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1. (WO1998048768) COMPOSITIONS FOR COSMETIC APPLICATIONS
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COMPOSITIONS FOR COSMETIC APPLICATIONS

This application is a continuation-in-part application of copending application U.S.S.N. 60/034,805 filed January 2, 1997, and entitled "Responsive Polymer
Networks and Methods of Their Use", which is a continuation-in-part application of copending application PCT/US 96/ 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. 08/580,986 filed January 3, 1996, and entitled "Responsive Polymer Networks and Methods of Their Use", each of which is incorporated entirely by reference.

Field of the Invention
The present invention relates to a cosmetic composition useful in a variety of topical and personal care products, including treatments of disorders and imperfections of the skin or other areas of the body. More particularly, the present invention is directed to a cosmetic composition comprising a poloxamer:poly(acrylic acid) polymer network that can be designed to reversibly gel over a wide range of conditions to provide a composition having a controllable range of viscosities, making it useful in a variety of cosmetic and personal care applications.

Background of the Invention
Many examples are known of cosmetic compositions intended for treatment of the skin or elsewhere on the body, where it is desired to have certain properties of viscosity. Hydrogels, such as cellulosics, have been included as thickeners in cosmetic 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 form a gel region. The extent of gelation depends upon the volume of the solution which the gel region occupies.
Reversibly gelling solutions are known in which the solution viscosity increases and 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 performance is preferably in a gelled or more viscous state.
A known material with these properties is a thermal setting gel using block copolymer polyols, available commercially as Pluronic® polyols (BASF,
Ludwigshafen, Germany), 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 to produce a composition which exhibits such a transition at commercially or
physiologically useful temperatures. Also, solutions containing 18-20 % by weight of 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 is required 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 block polymers of polyoxyethylene and polyoxypropylene condensed with ethylenediamine. 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(ethylene glycol) and poly(propylene glycol)). 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® polyols, commercially available forms of poly(ethylene glycol)/poly(propylene glycol) 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 regularly repeating 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. Light transmission 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 exhibit reversible gelation art limited in that they require large solids content and/or in that the increase in viscosity less than 10-fold. In addition, some known systems exhibit an increase in viscosity which is accompanied with the undesirable opacification of the composite.

Summary of the Invention
It is an object of the present invention to provide a cosmetic composition which is includes a component capable of reversible gelation or viscosification.
It is a further object of the invention to provide a cosmetic composition which includes an ingredient capable of gelation or viscosification at very low solids content. It is another object of the present invention to provide a cosmetic 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 composition for use in cosmetic compositions useful as a surfactant or emulsifier in the
solubilization of additives and, in particular, hydrophobic additives.
It is a further object of the invention to provide a cosmetic composition which possesses the appropriate thickness, emolliency and cosmetic effect with a minimum of solids content.
It is a further object of the invention to provide a polymer network for use in cosmetic compositions useful as a suspending agent for otherwise insoluble additives.

It is yet a further object of the present invention to provide a composition capable of solubilizing emulsions at elevated temperatures.
It is yet a further object of the invention to provide new and useful cosmetic compositions incorporating the reversibly gelling polymer network composition of the present invention, which take advantage of its unique advantageous properties.
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 with a cosmetic composition which incorporates a poloxamer:poly(acrylic acid) polymer network as a cosmetically acceptable carrier. The polymer network comprises a poloxamer component randomly bonded to a poly(acrylic acid), or PAA. component in an aqueous-based medium, the polymer network being capable of aggregating in response to an increase in temperature. The reverse thermal viscosifying
poloxamer:poly(acrylic acid) polymer network includes random covalent bonding between the poly(acrylic acid) component and the poloxamer component of the network. The polymer network may also include some unbound or "free" poloxamer or other additives which contribute to or modify the characteristic properties of the polymer composition.
In addition, the cosmetic composition includes a cosmetic agent selected to provide a preselected cosmetic effect. By "cosmetic agent", as that term is used herein, it is meant that the additive imparts a cosmetic effect. A cosmetic effect is distinguishable from a pharmaceutical effect in that a cosmetic effect relates to the promoting bodily attractiveness or masking the physical manifestations of a disorder or disease. In contrast, a pharmaceutic seeks to treat the source or symptom of a disease or physical disorder. It is noted however, that the same additives may have either a cosmetic or pharmaceutical effect, depending upon the amounts used and the manner of administration.
By "cosmetic" as that term is used herein, it is meant the cosmetic and personal-care applications intended to promote bodily attractiveness or to cover or mask the physical manifestations of a disorder or disease. Cosmetics include those products subject to regulation under the FDA cosmetic guidelines, as well as sunscreen products, acne products, skin protectant products, anti-dandruff products, and deodorant and antiperspirant products.
By "gelation" or viscosification, as that term is used herein, it is meant a drastic increase in the viscosity of the polymer network solution. Gelation is dependent on the initial viscosity of the solution, but typically a viscosity increase in the range of preferably 2- to 100-fold, and preferably 5- to 50-fold, and more preferably 10- to 20-fold is observed in the polymer network which is used in the preparation of the cosmetic 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 cosmetic composition.
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 it is generally known that solution viscosity decreases with an increase in temperature.
As used herein, "poloxamer" is a triblock copolymer derived from
poIy(ethylene glycol)-poly(propylene glycol)-poly(ethylene glycol) blocks. The poloxamer is capable of responding to a change in temperature by altering its degree of association and/or agglomeration. The aggregation may be in the form of micelle formation, precipitation, labile crosslinking or other factors. The poloxamer has the general formula of a triad ABA block copolymer, (P1)a(P2)b(P 1)a, where P 1= poly(ethylene glycol) and P2 = poly(propylene glycol) blocks, where a is in the range of 10-50 and where b is in the range of 50-70.
The poly(acrylic acid) component includes poly(acrylic acid) and its salts. The poly(acrylic acid) supports and interacts with the poloxamer component so that a multi-material, responsive polymer network is formed. The interaction of the poloxamer and poly(acrylic acid) exhibits a synergistic effect, which magnifies the effect of the poloxamer component in viscosifying and/or gelling the solution.

The novel interaction between the constituent polymers components of the 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 poloxamer component and about 0.01 to 20 wt% of the poly(acrylic acid) component. A typical reversibly gelling polymer network may be comprised of less than about 4 wt% of total polymer solids (e.g., poloxamer and poly(acrylic acid))and even less than 1wt% total polymer solids while still exhibiting reverse thermal viscosification. Of course, the total solids content including additives of a reversibly gelling polymer network composition may be much higher. The viscosity of the gel increases at least ten-fold with an increase in temperature of about 5°C at pH 7 and 1 wt% polymer. Viscosity increases may be even greater over a larger temperature range at pH 7 and 1% polymer network content.
The relative proportion of poloxamer and poly(acrylic acid) may vary dependent upon the desired properties of the polymer composition. In one
embodiment, the poloxamer is present in a range of about 1 to 20 wt% and the poly(acrylic acid) is present in a range about of 99 to 80 wt%. In another
embodiment, the poloxamer component is present in a range of about 21 to 40 wt% and the poly(acrylic acid) component is present in a range of about 79 to 60 wt%. In another embodiment, the poloxamer component is present in a range of about 41 to 50 wt% and the poly(acrylic acid) component is present in a range of about 59 to 50 wt%. In another embodiment, the poloxamer component is present in a range of about 51 to 60 wt% and the poly(acrylic acid) component is present in a range of about 49 to 40 wt%. In yet another embodiment, me poloxamer component is present in a range of about 61 to 90 wt% and the poly(acrylic acid) component is present in a range of about 39 to 20 wt%. In another embodiment, the poloxamer component is present in a range of about 81 to 99 wt% and me poly(acrylic acid) component is present in a range of about 19 to 1 wt%.
The poloxamer:poly(acrylic acid) polymer network described above is included in a cosmetic composition to improve the flow characteristics, thickness and other properties of the composition. The composition includes additional cosmetic agents.

such as are needed for the cosmetic purpose 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 poloxamer:poly(acrylic acid) polymer network is incorporated into a cosmetic compositions to impart thickening properties to the cosmetic composition at the use and/or application temperature. Such thickening properties include enhanced overall viscosity, as well as a desirable viscosity response with temperature. The polymer network may be useful as a thickener in pH ranges where other thickeners are not effective.
In another aspect of the invention, the poloxamer:poly(acrylic acid) polymer network is incorporated into a cosmetic composition to stabilize and solubilize hydrophobic agents in the cosmetic composition. The polymer network may be included to increase emulsion stability. Many emulsions, i.e.. suspension of small droplets or particles of a first material in a second material, lose viscosity upon heating. As will be demonstrated herein, the poloxamer:poly(acrylic acid) polymer network retains its emulsifying properties even with temperature increase.
In addition, it 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. This film-forming agent may be used as a barrier to prevent water loss from the skin which contributes to the moisturization of the skin.
In another aspect of the invention, the poloxamer:poly(acrylic acid) polymer network may be included as an additive in cosmetic applications to prevent viscosity loss at elevated temperatures.

Brief Description of the Drawing
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 graph of viscosity vs. temperature for a 1 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-1;
Figure 2 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 3 shows the viscosity response of a 2 wt% poloxamer:poly(acrylic acid) polymer composition at various shear rates;
Figure 4 shows a viscosity response curve for a 2 wt% poloxamer: poly(acrylic acid) polymer network composition prepared with nominal mixing and stirring and prepared using high shear homogenization (8000 rpm, 30 min);
Figure 5 is a graph of viscosity vs. temperature for a 1 wt% poloxamer:
poly(acrylic acid) polymer network composition at various pHs;
Figure 6 is a graph of viscosity vs. temperature for a 1 wt% poloxamer:
poly(acrylic acid) polymer network composition with and without addition of 0.25 wt% KCl;
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 0.5 wt% acetamide MEA;
Figure 8 is a graph of viscosity vs. temperature for a 1 wt% poloxamer:
poly(acrylic acid) polymer network composition without and with 5 wt%, 10 wt% and 20 wt% added ethanol, respectively;
Figure 9 is an illustration of a reversibly gelling polymer network used as an emuisifier and stabilizer for a hydrophobic agent;
Figure 10 is a schematic illustration of me poloxamer:poly(acrylic acid) polymer network below and above the transition temperature illustrating the
aggregation of the hydrophobic poloxamer regions;
Figure 1 1 is a graph of viscosity vs. pH for a 1 wt% responsive polymer network aqueous composition of a poloxamer/poly(acrylic acid) (1 :1) measured at a shear rate of 0.44 sec-1;
Figure 12 is a plot of viscosity vs. temperature for (a) a 1 wt% responsive polymer network aqueous composition of Pluronic® F127 poloxamer/poly(acrylic acid) (1 : 1) and (b) a 1 wt% physical blend of Pluronic® F127 poloxamer/poly(acrylic acid) (1 : 1) at pH 7.0 measured at a shear rate 0.22 sec-1;
Figure 13 is a plot of viscosity vs. temperature for a 1 wt% responsive polymer network aqueous composition of Pluronic® F88 poloxamer/poly(acrylic acid) (1 : 1) at pH 7.0 measured at a shear rate 2.64 sec-1;
Figure 14 is a graph of the viscosity vs. temperature effect for a responsive polymer network composition of 2 wt% Pluronic® PI 04 poloxamer/poly(acrylic acid) (1 : 1) in deionized water at pH 7.0 measured at shear rate of 22 sec-1;
Figure 15 is plot of viscosity vs. temperature for a responsive polymer network composition of 2 wt% Pluronic® F123 poloxamer/poly(acrylic acid) (1 : 1) at pH 7.0 measured at a shear rate of 22 sec-1:
Figure 16 is a plot of viscosity vs. temperature for 1 wt% made of series of poloxamers and poly(acrylic acid) (1 : 1) in deionized water at a shear rate of 132 sec-1;

Figure 17 is a plot showing release of hemoglobin from a
poloxamer/poly(acrylic acid) polymer network of the invention;
Figure 18 is a plot showing the release of lysozyme from the
poloxamer/poly(acrylic acid) polymer complex of the invention:
Figure 19 is a plot showing release of insulin from a poloxamer/poly(acrylic acid) polymer network composition of the invention:
Figure 20 is a plot of viscosity vs. temperature for a poloxamer/poly(acrylic acid) polymer network composition (a) before and (b) after sterilization by autoclave;

Figure 21 is a plot of viscosity vs. temperature for an oil-free moisturizing formulation prepared from (a) a responsive polymer network composition of the invention and (b) a conventional oil-in-water formulation;
Figure 22 is a plot of equilibrium solubility of estradiol (A, B) and
progesterone (C, D) in aqueous solutions (pH 7) of Pluronic® F127 (A, C) and responsive polymer network (B, D) vs. temperature;
Figure 23 is a plot of the ratio of equilibrium solubilities of estradiol in responsive polymer network and water vs. polymer concentration in the responsive polymer network solutions;

Figure 24 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 25 is a plot of the percentage of a) estradiol and b) progesterone release from responsive polymer network vs. time;
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 concentration in responsive polymer network and,
Figure 28 is a plot of the relative diffusivity of poly(styrene) latex panicles in water and responsive polymer network.

Detailed Description of the Invention
The present invention is directed to a cosmetic composition comprising a cosmetically acceptable carrier comprising a novel poloxamer:poly(acrylic acid) polymer network. The polymer network functions as a temperature sensitive thickening agent, and in addition possesses surfactant and emulsifying capabilities which may be beneficial to the cosmetic composition. The polymer network composition according to the invention includes a poloxamer component randomly bonded to a poly(acrylic acid) component. The two polymer components may interact with one another on a molecular level. The polymer network contains about 0.01-20 wt% each of poloxamer and poly(acrylic acid). Exemplary polymer network-compositions range from about 1 : 10 to about 10:1 poloxamer:poly(acrylic acid).
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 environments up to pH 13 (hair care) are particularly preferred for cosmetic applications.
In one embodiment of the invention, a 1 :1 poloxamer:poly(acrylic acid) polymer network at appropriate pH exhibits flow properties of a liquid at about room temperature, yet rapidly thickens into a gel consistency of at least about five times greater, preferably at least about 10 times greater, and even more preferably at least about 30 times and up to 100 times greater, viscosity upon increase in temperature of about 10 °C and preferably about 5 °C. The reversibly gelling polymer network of the present invention exhibit gelation even at very low polymer concentrations. For example, polymer network compositions at pH 7 comprising about 0.5 wt% poloxamer component and about 0.5 wt% PAA exhibits a significant increase in viscosity from a free-flowing liquid (50 cps) to a gel (6000 cps). The observed gelation takes place at low solids contents, such as less than 20 wt% or preferably less than about 10 wt%, or more preferably less than about 2.5 wt% or most preferably less than about 0.1 wt%. Thus, only a small amount by weight of the polymer network need be incorporated into a cosmetic composition in order to provide me desired thickening or viscosifying effect.
The reverse viscosification effect at low polymer concentrations provides clear, colorless gels which are particularly well-suited to cosmetic applications. For example, very little residue is formed upon dehydration which may be important in some applications, such as in topically applied cosmetics. An additional advantage of the polymer network of the invention is that it remains clear and translucent above and below the critical temperature or pH. These characteristics of the reversibly gelling polymer network make it well suited for use in cosmetic compositions.
The polymer network of the present invention technology may be added to cosmetic formulations to increase the thickness and viscosity of the composition. The poloxamer:poly(acrylic acid) polymer network possesses hydrophobic regions capable of aggregation. Unlike conventional thickeners, the aggregation of the polymer network of the present invention is temperature sensitive. Thus, the inventive polymer network of the present invention may have a transition temperature (i.e. temperature of aggregation) above room temperature so that the cosmetic composition is of low viscosity at or below room temperature and is of high viscosity at or around body temperature (body temperature includes both surface and internal body temperature). 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 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 cosmetic composition comprising poloxamer:poly(acrylic acid) polymer network may be spread thinly to allow for even application, due to its low viscosity at room temperature, but will thicken and "fill" the skin contours upon warming up to body surface temperature. In another aspect of the invention, the composition may be applied through a nozzle that provides high shear to reduce viscosity, yet the composition regains its viscosity after application to the skin. This contrasts with conventional formulations which permanently lose viscosity after being subjected to high shear.
In another aspect of the invention, the composition may be formulated and applied as a liquid, spray, semi-solid gel, cream, ointment, lotion, stick, roll-on formulation, mousse, pad-applied formulation, and film-forming formulation.
The poloxamer:poly(acrylic acid) polymer network may also be included in a cosmetic composition for use as a stabilizing, solubilizing or emulsifying agent for a hydrophobic component of the cosmetic formulation. The strong hydrophilic regions of the poloxamer resulting from aggregation and micelle formation create hydrophobic domains which may be used to solubilize and control release of hydrophobic agents. Similar micelle-based systems have been shown to protect trapped peptides against enzymatic degradation from surface enzymes.
The reversibly gelling polymer network of the present invention is a unique polymer composition designed to abruptly change its physical characteristics or the characteristics and properties of materials mixed therewith with a change in
temperature. Without intending to be bound by any particular mechanism or chemical structure, it is believed that the structure of the polymer network involves a random bonding of the poloxamer onto the backbone of the poly(acrylic acid). A portion of the poloxamer which is present during the polymerization reaction which forms the poly(acrylic acid) is bonded to the backbone of the forming poly(acrylic acid) through hydrogen abstraction and subsequent reaction. See detailed discussion of the mechanism, below. The combination of the poly(acrylic acid) and randomly bonded poloxamer gives the composition its unique properties. Any free poloxamer remaining after polymerization of PAA remains associated with the random co-polymer, resulting in a miscible composition. Free poloxamer may also be present in the polymer network composition; however, its presence is not required in order to observe reverse thermal viscosification.
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 the poly(acrylic acid); however, reverse thermal gelling may occur without ionization. Changes to the ionic state of the polymer causes the polymer to experience attractive (collapsing) or repulsive (expanding) forces. Where there is no need or desire for the composition to be applied in a high viscosity state, it may be possible to prepare the composition as non-ionized poly(acrylic acid). The body's natural buffering ability will adjust the pH of the applied composition to ionize the poly(acrylic acid) and thereby develop its characteristic viscosity.
The poloxamer possesses regions of hydrophobic character, e.g., polypropylene glycol) blocks, and hydrophilic character, e.g.. poly(ethylene glycol) blocks. The poloxamer may be linear or branched. Suitable poloxamers include triad block copolymers of poly(ethylene glycol) and poly(propylene glycol) having the general formula (P1)a(P2)b(P1)a, where P1 = poly(ethylene glycol) and P2 = poly(propylene glycol) blocks, where a is in the range of 10-50 and where b is in the range of 50-70. where poly(propylene glycol) represents the hydrophobic portion of the polymer and poly(ethylene glycol) represents the hydrophilic portion of the polymer. Pluronic® polymers (BASF) are commercially available for a in the range of 16 to 48 and b ranging from 54-62. One or more poloxamers may be used in the reversibly gelling polymer network composition of the present invention.
The reversibly gelling responsive polymer networks compositions of the present invention are highly stable and do not exhibit any phase separation upon standing or upon repeated cycling between a liquid and a gel state. Samples have stood at room temperature for more than three months without any noticeable decomposition, clouding, phase separation or degradation of gelation properties. This is in direct contrast to polymer blends and aqueous mixed polymer solutions, where phase stability and phase separation is a problem, particularly where the constituent polymers are immiscible in one another.
An example of the dramatic increase in viscosity and of the gelation of the reversibly gelling polymer network compositions of the invention is shown in Figure 1. Figure 1 is a graph of viscosity vs. temperature for 1 wt%, 2 wt% and 3 wt% polymer network compositions comprising 1 : 1 poloxamer:poly(acrylic acid), hydrated and neutralized. The viscosity measurements were taken on a Brookfield viscometer at a shear rate of 0.44 sec-1 at pH 7.0. 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 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 1 wt%, 2 wt% 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 is demonstrated in Figure 2. where a 1 wt% poloxamer:poly(acrylic acid) composition 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 box 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 3 shows the viscosity response of a 2 wt% poloxamer:poly(acrylic acid) polymer composition at various shear rates. The viscosity response is consistent between 24 ºC and 34 ºC; however, the final viscosity is reduced with increasing shear rate.
However, unlike many prior art hydrogels, e.g., carbomers, the poloxamer:poly(acrylic acid) polymer network composition does not permanently loose viscosity after being subjected to high shear conditions. The poloxamer:poly(acrylic acid) polymer network composition remains unaffected by such shear conditions as homogenization. Figure 4 compares the viscosity response curve of a 2 wt%
poloxamer:poly(acrylic acid) polymer composition prepared with nominal mixing (simple lime) 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.
A number of factors influence me 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 5. 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. This may be clearly seen in Figure 5 when comparing the viscosity response of a 1 wt% poloxamer:poly(acrylic acid) polymer composition at pH 5 and pH 11. Satisfactory viscosities can be obtained at high pHs indicating the potential value of the reversibly gelling polymer network in products such as depilatories, hair straighteners and hair relaxers.
The responsive polymer network may also include additives for influencing the performance of the polymer composition, such as the transition temperature and the viscosity of the polymer composition above the transition temperature. The following 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), preservatives (benzalkonium chloride, phenoxyethanol, sodium
hydroxymethylglycinate. 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-12-PEG-50-lanolin, PPG-2 myristyl ether
propionate) and surfactants.
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 CO-436. Nonionic surfactants include Surfynol CT-111, 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-210 and 430, dimethicone copolyols such as Dow Corning 190, 193, and Silwet L7001.
The addition of polymers has been studied including xanthan gum. cellulosics such as hydroxyethylcellulose (HEC), carbomethoxycellulose (CMC), lauryldimonium hydroxypropyl oxyethyl cellulose (Crodacel QL). hydroxypropylcellul.se (HPC), and hydroxypropylmethylcellulose (HPMC). poly(acrylic acid), cyclodextrins. methyl acrylamido propyl triammonium chloride (MAPTAC), polyethylene oxide,
polyvinylpyroliddone, polyvinyl alcohol, and propylene oxide/ethylene oxide random copolymers. Poloxamers may also be used as additives. Examples include both the Pluronic® polyols having an (P1)a(P2)b(P1)a structure such as Pluronic® F38. L44. P65, F68, F88, L92, P103, P104, P105, F108, L 122 and F127, as well as the reverse

Pluronic® R series (P2)a(P1)b(P2)a structure such as Pluronic® 17R2 and 25R8. Other miscellaneous materials include propylene glycol. urea, triethanolamine, alkylphenol ethoxylates (Iconol series), and linear alcohol 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.
Potassium chloride and acetamide MEA are two examples of additives which decrease the final viscosity of the composition (see, Example 30). K Cl (0.25%) added to a 1 wt% reversibly gelling polymer composition reduces the viscosity by about 3000 cps. See, Figure 6. The humectant, acetamide MEA, lowers the viscosity of a 1 wt% solution by approximately 1,500 cps (see, Figure 7).
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 24-30 °C, but does not affect the final viscosity (see, Example 44). The effect of ethanol on the viscosity is different at different concentration levels. At 5 wt% and 10 wt% added ethanol, the transition temperature is shifted to lower ranges, e.g., 24-29 °C and 20-29 °C. respectively. At 20 wt% added ethanol. the composition not only exhibits a lowering of the transition temperature, but also a marked increase in initial and final viscosity. See, Figure 8. Dimethicone copolymer ( 1 wt%) also changed the transition temperature, but in this instance the transition temperature range was raised to 28-41 °C. Thus, proper selection of additives permits me formulator to adjust the transition temperature to various ranges.
Those skilled in the art will appreciate that the polymer network compositions of the present invention may be utilized for a wide variety of cosmetic and personal care applications. To prepare a cosmetic composition, an effective amount of cosmetically active agent(s) which imparts the desirable cosmetic effect is incorporated into the reversibly gelling polymer network composition of the present invention. Preferably the selected agent 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 significantly solubilize or suspend hydrophilic agents in order to improve formulation homogeneity (see. Example 36). 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 powders or oil (lipophilic materials) throughout the polymer network composition. It will also be appreciated that some applications may require a sterile environment. It is contemplated as within the scope of the invention that the reversibly gelling polymer network compositions of the present invention may be prepared under sterile conditions. An additional feature of the reversibly gelling polymer composition is that is prepared from constituent polymers that have known accepted toxicological profiles.
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 1. The non-toxicity of the polymer network makes it an ideal candidate for use in cosmetic compositions.

Exemplary cosmetic and personal care applications, for which the reversibly gelling polymer network composition may be used include, but are not limited to, baby products, such as baby shampoos, lotions, powders and creams: bath preparations, such as bath oils, tablet and salts, bubble baths, bath fragrances and bath capsules; eye makeup preparations, such as eyebrow pencil, eyeliner, eye shadow, eye lotion, eye makeup remover and mascara; fragrance preparations, such as colognes and toilet waters, powders and sachets; noncoloring hair preparations, such as hair conditioner, hair spray, hair straighteners, permanent waves, rinses shampoos, tonics, dressings and other grooming aids; color cosmetics; hair coloring preparations such as hair dye, hair tints, hair shampoos, hair color sprays, hair lighteners and hair bleaches; makeup preparations such as face powders, foundations, leg and body paints, lipstick, makeup bases, rouges and makeup fixatives; manicuring preparations such as basecoats and undercoats, cuticle softeners, nail creams and lotions, nail extenders, nail polish and enamel, and nail polish and enamel remover; oral hygiene products such as dentrifices and mouthwashes; personal cleanliness, such as bath soaps and detergents, deodorants, douches and feminine hygiene product; shaving preparations such as aftershave lotion, beard softeners, men's talcum, shaving cream, shaving soap and preshave lotions; skin care preparations such as cleansing preparations, skin antiseptics, depilatories, face and neck cleansers, body and hand cleansers, foot powders and sprays, moisturizers, night preparations, paste masks, and skin fresheners; and suntan preparations such as suntan creams, gels and lotions, indoor tanning preparations.
Preparation of the above-named cosmetic compositions and others may be accomplished with reference to any of the cosmetic formulation guidebooks and industy journals which are available in the cosmetic 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 include Cosmetics and Toiletries Magazine. Vol. 1 1 1 (March, 1996); Formulary: Ideas for Personal Care; Croda. Inc. Parsippany, NJ (1993); and Cosmeticon: Cosmetic Formulary, BASF, which are hereby incorporated in their entirety by reference.
The cosmetic composition may be in any form. Suitable forms include but are not limited to lotions, creams, sticks, roll-ons formulations, mousses, aerosol sprays, pad-applied formulations, and film-forming formulations.
As those skilled in the art will appreciate, the foregoing list is exemplary only. Because the reversibly gelling polymer network composition of the present invention is suited for application under a variety of physiological conditions, a wide variety of cosmetically active agents may be incorporated into and administered from the polymer network composition. In addition to the poloxamer:poly(acrylic acid) polymer network, additional cosmetically acceptable carriers may be included in the composition, such as by way of example only, emollients, surfactants, humectants, powders and other solvents. By way of example only, the cosmetic composition also may include additional components, which serve to provide additional aspects of the cosmetic affect or to improve the stability and/or administration of the cosmetic. Such additional components include, but are not limited to, preservatives, abrasives, acidulents, antiacne agents, anti-aging agents, antibacterials, anticaking, anticaries agents, anticellulites, antidandruff, antifungal, anti-inflammatories, anti-irritants, antimicrobials, antioxidants, astringents, anitperspirants, antiseptics, antistatic agents, astringents, binders, buffers, additional carriers, chelators, cell stimulants, cleansing agents, conditioners, deodorants, dipilatories, detergents, dispersants, emollients, emulsifiers, enzymes, essential oils, exfoliants, fibers, film forming agents, fixatives, foaming agents, foam stabilizers, foam boosters, fungicides, gellants, glosser. hair conditioner, hair set resins, hair sheen agents, hair waving agents, humectants.
lubricants, moisture barrier agents, moisturizers, ointment bases, opacifier. plasticizer. polish, polymers, powders, propellant, protein, refatting agents, sequestrant, silicones. skin calming agents, skin cleansers, skin conditioners, skin healing, skin lightening agents, skin protectants, skin smoothing agents, skin softening agents, skin soothing agents, stabilizers, sunscreen agents, surfactants, suspending agents, tanning accelerators, thickeners, vitamins, waxes, wetting agents, liquefiers. colors, flavors and/or fragrances . Suitable materials which serve the additive functions listed here are well known in the cosmetic industry. A listing of the additive function and materials suitable for incorporation into the cosmetic composition may be found in Appendix A, which is appended hereto at the end of the specification. Further information may be obtained by reference to The Cosmetic Bench Handbook,
Cosmetics & Toiletries; C.C. Urbano, editor, Allured Publ. Corp., 1996, which is hereby incorporated in its entirety by reference.
A brief description of some preferred additives and cosmetically active agents follows. The compositions of the invention include a safe and effective amount of a cosmetically 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 cosmetic effect to be obtained, but low enough to avoid serious side effects.
Preservatives can be desirably incorporated into the cosmetic compositions of the invention to protect against the growth of potentially harmful microorganisms.

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 benzoiconjure, and a variety of zinc and aluminum salts. Cosmetic chemists are familiar with appropriate 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 weight of the composition.
Emollients can be desirably incorporated into the cosmetic 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%. By way of example only, suitable silicones include cyclic or linear polydimethylsiloxanes, polyalkylsiloxanes, polyalkylarylsiloxanes and polyether siloxanes. By way of example only, suitable ester emollients include alkenyl esters of fatty acids, polyhydric alcohols, such as ethylene glycol mono and di-fatty acid esters, polyethylene glycol and the like, ether-esters, such as fatty acid esters of ethoxylated fatty alcohols, wax esters, such as beeswax, spermaceti, mysristyl myristate and stearyl stearate. and sterol esters, such as cholesterol fatty acids.
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: 1. Triglyceride esters such as vegetable and animal fats and oils. Examples include castor oil. cocoa butter, safflower oil, cottonseed oil. corn oil, olive oil, cod liver oil, almond oil, avocado oil, palm oil, sesame oil, squalene. Kikui oil and soybean oil; 2. Acetoglyceride esters, such as acetylated monoglycerides; 3.
Ethoxylated glycerides. such as ethoxylated glyceryl monostearate: 4. Alkyl esters of fatty acids having 10 to 20 carbon atoms, such as. methyl, isopropyl, and butyl esters of fatty acids, and including hexyl laurate, isohexyl laurate, isohexyl palmitate, isopropyl palmitate, decyl oleate, isodecyl oleate, hexadecyl stearate decyl stearate, isopropyl isostearate, diisopropyl adipate. diisohexvl adipate. dihexyldecyl adipate, diisopropyl sebacate, lauryl lactate, myristyl lactate, and cetyl lactate; 5. alkenyl esters of fatty acids having 10 to 20 carbon atoms, such as oleyl myristate, oleyl stearate, and oleyl oleate and the like; 6. fatty acids having 10 to 20 carbon atoms, such as pelargonic, lauric, myristic, palmitic, stearic, isostearic, hydroxystearic, oleic, linoleic, ricinoleic, arachidic, behenic, and erucic acids and the like; 7. fatty alcohols having 10 to 20 carbon atoms, such as, lauryl, myristyl, cetyl, hexadecyl, stearyl, isostearyl, hydroxystearyl, oleyl, ricinoleyl, behenyl, erucyl, and 2-octyl dodecanyl alcohols are examples of satisfactory fatty alcohols and the like, 8. fatty alcohol ethers, such as ethoxylated fatty alcohols of 10 to 20 carbon atoms including the lauryl, cetyl, stearyl, isostearyl, oleyl. and cholesterol alcohols, having attached thereto from 1 to 50 ethylene oxide groups or 1 to 50 propylene oxide groups: 9. ether-esters such as fatty acid esters of ethoxylated fatty alcohols; 10. Lanolin and derivatives, such as lanolin, lanolin oil, lanolin wax. lanolin alcohols, lanolin fatty acids, isopropyl lanolate.
ethoxylated lanolin, ethoxylated lanolin alcohols, ethoxylated cholesterol, propoxylated lanolin alcohols, acetylated lanolin alcohols, lanolin alcohols linoleate. lanolin alcohols ricinoleate. acetate of lanolin alcohols ricinoleate. acetate of ethoxylated alcohols-esters, hydrogenolysis of lanolin, ethoxylated hydrogenated lanolin, ethoxylated sorbitol lanolin, and liquid and semisolid lanolin absorption basesand the like; 1 1. polyhydric alcohol esters, such as. ethylene glycol mono and di-fatty acid esters, diedrylene glycol mono-and di-fatty acid esters, polyethylene glycol (200-6000) mono-and di-fatty acid esters, propylene glycol mono- and di-fatty acid esters, polypropylene glycol 2000 monooleate, polypropylene glycol 2000 monostearate, ethoxylated propylene glycol monostearate, glyceryl mono- and di-fatty acid esters, polyglycerol polyfatty esters, ethoxylated glyceryl monostearate, 1,2-butylene glycol monostearate, 1,2-butylene glycol distearate. polyoxyetivylene polyol fatty acid ester, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters are satisfactory polyhydric alcohol esters; 12. wax esters such as beeswax, spermaceti, myristyl myristate, stearyl stearate: 13. beeswax derivatives, e.g. polyoxyethylene sorbitol beeswax; 14.
vegetable waxes including carnauba and candelilla waxes; 15. phospholipids such as lecithin and derivatives; 16. sterol including cholesterol and cholesterol fatty acid esters; 17. 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 stimulate removal of built-up scale and improve skin feel. By way of example only, suitable humectants include polyhydric alcohols, such as glycerol, polyalkylene glycols, alkylene polyols their derivatives, propylene glycol, dipropylene glycol, polypropylene glycol, polyethylene glycol, sorbitol, hydroxypropyl sorbitol, hexylene glycol, 1,3-butylene glycol, 1,2,6-hexanetriol, ethoxylated glycerol, propoxylated glycerol and the like. The amount of humectant may be in the range of about 0.5-30 wt% and preferably between 1-15 wt%.
In topical skin care applications, a variety of active substances may be advantageously employed. By way of example only suitable active agents which may be incorporated into the cosmetic composition include anti-aging active substances, anti-wrinkle active substances, hydrating or moisturizing or slimming active substances, depigmenting active substances, substances active against free radicals, anti- irritation active substances, sun protective active substances, anti-acne active substances, firming-up active substances, exfoliating active substances, emollient active substances, and active substances for the treating of skin disorders such as dermatitis and the like.
By way of example only, in the case of hydration, one or more moisturizers may be used, such as glycerin or urea, in combination with one or more precursor agents for the biosythesis of structural proteins, such as hydroxyproline, collagen peptides and the like.
By the way of example only, in case of slimming, at least one ketolytic agent or an alpha-hydroxyacid such a salicylic acid or 5-n-octanoicsalicylic acid may be used in combination with at least on liporegulating agent such as caffeine.
By way of example only, in the case of depigmentation, at least one keratolytic agent is used in combination with a depigmenting agent such as hydroquinone, tyrosinasee inhibitor (kosic acid), ascorbic acid, kojic acid and sodium metabisulfite an the like.

By way of example only, in the case of protection against free radical agents, vitamin E (against COO radicals), superoxide dismutase (against O2 free radicals) and sugar and caffeine (against OH free radicals).
By way of example only, in the case of anti-aging, moisturizers, sunscreens, alpha-hydroxyacids, salicylic acid or surface restructuring agents may be used in combination with enzymes for the repair of DNA, vascular protective agents or phospholipids rich in oligoelements and polyunsaturated fatty acids.
By way of example only, in the case of anti-acne agents, keratolytics, such as salicylic acid, sulfur, lactic acid, glycolic, pyruvic acid, urea, resorcinol and N-acetylcysteine, and retinoids. such as retinoic acid and its derivatives may be used.
By way of example only, in the case of anti-inflammation, non-steroidal anti-inflammatory agents (NSAIDS) may be used, such as propionic acid derivatives, acetic acid, fenamic acid derivatives, biphenylcarboxylic acid derivatives, oxicams. including but not limited to aspirin, acetaminophen, ibuprofen. naproxen. benoxaprofen, flurbiprofen, fenbufen, ketoprofen. indoprofen. pirprofen, carporfen, and bucloxic acid and the like.
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 β-lactam drugs. quinolone drugs, ciprofloxacin, norfloxacin. tetracycline, erythromycin, amikacin, triclosan. doxycycline, capreomycin, chlorhexidine, chlortetracycline, oxytetracycline. clindamycin, ethambutol. hexamidine isethionate, metronidazole, pentamidine, gentamicin, kanamycin, lineomycin, methacycline. methenamine, minocycline, neomycin, netilmicin, paromomycin, streptomycin, tobramycin, miconazole and amanfadine and the like.
By way of example only, in the case of sunscreen protection, suitable agents include 2-edιylhexyl p-methoxycinnamate, 2-ethylhexyl N,N-dimethyl-p-aminobenzoate, p-aminobenzoic acid, 2-phenyl p-methoxycinnamate, 2-ethylhexyl octocrylene, oxybenzone, homomenmyl salicylate, octyl salicylate, 4,4'-methoxy-1-butyldibenzoylmethen, 4-isopropyl dibenzoylmethane, 3-benzylidene camphor, 3-(4- methylbenzylidene) camphor, titanium dioxide, zinc oxide, silica, iron oxide, and mixtures thereof and the like. The sunscreening agents disclosed therein have, in a single molecule, two distinct chromophore moieties which exhibit different ultra-violet radiation absorption spectra. One of the chromophore moieties absorbs predominantly in the UVB radiation range and the other absorbs strongly in the UNA radiation range. These sunscreening agents provide higher efficacy, broader UN absorption, lower skin penetration and longer lasting efficacy relative to conventional sunscreens. Generally, the sunscreens can comprise from about 0.5% to about 20% of the compositions useful herein. Exact amounts will vary depending upon the sunscreen chosen and the desired Sun Protection Factor (SPF). SPF is a commonly used measure of photoprotection of a sunscreen against erythema.
By way of example only, in the case of sunless tanning agents include, dihydroxyacetone, glyceraldehyde, indoles and their derivatives, and the like.
The composition may include cleansing surfactants. Cleansing surfactants are cationic, anionic. amphoteric or non-ionic surfactants which are water-soluble and produce a consumer-acceptable amount of foam. Νonionic surfactants are well-known materials and have been used in cleansing compositions. Therefore, suitable nonionic surfactants include, but are not limited to, compounds in the classes known as alkanolamides, block copolymers of ethylene and propylene. ethoxylated alcohols, ethoxylated alkylphenols, alkyl polyglycosides and mixtures thereof. In particular, the nonionic surfactant can be an ethoxylated alkylphenol. i.e., a condensation product of an alkylphenol having an alkyl group containing from about 6 to about 12 carbon atoms in either a straight chain or branched chain configuration with ethylene oxide, the etirylene oxide being present in an amount equal to at least about 8 moles ethylene oxide per mole of alkylphenol. Examples of compounds of this type include nonylphenol condensed with about 9.5 moles of ethylene oxide per mole of phenol; dodecylphenol condensed with about 12 moles of ethylene oxide per mole of phenol; dinonylphenol condensed with about 15 moles of ethylene oxide per mole of phenol; octylphenol condensed with about ten moles of ethylene oxide per mole of phenol; and diisooctyl phenol condensed with about 15 moles of ethylene oxide per mole of phenol.
A wide variety of acids, bases, buffers, and sequestrants can be utilized to adjust and/or maintain the pH and ionic strength of the compositions useful in the instant invention. Materials useful for adjusting and/or maintaining 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, triethanolamine, EDTA, disodium EDTA, tetrasodium EDTA, and the like.
The polymer network may be useful as a solubilization agent in cosmetic and personal care applications. A self-assembling system comprising the reversibly gelling polymer network exhibits thermogelation. pH sensitivity, and the ability to solubilize hydrophobic agents in aqueous media. When poloxamer is copolymerized with poly(acrylic acid) (PAA) according to the invention, the resulting copolymer network is bioadhesive and can be applied in a number 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 cosmetic and personal care products.
The reversible viscosification of the polymer network at elevated temperatures makes the materials ideal for use as thickening agents in cosmetic and personal care products at any temperature above the transition. Another use of the "thickening" of solutions containing 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 exactly the opposite way, increasing its ability to emulsify as it gained three-dimensional structure upon heating above its transition temperature.
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 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 an oil droplet, as is illustrated in Figure 9. These two features of the material of the invention would enable it to be used as a base in a cosmetic formulation that would be non-greasy due to lack of oils, such as petrolatum and mineral oil. The increase in viscosity above the transition temperature adds structure and yield value to the water phase and results in a highly stable emulsion.
Thus, poloxamer:poly(acrylic acid) polymer network compositions are valuable materials in the formulation of cosmetic and personal care products. In particular, they may be useful as rheology modifiers, provide a cushioning effect on :ne skin, offer barrier properties and controlled release of actives. In addition, the polymer composition may serve as a surfactant and is compatible with most ingredients used in the cosmetic industry.
The above properties of the poloxamer:poly(acrylic acid) polymer network provides a cosmetic composition that spreads evenly and smoothly and which leaves a lubricious feel to the skin. A sensory evaluation was conducted with seven random volunteers in order to determine the sensory effect of a cream formulation on the skin. An oil-free cosmetic formulation was prepared substantially as set forth in Example 33(b) and was compared to Nivea Oil Free, a product of Beiersdorf of Germany.
Volunteers placed unmarked samples on the skin and evaluated the formulation based upon its feel and texture. The samples were rated on a scale of 1 (bad) to 5 (good). The oil-free cosmetic formulation of the present invention scored equally to the Nivea Oil Free moisturizing product. Both samples scored a 3.5 on the rating scale.
The observed thermal behavior of the reversibly gelling polymer network suggests that the increase in viscosity is due to aggregation of the 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 as shown in Figure 10, in which a backbone 20 represent poly( acrylic acid), a thin band 24 represents the hydrophobic poly(propylene) glycol region of the poloxamer and a thick band 26 represents the hydrophilic poly(ethylene glycol) region of the poloxamer. Below the transition temperature, the polymer network is randomly arranged, as is shown in Figure 10(a). At or above the transition temperature, the hydrophobic regions 24 associate to form aggregations or micelles 28, as is shown in Figure 10(b). The association increases the effective molecular weight of the polymer network composition with the corresponding increase in viscosity.
A general method of making the poloxamer:PAA polymer network
compositions of the present invention comprises solubilization of the poloxamer in acrylic acid monomer, followed by polymerization of the monomer to P.AA.
Polymerization 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-dimethylpentanitrile) (Vazo 52) and azobisisobutyronitrile (AIBN). Initiation may also be 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 monomer and/or free poloxamer from the resultant polymer network. This may be accomplished using conventional techniques, such as. by way of example, dialysis or sohxlet extraction.
Without intending to be bound by a particular mechanism or structure, the following scheme represents a possible chemical mechanism for the formation of the system here described. These mechanisms are presented by way of explanation and 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.


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 3), and attachment to acrylic acid via addition across the unsaturated bond (eq 10). Propagation (eq 8) leads to the final PAA.
Alternatively, the mechanism may proceed by initiation according to eqs. (1) and (2), propagation to form PAA (eq.8), a chain transfer reaction to generate a reactive poloxamer moiety (eq. 5), followed by addition of the reactive poloxamer 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 1 This example describes the synthesis of a polymer network and an aqueous responsive polymer network solution prepared using a triblock polymer of poly(ethylene glycol) and poly(propylene glycol), Pluronic® F27 polyol, and poly(acrylic acid). This example also characterizes the gelation and the physical properties of the resultant polymer network.
Synthesis. Block copolymer of poly(propylene glycol) (PPG) and
polyethylene glycol) (PEG) having triad ABA structure (PEG)A(PPG)B(PEG)A (Pluronic® F127 NF polyol, Poloxamer 407 NF polyol, where "F" means Flakes, "12" means 12X300=3600 - MW of the PPG section of the block copolymer, "7" PEG in 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 was deaerated by N2 bubbling for 0.5 h and following addition of 100 ml 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.
Viscosity measurements. A known amount of the resultant polymer was suspended in 100 ml deionized water into which NaOH was added. Following swelling for 3 days while stirring, the pH of the resulting fine suspension was adjusted to 7. Samples of 15 ml each were taken, and pH in each vial was adjusted to desired value by addition of 1 M HCl or NaOH. Samples 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® 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 wt% total polymer 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 Figs. 1. 1 1 and 12. Figs. 1 and 2 clearly demonstrate that the synthetic route outlined above resulted in a polymer network system that is sensitive to pH and temperature of the environment. Note that the liquid-gel transition is very sharp, occurring over a very small temperature change or pH (see, Figure 1 1). Figure 12 is a viscosity vs. temperature graph comparing the gelling characteristics of the responsive polymer network composition and the physical blend. The blend prepared by physically mixing of the triblock PEG/PPG/PEG polymer and 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) viscosity at temperatures of around 30 °C and higher if pH is adjusted to 6 or higher. The gelling effect was observed in polymer network compositions standing 3 months or longer. Repeated heating and 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 aery late 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 ueutralized to sodium 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 minutes and then heating began. Heating began at a rate of 0.5-1.0 ºC/min up to

75 ºC. The reaction began to exotherm at about 45-50 ºC and is allowed to continue without cooling until a maximum is reached. It is then cooled to 75 ºC using forced cooling. The reaction continued for 12 hours and was then cooled to 35 ºC. 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 μm pore size) until the bulk of the Norpar had been removed from the beads. The beads were 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 ºC. The dried beads were analyzed as follows.
Elemental analysis. The elemental analysis was performed by Quantitative

Technologies, Inc., Whitehouse, NJ using a Perkin Elmer 2400 CHN Elemental Analyzer. Analysis provided C (52.49%), H (7.50%), N (< 0.05%), the balance assumed to be oxygen (39.96%).
Thermal Gravimetric Analysis (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 ºC/min. The resolution for the system was set to 4 (1.0 ºC/min for all slope changes). The data was analyzed using the first derivative of the curve and using maxima and minima 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% remained).
Molecular weight determination bv gel permeation chromatography (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 A. were used for the separation. The mobile phase was 0.1M NaNO3 and 0.01M K2HPO4 salt solution, pH adjusted with phosphoric acid to a pH of 8.0 ± 0.1. The flow rate for the separation was 0.9 mL/min. The column temperature was maintained at 15 ºC. The injection volume for the assay was 50 μL. A PEG molecular weight standard of 23,000 Daltons was used to align the detectors. The result for the assay were:
Mn: 341,700 Daltons
Mp: 1,607,000 Daltons
Mw: 2,996,000 Daltons
Free poloxamer determination by GPC. The amount of free (unbound) poloxamer in the polymer matrix was determined using the above GPC method and 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 poloxamer on the gelation properties of the responsive polymer network has been determined 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 transition and assists in a more controlled and reproducible transition.
Bound poloxamer determination by ethylene 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 is removed and dried under a vacuum for 12 hours at room temperature. The dry 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 amount of poloxamer bound to the polymer. The typical result is approximately 15 % by weight of EO.
The relative amount of free poloxamer may be varied dependent upon the 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
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 of viscosification. 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 changes in temperature.
Residual acrylic monomer determination by gas chromatography (GC). The residual acrylic acid monomer was determined by GC analysis using a Hewlet Packard GC 5890A, using a HP-FFDAP-TPA 10 m × 0.53 mm × 1μm column. The sample was extracted and run in methanol. Using an internal standard ratio, the sample was compared to a one point calibration. The typical results for this assay were below 70 ppm acrylic acid monomer.
Residual Norpar solvent by GC. The residual Norpar in the sample was determined by GC using the above method and comparing the Norpar peaks to that of a standard. The typical results were below 1.5 wt%.
UV-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 scanning calorimetry (DSC). The DSC was performed by
Massachusetts Material Research. Inc., West Boylston. MA using a temperature ramp from 30 to 350 ºC at 5 ºC/min. The resolution for the system was set to 4 (1.0ºC/min for all slope changes). The assay yielded one endothermic event at 265 ºC, typically 270 J/g.
Examples 3-9. This example describes the synthesis of a several reversible thermal gelling polymer network prepared using a variety of poloxamers and poly(acrylic acid). The gelation and the physical properties of the resultant polymer network compositions are reported in Table 2.



Example 10. The following example demonstrates the effect of hydrophilic/hydrophobic ratio on the gelling temperature. Polymer network compositions were prepared from the following poloxamers shown in Table 3.

Table 3 shows that in this series, the fraction of PEG is reduced when the molecular weight of the PPG 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 PEG/PPG ratio, whereas these boundaries shifted to lower temperature as the PEG content of the polymer is reduced at constant mass. The strong dependence of the PEG/PPG ratio is a consequence of the differing solubilities of PEG and PPG 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 PEG 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 following addition of the 100 :1 of freshly 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 solutions were subjected to the viscosity measurement at shear rate of 132 or 13.2 sec-1 using a SC4-18 spindle. It can be seen from Figure 16 that, firstly, viscosity of the 1 wt% responsive polymer network solutions before viscosification (at 20-24°C) decreases in the series (PEG)37(PPG)56(PEG)37(F103) > (PEG)25(PPG)56(PEG)25(F104) >
(PEG)16(PPG)56(PEG)16(F105) and, secondly, the temperature at which gelation shifts from about 45 °C for (PEG)37(PPG)56(PEG)37 to about 35 °C for
(PEG)25(PPG)56(PEG)25 and (PEG)16(PPG)56(PEG)16. Both results are in excellent agreement with the theory set forth in Linse.
Example 11. The following example is related to release of and active agent from a poloxamer: poly(acryIic acid) polymer network. Drug loading and kinetics of release of the protein hemoglobin from poloxamer:poIy(acryIic acid) polymer network is described.
Synthesis. Pluronic® F127 (3.0 g) was dissolved in 3.0 g acrylic acid. The solution was deaerated by N2 bubbling for 0.5 h and following addition of 100 FI 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 water into which NaOH was added. The resulting suspension was allowed to swell for 7 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, 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 (pH 7.4), respectively. In the control experiment, the feed phase was made of 1 g of 0.25 mg/ml hemoglobin solution. After the feed solution had been loaded into the cell, the kinetic time commenced. Samples of the receiver phase was withdrawn from time to time and their absorbance was measured spectrophotometrically at 400 nm.

To calculate hemoglobin concentrations, corresponding calibration curves (absorbance in PBS versus hemoglobin concentration) were generated. The results of the kinetic experiment are presented in Figure 17. It can be seen that the rate of hemoglobin release from the polymer network was substantially lowered at 37 °C when compared to that at 25 °C, because of viscosity increase in the polymer network at elevated temperatures (see Figure 1). The protein released from the polymer network composition still retained its native structure, as was determined by comparison of uv-vis spectra of release hemoglobin and natural hemoglobin.
Example 12. The following example is related to release of an active agent from a poloxamer: poly (acryIic acid) polymer network. Drug loading and kinetics of release of the protein lysozyme 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 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 lysozyme-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 1 mg/ml lysozyme solution. After the feed solution had been loaded into the cell, the kinetic time commenced. 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 results of the kinetic experiment are presented in Figure 18. It can be seen that the 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 1).

In order to demonstrate the retention of the enzymatic activity of lysozyme, 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 lysozyme in presence of sodium dodecyl sulfate did not show any appreciable lysis of the cells.
Example 13. 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 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 adjusted 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 commenced. Samples were withdrawn and their absorbance was measured spectrophotometrically at 280 nm. A calibration curve was prepared for insulin concentration ranging from 0 mg/ml to 1.25 mg/ml in phosphate buffered saline. The results of the kinetic experiment are presented in Figure 19. 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 1).
Example 14. 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® F127 polyol/poly (aerylic acid). After 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 minutes.
Viscosity is determined after sterilization. The corresponding curves for viscosity (a) before and (b) after sterilization are shown in Figure 20 and establish that minimal change in the viscosity profile of the material has occurred with sterilization.
Examples 15-30. 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 Brookfield viscosification curve. Results are reported in Table 4.

Example 31. Because of the surfactant nature of the polymer network composition coupled with the gelation effect of the polymer network composition, it is possible to prepare formulation which are 100% water-based, but which are lubricous and thick.
Formulations including a nonionic surfactant formulation: An O/W (oil-in-water) emulsion was made by combining me following ingredients utilizing
conventional mixing techniques:



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 homogeneity. This formulation contains a nonionic surfactant and gives an emulsion that is fluid at room temperature but viscosifies above 32 ºC.
Formulations including a cationic surfactant formulation: An O/W (oil-in-water) emulsion was made by combining the following ingredients utilizing
conventional mixing techniques:



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 contains a cationic surfactant and gives an emulsion that is fluid at room temperature but viscosities above 32°C.
Formulations including an anionic surfactant formulation: An O/W (oil-in-water) emulsion was made by combining me following ingredients utilizing
conventional mixing techniques:



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 homogeneity. This formulation contains a anionic surfactant and gives an emulsion that is fluid at room temperature but viscosifies above 32°C.
Example 32. Acne Medication: An oil-free, clear, anti-acne treatment is made by combining the following ingredients utilizing conventional mixing
techniques:



To one vessel, equipped with a Lightnin' Mixer with a 3 blade paddle prop, the full amount of USP Purified Water to 100% w/w is added. While maintaining the temperature, with moderate to vigorous mixing, the formula amount of Disodium EDTA, Citric Acid, DL-Panthenol, Glycerin, Salicylic Acid, and Germaben® II is added. These materials are allowed to dissolve at 50°C. After dissolution, the vessel is then cooled to 20°C. To another vessel, equipped with a high efficiency homogenizer, me 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 homogeneity.
The composition displays a flowable clear jelly appearance with excellent spreadability and absorption characteristics at room temperature, and after heating the formulation to 32°C, the composition thickens to a gel-like consistency.
Example 33. (a) Oil-free Moisturizer (formulation I): An oil-free, lubricous moisturizer was made by combing the following ingredients utilizing conventional mixing techniques:



The above ingredients were added and processed as described above for the acne composition. The composition displayed a flowable creamy lotion appearance with excellent emolliency, spreadability and absorption characteristics at room temperature. After heating the formulation to above 26°C, the composition thickened to a gel-like consistency. The viscosity vs. temperature curve is shown in Figure 21 and demonstrates that addition of adjuvants to the composition significantly enhances the responsive polymer network maximum viscosity ( > 900,000 cps). The use of the poloxamer: poly(acrylic acid) polymer network in the formulation also imparts a unique viscosification effect after application to the skin, which is not evident in typical commercial O/W emulsion formulations (See, Figure 21b).
(b) Oil-free Moisturizer (formulation II): An oil-free, lubricious moisturizer was made by combing the following ingredients utilizing conventional mixing techniques:

The above ingredients were added and processed as described above for the acne composition. The composition displayed a flowable creamy lotion appearance with excellent emolliency, spreadability and absorption characteristics at room temperature. After heating the formulation to 26ºC, the composition thickens to a gel-like consistency. The addition of adjuvants to the composition significantly enhances the polymer network maximum viscosity.
Example 34. Sunscreen Lotion. An oil-free, lubricious sunscreen lotion was made by combining the following ingredients utilizing conventional mixing techniques:


The above ingredients were added and processed as described above for the acne composition. The composition displayed a flowable creamy lotion appearance with excellent emolliency, spreadability and absorption characteristics at room temperature . After heating the formulation to above 26ºC, the composition thickened to a gel-like consistency. The addition of adjuvants to the composition significantly enhances the polymer network maximum viscosity.
Example 35. Facial mask. A face mask was made by combing the following ingredients utilizing conventional mixing techniques:


The above ingredients were added and processed as described above for the acne composition. The composition displayed a flowable creamy lotion appearance with excellent emolliency, spreadability and absorption characteristics at room temperature. After heating the formulation to above 26ºC, the composition thickened to a gel-like consistency. The addition of adjuvants to the composition significantly enhances me polymer network maximum viscosity.
Example 36. Facial toner. A face mask was made by combing the following ingredients utilizing conventional mixing techniques:


The above ingredients were added and processed as described above for the acne composition. The composition displayed a flowable appearance with excellent emolliency, spreadability and absorption characteristics at room temperature . After heating the tormulation to above 26ºC, the composition thickened to a gel-like consistency. The addition of adjuvants to the composition significantly enhances the polymer network maximum viscosity.
Example 36. Solubilization studies of model hydrophobic agents in the poloxamer: polv(acrylic acid) polymer network: estradiol and progesterone. This example is presented to demonstrate the solubilization of a hydrophobic agent in the polymeric network. Progesterone and estradiol were used as the hydrophobic agents in this model solubilization study.
Acrylic acid (99%), fluorescein (98%), β-estradiol (98%), and progesterone (98%) were all obtained from Aldrich and used as received. Pluronic® F127 NF was obtained 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 polymer network copolymers discussed here were composed of about 1 : 1 ratio of PAA 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 1 w% reversibly gelling polymer network was measured using He-Ne laser as described 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
(progesterone) or 280 nm (estradiol), or by using 70/30 w/w H2SO4/MeOH
(Tsilifonis-Chafetz reagent). In vitro hormone release studies were conducted using thermostatted, vertical Franz cells. Spunbonded polypropylene microfilters (micron retention, 15-20) were used as a membrane separating feed and receiver phases in Franz 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% PEG in water (pH 7) and were stirred by magnetic bars. The feed phases composed of responsive 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 aqueous solutions of Pluronic® F127 polyol and responsive polymer network are presented in Figure 22. It can be seen that increasing temperature and concentration (C) of polymers in the solution raises the amount of the hormone dissolved. In Figure 22a, 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 responsive polymer network solutions. The S values in 5% aqueous solutions of branched PAA did not exceed 15 and 40 μg/mL at 60 °C for estradiol and progesterone, respectively. The solubility values found for responsive polymer network were the same as S in parent Pluronic solutions of equivalent concentrations. Therefore, it may be suggested that solubilization behaviors of the responsive polymer network are governed by the properties of the poloxamer incorporated into it. Thermodynamic parameters of the solubilization process with responsive polymer network were calculated using the same
approximations as in the micellar solubilization with Pluronic polyols. See, Saito,Y. , Kondo, Y. , Abe, M. , Sato, T. , Chem. Pharm. Bull. , 1994, 42, 1348. Namely, partition coefficient P was estimated from equilibrium solubilities of estradiol in responsive polymer network and water:
P=SSH/SW (13) by extrapolating the solubility plots of the steroid in Figure 22 to 100 % responsive polymer network. Using P values obtained from data in Figure 23, we calculated the standard free energy change (ΔG), standard enthalpy of solubilization (ΔH), and standard entropy of solubilization (ΔS) using the following expressions:
ΔG = -RTlnP; ΔH = -RΔlnP/Δ(l/T); ΔS = (ΔH - ΔG)/T (14)

Thermodynamic parameters obtained along with P values are given in Table 13.
Apparent partition coefficients and thermodynamic parameters for solubilization of estradiol by responsive polymer network.


Negative ΔG values indicate spontaneous solubilization at all temperatures, whereas positive ΔH shows that the solubilization was endothermic, similar to the solubilization of estriol, as well as indomethacin, by the poloxamer. Notably, ΔS of solubilization was always positive, suggesting that the more ordered water molecules surrounding hydrophobic estradiol molecules moved to the less ordered bulk phase when the estradiol was transferred to the hydrophobic core of PPG segments in responsive polymer network. The aggregation of the PPG segments at elevated temperatures provides not only temporary cross-linking in the gel, but also a thermodynamically "friendly" environment for the hydrophobic drugs. Indeed, one can express the free energy of formation of the aggregate core-water interface in responsive polymer network as:
ΔG = [σPw(1- ∅) + σWD∅](4πR2/n) (15) where σPw and σWD are the interfacial tensions between pure PPO polymer and water and between water and the drug, respectively; ∅ is the volume fraction of the drug within PPO core; R is the effective radius of the core, and n is the aggregation number.

Equation (3) shows that solubilization of a hydrophobic drug of high σWD should increase the stability of the aggregate. The solubilization process was found to decrease the critical micellization concentration and substantially increase the micellar core radius in Pluronic surfactants (Hurter, P.N. et al. , "In Solubilization in
Surfactant Aggregates", Christian, S.D., Ed. , Marcel Dekker, New York, 1995). A similar trend is indicated by the lowering the onset of gelation of the responsive polymer network upon solubilization of fluorescein (LogP 2.1) (Figure 24). The solubilization of hydrophobic drugs by responsive polymer network, analogous to the micellar solubilization of drugs by poloxamer, suggests that the responsive polymer network can be an effective vehicle in drug delivery.
Our in vitro study of hormone release from responsive polymer network shows an increase in the initial transport rate with either decreasing total polymer concentration in the formulation or decreasing temperature (Figure 25). 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 into the receiver compartment as the viscosity decreases (Figure 26). The degree of the responsive polymer network erosion was measured by weighing hormone-loaded 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, whereas the total relative amount of progesterone stayed almost constant as total polymer concentration in the responsive polymer network increased. 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 responsive polymer network system can flow through the membrane along with the erosion of the responsive polymer network; secondly, the drug not associated with the responsive polymer network aggregates can diffuse out of the responsive polymer network in the feed phase. The second process should not be related to the viscosity of the responsive polymer network. Indeed, the dynamic light scattering experiment shows no dramatic change of diffusivity of poly(styrene) latex particles in the responsive polymer network as temperature rises thereby increasing macroscopic viscosity more than 10-fold (Figure 28). This result indicates that the viscosity of the responsive polymer network is essentially unaffected on the microscopic scale.

Appendix A attached.