CN101087822B - Hydrogel composition - Google Patents
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- CN101087822B CN101087822B CN2005800446261A CN200580044626A CN101087822B CN 101087822 B CN101087822 B CN 101087822B CN 2005800446261 A CN2005800446261 A CN 2005800446261A CN 200580044626 A CN200580044626 A CN 200580044626A CN 101087822 B CN101087822 B CN 101087822B
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Abstract
An electrochemical sensor system comprises an electrochemical sensor and a hydrogel composition. The electrochemical sensor has at least a counter electrode and a working electrode. The hydrogel composition contacts the working electrode. The hydrogel composition comprises a first monomer, a second monomer, a cross-linking agent, and a solvent. The first monomer has hydrophilic characteristics. The second monomer has hydrophobic characteristics. The ratio of the first monomer to the second monomer is from about 0.1:99.9 to about 99.9:0.1.
Description
Invention field
The present invention relates generally to hydrogel composition.Said hydrogel composition in an application is applicable to the transdermal methods of measuring assay (like, glucose) concentration.Background of invention
Assay in the quantitatively determined body fluid is in some physically different diagnosis with extremely important in keeping.For example, in some individuality, should monitor lactic acid salt, SUV and UCB.The particularly important is, the glucose level that the diabetic subject frequently detects in its body fluid is taken in the glucose of adjusting in their meals.The result of such test can be used to decision need take which kind of Regular Insulin or other medicines (if any this type of medicine is arranged).
In some prior aries, available lancet extracts liquid (like blood) from the user.Then, this liquid is used to instrument or instrument to measure analyte concentration.Get rid of the needs that use lancet, and still accurately measure analyte concentration, will expect.
A kind of noninvasive method that does not use lancet to obtain sample is to use the transdermal sample of the assay that is found in interstitial fluid (ISF).In this method, compsn is placed on the skin and auxiliary ISF is easy to from user's skin extraction to induced instrument or instrument.Said composition need have enough machinery and thermostability to be provided at the conduction of static relatively, the reactive and water-based between skin sampling spot and the induced instrument.Need to find to contain such characteristic and be applicable to such compsn that transdermal is taken a sample.The invention summary
According to an embodiment, hydrogel composition comprises first monomer, second monomer, linking agent and solvent.First monomer is selected from formula I:
Wherein R and R1 independently are selected from H, (C
1-C
3) alkyl, (C
3-C
6) dihydroxyl alkyl and (C
2-C
6) hydroxyalkyl; Or the combination of R and R1 (combination) is selected from 1-5 carbon atom, forms 3-7 unit heterocyclic moiety like this.
Second monomer is selected from formula II and formula III, and its Chinese style II does
Wherein R3 and R4 independently are selected from H, CH
3, (C
3-C
18) alkyl, (C
3-C
7) naphthenic base or aromatics part.Alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety.Heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid.Naphthenic base is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid.The aromatics part is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid.If R3 is H or CH
3The time, then R4 is (C
3-C
18) alkyl, (C
3-C
7) naphthenic base or aromatics part.Alkyl, naphthenic base or aromatics part are by the optional replacement of one or more substituting groups.If R4 is H or CH
3The time, then R3 is (C
3-C
18) alkyl, (C
3-C
7) naphthenic base or aromatics part.Alkyl, naphthenic base or aromatics part are by the optional replacement of one or more substituting groups.
Formula III
Wherein
R5 is selected from (C
3-C
18) alkyl, (C
3-C
7) naphthenic base or aromatics part.Alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety.Heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid.Naphthenic base is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid.The aromatics part is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid.First monomer is about 0.1: 99.9 to about 99.9: 0.1 to the second monomeric ratio.
According to an embodiment, electrochemical sensor system comprises electrochemical sensor and hydrogel composition.Electrochemical sensor has counter electrode and working electrode at least.Hydrogel composition contacts with working electrode.Hydrogel composition comprises first monomer, second monomer, linking agent and solvent.First monomer is selected from methylacrylic acid hydroxyl alkyl ester, acrylic amide, N; N two-alkyl acrylamide, methylacrylic acid, vinylformic acid, methacrylic acid metal salt, acrylate metal salt, methylene-succinic acid, maleic acid, USAF RH-1, N; N-dialkyl group acrylic amide, styrene sulfonic acid, styrene sulfonic acid metal-salt, vinylbenzene carboxylic acid, vinylbenzene carboxylic metallic salt, acrylamido-2-methyl propane sulfonic acid, acrylamido-2-methyl propane sulfonic acid metal-salt, 2-vinyl N-alkyl pyridine halogenide, 4-vinyl N-alkyl pyridine halogenide, or formula I discussed above.Second monomer is selected from (methyl) alkyl acrylate, formula II, formula III and formula IV, its Chinese style II and discussing more than the formula III.
Formula IV does
Formula IV wherein R2 is selected from (C
1-C
18) alkyl, (C
3-C
7) naphthenic base and aromatics part.Alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety.Heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid.Naphthenic base is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid.The aromatics part is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid.First monomer is from about 0.1: 99.9 to about 99.9: 0.1 to the second monomeric ratio.
According to an embodiment, electrochemical sensor system comprises electrochemical sensor and hydrogel composition.Electrochemical sensor has counter electrode and working electrode at least.Hydrogel composition contacts with working electrode.Hydrogel composition comprises first monomer, second monomer, linking agent and solvent.First monomer is selected from formula I discussed above.Second monomer is selected from (methyl) alkyl acrylate, formula II discussed above, formula III and formula IV.
According to another embodiment, electrochemical sensor system comprises electrochemical sensor and hydrogel composition.Electrochemical sensor has counter electrode and working electrode at least.Hydrogel composition contacts with working electrode.Hydrogel composition comprises first monomer, second monomer, linking agent and solvent.First monomer is selected from N-vinyl pyrrolidone, methylacrylic acid hydroxyl alkyl ester, acrylic amide and N, N two-alkyl acrylamide.Second monomer is selected from (methyl) alkyl acrylate, N-vinyl acrylic amide, vinyl acetate and vinyl ether.First monomer is from about 0.1: 99.9 to about 99.9: 0.1 to the second monomeric ratio.
According to going back an embodiment, electrochemical sensor system comprises electrochemical sensor and hydrogel composition.Electrochemical sensor has counter electrode and working electrode at least.Hydrogel composition contacts with working electrode.Hydrogel composition comprises first monomer, second monomer, linking agent and solvent.First monomer has water-wet behavior.Second monomer has hydrophobic property.First monomer is from about 0.1: 99.9 to about 99.9: 0.1 to the second monomeric ratio.
According to a kind of method,, hydrogel composition measures analyte concentration on the skin through being placed.Hydrogel composition comprises first monomer, second monomer, linking agent and solvent.First monomer is selected from methylacrylic acid hydroxyl alkyl ester, acrylic amide, N; N two-alkyl acrylamide, methylacrylic acid, vinylformic acid, methacrylic acid metal salt, acrylate metal salt, methylene-succinic acid, maleic acid, USAF RH-1, N; N-dialkyl group acrylic amide, styrene sulfonic acid, styrene sulfonic acid metal-salt, vinylbenzene carboxylic acid, vinylbenzene carboxylic metallic salt, acrylamido-2-methyl propane sulfonic acid, acrylamido-2-methyl propane sulfonic acid metal-salt, 2-vinyl N-alkyl pyridine halogenide, 4-vinyl N-alkyl pyridine halogenide, or formula I discussed above.Second monomer is selected from (methyl) alkyl acrylate, formula II discussed above, formula III and formula IV.Transmitter is provided, and common said hydrogel composition is located between skin and the transmitter and connects them.To the interstitial fluid sampling, use the sensor determination analyte concentration.
According to another kind of method, measure analyte concentration.This method comprises hydrogel composition is placed on the skin.Hydrogel composition comprises first monomer, second monomer, linking agent and solvent.First monomer is selected from formula I discussed above.Second monomer is selected from (methyl) alkyl acrylate, formula II discussed above, formula III and formula IV.Transmitter is provided, and common said hydrogel composition is located between skin and the transmitter and connects them.To the interstitial fluid sampling, use the sensor determination analyte concentration.
According to another method, measure analyte concentration.This method comprises hydrogel composition is placed on the skin.Hydrogel composition comprises first monomer, second monomer, linking agent and solvent.First monomer is selected from N-vinyl pyrrolidone, methylacrylic acid hydroxyl alkyl ester, acrylic amide and N, N two-alkyl acrylamide.Second monomer is selected from (methyl) alkyl acrylate, N-vinylamide, vinyl acetate and vinyl ether.First monomer is from about 0.1: 99.9 to about 99.9: 0.1 to the second monomeric ratio.Transmitter is provided, and common said hydrogel composition is located between skin and the transmitter and connects them.Interstitial fluid is taken a sample to measure analyte concentration.
Foundation is a kind of method also, measures analyte concentration.This method comprises hydrogel composition is placed on the skin.Hydrogel composition comprises first monomer, second monomer, linking agent and solvent.First monomer has water-wet behavior.Second monomer has hydrophobic property.First monomer is from about 0.1: 99.9 to about 99.9: 0.1 to the second monomeric ratio.Transmitter is provided, and common said hydrogel composition is located between skin and the transmitter and connects them.To the interstitial fluid sampling, use the sensor determination analyte concentration.The summary of figure
Fig. 1 is exsiccant hydrogel and the mechanical jack (support) according to an embodiment.
Fig. 2 is the electrochemical sensor according to an embodiment.
Fig. 3 is the electrochemical sensor system that comprises the electrochemical sensor of Fig. 2.
Fig. 4 a is the electric current drawn, the glucose concn graphic representation to the time.
Fig. 4 b is the electric current of the normalization of Fig. 4 a, the graphic representation that glucose concn was drawn the time.
Fig. 5 is the electric current drawn, the glucose concn graphic representation to the time.The detailed description of exemplary
The present invention relates to new hydrogel composition.Said hydrogel composition comprises first monomer, second monomer, linking agent and solvent (like water).Hydrogel composition be at random, the interpolymer reticulattion, it combines at least the first and second monomers in the formation of polymer chain.Through first and second monomer stereometry (volumetric) per-cents interpolymer reticulattion is controlled at least in certain scope (some extent).
Have following implication in the whole text with undefined term:
Term " alkyl " means the saturated carbon-based group of straight or branched.Term " (C
1-C
3) alkyl ", " (C
1-C
18) alkyl " and " (C
3-C
18) alkyl " and mean have respectively from 1 to about 3 carbon atoms, from 1 to about 18 carbon atoms or from about 3 to about 18 carbon atom straight chains or the saturated carbon-based group of side chain.Such group include, but are not limited to methyl, ethyl, just-propyl group, sec.-propyl, just-butyl, isobutyl-, the second month in a season-butyl, tert-butyl etc.
Term " optional substituted ", only if refer else, the part that means modification like this can have one or more specified substituting groups.When displacement chemically is being feasible and chemically is being stable, the replaceable any H atom on the part of so modifying of each substituting group.For example, chemically unstable compounds will be that in two substituting groups each is through each substituent heteroatoms and single C atom bonded compound.Chemically another instance of unstable compounds will be the compound of the unsaturated carbon formation enol ether of alkoxyl group and alkene.When two substituting groups were arranged in any part, each substituting group was independent of other substituting group and is selected, and therefore, substituting group can be identical or different.
Term " naphthenic base " means saturated monocycle alkyl.Term " (C
3-C
7) naphthenic base " mean from the about 3 saturated monocycle alkyl to about 7 carbon atoms.Such group includes, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.
Term " (C
3-C
6) the dihydroxyl alkyl " and mean as above describe, comprise two hydroxyls (OH) alkyl of composition that is connected in saturated carbon.(C
3-C
6) the dihydroxyl alkyl can be straight or branched.(C
3-C
6) the hydroxyl composition of dihydroxyl alkyl is typically adjacent one another are.Yet, (C
3-C
6) the dihydroxyl composition can add on any available carbon.(C like this
3-C
6) the dihydroxyl alkyl includes, but are not limited to 2,3-dihydroxypropyl, 3,4-dihydroxyl butyl, 5,6-dihydroxyl hexyl etc.
Term " (C
2-C
6) hydroxyalkyl " and mean as above describe, comprise a hydroxyl (OH) alkyl of composition that is connected in saturated carbon.(C
2-C
6) hydroxyalkyl can be straight or branched.(C
2-C
6) the hydroxyl composition of hydroxyalkyl can be positioned on any available carbon.(C like this
2-C
6) hydroxyalkyl includes, but are not limited to 2-hydroxyethyl, 3-hydroxypropyl etc.
Term " halo " means the atom that is selected from Cl, Br and F.
Term " haloalkyl " means alkyl as above that describe, that comprise the one or more halo compositions that are connected in saturated carbon.Haloalkyl can be straight or branched.The halo composition of haloalkyl can be positioned on any available carbon.Such haloalkyl includes, but are not limited to 2-chloroethyl, 3-bromopropyl, 2,2,3,3,3-five fluoropropyls etc.
Term " nitro " means and is selected from-NO
2, cyanic acid (CN) ,-NHCH
3With-NHC
2H
5Atom.
Term " heterocyclic moiety " is for containing the material of ring texture, and wherein non-carbon atom (like sulphur, oxygen or nitrogen) becomes the part of ring.For example, 3-7 unit heterocyclic moiety comprises the non-carbon atom of the skeleton part of at least one part that becomes ring or 3-7 ring structure.4-8 unit heterocyclic moiety comprises the non-carbon atom of the skeleton of at least one part that becomes ring or 4-8 ring structure.
Term " water-wet behavior " means the avidity that has water or other polar solvent; Be easy to absorb or be dissolved in water or other polar solvent.
Term " hydrophobic property " means the avidity that does not have water or other polar solvent; Be not easy to absorb or be dissolved in water or other polar solvent.
Term " aromatics part " means the material that contains one or more phenyl ring.Aromatic substituent can be monocycle, dicyclo or three rings.The non-limiting instance of aromatic substituent comprises phenyl, benzyl, naphthyl, anthryl etc.
The symbol that uses among this paper such as " (methyl) vinylformic acid " refers to optional methyl substituted.Therefore, for example, " (methyl) vinylformic acid " comprises methylacrylic acid and vinylformic acid.
As above discuss, hydrogel composition comprises first monomer and second monomer.A first monomeric embodiment is related to the formula I compound of N-vinylamide.
Wherein R and R1 independently are selected from H, (C
1-C
3) alkyl, (C
3-C
6) dihydroxyl alkyl and (C
2-C
6) hydroxyalkyl; Or the combination of R and R1 is selected from 1-5 carbon atom, forms 3-7 unit heterocyclic moiety like this.
Wherein R is CH
3With R1 be that the limiting examples of the formula I of H is the N-vinyl acetamide.Comprise that R is CH
2CH
3With R1 be that other the instance of the formula I of H is a N-vinyl propionic acid amide.
The limiting examples of the ring structure of formula I comprises the N-vinyl pyrrolidone, and it is for containing 5 membered heterocyclic compounds of 4 carbon and 1 nitrogen in skeleton.The N-vinyl pyrrolidone is represented as follows with compd A:
another instance of ring structure of formula I be the N-caprolactam.
For formula I, it is gratifying having water-wet behavior.That need is independent R of selection and R1, so that formula I has water-wet behavior.Select the combination of R and R1 also to need with the formula I ring structure that formation has water-wet behavior.
In one embodiment, second monomer of first monomer of formula I and formula II (following discussion), linking agent and solvent form hydrogel composition.First monomer is from about 0.1: 99.9 to about 99.9: 0.1 to the second monomeric ratio.More particularly, first monomer is from about 20: 80 to about 80: 20 to the second monomeric ratio, and especially more particularly from about 40: 60 to about 60: 40.A second monomeric embodiment is related to the formula II compound of N-vinylamide.
Wherein R3 and R4 independently are selected from H, CH
3, (C
3-C
18) alkyl; Wherein alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; (C
3-C
7) naphthenic base, wherein naphthenic base is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; With the aromatics part, wherein aromatics part is by one or more optional replacements of substituting groups that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid, condition be when R3 be H or CH
3The time, then R4 is (C
3-C
18) alkyl, (C
3-C
7) naphthenic base or aromatics part, wherein alkyl, naphthenic base or aromatics part is replaced by one or more substituting groups are optional, condition be when R4 be H or CH
3The time, then R3 is (C
3-C
18) alkyl, (C
3-C
7) naphthenic base or aromatics part, wherein alkyl, naphthenic base or aromatics part are by the optional replacement of one or more substituting groups.
Wherein R3 or R4 are (C
3-C
18) alkyl, and wherein alkyl is included, but are not limited to N-vinyl yulocrotine, N-vinyl valeramide, N-vinyl lauramide, N-vinyl 4-neoprene acid amides etc. by the instance of the optional substituted formula II of one or more substituting groups.
Wherein R3 or R4 are (C
3-C
7) naphthenic base and wherein naphthenic base included, but are not limited to N-vinyl cyclohexyl carboxylic acid amides, N-vinyl cyclopentyl carboxylic acid amides, N-vinyl 4-bromo cyclohexyl carboxylic acid amides etc. by the instance of the optional substituted formula II of one or more substituting groups.
Wherein R3 or R4 be aromatics part and wherein the aromatics part included, but are not limited to N-vinyl benzene methane amide, N-vinyl 4-nitrobenzamide, N-vinyl naphthalene methane amide etc. by the instance of the optional substituted formula II of one or more substituting groups.
It is gratifying for formula II, having hydrophobic property.That need is independent R3 of selection and R4, so that formula II has hydrophobic property.
In another embodiment, second monomer of first monomer of formula I and formula III (following discussion), linking agent and solvent form hydrogel composition.Second monomeric another embodiment is related to the formula III compound of vinyl ether.
Wherein R5 is selected from (C
3-C
18)Alkyl; Wherein alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; (C
3-C
7) naphthenic base, wherein naphthenic base is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; With the aromatics part, wherein the aromatics part is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid.
Wherein R5 is (C
3-C
18) alkyl, and wherein alkyl is included, but are not limited to vinyl propyl ether, vinyl hexyl ether, vinyl dodecyl ether, vinyl 4-cyclobutyl ether etc. by the instance of the optional substituted formula III of one or more substituting groups.
Wherein R5 is (C
3-C
7) naphthenic base and wherein naphthenic base included, but are not limited to vinyl cyclohexyl ether, vinyl cyclopentyl ether, vinyl 4-bromo cyclohexyl ether etc. by the instance of the optional substituted formula III of one or more substituting groups.
Wherein R5 be aromatics part and wherein the aromatics part included, but are not limited to vinyl phenyl ether, vinyl 4-nitrophenyl ether, vinyl 2-naphthyl ether etc. by the instance of the optional substituted formula III of one or more substituting groups.
When first and second monomers and solvent (like water) when mixing, the structural integrity of raw material can be strong not as needed.When if first and second monomers mix with high amounts of solvents, situation especially maybe be so.In order further to strengthen physical strength, linking agent is joined in first monomer and second monomer.
The non-limiting example of spendable linking agent includes, but are not limited to following: polyfunctional vinyl ether, Vinylstyrene, polyfunctional propenoate and polyfunctional acrylic amide.As the ideal first and second monomeric linking agents, linking agent must have the geometricdrawing (geometry) that can connect two polymer chain.
According to an embodiment, can use formula V cross-linking compounds (polyfunctional vinyl ether).
wherein " x " is 0-4.In formula V, " x " helps to measure the character of cross-linking compounds.Especially, " x " composition of formula V is big more, and the elasticity of formula V and tear strength (tear strength) are good more.For improving elasticity and tear strength, form hydrogel and to add the amount of solvent more.
The instance that can be used as the polyfunctional vinyl ether of linking agent is the diethylene glycol divinyl ether propenoate, and it is expressed as following compd B.
Expected is to can be used as other polyfunctional vinyl ether such as triethylene glycol divinyl ether and four (glycol) (tetra (ethylene glycol)) divinyl ether of linking agent.
According to another embodiment, the cross-linking compounds of available formula VI (Vinylstyrene).
Wherein R6 is selected from CH
2, O or CH
2-CH
2
The instance that can be used as the polyfunctional propenoate of linking agent is diethylene glycol dimethacrylate (EGDMA), and it is expressed as following Compound C.
is expected to be; Other the polyfunctional propenoate that can be used as linking agent is such as gathering diacrylate second diester, diethylene glycol dimethacrylate, diethylene glycol diacrylate, glycol diacrylate and 1,3-dihydroxypropyl dimethacrylate.
The instance that can be used as the polyfunctional acrylic amide of linking agent is N, N ' methylene diacrylamine, and it is expressed as following Compound D.
is expected to be that other polyfunctional acrylic amide can be used as linking agent.
Interpolymer reticulated structure (network) compsn generally comprises from about linking agent of 0.01 to about 10vol.%.Interpolymer reticulated structure compsn this paper be defined as comprise first monomer, second monomer, linking agent and below to discuss solidifying before other composition.Such as definition, interpolymer reticulated structure compsn does not comprise solvent (like, water).More particularly, polymer reticulated structure compsn comprises from about linking agent of 0.1 to about 1vol.%.
In order to help polymerization, can photoinitiator be added in first monomer, second monomer and the linking agent.An instance of photoinitiator is Ciba Specialty Chemicals Pty, the 2-hydroxyl-4 of Ltd. as Irgacure
2959 listings '-(2-hydroxyl-oxethyl)-2-aminomethyl phenyl ethyl ketone.Can conceive the photoinitiator that adds other.Polymer reticulated structure compsn generally comprises from 0.0001 to about 5wt.% photoinitiator.
First and second monomers and solvent.An instance of the conventional solvent that uses is a water.Another instance of solvent is a water mixture.Expected is to use other solvent in the present invention.The amount of water can be different, and main different and different with the second monomeric amount according to first monomer in the hydrogel composition.Can conceive in the hydrogel composition of raw material to the first monomer, second monomer, linking agent and the solvent that add other.
After adding linking agent, first and second monomers form crosslinked interpolymer reticulated structure.In order to realize the polymerization of first and second monomers and linking agent; For example can adopt the method initiated polymerization of ultraviolet ray (adding that UV causes the UV radiation of appearance (UV initiator)), thermal initiation effect (adding), gamma-radiation and electron beam with thermal initiator (thermal initiator).In order to help polymerization, can photoinitiator be added in first monomer, second monomer and the linking agent.In one approach interpolymer reticulated structure is soaked in the solvent (like, water) to produce hydrogel composition.
In one embodiment, hydrogel composition can be suitable for as the interface between skin and the transmitter (like, electrochemical sensor).In one approach, transmitter uses hydrogel composition in ISF (interstitial fluid), to measure the concentration of required assay.Detectable assay comprise glucose, blood fat distribute (lipid profiles) (as, SUV, tri-glyceride, LDL and HDL), little BSA, hemoglobin A
1C, fructose, lactic acid salt or UCB.Expected is to measure other analyte concentration.As employed in this application, term " concentration " refer to analyte concentration, activity (as, enzyme and ionogen), titre (like, antibody), or any other is used to detect the detectable level of required assay.
In this embodiment will be as the hydrogel composition at the interface between skin and the transmitter, comprise first monomer, second monomer, linking agent and solvent (like, water).Hydrogel composition is an interpolymer reticulated structure at random, and it combines at least the first and second monomers in the formation of polymer chain.Per-cent through the first and second monomer stereometries is controlled the interpolymer reticulated structure at least in certain scope.In this application, the balance that hydrogel composition is had between gel strength and the elasticity is favourable.For hydrogel composition, having the strength of signal that needs also is ideal.
First monomer is suitable for hydrogel composition water-wet behavior is provided.First monomer comprises above formula I compound discussed in detail (N-vinylamide).
Formula I wherein R and R1 independently is selected from H, (C
1-C
3) alkyl, (C
3-C
6) dihydroxyl alkyl and (C
2-C
6) hydroxyalkyl; Or the combination of R and R1 is selected from 1-5 carbon atom, forms 3-7 unit heterocyclic moiety like this.
Expectedly be; Other first monomer of available comprises methylacrylic acid hydroxyl alkyl ester, acrylic amide, N; N two-alkyl acrylamide, methylacrylic acid, vinylformic acid, methacrylic acid metal salt, acrylate metal salt, methylene-succinic acid, maleic acid, USAF RH-1, N, N-dialkyl group acrylic amide, styrene sulfonic acid, styrene sulfonic acid metal-salt, vinylbenzene carboxylic acid, vinylbenzene carboxylic metallic salt, acrylamido-2-methyl propane sulfonic acid, acrylamido-2-methyl propane sulfonic acid metal-salt, 2-vinyl N-alkyl pyridine halogenide or 4-vinyl N-alkyl pyridine halogenide.
The instance that can be used as the first monomeric methylacrylic acid hydroxyl alkyl ester is a methylacrylic acid hydroxyl ethyl ester, and it is shown in following compd E.
is expected to be; Can be used as first monomeric other methylacrylic acid hydroxyl alkyl ester such as methylacrylic acid hydroxyl propyl diester, vinylformic acid hydroxyethyl ester, methylacrylic acid 2; 3-dihydroxypropyl ester and vinylformic acid 2,3-dihydroxypropyl ester.
Can be used as the first monomeric acrylic amide shown in following compound F 17-hydroxy-corticosterone.
Can be used as the first monomeric N, the instance of N two-alkyl acrylamide is N, N two-USAF RH-1, and it is shown in following compound G.
can conceive as first monomeric other N; N two-alkyl acrylamide is such as N; N two just-propyl group acrylic amide, N-NSC 11448 and N, the N-dimethylmethacryl amide.
According to another embodiment; First monomer can be methylacrylic acid, and it is shown in following compound H:
Second monomer is suitable for hydrogel composition physical strength is provided.Second monomer also is suitable for hydrogel composition hydrophobic property is provided.Through offering the hydrogel composition hydrophobic property, control the solvent amount of (like, water) better.
In one embodiment, second monomer relates to above formula II compound discussed in detail (N-vinylamide).
Wherein R3 and R4 independently are selected from H, CH
3, (C
3-C
18) alkyl; Wherein alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; (C
3-C
7) naphthenic base, wherein naphthenic base is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; With the aromatics part, wherein aromatics part is by one or more optional replacements of substituting groups that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid, condition be when R3 be H or CH
3The time, then R4 is (C
3-C
18) alkyl, (C
3-C
7) naphthenic base or aromatics part, wherein alkyl, naphthenic base or aromatics part is replaced by one or more substituting groups are optional, condition be when R4 be H or CH
3The time, then R3 is (C
3-C
18) alkyl, (C
3-C
7) naphthenic base or aromatics part, wherein alkyl, naphthenic base or aromatics part are by the optional replacement of one or more substituting groups.
In another embodiment, second monomer relates to above formula III compound discussed in detail (vinyl ether).
Wherein R5 is selected from (C
3-C
18) alkyl; Wherein alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; (C
3-C
7) naphthenic base, wherein naphthenic base is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; With the aromatics part, wherein the aromatics part is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid.
Second monomeric another embodiment is related to the formula IV compound of vinyl acetate.
Wherein R2 is selected from (C
1-C
18) alkyl; Wherein alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; (C
3-C
7) naphthenic base, wherein naphthenic base is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; With the aromatics part, wherein the aromatics part is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid.
Wherein R2 is (C
1-C
18) alkyl and wherein alkyl included, but are not limited to 2-chloroethyl, 3-bromopropyl, 2,2,3,3,3-five fluoropropyls etc. by the instance of the optional substituted formula IV of one or more substituting groups.
Wherein R2 is (C
3-C
7) naphthenic base and wherein naphthenic base included, but are not limited to cyclopentyl, cyclohexyl, 2-chlorine cyclohexyl, 4-bromo cyclohexyl etc. by the instance of the optional substituted formula IV of one or more substituting groups.
Wherein R2 be aromatics part and wherein the aromatics part by the instance of the optional substituted formula IV of one or more substituting groups; Include, but are not limited to vinyl benzoate, phenylacetic acid vinyl acetate, 4-bromobenzene vinyl formate, 4-nitrobenzoyl vinyl acetate, 1-naphthoic acid vinyl acetate, 2-naphthoic acid vinyl acetate etc.
Vinyl acetate such as vinyl-acetic ester or laurostearic acid vinyl acetate, can be used as second monomer.Vinyl-acetic ester is shown in following compound J, and the laurostearic acid vinyl acetate is shown in following compound K.
can conceive as second monomeric other vinyl acetate such as propionate and vinyl butyrate.It is gratifying that formula IV has hydrophobic property.Select R2 to make formula IV have needing of hydrophobic property.
Except being formed second monomer by formula II-IV, also expected is that second monomer also can include, but are not limited to comprise (methyl) alkyl acrylate of alkyl methacrylate and alkyl acrylate.The instance that can be used as the second monomeric alkyl methacrylate is as being shown in following compound L, methyl methacrylate.
is expected to be, can be used as second monomeric other alkyl methacrylate such as the methylacrylic acid ethyl ester, methylacrylic acid propyl diester, methylacrylic acid butyl ester, methylacrylic acid phenylester, methylacrylic acid polyhexamethylene, methylacrylic acid heptyl ester, methylacrylic acid octyl group ester, methylacrylic acid 2-(ethyl hexyl) ester, methylacrylic acid nonyl ester, methylacrylic acid decyl ester, methylacrylic acid undecyl ester and methylacrylic acid dodecyl ester.
First monomer is about 0.1: 99.9 to about 99.9: 0.1 to the second monomeric ratio.More particularly, first monomer is about 80: 20 to about 20: 80 to the second monomeric ratio, especially more particularly from about 60: 40 to about 40: 60.
Adopt the cancellated instance of first monomer and the second monomeric interpolymer to be shown in following formula M: first monomer that
uses in formula M is vinyl-acetic ester as N-vinyl pyrrolidone and second monomer that is used for formula M." n and m " among the formula M multiple monomeric unit that expresses possibility, wherein " n " and " m " is more than or equal to 1." n " among the formula M and " m " depend on first monomer of existence to the second monomeric ratio.Expectedly be, more than disclosed first monomer and second monomeric other combination can be used for forming hydrogel composition.
Interpolymer reticulated structure compsn generally comprises from about linking agent of 0.01 to about 10vol.%.As discussed above, interpolymer reticulated structure compsn is defined as and comprises first monomer, second monomer, linking agent and following other composition before solidifying that will discuss in this article.Defined interpolymer reticulated structure compsn does not comprise solvent (like, water).More specifically, polymer reticulated structure compsn comprises from about linking agent of 0.1 to about 1vol.%.
As discussed above, in order to help polymerization, can photoinitiator be added in first monomer, second monomer and the linking agent.An instance of photoinitiator is CibaSpecialty Chemicals Pty, the 2-hydroxyl-4 of Ltd. as Irgacure
2959 listings '-(2-hydroxyl-oxethyl)-2-aminomethyl phenyl ethyl ketone.Can conceive the adding photoinitiator.
First and second monomers and solvent.An instance of normally used solvent is a water.Another instance of solvent is a water mixture.Expectedly be, other solvent can be used among the present invention, yet in the application of measuring analyte concentration, solvent need be biocompatible basically with skin.The amount of water can be different, and depend primarily on first monomer and the second monomeric amount in the hydrogel composition.
Can conceive other raw material is added in the hydrogel composition of first monomer, second monomer, linking agent and solvent.For example, can ionogen be added in the hydrogel composition.The application that depends on hydrogel composition is different, and ionogen can play multiple efficacies.At first, ionogen is ionized compound when dissolving produces the medium of electricity-conduction.Secondly, ionogen preferably contains high salt concn, helps when being used for contacting skin with box lunch skin is applied osmotic pressure.Through skin is applied osmotic pressure, ionogen helps to force the interstitial fluid (ISF) that contains assay to ooze out.The electrolytical limiting examples of available comprises the sodium salt and the sylvite of hydrochloric acid, phosphoric acid, Hydrocerol A, acetate and lactic acid.
Also can comprise enzyme in the said solution to help to measure analyte concentration.Depend on assay, enzyme can help assay is converted into can be to be detected, such as the material of Electrochemical Detection.The instance of enzyme that can be used for measuring glucose is a P-FAD.Can conceive and use other enzyme such as Hexose phosphate dehydrogenase.If other assay has meaning, then can select suitable enzyme to help to measure analyte concentration.If the use enzyme then solidifies this enzyme of back adding at first monomer and second monomer usually.The first and second monomeric curing generally include uses thermal stresses or application of electromagnetic radiation, and its activity for enzyme has negative interaction.Yet expected is that before solidifying, enzyme can mix with first and second monomers.
Said solution also can comprise penetration enhancer.Penetration enhancer needs in hydrogel composition is used in the application of skin.Penetration enhancer helps to open the pore of skin.The limiting examples of available penetration enhancer includes, but are not limited to glycerol derivatives, DMSO 99.8MIN. and the effective for treatment of premature ejaculation of Supraene, unsaturated fatty acids, Fatty Alcohol(C12-C14 and C12-C18).
Other raw material that can add in the hydrogel composition comprises sterilant, wetting agent, tensio-active agent and combination thereof.Sterilant helps bacteria growing inhibiting.The limiting examples of available sterilant comprises nipagin esters series sanitas, Sodium Benzoate, Neotran ammonium and trialkylamine.
Wetting agent helps to make skin to keep moistening the needs in application.The limiting examples of available wetting agent comprises USP Kosher, pinakon and sorbyl alcohol, maltose alcohol, VISOSE (polydextrose), Ucar 35, lactic acid and lactic acid metal-salt.Tensio-active agent helps to make hydrogel composition and skin to combine (coupling) to contact with what between them, be improved.Available tensio-active agent non-limiting example comprises that the korenyl phenols is such as TRITON
X-100 (has molecular formula C
14H
22O (C
2H
4O)
nOctyl phenol ethoxylate (ethoxylate), " n " average out to 9 or 10 wherein) and sorbyl alcohol and glucitol derivative such as TWEEN
TMSeries.
If be used in the electrochemical applications, can make hydrogel composition reconstitute (reconstituted) in the electrode surface drying and before its use.When reconstituting, the solvent of adding can comprise ionogen.
In electrochemical applications, said hydrogel composition general thickness is from about 0.1mil to about 100mils, and more particularly, thickness is from about 1mil to about 30mils.In one embodiment, be to about 100cm from about 0.1 by the surface-area of the electrochemical sensor of hydrogel composition covering
2
Hydrogel composition has enough machinery and thermostability to be provided at the conduction of static relatively, the reactive and water-based between skin sampling site and the transmitter.More particularly, for hydrogel composition, the homogeneity and the mechanical stability of elasticity and anti-shearing force (shear force) that have physically need.In the application of selecting, need make hydrogel composition keep from about water cut of 50 to about 90wt.% one period of wanting (as, from about 24 to about 72 or more hours).
In addition, said hydrogel composition has high-hydrophilic with the dehydration of opposing in the use of delaying.Through reducing or fully eliminating dehydration, the transport property of hydrogel composition can not change.For hydrogel composition, the porousness of keeping skin also needs.Ideally, hydrogel composition shows the quite compressibility of height, to help to obtain the connectedness or the skin adherence property of good skin/sensor.
For hydrogel composition, have and be applicable to that enzyme holds back the enough big porousness of (entrapment) and also need.For example, relate at some and to measure during glucose concn uses, hydrogel composition provides the matrix that is applicable to P-FAD (GO) and the diffusion admittance of glucose and hydrogen peroxide to need.
After adding linking agent, first and second monomers form crosslinked, interpolymer reticulated structure.For realizing the polymerization of first and second monomers and linking agent, for example can adopt, ultraviolet (UV) ray (like, high-intensity UV ray), thermal initiation effect (as, freeze-melt circulation), the method initiated polymerization of gamma-radiation and electron beam.In order to help polymerization, can photoinitiator be added in first monomer, second monomer and the linking agent.
In one approach, the interpolymer reticulated structure is soaked in the solvent (like, water) produces hydrogel composition.Solvent can comprise composition discussed above such as ionogen, enzyme, penetration enhancer, sterilant, wetting agent, tensio-active agent and combination thereof.Can conceive ionogen, enzyme, penetration enhancer, sterilant, wetting agent, tensio-active agent and combination thereof and solvent are joined respectively in the interpolymer reticulated structure.
In one approach, with said hydrogel composition drying to remove solvent and to form exsiccant interpolymer reticulated structure or the exsiccant hydrogel composition.The exsiccant hydrogel composition can be the form of film.The exsiccant hydrogel composition also can comprise mechanical jack.Mechanical jack helps to offer exsiccant hydrogel composition film with physical strength.The instance of mechanical jack comprises polymer reticulattion (mesh), woven fabrics (woven fabric), supatex fabric, Mierocrystalline cellulose (like, paper) or its combination.The instance of cellulosic material comprise commercial obtainable paper (as, cleansing tissue (wipes), paper handkerchief or filter paper) or cloth.Conceived other mechanical jack can have been used with exsiccant hydrogel composition film.
Usually, have from about 10 to about 90wt.% cellulose matrix, and remaining is the interpolymer reticulated structure.Thereby, in one embodiment, the cellulose matrix of 10wt.% and the interpolymer reticulated structure of 90wt.% are arranged.
In one embodiment, the interpolymer reticulated structure is absorbed in the porous cellulose matrix.For example, graft copolymerization can occur between first and second monomers in the porous cellulose matrix.In the presence of photoinitiator, through using high-octane ray, chemical initiation and ultraviolet (UV) ray, starting should reaction.
An instance of hydrogel composition is shown among Fig. 1, and exsiccant hydrogel thin film system 10 comprises exsiccant hydrogel composition film 12 and mechanical jack 14.Expected is that mechanical jack can be more than one deck.According to another embodiment, mechanical jack can be deep in (embedded) hydrogel composition.
In a process, useable solvents (like, water) reconstitutes exsiccant hydrogel composition film.The hydrogel composition that comprises interpolymer reticulated structure and solvent can comprise from about water of 1 to about 99vol.%.
In one approach, said hydrogel composition is used for helping to use the analyte concentration of sensor determination interstitial fluid (ISF).More specifically, said hydrogel composition be suitable for as general between skin and transmitter the interface and skin and transmitter linked together.In the method, sensor determination is from the required analyte concentration in the sample of ISF.In one embodiment, transmitter is an electrochemical sensor.The instance of electrochemical sensor comprise utilize standard catalyzer, the platiniferous working electrode, three-phase-electrode potentiostat.Expected is that other electrochemical sensor of available comprises that those have the for example electrochemical sensor of two electrodes (comprising counter electrode and working electrode) of less electrode.Also conceived other transmitter of available such as optical pickocff.
With reference to figure 2, shown electrochemical sensor according to an embodiment.Electrochemical sensor 30 comprises counter electrode 32, working electrode 34 and reference electrode 36.A special instance of such electrochemical sensor comprises carbon counter electrode, platinum working electrode and silver/Silver monochloride reference electrode.Available other feedstock production counter electrode, working electrode and reference electrode have been conceived.
As shown in Figure 3, electrochemical sensor system 50 comprises electrochemical sensor 30, the exsiccant hydrogel thin film 52 of Fig. 2 and adheres to ring 54.Exsiccant hydrogel thin film 52 comprise such as describe more than those but lack the hydrogel composition of solvent.In this embodiment, adhere to ring 54 and have two functions: (a) cover the part of exsiccant hydrogel thin film 52 and it is fixed on the electrochemical sensor 30; The electrochemical sensor system 50 that (b) will comprise exsiccant hydrogel thin film 52 is fixed on the skin.
In one approach, hydrogel composition is added on the skin.Can hydrogel composition be positioned on the skin site such as the preceding wrist palmar skin between wrist joint and the elbow joint.Can conceive hydrogel composition is positioned on other skin site such as belly.Then, with this method skin is carried out pre-treatment to increase the perviousness of skin.A pretreated instance is to use ultrasonic energy that cuticular double-layer of lipoid is broken, like this to increase the perviousness of skin.Through increasing the perviousness of skin, increase the amount of the interstitial fluid (ISF) that is used for the transdermal sampling.This causes improving to being found in the sampling of (like, glucose) of interesting assay among the ISF.After making hydrogel composition and ISF contact, the concentration of the required assay of sensor determination.
A non-limiting source of ultrasonic energy system is the ultrasonic dermal osmosis of Sontra SonoPrep
system of being sold by Sontra MedIcal company.SonoPrep
system is applied to the limited time-histories of skin (about 10 to 20 seconds) with low-frequency relatively ultrasonic energy.In the instrument contained ultrasonic transducer (horn) with 55,000 (55KHz) vibrations of about per second with through liquid-medium that is connected with energy apply on skin, to be created in the cavitation foam that connects expansion and contraction in the medium (couplingmedium).
In another method, hydrogel composition is added on the skin from electrochemical sensor system (like, electrochemical sensor system 50).Then skin is carried out pre-treatment to increase the perviousness of skin.A pretreated instance is to use ultrasonic energy discussed above; Use the ultrasonic dermal osmosis of Sontras SonoPrep
system of for example selling by Sontra Medical company.With hydrogel composition with after ISF contacts, electrochemical sensor is measured required analyte concentration.
EXAMPLE Example 1
Use Noninvasive test determines glucose concn.The method of drawing is shown in figure below 4a, b.
The interpolymer mixture comprises first monomer (N-vinyl pyrrolidone), second monomer (vinyl-acetic ester), photoinitiator (2-hydroxyl-4 '-(2-hydroxyl-oxethyl)-2-aminomethyl phenyl ethyl ketone) (by Ciba Specialty Chemicals Pty, Ltd. sells as Irgacure
2959) and linking agent (diethylene glycol divinyl ether).The interpolymer mixture comprises 50 parts of N-vinyl pyrrolidones, 50 parts of vinyl-acetic esters, 2959 and 0.5 parts of diethylene glycol divinyl ethers of 0.5 part of Irgacure
.First monomer, second monomer, photoinitiator and linking agent are mixed.Feed nitrogen (N to interpolymer mixture bubbling
2) about 5 minutes.Then the interpolymer mixture was placed under the uv lamp about 2.25 hours.Then the interpolymer mixture is removed and is stored in the refrigerator.
Make the interpolymer mixture solidified to form exsiccant interpolymer film.Through in the deionized water of heat, exsiccant interpolymer film being purified in 80 ℃ of rinsings.The interpolymer film is cooled off in air to form (reform) exsiccant interpolymer film again.
In 4 ℃ exsiccant interpolymer film is mixed with solution above 16 hours to form hydrogel thin film.Said solution is the phosphoric acid buffers saline solution for preparing before, contains the P-FAD of 5wt.%.Only other additive that is included in this solution is tensio-active agent (0.05wt.%Triton
X-100).
Hydrogel thin film is cut into required size and makes its working area that is dried to electrochemical sensor system size.Use buffer solvent (PBS) to reconstitute exsiccant hydrogel thin film on the electrochemical sensor to form hydrogel composition.Hydrogel composition is applied on three different positionss of the preceding wrist palmar skin between wrist joint and the elbow joint, forearm site 1 is positioned between forearm site 1 and 3 near elbow joint and forearm site 2 near wrist joint, forearm site 3.
Through using additional ultrasonic energy, the preceding wrist palmar skin that is positioned at forearm site 1-3 is carried out pre-treatment.Make P-FAD contacting skin and the interstitial fluid (ISF) that contains glucose in the hydrogel composition.It is superoxide that P-FAD helps to make the conversion of glucose among the ISF.To detecting the response of superoxide, electrochemical sensor produces electric current.Strength of current is corresponding with the glucose concn among the ISF.
The electric current of measuring each site of forearm site 1-3 surpasses certain hour.In cycle, also adopt the ANALOX-glucose analyser GM 10 that is sold by Analis to detect actual glucose concn at one time, it is a relative method.This is labeled as " plasma glucose " in Fig. 4 a, 4b.
With reference to figure 4a, will adopt forearm site 1-3 and relative method to measure electric current (in nanoampere) (in Fig. 4 a, being labeled as plasma glucose) through above method the time (in second) will be mapped.In addition, the figure of Fig. 4 a comprise relevant with the electric current of measuring, in the glucose of mg/dL.For the data of comparison of aforementioned better, with the reading of forearm site 2 and 3 through with respect to the stdn of observed maximum sensor signal flow.Forearm site 2 and 31 be shown among Fig. 4 b with plasma glucose through standardized reading and forearm site.
The result of test shows that the dextrose equivalent value (forearm site 1-3) that use the inventive method is measured is relevant with the subject's in relative method (plasma glucose) parallel dextrose equivalent value.
Embodiment 2
In embodiment 2, prepare two kinds of different compsns of the present invention.Combine (grafted) to be in the same place hydrogel pad of the present invention 1, interpolymer reticulated structure and cellulose matrix.In hydrogel pad 2 of the present invention, form the interpolymer reticulated structure, be placed on the nylon mesh then.
Especially, in hydrogel pad 1 of the present invention, interpolymer reticulated structure and cellulose matrix are grafted on together.The interpolymer reticulated structure comprise 60 parts of N-vinyl pyrrolidones (first monomer), 40 parts of vinyl-acetic esters (second monomer), 1 part of diethylene glycol divinyl ether and 1 part for ultraviolet ray (UV) initiator (2-hydroxyl-4 '-(2-hydroxyl-oxethyl)-2-aminomethyl phenyl ethyl ketone.Interpolymer reticulated structure thing is 2: 1 to the part by weight of cellulose matrix.Used cellulose matrix is Kimwipes
absorbent test paper (wipers) EX-L from Kimberly-Clark.
Monomer mixture is absorbed into the absorbent rag EX-L of porous KImwipes
, is exposed to UV ray 2 hours then to accomplish polyreaction.After the reaction, gel interpolymer reticulated structure and cellulose matrix are immersed entry to remove unreacted monomer.Mierocrystalline cellulose and crosslinked interpolymer reticulated structure interpenetrate, and, therefore chemically combine.First and second monomers also chemically combine each other.
Will be chemically the netted structure of bonded interpolymer/Mierocrystalline cellulose carry out hydration formation hydrogel thin slice with water fully.After complete hydration, the damping fluid that will contain enzyme (P-FAD) adds to the hydrogel thin slice.Dried hydrogel thin slice and storage then.
The hydrogel shearing of thin disc become the size want to form hydrogel pad.Hydrogel pad is attached to the surface of electrochemical sensor.The hydrogel pad hydration again that to adhere to the water that comprises damping fluid then.Hydrogel pad 1 of the present invention comprises from about water of 60 to about 90wt.% and normally uniform and mechanically stable.
Adopting the ultrasonic dermal osmosis of Sontra SonoPrep
system that skin is carried out ultrasonic energy handles.Test on skin at two different sites--wrist and the ancon.Hydrogel pad 1 of the present invention is adhered on the everywhere skin of these positions.Measure electric current and measure glucose concn with electrochemical sensor at each allocation.
Hydrogel pad 2 of the present invention comprises the interpolymer reticulated structure.The interpolymer reticulated structure comprise 60 parts of N-vinyl pyrrolidones (first monomer), 40 parts of vinyl-acetic esters (second monomer), 1 part of diethylene glycol divinyl ether and 1 part (2-hydroxyl-4 '-(2-hydroxyl-oxethyl)-2-aminomethyl phenyl ethyl ketone.The interpolymer reticulated structure is exposed to UV ray 2 hours to accomplish polyreaction.After the reaction, with gel interpolymer reticulated structure soaked in water to remove unreacted monomer.First and second monomers chemically combine each other.
The interpolymer reticulated structure is fully carried out hydration with water, formation hydrogel thin slice.After complete hydration, the damping fluid that will contain enzyme (P-FAD) adds to the hydrogel thin slice.Dried hydrogel thin slice and storage then.In order to improve processing, use nylon mesh to support the hydrogel thin slice to the hydrogel thin slice.The hydrogel shearing of thin disc that will have nylon mesh becomes the size want to form hydrogel pad 2 of the present invention.Hydrogel pad 2 of the present invention is attached to the surface of electrochemical sensor.Hydrogel pad of the present invention 2 hydration again that to adhere to the water that comprises damping fluid then.The hydrogel pad of the present invention 2 of hydration comprises from about water of 60 to about 90wt.% and normally uniform and mechanically stable.
Adopting the ultrasonic dermal osmosis of Sontra SonoPrep
system that skin (forearm) is carried out ultrasonic energy handles.The hydrogel pad of the present invention 2 of hydration is adhered on the skin (forearm).Measure electric current and measure glucose concn with electrochemical sensor.
Use the test result of hydrogel pad 1 of the present invention and 2 to be shown in Fig. 5.Fig. 5 has described electric current (nanoampere) and glucose concn (mg/dL) figure to the time.Especially, Fig. 5 has described to use electrochemical sensor to detect the relative method (plasma glucose of mark in Fig. 5) of blood and measure glucose concentration.The relative method of Fig. 5 is not used hydrogel composition.In relative method, to take blood sample in per 30 minutes and used Analox Instruments U.S.A. by Massachusetts Lunenberg, the Analox GM9D analyser that Inc. sells is analyzed.Also the result to the method for using hydrogel pad 1 of the present invention (in wrist and ancon two places) and hydrogel pad 2 (forearm) draws.As shown in fig. 5, the common plasma glucose concentration with the subject who gets self-comparison method 1 of glucose concn that derives from method of the present invention (using hydrogel pad 1 of the present invention and 2) is relevant.
Alternate embodiment A
Hydrogel composition comprises first monomer, second monomer, linking agent and solvent, and first monomer is selected from formula I:
Wherein R and R1 independently are selected from H, (C
1-C
3) alkyl, (C
3-C
6) dihydroxyl alkyl and (C
2-C
6) hydroxyalkyl; Or the combination of R and R1 is selected from 1-5 carbon atom, forms 3-7 unit heterocyclic moiety like this; Second monomer is selected from formula II and formula III, and its Chinese style II does
Wherein R3 and R4 independently are selected from H, CH
3, (C
3-C
18) alkyl; Wherein alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; (C
3-C
7) naphthenic base, wherein naphthenic base is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; With the aromatics part, wherein aromatics part is by one or more optional replacements of substituting groups that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid, condition be when R3 be H or CH
3The time, then R4 is (C
3-C
18) alkyl, (C
3-C
7) naphthenic base or aromatics part, wherein alkyl, naphthenic base or aromatics part is replaced by one or more substituting groups are optional, condition be when R4 be H or CH
3The time, then R3 is (C
3-C
18) alkyl, (C
3-C
7) naphthenic base or aromatics part, wherein alkyl, naphthenic base or aromatics part are by the optional replacement of one or more substituting groups; Wherein formula III does
Wherein R5 is selected from (C
3-C
18) alkyl; Wherein alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; (C
3-C
7) naphthenic base, wherein naphthenic base is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; With the aromatics part, wherein the aromatics part is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid, and wherein first monomer is from about 0.1: 99.9 to about 99.9: 0.1 to the second monomeric ratio.
Alternative embodiment B
The hydrogel composition of alternative embodiment A, wherein said linking agent are polyfunctional vinyl ether, Vinylstyrene, polyfunctional propenoate or polyfunctional acrylic amide.
Alternative embodiment C
The hydrogel composition of alternative embodiment B, wherein said linking agent are polyfunctional vinyl ether, and said polyfunctional vinyl ether is diethylene glycol divinyl ether propenoate, triethylene glycol divinyl ether and four (glycol) divinyl ether.
Alternative embodiment D
The hydrogel composition of alternative embodiment B, wherein said linking agent are Vinylstyrene.
Alternative embodiment E
The hydrogel composition of alternative embodiment B; Wherein said linking agent is polyfunctional propenoate; Said polyfunctional propenoate is ethylene glycol dimethacrylate (EGDMA), gather diacrylate second diester, diethylene glycol dimethacrylate, diethylene glycol diacrylate, glycol diacrylate or 1,3-dihydroxypropyl dimethacrylate.
Alternative embodiment F
The hydrogel composition of alternative embodiment B, wherein said linking agent are polyfunctional acrylic amide.
Alternative embodiment G
The hydrogel composition of alternative embodiment A, wherein solvent is a water.
Alternative embodiment H
The hydrogel composition of alternative embodiment A, it also comprises photoinitiator.
Alternative embodiment I
The hydrogel composition of alternative embodiment A, wherein first monomer is from about 20: 80 to about 80: 20 to the second monomeric ratio.
Alternative embodiment J
The hydrogel composition of alternative embodiment A, wherein second monomer is selected from formula II.
Alternative embodiment K
The hydrogel composition of alternative embodiment A, wherein second monomer is selected from formula III.
Alternative embodiment L
The hydrogel composition of alternative embodiment A, wherein first monomer is N-vinyl acetamide, N-vinyl propionic acid amide, N-vinyl pyrrolidone or N-caprolactam, second monomer is selected from wherein R3 or R4 is optional substituted (C
3-C
18) the formula II of alkyl.
Alternative embodiment M
The hydrogel composition of alternative embodiment A, wherein first monomer is N-vinyl acetamide, N-vinyl propionic acid amide, N-vinyl pyrrolidone or N-caprolactam, second monomer is selected from wherein R3 or R4 is optional substituted (C
3-C
7) the formula II of naphthenic base.
Alternative embodiment N
The hydrogel composition of alternative embodiment A, wherein first monomer is N-vinyl acetamide, N-vinyl propionic acid amide, N-vinyl pyrrolidone or N-caprolactam, second monomer is selected from R3 wherein or the R4 formula II for optional substituted aromatics part.
Alternative embodiment O
The hydrogel composition of alternative embodiment A, wherein first monomer is N-vinyl acetamide, N-vinyl propionic acid amide, N-vinyl pyrrolidone or N-caprolactam, second monomer is selected from wherein R3 or R4 is optional substituted (C
3-C
18) formula III of alkyl.
Alternative embodiment P
The hydrogel composition of alternative embodiment A, wherein first monomer is N-vinyl acetamide, N-vinyl propionic acid amide, N-vinyl pyrrolidone or N-caprolactam, second monomer is selected from wherein R3 or R4 is optional substituted (C
3-C
7) formula III of naphthenic base.
Alternative embodiment Q
The hydrogel composition of alternative embodiment A; Wherein first monomer is N-vinyl acetamide, N-vinyl propionic acid amide, N-vinyl pyrrolidone or N-caprolactam, and second monomer is selected from R3 wherein or the R4 formula III for optional substituted aromatics part.
Alternative embodiment R
Electrochemical sensor system comprises: the electrochemical sensor that has counter electrode and working electrode at least; With the hydrogel composition that contacts working electrode; Said hydrogel composition comprises first monomer, second monomer, linking agent and solvent; First monomer is selected from methylacrylic acid hydroxyl alkyl ester, acrylic amide, N; N two-alkyl acrylamide, methylacrylic acid, vinylformic acid, methacrylic acid metal salt, acrylate metal salt, methylene-succinic acid, maleic acid, USAF RH-1, N; N-dialkyl group acrylic amide, styrene sulfonic acid, styrene sulfonic acid metal-salt, vinylbenzene carboxylic acid, vinylbenzene carboxylic metallic salt, acrylamido-2-methyl propane sulfonic acid, acrylamido-2-methyl propane sulfonic acid metal-salt, 2-vinyl N-alkyl pyridine halogenide, 4-vinyl N-alkyl pyridine halogenide or formula I, its Chinese style I does
Formula I wherein R and R1 independently is selected from H, (C
1-C
3) alkyl, (C
3-C
6) dihydroxyl alkyl and (C
2-C
6) hydroxyalkyl; Or the combination of R and R1 is selected from 1-5 carbon atom, forms 3-7 unit heterocyclic moiety like this; Second monomer is selected from (methyl) alkyl acrylate, formula II, formula III and formula IV, and its Chinese style II does
Wherein R3 and R4 independently are selected from H, CH
3, (C
3-C
18) alkyl; Wherein alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; (C
3-C
7) naphthenic base, wherein naphthenic base is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; With the aromatics part, wherein aromatics part is by one or more optional replacements of substituting groups that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid, condition be when R3 be H or CH
3The time, then R4 is (C
3-C
18) alkyl, (C
3-C
7) naphthenic base or aromatics part, wherein alkyl, naphthenic base or aromatics part is replaced by one or more substituting groups are optional, condition be when R4 be H or CH
3The time, then R3 is (C
3-C
18) alkyl, (C
3-C
7) naphthenic base or aromatics part, wherein alkyl, naphthenic base or aromatics part are by the optional replacement of one or more substituting groups; Wherein formula III does
Wherein R5 is selected from (C
3-C
18) alkyl; Wherein alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; (C
3-C
7) naphthenic base, wherein naphthenic base is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; With the aromatics part, wherein the aromatics part is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid, and its Chinese style IV does
Wherein R2 is selected from (C
1-C
18) alkyl; Wherein alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; (C
3-C
7) naphthenic base, wherein naphthenic base is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; With the aromatics part, wherein the aromatics part is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid, and wherein first monomer is from about 0.1: 99.9 to about 99.9: 0.1 to the second monomeric ratio.
Alternative embodiment S
The electrochemical sensor system of alternative embodiment R, it also comprises makes hydrogel composition be fixed in the adhesion arrangement (adhesive structure) on the electrochemical sensor.
Alternative embodiment T
The electrochemical sensor system of alternative embodiment R, wherein said electrochemical sensor also comprises reference electrode.
Alternative embodiment U
The electrochemical sensor system of alternative embodiment R, wherein hydrogel composition is the exsiccant hydrogel composition.
Alternative embodiment V
The electrochemical sensor system of alternative embodiment U, wherein the exsiccant hydrogel composition is a film.
Alternative embodiment W
The electrochemical sensor system of alternative embodiment R, it also comprises the auxiliary mechanical jack that the hydrogel composition physical strength is provided.
Alternative embodiment X
The electrochemical sensor system of alternative embodiment W, wherein mechanical jack is polymer reticulattion, woven fabrics, supatex fabric, Mierocrystalline cellulose or its combination.
Alternative embodiment Y
The electrochemical sensor system of alternative embodiment R, wherein the thickness of hydrogel composition is from about 0.1mil to about 100mils.
Alternative embodiment Z
The electrochemical sensor system of alternative embodiment Y, wherein the thickness of hydrogel composition is from about 1mil to about 30mils.
Alternative embodiment AA
The electrochemical sensor system of alternative embodiment R, wherein first monomer is from about 20: 80 to about 80: 20 to the second monomeric ratio.
Alternative embodiment BB
Electrochemical sensor system comprises: the electrochemical sensor that has counter electrode and working electrode at least; With the hydrogel composition that contacts working electrode, said hydrogel composition comprises first monomer, second monomer, linking agent and solvent, and first monomer is selected from formula I
Wherein R and R1 independently are selected from H, (C
1-C
3) alkyl, (C
3-C
6) dihydroxyl alkyl and (C
2-C
6) hydroxyalkyl; Or the combination of R and R1 is selected from 1-5 carbon atom, forms 3-7 unit heterocyclic moiety like this; Second monomer is selected from (methyl) alkyl acrylate, formula II, formula III and formula IV, and its Chinese style II does
Wherein R3 and R4 independently are selected from H, CH
3, (C
3-C
18) alkyl; Wherein alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; (C
3-C
7) naphthenic base, wherein naphthenic base is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; With the aromatics part, wherein aromatics part is by one or more optional replacements of substituting groups that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid, condition be when R3 be H or CH
3The time, then R4 is (C
3-C
18) alkyl, (C
3-C
7) naphthenic base or aromatics part, wherein alkyl, naphthenic base or aromatics part is replaced by one or more substituting groups are optional, condition be when R4 be H or CH
3The time, then R3 is (C
3-C
18) alkyl, (C
3-C
7) naphthenic base or aromatics part, wherein alkyl, naphthenic base or aromatics part are by the optional replacement of one or more substituting groups; Wherein formula III does
Wherein R5 is selected from (C
3-C
18) alkyl; Wherein alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; (C
3-C
7) naphthenic base, wherein naphthenic base is selected from optional replacement of one or more substituting groups of alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; With the aromatics part, wherein the aromatics part is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid, and its Chinese style IV does
Wherein R2 is selected from (C
1-C
18) alkyl; Wherein alkyl is selected from optional replacement of one or more substituting groups of halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; (C
3-C
7) naphthenic base, wherein naphthenic base is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; With the aromatics part, wherein the aromatics part is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid, and wherein first monomer is from about 0.1: 99.9 to about 99.9: 0.1 to the second monomeric ratio.
Alternative embodiment CC
The electrochemical sensor system of alternative embodiment BB, it also comprises makes hydrogel composition be fixed in the adhesion arrangement on the electrochemical sensor.
Alternative embodiment DD
The electrochemical sensor system of alternative embodiment BB, wherein said electrochemical sensor also comprises reference electrode.
Alternative embodiment EE
The electrochemical sensor system of alternative embodiment BB, wherein hydrogel composition is the exsiccant hydrogel composition.
Alternative embodiment FF
The electrochemical sensor system of alternative embodiment EE, wherein the exsiccant hydrogel composition is a film.
Alternative embodiment GG
The electrochemical sensor system of alternative embodiment BB, it also comprises the auxiliary mechanical jack that the hydrogel composition physical strength is provided.
Alternative embodiment HH
The electrochemical sensor system of alternative embodiment GG, wherein mechanical jack is polymer reticulattion, woven fabrics, supatex fabric, paper or its combination.
Alternative embodimentII
The electrochemical sensor system of alternative embodiment BB, wherein said linking agent are polyfunctional vinyl ether, Vinylstyrene, polyfunctional propenoate or polyfunctional acrylic amide.
Alternative embodiment JJ
The electrochemical sensor system of alternative embodiment BB, wherein first monomer is from about 20: 80 to about 80: 20 to the second monomeric ratio.
Alternative embodiment KK
Electrochemical sensor system comprises: the electrochemical sensor that has counter electrode and working electrode at least; With the hydrogel composition that contacts working electrode; Said hydrogel composition comprises first monomer, second monomer, linking agent and solvent; First monomer is selected from N-vinyl pyrrolidone, methylacrylic acid hydroxyl alkyl ester, acrylic amide and N; N two-alkyl acrylamide, second monomer be selected from (methyl) alkyl acrylate, N-vinyl acrylic amide, vinyl acetate and vinyl ether and wherein first monomer to the second monomeric ratio for from about 0.1: 99.9 to about 99.9: 0.1.
Alternative embodiment LL
The electrochemical sensor system of alternative embodiment KK, it also comprises makes hydrogel composition be fixed in the adhesion arrangement on the electrochemical sensor.
Alternative embodiment MM
The electrochemical sensor system of alternative embodiment KK, wherein said electrochemical sensor also comprises reference electrode.
Alternative embodiment NN
The electrochemical sensor system of alternative embodiment KK, wherein hydrogel composition is the exsiccant hydrogel composition.
Alternative embodiment OO
The electrochemical sensor system of alternative embodiment NN, wherein the exsiccant hydrogel composition is a film.
Alternative embodiment PP
The electrochemical sensor system of alternative embodiment KK, it also comprises the auxiliary mechanical jack that the hydrogel composition physical strength is provided.
Alternative embodiment QQ
The electrochemical sensor system of alternative embodiment PP, wherein mechanical jack is polymer reticulattion, woven fabrics, supatex fabric, paper or its combination.
Alternative embodiment RR
The electrochemical sensor system of alternative embodiment KK, wherein first monomer is that the N-vinyl pyrrolidone and second monomer are vinyl acetate.
Alternative embodiment SS
The electrochemical sensor system of alternative embodiment KK, wherein said linking agent are polyfunctional vinyl ether, Vinylstyrene, polyfunctional propenoate or polyfunctional acrylic amide.
Alternative embodiment TT
The electrochemical sensor system of alternative embodiment KK, wherein first monomer is from about 20: 80 to about 80: 20 to the second monomeric ratio.
Alternative embodiment UU
Electrochemical sensor system comprises: the electrochemical sensor that has counter electrode and working electrode at least; With the hydrogel composition that contacts working electrode; Said hydrogel composition comprises first monomer, second monomer, linking agent and solvent; First monomer has water-wet behavior; Second monomer has hydrophobic property, and wherein first monomer is from about 0.1: 99.9 to about 99.9: 0.1 to the second monomeric ratio.
Alternative approach A
Measure the method for analyte concentration; Said method comprising the steps of: hydrogel composition is placed on the skin; Said hydrogel composition comprises first monomer, second monomer, linking agent and solvent; First monomer is selected from methylacrylic acid hydroxyl alkyl ester, acrylic amide, N; N two-alkyl acrylamide, methylacrylic acid, vinylformic acid, methacrylic acid metal salt, acrylate metal salt, methylene-succinic acid, maleic acid, USAF RH-1, N; N-dialkyl group acrylic amide, styrene sulfonic acid, styrene sulfonic acid metal-salt, vinylbenzene carboxylic acid, vinylbenzene carboxylic metallic salt, acrylamido-2-methyl propane sulfonic acid, acrylamido-2-methyl propane sulfonic acid metal-salt, 2-vinyl N-alkyl pyridine halogenide, 4-vinyl N-alkyl pyridine halogenide or formula I, its Chinese style I does
Wherein R and R1 independently are selected from H, (C
1-C
3) alkyl, (C
3-C
6) dihydroxyl alkyl and (C
2-C
6) hydroxyalkyl; Or the combination of R and R1 is selected from 1-5 carbon atom, forms 3-7 unit heterocyclic moiety like this; Second monomer is selected from (methyl) alkyl acrylate, formula II, formula III and formula IV, and its Chinese style II does
Wherein R3 and R4 independently are selected from H, CH
3, (C
3-C
18) alkyl; Wherein alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; (C
3-C
7) naphthenic base, wherein naphthenic base is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; With the aromatics part, wherein aromatics part is by one or more optional replacements of substituting groups that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid, condition be when R3 be H or CH
3The time, then R4 is (C
3-C
18) alkyl, (C
3-C
7) naphthenic base or aromatics part, wherein alkyl, naphthenic base or aromatics part is replaced by one or more substituting groups are optional, condition be when R4 be H or CH
3The time, then R3 is (C
3-C
18) alkyl, (C
3-C
7) naphthenic base or aromatics part, wherein alkyl, naphthenic base or aromatics part are by the optional replacement of one or more substituting groups; Wherein formula III does
Wherein R5 is selected from (C
3-C
18) alkyl; Wherein alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; (C
3-C
7) naphthenic base, wherein naphthenic base is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; With the aromatics part, wherein the aromatics part is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid, and its Chinese style IV does
Wherein R2 is selected from (C
1-C
18) alkyl; Wherein alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; (C
3-C
7) naphthenic base, wherein naphthenic base is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; With the aromatics part, wherein the aromatics part is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid, and wherein first monomer is from about 0.1: 99.9 to about 99.9: 0.1 to the second monomeric ratio; Transmitter is provided, and common said hydrogel composition is located between skin and the transmitter and makes its connection (coupling) skin and transmitter; With to interstitial fluid sampling, use the sensor determination analyte concentration.
Alternative approach B
The method of alternative approach A, this method also comprise the skin pre-treatment, to improve the perviousness of skin.
Alternative approach C
The method of alternative approach B, wherein said pre-treatment comprise skin are applied ultrasonic energy.
Alternative approach D
The method of alternative approach A, wherein said skin are preceding wrist palmar (volarforearm) skin.
Alternative approach E
The method of alternative approach A, wherein assay is a glucose.
Alternative approach F
The method of alternative approach A, wherein transmitter is an electrochemical sensor.
Alternative approach G
The method of alternative approach A, wherein first monomer is from about 20: 80 to about 80: 20 to the second monomeric ratio.
Alternative approach H
Measure the method for analyte concentration, said method comprising the steps of: hydrogel composition is placed on the skin, and said hydrogel composition comprises first monomer, second monomer, linking agent and solvent, and first monomer is selected from formula I
Wherein R and R1 independently are selected from H, (C
1-C
3) alkyl, (C
3-C
6) dihydroxyl alkyl and (C
2-C
6) hydroxyalkyl; Or the combination of R and R1 is selected from 1-5 carbon atom, forms 3-7 unit heterocyclic moiety like this; Second monomer is selected from (methyl) alkyl acrylate, formula II, formula III and formula IV, and its Chinese style II does
Wherein R3 and R4 independently are selected from H, CH
3, (C
3-C
18) alkyl; Wherein alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; (C
3-C
7) naphthenic base, wherein naphthenic base is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; With the aromatics part, wherein aromatics part is by one or more optional replacements of substituting groups that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid, condition be when R3 be H or CH
3The time, then R4 is (C
3-C
18) alkyl, (C
3-C
7) naphthenic base or aromatics part, wherein alkyl, naphthenic base or aromatics part is replaced by one or more substituting groups are optional, condition be when R4 be H or CH
3The time, then R3 is (C
3-C
18) alkyl, (C
3-C
7) naphthenic base or aromatics part, wherein alkyl, naphthenic base or aromatics part are by the optional replacement of one or more substituting groups; Wherein formula III does
Wherein R5 is selected from (C
3-C
18) alkyl; Wherein alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; (C
3-C
7) naphthenic base, wherein naphthenic base is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; With the aromatics part, wherein the aromatics part is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid, and its Chinese style IV does
Wherein R2 is selected from (C
1-C
18) alkyl; Wherein alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; (C
3-C
7) naphthenic base, wherein naphthenic base is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid; With the aromatics part, wherein the aromatics part is by one or more optional replacements of substituting group that are selected from alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid, and wherein first monomer is from about 0.1: 99.9 to about 99.9: 0.1 to the second monomeric ratio; Transmitter is provided, and common said hydrogel composition is located between skin and the transmitter and makes it connect skin and transmitter; With to interstitial fluid sampling, use the sensor determination analyte concentration.
Alternative approach I
The method of alternative approach H, this method also comprise the skin pre-treatment, to improve the perviousness of skin.
Alternative approach J
The method of alternative approach I, wherein said pre-treatment comprise skin are applied ultrasonic energy.
Alternative approach K
The method of alternative approach H, wherein skin is preceding wrist palmar skin.
Alternative approach L
The method of alternative approach H, wherein assay is a glucose.
Alternative approach M
The method of alternative approach H, wherein transmitter is an electrochemical sensor.
Alternative approach N
The method of alternative approach H, wherein first monomer is from about 20: 80 to about 80: 20 to the second monomeric ratio.
Alternative approach O
Measure the method for analyte concentration; Said method comprising the steps of: hydrogel composition is placed on the skin; Said hydrogel composition comprises first monomer, second monomer, linking agent and solvent; First monomer is selected from N-vinyl pyrrolidone, methylacrylic acid hydroxyl alkyl ester, acrylic amide and N; N two-alkyl acrylamide, second monomer be selected from (methyl) alkyl acrylate, N-vinylamide, vinyl acetate and vinyl ether and wherein first monomer to the second monomeric ratio for from about 0.1: 99.9 to about 99.9: 0.1; Transmitter is provided, and common said hydrogel composition is located between skin and the transmitter and with skin and is connected with transmitter; With to interstitial fluid sampling, use the sensor determination analyte concentration.
Alternative approach P
The method of alternative approach O, this method also comprise the skin pre-treatment, to improve the perviousness of skin.
Alternative approach Q
The method of alternative approach P, its said pre-treatment comprise skin are applied ultrasonic energy.
Alternative approach R
The method of alternative approach O, wherein skin is preceding wrist palmar skin.
Alternative approach S
The method of alternative approach O, wherein assay is a glucose.
Alternative approach T
The method of alternative approach O, wherein transmitter is an electrochemical sensor.
Alternative approach U
The method of alternative approach O, wherein first monomer is that the N-vinyl pyrrolidone and second monomer are vinyl acetate.
Alternative approach V
The method of alternative approach U, wherein said linking agent are polyfunctional vinyl ether, Vinylstyrene, polyfunctional propenoate or polyfunctional acrylic amide.
Alternative approach W
The method of alternative approach O, wherein first monomer is from about 20: 80 to about 80: 20 to the second monomeric ratio.
Alternative approach X
Measure the method for analyte concentration; Said method comprising the steps of: hydrogel composition is placed on the skin; Said hydrogel composition comprises first monomer, second monomer, linking agent and solvent; First monomer has water-wet behavior, and second monomer has hydrophobic property, and wherein first monomer is from about 0.1: 99.9 to about 99.9: 0.1 to the second monomeric ratio; Transmitter is provided, is positioned said hydrogel composition between skin and the transmitter usually and it is connected with transmitter with skin; With to interstitial fluid sampling, use the sensor determination analyte concentration.
Though describe the present invention with reference to one or more concrete embodiments, this area the professional and technical personnel will recognize that, under the situation that does not break away from the spirit and scope of the present invention, can carry out many variations.In these embodiments each and considerable change thereof all should comprise within the spirit and scope of the present invention.
Claims (45)
1. hydrogel composition that comprises first monomer, second monomer, linking agent and solvent, said first monomer is selected from formula I:
Formula I
Wherein
The combination of R and R1 is selected from 1-5 carbon atom, forms 3-7 unit heterocyclic moiety like this;
Second monomer is selected from formula IV,
Its Chinese style IV does
Formula IV
Wherein
R2 is selected from C
1-C
18Alkyl; Wherein alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid;
Wherein first monomer is from 0.1: 99.9 to 99.9: 0.1 to the second monomeric ratio.
2. the hydrogel composition of claim 1, wherein said linking agent is polyfunctional vinyl ether, Vinylstyrene, polyfunctional propenoate or polyfunctional acrylic amide.
3. the hydrogel composition of claim 2, wherein said linking agent is polyfunctional vinyl ether, said polyfunctional vinyl ether is diethylene glycol divinyl ether propenoate, triethylene glycol divinyl ether and four (glycol) divinyl ether.
4. the hydrogel composition of claim 2, wherein said linking agent is a Vinylstyrene.
5. the hydrogel composition of claim 2; Wherein said linking agent is polyfunctional propenoate; Said polyfunctional propenoate is ethylene glycol dimethacrylate, gather diacrylate second diester, diethylene glycol dimethacrylate, diethylene glycol diacrylate, glycol diacrylate or 1,3-dihydroxypropyl dimethacrylate.
6. the hydrogel composition of claim 2, wherein said linking agent is polyfunctional acrylic amide.
7. the hydrogel composition of claim 1, wherein said solvent is a water.
8. the hydrogel composition of claim 1, it also comprises photoinitiator.
9. the hydrogel composition of claim 1, wherein first monomer is from 20: 80 to 80: 20 to the second monomeric ratio.
10. the hydrogel composition of claim 1, wherein first monomer is N-vinyl pyrrolidone or N-caprolactam.
11. an electrochemical sensor system, it comprises:
At least the electrochemical sensor that has counter electrode and working electrode; With
The hydrogel composition of contact working electrode, said hydrogel composition comprises first monomer, second monomer, linking agent and solvent, and first monomer is selected from formula I, and its Chinese style I does
Formula I
Wherein
The combination of R and R1 is selected from 1-5 carbon atom, forms 3-7 unit heterocyclic moiety like this;
Second monomer is selected from formula IV,
Its Chinese style IV does
Formula IV
Wherein
R2 is selected from C
1-C
18Alkyl; Wherein alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid;
Wherein first monomer is 0.1: 99.9 to 99.9: 0.1 to the second monomeric ratio.
12. the electrochemical sensor system of claim 11, it also comprises makes hydrogel composition be fixed in the adhesion arrangement on the electrochemical sensor.
13. the electrochemical sensor system of claim 11, wherein said electrochemical sensor also comprises reference electrode.
14. the electrochemical sensor system of claim 11, wherein said hydrogel composition are the exsiccant hydrogel composition.
15. the electrochemical sensor system of claim 11, wherein said exsiccant hydrogel composition is a film.
16. the electrochemical sensor system of claim 11, it also comprises the auxiliary mechanical jack that the hydrogel composition physical strength is provided.
17. the electrochemical sensor system of claim 16, wherein said mechanical jack are polymer reticulattion, woven fabrics, supatex fabric, Mierocrystalline cellulose or its combination.
18. the electrochemical sensor system of claim 11, the thickness of wherein said hydrogel composition are from 0.1 mil to 100 mil.
19. the electrochemical sensor system of claim 18, the thickness of wherein said hydrogel composition are from 1 mil to 30 mil.
20. the electrochemical sensor system of claim 11, wherein first monomer is from 20: 80 to 80: 20 to the second monomeric ratio.
21. the electrochemical sensor system of claim 11, linking agent wherein are polyfunctional vinyl ether, Vinylstyrene, polyfunctional propenoate or polyfunctional acrylic amide.
22. an electrochemical sensor system, it comprises:
At least the electrochemical sensor that has counter electrode and working electrode; With
The hydrogel composition of contact working electrode; Said hydrogel composition comprises first monomer, second monomer, linking agent and solvent; First monomer is selected from the N-vinyl pyrrolidone; Second monomer is selected from vinyl acetate, and wherein first monomer is 0.1: 99.9 to 99.9: 0.1 to the second monomeric ratio.
23. the electrochemical sensor system of claim 22, it also comprises makes hydrogel composition be fixed in the adhesion arrangement on the electrochemical sensor.
24. the electrochemical sensor system of claim 22, wherein said electrochemical sensor also comprises reference electrode.
25. the electrochemical sensor system of claim 22, wherein said hydrogel composition are the exsiccant hydrogel composition.
26. the electrochemical sensor system of claim 25, wherein said exsiccant hydrogel composition is a film.
27. the electrochemical sensor system of claim 22, it also comprises the auxiliary mechanical jack that the hydrogel composition physical strength is provided.
28. the electrochemical sensor system of claim 27, wherein said mechanical jack are polymer reticulattion, woven fabrics, supatex fabric, paper or its combination.
29. the electrochemical sensor system of claim 22, wherein said linking agent are polyfunctional vinyl ether, Vinylstyrene, polyfunctional propenoate or polyfunctional acrylic amide.
30. the electrochemical sensor system of claim 22, wherein first monomer is from 20: 80 to 80: 20 to the second monomeric ratio.
31. a method of measuring analyte concentration said method comprising the steps of:
Hydrogel composition is placed on the skin, and said hydrogel composition comprises first monomer, second monomer, linking agent and solvent, and first monomer is selected from formula I, and its Chinese style I does
Formula I
Wherein
The combination of R and R1 is selected from 1-5 carbon atom, forms 3-7 unit heterocyclic moiety like this;
Second monomer is selected from formula IV,
Its Chinese style IV does
Formula IV
Wherein
R2 is selected from C
1-C
18Alkyl; Wherein alkyl is by one or more optional replacements of substituting group that are selected from halo, haloalkyl, naphthenic base, nitro, cyanic acid, 4-8 unit heterocyclic moiety, and wherein heterocyclic moiety is by the optional replacement of one or more alkyl, halo, haloalkyl, naphthenic base, nitro and cyanic acid;
Wherein first monomer is from 0.1: 99.9 to 99.9: 0.1 to the second monomeric ratio;
Transmitter is provided, and said hydrogel composition is located between skin and the transmitter and connects them; With
To the interstitial fluid sampling, use the sensor determination analyte concentration.
32. the method for claim 31, it also comprises the skin pre-treatment, to improve the perviousness of skin.
33. the method for claim 32, wherein said pre-treatment comprise skin is applied ultrasonic energy.
34. the method for claim 31, wherein said skin are preceding wrist palmar skin.
35. the method for claim 31, wherein said assay are glucose.
36. the method for claim 31, wherein said transmitter are electrochemical sensor.
37. the method for claim 31, wherein first monomer is from 20: 80 to 80: 20 to the second monomeric ratio.
38. a method of measuring analyte concentration said method comprising the steps of:
Hydrogel composition is placed on the skin; Said hydrogel composition comprises first monomer, second monomer, linking agent and solvent; First monomer is selected from the N-vinyl pyrrolidone; Second monomer is selected from vinyl acetate, and wherein first monomer is from 0.1: 99.9 to 99.9: 0.1 to the second monomeric ratio;
Transmitter is provided, and said hydrogel composition is located between skin and the transmitter and connects them; With
To the interstitial fluid sampling, use the sensor determination analyte concentration.
39. the method for claim 38 also comprises the skin pre-treatment, to improve the perviousness of skin.
40. the method for claim 39, wherein said pre-treatment comprise skin is applied ultrasonic energy.
41. the method for claim 38, wherein said skin are preceding wrist palmar skin.
42. the method for claim 38, wherein said assay are glucose.
43. the method for claim 38, wherein said transmitter are electrochemical sensor.
44. the method for claim 38, wherein said linking agent are polyfunctional vinyl ether, Vinylstyrene, polyfunctional propenoate or polyfunctional acrylic amide.
45. the method for claim 38, wherein first monomer is from 20: 80 to 80: 20 to the second monomeric ratio.
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US97496304A | 2004-10-28 | 2004-10-28 | |
| US10/974,963 | 2004-10-28 | ||
| US67645305P | 2005-04-29 | 2005-04-29 | |
| US60/676,453 | 2005-04-29 | ||
| US20133405A | 2005-08-11 | 2005-08-11 | |
| US11/201,334 | 2005-08-11 | ||
| US71706405P | 2005-09-14 | 2005-09-14 | |
| US60/717,064 | 2005-09-14 | ||
| PCT/US2005/038966 WO2006050115A1 (en) | 2004-10-28 | 2005-10-27 | Hydrogel composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101087822A CN101087822A (en) | 2007-12-12 |
| CN101087822B true CN101087822B (en) | 2012-05-30 |
Family
ID=38938232
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200580040628A Expired - Fee Related CN100574700C (en) | 2004-10-28 | 2005-10-27 | Use the system and method for hydrogel to analyte sampling and analysis |
| CN2005800446261A Active CN101087822B (en) | 2004-10-28 | 2005-10-27 | Hydrogel composition |
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| CN200580040628A Expired - Fee Related CN100574700C (en) | 2004-10-28 | 2005-10-27 | Use the system and method for hydrogel to analyte sampling and analysis |
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| US20120006100A1 (en) * | 2010-07-06 | 2012-01-12 | Medtronic Minimed, Inc. | Method and/or system for determining blood glucose reference sample times |
| US9821159B2 (en) | 2010-11-16 | 2017-11-21 | The Board Of Trustees Of The Leland Stanford Junior University | Stimulation devices and methods |
| AU2011328900B2 (en) | 2010-11-16 | 2015-03-19 | The Board Of Trustees Of The Leland Stanford Junior University | Systems and methods for treatment of dry eye |
| MX353647B (en) | 2011-02-28 | 2018-01-15 | Coopervision Int Holding Co Lp | Silicone hydrogel contact lenses. |
| JP2013078463A (en) * | 2011-10-04 | 2013-05-02 | Canon Inc | Acoustic wave acquiring apparatus |
| EP2967817B1 (en) | 2013-03-12 | 2021-03-10 | Oculeve, Inc. | Implant delivery devices and systems |
| CA2883874A1 (en) | 2013-04-19 | 2014-10-23 | Oculeve, Inc. | Nasal stimulation devices and methods |
| ES2812752T3 (en) | 2014-02-25 | 2021-03-18 | Oculeve Inc | Polymer formulations for nasolacrimal stimulation |
| EP3171928B1 (en) | 2014-07-25 | 2020-02-26 | Oculeve, Inc. | Stimulation patterns for treating dry eye |
| EP3209370A4 (en) | 2014-10-22 | 2018-05-30 | Oculeve, Inc. | Contact lens for increasing tear production |
| CN107106843A (en) | 2014-10-22 | 2017-08-29 | 奥库利维公司 | Stimulating apparatus and method for treating xerophthalmia |
| CN108473632B (en) * | 2015-11-26 | 2021-02-19 | 新加坡科技研究局 | Polymeric compositions |
| US10426958B2 (en) | 2015-12-04 | 2019-10-01 | Oculeve, Inc. | Intranasal stimulation for enhanced release of ocular mucins and other tear proteins |
| US10252048B2 (en) | 2016-02-19 | 2019-04-09 | Oculeve, Inc. | Nasal stimulation for rhinitis, nasal congestion, and ocular allergies |
| CA3022683A1 (en) | 2016-05-02 | 2017-11-09 | Oculeve, Inc. | Intranasal stimulation for treatment of meibomian gland disease and blepharitis |
| JP2020500609A (en) | 2016-12-02 | 2020-01-16 | オキュリーブ， インコーポレイテッド | Apparatus and method for dry eye prediction and treatment recommendations |
| CN109199400B (en) * | 2018-09-10 | 2021-08-31 | 中山大学 | Blood glucose electrochemical sensor based on microneedle array |
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| US7105352B2 (en) * | 1996-11-06 | 2006-09-12 | University Of Pittsburgh | Intelligent polymerized crystalline colloidal array carbohydrate sensors |
| US20040171980A1 (en) * | 1998-12-18 | 2004-09-02 | Sontra Medical, Inc. | Method and apparatus for enhancement of transdermal transport |
| US7181261B2 (en) * | 2000-05-15 | 2007-02-20 | Silver James H | Implantable, retrievable, thrombus minimizing sensors |
| US6875613B2 (en) * | 2001-06-12 | 2005-04-05 | Lifescan, Inc. | Biological fluid constituent sampling and measurement devices and methods |
| US6793632B2 (en) * | 2001-06-12 | 2004-09-21 | Lifescan, Inc. | Percutaneous biological fluid constituent sampling and measurement devices and methods |
| US7150975B2 (en) * | 2002-08-19 | 2006-12-19 | Animas Technologies, Llc | Hydrogel composition for measuring glucose flux |
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| CN101065060A (en) | 2007-10-31 |
| ZA200704127B (en) | 2008-08-27 |
| CN101087822A (en) | 2007-12-12 |
| CN100574700C (en) | 2009-12-30 |
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