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|Número de publicación
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|Número de solicitud
|Fecha de publicación
|11 Nov 2004
|Fecha de presentación
|20 Abr 2004
|Fecha de prioridad
|25 Abr 2003
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|Hossein Omidian, Jose Gutierrez-Rocca
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|Hossein Omidian, Jose Gutierrez-Rocca
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|Citas de patentes (2), Citada por (10), Clasificaciones (34), Eventos legales (6)
|Enlaces externos: USPTO, Cesión de USPTO, Espacenet
[0001] This application claims priority under 35 U.S.C 119 from provisional application U.S. Ser. No. 60/465,755, filed Apr. 25, 2003, the contents of which are incorporated herein by reference.
[0002] The present invention relates to a method for the formation of superporous hydrogels having improved physical and mechanical properties.
[0003] superporous hydrogels (SPH) are chemically crosslinked hydrophilic polymers that contain a multiplicity of pores with diameters in the micrometer to millimeter range, enabling them to absorb tens of times their weight of aqueous fluids i just a fraction of a minute. SPH pores are interconnected in the hydrogel matrix such that absorbing fluid can move freely through the channels (capillaries), allowing them to swell much faster than conventional hydrogels that have the same swelling capacity.
[0004] To prepare a superporous hydrogel, a monomer, a crosslinker, a solvent (normally water), a surfactant (for foam stabilization), and a foaming aid are first mixed together, followed by the addition of an initiator. A blowing agent is then added to the mixture for the generation of gas bubbles such as, for example, the generation of caron dioxide. Once the initiator and blowing agent are added, foaming and polymerization (also refer as gelling) processes take place simultaneously. As polymerization proceeds, the viscosity of the reaction mixture increases and the bubbles being generated are trapped within the highly viscous polymer matrix. The foaming resulting from simultaneous gelation and bubble formation continues until both processed are stopped. At this stage, the product takes the form of flexible foam. To remove residual monomer, non-reacted crosslinker, and initiator impurities, the flexible foam is washed thoroughly with water. After this purification process, a water miscible alcohol such as, for example, ethanol, is added and subsequently removed to dehydrate the hydrogel. A final drying step is usually performed in an oven, preferably in a vacuum oven at low temperatures. U.S. Pat. No. 6,271,278 describes the preparation of various SPHs in detail. SPHs are also described by Chen, et al., in J Biomed. Mater. Res. 44:53-62 (1999).
[0005] Superporous hydrogels are generally prepared based on hydrophilic monomers, including acrylic acid and its salts, acrylamide, the potassium salt of sulfopropyl acrylate, hydroxyethyl acrylate, and hydroxyethyl methacrylate. A desirable superporous hydrogel would possess high solvent absorption properties yet be able to withstand external forces such as tension, compression, and bending. Some hydrogels have been prepared that have desirable swelling capacity and swelling rate properties. However, very high swelling superporous hydrogels are normally very loose after swelling and, when a small amount of pressure is applied, easily break apart. Some hydrogels have also been prepared that have reasonable mechanical properties, such as strength, ruggedness, and resiliency. However, very strong superporous hydrogels absorb limited amounts of water and thus have undesirable swelling properties. A preparation method for producing a hydrogel with both adequate swelling and mechanical properties is still lacking in the art.
[0006] This invention features a method for the preparation of a superporous hydrogel (SPH) in which its resulting physical and mechanical properties can be controlled by using a relatively simple ion-equilibration process, thereby producing a highly absorbent, yet structurally rugged and resilient, superporous hydrogel.
[0007] In a first aspect, the invention features a method of forming a hydrogel that includes the steps of, a) combining at least one ethylenically-unsaturated monomer, a cross-linking agent, and an ionic polysaccharide to form a mixture, b) subjecting the mixture to polymerization conditions to form a hydrogel, and c) reacting the hydrogel with one or more cations under equilibrating conditions, where at least one cation is used that was not used in step a) or, if the same mixture of cations is used in steps a) and c), the ratio of cations used in these steps is different. Preferably, the hydrogel that is formed by this method is a superporous hydrogel.
[0008] In one embodiment, the mixture includes one or more members of the group consisting of: a diluent, a foam stabilizer, a foaming aid, a reductant, an oxidant, and a blowing agent. Preferably, the mixture includes all of the members of this group.
[0009] In another embodiment, at least one of the cations used in step a) is monovalent and at least one of the cations used in step c) is divalent. Preferably the monovalent cations include Na+, K+, or NH4 + while divalent cations include Ca2+, Mg2+, Ba2+, Cu2+, Zn2+, Mn2+, or Fe2+.
[0010] In yet another embodiment, the method includes an additional step of reacting the superporous hydrogel (SPH) formed in step c) with one or more cations under equilibrating conditions where at least one cation is used that was not used in step c), or if the same mixture of cations is used as in step c), the ratio of cations used in this additional step is different. Preferably, the additional step includes reaction of the hydrogel with Ca2+, Cu2+, Zn2+, Ba2+, Mg2+, Mn2+, Fe2+, Fe3+, Cr3+, Al3+, or Ce4+. Most preferably, at least one of the cations reacted with said superporous hydrogel (SPH) formed in step c) has a valency of three or higher.
[0011] The polysaccharide of the invention can be, for example, salts of carboxymethylcellulose, alginate, hyaluronic acid, starch glycolate, carboxymethyl starch, dextran sulfate, pectinate, xanthan, carrageenan and chitosan. Preferably, the polysaccharide includes sodium salt of carboxymethylcellulose.
[0012] The ethylenically-unsaturated monomer of the invention can be, for example, (meth)acrylamide, N-isopropylacrylamide (NIPAM), N-cyclopropylacrylamide, diallyldimethylammonium chloride (DADMAC), 2-methacryloloxyethyl trimethylammonium chloride, N,N-dimethylaminoethyl acrylate, 2-hydroxyethyl acrylate (HEA), 2-hydroxyethyl methacrylate (HEMA), 2-hydroxypropyl methacrylate (HPMA), N-vinyl pyrrolidone (VP), (meth)acrylic acid (AA), salts of (meth)acrylic acid, salts and acids of esters of (meth)acrylic acid, amides of (meth)acrylic acid, N-alkyl amides of (meth)acrylic acid, salts and acids of N-alkyl amides of (meth)acrylic acid, itaconic acid, 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS), 3-sulfopropyl acrylate potassium salt (SPAK), 3-sulfopropyl methacrylate potassium salt or 2-(acryloyloxy)ethyltrimethyl-ammonium methyl sulfate (ATMS). Preferably, the mixture used in the formation of the hydrogel includes 2-hydroxyethyl acrylate as the ethylenically-unsaturated monomer.
[0013] The crosslinking agent of the invention can be, e.g., N,N′-methylenebisacrylamide, N, N′-ethylenebisacrylamide, poly(ethylene glycol) di(meth)acrylate, ethylene glycol di(meth)acrylate, ethyleneglycol diglycidyl ether, glycidyl methacrylate, polyamidoamine epichlorohydrin resin, trimethylolpropane triacrylate (TMPTA), piperazine diacrylamide, glutaraldehyde, epichlorohydrin, a crosslinking agent that includes one or more 1,2-diol structures, a crosslinking agent that includes one or more functionalized peptides, or a crosslinking agent that includes one or more functionalized proteins. Preferably, the mixture used in the formation of the hydrogel includes poly(ethylene glycol) diacrylate as the crosslinking agent.
[0014] In a second aspect, the invention features a method of dehydrating a hydrogel, preferably a superporous hydrogel, by lyophilization, such that a water/SPH weight to weight ratio of from 0.005 to 0.1 is achieved. In one embodiment, the dehydrating method includes the steps of, a) freezing the superporous hydrogel to about −10° C., with a cooling rate of about 3° C. per hour, b) maintaining the superporous hydrogel at about −10° C. for 16 to 24 hours, c) lyophilizing the superporous hydrogel at about −10° C. and at less than about 0.2 Torr for 60 to 80 hours, d) increasing the superporous hydrogel temperature to 10° C. at a rate of about 3° C. per hour, and e) maintaining the superporous hydrogel at 10° C. and at less than about 200 mTorr for at least 12 hours. In another embodiment of this aspect, the superporous hydrogel is prepared by a method of the present invention.
[0015] In a related aspect, the invention features a method for the dehydration of a hydrogel, preferably a superporous hydrogel, such that a water/SPH weight to weight ratio of from 0.005 to 0.1 is achieved, where the method includes the steps of, a) displacing water contained in the hydrogel with a non-aqueous, water-miscible solvent or solvent mixture, and b) removal of said non-aqueous solvent or solvent mixture at a pressure of less than 50 Torr or by heat. In one embodiment, the non-aqueous solvent can be, e.g., methanol, ethanol, 1-propanol, 2-propanol, tetrahydrofuran, dioxane, formic acid, acetic acid, acetonitrile, nitromethane, acetone, or 2-butanone. Preferably, the non-aqueous solvent includes ethanol. In another embodiment, the superporous hydrogel is prepared by a method of the present invention.
[0016] A dehydrated superporous hydrogel of the invention can include a medicament, a nutritional substance, or a fertilizer and be in the form of a film, a sheet, a particle, a granule, a fiber, a rod, or a tube. Preferably, the dehydrated hydrogel additionally includes a controlled release system for any of these substances.
[0017] By "crosslinking agent" is meant a molecule able to form a chemical bond to another substrate in the formation of a matrix.
[0018] By "monosaccharides" are meant polyhydric alcohols from three to ten or more carbon atoms containing either an aldehyde group (e.g., aldoses) or a keto group (e.g., ketoses), or masked aldehyde or keto groups, or derivatives thereof. Examples of monosaccharide units are the D and L configurations of glyceraldehyde, erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose, dihydroxyacetone, erythrulose, ribulose, xylulose, puscose, fructose, sorbose and/or tagatose. Examples of monosaccharides also include those monosaccharide deoxy sugars, such as, for example, fucose, rhamnose, and digitoxose; deoxyamino sugars such as, for example, glucosamine, mannosamine, galactosamine; deoxyacylamino sugars such as, for example, N-acetylglucosamine, N-acetylmannosamine, and N-acetylgalactosamine; and aldonic, aldaric and/or uronic acids such as, for example, gluconic acid or glucuronic acid. Monosaccharides also include ascorbic acid, amino acid-carrying monosaccharides and monosaccharides which carry lipid, phosphatidyl or polyol residues.
[0019] By "peptide" is meant a molecule that contains from 2 to 100 natural or unnatural amino acid residues joined by amide bonds formed between a carboxyl group of one amino acid and an amino group from the next one. When referring to a crosslinking agent, the term "functionalized peptide" refers to those peptides that have at least two groups suitable for carrying out a crosslinking reaction. These groups include olefins, carbonyls, esters, acyl halides, alkyl halides, and the like.
[0020] By "protein" is meant a molecule that contains greater than 100 natural or unnatural amino acid residues joined by amide bonds formed from a carboxyl group of one amino acid and an amino group from the next one. When referring to a crosslinking agent, the term "functionalized protein" refers to those proteins that have at least two groups suitable for carrying out a crosslinking reaction. These groups include olefins, carbonyls, esters, acyl halides, alkyl halides, and the like.
[0021] The term "polysaccharide" is meant to include any polymer of monosaccharides, or mixtures of polymers of monosaccharides, or salts therein, and includes disaccharides, oligosaccharides, etc. Polysaccharides include starch, carrageenan, xanthan, dextran, cellulose, chitosan, glycogen, hyaluronic acid, alginic acid, pectin and glycosylaminoglycans. The polysaccharide of this invention may be unmodified or modified and the term polysaccharide is used herein to include both types. By modified polysaccharide it is meant that the polysaccharide can be derivatized or modified by typical processes known in the art, e.g., esterification, etherification, grafting, oxidation, acid hydrolysis, cross-linking and/or enzyme conversion. Typically, modified polysaccharides include esters such as the acetate and the half-esters of dicarboxylic acids, particularly the alkenylsuccinic acids; ethers, such as hydroxyethyl and hydroxypropyl starches and starches reacted with hydrophobic cationic epoxides; starches oxidized with hypochlorite; starches reacted with cross-linking agents such as phosphorous oxychloride, epichlorohydrin or phosphate derivatives prepared by reaction with sodium or potassium orthophosphate or tripolyphosphate and combinations thereof. These and other conventional modifications of starch are described in publications such as Starch: Chemistry and Technology, 2nd Edition, Ed. Whistler, BeMiller, and Paschall, Academic Press, 1984, Chapter X.
[0022] By "hydrogel" is meant a crosslinked polymer network that is not soluble in water but swells to an equilibrium size in the presence of water.
[0023] By "superporous hydrogel" is meant a hydrogel that has interconnecting pores.
[0024] To prepare a superporous hydrogel of the invention, an ethylenically-unsaturated monomer is mixed with several ingredients, including a crosslinker and a certain amount of an ionic polysaccharide, in a polymerization reaction. The mixture can also include one or more co-monomers, diluents, surfactants, foaming aids, initiators, and blowing agents. The mixture can be polymerized by any method known to those skilled in the art, as described by Odian in Principles of Polymerization, 3rd Edition (1991), Wiley-Interscience. Polymerization techniques can include, for example, solution, suspension, microsuspension, inverse suspension, dispersion, emulsion, microemulsion, and inverse emulsion polymerization.
[0025] The ethylenically-unsaturated monomer used to make the superporous hydrogel of the invention can be (meth)acrylic acid, salts of (meth)acrylic acid, esters of (meth)acrylic acid, salts and acids of esters of (meth)acrylic acid, amides of (meth)acrylic acid, N-alkyl amides (meth)acrylic acid, salts and acids of N-alkyl amides of (meth)acrylic acid, N-vinyl pyrrolidone, acrylamide, acrylamide derivatives (e.g., N-1-propylacrylamide, N-isopropylacrylamide), methacrylamide, methacrylamide derivatives (e.g., N-cyclopropylmethacrylamide), and the like, and mixtures thereof. Preferred monomers include acrylamide (AM), N-isopropylacrylamide (NIPAM), 2-hydroxyethyl acrylate (HEA), 2-hydroxyethyl methacrylate (HEMA), 2-hydroxypropyl methacrylate (HPMA), N-vinyl pyrrolidone (VP), acrylic acid (AA), sodium acrylate (Na+AA), potassium acrylate (K+AA), ammonium acrylate (NH4 +AA), methacrylic acid and its salts, N, N-dimethylaminoethyl acrylate, diallyldimethylammonium chloride (DADMAC), 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS), 3-sulfopropyl acrylate, potassium salt (SPAK), 3-sulfopropyl methacrylate, potassium salt (SPMAK), 2-(acryloyloxy)ethyltrimethyl-ammonium methyl sulfate (ATMS), inorganic salts thereof, or mixtures thereof. Preferably, the concentration of monomer is from about 5% to about 50% (v/v) of the total reaction mixture volume when used as the primary monomer and from about 0.5% to about 10% (v/v) of the total reaction mixture volume when used as a secondary co-monomer. Most preferably, the reaction mixture includes 2-hydroxyethyl acrylate (HEA) as a primary monomer and a 50% (w/w) aqueous solution of 3-sulfopropyl acrylate, potassium salt as a co-monomer in a 4:1 (v/v) ratio, respectively, the combined volume of the two accounting for about 23% (v/v) of the total reaction mixture volume.
[0026] Crosslinking agents can be glutaraldehyde, epichlorohydrin, and degradable crosslinking agents including crosslinkers containing 1,2-diol structures (e.g., N,N′-diallyltartardiamide and ethylene glycol dimethacrylate), functionalized peptides and proteins (e.g., albumin modified with vinyl groups), ethylene glycol di(meth)acrylate, trimethylolpropane triacrylate (TMPTA), N,N′-methylenebisacrylamide (BIS), and piperazine diacrylamide. Multiolefinic crosslinking agents containing at least two vinyl groups, such as ethylene glycol di(meth)acrylate, poly (ethylene glycol) di(meth)acrylate, trimethylolpropane triacrylate (TMPTA), N,N′-methylenebisacrylamide (BIS), piperazine diacrylamide, crosslinkers containing 1,2-diol structures and two vinyl groups (e.g., N,N′-diallyltartardiamide or ethylene glycol dimethacrylate) are preferred. A most preferred crosslinking agent is poly(ethylene glycol) diacrylate. Preferably, the (v/v) ratio of crosslinker to monomer is from about 0.01/100 to about 1/10. Most preferably, the (v/v) ratio of crosslinker to monomer is from about 1/100 to 1/10.
[0027] In the preparation of the hydrogel, foam stabilization can be accomplished by physical or chemical means. For example, a rapid cooling or hot drying (for example, flash drying at a high temperature under an inert atmosphere) process can be used to stabilize the foam that has been produced by a gas blowing technique. Desirably, a surfactant can be used to stabilize the foam until the beginning of the gelling process. Useful surfactants include Triton surfactants, Tween and Span surfactants, Pluronic® surfactants (poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) tri-block copolymers) (BASF), Silwet® surfactants (OSi Specialties Inc.), sodium dodecyl sulfate (Bio-Rad Laboratories), albumin (Sigma Chemical Company), gelatin, or combinations thereof. Preferably, Pluronic® F127 (PF127) is used. Surfactant concentrations in the range of about 0.2% to about 2% (w/v) of the total solution were found to be adequate. Preferably, the surfactant concentration is in the range of about 0.4% to about 1% (w/v). Most preferably, the surfactant concentration is about 0.7% (w/v)
[0028] Any gas blowing technique, for example, chemical or mechanical, can be used to prepare the superporous hydrogels of the invention. Because of the foaming technique used in the preparation of these hydrogels, they may also be called hydrogel foams. In the synthesis of a superporous hydrogel by a gas blowing technique, foaming and polymerization have to occur simultaneously, making it important to control the timing of these reactions. Inorganic carbonates, such as sodium carbonate, potassium carbonate, potassium bicarbonate, or, most preferably, sodium bicarbonate, can be used as a blowing agent. For the large-scale production of a superporous hydrogel, mechanical blowing through one or more atomizers is a satisfactory alternative to the chemical blowing method, since the heat generated during polymerization may not be dissipated quickly. Thus, a smaller amount of initiator may be used to delay the gelling time (e.g., more than 10 minutes) and, since mechanical blowing can start at any time for any duration, the foaming process may be initiated at the desired time with the foam height maintained as necessary.
[0029] Polymerization may be initiated by any polymerization-initiator system which is suitable for the polymerization of unsaturated monomers in the homogeneous or heterogeneous phase. In general terms, initiator systems that may be used in the process according to the present invention are those known to the person skilled in the art of polymer chemistry. Without restricting the present invention, such initiators are preferably free-radical or free-radical forming compounds or mixtures of substances, such as for example hydroperoxides, preferably cumyl hydroperoxide or tert.-butyl hydroperoxide, organic peroxides, preferably dibenzoyl peroxide, dilauryl peroxide, dicumyl peroxide, di-tert.-butyl peroxide, methyl ethyl ketone peroxide, tert.-butylbenzoyl peroxide, diisopropyl peroxydicarbonate, dicyclohexyl peroxydicarbonate, di-tert.-butyl peroxalate, inorganic peroxides, preferably potassium persulfate, potassium peroxydisulfate or hydrogen peroxide, azo compounds, preferably azobis(isobutyronitrile), 1,1′-azobis(1-cyclohexane nitrile), 4,4′-azobis(4-cyanovaleric acid) or triphenyl-methylazobenzene, redox systems, preferably mixtures of peroxides and amines, mixtures of peroxides and reducing agents, optionally in the presence of metal salts and/or chelating agents. The initiator systems can be pure or in the form of mixtures of two, three or more different initiator systems. In another example, portions of the initiator system are added to the reaction separately in solid, liquid or gaseous form. This procedure is particularly suitable for redox initiator systems. In the present invention, preferably a combination of an oxidant and a reductant (a redox pair) is used as an initiator. Most preferably, the redox pair of ammonium persulfate (APS) and N,N,N′,N′-tetramethylethylenediamine (TEMED) is used.
[0030] The pore size of the superporous hydrogels prepared by the foaming technique is usually larger than 100 μm, and it can easily reach the millimeter range. Usually, the pores are so large that they are visible with the unaided eye.
[0031] The ionic polysaccharide used can be any polysaccharide that includes negatively/positively charged groups that can counter the positive/negative charge of a cation/ anion. Ordinarily, a primary cation is initially provided with the ionic polysaccharide of the superporous hydrogel formulation, with the polysaccharide playing a critical role in the process of subsequent ion-equilibration(s). Preferably, the polysaccharide is chosen from the list that includes sodium carboxymethylcellulose, sodium starch glycolate, sodium carboxymethyl starch, dextran sulfate, chitosan, hyaluronic acid, xanthan, carrageenan, gellan, sodium alginate, and sodium pectinate. Most preferably, the polysaccharide is sodium carboxymethylcellulose. The ratio of polysaccharide to total solution can be in the range of 0.1-10% w/v. Preferably, the range is 0.2-5% w/v. Most preferably, the range is 0.2-1.5% w/v.
[0032] Ion equilibration is a process by which ion exchange happens within the substrate structure. The exchange process may take place between any kinds of ions of different valences (e.g., monovalent, divalent, trivalent or higher). For example, 2-valent cations within the substrate can partially be replaced by 3-valent cations or vice versa. When the process of ion-equilibration is completed, the product contains equilibrium amounts of two or more cations. The equilibration just described results in considerable change in substrate properties. For example, sodium salt of carboxymethylcellulose is soluble in water, while its calcium-treated derivative is water-insoluble. Therefore, a simple partial replacement of sodium with calcium cation makes the final polymer sparingly soluble or insoluble in water. The general process of dramatically changing the properties of a substrate based on ion-exchange can also be applied to a superporous hydrogel formulation of the invention.
[0033] A hydrogel substrate can originally contain ions or can be ionized after its formation. A salt, ionic monomer, an ionic polymer, or any other ionic ingredient can provide the original or primary cation. This original cation is called primary, since it has to be partially replaced by another cation, i.e. secondary. The equilibrium mixture of primary and secondary cations can also be equilibrated with the third cation, i.e. tertiary cation and so on. To achieve desirable hydrogel properties, the process of ion-equilibration can be repeated with a number of different cations. A simple salt, ionic monomer, ionic polymer or another ion source can provide the secondary or tertiary cation. The ion-equilibration process can take place in an aqueous or a mixed aqueous/alcoholic medium, where the ions can move with freedom.
[0034] After foaming and polymerization are completed, a polysaccharide-containing superporous hydrogel can be immediately placed into an aqueous or mixed aqueous/alcoholic solution that includes any 2-valent cation, 3-valent cation or mixture of 2-, 3- or higher-valent cations like cerium. Preferably, the two-valent cation is Ca2+, Ba2+, Mg2+, Cu2+, Zn2+, Mn2+, or Fe2+. Most preferably, the 2-valent cation is Ca2+. Normally, the ion-exchange process between monovalent and two-valent cations is rapid and swelling of the hydrogel occurs. Although the process of ion-equilibration is fast, to ensure that the ion-equilibration process has been completed, a treatment time in the range from 0.5 hour to 24 hours is recommended. To obtain additional desirable properties, the ion-equilibrated superporous hydrogel may be retreated with a solution that includes a tertiary cation. Preferably, the 3-valent cation is iron or aluminum. As before with the secondary cation equilibration, the superporous hydrogel is placed into medium that includes a trivalent cation and cation equilibration occurs rapidly. To ensure that ion-equilibration has been completed, the hydrogel is left in the solution for period of time, preferably from 0.5 hour to 24 hours. The ion-equilibrated hydrogel is then thoroughly washed with pure water, washed with a non-aqueous, water-miscible solvent, and dried out in an oven or in a vacuum oven. Alternatively, the purified superporous hydrogel can be dried out in an oven/vacuum oven or by a lyophilization technique.
[0035] Examples of how the ion-equilibration process can considerably change the final physical and mechanical properties of the superporous hydrogel produced are shown in Table 1.
TABLE 1 Influence of Cations on Superporous Hydrogel properties Na+1 exchange Na+1/Ca+2 Na+1 exchange with Al+3 or exchange with Na+1 (a) with Ca+2 (b) Fe+3 (c) Al+3 (c) or Fe+3 Swelling Very High Low Medium capacity in high water Swelling Very Slow Very fast Fast rate in slow water Hydrogel Very Low Very high High Strength low Surface Very Slippery Very rough Rough property slippery Handling Very Diffi- Very easy Easy difficult cult Gel Very Loose Very tough Tough consistency loose
[0036] For dehydration of an ion-equilibrated superporous hydrogel using a non-aqueous solvent the method includes the steps of, a) displacing water contained in the hydrogel matrix with a non-aqueous, water-miscible solvent or solvent mixture through a series of washings, and b) removal of said non-aqueous solvent or 10 solvent mixture at a pressure of less than 50 Torr or by heat. The non-aqueous solvent can include methanol, ethanol, 1-propanol, 2-propanol, tetrahydrofuran, dioxane, formic acid, acetic acid, acetonitrile, nitromethane, acetone, or 2-butanone. Preferably, the non-aqueous solvent includes ethanol. When dehydrating a superporous hydrogel by lyophilization, a preferred method includes the steps of, a) freezing the superporous hydrogel sample from about 23° C. to about −10° C. with a cooling rate of about 3° C. per hour, b) maintaining the sample at about −10° C. for 16 to 24 hours, c) lyophilizing the sample at about −10° C. and at less than about 0.2 Torr for 60 to 80 hours, d) increasing the sample temperature to 10° C. at a rate of about 3° C. per hour, and e) maintaining the sample at 10° C. and at less than about 200 mTorr for at least 12 hours.
[0037] The dehydrated superporous hydrogels of the present invention rapidly swell to a relatively large size when placed in contact with aqueous fluids, yet remain mechanically strong in their swollen state. Taking advantage of these properties, these hydrogels can be useful as drug delivery systems (DDSs), as described by Park, et al., in Biodegradable Hydrogels for Drug Delivery, 1993, Technomic Pub. Co. or in Hydrogels and Biodegradable Polymers for Bioapplications (ACS Symposium Series, 627), 1996, Eds., Ottenbrite, et al., American Chemical Society.
[0038] Many DDSs release pharmaceutical agents from specific locations in the body over specific periods of time. Without additional measures taken to retard its passage through the alimentary canal, there is usually a ten hour limit for the absorption through the lining of the small intestine of an orally administered drug. In addition, some drugs are preferentially absorbed in certain regions in the gastrointestinal tract (GI), with many preferentially absorbed in the upper GI. In these cases, it is desirable to prolong the residence of a DDS in the upper GI tract (gastric retention) to enhance drug absorbance. Other hydrogels have also been used for this purpose, such as those described by Park, et al., in U. S. Pat. No. 6,271,278, which is hereby incorporated by reference.
[0039] Drug delivery can involve implanting a controlled release system within a matrix of a dehydrated superporous hydrogel of the invention. This, in turn, would be contained in a capsule (e.g., a gelatin capsule) or similar housing system that can be eroded by the acidic conditions in the stomach. The gastric retention of superporous hydrogels is based on their fast swelling property. Once a superporous hydrogel of the invention is exposed to gastric fluid, it rapidly swells to its maximum swelling capacity, typically in less than ten minutes. For their use in humans, superporous hydrogels that swell to a diameter of greater than 2 cm at low pH conditions are desirable as they are then unable to pass through the pylorus sphincter, ensuring prolonged residence in the stomach and better absorption of the drug through the upper GI.
[0040] In addition to drug delivery, the hydrogels of the invention can have a variety of applications including, for example, tissue engineering, vascular surgery (e.g., angioplasty) and drainage (e.g., from the kidney). Devices prepared using hydrogels of the invention can include vascular grafts, stents, catheters, cannulas, plugs, constrictors, tissue scaffolds, and tissue or biological encapsulants, and the like.
[0041] They may be applied to any use which requires a porous hydrogel material, particularly with an open pore structure. For example, the materials are useful as matrices or scaffolds into which cells can migrate, the cells being compatible therein and growing to achieve their intended function, such as in tissue replacement, eventually replacing the matrix depending on its biodegradability. Furthermore, the materials can be used to provide matrices already bound to cells, which may then be surgically implanted into a body. Further, the materials can be used as wound healing matrix materials, as matrices for in vitro cell culture studies or uses similar thereto. The stable structure of the materials of the invention provides ideal cell culture conditions.
[0042] The materials of the invention may also have application in cell transplantation, including for hepatocytes (see, D. J. Mooney, P. M. Kaufmann, K. Sano, K. M. McNamara, J. P. Vacanti, and R. Langer, "Transplantation of hepatocytes using porous biodegradable sponges," Transplantation Proceedings, 1994, 26:3425-3426; D. J. Mooney, S. Park, P. M. Kaufmann, K. Sano, K. McNamara, J. P. Vacanti, and R. Langer, "Biodegradable sponges for hepatocyte transplantation," Journal of biomedical Materials Research, 1995, 29:959-965), chondrocytes and osteoblasts (see, S. L. Ishaug, M. J. Yaszemski, R. Biciog, A. G. Mikos; "Osteoblast Function on Synthetic Biodegradable Polymers", J. of Biomed. Mat. Res., 1994, 28:1445-1453).
[0043] Smooth muscle cells may readily adhere to the material prepared according to the invention and create three-dimensional tissues especially if appropriate cell adhesion ligand are coupled to the hydrogel structure within these porous structures; thus, they provide a suitable environment for cell proliferation. In addition, these materials have potential to incorporate growth factors.
[0044] Another useful application for the hydrogels of the invention is for guided tissue regeneration (GTR). This application is based on the premise that progenitor cells responsible for tissue regeneration reside in the underlying healthy tissue and can be induced to migrate into a defect and regenerate the lost tissue. A critical feature of materials for GTR is the transport of cells into the material, a property which is dictated by the pore size distribution and pore continuity, i.e., interconnectivity. The material must allow the desired cells to invade the material while preventing access to other cell types.
[0045] Because of the absorbent properties of the hydrogels of the invention they are very suitable for use in absorbent articles, and especially disposable absorbent articles. By "absorbent article" herein is meant a consumer product which is capable of absorbing significant quantities of water and other fluids (i.e., liquids), like body fluids. Examples of absorbent articles include disposable diapers, sanitary napkins, incontinence pads, paper towels, facial tissues, and the like.
[0046] Hydrogels of the invention can also be useful for protecting, holding or transplanting growing plants in the form of seeds, seedlings, tubers, cuttings, nursery stock, roots, transplants and the like. These hydrogels can aid a growing plant, either alone or in combination with fertilizer, agricultural modified minerals, and the like uniformly dispersed throughout.
[0047] The following non-limiting examples are illustrative of the invention.
[0048] All reaction mixture components in the following example were used in the amounts indicated in Table 2.
[0049] In a glass tube were placed, hydroxyethylacrylate, poly(ethylene glycol) diacrylate (as a 1:2 (v/v) solution in hydroxyethylacrylate), water, Pluronic® F127, SPAK and CMC solutions. The components were mixed well until homogeneity was achieved. The reaction mixture was placed on a shaker and continually mixed. Glacial acetic acid was added, followed by the addition of tetramethylethylenediamine and ammonium persulfate. After all ingredients were thoroughly mixed, sodium bicarbonate was well dispersed into the reaction mixture. The resulting mixture began foaming and simultaneous gelation and foaming resulted in a superporous hydrogel foam. The foam was removed from the tube and placed into an aqueous solution of calcium chloride (1:200 (w/v) of hexahydrated calcium chloride in distilled water). The suspension was incubated for 2 hrs. The calcium-treated superporous hydrogel was immersed into an aqueous ferric chloride solution (1:300 (w/v) of hexahydrated ferric chloride in distilled water). The suspension was incubated for another 2 hrs.
[0050] Similar to Example 1 except the foam was removed from the tube and placed into a mixture of an aqueous solution of hexahydrated calcium chloride (1:200 (w/v)) and hexahydrated aluminum chloride (0.5: 200 (w/v)). The suspension was incubated for 2 hrs.
[0051] Similar to Example 1 except the foam was removed from the tube and 5 placed into an ethanolic aqueous solution of hexahydrated ferric chloride (1:200 (w/v)). The ethanol/ water ratio was 1/3 v/v. The suspension was incubated for 2 hrs.
TABLE 2 Reaction mixture components Applicable Ingredient Acting as: Amount range Hydroxyethylacrylate Monomer 2000 μL 2000 μL (HEA) Poly(ethylene glycol) di- Crosslinker 80 μL 50-250 μL acrylate solution in HEA; 1:2 v/v De-ionized water Diluent/Solvent 2000 μL 500-3000 μL Pluronic ® F127, Surfactant 800 μL 100-1000 μL 10 wt % aqueous solu- tion Glacial acetic acid Foaming aid 160 μL 40-200 μL Sulfopropylacrylate, Co-monomer 500 μL 0-3000 μL Potassium salt, 50 wt % aqueous solution Carboxymethylcellulose, Polysaccharide 3000 μL 500-7000 μL Sodium salt, 2 wt % aqueous solution Tetramethylethylenedi- Reductant 200 μL 80-400 μL amine, 40 v/v % aqeuous solution Ammonium persulfate, Oxidant 200 μL 40-400 μL 20 wt % aqueous solu- tion Sodium bicarbonate Blowing agent 250 mg 60-300 mg
[0052] With each example, the ion-equilibrated superporous hydrogel was thoroughly washed with de-ionized water (100 mL, five to ten times) until all impurities were removed. The purified ion-equilibrated superporous hydrogel was then dehydrated by treating it with ethyl alcohol (100 mL, one to three times), followed by drying in an air-forced oven at 40° C. Alternatively, the purified ion-equilibrated superporous hydrogel may directly be dried out in an oven or vacuum oven. As another alternative, the purified ion-equilibrated superporous hydrogel can be freeze-dried using the following lyophilization schedule: a) freezing the superporous hydrogel from room temperature to −10° C., with a freezing rate of −3° C./hr., b) keeping the sample at a temperature of −10° C. for 24 hrs., d) lyophilizing at 10-100 mTorr for 72 hrs., e) raising the temperature to 10° C. at a rate of 3° C./hr., and f) drying at 10° C. for 24 hrs.
[0053] From the foregoing description, it will be apparent that variations and modifications may be made to the invention described herein to adopt it to various applications and conditions. Such embodiments are also within the scope of the following claims.
[0054] All publications mentioned in this specification are herein incorporated by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference.
|Patente citada
|Fecha de presentación
|Fecha de publicación
|13 May 1997
|7 Ago 2001
|Purdue Research Foundation
|Hydrogel composites and superporous hydrogel composites having fast swelling, high mechanical strength, and superabsorbent properties
|22 Abr 2003
|18 Dic 2003
|Hossein Omidian
|Hydrogels having enhanced elasticity and mechanical strength properties
|Patente citante
|Fecha de presentación
|Fecha de publicación
|9 Feb 2007
|22 Nov 2011
|Fossa Medical, Inc.
|Methods and apparatus for temporarily occluding body openings
|18 May 2007
|10 Ene 2012
|Beijing Dingguochangsheng Biotech, Co. Ltd.
|Simple method for introducing magnetic particles into a polymer
|9 Abr 2009
|29 Ene 2013
|Biolife, Llc
|Materials and methods for wound treatment
|30 Nov 2009
|12 Feb 2013
|Biolife, Llc
|Materials and methods for preparation of alkaline earth ferrates from alkaline earth oxides, peroxides, and nitrates
|1 Feb 2012
|24 May 2012
|Nellcor Puritan Bennett Llc
|Endotracheal cuff and technique for using the same
|10 Jun 2010
|13 Oct 2010
|Chitin hydrogel and preparation method and application thereof
|9 Oct 2010
|16 Mar 2011
|Method for preparing dual-parent nitrogen-containing super water absorbent resin from carboxymethyl starch and phosphate starch serving as raw materials
|9 Oct 2010
|16 Mar 2011
|Method for preparing double-matrix nitrogen and potassium-containing super absorbent resin from carboxymethyl starch and phosphate starch serving as raw materials
|20 Abr 2011
|26 Oct 2011
|Preparation method of macroporous sodium carboxymethylcellulose grafted copolymer with rapid swelling absorption property
|25 Oct 2010
|16 May 2012
|Polymer hydrogel for absorbing heavy metals and preparation method and application thereof
|Clasificación de EE.UU.
|424/484, 525/54.3, 525/330.3, 524/556, 521/61, 521/134
|Clasificación internacional
|Clasificación cooperativa
|Clasificación europea
|27 Ago 2004
Owner name: KOS PHARMACUETICALS, INC., FLORIDA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:OMIDIAN, HOSSEIN;GUTIERREZ-ROCCA, JOSE;REEL/FRAME:015089/0593
Effective date: 20040729
|22 Jun 2006
Owner name: KOS LIFE SCIENCES, INC., FLORIDA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:KOS PHARMACEUTICALS, INC.;REEL/FRAME:017838/0029
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KAR Auction Services announced that its subsidiary, Openlane, Inc., has agreed to build a private label website for Auction Edge utilizing Openlane's proprietary technology platform. The private label website created for Auction Edge will be known as the EDGE Marketplace. Openlane will be delivering to Auction Edge and its member auctions a customized version of its leading online auction system already used by commercial consignors, automotive dealers and a number of ADESA and Auction Edge's mutual customers. Auction Edge is expected to offer this private label program to independent auctions in early 2016.
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Danaher Jobs in Washington, DC
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Danaher Reviews
Helpful (6)
"By far the worst company to work for "
Doesn't RecommendNeutral OutlookDisapproves of CEO
- Work/Life Balance
- Culture & Values
- Career Opportunities
- Comp & Benefits
- Senior Management
I worked at Danaher full-time (More than a year)
Salary is fairly decent buts thats about it.
Work / Life Balance is horrible they expect you to work whenever they say but you unable to carry any time off over to the next year. Did i mention you only get 10 days per year. Danaher considers there employees as a statistics you are just another number on a sheet to them. Once your project ends be prepared to look for another opportunity because they already forecasted the end of your job. There is ZERO culture at Danaher you feel like a drone working here & you can be easily replaced. I believe the average lifespan of an employees is 1-3 years if your not senior management expect to get canned within that timeframe. I would avoid working for them or any of there subsidiaries at all cost.
Advice to Management
Care more about your employees welfare then just what they can do for you. Provide opportunities for growth not just for senior management but for all the other associates.


text:
Matt Rasmussen
Rasmussen's honors and awards include fellowships from Yaddo, the Loft Literary Center, the Jerome Foundation, Intermedia Arts, and the McKnight Foundation. He is a founding member of the poetry press Birds, LLC. Rasmussen has taught at his alma mater, Gustavus Adolphus College.
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Poems By MATT RASMUSSEN
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Audio & PodcastsPoetry Off the Shelf
Stop the Milk
Kathleen Rooney on the poetry of Matt Rasmussen.
Poet Categorization
POET'S REGION U.S., Midwestern
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It's a sort of wonderful treat when an artist you like gets to reveal their own musical tastes and said revealed musical taste match up with yours. Such is the case with electro pop duo Sylvan Esso who've taken to performing a cover of Porches. "The Cosmos" on their current batch of shows. It's delightful to say the least as the band leave behind their dancefloor ready jams in favor of a more intimate kind of number. Their take on "The Cosmos" is surprisingly sparse – a blanket of synthy hum while Amelia Randall Meath's vocals arc and glide (and Nicholas Sanborn adds a bit of flavor with backing vocals). It's appropriately chill, an enjoyable homage that highlight's Aaron Maine's quirky but intelligent songwriting talents while also showcasing Meath's powerful vocal ability.
Listen | Salt Cathedral: "Tease"
Brooklyn experimentalists Salt Cathedral continue their genre switch up and the results are a lot more infectious than previous venture "Good Winds". That's fair, considering the newly trimmed down quartet have already established they very much know what they're doing with b-side/first dip into electronica "Rainy Days".
"Tease", another peek at their upcoming EP, is a good example of the type of brilliance their previous characteristics can bring to the electro pop arena: Juliana Ronderos' vocals still remarkably alluring over the surging beats while Salt Cathedral employ their complex rhythms/textural interplay on a much smaller scale, with many of the intricate layering reserved for cool background effects. Aside from a bit of it at the track's introduction – Salt Cathedral avoid the stuttering glitchy approach towards dance and instead make full use of beautifully flowing melodies aided no doubt by Ronderos' magnificently fluid delivery.
Listen| Mirage: "Something"
Los Angeles experimentalist Robin Nydal aka Mirage manages to blend bedroom pop intimacy with technicolor psychedelic deviations and that's just the starting point. With songs that function more or less like sound collages, Mirage's songs run the range of everything from orchestral pop flights of fancy to jittery electronic pop all stitched together with the consistency of a ransom letter crafted from newspaper scraps. The same skill for small scale musical metamorphoses applies not only to Nydal's production but the man himself – vocals going from svelte whisper to warbling croon at the drop of the hat when Nydal requires another timbre to throw into his impressive textural play. "Something" is one of the rare cuts on Blood For The Return that blunts its abrasive edge in favor of the crisp elegance string arrangements. And yet, it's not without an obvious air of whimsy and certainly doesn't sideline Nydal during its forays into beauty – the track's true lushness comes from Nydal's machinations at the helm- harmonies and various effects swirling around the sweeping string ornaments. "Something" is a work of surprising tension release – swinging with ease between sections while never losing its off-kilter footing.
Mirage's Blood For the Return is out in August on Olde English Spelling Bee but available to stream via Bandcamp.
Video | Hundred Waters: "Murmurs"
It may be too soon to call it but today art pop collective Hundred Waters released a music video for what may arguably be my favorite track on their enthralling sophomore record and album of the year contender The Moon Rang Like A Bell.
Directed by BANGS, the video takes a decidedly direct and minimalistic approach towards the track's multitudinous layers. Beginning with an closeup of vocalist Nicole Miglis as she sings the tracks' stuttering opening while the camera subtly follows the incomplete non-delivery with slow clean jerks, BANGS quickly establishes a dreamy quality before any of the action truly begins. While Miglis wanders around a beautiful home in the midst of destruction, there's both an unshakeable melancholy and an unsettling resilience in her mere presence. As pieces of debris rain down just right of her, and lights flicker, Miglis sits unshaken and dare I say comfortable.
BANGS' vision is quietly surrealist to the point that the video's plot remains for the most part indiscernible. Is it all a dream? And while Miglis stalks the grounds like a ghost, there's a twist every so often that turns that theory on its head. Whether its the demolition crew's relative inattention to her subverted by a shot of her standing hand in hand with one or their own dreamlike qualities, nothing is quite what it seems and that makes the video all the more intriguing.
Listen | Ásgeir : "Torrent"
It's pretty much inevitable when you go to a large festival that you won't see all the bands you meant to and such is certainly the case with Iceland's Ásgeir at SXSW – a musical act I was attracted to based more on name and country of origin than through actual listening habits. That was a huge misstep on part though as if I had made time to listen before my Texas excursion I certainly would've made time to see them perform.
The brainchild of singer/songwriter Ásgeir Trausti Einarsson, the band are most likely to draw comparisons to Sigur Rós due to their shared homeland but other than that the similarities end there. Where Sigur Rós are atmospheric and ethereal, Ásgeir is much more direct; embracing pop conventions but by no means solely defined by them. On In The Silence (the English language version of debut album Dýrð í dauðaþögn and US debut), Ásgeir manages to create a cohesive collection of songs that elude any concrete genre descriptors incorporating elements of electronica, chamber pop, and folk in good measure without getting bogged down by their inclusion.
"Torrent", the latest single from his debut, is perhaps the most telling of the band. Surging forth like its namesake, "Torrent" is a deluge of melodic grandeur – from its thundering drums to its piano pop flourishes, Ásgeir effortlessly invokes wide open expanses with a life-affirming brilliance. Ásgeir's vocals are silvery and pristine but there's no deny they're elevated by a knack for melodic songcraft – lending them a necessary insistence, a heightened state of drama that renders the track's 3 minute length tragically brief.


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Download Collect `em all Space iPhone iPad iOS
Fly your rocket around to collect the stars! Swipe your finger on the screen to see it move to it`s target! However, mind you don`t crash into an alien spaceship! Also, keep a close eye on your fuel as you`re flying; to gain more fuel, land on the planet surface below. If you run out of fuel then you will lose a life! But don`t worry! Collect the rare fuel containers to regain lives! Don`t touch the comet or else it will be game over. Also, collect the rare power up which gives you a shield, leaving you immune to aliens and comets. Have fun!
Also, be sure to get the iPad version for your other devices! Available to download from the App Store now!
Click4more: Related apps collect em all space
The Collect `em all Space is now available for $0.99 for both iPhone and iPad owners.The application is designed for use in English language. It weighs in at only 0.9 MB to download. The new Collect `em all Space app version 1.0 has been updated on 2014-11-09. For ensuring consistency with the device you should take into account the following app compatibility information: Compatible with iPhone 3GS, iPhone 4, iPhone 4S, iPhone 5, iPod touch (3rd generation), iPod touch (4th generation), iPod touch (5th generation) and iPad. Requires iOS 5.0 or later.
Bottom Line: For more information about Collect `em all Space check developer Jeff Williams`s website : http://twitter.com/FMercury7102
Tags : collect , collect the
iOS Collect `em all Space 1.0 Mobile
Related - Games - Collect `em all Space 1.0
More in Games - for Collect `em all Space iPhone
More by Jeff Williams - for Collect `em all Space app ioS


text:
Illinois Public Media
All articles tagged Champaign School District
Students Counter Negative Images Of African-Americans
Champaign Police Looking For Man Accused Of Sexual Abusing Minor
Champaign School Board Approves Teachers' Contract
Champaign Teachers Ratify Contract Agreement
Champaign School District, Union Reach Tentative Agreement
Champaign Teachers Show Support During Contract Talks
Unit 4 District, Union Release Contract Proposals
Early School Dismissals Tuesday Due To Heat
Kerris Lee To Join Unit 4 School Board
Champaign Parents Organize Fund Drive for Tornado Victims
Community Conversations: Champaign Unit 4 School District
Champaign Unit 4 Officials Back Lockman Hiring
Champaign Teacher Finalist for Illinois Teacher of the Year
Page 1 of 1 pages
WILL Highlights
Vintage Vinyl is coming!
The Vintage Vinyl Sale to benefit Illinois Radio Reader returns on October 3. Click for the latest info.
WILL News wins PRNDI Award for "Unmet Needs" Radio Doc
The 2014 radio documentary, produced by former WILL staff and hosted by Scott Cameron, won second place in the Long Form Documentary category among medium-sized stations.
WILL Ag Director Dave Dickey retires
He carried on the farm broadcasting tradition, while innovating on the Internet.


text:
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A Rainbow Formed Outside of Nintendo's HQ Yesterdayin Nintendo Discussion on 14 July 2015
Some people in this thread are a disgrace /:(...
Will the next CEO of Nintendo make powerful consoles to their fullest? Since Iwata has passed away?in Nintendo Discussion on 14 July 2015
Mr. Iwata has already set the foundations for Nintendo's future, with the coming NX, the toys to life market with Amiibo, the mobile market with Dena, getting into theme parks with Universal, will all stem from this man....
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My partners son loves his WiiU, his friends even lied to him about they can get Splatoon on there playstations as well lol...
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To Name but a few


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Philadelphia Voices: How Philly Plays: 115 Years at Smith Memorial Playground
Philadelphia History Museum
Ends Friday, October 9
Philadelphia Cityscape 2015: Contemporary Plein Air Views of the Urban Landscape
Wayne Art Center
Ends Saturday, October 10
Herman Leonard: Jazz Portraits
James A. Michener Art Museum
Ends Sunday, October 11
Marie Alarcon: A POST Featured Artist
University City Arts League
Ends Sunday, October 18
Asian Arts Initiative
Ends Friday, October 23
Shipwrecked! An Entertainment
The Amazing Adventures of Louis de Rougemont
(as Told by Himself)
Walnut Street Theatre
Starts Today!
Giargiari Bel Canto Competition
Academy of Vocal Arts
Coming Tomorrow
Mia Rosenthal: Paper Lens
Pennsylvania Academy of the Fine Arts (PAFA)
Starts Friday, October 9
Lemony Snicket's A Series of Unfortunate Events
Bryn Mawr Film Institute
Coming Saturday, October 10
Chitravina Ravikiran
Annenberg Center for the Performing Arts
Coming Saturday, October 10
The Wrath Of The Gods: Epic, Approachable September 14, 2015
The Philadelphia Museum of Art presents Inside Out September 1, 2015
Out of Order. Welcome to Philadelphia. August 30, 2015