WO1997000275A2 - Reticulats polymeriques sensibles a des changements intervenus dans des stimulus environnementaux et leurs procedes d'utilisation - Google Patents

Reticulats polymeriques sensibles a des changements intervenus dans des stimulus environnementaux et leurs procedes d'utilisation Download PDF

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Publication number
WO1997000275A2
WO1997000275A2 PCT/US1996/010376 US9610376W WO9700275A2 WO 1997000275 A2 WO1997000275 A2 WO 1997000275A2 US 9610376 W US9610376 W US 9610376W WO 9700275 A2 WO9700275 A2 WO 9700275A2
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Prior art keywords
component
associating
temperature
solvophilic
composition
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PCT/US1996/010376
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English (en)
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WO1997000275A3 (fr
Inventor
Lev Bromberg
E. Cornelius Lupton
Matthew E. Schiller
Mary J. Timm
George W. Mckinney, Iii
Michal Orkisz
Barry Hand
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Gel Sciences, Inc.
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Priority claimed from US08/580,986 external-priority patent/US5939485A/en
Application filed by Gel Sciences, Inc. filed Critical Gel Sciences, Inc.
Priority to JP50336897A priority Critical patent/JP2002516617A/ja
Priority to EP96923310A priority patent/EP0832151A2/fr
Priority to AU63857/96A priority patent/AU6385796A/en
Publication of WO1997000275A2 publication Critical patent/WO1997000275A2/fr
Publication of WO1997000275A3 publication Critical patent/WO1997000275A3/fr

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    • A—HUMAN NECESSITIES
    • A43—FOOTWEAR
    • A43B—CHARACTERISTIC FEATURES OF FOOTWEAR; PARTS OF FOOTWEAR
    • A43B7/00—Footwear with health or hygienic arrangements
    • A43B7/14—Footwear with health or hygienic arrangements with foot-supporting parts
    • A43B7/1405—Footwear with health or hygienic arrangements with foot-supporting parts with pads or holes on one or more locations, or having an anatomical or curved form
    • A43B7/1415—Footwear with health or hygienic arrangements with foot-supporting parts with pads or holes on one or more locations, or having an anatomical or curved form characterised by the location under the foot
    • A43B7/142—Footwear with health or hygienic arrangements with foot-supporting parts with pads or holes on one or more locations, or having an anatomical or curved form characterised by the location under the foot situated under the medial arch, i.e. under the navicular or cuneiform bones
    • A—HUMAN NECESSITIES
    • A43—FOOTWEAR
    • A43B—CHARACTERISTIC FEATURES OF FOOTWEAR; PARTS OF FOOTWEAR
    • A43B1/00—Footwear characterised by the material
    • A43B1/0027—Footwear characterised by the material made at least partially from a material having special colours
    • A43B1/0036—Footwear characterised by the material made at least partially from a material having special colours with fluorescent or phosphorescent parts
    • A—HUMAN NECESSITIES
    • A43—FOOTWEAR
    • A43B—CHARACTERISTIC FEATURES OF FOOTWEAR; PARTS OF FOOTWEAR
    • A43B1/00—Footwear characterised by the material
    • A43B1/0054—Footwear characterised by the material provided with magnets, magnetic parts or magnetic substances
    • A—HUMAN NECESSITIES
    • A43—FOOTWEAR
    • A43B—CHARACTERISTIC FEATURES OF FOOTWEAR; PARTS OF FOOTWEAR
    • A43B13/00—Soles; Sole-and-heel integral units
    • A43B13/14—Soles; Sole-and-heel integral units characterised by the constructive form
    • A43B13/18—Resilient soles
    • A43B13/189—Resilient soles filled with a non-compressible fluid, e.g. gel, water
    • A—HUMAN NECESSITIES
    • A43—FOOTWEAR
    • A43B—CHARACTERISTIC FEATURES OF FOOTWEAR; PARTS OF FOOTWEAR
    • A43B7/00—Footwear with health or hygienic arrangements
    • A43B7/14—Footwear with health or hygienic arrangements with foot-supporting parts
    • A43B7/1405—Footwear with health or hygienic arrangements with foot-supporting parts with pads or holes on one or more locations, or having an anatomical or curved form
    • A43B7/1415—Footwear with health or hygienic arrangements with foot-supporting parts with pads or holes on one or more locations, or having an anatomical or curved form characterised by the location under the foot
    • A43B7/144—Footwear with health or hygienic arrangements with foot-supporting parts with pads or holes on one or more locations, or having an anatomical or curved form characterised by the location under the foot situated under the heel, i.e. the calcaneus bone
    • A—HUMAN NECESSITIES
    • A43—FOOTWEAR
    • A43B—CHARACTERISTIC FEATURES OF FOOTWEAR; PARTS OF FOOTWEAR
    • A43B7/00—Footwear with health or hygienic arrangements
    • A43B7/14—Footwear with health or hygienic arrangements with foot-supporting parts
    • A43B7/18—Joint supports, e.g. instep supports
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/042—Gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/91—Graft copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/02—Preparations for cleaning the hair
    • A—HUMAN NECESSITIES
    • A63—SPORTS; GAMES; AMUSEMENTS
    • A63B—APPARATUS FOR PHYSICAL TRAINING, GYMNASTICS, SWIMMING, CLIMBING, OR FENCING; BALL GAMES; TRAINING EQUIPMENT
    • A63B71/00—Games or sports accessories not covered in groups A63B1/00 - A63B69/00
    • A63B71/08—Body-protectors for players or sportsmen, i.e. body-protecting accessories affording protection of body parts against blows or collisions
    • A63B71/14—Body-protectors for players or sportsmen, i.e. body-protecting accessories affording protection of body parts against blows or collisions for the hands, e.g. baseball, boxing or golfing gloves
    • A63B71/141—Body-protectors for players or sportsmen, i.e. body-protecting accessories affording protection of body parts against blows or collisions for the hands, e.g. baseball, boxing or golfing gloves in the form of gloves
    • A63B71/143—Baseball or hockey gloves
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29D—PRODUCING PARTICULAR ARTICLES FROM PLASTICS OR FROM SUBSTANCES IN A PLASTIC STATE
    • B29D35/00—Producing footwear
    • B29D35/12—Producing parts thereof, e.g. soles, heels, uppers, by a moulding technique
    • B29D35/126—Uppers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/54—Polymers characterized by specific structures/properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • A—HUMAN NECESSITIES
    • A63—SPORTS; GAMES; AMUSEMENTS
    • A63B—APPARATUS FOR PHYSICAL TRAINING, GYMNASTICS, SWIMMING, CLIMBING, OR FENCING; BALL GAMES; TRAINING EQUIPMENT
    • A63B71/00—Games or sports accessories not covered in groups A63B1/00 - A63B69/00
    • A63B71/08—Body-protectors for players or sportsmen, i.e. body-protecting accessories affording protection of body parts against blows or collisions
    • A63B71/081—Body-protectors for players or sportsmen, i.e. body-protecting accessories affording protection of body parts against blows or collisions fluid-filled, e.g. air-filled

Definitions

  • the present invention relates to a polymer composition which exhibits a reversible gelation in response to a change in temperature or other environmental stimulus. More particularly, the present invention is directed to a viscosifying 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 pharmaceutical, cosmetic and industrial applications.
  • a polymer network is a special type of polymer-polymer composition having favorable interactions between the constituent polymers on a molecular level.
  • Many polymer networks of the prior art utilize covalent bonding between the constituent polymers to establish a permanent network structure.
  • interactions which promote the formation of a polymer network include coulombic attraction in the case of polyelectrolyte network complexes, hydrogen bonding in the case of polyether:poly(carboxyvinyl) complexes or Van der Waals attractions in case of nonpolar polymers.
  • physical interactions such as entanglement, contribute to the interacting nature of these systems. Because of the nature of these interactions, interpolymer systems may possess unique synergistic properties that none of the constituent polymers alone exhibit.
  • a preformed polymer may be used as a template in the polymerization of a second polymer. It has been established that the rate of polymerization and the polymerization molecular weight of poly(acrylic acid) is affected by the template polymer used for template polymerization.
  • Adachi et al. Polymer J. 14(12):985-992 (1982) report that polymerization of acrylic acid in the presence of polyoxyethylene resulted in an interpolymer complex having a ladder-like structure in which each oxyethylene residue forms a hydrogen bond with an acrylic acid residue.
  • polyme ⁇ polymer complexes provides a stable composition of two or more polymers.
  • polymer network compositions which possess all the properties of constituent polymers, but which have improved stability and compatibility over simple blends of the constituent polymers. It is also desirable to provide polymer network compositions in which a synergistic effect between the constituent polymers impart properties not possessed by the constituent polymers, either alone or in a simple blend.
  • Tanaka et al. (U.S. Patent No. 5,503,893) discloses a polymer network in which the interpolymer attractions are strong enough to permit a three-dimensional polymer network without the use of covalent crosslinking between the constituent polymers.
  • the polymer composition of Tanaka is a gel which exhibits a volume change in response to an external trigger.
  • Reversibly gelling solutions are known. Efforts have been directed to the developl ent of gelatinous drug delivery systems for topical applications and for ophthalmic delivery to the eye. 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.
  • thermosetting gel using poloxamers available commercially as Pluronic ® , which is described in U.S. Patent No. 4,188,373. Adjusting the concentration of the polymer gives the desired liquid-gel transition.
  • concentrations of the poloxamer of at least 15-20 % by weight are needed to produce a composition which exhibits such a transition at commercially or physiologically useful temperatures.
  • solutions containing 15-20 % by weight of responsive polymer are typically very viscous even under the lower viscosity state of responsiveness, so that these solutions can not fun ⁇ ion under conditions where low viscosity, free-flowing chara ⁇ eristics are required prior to transition.
  • these polymer concentrations are so high that the material itself may cause unfavorable intera ⁇ ions during use.
  • 5,252,318 reports reversible gelling compositions which are made up of physical blend of a pH-sensitive gelling polymer (such as a cross ⁇ linked polyacrylic acid) and a temperature-sensitive gelling polymer (such as methyl cellulose or block copolymers of polyoxyethylene and polyoxypropylene).
  • a pH-sensitive gelling polymer such as a cross ⁇ linked polyacrylic acid
  • a temperature-sensitive gelling polymer such as methyl cellulose or block copolymers of polyoxyethylene and polyoxypropylene.
  • compositions including Pluronic ® and Tetronic ® poloxamers commercially available forms of polyoxyethylene/polyoxypropylene block copolymer, commercially useful increases in viscosity (5- to 8-fold) upon a simultaneous change in temperature and pH are observed only at much higher polymer levels (> 12% by weight). See, Figs. 3-6 of Joshi et al.
  • WO 95/24430 published September 14, 1995, describes graft and block copolymers of component temerature-sensitive polymers and a pH-sensitive polymers.
  • the graft and/or block copolymers possess a lower critical solution temperature (LCS1) or cloud point between 20 °C and 40 °C at a pH of 6.0-8.0.
  • the LCST represents the temperature at which the polymer phase separates from the solvent. This results in an opaque or translucent mixture or suspension. In medical applications, particularly opthalmic applications, this undesirable.
  • the known systems which exhibit reversible gelation are limited in that they require large solids content and/or in that the increase in viscosity are less than 10- fold and/or exhibit a cloud point before viscosification.
  • the obje ⁇ s of the invention are achieved with a viscosifying polymer network containing an associating component capable of aggregating in response to an increase in temperature, and a solvophilic component which is linked to the associating component in a solvent.
  • the associating component may exhibit aggregation at a temperature where no macrophase separation occurs.
  • Both the associating and/or solvophilic components may be oligomers or polymers.
  • as associating component is an oligomer or polymer which will respond to a temperature change to change its degree of association and/or agglomeration.
  • the stimulus may be temperature, and additionally, pH, ionic concentration, solvent concentration, light, magnetic field, ele ⁇ rical field, pressure or other triggers commonly used to trigger a responsive gel material.
  • the aggregation is most commonly in the form of micelle formation, however, precipitation, labile crosslinking or other fa ⁇ ors may be contemplated as within the scope of the invention.
  • the solvophilic component is an oligomer or polymer which is linked to the associating component so that a copolymer network is formed.
  • the solvophilic component may be, but is not required to be, responsive in that it may also exhibit a change in conformation, upon a change in environmental stimulus.
  • the intera ⁇ ion of the solvophilic and associating components exhibits a synergistic effe ⁇ , which magnifies the effe ⁇ of the associating component in viscosifying and/or gelling the solution. It may also cause aggregation and/or micellation to occur under conditions which would show no apparent effect in the absence of the polymer network.
  • solvophilic as that term is used herein, it is meant a component which has an affinity for the solvent used in solvation of the polymer network.
  • the associating component may or may not show a change in viscosity in response to a change in temperature. However, if it does show a response in the absence of the solvophilic component, that response is qualitatively or quantitatively different. That is, the response is amplified or altered in the presence of the solvophilic components.
  • the viscosifying polymer network is formed by solvation of the linked associating and solvophilic components. Since a gel comprises a three-dimensional polymeric network containing a solvent, the liquid component makes up the responsive viscosifying polymer network.
  • the composition may of course include additional elements, such as are needed for the commercial purpose of the composition.
  • additives may have no beneficial or detrimental effe ⁇ on the polymer network (i.e., inert additives) but have a beneficial aspe ⁇ for the particular commercial application or formulation.
  • additives may have some detrimental effe ⁇ to the polymer network (i.e., compromising additives) but have a beneficial effe ⁇ or the particular commercial application or formulation.
  • polymer networks may represent a compromise between the requirements of the application or formulation and the requirements of the polymer network.
  • the novel intera ⁇ ion between the constituent polymers in the responsive viscosifying 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 associating component and about 0.01 to 20 wt% of the solvophilic component.
  • a typical reversibly gelling polymer network may advantageously be comprised of less than about 4 wt% of total polymer solids of which less than about 2 wt% is the associating component and less than about 2 wt% is the solvophilic component.
  • the balance is made of the aqueous-based solvent.
  • An exemplary associating component is a poloxamer having the formula (EO)(PO)(EO).
  • An exemplary solvophilic component is sodium acrylate.
  • the viscosifying polymer network is formed by polymerization of acrylic acid in the presence of the poloxamer followed by hydration and neutralization of the polyacrylic acid. The viscosity of the gel increases at least ten-fold with an increase in temperature of about 5°C.
  • gelation as that term is used herein, it is meant a drastic increase in the viscosity of the solution. Gelation is dependent on the initial viscosity of the solution, but typically a viscosity increase in the range of 5- to 100-fold, and preferably 10- to 100- fold, is observed in the present systems.
  • polyxamer a polymeric or oligomeric structure having a general formula of (P)) a (P_) b (P ⁇ ) a> where P, and P 2 represent two different poloxamer blocks.
  • Pj may be a poloxamer of the general formula (CH 2 CH 2 0) a , where a is in the range of 10-50 and P 2 may be a poloxamer of the general formula, (CHR,CHR 2 O) b , where Rj may be H or an alkyl group, R 2 may be an alkyl group, and where b is in the range of 50-70.
  • Other possible poloxamer combinations are contemplated within the scope of the invention.
  • Figure 1 is a graph of viscosity vs. temperature for a 1 wt%, 2 wt% and 3 wt% viscosifying polymer network aqueous composition of a triblock poloxamer/polyacrylic acid (1:1) at pH 7.0 measured at a shear rate of 0.44 sec '1 ;
  • Figure 2 is a graph of viscosity vs. pH for a 1 wt% viscosifying polymer network aqueous composition of a triblock poloxamer/polyacrylic acid (1:1) at pH 7.0 measured at a shear rate of 0.44 sec '1 ;
  • Figure 3 is a graph of viscosity vs. temperature for a 2 wt% viscosifying polymer network aqueous composition of a triblock poloxamer/polyacrylic acid (1:1) in sea water at pH 7.0 measured at a shear rate of 0.22 sec "1 ;
  • Figure 4 is a plot of endotherms for (a) 1 wt% Pluronic ® F127 and (b) 1 wt% viscosifying polymer network aqueous composition of Pluronic ® F127/polyacrylic acid
  • Figure 5 is a plot of viscosity vs. temperature for (a) a 1 wt% viscosifying polymer network aqueous composition of Pluronic ® F127/polyacrylic acid (1:1) and (b) a 1 wt% physical blend of Pluronic ® F127/polyacrylic acid (1:1) at pH 7.0 measured at a shear rate 0.22 sec" 1 ;
  • Figure 6 is a plot of viscosity vs. temperature for a 1 wt% viscosifying polymer network aqueous composition of Pluronic ® F108/ ⁇ olyacrylic acid (1:1) at pH 7.0 measured at a shear rate 2.64 sec '1 with a SC4-18 spindle;
  • Figure 7 is a plot of endotherms for 1 wt% viscosifying polymer network composition of Pluronic ® F108/polyacrylic acid (1:1);
  • Figure 8 is a plot of viscosity vs. temperature for a 1 wt% viscosifying polymer network aqueous composition of Pluronic ® F88/polyacrylic acid (1:1) at pH 7.0 measured at a shear rate 2.64 sec '1 with a SC4-18 spindle;
  • Figure 9 is a graph of the viscosity vs. temperature effe ⁇ for a viscosifying polymer network composition of 2 wt% Pluronic ® P104/polyacrylic acid (1:1) in deionized water at pH 7.0 measured at shear rate of 22 sec "1 using a SC4-25 spindle;
  • Figure 10 is plot of viscosity vs. temperature for a viscosifying polymer network composition of 2 wt% Pluronic ® F123/polyacrylic acid (1:1) at pH 7.0 measured at a shear rate of 22 sec "1 using a SC4-25 spindle;
  • Figure 11 is a plot of viscosity vs. temperature for 1 wt% viscosifying polymer network made of series of triblock copolymers and polyacrylic acid (1:1) in deionized water at a shear rate of 132 sec "1 ;
  • Figure 12 is plot of viscosity vs. temperature for a viscosifying polymer network composition of 2.5 wt% Pluronic ® F127/polyacrylic acid (1:1) prepared in (a) deionized water and (b) 0.5M NaCl solution;
  • Figure 13 is plot of viscosity vs. temperature for a viscosifying polymer network composition of 2 wt% Pluronic ® F127/poly (acrylic acid-co-methacrylic acid) (1:1) in deionized water at a shear rate of 22 sec "1 ;
  • Figure 14 is plot of viscosity vs. temperature for a viscosifying polymer network composition of 2.5 wt% Pluronic ® F88/polyacrylic acid (1:1) in deionized water and at 5000 psi;
  • Figure 15 is a plot of viscosity vs. temperature for a viscosifying polymer network composition of a 2 wt% polyethyleneglycol mono(nonylphenylether)/ polyacrylic acid (1:1) at pH 7.0 at a shear rate of 2.64 sec '1 ;
  • Figure 16 is a plot showing the release of hemoglobin from a polymer network composition of the invention.
  • Figure 17 is a plot showing the release of lysozyme from a polymer network composition of the invention.
  • Figure 18 is a plot showing the release of insulin from a polymer network composition of the invention.
  • Figure 19 is a plot showing the release of timolol from (a) a control; (b) a 2 wt% polymer network composition and (c) a 3 wt% responsive polymer network composition of the invention;
  • Figure 20 is a plot of viscosity vs. temperature for a polymer network composition (a) before and (b) after sterilization by autoclave;
  • Figure 21 is a plot of viscosity vs. temperature for a 5 wt% polymer network prepared from polyacrylamide and Pluronic F127 (1:1) after standing for 10 days
  • Figure 22 is plot of viscosity vs. temperature for a polymer network composition of 5 wt% Pluronic ® F127/poly (acrylamide) (1:1) in deionized water at a shear rate of 2 sec '1 (a) after standing one day and (b) after standing six days;
  • Figure 23 is plot of viscosity vs. temperature for a polymer network composition of 20 wt% Pluronic ® F127/poly (acrylamide) (1:1) in deionized water at a shear rate of 0.066 sec "1 after standing 12 days;
  • Figure 24 is a plot of viscosity vs. temperature for an oil-free moisturizing formulation prepared from (a) polymer network composition of the invention and (b) a conventional oil-in-water formulation;
  • Figure 25 is a plot of (a) viscosity v. temperature and (b) abosrobance v. temperature for a 2 wt% viscosifying polymer network prepared from poly(acrylic acid) and Pluronic ® F127 (1:1); and
  • Figure 26 is a plot of (a) viscosity v. temperature and (b) abosrobance v. temperature for a 2 wt% viscosifying polymer network prepared from poly(acrylic acid) and Pluronic ® L92 (1:1).
  • the present invention is dire ⁇ ed to a novel reversibly gelling polymer network.
  • the polymer network advantageously contains less than about 20 wt% polymer solids, and preferably less than about 4 wt% polymer solids and exhibits an at least five-fold increase in viscosity with an increase of temperature of about 5°C.
  • the responsive polymer network composition according to the invention includes an associating component and a solvophilic component. The two polymer phases are linked with one another on a molecular level, typically through a dire ⁇ covalent bond, although linkages through atoms or other moieties is contemplated.
  • Exemplary concentrations of the constituent polymers range from about 10 wt% to about 75 wt% for the associating component and from about 90 wt% to about 25 wt% for the solvophilic polymer.
  • a viscosifying polymer network of the present invention is a special type of polymer-polymer composition, in which the two or more polymer phases are covalently linked, although other associating mechanisms, such as hydrogen bonding and van der Waals force may also be present.
  • the interacting nature of the two (or more) polymer phases provide a stable miscible composition, irrespe ⁇ ive of the immiscibility of the constituent polymers, and unique properties. Such stability and properties may be attributed to specific intera ⁇ ions of the constituent polymers.
  • the associating component undergoes a change in conformation in solution.
  • One type of associating component is a temperature-sensitive aggregating polymer.
  • a temperature-sensitive aggregating polymer undergoes conformational changes and changes to the critical micelle concentration as a fun ⁇ ion of temperature. The polymer will change from an open, non-aggregated form to a micellar, aggregated form with changes in temperature.
  • the solvophilic component may be a polymer which is capable of ionization with a change in ionic strength of the solution. Changes in ionic strength may be accomplished by a change in pH or by a change in salt concentration. Changes to the ionic state of the polymer causes the polymer to experience attra ⁇ ive (collapsing) or repulsive (expanding) forces. Ionization is not required, however, and the solvophilic component may be neutral or uncharged.
  • the associating component of the polymer network exhibits a reversible gelation upon exposure to a change in temperature.
  • the solvophilic component of the polymer network may also exhibit a reversible gelation in response to one or more environmental changes.
  • the gelation may occur in response to an indire ⁇ environmental trigger, for example, light irradiation or ele ⁇ ric field application which generates an increase in temperature.
  • gelation may be triggered by a change in pH, ionic strength or solvent composition.
  • Responsive polymer network gel compositions which exhibit a reversible gelation at body temperature (32-37 °C) and/or at physiological pH (ca. pH 7.0-7.5) are particularly preferred for certain medical and pharmaceutical uses.
  • Responsive polymer network compositions which exhibit a reversible gelation at 70°C or above are particularly preferred for oil field applications. Yet it is within the scope of the present invention for reversible gelation to occur at much higher or lower temperatures or pHs or in response to other stimuli.
  • the polymer network exhibits flow properties of a liquid at about room temperature, yet rapidly thicken 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 exposure to the particular environmental trigger.
  • the responsive polymer network of the present invention exhibit gelation even at very low polymer concentrations.
  • aqueous responsive polymer network compositions of about 0.5 wt% responsive component and about 0.5 wt% ionizing polymer will gel when exposed to a critical temperature or pH.
  • the low polymer concentration in the aqueous compositions of the present invention provide clear, colorless gels, both before and after viscosification, making them particularly well-suited for a variety of applications.
  • very little residue is formed upon evaporation which may be important in some applications, such as administration of ophthalmic drugs to the eyes or 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.
  • the associating component of the present invention may be any polymer which forms aggregates as a fun ⁇ ion of temperature.
  • the associating component typically possess regions, which are themselves sub-components of hydrophilic and hydrophilic chara ⁇ er.
  • the associating component may be linear or branched.
  • a nonionic surfa ⁇ ant due to its hydrophilic and hydrophilic chara ⁇ er, may be suitable for use in the invention.
  • Suitable associating components include poloxamers, such as block copolymers of different oxyalkylene units. At least one polyoxyalkylene unit should have associating chara ⁇ eristics and at least one polyoxyalkylene unit should have hydrophilic chara ⁇ eristics.
  • a poloxamer of polyoxyethylene and polyoxypropylene may be used in a preferred embodiment of the invention.
  • Another suitable responsive component includes Pluronic ® poloxamer (BASF) having the general formula (POE) a (POP) b (POE) c , where POP is polyoxypropylene and represents the associating portion of the polymer and POE is polyoxyethylene and represents the hydrophilic portion of the polymer.
  • Pluronic ® (BASF) triblock polymers are commercially available for a and c in the range of about 16 to 48 and b ranging from about 54-62.
  • alkyl poloxamers which are a product of alcohol condensation reactions with a terminal alkyl or arylalkyl group.
  • the alkyl group should have associating chara ⁇ er, such as butyl, hexyl and the like.
  • An alkyl poloxamer may have the general formula R-(OCH 2 CH 2 ) n OH, where R is a nonpolar pendant group such as alkyl and arylalkyl and the like, and n is in the range of 5-1000.
  • a preferred alkylpoloxamer is polyethyleneglycol mono(nonylphenyl)ether.
  • Still other exemplary responsive components may include cellulosic, cellulose ethers and guar gums which possess hydrophobic and hydrophilic regions along the polymer backbone which permit aggregation behavior.
  • One or more associating components may be used in the responsive polymer network composition of the present invention.
  • Another type of solvophilic components is an ionizable polymer. These materials typically are responsive to changes in pH and/or ionic strength.
  • the ionizable polymers of the present invention include linear, branched and/or crosslinked polymers. Of particular interest are carboxyvinyl polymers of monomers such as acrylic acid, methacrylic acid, ethac-ylic acid, phenyl acrylic acid, pentenoic acid and the like.
  • Polyacrylic acid is a preferred carboxyvinyl polymer.
  • One or more poly(carboxyvinyl) polymers may be used in the responsive polymer network compositions of the present invention.
  • Acrylamides or substituted acrylamides are also preferred embodiments.
  • Copolymers such as by way of example only, copolymers of acrylic acid and methacrylic acid, are also contemplated.
  • Naturally occurring polymers such as chitosan or hyaluronic acids are also possible as solvophilic polymers since they are capable of forming an ionized network as polymers or copolymers of other solvophilic polymers.
  • covalent cross-linking within an particular polymer component of the responsive polymer network is not required in order to observe gelation at low solids contents, such as less than 20 wt% or preferably less than about 10 wt%, or more preferably less than about 5 wt% or most preferably less than about 2.5 wt%.
  • This is in contrast to Joshi et al. (U.S. Patent No. 5,252,318) which discloses the use of at least one crosslinked polymer in the formation of their reversibly viscosifying blends.
  • 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 dire ⁇ 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.
  • the fun ⁇ ioning of a component as the associating or solvophilic component may be dependent upon the specific environmental trigger being considered.
  • a component as the associating or solvophilic component may be dependent upon the specific environmental trigger being considered.
  • the poly(acrylic acid)/EO/PO/EO system when temperature is the trigger, EO/PO/EO is the associating component, however at pH of 2-5, where the polymer is completed protonated, the poly(acrylic acid) may be the associating component.
  • Fig. 1 is a graph of viscosity vs. temperature for 1%, 2% and 3% aqueous responsive polymer network compositions comprising a poloxamer of the general formula (POP) (POE) (POP) and polyacrylic acid (1:1), which has been hydrated and neutralized.
  • POP general formula
  • POP polyacrylic acid
  • Fig. 2 is a graph of viscosity vs. pH for a responsive polymer network composition comprising 1 wt% poloxamer/polyacrylic acid (1:1), hydrated and neutralized, taken on a Brookfield viscometer at a shear rate of 0.11 sec '1 at 37 °C.
  • the solutions had an initial viscosity of about 15 cP and exhibited a dramatic increase in viscosity to gel point at about pH 5.0.
  • Fig. 3 Another possible application of the observed viscosifying phenomenon is illustrated in Fig. 3 where the viscosifying effect of temperature is shown in a 2 wt% responsive polymer network composition comprising a poloxamer/polyacrylic acid in sea water.
  • Sea water is represented by a synthetic formulation (NaCl, 23.84 g/1; CaCl 2 , 0.93 g/1; MgCl 2 6H 2 O, 10.76 g/1; Na 2 S0 4 , 4.29 g/1; NaHCO j , 0.205 g/1) in water.
  • a viscosifying effe ⁇ is observed at temperatures higher than 70 "C which is relevant for oil field applications.
  • the responsive polymer network of the invention preferably is prepared by initiation of polymerization of one component, i.e., the solvophilic component, of the polymer network in the presence of the fully formed second component, i.e., the associating component.
  • a general method of making the responsive polymer network compositions generally involves solubilization of the associating component in a monomer capable or a concentrated monomer solution of forming a solvophilic component. The monomer is then polymerized to the solvophilic component. 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.
  • the fully formed associating component is linked to or grafted onto the developing polymer chain of the first solvophilic component.
  • the terminal end of the associating and/or the solvophilic component may contain a reactive moiety, which is capable of reacting with and linking to the respe ⁇ ive end of the complementary polymer component.
  • Copolymerizations may take place by proton abstraction from a secondary or tertiary carbon upon free radical formation or ⁇ -irradiation.
  • the copolymerizations proceeds via the following scheme:
  • Rea ⁇ ions in Scheme 1 are exemplified by propylene oxide residue, but they are equally applicable to other alkylene oxides.
  • rea ⁇ ion (3) in presence of vinyl monomers (typically, acrylic acid) leads to the grafting of growing poly(acrylic acid) chain onto the polyether backbone with the possibility of crosslinking, resulting in the appearance of a "classical" three-dimensional gel stru ⁇ ure.
  • These gel structures may form aggregates, which scatter light even at very low concentrations far below gelation temperatures.
  • the grafting of the associating component onto the growing solvophilic chain is random.
  • the degree of grafting may be adjusted by sele ⁇ ion of the alkylene oxide (ease of free radical formation) and the quantity and type of free radical initiation used.
  • the polyoxyalkylene chains such as those of poloxamer polymers are known to be substantially unfolded and free-flowing at temperatures below a critical temperature of gelling. Above this temperature, the polyoxyalkylene chains have been demonstrated to form agglomerations due to the temperature-dependent association of the associating component of the polymer. See, Atwood et al. Intl. J. Pharm. 26:25-333 (1985), herein incorporated by reference. The polymer chains fold in on themselves due to associating intera ⁇ ions among associating chain blocks.
  • the polymer morphology of the solvophilic polymer imparts stability to the polymer network.
  • the water-soluble solvophilic component improves the stability of the polymer network in aqueous solution, and discourages phase separation.
  • linkage of the solvophilic and associating components increases the effe ⁇ ive size and molecular weight of the polymer network. This amplifies the aggregation effe ⁇ of the associating component.
  • Adachi et al. which is incorporated herein by reference, report that the polymerization of acrylic acid in the presence of dilute polyoxyethylene solution resulted in an interpolymer network having a ladder-like stru ⁇ ure in which each oxyethylene residue forms a hydrogen bond with an acrylic acid residue.
  • template-formed polyacrylic acids of this type may contribute to the bonding observed in these new responsive polymer networks.
  • the properties of the responsive polymer network gel composition may be modified by varying the components and/or the microstru ⁇ ure of the polymer network.
  • use of different polymerization initiators in the formation of the constituent stru ⁇ ural component of the responsive polymer network gel was found to decrease the temperature for onset of viscosity by 5°C (see, Example 12).
  • different responsive components have been found to exhibit different reversible gelation temperatures. For example, see Examples 18-19.
  • solvation of a responsive polymer network in a 0.5 M NaCl solution (as compared to distilled water) will result in a 10 °C decrease in the temperature of gelation.
  • the ionic strength of the aqueous solution may be used to modify the properties of the composition (see, Example 8).
  • thermothickening polymer systems are in the prior art; however, these systems typically operate at much higher polymer concentrations, exhibit cloud point transitions or require a complicated multistep solution synthesis.
  • PEO-PPO-PEO block copolymers Alexandritis, et al. Colloids Surf., 96:1 (1995)
  • other block- and graft-copolymers such as PEO-PPO-PEO block copolymers-g- polyacryliamide (de Vos, et al. Polymer, 35:2644 (1994)), and PEO-g-poly(acrylic acid) (Hourdet, et l. Polymer, 35:2624 (1994); L'Allouret, et al. Colloid Polym. Sci., 273:1163 (1995)).
  • Thermoassociation is attributed to aggregation of the corresponding grafts or blocks into relative associating microdomains which effe ⁇ ively crosslink adjacent polymer chains.
  • aggregation results from a balance between hydrogen bonding, ele ⁇ rostatic intera ⁇ ions, and associating effe ⁇ s in aqueous systems.
  • Specific orientations of water that arise upon polymer dissolution lead to increasingly unfavorable entropic ( ⁇ S) contributions to the free energy of mixing as the temperature is raised. This tendency overcomes the favorable enthalpy ( ⁇ H) changes due to the formation of hydrogen bonds between polymer and solvent.
  • Pluornic L-92 a triblock copolymer with a relatively major hydrophobic component (MW of the poly(propylene oxide) se ⁇ ion of the block copolymer is 2700, weight percentage of ethylene oxide in the copolymer is only 20%, nominal total molecualr weight is 3650), a very marked cloudiness is observed that is followed by gelation (Figs. 26(a) and (b)).
  • Fig. 4 shows endotherms of (a) 1% Pluronic ® F127 and (b) 1% responsive polymer network (Pluronic ® F127/polyacrylic acid 1:1) obtained using a MCS
  • Pluronic ® F127 is a triblock polymer made up of ethylene oxide (EO) and propylene oxide (PO) blocks and having the general formula (EO)(PO)(EO), where 70 wt% of the polymer is EO.
  • EO ethylene oxide
  • PO propylene oxide
  • Broad or sharp endothermic peaks are seen at chara ⁇ eristic temperature of 29°C which coincides with the onset of gelation in the responsive polymer network composition (see, Fig. 1). The peaks are measured to have enthalpy value of 1.26 cal/g.
  • a general method of making the responsive polymer network compositions of the present invention comprises solubilization of the associating component in a monomer capable of forming a solvophilic component or formation of a melt of the component materials.
  • Solvophilic components suitable for use in the method are those which exhibit expansion and contra ⁇ ion in response to a change in ionic strength.
  • the monomer is polymerized to the solvophilic component.
  • 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.
  • free radical initiators may be used according to the invention, including, but in no way limited to ammonium persulfate, benzoin ethyl ether, l,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 solvophilic component may be dissolved in a monomer/water mixture instead of pure monomer.
  • a nonpolar solvent such as heptane or hexane
  • 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.
  • a initiator or irradiation i.e., addition of a initiator or irradiation
  • Such a method may be particularly desirable to provide a heat sink for the heat generated in the exothermic polymerization rea ⁇ ion.
  • the polymer network compositions of the present invention may be utilized for a wide variety of pharmaceutical applications.
  • an effe ⁇ ive amount of the desired pharmaceutical agent is incorporated into the aqueous responsive polymer network composition of the present invention.
  • the sele ⁇ ed compound is soluble in water which will readily lend itself to a homogeneous dispersion through out the responsive polymer network composition. It is also preferred that the compound is nonrea ⁇ ive with the responsive polymer network composition. For materials which are not soluble with the responsive polymer network composition, it is also within the scope of the invention to disperse or suspend powders throughout the responsive polymer network composition. It will also be appreciated that many applications will require a sterile environment.
  • the aqueous responsive polymer network compositions of the present invention may be prepared under sterile conditions.
  • An additional feature of the intera ⁇ ing polymer gels of the invention is that they may be prepared from constituent polymers that have known accepted toxicological profiles.
  • the intera ⁇ ing polymer gel may be prepared from polymers which already have FDA-approval.
  • Exemplary drugs or therapeutics delivery systems which may be administered using the aqueous responsive polymer network compositions of the invention include, but are in no way limited to, mucosal therapies, such as esophageal, otic, re ⁇ al, buccal oral, vaginal, and urological applications; topical therapies, such as wound care, skin care and teat dips; and intravenous/subcutaneous therapies, such as intramuscular, intrabone (e.g., joints), spinal and subcutaneous therapies, tissue supplementation, adhesion prevention and parenteral drug delivery.
  • mucosal therapies such as esophageal, otic, re ⁇ al, buccal oral, vaginal, and urological applications
  • topical therapies such as wound care, skin care and teat dips
  • intravenous/subcutaneous therapies such as intramuscular, intrabone (e.g., joints), spinal and subcutaneous therapies, tissue supplementation, adhesion prevention and parenteral drug delivery.
  • intravenous/subcutaneous therapies such as intramuscular, intrabone
  • the biologically a ⁇ ive compounds that may be loaded into the polymer networks of the present invention are any substance having biological a ⁇ ivity, including proteins, polypeptides, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, and synthetic and biologically engineered analogs thereof.
  • the drug is one that has already been deemed safe and effective for use by the appropriate governmental agency or body.
  • drugs for human use listed by the FDA under 21 C.F.R. 330.5, 331 through 361; 440-460; drugs for veterinary use listed by the FDA under 21 C.F.R. 500-582, incorporated herein by reference are all considered acceptable for use in the present novel polymer networks. Drugs that are not themselves liquid at body temperature can be incorporated into polymers, particularly gels.
  • peptides and proteins which may normally be lysed by tissue-a ⁇ ivated enzymes such as peptidases, can be passively prote ⁇ ed in gels as well. See, Gehrke et al. Proceed. Intern. Symp. Control. Rel. Bioa ⁇ . Mater., 22:145 (1995).
  • biologically active compound includes pharmacologically a ⁇ ive substances that produce a local or systemic effect in animals, plants, or viruses.
  • the term thus means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease or in the enhancement of desirable physical or mental development and conditions in an animal, plant, or virus.
  • animal used herein is taken to mean mammals, such as primates, including humans, sheep, horses, cattle, pigs, dogs, cats, rats, mice; birds; reptiles; fish; inse ⁇ s; arachnids; protists (e.g. protozoa); and prokaryotic ba ⁇ eria.
  • plant means higher plants (angiosperms, gymnosperms), fungi, and prokaryotic blue-green "algae” ( i.e. cyanoba ⁇ eria).
  • the pharmaceutically active compound may be any substance having biological activity, including proteins, polypeptides, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, and synthetic and biologically engineered analogs thereof.
  • protein is art-recognized and for purposes of this invention also encompasses peptides.
  • the proteins or peptides may be any biologically a ⁇ ive protein or peptide, naturally occurring or synthetic.
  • proteins include antibodies, enzymes, steroids, growth hormone and growth hormone-releasing hormone, gonadotropin-releasing hormone, and its agonist and antagonist analogues, somatostatin and its analogues, gonadotropins such as luteinizing hormone and follicle-stimulating hormone, peptide-T, thyrocalcitonin, parathyroid hormone, glucagon, vasopressin, oxytocin, angiotensin I and II, bradykinin, kallidin, adrenocorticotropic hormone, thyroid stimulating hormone, insulin, glucagon and the numerous analogues and congeners of the foregoing molecules.
  • gonadotropins such as luteinizing hormone and follicle-stimulating hormone, peptide-T, thyrocalcitonin, parathyroid hormone, glucagon, vasopressin, oxytocin, angiotensin I and II, bradykinin, kallidin, a
  • Classes of pharmaceutically a ⁇ ive compounds which can be loaded into responsive polymer network compositions of the invention include, but are not limited to, anti-AIDS substances, anti-cancer substances, antibiotics, immunosuppressants (e.g. cyclosporine) anti-viral substances, enzyme inhibitors, neurotoxins, opioids, hypnotics, antihistamines, lubricants tranquilizers, anti-convulsants, muscle relaxants and anti-Parkinson substances, anti-spasmodics and muscle contractants, miotics and anti- cholinergics, anti-glaucoma compounds, anti-parasite and/or anti-protozoal compounds, anti-hypertensives, analgesics, anti-pyretics and anti-inflammatory agents such as NSAIDs, local anesthetics, ophthalmics, prostaglandins, anti-depressants, anti-psychotic substances, anti-emetics, imaging agents, specific targeting agents, neurotransmitters, proteins, cell response modifiers, and vaccines.
  • AIDS Deficiency Syndrome
  • examples of such substances include CD4, 3'-azido-3'-deoxythymidine (AZT), 9-(2-hydroxyethoxymethyl)-guanine acyclovirO, phosphonoformic acid, 1-adamantanamine, peptide T, and 2', 3' dideoxycytidine.
  • Anti-cancer substances are substances used to treat or prevent cancer. Examples of such substances include methotrexate, cisplatin, prednisone, hydroxyprogesterone, medroxyprogesterone acetate, megestrol acetate, diethylstilbestrol, testosterone propionate, fluoxymesterone, vinblastine, vincristine, vindesine, daunorubicin, doxorubicin, hydroxyurea, procarbazine, aminoglutethimide, mechlorethamine, cyclophosphamide, melphalan, uracil mustard, chlorambucil, busulfan, carmustine, lomusline, dacarbazine (D ⁇ C: dimethyltriazenomidazolecarboxamide), methotrexate, fluorouracil, 5-fluorouracil, cytarabine, cytosine arabinoxide, mercaptopurine, 6-mercaptopurine, thioguanine.
  • Antibiotics are art recognized and are substances which inhibit the growth of or kill microorganisms. Antibiotics can be produced synthetically or by microorganisms. Examples of antibiotics include penicillin, tetracycline, chloramphenicol, minocycline, doxycycline, vanomycin, bacitracin, kanamycin, neomycin, gentamycin, erythromicin and cephalosporins.
  • Anti-viral agents are substances capable of destroying or suppressing the replication of viruses.
  • Examples of anti-viral agents include a-methyl-P-adamantane methylamine, l,-D-ribofuranosyl-l,2,4-triazole-3 carboxamide,
  • Enzyme inhibitors are substances which inhibit an enzymatic rea ⁇ ion.
  • enzyme inhibitors include edrophonium chloride, N-methylphysostigmine, neostigmine bromide, physostigmine sulfate, tacrine HCl, tacrine,l-hydroxy maleate, iodotubercidin, p-bromotetramisole, l ⁇ -(alpha-diethylaminopropionyl)- phenothiazine hydrochloride, calmidazolium chloride, hemicholinium-3, 3,5-dinitrocatechol, diacylglycerol kinase inhibitor I, diacylglycerol kinase inhibitor II, 3-phenylpropargylamine, N 6 -monomethyl-L-arginine acetate, carbidopa,
  • 2-cyclooctyl-2-hydroxyethylamine hydrochloride 2,3-dichloro-a-methylbenzylamine (DCMB), 8,9-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine hydrochloride, p-aminoglutethimide, p-aminoglutethimide tartrate,R(+)-, p-aminoglutethimide tartrate,S(-)-, 3-iodotyrosine, alpha-methyltyrosine,L-, alpha -methyltyrosine,D L-, acetazolamide, dichlorphenamide, 6-hydroxy-2-benzothiazolesulfonamide, and allopurinol.
  • DCMB 2,3-dichloro-a-methylbenzylamine
  • DCMB 2,3-dichloro-a-methylbenzylamine
  • Neurotoxins are substances which have a toxic effe ⁇ on the nervous system, e.g. nerve cells.
  • Neurotoxins include adrenergic neurotoxins, cholinergic neurotoxins, dopaminergic neurotoxins, and other neurotoxins.
  • adrenergic neurotoxins include N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride.
  • cholinergic neurotoxins include acetylethylcholine mustard hydrochloride.
  • dopaminergic neurotoxins include 6-hydroxydopamine HBr, l-methyl-4-(2-methylphenyl)-l,2,3,6- tetrahydro-pyridine hydrochloride, l-methyl-4-phenyl-2,3- dihydropyridinium perchlorate, N-methyl-4-phenyl-l,2,5,6- tetrahydropyridine HCl, l-methyl-4-phenylpyridinium iodide.
  • Opioids are substances having opiate like effects that are not derived from opium.
  • Opioids include opioid agonists and opioid antagonists.
  • Opioid agonists include codeine sulfate, fentanyl citrate, hydrocodone bitartrate, loperamide HCl, morphine sulfate, noscapine, norcodeine, normorphine, thebaine.
  • Opioid antagonists include nor-binaltorphimine HCl, buprenorphine, chlornaltrexamine 2HC1, funaltrexamione HCl, nalbuphine HCl, nalorphine HCl, naloxone HCl, naloxonazine, naltrexone HCl, and naltrindole HCl.
  • Hypnotics are substances which produce a hypnotic effe ⁇ .
  • Hypnotics include pentobarbital sodium, phenobarbital, secobarbital, thiopental and mixtures, thereof, heterocyclic hypnotics, dioxopiperidines, glutarimides, diethyl isovaleramide, a-bromoisovaleryl urea, urethanes and disulfanes.
  • Antihistamines are substances which competitively inhibit the effe ⁇ s of histamines. Examples include pyrilamine, chlorpheniramine, tetrahydrazoline, and the like.
  • Lubricants are substances that increase the lubricity of the environment into which they are delivered.
  • biologically a ⁇ ive lubricants include water and saline.
  • Tranquilizers are substances which provide a tranquilizing effe ⁇ .
  • Examples of tranquihzers include chloropromazine, promazine, fluphenzaine, reserpine, deserpidine, and meprobamate.
  • Anti-convulsants are substances which have an effe ⁇ of preventing, reducing, or eliminating convulsions. Examples of such agents include primidone, phenytoin, valproate, Chk and ethosuximide.
  • Muscle relaxants and anti-Parkinson agents are agents which relax muscles or reduce or eliminate symptoms associated with Parkinson's disease. Examples of such agents include mephenesin, methocarbomal, cyclobenzaprine hydrochloride, trihexylphenidyl hydrochloride, levodopa/carbidopa, and biperiden.
  • Anti-spasmodics and muscle contra ⁇ ants are substances capable of preventing or relieving muscle spasms or contra ⁇ ions.
  • examples of such agents include atropine, scopolamine, oxyphenonium, and papaverine.
  • Miotics and anti-cholinergics are compounds which cause bronchodilation. Examples include echothiophate, pilocarpine, physostigmine salicylate, diisopropylfluorophosphate, epinephrine, neostigmine, carbachol, methacholine, bethanechol, and the like.
  • Anti-glaucoma compounds include betaxalol, pilocarpine, timolol, timolol salts, and combinations of timolol, and/or its salts, with pilocarpine.
  • Anti-parasitic, -protozoal and -fungals include iverme ⁇ in, pyrimethamine, trisulfapyrimidine, clindamycin, amphotericin B, nystatin, flucytosine, natamycin, and miconazole.
  • Anti-hypertensives are substances capable of countera ⁇ ing high blood pressure. Examples of such substances include alpha-methyldopa and the pivaloyloxyethyl ester of alpha-methyldopa.
  • Analgesics are substances capable of preventing, reducing, or relieving pain.
  • Examples of analgesics include morphine sulfate, codeine sulfate, meperidine, and nalorphine.
  • Anti-pyretics are substances capable of relieving or reducing fever and anti-inflammatory agents are substances capable of countera ⁇ ing or suppressing inflammation.
  • anti-inflammatory agents include aspirin (salicylic acid), indomethacin, sodium indomethacin trihydrate, salicylamide, naproxen, colchicine, fenoprofen, sulindac, diflunisal, diclofenac, indoprofen and sodium salicylamide.
  • Local anesthetics are substances which have an anesthetic effe ⁇ in a localized region.
  • anesthetics include procaine, lidocain, tetracaine and dibucaine.
  • Ophthalmics include diagnostic agents such as sodium fluorescein, rose bengal, methacholine, adrenaline, cocaine, and atropine.
  • Ophthalmic surgical additives include alpha-chymotrypsin and hyaluronidase.
  • Prostaglandins are art recognized and are a class of naturally occurring chemically related, long-chain hydroxy fatty acids that have a variety of biological effe ⁇ s.
  • Anti-depressants are substances capable of preventing or relieving depression.
  • Examples of anti-depressants include imipramine, amitriptyline, nortriptyline, protriptyline, desipramine, amoxapine, doxepin, maprotiline, tranylcypromine, phenelzine, and isocarboxazide.
  • Anti-psychotic substances are substances which modify psychotic behavior. Examples of such agents include phenothiazines, butyrophenones and thioxanthenes.
  • Anti-emetics are substances which prevent or alleviate nausea or vomiting.
  • An example of such a substance includes dramamine.
  • Imaging agents are agents capable of imaging a desired site, e.g. tumor, in vivo.
  • imaging agents include substances having a label which is dete ⁇ able in vivo, e.g. antibodies attached to fluorescent labels.
  • the term antibody includes whole antibodies or fragments thereof.
  • Specific targeting agents include agents capable of delivering a therapeutic agent to a desired site, e.g. tumor, and providing a therapeutic effect.
  • Examples of targeting agents include agents which can carry toxins or other agents which provide beneficial effe ⁇ s.
  • the targeting agent can be an antibody linked to a toxin, e.g. ricin A or an antibody linked to a drug.
  • Neurotransmitters are substances which are released from a neuron on excitation and travel to either inhibit or excite a target cell.
  • Examples of neurotransmitters include dopamine, serotonin, q-aminobutyric acid, norepinephrine, histamine, acetylcholine, and epinephrine.
  • Cell response modifiers are chemota ⁇ ic fa ⁇ ors such as platelet-derived growth fa ⁇ or (PDGF).
  • Other chemotactic fa ⁇ ors include neutrophil-a ⁇ ivating protein, monocyte chemoattrattant protein, macrophage-inflammatory protein, platelet fa ⁇ or, platelet basic protein, and melanoma growth stimulating a ⁇ ivity; epidermal growth fa ⁇ or, transforming growth fa ⁇ or (alpha), fibroblast growth fa ⁇ or, platelet-derived endothelial cell growth fa ⁇ or, insulin-like growth fa ⁇ or, nerve growth fa ⁇ or, and bone growtbJcartilage-inducing fa ⁇ or (alpha and beta), or other bone morphogenetic protein.
  • cell response modifiers are the interleukins, interleukin inhibitors or interleukin receptors, including interleukin 1 through interleukin 10; interferons, including alpha, beta and gamma; hematopoietic fa ⁇ ors, including erythropoietin, granulocyte colony stimulating fa ⁇ or, macrophage colony stimulating fa ⁇ or and granulocyte-macrophage colony stimulating fa ⁇ or; tumor necrosis fa ⁇ ors, including alpha and beta; transforming growth fa ⁇ ors (beta), including beta-1, beta-2, beta-3, inhibin, and a ⁇ ivin; and bone morphogenetic proteins.
  • interleukins interleukin inhibitors or interleukin receptors, including interleukin 1 through interleukin 10
  • interferons including alpha, beta and gamma
  • hematopoietic fa ⁇ ors including erythropoie
  • aqueous responsive polymer network composition of the present invention is suited for application under a variety of physiological conditions, and in particular is well-suited for transmucosal applications, a wide variety of pharmaceutical agents may be incorporated into and administered from the responsive polymer network composition.
  • routes of delivery include, but are not limited to, opthalmic, otic, nasal, buccal, sublingual, inje ⁇ able, dermal, subdermal, oral, vaginal and re ⁇ al. These routes benefit from the responsive polymer network being a system that has reverse viscosification, bioadhesion, and emulsification propertes.
  • the responsive polymer network composition may be used as a liquid vehicle at ambient temperature, and after administration to the eye, the responsive polymer network would become viscous to facilitate the delivery of a ⁇ ives or act as an adjuvant for lubricity and hume ⁇ ancy.
  • the responsive polymer could be delivered as a spray to the nasal cavity which would then viscosify in place, and provide a film for coating the nasal mucosa.
  • the responsive polymer network compositions may be used as an enteric coating for tablets or as a suspension for delivery of a ⁇ ive agents that benefit from extended release through viscosification in the gastrointestinal tract.
  • typical formulations exhibit viscosity decreases at body temperature and exude out of the vaginal or rectal cavity. The increase in viscosity at body temperature that the responsive polymer network exhibits will help to prevent leakage.
  • the responsive polymer network composition may be used in a variety of applications where it is desired to change the viscosity of a liquid environment.
  • the responsive polymer network composition may be used to reversibly modify the viscosity of an article, device or composition, by incorporating an aqueous responsive polymer network composition comprised of about 0.01 to 20 wt%, and preferably about 0.1 to 5 wt%, of associating responsive component and about 0.01 to 20 wt%, and preferably about 0.1 to 5 wt%, of a solvophilic component capable of expansion and contraction as a fun ⁇ ion of ionic strength into the article, device or composition.
  • the aqueous composition exhibits at least a five-fold increase in viscosity upon gelation, and by reducing temperature, the composition exhibits at least a five-fold decrease in viscosity upon liquification.
  • Reversible Viscosification The reversible viscosification of the responsive polymer network family at elevated temperatures makes the materials ideal for a magnitude of fun ⁇ ions in several different fields.
  • One application would be in the industrial and automotive use of oils and lubricants.
  • Traditional lubricating produ ⁇ s tend to thin under high temperature conditions, often to the point where they become completely ineffe ⁇ ive in reducing fri ⁇ ion.
  • An oil or lubricant which contained the correct proportion of a reverse thermal gel would be just as effe ⁇ ive at high temperatures as at low temperatures, as the viscosifying effect of the responsive polymer network would countera ⁇ the thinning of the other constituents of the lubricant as the temperature rose above the responsive polymer network's transition temperature.
  • the responsive polymer network will have the ability to a ⁇ as a primary emulsifier without any (or with very little) addition of traditional surfa ⁇ ant.
  • the responsive polymer network will also a ⁇ as a stabilizer for oil-soluble ingredients that would conventionally need to be solubilized by oils in formulation.
  • the associating portion of the intera ⁇ ing penetrating network forms domains that a ⁇ as reservoirs for such materials.
  • the emulsification abilities of the responsive polymer network would allow a material to be maintained in a system for an indefinite period of time.
  • the emulsification could provide a barrier around the material.
  • An example would be a pigment or a dye in a mascara.
  • the emulsification abilities of the responsive polymer network could also provide a controlled diffusion from the material upon a ⁇ ivation. Two examples would be the continuous release of a fragrance in a deodorant or cologne, or the release of an a ⁇ ive ingredient such as an antiperspirant.
  • the responsive polymer network's ability to viscosify with increased temperature could provide a semi-permeable or impermeable barrier. In a cosmetic formulation, this feature would provide a prote ⁇ ive barrier or allow for a slow diffusion of other materials.
  • the responsive polymer network may also become increasingly rigid with increasing temperature and thereby create rigidity in cosmetics.
  • the responsive polymer network exhibits bioadhesive chara ⁇ eristics. In cosmetic formulations, the responsive polymer network would adhere to the skin or hair or hold other materials to the skin or hair.
  • the reversible gels of the invention could also have a significant benefit in cases where on wished to maintain or establish a viscosity property in a change from a cold (e.g., refrigerated) to a heated environment.
  • a cold e.g., refrigerated
  • Two examples are dripless ice cream (where the gel serves to add viscosity to the ice cream as it melts) and a repair system for the Alaska pipeline (where a joint might contain a liquid version of the gel which would viscosify in the event of an oil leak to keep oil from leaking, the oil being at an elevated temperature compared to the cold Alaskan environment).
  • the gel could also provide a dye to indicate that something had been exposed to too low a temperature.
  • a dye to indicate that something had been exposed to too low a temperature.
  • this dye could indicate, for example, that a material that changes state, i.e., crystallinity, has been frozen and therefore the change of state indicated by the change of color would be important.
  • the material can also be useful to help introduce a gel-like material into a space where a semi-solid material would be difficult to introduce.
  • a gel-like material For example, in capillary ele ⁇ rophoresis, it would be useful to introduce the separations material in a liquid form and then to gel it in situ, thereby greatly reducing the time required.
  • ele ⁇ rical and optical wires are often prote ⁇ ed by gels, and the gel of the present invention could help protect such wires by allowing field repair and coating in difficult to reach areas.
  • the ability to form a highly viscous solution reversibly may be especially useful in ele ⁇ rophoresis and other types of chromatography.
  • the material could be poured into columns or plates at low temperatures, warmed above the transition to produce a matrix with separation capabilities, and then cooled after separation for easy replacement of contaminated material and recovery of produ ⁇ s.
  • the second property of the responsive polymer network's can be viewed as an extension of the viscosifying effe ⁇ but has somewhat different applications. In the food industry for instance, this chara ⁇ eristic would be useful in the manufa ⁇ uring process.
  • the fast setting of the responsive polymer network could be utilized in the manufa ⁇ ure of hard candies where it would be useful to have the produ ⁇ take on more manageable handling properties quickly, before the slower process of hardening by cooling sets in.
  • the responsive polymer network's could be introduced into the candy formulation in appropriate amounts to cause tne candy to harden enough to be moved along in the manufa ⁇ uring process long before the candy has cooled enough to become solid and non-tacky on its own. This process might also introduce further desired properties in the end-produ ⁇ by making the candy slower melting and longer lasting.
  • the responsive polymer network might serve in binding, extrusion, molding, cementing, and modified coating applications.
  • An example of the use of the responsive polymer network as a binding agent would be in ceramics. In this case, the binding agent holds together the fine particles of the ceramic object until the firing process is complete.
  • the responsive polymer network is ideal for this application because it can be easily applied as a solution and will hold the particles in place until the object is fully fired, since it will begin to viscosify and bind particles as soon as the temperature is slightly elevated and will continue to do so even at the high temperatures involved in the firing process.
  • the system can also serve as a thixatrope or a viscosity modifying agent below gellation temperature.
  • the responsive polymer network solutions could be useful for sheet and fiber extrusion as well as molding processes, as they would supply the cohesion which is necessary prior to the completion of curing.
  • the reverse thermal gelation would be useful in any instance in which it would be desirable to have the cement set up quickly.
  • Exothermic rea ⁇ ions, such as cement curing would be particularly interesting because the heat generated would cause a significant thickening of the uncured cement.
  • the corre ⁇ amount of responsive polymer network would help the cement to set even before the curing process was complete.
  • the responsive polymer network solutions could be used in modified setups where the coating material is mixed with the responsive polymer network solution and applied to the surface to be coated.
  • the temperature could then be elevated above the transition temperature, firmly but temporarily fixing the coating in place. The temperature could then be further elevated to drive off the remaining water, leaving behind the smoothly coated material.
  • Another industrial application for the responsive polymer network family is in adhesive applications and pastes. In those instances where it is preferred that one have an adhesive which can be made to adhere and then easily reverse its properties, the responsive polymer network's could be ideal candidates.
  • a correctly formulated solution could be designed with the needed degree of strength and adherence when the responsive polymer network sets up above its transition temperature. The adhesion could then be reversed simply by reducing the temperature below the transition. Controlled Release.
  • the ability to provide controlled release of relatively small molecules, previously examined in detail for personal care and pharmaceutical applications, could also be applied to the agricultural and industrial fields.
  • a "plant food” solution applied to soil as a liquid at low temperature and allowed to viscosify at ground temperature, would provide prolonged release of nourishment to crops by significantly reducing runoff and isolating the nutrients around the roots of the plants.
  • the same principle could be exploited to provide a slow and continuous stream of any additive, slowing the rate of introdu ⁇ ion of the additive at elevated temperatures.
  • the release could be utilized in coating systems, cleaning systems, and manufa ⁇ uring processes in which it is desirable to keep the additive in physical proximity to other materials involved in the process, without allowing the total amount of additive to become involved in the system's activities at the time it is introduced.
  • the controlled release of materials is also very applicable to the food industries, where one could envision the use of controlled diffusion from the material above its transition temperature to provide a constant release of flavors and fragrances in the mouth.
  • the ability of the highly viscosified responsive polymer network to impede movement of large molecules could be utilized to produce "enzyme factories" where the enzyme is immobilized by the rigid structure, but substrate and product molecules are allowed to diffuse in and out of the matrix.
  • the ability of the responsive polymer network's to conform to any shape upon formation of the semi-solid state has applications in a variety of consumer produ ⁇ s.
  • the reversibly gelling polymer networks could be used in a variety of footwear applications, such as in the insoles (factory or aftermarket), ankle collar, tongue, etc. to give the wearer a custom fit and to enhance comfort and support. This could be incorporated into almost any type of footwear including athletic shoes (walking, running, cross training, basketball, tennis, golf, cieated, etc.) casual or dress shoes, slippers, sandals, hiking boots, work boots, ski boots, in line skates, ice skates, etc.
  • gels can also be used to provide conformable fit and support in a variety of different prote ⁇ ive gear and sporting goods applications such as helmets
  • Conformable gels could be used in health care applications like orthopedic devices, prosthetic appliances, denture plates, hearing aids, various braces (ankle, neck, knee, etc.), conformable padding for crutches, wheelchairs, casting bandaging, splints, etc.
  • conformable gels A variety of other consumer and industrial uses are also possible for these conformable gels. These would include women's brassieres, eyeglass and sunglass nose bridges and ear supports, seating and furniture (chairs, beds, sofas, car seats, baby seats etc.), headphones (aviation, prote ⁇ ive, studio, consumer audio), shoulder and hand rests for telephones, keyboards, etc., conformable toys and models, teething rings, and conformable packaging for shipping.
  • the applications will include all those where an increase in viscosity is advantageous.
  • the applications also include those where a controllable decrease in viscosity would also be advantageous, such as underbalanced drilling.
  • the polymer system would allow good gas entrainment inside the well, which would help maintain a homogeneous density and uniform pressure throughout the well. While at the surface the decrease in viscosity would allow for good separation of the gases and particulate (cuttings), allowing for a cleaner mud to be pumped back into the hole.
  • the polymer system would have the properties of Xantham gum while in the well without the negative property of being a food source for microbial growth and solid and gas entrainment at the surface. Also, the current fluids for underbalanced drilling are quite thin.
  • Viscosity is not a desirable trait of a drilling fluid while being pumped into the well.
  • the viscosity is desirable in the annulus of the hole to remove cuttings from the well.
  • the drilling fluid would be pumped into the well down the drill string.
  • the drill string is usually cooler than the rest of the well, because it contains fluid that has recently been on the surface.
  • the fluid would then leave the drill string and heat up.
  • the increased viscosity would carry the cuttings to the surface.
  • the current technology requires rigorous methods to then remove the cuttings from the fluid.
  • the responsive polymer network based drilling fluid would cool and the carrying capacity would decrease and simple settling could be employed.
  • the behavior would then be analogous to Xanthan gum, but in a synthetic material wherein the temperature could be modified.
  • the responsive polymer network could also be used as a plug for cleaning out the well. Drilling would cease and the responsive polymer network-based fluid would be pumped down and the increased viscosity would clean the hole of any cuttings. Drilling with the regular fluid would then resume.
  • Filtration control fluid During drilling the formation porosity could change drastically causing whole mud to enter the formation.
  • the responsive polymer network could be pumped into the formation and as the heat from the formation warms the invading fluid, the fluid would viscosify and effe ⁇ ively stop the fluid from continuing to enter the formation. This could be permanent or a solution of high salinity could be pumped down to remove the viscosifying property of the responsive polymer network.
  • the responsive polymer network may have additional benefits not described above.
  • the ability of the responsive polymer network gel to hold a hydrophobic material in the presence of an aqueous solution will also be useful in the preparation of non-greasy ointments, where it is desired to reduce the amount of organic solvent.
  • the reverse thermal gel could be useful in a gel preform, as reverse of "lost wax" castings. In this case, the gel would retain its shape as the obje ⁇ is formed and on cooling, it would turn to liquid and could then be drained from the preform.
  • reversibly gelling composition examples include, by way of example only, as oil and lubricant additives, food additives, emulsion additives, use in ele ⁇ rophoresis and chromatography, as adhesives and binding agents, and as curing agents. They may be useful to provide initial green strength in a liquid system while it is being cured or may be used to slow delivery of an additive at high temperature.
  • the responsive polymer network composition may be used in shoes, shoe liners, brassieres or other articles of clothing, or medical prosthetic devices to provide conformation, fit and comfort.
  • the responsive polymer network composition may be useful in a condom as a coating which would in response to body temperature provide a degree of mechanical stiffness to the condom-responsive polymer network system.
  • the responsive polymer network composition may be used in thermo ⁇ mechanical device, such as a sensor or valve. It may also be used as an in-situ plug which gels at higher temperature and then releases at a lower temperature. As an example, the responsive polymer network composition would be useful as a temporary block to the flow of urine. Then, for example, by lowering the temperature or by exceeding the holding strength of the plug, the flow of urine could be made to occur.
  • the thermally reversible gel could be useful for fire containment, such that it would viscosify when a first started and keep burning liquid from spreading. Another example is a gel which is liquid in a fire extinguisher and becomes a gel when it comes in conta ⁇ with a hot object.
  • the gel composition of the invention may be useful as an energy absorber at high temperatures where other systems break down.
  • the gel may be useful to open and close pores in clothing or other fabric articles in response to heat.
  • An example is a hot mitt, which is "breathable" at room temperature and would close down when exposed to heat.
  • the gel may be useful in supercritical fluids system. The gel retains its properties at supercritical conditions and could therefore provide a mechanism for separating something in a supercritical system.
  • the gel is a liquid at room temperature, and is raised to supercritical conditions at which point a gel is formed. The pressure is then lowered but not to room temperature, so that the gel retains whatever it surrounded.
  • responsive polymer network complexes and aqueous gels 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 not way limiting of the invention.
  • Example 1 This example describes the synthesis of a responsive polymer network and an aqueous responsive polymer network solution prepared using a triblock polymer of ethylene oxide and propylene oxide (Pluronic ® F27) and poly (acrylic acid). This example also chara ⁇ erizes the gelation and the physical properties of the resultant responsive polymer network.
  • Block copolymer of propylene oxide (PO) and ethylene oxide (EO) having sandwich stru ⁇ ure (EO) A (PO) B (EO) A (Pluronic F127 NF, Poloxamer 407 NF, where "F” means Flakes, "12” means 12X300 3600 - MW of the polypropylene oxide) se ⁇ ion of the block copolymer, "7" ethylene oxide 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 molar ratio of Pluronic ® F127 and polyacrylic acid.
  • 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.
  • Figs. 1, 2 and 5 clearly demonstrate that the synthetic route outlined above resulted in a responsive polymer network polymeric 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.
  • Fig. 5 is a viscosity vs.
  • Responsive polymer network structure Responsive polymer network structure. Solutions (1 wt% each) of responsive polymer network composition, a polyacrylic acid (alone) polymerized without Pluronic ® and Pluronic ® F127 (alone) were subje ⁇ ed to gel permeation chromatography analysis using triple dete ⁇ or system (light scattering, viscometer, and refra ⁇ ive index dete ⁇ ion, Viscotek). The results of molecular weight determination are outlined in Table 1.
  • polyacrylic acid of the responsive polymer network composition and polyacrylic acid synthesized alone are substantially different in molecular weights and polydispersity.
  • the presence of the triblock (EO)(PO)(EO) polymer and its interaction with the developing polyacrylic acid chains had a measurable effe ⁇ on the final responsive polymer network composition.
  • polyacrylic acid synthesized in presence of the triblock (EO)(PO)(EO) polymer is of lower molecular weight and is much more monodisperse than the polyacrylic acid prepared alone.
  • Pluronic ® was very monodisperse and it's molecular weight corresponded to the data provided by the supplier.
  • the responsive polymer network compositions of the present invention are more than the sum of two individual polymers.
  • Branching of polyacrylic acid in the responsive polymer network composition can explain its stability (i.e. ability of responsive polymer network composition to remain thermo-responsive in dilute solutions for many months) and also may explain the phenomena of viscosification at temperatures below the cloud point.
  • Branched polyacrylic acid molecules interpenetrate and become entangled with each other and with the triblock (EO)(PO)(EO) polymer and thereby forms a constrained, stable structure.
  • the constituent polymers experience a much stronger degree of intera ⁇ ion than physically mixed polymers. These structures interact even more strongly because of the tendency of responsive components, such as the triblock (EO)(PO)(EO) polymers to form aggregates in solution.
  • Example 2 This example describes the synthesis of a responsive polymer network and an aqueous responsive polymer network composition prepared using Pluronic ® F108 and poly(acrylic acid). This example also chara ⁇ erizes the gelation and the physical properties of the resultant responsive polymer network composition.
  • Block copolymer of propylene oxide (PO) and ethylene oxide (EO) having sandwich stru ⁇ ure (EO) A (PO) B (EO) A (Pluronic F108 NF, Poloxamer 338 NF, where "F” means Flakes, "10” means 10X300 3000 - MW of the polypropylene oxide) section of the block copolymer, "8” means that the weight percentage of ethylene oxide in the copolymer is 80%, and nominal molecular weight is 14,600, 3.0 g) was dissolved in 3.0 g acrylic acid (Aldrich). The solution was prepared as described above for Example 1.
  • 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.
  • the responsive polymer network composition was studied as described in Example 1. responsive polymer network compositions of 1 wt% Pluronic ® F108 and polyacrylic acid (1:1) viscosified at temperatures of around 34 °C and higher at pH 7, as illustrated in the viscosity vs. temperature graph in Fig. 6. Repeated heating and cooling of the responsive polymer network composition did not degrade the gelling effe ⁇ .
  • the liquid to gel transition of 34 °C correlates well with the observed chara ⁇ eristic temperature of 33.7 °C of the endothermic peaks that are seen in the DSC endotherm (see Fig. 7).
  • the peaks are measured to have enthalpy value of 1.504 cal/g. This also corresponds closely to a similar endotherm observed for Pluronic ® F108 alone.
  • the observed correlation supports the conclusion that it is the formation of the triblock (EO)(PO)(EO) polymer aggregates that contribute to the gelation of the responsive polymer network compositions.
  • Example 3 This example describes the synthesis of a responsive polymer network and an aqueous responsive polymer network composition prepared using Pluronic ® F88 Prill and poly(acrylic acid). This example also chara ⁇ erizes the gelation and the physical properties of the resultant responsive polymer network composition. Synthesis.
  • Block copolymer of propylene oxide (PO) and ethylene oxide (EO) having sandwich stru ⁇ ure (EO) A (PO) B (EO) A (Pluronic F88 Prill, where "F” means Flakes, “8” means 8X300 2400 - MW of the polypropylene oxide) se ⁇ ion of the block copolymer, “8” means 80 wt% ethylene oxide in the copolymer is 80%, and the nominal molecular weight is 11,400, 3.0 g) was dissolved in 3.0 g acrylic acid (Aldrich). The solution was prepared as described above for Example 1.
  • Viscosity measurements A responsive polymer network composition was prepared and studied as described in Example 1.
  • responsive polymer network compositions of 1 wt% Pluronic ® F88 and polyacrylic acid (1:1) viscosified at temperatures of around 48 °C and higher at pH 7, as is illustrated in the viscosity vs. temperature graph of Fig. 8.
  • Repeated heating and cooling of responsive polymer network suspensions was not observed to cause deterioration of the gelation effe ⁇ .
  • This measurement correlates well with the observed characteristic temperature of 47 °C of the endothermic peaks that are seen in the DSC endotherm. The peaks are measured to have enthalpy value of 0.9 cal/g.
  • Example 4 This Example is dire ⁇ ed toward demonstrating that covalent cross ⁇ linking of polyacrylic acid component of responsive polymer network may be used without detrimental effe ⁇ to the responsive polymer network gelation.
  • Pluronic ® F127 NF (3.0 g) and 7.5 mg of pentaerythritol triallyl ether (crosslinking agent, Aldrich, tech., 70%) were dissolved in 3.0 g acrylic acid (Aldrich).
  • the crosslinking agent was sufficient to lightly crosslink the polyacrylic acid.
  • the solutiof ⁇ was deaerated by N 2 bubbling for 20 min and following addition of 50 ⁇ l of freshly prepared 300 mg/ml solution of ammonium persulfate (Kodak) in deionized water was kept at 70 °C for 2 h resulting in a strong whitish polymer.
  • a sample of the polymer obtained (2.0 g) was suspended in 100 ml deionized water into which 0.32 g NaOH was added. Suspended responsive polymer network particles were allowed so swell for 3 days under constant stirring. The resulting fine suspension exhibited very high viscosity at T > 30 °C and low viscosity at T ⁇ 30 °C.
  • Example 5 This example describes the synthesis of a responsive polymer network and an aqueous responsive polymer network composition prepared using Pluronic ® P104 and poly (acrylic acid). This example also chara ⁇ erizes the gelation and the physical properties of the resultant responsive polymer network composition.
  • Block copolymer of propylene oxide (PO) and ethylene oxide (EO) having sandwich structure (EO) A (PO) B (EO) A (Pluronic P104, where "P” means Paste, “10” means 10X300 3000 - MW of the poly (propylene oxide) se ⁇ ion of the block copolymer, “4" means 40 wt% ethylene oxide in the copolymer and the nominal molecular weight is 5,900, 3.0 g) was dissolved in 3.0 g acrylic acid (Aldrich). The solution was prepared as described above for Example 1. A responsive polymer network composition was prepared and studied as described in Example 1.
  • Example 6 This example describes the synthesis of a responsive polymer network and an aqueous responsive polymer network composition prepared using Pluronic ® P123 and poly (acrylic acid). This example also characterizes the gelation and the physical properties of the resultant responsive polymer network composition.
  • Block copolymer of propylene oxide (PO) and ethylene oxide (EO) having sandwich structure (EO) A (PO) B (EO) A (Pluronic ® P123, where "P ⁇ means Paste, "12” means 12X300 3600 - MW of the poly(propylene oxide) se ⁇ ion of the block copolymer, "3” means 30 wt% ethylene oxide in the copolymer and the nominal molecular weight is 5,750, 3.0 g) was dissolved in 3.0 g acrylic acid (Aldrich). The solution was prepared as described above for Example 1. A responsive polymer network composition was prepared and studied as described in Example 1.
  • Example 7 The following example demonstrates the effe ⁇ of hydrophilic/hydrophobic ratio on the gelling temperature.
  • Responsive polymer network compositions were prepared from the following triblock copolymers shown in Table 3.
  • Table 3 shows that in this series, the fra ⁇ ion of EO is reduced when the molecular weight of the PO block is kept constant.
  • 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 unaffe ⁇ ed by the molecular mass, given a constant EO/PO ratio, whereas these boundaries shifted to lower temperature as the EO content of the polymer is reduced at constant mass.
  • the strong dependence of the EO/PO ratio is a consequence of the differing solubilities of EO and PO in water at the elevated temperatures.
  • the polymer network was prepared as described in Example 1.
  • the dry polymer was placed into either deionized water or a 0.5 M NaCl solution, in proportions to provide a 2.5 wt% solution.
  • Viscosity profiles for the two aqueous solutions were determined and are reported in Fig. 12.
  • the viscosity of a 2.5 wt% solution in deionized water has a higher initial viscosity than that in a 0.5M NaCl solution at 20 °C.
  • the temperature at which gelation occurs shifts from about 35 °C in water to about 30 °C in the NaCl solution.
  • a change in the ionic strength of the aqueous gel composition alters its gelling properties.
  • Example 9 This example describes the synthesis of a responsive polymer network and an aqueous responsive polymer network composition prepared using Pluronic ® F127 and poly(acrylic acid) with a 75% redu ⁇ ion in ammonium persulfate initiator, relative to Example 1.
  • Pluronic F127 NF grade from BASF was dissolved in 5 grams of Acrylic Acid (Aldrich). The solution took approximately 30 minutes to solubilize. The solution was dearated for 15 minutes and 25uL of a 0.1gram/2mL ammonium persulfate (Kodak) in deionized water solution was added. The solution was heated in a bead bath at 70°C for 20 minutes. A white polymer is formed and is then removed from the tube, cut into small pieces, and placed in a dish to dry overnight. A 3% by weight solution of dry polymer to deionized water is prepared to allow the polymer to solubilize.
  • Acrylic Acid Aldrich
  • Example 10 This example describes the synthesis of a responsive polymer network and an aqueous responsive polymer network composition prepared using Pluronic ® F127 and poly (acrylic acid) with a 50% redu ⁇ ion in ammonium persulfate initiator, as compared to example 1.
  • Pluronic F127 NF grade from BASF (3.0g) was dissolved in 5 grams of Acrylic acid
  • Example 11 This example describes the synthesis of a responsive polymer network and an aqueous responsive polymer network composition prepared using Pluronic ® F127 and poly (acrylic acid) with twice the amount of ammonium persulfate initiator, as compared to Example 1.
  • Pluronic F127 NF grade from BASF (3.0g) was dissolved in 5 grams of Acrylic acid
  • Example 12 This example describes the synthesis of a responsive polymer network and an aqueous responsive polymer network composition prepared using Pluronic ® F127 and poly (acrylic acid) with AIBN as initiator.
  • Pluronic F127 NF grade from BASF (3.0g) was dissolved in 5 grams of Acrylic acid
  • Example 13 This example describes the synthesis of a responsive polymer network and an aqueous responsive polymer network composition prepared using Pluronic ® F127 and poly(acrylic acid) with Vazo 52 as initiator.
  • Pluronic F127 NF grade from BASF was dissolved in 5 grams of Acrylic Acid (Aldrich). The solution took approximately 30 minutes to solubilize. The solution was dearated for 15 minutes and 200uL of a O.lgram/lmL Vazo 52 (Dupont) in acetone solution was added. The solution was heated in a bead bath at 70°C for 20 minutes. A white polymer is formed and is then removed from the tube, cut into small pieces, and placed in a dish to dry overnight. A 3% by weight solution of dry polymer to deionized water is prepared to allow the polymer to solubilize.
  • Example 14 This example describes the synthesis of a responsive polymer network and an aqueous responsive polymer network composition prepared using Pluronic ® F127 and poly(acrylic acid) with 25% water added.
  • Pluronic F127 NF grade from BASF (2.25g) was dissolved in 3.75 grams of Acrylic Acid (Aldrich) and 2g of deionized water. The solution took approximately 30 minutes to solubilize. The solution was dearated for 15 minutes and 50uL of a O.lgram/lmL ammonium persulfate (Kodak) in deionized water solution was added. The solution was heated in a bead bath at 70°C for 20 minutes. A white polymer is formed and is then removed from the tube, cut into small pieces, and placed in a dish to dry overnight. A 3% by weight solution of dry polymer to deionized water is prepared to allow the polymer to solubilize.
  • Acrylic Acid Aldrich
  • deionized water solution was added. The solution was heated in a bead bath at 70°C for 20 minutes. A white polymer is formed and is then removed from the tube, cut into small pieces, and placed in a dish to dry overnight.
  • Example 15 This example describes the synthesis of a responsive polymer network and an aqueous responsive polymer network composition prepared using Pluronic ® F127 and poly(acrylic acid) with 35% water added.
  • Pluronic F127 NF grade from BASF (1.95g) was dissolved in 3.25grams of Acrylic Acid (Aldrich) and 2.8g of deionized water. The solution took approximately 30 minutes to solubilize. The solution was dearated for 15 minutes and 50uL of a O.lgram/lmL ammonium persulfate (Kodak) in deionized water solution was added. The solution was heated in a bead bath at 70°C for 20 minutes. A white polymer is formed and is then removed from the tube, cut into small pieces, and placed in a dish to dry overnight. A 3% by weight solution of dry polymer to deionized water is prepared to allow the polymer to solubilize.
  • Example 16 This example describes the synthesis of a responsive polymer network and an aqueous responsive polymer network composition prepared using Pluronic ® F127 and poly(acrylic acid) with 25% water added and a 50% redu ⁇ ion in ammonium persulfate initiator, as compared to Example 1.
  • Pluronic F127 NF grade from BASF (2.25g) was dissolved in 3.75 grams of Acrylic Acid (Aldrich) and 2g of deionized water. The solution took approximately 30 minutes to solubilize. The solution was dearated for 15 minutes and 50uL of a
  • Pluronic F127 NF grade from BASF (1.50g) and Pluronic F108 from BASF (1.50g) was dissolved in 5 grams of Acrylic Acid (Aldrich). The solution took approximately 30 minutes to solubilize. The solution was dearated for 15 minutes and 50uL of a O.lgram/lmL ammomum persulfate (Kodak) in deionized water solution was added. The solution was heated in a bead bath at 70°C for 20 minutes. A white polymer is formed and is then removed from the tube, cut into small pieces, and placed in a dish to dry overnight. A 3% by weight solution of dry polymer to deionized water is prepared to allow the polymer to solubilize.
  • Acrylic Acid Aldrich
  • Example 18 This example describes the synthesis of a responsive polymer network and an aqueous responsive polymer network composition prepared using Pluronic ® F88 and poly (acrylic acid). This example illustrates the effe ⁇ of the responsive component on the gelation temperature of the composition.
  • Pluronic F88 from BASF was dissolved in 5 grams of Acrylic Acid (Aldrich). The solution took approximately 30 minutes to solubilize. The solution was dearated for 15 minutes and 50uL of a O.lgram/lmL ammonium persulfate (Kodak) in deionized water solution was added. The solution was heated in a bead bath at 70°C for 20 minutes. A white polymer is formed and is then removed from the tube, cut into small pieces, and placed in a dish to dry overnight. A 3% by weight solution of dry polymer to deionized water is prepared to allow the polymer to solubilize.
  • Acrylic Acid Aldrich
  • Example 19 This example describes the synthesis of a responsive polymer network and an aqueous responsive polymer network composition prepared using Pluronic ® F127/Pluronic ® F88 blend (1:1) and poly(acrylic acid).
  • This example illustrates the effe ⁇ of the responsive component on the gelation temperature of the composition.
  • Pluronic F127 NF grade from BASF (1.50g) and Pluronic F88 from BASF (1.50g) was dissolved in 5 grams of Acrylic Acid (Aldrich). The solution took approximately 30 minutes to solubilize. The solution was dearated for 15 minutes and 50uL of a O.lgram/lmL ammonium persulfate (Kodak) in deionized water solution was added.
  • Kodak O.lgram/lmL ammonium persulfate
  • the solution was heated in a bead bath at 70°C for 20 minutes. A white polymer is formed and is then removed from the tube, cut into small pieces, and placed in a dish to dry overnight. A 3% by weight solution of dry polymer to deionized water is prepared to allow the polymer to solubilize.
  • To neutralize the solution approximately 0.3g of NaOH (Fisher) is added to the solution prior to solubilizing of the polymer. The polymer pieces solubilize at neutral pH over a period of 48 - 72 hours. The viscosity of the solution increased at 85°C when tested using a Brookfield viscometer.
  • Example 20 This example describes the synthesis of a responsive polymer network and an aqueous responsive polymer network composition prepared using Pluronic ® F127 and poly(acrylic acid) using suspension polymerization.
  • Pluronic F127 NF grade from BASF (15.0g) was dissolved in 25 grams of acrylic acid (Aldrich). The solution was dearated for 40 minutes while it solubilized and 250uL of a 0.5gram/lmL ammonium persulfate (Kodak) in deionized water solution was added.
  • the continuous phase solvent, heptane was added to a 500mL baffled rea ⁇ ion vessel equipped with an R100 impeller blade.
  • a surfa ⁇ ant Ganex V216 0.5 wt% was added to the continuous phase.
  • the continuous phase was heated to 60 °C while being dearated for 75 minutes.
  • the polymer solution is then added to the reaction vessel while stirring and allowed to react 2 hours.
  • Example 21 This example describes the synthesis of a responsive polymer network gel composition prepared using Pluronic ® F127 and a copolymer of methacrylic and acrylic acid.
  • Ganex V-126 surfa ⁇ ants was added to the continuous phase at 0.3 wt% (based on total batch size).
  • the continuous phase was deaerated for three (3) hours with agitation.
  • 26.7g benzoyl peroxide 75% (Akzo) was dissolved in 0.5 kg acrylic acid.
  • This initiator system was then added ot the Pluoronic/acrylic acid monomer solution and allowed to mix for 30 minutes.
  • the monomer solution was transferred to the rea ⁇ ion vessel via a diaphragm pump.
  • the rea ⁇ ion vessel agitator was set at 600 RPM, and the entire contents of the vessel were deaerated for an additional one (1) hour.
  • the reaction vessel temperature was ramped to rea ⁇ ion temperature using a tempered heating water unit.
  • Example 23 This example describes the formation of gel beads of the invention.
  • Pluoronic F88 from BASF (35.2) was dissolved in 42.1 grams of Acrylic Acid (Aldrich) with 1.32 NaOH in 2.5 mL deionized water. The solution took approximately 30 minutes to solubilize.
  • the solution was deaerated for 20 minutes and a 0.53 gram/5 gram benzoyl peroxide in acrylic acid solution was added.
  • the continuous phase Norpar (Exxon)
  • Ganez V216 0.2 wt% was added to the continuous phase.
  • the continuous phase was then deaerated for 35 minutes.
  • the polymer solution is then added to the rea ⁇ ion vessel with stirring.
  • the vessel is heated to 70° C and allowed to rea ⁇ for 12 hours.
  • the bulk of the Norpar is decanted from the white polymer beads and the polymer is vacuum filtered and washed once with heptane. Then the beads are vacuum oven dried for 3 hours at 50° C.
  • a 1 wt% solution is prepared with approximately 300 mL of a 5N NaOH (Fisher) solution added to neutralize. This solution shows reverse thermal viscosification.
  • Example 24 Pluoronic F127 NF grade from BASF (140.8 g) was dissolved in 169.96 grams of acrylic acid (Aldrich) with 10.5 grams of a 50 wt% NaOH solution. The solution was deaerated for 45 minutes while it solubilized and of a 1.1 gram/25.2 gram benzoyl peroxide in acrylic acid solution was added.
  • the continuous phase solvent, Norpar (Exxon) was added to a 2000 ml water jacketed baffled rea ⁇ ion vessel equipped with three A200 impellar blades. Ganez V216 (0.3 wt%) was added to the continuous phase. The continuous phase was deaerated for 60 minutes.
  • the polymer solution is then added to the rea ⁇ ion vessel with stirring at a speed 650 rpm.
  • the vessel is heated to 70° C and the rea ⁇ ion continues for 12 hours.
  • the bulk of the Norpar is decanted from the white polymer beads and the polymer is vacuum filtered and rinsed once with heptane. Then the beads are vacuum oven dried for 3 hours at 50° C.
  • a 1 wt% solution is prepared with approximately 300 mL of a 5N NaOH (Fisher) solution added to neutralize. This solution shows reverse thermal viscosification.
  • Example 25 This example describes the synthesis of a responsive polymer network gel composition prepared using Pluronic ® F88 and poly (acrylic acid), this example demonstrates gelation of the responsive polymer network under conditions typically found in oil drillings.
  • a 3 wt% responsive polymer network gel was prepared from Pluronic F88 and polyacrylic acid (1:1) according to the method described in Example 1.
  • the viscosity profile of the solution was determined at elevated pressures.
  • Fig. 14 illustrates the solution performance at 5000 psi.
  • the responsive polymer network experiences an increase in viscosity at above 100°F and remains viscous under oil drilling conditions, namely temperatures in the range of 150-200°F.
  • Example 26 The aim of this Example is three-fold: ( i ) to demonstrate responsive polymer network compositions using a responsive component other than triblock polyoxyalkylene copolymers, (ii) to preserve useful properties of responsive polymer network, namely, ease of synthesis, viscosifying at body temperature, bioadhesiveness, and entirely benign components, and (iii) to incorporate drug into the responsive polymer network composition.
  • a responsive component other than triblock polyoxyalkylene copolymers e.g., polyethyleneglycol (Nonoxynol 9, drug name is Igepal CO-630) was chosen. This remarkable compound is surface a ⁇ ive, possesses cloud point at around 55 °C and is used as a spermicide and anti-HIV agent in vaginal applications. Synthesis and properties of the resulted responsive polymer network are described below.
  • IgepaTCO-630 (Rhone-Poulenc) (3.0 g) was dissolved in 3.0 g acrylic acid (Aldrich). The solution was deaerated by N 2 bubbling for 30 min and following addition of 100 ⁇ l of freshly prepared 300 mg/ml solution of ammonium persulfate (Kodak) in deionized water was kept at 70 °C for 16 h resulting in a transparent solid polymer. A sample of the polymer obtained (2.0 g) was suspended in 100 ml deionized water into which 0.18 g NaOH was added. Suspended responsive polymer network particles were allowed so swell for 1 day under constant stirring. The pH of the solution was adjusted to 7.0.
  • Viscosity measurement Viscosity vs temperature effe ⁇ for responsive polymer network made of Nonoxanol 9 and polyacrylic acid (1:1) in deionized water (pH 7) is presented in Fig. 15. The viscosity is measured at shear rate of 2.64 sec "1 using a SC4-18 spindle which allows a very sensitive measurement. It can be seen that the responsive polymer network starts to viscosify at about 30 °C and the viscosity approaches maximum at 55 °C at which point aggregates are formed (cloudiness is developed) and the viscosity drops precipitously.
  • Example 27 The following example is related to responsive polymer network performance in drug release. Drug loading and kinetics of release of the protein hemoglobin from a responsive polymer network composition are presented.
  • Pluronic F127 ® (3.0 g) was dissolved in 3.0 g acrylic acid. The solution was deaerated by N 2 bubbling for 0.5 h and following addition of 100 ⁇ l 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.
  • Kodak ammonium persulfate
  • 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), respe ⁇ ively.
  • the feed phase was made of 1 g of 0.25 mg/ml hemoglobin solution.
  • the kinetic time commenced.
  • Samples of the receiver phase was withdrawn from time to time and their absorbance was measured spe ⁇ rophotometrically at 400 nm.
  • corresponding calibration curves (absorbance in PBS versus hemoglobin concentration) were generated.
  • the results of the kinetic experiment are presented in Fig. 16. It can be seen that the rate of hemoglobin release from responsive polymer 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
  • Example 28 Drug loading and kinetics of release of the protein lysozyme from a responsive polymer network composition is reported.
  • the responsive polymer network composition was prepared as described in Example 19.
  • 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), respe ⁇ ively.
  • the feed phase was made of 1 g of 1 mg/ml lysozyme solution.
  • the kinetic time commenced. Samples were withdrawn and their absorbance measured spe ⁇ rophotometrically 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 Fig. 17.
  • the lysozyme released from the responsive polymer network composition was assayed using Micrococcus lysodeikticus cells and compared to that of original lysozyme.
  • the enzymatic a ⁇ ivity 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 29 Drug loading and kinetics of release of insulin from a responsive polymer network composition is reported.
  • the responsive polymer network composition was prepared as described in Example 19.
  • 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 Zn 2+ -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.
  • 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 spe ⁇ rophotometrically 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 Fig. 18.
  • 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 Fig. 1).
  • Example 30 Drug loading and kinetics of release of insulin from a responsive polymer network composition is reported.
  • the responsive polymer network composition was prepared as described in Example 19.
  • Solutions for release studies were prepared as follows.
  • a simulated tear solution including 3.35 g NaCl, 1.00 g NaHCOj, and 0.04g CaCl 2 . 2H 2 0 was prepared by dissolving the salts in 500 ml total volume deionized water.
  • Solution A was prepared by dissolving 0.34 g Timolol in a 3% w/w solution of responsive polymer network in simulated tear solution to a total weight of 10.0 g.
  • Solution B was prepared by dissolving 0.34 g Timolol in simulated tear solution to a total weight of 10.0 g.
  • Solution C was prepared by dissolving 0.34 g Timolol in a 2% w/w solution of responsive polymer network lightly crosslinked with 25% crosslinker in simulated tear solution to a total weight of 10.0 g.
  • a 25.0 ml sample of the tear solution was placed in each of five small beakers. Three of the beakers were left on the counter top, and two were placed in an incubator set at 34.0 °C to equilibrate for about 30 minutes. Samples of Solutions A and B intended for testing at 34 °C were placed in the same incubator so that they too would rise to the desired temperature.
  • Example 31 This example demonstrates the preparation of a sterile 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/polyacrylic 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 Fig. 20 and establish that minimal change in the viscosity profile of the material has occurred with sterilization.
  • Example 32 This example is presented to describe the formation of a neutral responsive polymer network and to describe the formation of such a network from an acrylamide monomer.
  • UV-illuminated with a Light-Welder 3010 EC UV spot/wand lamp (spettral output 300-500 nm, intensity 6000 mW/cm 2 , Dymax Co, Torrington, CT) for 60 min at 90 °C. A white powder was recovered and air dried overnight.
  • Example 33 This example is presented to illustrate the performance changes of a polyacrylamide-based responsive polymer network with time.
  • Example 34 This example is presented to demonstrate an acrylamide-based responsive polymer gel prepared with differeing proportions of responsive and structural polymer components and to show performance under physiological conditions.
  • Medicinal and Cosmetic Formulations Because of the surfa ⁇ ant nature of the responsive component of the responsive polymer network composition coupled with the gelation effe ⁇ of the responsive polymer network composition, it is possible to prepare a formulation which is 100% water-based, but which is lubricous and thick.
  • Formulations including nonionic. anionic and cationic surfa ⁇ ants include nonionic. anionic and cationic surfa ⁇ ants.
  • a nonionic surfactant formulation An O/W (oil-in-water) emulsion was made by combining the following ingredients utilizing conventional mixing techniques: Ingredient % w/w
  • This formulation contains a cationic surfactant and gives an emulsion that is fluid at room temperature but viscosifies above 32 °C.
  • Crodatos CES available Irom Croc ia
  • Vaginal Moisturizer An oil-free, lubricous, vaginal moisturizer is made by combining the following ingredients utilizing conventional mixing techniques: Ingredient % w/w
  • the composition displays a flowable creamy lotion appearance with excellent moisturizing, emolliency, spreadability and absorption characteristics at room temperature, and after heating the formulation to 32°C, the composition thickens to a gel-like consistency.
  • the composition displays a flowable jelly appearance with excellent spreadability and absorption characteristics at room temperature, and after heating the formulation to 32°C, the composition thickens to a gel-like consistency.
  • the composition displays a flowable jelly appearance with excellent spreadability and absorption characteristics at room temperature, and after heating the formulation to 32°C, the composition thickens to a gel-like consistency.
  • 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.
  • Topical Hormone Delivery Formulation An oil-free, spreadable, topical hormone treatment using estradiol as the hormone is made by combining the following ingredients utilizing conventional mixing techniques:
  • the composition displays a flowable jelly appearance with excellent spreadability and absorption characteristics at room temperature, and after heating the formulation to 32°C, the composition thickens to a gel-like consistency.
  • Topical Anti-Inflammatory Delivery Formulation with Penetration Enhancer An oil- free, spreadable, topical anti-inflammatory treatment using indomethacin as the anti-inflammatory and Azone as the penetration enhancer is made by combining the following ingredients utilizing conventional mixing techniques:
  • the composition displays a flowable jelly appearance with excellent spreadability and absorption characteristics at room temperature, and after heating the formulation to 32°C, the composition thickens to a gel-like consistency.
  • Topical Anti-Inflammatory Delivery Formulation An oil-free, spreadable, topical anti ⁇ inflammatory treatment using hydrocortisone as the anti-inflammatory is made by combining the following ingredients utilizing conventional mixing techniques:
  • the composition displays a flowable jelly appearance with excellent spreadability and absorption characteristics at room temperature, and after heating the formulation to 32°C, the composition thickens to a gel-like consistency.
  • Topical Analgesic Delivery Formulation with Penetration Enhancer An oil-free, spreadable, topical analgesic treatment using Ibuprofen as the anti-inflammatory and Azone as the penetration enhancer is made by combining the following ingredients utilizing conventional mixing techniques:
  • the composition displays a flowable jelly appearance with excellent spreadability and absorption characteristics at room temperature, and after heating the formulation to 32°C, the composition thickens to a gel-like consistency.
  • Topical Hair Loss Treatment with Penetration Enhancer An oil-free, spreadable, topical hair loss treatment using Minoxidil as the hair growth stimulant and Azone as the penetration enhancer is made by combining the following ingredients utilizing conventional mixing techniques:
  • the composition displays a flowable jelly appearance with excellent spreadability and absorption characteristics at room temperature, and after heating the formulation to 32°C, the composition thickens to a gel-like consistency.
  • Topical Local Anesthetic Delivery Formulation An oil-free, spreadable, topical local anesthetic treatment using lidocaine as the anti-inflammatory is made by combining the following ingredients utilizing conventional mixing techniques:
  • the composition displays a flowable jelly appearance with excellent spreadability and absorption characteristics at room temperature, and after heating the formulation to 32°C, the composition thickens to a gel-like consistency.
  • Insomnia Treatment with Penetration Enhancer An oil-free, spreadable, topical hair loss treatment using Melatonin as the sleep stimulant and Azone as the penetration enhancer is made by combining the following ingredients utilizing conventional mixing techniques:
  • the composition displays a flowable jelly appearance with excellent spreadability and absorption chara ⁇ eristics at room temperature, and after heating the formulation to 32°C, the composition thickens to a gel-like consistency.
  • a gel wound dressing for decubitis ulcer treatment containing a proteolytic enzyme and antiseptic is made by combining the following ingredients utilizing conventional mixing techniques: Ingredients % w/w
  • the composition displays a flowable jelly appearance with excellent spreadability and absorption chara ⁇ eristics at room temperature, and after heating the formulation to 32° C, the composition thickens to a gel-like consistency.
  • Oil-free Moisturizer An oil-free, lubricous moisturizer is made by combing the following ingredients utilizing conventional mixing techniques: Ingredient % w/w
  • the above ingredients are added and processed as described above for the vaginal moisture.
  • the composition displays a flowable creamy lotion appearance with excellent emolliency, spreadability and absorption chara ⁇ eristics at room temperature. After heating the formulation to 26 °C, the composition thickens to a gel-like consistency.
  • the viscosity vs. temperature curve is shown in Fig. 24 and demonstrates that addition of adjuvants to the composition significantly enhances the responsive polymer network maximum viscosity (> 900,000 cps).
  • the use of the responsive polymer network in the formulation also imparts a unique viscosification effe ⁇ after application to the skin, which is not evident in typical commercial O/W emulsion formulations (See, Fig. 24).

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Abstract

Réticulat polymérique présentant la propriété de gélification réversible en réponse à un changement intervenu dans un stimulus environnemental. Le réticulat polymérique solvaté comprend environ 0,01 à 20 % en poids d'un composant d'association et environ 0,01 à 20 % en poids d'un composant solvophile lié au composant d'association. La composition solvatée présente un accroissement d'au moins cinq fois sa viscosité lors de la gélification. Un changement intervenu dans un stimulus environnemental, tel que la température, le pH et la force ionique, peut déclencher la gélification.
PCT/US1996/010376 1995-06-16 1996-06-14 Reticulats polymeriques sensibles a des changements intervenus dans des stimulus environnementaux et leurs procedes d'utilisation WO1997000275A2 (fr)

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AU63857/96A AU6385796A (en) 1995-06-16 1996-06-14 Responsive polymer networks and methods of their use

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