WO1998029487A1 - Reticulats polymeres sensibles et leurs procedes d'utilisation - Google Patents
Reticulats polymeres sensibles et leurs procedes d'utilisation Download PDFInfo
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- WO1998029487A1 WO1998029487A1 PCT/US1998/000062 US9800062W WO9829487A1 WO 1998029487 A1 WO1998029487 A1 WO 1998029487A1 US 9800062 W US9800062 W US 9800062W WO 9829487 A1 WO9829487 A1 WO 9829487A1
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- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000008256 whipped cream Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
Classifications
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- 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
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0014—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0019—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- 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
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- A—HUMAN NECESSITIES
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- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q5/00—Preparations for care of the hair
- A61Q5/02—Preparations for cleaning the hair
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F283/00—Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G
- C08F283/06—Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G on to polyethers, polyoxymethylenes or polyacetals
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- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/54—Polymers characterized by specific structures/properties
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- A61Q7/00—Preparations for affecting hair growth
Definitions
- the present invention relates to a polymer composition which exhibits 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(carboxy- vinyl) 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.
- 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.
- 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 development 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.
- a known material with these properties is a thermal setting 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 function under conditions where low viscosity, free-flowing characteristics are required prior to transition.
- these polymer concentrations are so high that the material itself may cause unfavorable interactions during use.
- 5,252,318 reports reversible gelling compositions which are made up of physical blends 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.
- WO 95/24430 published September 14, 1995 describe graft and block copolymers of component temperature -sensitive polymers and pH-sensitive polymers.
- the graft and/or block copolymers possess a lower critical solution temperature (LCST) or cloud point between 20°C and 40°C at a pH of 6.0 to 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 ophthalmic applications, this is undesireable.
- 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.
- This invention is directed, in part, to a viscosifying polymer network containing an associating component capable of aggregating in response to an increase in temperature or other change in an environmental stimulus, 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 component may be oligomers or polymers.
- an associating component is an oligomer or polymer which will respond to a temperature change or other stimulus to change its degree of association and/or agglomeration.
- the stimulus may be temperature, pH, ionic concentration, solvent concentration, light, magnetic field, electrical 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 factors 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 interaction of the solvophilic and associating components exhibits a synergistic effect, which magnifies the effect 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 or other environmental stimulus. 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 effect on - the polymer network (i.e. , inert additives) but have a beneficial aspect for the particular commercial application or formulation.
- additives may have some detrimental effect to the polymer network (i.e. , compromising additives) but have a beneficial effect for 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 interaction 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 ethylene glycol dimethacrylate
- PO poly(ethylene glycol)(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 poly aery lie 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 50-fold, is observed in the present systems.
- polyxamer a polymeric or oligomeric structure having a general formula of (P 1 ) a (P 2 ) b (P ⁇ ) a where Pj and P 2 represent two different poloxamer blocks.
- P[ may be a poloxamer of the general formula (CH 2 CH 2 O) a , where a is in the range of 10-50 and P 2 may be a poloxamer of the general formula, (CHRjCHRjO),, where R j 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.
- FIG. 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 ;
- FIG. 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 ;
- FIG. 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 ;
- FIG. 4 is a plot of endofhe ⁇ ns for (a) 1 wt% Pluronic ® F127 and (b) 1 wt% viscosifying polymer network aqueous composition of Pluronic ® F127/polyacrylic acid (1 : 1);
- FIG. 5 is a plot of viscosity vs. temperature for (a) a 1 wt% viscosifying polymer network aqueous composition of Pluronic ® F127/poly aery lie 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 ;
- FIG. 6 is a plot of viscosity vs. temperature for a 1 wt% viscosifying polymer network aqueous composition of Pluronic ® F108/polyacrylic acid (1: 1) " at pH 7.0 measured at a shear rate 2.64 sec "1 with a SC4-18 spindle;
- FIG. 7 is a plot of endotherms for 1 wt% viscosifying polymer network composition of Pluronic ® F108/polyacrylic acid (1: 1);
- FIG. 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;
- FIG. 9 is a plot of the viscosity vs. temperature for a viscosifying polymer network composition of 2 wt% Pluronic ® PI 04 /poly aery lie acid (1 : 1) in deionized water at pH 7.0 measured at shear rate of 22 sec "1 using a SC4-25 spindle;
- FIG. 10 is plot of viscosity vs. temperature for a viscosifying polymer network composition of 2 wt% Pluronic ® F 123 /poly aery lie acid (1: 1) at pH 7.0 measured at a shear rate of 22 sec "1 using a SC4-25 spindle;
- FIG. 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 ;
- FIG. 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;
- FIG. 13 is plot of viscosity vs. temperature for a viscosifying polymer network composition of 2 wt% Pluronic ® F127/poly (aery lie acid-c ⁇ -methacrylic acid) (1 : 1) in deionized water at a shear rate of 22 sec "1 ;
- FIG. 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;
- FIG. 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 ;
- FIG. 16 is a plot showing the release of hemoglobin from a polymer network composition of the invention;
- FIG. 17 is a plot showing the release of lysozyme from a polymer network composition of the invention.
- FIG. 18 is a plot showing the release of insulin from a polymer network composition of the invention.
- FIG. 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% polymer network composition of the invention;
- FIG. 20 is a plot of viscosity vs. temperature for a polymer network composition (a) before and (b) after sterilization by autoclave;
- FIG. 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;
- FIG. 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;
- FIG. 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;
- FIG. 24 is a plot of viscosity vs. temperature for an oil-free moisturizing formulation prepared from (a) a polymer network composition of the invention and (b) a conventional oil-in-water formulation;
- FIG. 25 A is a plot of viscosity vs. temperature for a 2 wt% viscosifying polymer network prepared from poly(acrylic acid) and Pluronic ® F127 (1 : 1) and FIG. 25B is a plot of absorbance vs. temperature for the same network; and
- FIG. 26A is a plot of viscosity vs. temperature for a 2 wt% viscosifying polymer network prepared from poly(acrylic acid) and Pluronic ® L92 (1 : 1) and FIG. 26B is a plot of absorbance vs. temperature for the same network.
- the present invention is directed 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 direct 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 component.
- a viscosifying polymer network of the present invention is a special type of a 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 forces may also be present.
- the interacting nature of the two (or more) polymer phases provide a stable miscible composition, irrespective of the immiscibility of the constituent polymers, and unique properties. Such stability and properties may be attributed to specific interactions 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 function of temperature. The polymer will change from an open, non-aggregated form to a micellular, 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 attractive (collapsing) or repulsive (expanding) forces. Ionization is not required, however, and the structural component may be neutral or uncharged.
- the associating component of the polymer network preferably exhibits reversible gelation upon exposure to a change in temperature.
- the solvophilic component of the polymer network may also exhibit reversible gelation in response to one or more environmental changes or stimuli.
- gelation may occur in response to an indirect environmental trigger, for instance, light irradiation or electric 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 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 polymer network compositions of about 0.5 wt% associating component and about 0.5 wt% - solvophilic component 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 (or responsive) component of the present invention may be any polymer which forms aggregates as, e.g. , a function of temperature.
- the associating component typically possess regions of hydrophobic and hydrophilic character.
- the associating component may be linear or branched.
- nonionic surfactant due to its hydrophobic and hydrophilic character, 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 characteristics and at least one polyoxyalkylene unit should have hydrophilic characteristics.
- a poloxamer of polyoxyethylene and polyoxypropylene may be used in a preferred embodiment of the invention.
- Another suitable associating component includes Pluronic ® poloxamers (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 16 to 48 and b ranging from 54 to 62.
- Other exemplary polyoxyalkylene polymers include alkyl poloxamers, which are a product of alcohol condensation reactions with a terminal alkyl or arylalkyl group. The alkyl group should have associating character, such as butyl, hexyl and the like.
- An alkyl poloxamer may have the general formula R-(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 responsive components may be used in the responsive polymer network composition of the present invention.
- solvophilic component 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 carboxy vinyl polymers of monomers such as acrylic acid, methacrylic acid, ethacrylic acid, phenyl acrylic acid, pentenoic acid and the like. Polyacrylic acid is a preferred carboxy vinyl 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 (structural) polymers since they are capable of forming an ionized network as polymers or copolymers of other solvophilic polymers.
- covalent cross-linking within a 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 network compositions of the present invention are highly stable and do not exhibit any phase separation upon standing or upon repeated cycling between a liquid and a gel state. Samples have stood at room temperature for more than three months without any noticeable decomposition, clouding, phase separation or degradation of gelation properties. This is in direct contrast to polymer blends and aqueous mixed polymer solutions, where phase stability and phase separation is a problem, particularly where the constituent polymers are immiscible in one another.
- 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 poly(acrylic acid) is completely protonated, the poly(acrylic acid) component may be the associating component.
- Exemplary of the dramatic increase in viscosity and of the gelation of the responsive polymer network aqueous compositions of the invention with a change in temperature are the aqueous responsive polymer network compositions shown in FIG. 1.
- FIG. 1 is a graph of viscosity vs.
- 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 poloxamer of the general formula (POP)(POE)(POP)
- polyacrylic acid (1 : 1) which has been hydrated and neutralized.
- the viscosity measurements were taken on a Brookfield viscometer at a shear rate of 0.44 sec "1 at pH 7.0. All solutions had an initial viscosity of about 1080 cP at 20°C and exhibited a dramatic increase in viscosity to gel point at about
- 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.
- Final viscosities was approximately 3000 cP, which represented a viscosity increase of about 200-fold.
- 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; MgClv6H 2 0, 10.76 g/1;
- 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 of the present invention generally involves solubilization of the associating component in a monomer or a concentrated monomer solution capable 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 respective end of the complementary polymer component.
- Copolymerization may take place by proton abstraction from a secondary or tertiary carbon atom upon free radical formation or gamma irradiation.
- the copolymerization proceeds via the following scheme:
- reactions in Scheme 1 are exemplified by propylene oxide residues, but they are equally applicable to other alkylene oxides.
- reaction (3) in the presence of vinyl monomers (typically acrylic acid) leads to grafting of the growing poly(acrylic acid) chain onto the polyether backbone with the possibility of crosslinking, resulting in the appearance of a "classical" three- dimensional gel structure. These gel structures may form aggregates, which scatter light even at very low concentrations far below gelation temperatures.
- the degree of grafting may be adjusted by selection 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 temperamre, the polyoxyalkylene chains have been demonstrated to form agglomerations due to temperature-dependent association of the associating component of the polymer. See, for example, Atwood et al, Intl. J. Pharm. , 26:25-333 (1985), herein incorporated by reference. The polymer chains fold in on themselves due to associating interactions among associating chain blocks.
- the polymer morphology of the solvophilic polymer imparts stability to the polymer network.
- the water-soluble solvophilic component improves the stability of the polymer network in aqueous solutions, and discourages phase separation.
- linkage of the solvophilic and associating components increases the effective size and molecular weight of the polymer network. This amplifies the aggregation effect of the associating component.
- 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 microstructure of the polymer network. For example, use of different polymerization initiators in the formation of the constituent solvophilic component of the responsive polymer network gel was found to decrease the temperature for onset of viscosity by
- 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. These include PEO-PPO-PEO block copolymers (Alexandritis, et al, Colloids Surf.
- block- and graft- copolymers such as PEO-PPO-PEO block copolymers-g-polyacrylamide (de Vos, et al., Polymer, 35:2644 (1994)), and PEO-g-poly(acrylic acid) (Hourdet, et al, Polymer, 35:2624 (1994); L'Allouret, et al., Colloid Poly m. Sci., 273: 1163 (1995).
- Thermoassociation is attributed to aggregation of the corresponding grafts or blocks into relative associating microdomains which effectively crosslink adjacent polymer chains.
- aggregation results from a balance between hydrogen bonding, electrostatic interactions, and associating effects in aqueous systems.
- Specific orientations of water that arise upon polymer dissolution lead to increasing 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 the polymer and solvent.
- a polymer chain that consists of different segments (blocks), such that upon dissolution in water, not only segment-segment contact exist, but also segment-solvent and solvent-solvent contact.
- the energy change ( ⁇ G) per contact when two segment-solvent contacts (E 12 ) are replaced with a segment-segment (E u ) and a solvent-solvent (E, 2 ) contact is defined by Silverberg, A. , Adv. Chem. Ser. , 223: 1 (1989) by the equation:
- the Flory-Huggins parameter ( ⁇ ) is related to ⁇ G as defined by Flory, J. Chem. Phys. , 17:303 (1949) as follows:
- N is the size of the polymer chain.
- thermothickening behavior of the two different polymer network systems is supported by the observation of thermothickening behavior of the two different polymer network systems.
- Pluronic ® F127 a triblock copolymer with a minor hydrophobic component (MW of the poly(propylene oxide) (hydrophobic) section of the block copolymer is 3600, weight percentage of ethylene oxide in the copolymer is 70% , nominal total molecular weight is 12,600) exhibits no cloudiness while the system gels (FIGs. 25 A and 25B).
- Pluronic ® L-92 a triblock copolymer with a relatively major hydrophobic component (MW of the poly(propylene oxide) section of the block copolymer is 2700, weight percentage of ethylene oxide in the copolymer is only 20 % , nominal total molecular weight is 3650), a very marked cloudiness is observed that is followed by gelation (FIGs. 26A and 26B).
- MW of the poly(propylene oxide) section of the block copolymer is 2700
- weight percentage of ethylene oxide in the copolymer is only 20 %
- nominal total molecular weight is 3650
- d ⁇ is the increment of viscosity on the addition of a small increment of phase volume d ⁇ to a suspension viscosity ⁇ .
- POP-POE block copolymers Alexandritis, et al.
- Such systems are limited to dually responsive polymers which exhibit phase separation of the entire system.
- 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 Differential Scanning Calorimetry System (Microcal, Inc.) by heating samples at the rate of 15°C/hour.
- 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.
- Broad or sharp endothermic peaks are seen at characteristic temperamre 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. This enthalpy falls within the range reported for Pluronic ® solutions
- 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 contraction 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(2,4dimethylpentanitrile) (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 mixmre instead of pure monomer.
- thermosensitive aggregating monomer does not solubilize well in the monomer or in instances where the monomer of the solvophilic component is a solid. It may be desirable to remove unreacted monomer from the resultant responsive polymer network. This may be accomplished using conventional techniques, such as, by way of example, dialysis.
- Reverse phase polymerization may be used to prepare responsive polymer network beads by dispersion of the solvophilic component ionizable monomer mixmre in a nonpolar solvent such as heptane.
- the aggregating polymer/monomer solution is dispersed with agitation in a nonpolar solvent, such as heptane or hexane, in order to suspend droplets of the solution.
- Polymerization of the monomer is initiated by conventional means (i.e. , addition of an initiator or irradiation) in order to polymerize the monomer and form responsive polymer network beads. See, WO 96/02577 entitled “Useful Responsive Polymer Gel Beads” for further information on the preparation of polymer gel beads, herein incorporated by reference. Such a method may be particularly desirable to provide a heat sink for the heat generated in the exothermic polymerization reaction.
- the polymer network compositions of the present invention may be utilized for a wide variety of pharmaceutical applications.
- an effective amount of the desired pharmaceutical agent is incorporated into the aqueous responsive polymer network composition of the present invention.
- the selected compound is soluble in water which will readily lend itself to a homogeneous dispersion throughout the responsive polymer network composition. It is also preferred that the compound is nonreactive 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 interacting polymer gels of the invention is that they may be prepared from constiment polymers that have known accepted toxicological profiles.
- the interacting 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, rectal, 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, rectal, 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 (e
- the biologically active compounds that may be loaded into the polymer networks of the present invention are any substance having biological activity, including proteins, polypeptides, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, and synthetic and 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 that are not themselves liquid at body temperamre can be incorporated into polymers, particularly gels.
- peptides and proteins which may normally be lysed by tissue-activated enzymes such as peptidases, can be passively protected in gels as well. See, Gehrke et al, Proceed. Intern. Symp. Control. Rel. Bioact. Mater. , 22: 145 (1995).
- biologically active compound includes pharmacologically active 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; insects; arachnids; protists (e.g. protozoa); and prokaryotic bacteria.
- the term "plant” means higher plants (angiosperms, gymnosperms), fungi, and prokaryotic blue-green “algae” ( i.e. cyanobacteria).
- the 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 active protein or peptide, naturally occurring or synthetic.
- proteins include antibodies, enzymes, 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, adre
- Classes of pharmaceutically active 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.
- Anti-AIDS substances are substances used to treat or prevent Autoimmune Deficiency Syndrome (AIDS). Examples of such substances include CD4, 3'-azido-3'-deoxyfhymidine (AZT), 9-(2-hydroxyethoxymethyl)-guanine acycloviro, phosphonoformic acid,
- Anti-cancer substances are substances used to treat or prevent cancer. Examples of such substances include methotrexate, cisplatin, prednisone, hydro xyprogesterone, 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 (DTIC: dimethyltriazenomidazolecarboxamide), fluorouracil, 5-fluorouracil, cytarabine, cytosine arabinoxide, mercaptopurine, 6-mercaptopurlne and thloguanlne.
- 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, 9-[2-hydroxy-ethoxy]methylguanine, adamantanamine, 5-iodo-2'-deoxyuridine, trifluorothymidine, interferon, and adenine arabinoside.
- Enzvme inhibitors are substances which inhibit an enzymatic reaction.
- enzyme inhibitors include edrophonium chloride,
- Neurotoxins are substances which have a toxic effect 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- bromobenzy lamine hydrochloride.
- cholinergic neurotoxins include acetylethylcholine mustard hydrochloride.
- dopaminergic neurotoxins include 6-hydroxydopamine HBr, l-methyl-4-
- 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, and 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 effect.
- Hypnotics include pentobarbital sodium, phenobarbital, secobarbital, thiopental and mixmres thereof, heterocyclic hypnotics, dioxopiperidines, glutarimides, diethyl isovaleramide, ⁇ -bromoisovaleryl urea, urethanes and disulfanes.
- Antihistamines are substances which competitively inhibit the effects 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 active lubricants include water and saline.
- Tranquilizers are substances which provide a tranquilizing effect.
- tranquilizers include chloropromazine, promazine, fluphenzaine, reserpine, deserpidine, and meprobamate.
- Anti-convulsants are substances which have an effect 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 contractants are substances capable of preventing or relieving muscle spasms or contractions.
- examples of such agents include atropine, scopolamine, oxyphenonium, and papaverine.
- Miotics and anti-cholinergics are compounds which cause bronchodilation. Examples include echothiophate, pilocarpine, physostigamine 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 ivermectin, pyrimethamine, trisulfapyrimidine, clindamycin, amphotericin B, nystatin, flucytosine, natamycin, and miconazole.
- Anti-hypertensives are substances capable of counteracting 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 counteracting or suppressing inflammation. Examples of such 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 effect 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 effects.
- 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. mmor, in vivo.
- imaging agents include substances having a label which is detectable in vivo, e.g. antibodies attached to fluorescent labels.
- the term antibody includes whole antibodies or fragments thereof, including both monoclonal and polyclonal antibodies.
- Specific targeting agents include agents capable of delivering a therapeutic agent to a desired site, e.g. mmor, and providing a therapeutic effect.
- Examples of targeting agents include agents which can carry toxins or other agents which provide beneficial effects.
- 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 chemotactic factors such as platelet-derived growth factor PDGF).
- Other chemotactic factors include neutrophil-activating protein, monocyte chemoattractant protein, macrophage-inflammatory protein, platelet factor, platelet basic protein, and melanoma growth stimulating activity; epidermal growth factor, transforming growth factor (alpha), fibroblast growth factor, platelet-derived endothelial cell growth factor, insulin-like growth factor, nerve growth factor, and bone growth/cartilage- inducing factor (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 factors, including erythropoietin, granulocyte colony stimulating factor, macrophage colony stimulating factor and granulocyte-macrophage colony stimulating factor; mmor necrosis factors, including alpha and beta; transforming growth factors (beta), including beta-1 , beta-2, beta-3, inhibin, and activin; and bone morphogenetic proteins.
- interleukins interleukin inhibitors or interleukin receptors, including interleukin 1 through interleukin 10
- interferons including alpha, beta and gamma
- hematopoietic factors including erythropoietin, granulocyte colony stimulating factor, macrophage colony stimulating factor and granulocyte-macrophage colony
- 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, injectable, dermal, subdermal, oral, vaginal and rectal. These routes benefit from the responsive polymer network being a system that has reverse viscosification, bioadhesion, and emulsification properties.
- the responsive polymer network composition may be used as a liquid vehicle at ambient temperamre, and after administration to the eye, the responsive polymer network would become viscous to facilitate the delivery of actives or act as an adjuvant for lubricity and humectancy.
- 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 active agents that benefit from extended release through viscosification in the gastrointestinal tract.
- typical formulations exhibit viscosity decreases at body temperamre and exude out of the vaginal or rectal cavity. The increase in viscosity at body temperamre 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 function of ionic strength into the article, device or composition.
- the aqueous composition exhibits at least a five-fold increase in viscosity upon gelation
- by reducing temperamre 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 functions in several different fields. One application would be in the industrial and automotive use of oils and lubricants.
- the responsive polymer network will have the ability to act as a primary emulsifier without any (or with very little) addition of traditional surfactant.
- the responsive polymer network will also act as a stabilizer for oil-soluble ingredients that would conventionally need to be solubilized by oils in formulation.
- the associating portion of the interacting penetrating network forms domains that act 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 dye in a mascara.
- the emulsification abilities of the responsive polymer network could also provide a controlled diffusion from the material upon activation. Two examples would be the continuous release of a fragrance in a deodorant or cologne, or the release of an active ingredient such as an antiperspirant.
- the responsive polymer network's ability to viscosify with increased temperamre could provide a semi-permeable or impermeable barrier. In a cosmetic formulation, this feature would provide a protective barrier or allow for a slow diffusion of other materials.
- the responsive polymer network may also become increasingly rigid with increasing temperamre and thereby create rigidity in cosmetics.
- the responsive polymer network exhibits bioadhesive characteristics. 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 one 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 temperamre compared to the cold Alaskan environment).
- the gel could also provide a dye to indicate that something had been exposed to too low a temperamre.
- a dye to indicate that something had been exposed to too low a temperamre.
- 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 electrophoresis, it would be useful to introduce the separation material in a liquid form and then to gel it in situ, thereby greatly reducing the time required.
- electrical and optical wires are often protected by gels, and the gel of the present invention could help protect such wires by allowing field repair and coating in difficult to reach areas.
- the ability to form a highly viscous solution reversibly may be especially useful in electrophoresis and other types of chromatography.
- the material could be poured into columns or plates at low temperatures, warmed above the transition to produce a matrix with separation capabilities, and then cooled after separation for easy replacement of contaminated material and recovery of products.
- the second property of the responsive polymer network is the ability to set up with increased temperatures which can be viewed as an extension of the viscosifying effect but has somewhat different applications. In the food industry for instance, this characteristic would be useful in the manufacturing process.
- the fast setting of the responsive polymer network could be utilized in the manufacture of hard candies where it would be useful to have the product 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 the candy to harden enough to be moved along in the manufacturing 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-product by making the candy slower melting and longer lasting.
- the responsive polymer network might serve in binding, extension, 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 temperamre 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 thixotrope or a viscosity modifying agent below gelation temperamre.
- 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 reactions, such as cement curing would be particularly interesting because the heat generated would cause a significant thickening of the uncured cement.
- the correct 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 temperamre could then be elevated above the transition temperamre, firmly but temporarily fixing the coating in place.
- the temperamre 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 temperamre. The adhesion could then be reversed simply by reducing the temperamre 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 temperamre and allowed to viscosify at ground temperamre, 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 introduction of the additive at elevated temperatures.
- the release could be utilized in coating systems, cleaning systems, and manufacturing 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 temperamre 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 products.
- the reversibly gelling polymer networks could be used in a variety of footwear applications, such as in the insoles (factory or aftermarket), ankle collar, tongue, etc. to give the wearer a custom fit and to enhance comfort and support. This could be incorporated into almost any type of footwear including athletic shoes (walking, running, cross training, basketball, tennis, golf, cleated, etc.), casual or dress shoes, slippers, sandals, hiking boots, work boots, ski boots, in line skates, ice skates, etc.
- These gels can also be used to provide conformable fit and support in a variety of different protective gear and sporting goods applications such as helmets (football, baseball, hockey, bicycle, motorcycle, etc.), mouthpieces, headgear, (boxing, wrestling, etc.) sports glove (baseball, boxing, hockey, lacrosse, etc.), bike seats, masks (hockey, baseball, lacrosse, etc.), shoulder pads, knee pads, skin pads, elbow pads, weight belts, athletic supporters, goggles, saddles, hand grips (fitness equipment, tennis racquets, baseball bats, etc.) sporting clothes including wetsuits, drysuits, padded garments (biking shorts, etc.) and conformable garments.
- helmets football, baseball, hockey, bicycle, motorcycle, etc.
- mouthpieces headgear
- headgear sports glove
- bike seats masks (hockey, baseball, lacrosse, etc.)
- shoulder pads knee pads
- skin pads
- 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 woman's brassieres, eyeglass and sunglass nose bridges and ear supports, seating and furniture (chairs, beds, sofas, car seats, baby seats, etc.), headphones (aviation, protective, 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.
- 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.
- current fluids for underbalanced drilling are quite thin. During periods of overbalanced pressure, the fluid loss and formation damage can be quite severe because of the low viscosity of the fluid. With a thicker fluid, the invasion would be much less because the increase in viscosity would slow down the rate of formation penetration.
- 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 temperamre 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 effectively 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 object 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 electrophoresis 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 temperamre.
- 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 temperamre 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-si plug which gels at higher temperamre and then releases at a lower temperamre. 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 fire started and keep burning liquid from spreading.
- a gel which is liquid in a fire extinguisher and becomes a gel when it comes in contact with a hot object.
- the gel composition of the invention may be useful as an energy absorber at high temperatures where other systems break down.
- the gel may be useful to open and close pores in clothing or other fabric articles in response to heat.
- An example is a hot mitt, which is "breathable" at room temperamre 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 temperamre, and is raised to supercritical conditions at which point a gel is formed. The pressure is then lowered but not to room temperamre, 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 not in any way limiting of the invention.
- 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 (aery lie acid). This example also characterizes the gelation and the physical properties of the resultant responsive polymer network. Synthesis.
- Block copolymer of propylene oxide (PO) and ethylene oxide (EO) having sandwich structure (EO) A (PO) B (EO) A (Pluronic ® F127 NF, Poloxamer 407 NF, where "F” means Flakes, " 12" means 12 X 300 3600 - MW of the poly(propylene oxide) section 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 temperamres 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 temperamre of the environment. Note that the liquid-gel transition is very sharp, occurring over a very small temperamre change or ⁇ pH.
- 5 is a viscosity vs. temperamre graph comparing the gelling characteristics of the responsive polymer network composition and the physical blend.
- the blend prepared by physically mixing of the triblock EO/PO/EO polymer and polyacrylic acid did not exhibit viscosifying effect either as a function of temperamre or pH.
- 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 subjected to gel permeation chromatography analysis using triple detector system (light scattering, viscometer, and refractive index detection, 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 effect on the final responsive polymer network composition.
- polyacrylic acid (PAA) 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. Further information on the structure of the responsive polymer network may be gained using the Mark-Houwink equation. Analysis using Mark-Houwink equation:
- 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. Because of the branching nature of the responsive polymer network composition and the degree of entanglement which arises from the preparation of the interacting network, the constiment polymers experience a much stronger degree of interaction 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.
- 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 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 ® F108 NF, Poloxamer 338 NF, where "F” means Flakes, " 10” means 10 X 300 3000 - MW of the poly (propylene oxide) section of the block copolymer, "8” means that the weight percentage of ethylene oxide in the copolymer is 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 temperamres of around 34 °C and higher at pH 7, as illustrated in the viscosity vs. temperature graph in
- FIG. 6 Repeated heating and cooling of the responsive polymer network composition did not degrade the gelling effect.
- the liquid to gel transition of 34°C correlates well with the observed characteristic temperamre 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 ® 108 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 characterizes the gelation and the physical properties of the resultant responsive polymer network composition.
- Example 4 This Example is directed toward demonstrating that covalent cross-linking of a polyacrylic acid component of the responsive polymer network may be used without detrimental effect 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 solution 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.
- Kodak ammonium persulfate
- 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 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 strucmre (EO) A (PO) B (EO) A (Pluronic ® P104, where "P” means Paste, "10” means 10 X 300 3000 - MW of the poly (propylene oxide) section 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.
- Example 7 The following example demonstrates the effect of hydrophilic/hydrophobic ratio on the gelling temperamre. Responsive polymer network compositions were prepared from the following triblock copolymers shown in Table 3.
- Table 3 shows that in this series, the fraction 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 unaffected by the molecular mass, given a constant EO/PO ratio, whereas these boundaries shifted to lower temperamre 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 temperamres. Thus one would suppose that aggregation that causes viscosification in the responsive polymer network composition should shift to lower temperamre as EO fraction decreases.
- the poloxamer (3.0 g) was dissolved in 3.0 g acrylic acid. The solution was deaerated by N 2 bubbling for 20 min. and following addition of the 100 ⁇ l of freshly prepared saturated solution of ammonium persulfate in deionized water was kept at 70 °C for 16 h resulting in a strong whitish polymer. A sample of the polymer obtained (0.4 g) was suspended in 40 ml deionized water into which NaOH was added. Suspended responsive polymer network particles were allowed to dissolve under constant stirring. The resulting 1 wt% responsive polymer network solutions were subjected to the viscosity measurement at shear rate of 132 or 13.2 sec "1 using a SC4-18 spindle.
- Example 8 This example demonstrates the ability to shift the temperamre at which a polymer network gel viscosifies by addition of a salt into the aqueous solution.
- 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 temperamre 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 8 This example demonstrates the ability to shift the temperamre at which a polymer network gel viscosifies by addition of a salt into the aqueous solution.
- 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 temperamre 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.
- 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 % reduction in ammonium persulfate initiator, relative to Example 1.
- Pluronic ® F127 NF grade from BASF (3.0 g) 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 25 ⁇ L of a 0.1 g/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.
- 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 37 °C when tested using a Brookfield viscometer.
- Example 10 This example describes the synthesis of a responsive polymer network and an aqueous responsive polymer network composition prepared using Pluronic ® F127 and poly(acrylic acid) with a 50% reduction in ammonium persulfate initiator, as compared to example 1.
- Pluronic ® F127 NF grade from BASF (3.0 g) 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 50 ⁇ L of a 0.1 g/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
- Kodak ammonium persulfate
- 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 (3.0 g) 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 100 ⁇ L of a 0.1 g/ml 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
- Kodak ammonium persulfate
- 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 (3.0 g) 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 50 ⁇ L of a O. lg/mL ⁇ . ⁇ '-azoisobutyronitrile (Aldrich) in acetone 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 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 the initiator.
- Pluronic ® F127 NF grade from BASF (3.0 g) 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 200 ⁇ L of a 0.1 g/ml 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.
- 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 (2.25 g) was dissolved in 3.75 g of acrylic acid (Aldrich) and 2 g of deionized water. The solution took approximately 30 minutes to solubilize. The solution was dearated for 15 minutes and 50 ⁇ L of a 0.1 g/ml 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 mbe, 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 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 (1.95 g) was dissolved in 3.25 g of acrylic acid (Aldrich) and 2.8 g of deionized water. The solution took approximately 30 minutes to solubilize. The solution was dearated for 15 minutes and 50 ⁇ L of a 0.1 g/ml 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 mbe, 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 took approximately 30 minutes to solubilize.
- the solution was dearated for 15 minutes and 50 ⁇ L of a 0.1 g/ml ammonium persulfate (Kodak)
- 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% reduction in ammonium persulfate initiator, as compared to Example 1.
- Pluronic ® F127 NF grade from BASF (2.25 g) was dissolved in 3.75 grams of acrylic acid (Aldrich) and 2 g of deionized water. The solution took approximately 30 minutes to solubilize. The solution was dearated for 15 minutes and 50 ⁇ L of a 0.1 g/ml 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 mbe, 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.
- This example describes the synthesis of a responsive polymer network and an aqueous responsive polymer network composition prepared using Pluronic ® F127/Pluronic ® F108 blend (1 : 1) and poly(acrylic acid).
- Pluronic ® F127 NF grade from BASF (1.50 g) 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 50 ⁇ L of a 0.1 g/ml 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 mbe, 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 effect of the responsive component on the gelation temperamre of the composition.
- Pluronic ® F88 from BASF (3.0g) was dissolved in 5 g of acrylic acid (Aldrich). The solution took approximately 30 minutes to solubilize. The solution was dearated for 15 minutes and 50 ⁇ L of a 0.1 g/ml 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 mbe, 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 effect of the responsive component on the gelation temperamre of the composition.
- Pluronic ® F127 NF grade from BASF (1.50 g) and Pluronic ® F88 from BASF (1.50 g).
- BASF (1.50) 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 50 ⁇ L of a 0.1 g/ml 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 mbe, 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
- Kodak ammonium persulfate
- 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 (15.0 g) was dissolved in 25 g of acrylic acid (Aldrich). The solution was dearated for 40 minutes while it solubilized and 250 ⁇ L of a 0.5 g/ml ammonium persulfate (Kodak) in deionized water solution was added.
- the continuous phase solvent, heptane was added to a 500 mL baffled reaction vessel equipped with an R100 impeller blade.
- a surfactant 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 get composition prepared using Pluronic® F127 and a copolymer of methacrylic and acrylic acid.
- Ganex V-126 surfactants 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.
- 26.7 benzoyl peroxide 75% (Akzo) was dissolved in 0.5 kg acrylic acid.
- This initiator system was then added to the Pluoronic/acrylic acid monomer solution and allowed to mix for 30 minutes.
- the monomer solution was transferred to the reaction vessel via a diaphragm pump.
- the reaction vessel agitator was set at 600 RPM, and the entire contents of the vessel were deaerated for an additional one (1) hour.
- the reaction vessel temperature was ramped to reaction temperature using a tempered heating water unit. The reaction was allowed to continue for 14 hours under a continuous nitrogen sparge.
- the reactor contents were discharged into clean containers.
- the bulk of the Norpar phase is decanted from the polymer beads.
- the remaining slurry is vacuum filtered to remove residual Norpar.
- the filtered polymer beads are then dried under vacuum for three (3) hours at 50 degrees centigrade.
- 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 deoinized 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) was added to a 500 ml baffled reaction vessel equipped with a R100 impellar blade. 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 reaction vessel with stirring.
- the vessel is heated to 70°C and allowed to react 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 F 127 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 reaction 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 reaction vessel with stirring at a speed 650 rpm.
- the vessel is heated to 70°C and the reaction 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 get 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 get 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.
- nonylphenyl ether of polyehyleneglycol Nonoxynol 9, drug name is Igepal CO- 630
- This remarkable compound is surface active, possesses cloud point at around 55°C and is used as a spermicide an anti-HIV agent in vaginal applications. Synthesis and properties of the resulted responsive polymer network are described below. Synthesis. Igepal CO-630 (Rhone-Poulenc) (3.0 g) was dissolved in 3.0 acrylic acid
- Viscosity measurement Viscosity vs. temperature effect for responsive polymer network made of Nonoxanol 9 and polyacrylic acid (1 :1) in deionized was (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), respectively.
- 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 spectrophoto- metrically 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.
- 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), respectively.
- 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 spectrophotometrically at 280 nm.
- a calibration curve was prepared for lysozyme concentration ranging from 0 mg/ml to 0.5 mg/ml in phosphate buffered saline. The results of the kinetic experiment are presented in Fig. 17.
- the rate of lysozyme release from the responsive polymer network composition was substantially lowered at 37 C C when compared to that at 25 °C, because of viscosity increase in responsive polymer network at elevated temperatures (see Fig. 1).
- released from the responsive polymer network composition was assayed using Micrococcus lysodeikticus cells and compared to that of original lysozyme.
- the enzymatic activity of lysozyme was the same, within the error of the assay (15%), as that of the original lysozyme.
- Example 29 Drug loading 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 sell for 16 h in 10 ml of 5 mg/ml solution of bovine Zrr + -insulin (Sigma) in deionized water adjusted to pH7. The resulting mixture was well shaken and placed into the feed chambers of customized vertical, static, Franz-like 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 has been loaded into the cell, the timing commenced/ Samples were withdrawn and their absorbance was measured spectrophotometrically at 280 nm. A calibration curve was prepared for insulin concentration ranging from 0 mg/ml to 1.25 mg/ml in phosphate buffered saline. The results of the kinetic experiment are presented in Fig. l 8. 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 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 NaHCO 3 and 004g 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 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.
- 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 C, 16 psi for 30 minutes. Viscosify is determined after sterilization. The corresponding curves for viscosify (a) before and (b) after sterilization are shown in Fig. 20 and establish that minimal change in the viscosify 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.
- Three grams of acrylamide 99 + %, Aldrich, mp 84-86 °C
- Pluronic F127 NF 50 mg benzoin ethyl ether (99%, Aldrich, mp 59-61 °C).
- the resulting homogenous powder was placed into a plastic vial with a rubber septum and heated to up to 90 °C at which point a homogenous liquid was obtained (by melting of the component materials).
- the resultant liquid was purged with nitrogen for 5 min.
- 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 aery lam ide-based responsive polymer gel prepared with differing proportions of responsive and structural polymer components and to show performance under physiological conditions. Ten grams of acrylamide was thoroughly mixed with five grams Pluronic F127 NF and
- Medicinal and Cosmetic Formulations Because of the surfactant nature of the responsive component of the responsive polymer network composition coupled with the gelation effect of the responsive polymer network composition, it is possible to prepare a formulation which is 100% waster-based, but which is lubricous and thick.
- Formulations including nonionic. anionic and cationic surfactants (a) a nonionic surfactant formulation: An O/W (oil-in-water) emulsion was made by combining the following ingredients utilizing conventional mixing techniques:
- Crodatos CES available from Croda
- Vaginal Moisturizer An oil-free, lubricous, vaginal moisturizer is made by combining the following ingredients utilizing conventional mixing techniques:
- the formula amount of responsive polymer network is added to another vessel, equipped with a high efficiency homogenizer.
- the responsive polymer network vessel is then cooled to 4°C. After cooling, while vigorously homogenizing, the contents of the first vessel is added to the second vessel, and allowed to mix to homogeneity.
- the composition displays a flowable 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.
- 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.
- Formulation for Management of Bacterial Candidiasis An oil-free, lubricous, bacterial candidiasis treatment 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.
- 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:
- Germaben II available from Sutton Laboratories To one vessel, equipped with a Lightnin' Mixer with a 3 blade paddle prop, the full amount of USP Purified Water is added. The water is then heated to 80°C and held for 20 minutes. The water is then cooled to 50°C, while maintaining the temperature, with moderate to vigorous mixing, the formula amount of Disodium EDTA, Citric Acid, DL-Panthenol, Glycerin, Estradiol, and Germaben II is added. These materials are allowed to dissolve at 50°C. After dissolution, the vessel is then cooled to 20°C. To another vessel, equipped with a high efficiency homogenizer, the formula amount of responsive polymer network is added. The responsive polymer network vessel is then cooled to 4°C. After cooling, while vigorously homogenizing, the contents of the first vessel is added to the second vessel, and allowed to mix to homogeneity.
- the composition displays a flowable jelly appearance with excellent spreadability and absorption characteristics at room temperature, and after heating the formulation to 32°C, the composition 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:
- SUB 1 E SHEET RULE 26 polymer network vessel is then cooled to 4°C. After cooling, while vigorously homogenizing, the contents of the first vessel is added to the second vessel, and allowed to mix to homogeneity.
- the composition displays a flowable 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 Ibuprofen as the anti-inflammatory and Azone as the penetration enhancer is made by combining the following ingredients utilizing conventional mixing techniques:
- 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 characteristics at room temperature, and after heating the formulation to 32°C, the composition thickens to a gel-like consistency.
- a gel would dressing for decubitis ulcer treatment containing a proteolytic enzyme and antiseptic is made by combining the following ingredients utilizing conventional mixing techniques:
- the IPN vessel is then cooled to 4°C. After cooling, while vigorously homogenizing, the contents of the first vessel is added to the second vessel, and allowed to mix to homogeneity.
- the composition displays a flowable jelly appearance with excellent spreadability and absorpotion characteristics 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 combining the following ingredients utilizing conventional mixing techniques:
- the above ingredients are added and processed as described above for the vaginal moisture.
- the composition displays a flowable creamy lotion appearance with excellent emoiliency, spreadability and absorption characteristics 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 effect after application to the skin, which is not evident in typical commercial O/W emulsion formulations (See, Fig. 24).
- Example 35 Polymers of this invention prepared from benzoyl peroxide have excellent properties except that these polymers lack reproducibility in molecular weight.
- an azo initiator could be used as a replacement for all or some of the benzoyl initiator.
- azo initiators have less capacity to extract hydrogen radicals as compared to benzoyl initiators, there was significant concern that an azo initiator, by itself, would not provide for adequate covalent bonding of the poloxamer to the poly(acrylic acid).
- This example evaluates the percentage of poloxamer bound to ⁇ oly(acrylic acid) formed by adding about 56 weight percent acrylic acid to the about 44 weight percent poloxamer (e.g. , Pluronic ® F127) in the presence of only azo initiators and then using varying concentrations of azo/benzoyl peroxide initiators.
- the percentage of poloxamer bound to the poly (acrylic acid) reflects covalent attachment of the poloxamer to the poly(acrylic acid) formed in situ.
- the percentage bound is determined by measuring the amount of non-extractable poloxamer component after polymerization of the acrylic acid.
- the percentage of bound poloxamer was determined to be related to the quantity and type of initiator employed during polymerization of the acrylic acid.
- the percent poloxamer bound is a function of a mixmre of initiator employed.
- specific mixmres of azo/peroxide initiators provide for enhanced binding of the poloxamer to the poly (aery lie acid).
- 0.18 weight percent of azo initiator (Run 1) provides for 23 percent of the poloxamer bound to the poly(acrylic acid)
- 0.18 weight percent of azo initiator and 0.16 weight percent of benzoyl peroxide initiator provides for on average 41 percent of the poloxamer bound to the poly (acrylic acid) (average of runs 7 and 8).
- polymer compositions having more reproducible molecular weights are preferably prepared from a mixmre of azo and benzoyl peroxide initiators.
- this invention also relates to a method for the preparation of viscosifying polymers comprising a random copolymer comprising: an associating component comprising at least one hydrophilic region and at least one hydrophobic region and characterized by aggregation in solution in response to a change in an environmental condition selected from the group consisting of temperamre, pH, ionic strength and solvent compositions; and a solvophilic component randomly linked to the associating component and characterized in that the solvophilic component remains solvated under conditions which result in aggregation of the associating component wherein said method comprises adding a monomer or reactive oligomer which comprises the precursor of the solvophilic component to the associating component in the presence of a polymerization initiator comprising an non- hydrogen extracting initiator; and polymerizing said monomer or reactive oligomer to form the solvophilic component.
- the polymerization initiator preferably comprises a hydrogen extracting initiator. More preferably, the polymerization initiator comprises a 10: 1 to 1: 10 mole ratio of non- hydrogen extracting initiator: hydrogen extracting initiator.
- non-hydrogen extracting initiator refers to initiators having no more than 10% of the hydrogen extracting properties of benzyoyl peroxide.
- the non-hydrogen extracting initiator is an azo initiator (i.e., a polymerization initiator containing an azo group).
- hydrogen extracting initiators refer to those initiators having more than 10% of the hydrogen extracting properties of benzoyl peroxide.
- Preferred hydrogen extracting initiators include lauryl peroxide and benzoyl peroxide.
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Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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AU59068/98A AU5906898A (en) | 1997-01-02 | 1998-01-02 | Responsive polymer networks and methods of their use |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US3459797P | 1997-01-02 | 1997-01-02 | |
US60/034,597 | 1997-01-02 |
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WO1998029487A1 true WO1998029487A1 (fr) | 1998-07-09 |
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PCT/US1998/000062 WO1998029487A1 (fr) | 1997-01-02 | 1998-01-02 | Reticulats polymeres sensibles et leurs procedes d'utilisation |
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WO (1) | WO1998029487A1 (fr) |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1109563A2 (fr) * | 1998-08-04 | 2001-06-27 | Madash LLP | Hydrogels sensibles a la chaleur a terminaison modifiee |
WO2002032560A2 (fr) * | 2000-10-20 | 2002-04-25 | Rhodia Chimie | Procede de preparation d'une emulsion dont la phase organique est de forte viscosite |
WO2002055607A1 (fr) * | 2001-01-15 | 2002-07-18 | L'oreal | Dispersions stabilisees a des temperatures de 4 a 50 °c au moyen d'un polymere comportant des unites hydrosolubles et des unites a lcst |
WO2002055606A1 (fr) * | 2001-01-15 | 2002-07-18 | L'oreal | Emulsions et compositions moussantes contenant un polymere comprenant des unites hydrosolubles et des unites lcst, notamment pour des applications cosmetiques |
EP1315672A1 (fr) * | 2000-06-22 | 2003-06-04 | Rxkinetix, Inc. | Composition de vecteur d'administration et procede pour l'administration d'antigenes et d'autres medicaments |
WO2003080119A1 (fr) * | 2002-03-26 | 2003-10-02 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Composites biomedicaux sensibles |
WO2004112759A2 (fr) * | 2003-06-17 | 2004-12-29 | Peter William Richards | Timbres a coller sur la peau |
US7060663B1 (en) | 2001-06-05 | 2006-06-13 | Steven B Leeb | Smart cutting fluids |
US7115255B2 (en) | 2000-07-21 | 2006-10-03 | L'oreal | Polymer comprising water-soluble units and LCST units, and aqueous composition comprising same |
EP2034906A2 (fr) * | 2006-06-21 | 2009-03-18 | The Board Of Trustees Of The Leland Stanford Junior University | Compositions et méthodes pour joindre des lumières non unies |
EP2135525A2 (fr) | 2008-06-10 | 2009-12-23 | L'Oréal | Ensemble de maquillage et/ou de soin des cils |
WO2010079305A1 (fr) | 2009-01-07 | 2010-07-15 | Polymerexpert Sa | Composition anti-ronflement contenant un polymère thermogélifiant |
US7776803B2 (en) | 2001-06-05 | 2010-08-17 | Steven B Leeb | Working materials with smart cutting fluids |
US8067350B2 (en) | 2005-12-15 | 2011-11-29 | Kimberly-Clark Worldwide, Inc. | Color changing cleansing composition |
US9408785B2 (en) | 2012-10-15 | 2016-08-09 | L'oreal | Hair styling compositions containing aqueous wax dispersions |
US10413496B2 (en) | 2012-10-15 | 2019-09-17 | L'oreal | Aqueous wax dispersions |
US10561596B2 (en) | 2014-04-11 | 2020-02-18 | L'oreal | Compositions and dispersions containing particles comprising a polymer |
US10626294B2 (en) | 2012-10-15 | 2020-04-21 | L'oreal | Aqueous wax dispersions containing volatile solvents |
FR3091996A1 (fr) | 2019-01-24 | 2020-07-31 | Les Laboratoires Brothier | Composition cicatrisante |
CN114573751A (zh) * | 2020-11-28 | 2022-06-03 | 比亚迪股份有限公司 | 一种锂离子电池用分散剂及其制备方法、正极浆料、正极片和锂离子电池 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4188373A (en) * | 1976-02-26 | 1980-02-12 | Cooper Laboratories, Inc. | Clear, water-miscible, liquid pharmaceutical vehicles and compositions which gel at body temperature for drug delivery to mucous membranes |
US5252318A (en) * | 1990-06-15 | 1993-10-12 | Allergan, Inc. | Reversible gelation compositions and methods of use |
US5403893A (en) * | 1991-01-31 | 1995-04-04 | Massachusetts Institute Of Technology | Interpenetrating-polymer network phase-transition gels |
US5603955A (en) * | 1994-07-18 | 1997-02-18 | University Of Cincinnati | Enhanced loading of solutes into polymer gels |
-
1998
- 1998-01-02 AU AU59068/98A patent/AU5906898A/en not_active Abandoned
- 1998-01-02 WO PCT/US1998/000062 patent/WO1998029487A1/fr active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4188373A (en) * | 1976-02-26 | 1980-02-12 | Cooper Laboratories, Inc. | Clear, water-miscible, liquid pharmaceutical vehicles and compositions which gel at body temperature for drug delivery to mucous membranes |
US5252318A (en) * | 1990-06-15 | 1993-10-12 | Allergan, Inc. | Reversible gelation compositions and methods of use |
US5441732A (en) * | 1990-06-15 | 1995-08-15 | Allergan, Inc. | Reversible gelation emulsion compositions and methods of use |
US5403893A (en) * | 1991-01-31 | 1995-04-04 | Massachusetts Institute Of Technology | Interpenetrating-polymer network phase-transition gels |
US5603955A (en) * | 1994-07-18 | 1997-02-18 | University Of Cincinnati | Enhanced loading of solutes into polymer gels |
Cited By (37)
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EP1109563A2 (fr) * | 1998-08-04 | 2001-06-27 | Madash LLP | Hydrogels sensibles a la chaleur a terminaison modifiee |
EP1109563A4 (fr) * | 1998-08-04 | 2009-07-22 | Madash Llp | Hydrogels sensibles a la chaleur a terminaison modifiee |
EP1315672A4 (fr) * | 2000-06-22 | 2006-04-26 | Rxkinetix Inc | Composition de vecteur d'administration et procede pour l'administration d'antigenes et d'autres medicaments |
US7767197B2 (en) | 2000-06-22 | 2010-08-03 | Endo Pharmaceuticals Colorado LLC | Delivery vehicle composition and methods for delivering antigens and other drugs |
EP1315672A1 (fr) * | 2000-06-22 | 2003-06-04 | Rxkinetix, Inc. | Composition de vecteur d'administration et procede pour l'administration d'antigenes et d'autres medicaments |
US7883692B2 (en) | 2000-07-21 | 2011-02-08 | L'oreal | Polymer comprising water soluble units and LCST units, and aqueous composition comprising same |
US7115255B2 (en) | 2000-07-21 | 2006-10-03 | L'oreal | Polymer comprising water-soluble units and LCST units, and aqueous composition comprising same |
WO2002032560A2 (fr) * | 2000-10-20 | 2002-04-25 | Rhodia Chimie | Procede de preparation d'une emulsion dont la phase organique est de forte viscosite |
FR2815637A1 (fr) * | 2000-10-20 | 2002-04-26 | Rhodia Chimie Sa | Procede de preparation d'une emulsion dont la phase huileuse est de forte viscosite |
WO2002032560A3 (fr) * | 2000-10-20 | 2002-06-27 | Rhodia Chimie Sa | Procede de preparation d'une emulsion dont la phase organique est de forte viscosite |
FR2819415A1 (fr) * | 2001-01-15 | 2002-07-19 | Oreal | Dispersions stabilisees a des temperatures des 4 a 50 au moyen d'un polymere comportant des unites hydrosolubles et des unites a lcst |
US7652100B2 (en) | 2001-01-15 | 2010-01-26 | L'oreal | Dispersions stabilized at temperatures of from 4 to 50 degrees celsius by means of a polymer comprising water-soluble units and units with an LCST |
US7655702B2 (en) | 2001-01-15 | 2010-02-02 | L'oreal | Foaming emulsions and foaming compositions containing a polymer comprising water-soluble units and units with an LCST, especially for cosmetic uses |
FR2819429A1 (fr) * | 2001-01-15 | 2002-07-19 | Oreal | Emulsions et compositions moussantes contenant un polymere comprenant des unites hydrosolubles et des unites a lcst, notamment pour des applications cosmetiques |
WO2002055606A1 (fr) * | 2001-01-15 | 2002-07-18 | L'oreal | Emulsions et compositions moussantes contenant un polymere comprenant des unites hydrosolubles et des unites lcst, notamment pour des applications cosmetiques |
WO2002055607A1 (fr) * | 2001-01-15 | 2002-07-18 | L'oreal | Dispersions stabilisees a des temperatures de 4 a 50 °c au moyen d'un polymere comportant des unites hydrosolubles et des unites a lcst |
US7060663B1 (en) | 2001-06-05 | 2006-06-13 | Steven B Leeb | Smart cutting fluids |
US7776803B2 (en) | 2001-06-05 | 2010-08-17 | Steven B Leeb | Working materials with smart cutting fluids |
US7425322B2 (en) | 2002-03-26 | 2008-09-16 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Responsive biomedical composites |
WO2003080119A1 (fr) * | 2002-03-26 | 2003-10-02 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Composites biomedicaux sensibles |
WO2004112759A3 (fr) * | 2003-06-17 | 2005-03-24 | Peter William Richards | Timbres a coller sur la peau |
WO2004112759A2 (fr) * | 2003-06-17 | 2004-12-29 | Peter William Richards | Timbres a coller sur la peau |
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EP2034906A4 (fr) * | 2006-06-21 | 2010-07-28 | Univ Leland Stanford Junior | Compositions et méthodes pour joindre des lumières non unies |
EP2034906A2 (fr) * | 2006-06-21 | 2009-03-18 | The Board Of Trustees Of The Leland Stanford Junior University | Compositions et méthodes pour joindre des lumières non unies |
EP2135525A2 (fr) | 2008-06-10 | 2009-12-23 | L'Oréal | Ensemble de maquillage et/ou de soin des cils |
WO2010079305A1 (fr) | 2009-01-07 | 2010-07-15 | Polymerexpert Sa | Composition anti-ronflement contenant un polymère thermogélifiant |
US20110269839A1 (en) * | 2009-01-07 | 2011-11-03 | Polymerexpert Sa | Anti-snoring composition containing a termogelling polymer |
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US9408785B2 (en) | 2012-10-15 | 2016-08-09 | L'oreal | Hair styling compositions containing aqueous wax dispersions |
US10626294B2 (en) | 2012-10-15 | 2020-04-21 | L'oreal | Aqueous wax dispersions containing volatile solvents |
US10888504B2 (en) | 2012-10-15 | 2021-01-12 | L'oreal | Hair styling compositions containing aqueous wax dispersions |
US10561596B2 (en) | 2014-04-11 | 2020-02-18 | L'oreal | Compositions and dispersions containing particles comprising a polymer |
FR3091996A1 (fr) | 2019-01-24 | 2020-07-31 | Les Laboratoires Brothier | Composition cicatrisante |
EP3698768A1 (fr) | 2019-01-24 | 2020-08-26 | Les Laboratoires Brothier | Composition cicatrisante |
CN114573751A (zh) * | 2020-11-28 | 2022-06-03 | 比亚迪股份有限公司 | 一种锂离子电池用分散剂及其制备方法、正极浆料、正极片和锂离子电池 |
CN114573751B (zh) * | 2020-11-28 | 2023-12-12 | 比亚迪股份有限公司 | 一种锂离子电池用分散剂及其制备方法、正极浆料、正极片和锂离子电池 |
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