubilization of estriol, as well as
indomethacin, by the poloxamer. Notably, ~S of solubilization was always positive,
suggesting that the more ordered water molecules surrounding hydrophobic estradiol
. , . . ~ .
CA 022634ll l999-02-09
W 098/06438 PCTAUS97/13988
molecules moved to the less ordered bulk phase when the estradiol was transferred to
the hydrophobic core of PPO segments in responsive polymer network. The
aggregation of the PPO segments at elevated temperatures provides not only
temporary cross-linking in the gel, but also a thermodynamically "friendly"
5 environrnent for the hydrophobic drugs. A similar trend is indicated by the lowering
the onset of gelation of the responsive polymer network upon solubilization of
fluorescein (Log P 2.1) (Figure 25).
In vitro study of hormone release from responsive polymer network shows an
increase in the initial transport rate with either decreasing total polymer concentration
10 in the formulation or decreasing temperature (Figures 12 B and 13B). These effects
are related to the changes in macroscopic viscosity of the responsive polymer
network, which erodes more rapidly from the feed phase through the membrane intothe receiver compartment as the viscosity decreases (Figure 26). The degree of the
responsive polymer network erosion was measured by weighing hormone-loaded
15 responsive polymer network before and after kinetic experiment.
Figure 27 shows that the relative amount of progesterone penetrating into the
receiver phase decreased 4-fold with the increase of total polymer concentration (bar
graph A), whereas the total relative amount of progesterone stayed almost constant as
total polymer concentration in the responsive polymer network increased (bar graph
20 B). This result shows the existence of two routes of transport of hydrophobic drugs
in our model system. Firstly, the drug incorporated into aggregates within the
reversibly polymer network system can flow through the membrane along with the
erosion of the polymer network; secondly, the drug not associated with the reversibly
gelling polymer network aggregates can diffuse out of the polymer network in the25 feed phase. The second process should not be related to the viscosity of the reversibly
gelling polymer network.
Example 35. This example demonstrates delivery the ability of a
poloxamer:poly(acrylic acid) polymeric network in retaining a liquid formulation in
the precorneal area of the eye.
CA 02263411 1999-02-09
WO 98/06438 PCT/US97/13988
61
The delivery of drug across the tissues of the front surface of the eye is
hindered by the protective mech~ni~m~ of tearing, eyelid blinking, and the epithelial
barrier. Normal aqueous compositions that are applied to the high are cleared within
minutes. The following example illustrates the retention time of pharmaceutical
5 agents applied to the eye using the pharmaceutical composition of the invention.
A 50 ~L drop of a 0.0001% fluorescein solution in 1% of an aqueous
polymeric network was applied to the eye of two rabbits. The clearance of the
formulation from the eye was followed by slit-lamp fluorophotometry. A buffered
solution of fluorescein was used as the control. The fluorescence measurements as a
10 function of time, post instillation, are shown in Figure 28.
The results show that for the buffered solution (curve 290 in Figure 28) the
clearance half time was less than ten minutes, while that for the polymeric network
composition (curve 292 in Figure 28) was approaching 80 minutes. Thus, the
polymeric network significantly prolonged the fluorescein r~i(ienre time in the
15 precorneal area.
Example 36. This experirnent reports the result of gamma scintigraphy
employed as a non-invasive means of monitoring the residence time of the opthalmic
compositions of the invention in the rabbit cornea.
A two-way cross over study was carried out on six ~ew 7e~1~ntl White rabbits
20 comparing a poloxamer:poly(acrylic acid) polymer network with a control saline
solution. The hydrogel formulation was radiolabelled by the inclusion of 25 ,ul 99mTc-
DTPA to give an activity of 3MBq per dose (20 ~1). The saline solution was
similarly labeled. The dose was delivered directly onto the cornea using a positive
displacement pipette and the animal was immediately positioned for imaging.
25 Scintigraphic imaging was carried out using an IGE ma,Yicamera II with a pin-hole
collimator. Tm~ging for the hydrogel included a dynamic acquisilion for 15 minutes
(60 frames at lOsec/frame and 10 frames at 30 sec/frame) followed by two static
images at 30 and 60 minutes. The saline was imaged dyn:~mir~lly for only 10
mimltes (60 frames at 10sec/frame).
.... .
CA 02263411 1999-02-o9
W O 98/06438 PCT~US97113988
6~
Gelation of the hydrogel on the corneal surface occurred imrnediately and
could be visually observed. Dramatically increased rerention time was observed with
the poloxamer:poly(acrylic acid) polymer composition between the two forrnulations,
as is illustrated in Figure 29. Saline clearance half-time was 4~ seconds, as compared
to 1150 seconds for the poloxamer:poly(acrylic acid) polymer composition. Figure 29
includes comparison of clearance half-times for other commercially available
materials, which have been evaluated using the identical technique (J.~. Greaves et
al., Cllrrent I. ~es 9(5):415 (1990)). The ophthalmic formulation of the invention
exhibited comparable performance to GelRite ~ in humans and was far superior to all
other materials compared. GelRite~ is a trademark for a polysaccharide availablefrom Merck; HEC is hydroxyethylcellulose; and Carbopol~ is a polyacrylic acid
available from BF Goodrich.
Example 37. The following example reports on the results on the
bioavailability of the mydriatic dru_, tropicamide, in the eye.
l ~ A 0.1% solution of tropicamide was prepared in a 0.1% solution of the
polymeric network; a similar concentration of the drug in saline was used as thecontrol. Fif~y microliters of each solution was applied to the precorneal area a rabbit.
The pupillary diameter change was measured with a micrometer at predetermined
intervals post-instillation.
The calculated parameters of the response are presented in Table 16. These
results indicate that the polymeric network formulation of tropicamide increased the
area under the curYe for the mydriatic response as compared to saline. It also
prolonged the duration and increased in the intensity of the response.
CA 02263411 1999-02-09
W 098/06438 PCT~US97/13988
63
Table 16.
0.1% tropicamideAUC (relative I~ (mm) Tm~ (min) duration
solution in statedto saline)
carrier
0.1% solution of the 2.8 3.04 2.0 24
polymeric network
various 1.4-1.7 2.1-2.5 0.6-1 10.5-12.3
commerically used
polymeric vehicles' 2
saline 1.0 2.63 0 5 10
' using a 0.2% ~-u~icall"de solution; low MW hydroxypropylcel~ulose (4.5%); medium MW
hydroxypropylcellulose (1.4~0); carboxymethyl cellulose (1.63%); PVA (5.0%), PVP (7.5%).
2 I~!~er J Pha~ 0:187 (1984).
These results indicate that the polymeric network is useful in delivering drugs
to the eye by topically a~lmini~tering a formulation of the drug with the polymeric
network to the precorneal area. It demonstrates significant improved performanceover control saline solution and also other comrnerically available polymeric vehicles.
Example 38. In the following example, the clearance of the reversibly gelling
20 polymeric network from the nasal cavity has been mor~itored using gamma
scintigraphy, as described in Example 36.
A 5 mL sample of the formulation shown in Table 17 was mixed with 3mbq
99m-Tc-DTPA and mixed thoroughly. The formulation was loaded into a spray
device for nasal administration of ca. 200 ~L doses to each individual. The study
25 was performed on two healthy males on two occasions. The radiolabeled formulation
was a~lmini~tered to one nostril of each subject using the ~,pray device. Scintigraphy
images of thirty second duration were taken periodically following administration of
the formulation. The polymeric formulation was deposited anteriorly in each subject.
The averaged data that was corrected for background and isotope decay is presented
30 in Figure 30.
~ ,
CA 02263411 1999-02-09
W O 98/06438 PCTAUS97/13988
64
Table 17.
Ingredient % weight amount (g)
USP purified water 96.74 29.10
Polyvinyl alcohol; 78- 1.25 0.625
82% hydrolyzed (Airvol
603)
reversibly gelling polymer 0.8 20.0 g of a 2.0 wt%
network solution
poloxa}ner (Pluronic 0.4 0.2
F127)
5N NaOH 0.8 Added in 2 wt%
reversibly gelling polymer
network
ber.7allcorlium chloride 0.015 0.074 g of a 16 wt%
soln.
The experiment demonstrated that the polymeric formulation experienced a two
15 phase clearance from the nasal cavity. The half time clearance was approximately 1.5
hours, and at least 15% of the administered dose was retained in the nasal cavity for
at least 17 hours. The formulation was cleared via the esophageal and gastrointestinal
tract and it did not prove irritating to the nose.
The nasal formulation of the invention exhibited a t"2 of 96 minutes, which
20 compares favorably with conventional polymeric vehicles such as methylcellulose (40-
70 mimltes; J. Pharm. Sci. 77(5):405 (1988)) and hydroxypropylcellulose (60-140
minutes; Inler. J. Pharm.43:221 (1988)). However, the cellulose-based vehicles
exhibited a considerably higher initial viscosity, makin~ them ~In.~uit~hle for spray
application. In contrast, the poloxamer:poly(acrylic acid) polymeric vehicle, while
25 demonstrating sufficient viscosity and bioadhesiveness after application, was of low
initial viscosity and could be easily applied by spray.
CA 02263411 1999-02-09
W O 98/06438 PCTrUS97/13988
Example 39. In the following example, the clearance of the reversibly gelling
polymeric network from the nasal cavity has been monitored using fluorescein
retention.
A 3.3 ,uL dose of a 0.3% fluorescein solution in a 0.75 wt% and a 1.5 wt%
5 poloxamer:poly(acrylic acid) polymeric network was introduced into rat nasal
passages. The clearance of the forrnulation from the nose was determined by
spectrofluorometry. The fluorescein concentration in the plasma was determined by
high pressure liquid chromatography. An intravenous treatment of fluorescein wasused as the control. The clearance rate and bioavailability a function of time, post
lO instillation, are shown in Table 18.
Table 18.
Tre~rmen~ T"2 (min)'AUC ~1-120 min) bioavailability (%)
IV (control) - 5765 100
0.75 wt% 20 1060 18
l 5formulation
1.5 wt% 50 1915 33
fo;mulation
l T"2 = tirne to clear 50% fluorescein from nose
The results indicate a high level of availability of fluorescein using nasal delivery.
20 The results also indicate the effect of poloxamer:poly(acrylic acid) polymer
concentration on the effectiveness of the nasal formulation. Increasing concentration
levels of polymer increase the clearance time from the application site and the
bioavailability of the active agent to the host. Yet other paramelers may be
considered, such as ease of ~dmini.ctration, spraying, etc., which will be apparent to
25 those skilled in the art.
Example 40. The following example demonstrates the ability of the
polymeric network to delivery peptides via the nasal route.
Five milliliters of a 5.5% solution of the polymeric network, con~ining 100
ug of a GnRH analog, was delivered with a syringe through a blueline umbilical
. . .
CA 02263411 1999-02-09
W O 98/06438 PCT~US97/13988
66
c~nnl]l~ which had been inserted into the nostril of sheep to a depth of 10 cm. Serum
concentrations of luteinizing hormone (LH) were determined as a function of timeafter the nasal administration of the peptide.
The measured serum concentrations of LH are presented in Fiuure 31. The
5 maximum concentration of the LH was approximately 40 ng/mL, and the maximum
response was observed approxirnately 3 hours post-a~lmini~tration. These resultsdemonstrate that the polymeric network was an effective vehicle for delivering apeptide across the nasal mucosa as evidenced by the stiml~ ted release of luteinizing
hormone.
These results indicate the utility of the polymeric network in delivering
bioactive materials for local and systemic effects via the nasal route. Its usefulness in
delivering peptides across the nasal mucosa overcomes the signific~nr disadvantages of
oral delivery of such macromolecular materials. It further circumvents the less
consumer friendly route of parenteral :~dmini.ctration.
Example 41. The ability of the polymeric network to retain the forrnulation at
the site of application and to prevent roll back in nasal passages is illustrated in
human volunteers.
A blind double crossover study was performed on five human volunteers. A
nasal formulation was prepared using a 0.8 wt% poloxamer:poly(acrylic acid) and
0.025 wt% oxymetalzoline. A 3 wt% PVP K-29 with 5% PEG 1450, cornmercially
available as Afrin~ nasal spray (Schering Plough) was used as a comparison nasalformulation A 150 ~1 dose of each formulation was a-lmini~tered to the volunteers.
The volunteers were also asked to con~nelll on the bitterness of the
formulation. In a blind double crossover experiment, four of the five volunteers~5 reported no bitter aftertaste (roll-baclc) in the poloxamer:poly(acrylic acid) polymeric
formulation, whereas all volunteers reported a bitter aftertaste in the Afrin~ product.
Example 42. This example demonstrates the ability of the polymeric
network to control the transit of forrnulations through luminal tissues. For example,
there is great interest in controlling the release of drugs, i.e., with regard to location
CA 02263411 1999-02-09
W O 98/06438 PCTrUS97/13988
67
of release, as a formulation passes through the gastrointestinal tract. The two
previous residence time studies shovv the ability of the polymeric network to hold the
formulation at the site of immediate application. The following example, on the other
hand, shows the passage and clearance of a volume of liquid that contains the
5 polymeric network and that has been taken internally via the oral route.
The forrnulation in Table 17 was once again radiolabeled with the 99m-
Technitium(Tc)- DTPA complex. A 5 mL aliquot of the forrnulation was
~(lmini~tered orally via a syringe to three healthy male subjects at two occasions. The
presence of the radioactive label in the esophagus was monitored by scintigraphy.
The amount of the formulation that was retained in the esophagus as a function
of time is presented in Figure 32. About 65% of the formulation passed into the
stomach within 5 seconds, which is about the time that it takes for a solid control to
clear through the esophagus. However, up to 15 % of the formulation was retainedin the esophagus for 10 minutes. It was also observed that the polymeric forrnulation
15 coated the lower third of the esophagus. This is compared to a sucralfate suspension
(a ph~rm~celltical agent having pepsin-binding and antacid effects), which had a total
retention time of 1-2 minutes.
ExamT~le 43. This example demonstrates the utility of the polymeric network
in delivering medicaments and drugs to and across mucosal tissue. The example
20 demonstrates vaginal delivery of a steroid horrnone.
The test forrnulations were a 5.5% polymeric network solution conr~ining 60
ug estradiol in a 5 mL dose, American Home Products' Premarin vaginal suppository,
cont~inin~ 300 ug of estrogen conjugates, and Bristol Myers Squibb's Estrace vaginal
cream, conr~ining 300 ug of estradiol. The forrnulations were administered to five
25 sheep in a double crossover experiment, and the estradiol blood levels were
determined by radioirnrnunoassay. The blood levels of estradiol, following the
~lministration of the test formulations, are presented in Figure 33.
The results show that the forrnulation with the polymeric network, which
contained one-fifth the concentration of hormone as the comparable test formulation,
... . ...
CA 02263411 1999-02-09
W O 98/06438 PCTrUS97/13988
68
Estrace, provided equivalent blood levels of estradiol. The lower blood levels of
estradiol seen with the Premarin could be a result of Premarin being made up of
estrogen, and not solely estradiol, derivatives. The polymeric network formulation
was also found to coat the vaginal walls effectively before it set up and gelled.
5 Furthermore, there were no side effects or tissue irritation, and there was no sign of
outward leakage of the formulation.
The significant performance features observed from these results are the
effective delivery of agents at lower dosing and the absence of leakage of the
formulation.
Example 44. Since new ways are needed for delivering peptides and proteins
across mucosal surfaces, the value of the polymeric network in creating compositions
that promote such transport is further illustrated in the following example of the
vaginal delivery of gonadotropin releasing hormone (GnRH) and analogs of it.
GnRH, lupron, and deslorelin were mixed into 5.5% polymeric network
1~ solutions at concentrations ranginr, between 20 and 33 ug/mL. Sheep were treated
with an amount equivalent to 100 ug of peptide. The bioavailability of the peptides
was measured by monitoring the concentrations of circulating luteinizing hormone(LH). The LH levels in untreated sheep served as the control.
The concentrations of LH following administration of the test formulations are
20 presented in Figure 34. Each fo~mulation caused an increase in the LH levels, with
the most .signific:~n~ increases arising from the administration of deslorelin. Both
deslorelin and lupron provided increases in the LH levels that persisted at least eight
hours. These results demonstrate that the polymeric network is effective in delivering
peptides across the vaginal mucosa.
2~ Example 36 demonstrated the abili~y of the polymeric network to solubilize
hydrophobic materials. That example, in conjunclion with the vaginal delivery ofestradiol (Example 43), demonstrate the value of the polymeric network in
formulating and delivering more hydrophobic substances. The value is further
demonstrated by the ability of the polymeric network to deliver substances more
CA 02263411 1999-02-09
W O 98/06438 PCT~US97/13988
6g
effectively, thus allowing for dosing with lower amounts of the bioactive materials.
Examples 43 and 44 further demonstrate the ability of the polymeric network to
formulate and delivery materials with a wide range of molecular characteristics, such
as hydrophobicity-hydrophilicity and molecular weight.
What is claimed is:
, . .. . .
