CN1757662A - Interpenetrating network polymer type super porous aquogel, its prepn. method and application - Google Patents
Interpenetrating network polymer type super porous aquogel, its prepn. method and application Download PDFInfo
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- CN1757662A CN1757662A CN 200510027603 CN200510027603A CN1757662A CN 1757662 A CN1757662 A CN 1757662A CN 200510027603 CN200510027603 CN 200510027603 CN 200510027603 A CN200510027603 A CN 200510027603A CN 1757662 A CN1757662 A CN 1757662A
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Abstract
A super-porous aqueo-gel of an interpenetrating network polymer used for the orally applying system of protein polypeptide to suppress proteinase and break the close linking between epithelial cells contains two polymers: a cross-linked polymer and a cross-linked polyose polymer. Its preparing process includes such steps as mixing at least one unsaturated enylmonomer, at least one polyenyl cross-linking agent, a linear polyose polymer and a foaming agent to generate the super-porous aqueo-gel of semi-interpenetrating network polymer, and cross-linking with linear polyose.
Description
Technical field
The invention belongs to technical field of polymer materials, be specifically related to a kind of interpenetrating network polymer type super porous aquogel and preparation method thereof and the application in pharmaceutics.
Background technology
Hydrogel is the cross-linked hydrophilic high molecular polymer that contains network structure.It is insoluble in water, but can absorb a large amount of moisture.The research of hydrogel starts from nineteen sixties, because it has character such as biocompatibility and biodegradability, can be widely used in medical science, biology and pharmaceutical field, has up to the present invented multiple hydrogel.
Interpenetrating net polymer (Interpenetrating Polymer Networks, IPN), it is a class multi-phase multi-component macromolecular material, pass through the distinct polymer alloy that the permanent entanglement (or IPN) between the macromolecular chain forms by two or more polymer network that forms respectively, crosslinked between its polymer network, or not only polymerization but also crosslinked.Sequencing according to polymer network forms can be divided into IPN two classes: interpenetrating net polymer (SIN) and interpenetrating net polymer simultaneously step by step.Two kinds of polymer networks produce simultaneously and then are the while interpenetrating net polymer; And the polymerization in another kind of polymkeric substance of a kind of monomer, formed polymkeric substance then is the substep interpenetrating net polymer.IPN can be divided into two kinds of all-IP N and half IPN according to polymkeric substance whether crosslinked, polymkeric substance is crosslinked, is called all-IP N; A component is crosslinked in two kinds of polymkeric substance, and another component is linear, is called half IPN.The inierpeneirating network structure of polymkeric substance makes it have multiple special performance, and is higher and snappiness good as physical strength.
1998, Chen etc. synthesized Superporous hydrogels (Superporous Hydrogels, i.e. SPH) (Synthesis andcharacterization ofsuperporous hydrogel composites, J.Contr.Rel., 2002,65:73-82).It is a kind of novel hydrogel that contains a large amount of macropores.Compare with traditional hydrogel, it has quick swollen performance, but physical strength is relatively poor.Chen and Dorkoosh etc. have synthesized s-generation Superporous hydrogels-Superporous hydrogels mixture (SPHC) (Synthesis and characterization of superporous hydrogel composites, J.Contr.Rel., 2002,65:73-82; Preparation and NMR characterization of superporous hydrogels (SPH) and SPHcomposites, Polymer, 2000,41:8213-8220).Promptly in the original polyacrylic acid of SPH-acrylamide skeleton, add the hydrophilic polymer croscarmellose sodium.Make its character that had both had the rapid expansion of Superporous hydrogels, because of the adding of this material, physical strength increases simultaneously.SPH has the enzyme of pressing down with SPHC, urgees to ooze and with the effect that small intestinal mucosa closely contacts, can be used as the carrier of protein and peptide class drug oral administration.
Though the physical strength of s-generation Superporous hydrogels SPHC makes moderate progress, it is more crisp because of not having elasticity when complete swelling, and is under the effect of the various power in the external world, frangible.Yang etc. and Kim etc. have synthesized third generation Superporous hydrogels-Superporous hydrogels interpenetrating net polymer (IPN-SPH) (Semi-interpenetrating polymer networksuperporous hydrogels based on poly (3-sulfopropyl acrylate, potassium salt) and poly (vinylalcohol): Synthesis and characterization, J.Bioactive Compatible Polymers, 2004,19 (2): 81-100; Swelling and mechanical properties of superporous hydrogels ofpoly (acrylamide-co-acrylic acid)/polyethylenimine interpenetrating polymer networks, Polylmer, 2004,45:189-196).Be about to the water-soluble polymers swelling and join in the original polyacrylic acid of SPH-acrylamide skeleton, make its form interpenetration combination with network.This polymkeric substance has elasticity, can stand to stretch, pushes, the effect of various power such as distortion.The water-soluble polymers that uses in the above-mentioned polymkeric substance is polyvinyl alcohol and polyethyene diamine, because of the character and the toxic restriction of polyvinyl alcohol and polyethyene diamine itself, makes that they should not be as the carrier of protein and peptide class drug oral administration.
Summary of the invention
The object of the present invention is to provide interpenetrating network polymer type super porous aquogel of a kind of physical strength height, good springiness, nontoxicity restriction and preparation method thereof, and the application of this interpenetrating network polymer type super porous aquogel is provided, to overcome the deficiencies in the prior art and defective.
Design of the present invention and principle are as follows:
Chitosan (chitosan) is by a kind of natural polymer glycosaminoglycan that obtains behind the chitin deacetylation.Its water absorption and swelling can be used as disintegrating agent.Chitosan and derivative thereof can attach to mucous membrane, thereby the residence time of prolong drug in digestive tube delays the release of medicine, the raising bioavailability of medicament.As absorption enhancer, N, N, N-trimethyl chitin hydrochloride, N-cm-chitosan etc. can significantly improve digestive tube mucous membrane permeability under neutrality and slight alkalinity condition, this is because chitosan and derivative molecular thereof are positively charged, can be connected with cytolemma, make the iuntercellular proteic structure of combining closely change, thereby open intercellular tight connection, and this effect is reversible, can not cause damage the imporosity of mucosal epithelium.In addition, cofactor and the Zn that the carboxyl on the N-cm-chitosan can chelatase
2+, protected protein matter polypeptide drug avoids the destruction of plurality of enzymes in the digestive tube.
Sodium alginate (sodium alginate) belongs to the linear polyelectrolyte of polyose, is by mannuronic acid (M) and guluronic acid (G) 1,4 banded segmented copolymer, comprises the homopolymer of G and each self-forming of M and the alternating polymer that GM forms.Sodium alginate has solvability and biological degradability preferably under normal physiological condition.Glycosyl has the effect that strengthens protein stability on its molecule, helps the administration of protein and peptide class medicine.
The present invention adds inierpeneirating network structure in Superporous hydrogels; form a kind of novel interpenetrating network polymer type super porous aquogel; make it both have the quick swollen character of Superporous hydrogels; has inierpeneirating network structure because of polymkeric substance simultaneously; physical strength increases; and have open that iuntercellular closely connects, the effect of arrestin enzyme and protected protein matter peptide material, thereby make this interpenetrating net polymer hydrogel help the oral administration of protein and peptide class medicine.
Technical scheme of the present invention is as follows:
Interpenetrating network polymer type super porous aquogel provided by the invention, contain two kinds of polymkeric substance, a kind of is the cross-linked polymer that is formed by at least a ethylenic unsaturation monomer and polyene cross-linking agent polymerization, another kind is the cross-linked polysaccharides base polymer that linear polysaccharide base polymer and linking agent polymerization form, and has inierpeneirating network structure and super vesicular structure.Wherein the part by weight of linear polysaccharide base polymer and cross-linked polymer is in 0.05: 100 to 40: 100 scope.The monomeric part by weight of polyene cross-linking agent and ethylenic unsaturation is in 0.01: 100 to 10: 100 scope.The part by weight that is used for linear polysaccharide base polymer polymeric linking agent and linear polysaccharide base polymer is in 1: 100 to 100: 100 scope.
Said ethylenic unsaturation monomer is a vinylformic acid, methacrylic acid, the vinylformic acid salt, the methacrylic acid salt, esters of acrylic acid, methyl acrylic ester, the salt of acrylate or acids, the salt of methacrylic ester or acids, acrylic acid amides, the amides of methacrylic acid, acrylic acid N-alkylamide, the N-alkylamide of methacrylic acid, the salt of acrylic acid N-alkylamide and acids, the salt and the acids of the N-alkylamide of methacrylic acid, the N-vinyl pyrrolidone, acrylamide, acrylamide derivative, Methacrylamide, in the methacrylamide derivatives one or more.
Usually used ethylenic unsaturation monomer is one or more in acrylamide, N-N-isopropylacrylamide, 2-hydroxyethyl meth acrylate, 2-hydroxypropylmethyl acrylate, N-vinyl pyrrolidone, vinylformic acid, 2-acrylamide-2-methyl isophthalic acid-propanesulfonic acid, the 3-sulfopropyl-vinylformic acid sylvite.
Said polyene cross-linking agent is N, N-methylene radical-bisacrylamide (Bis), two (methyl) vinylformic acid glycol ester, piperazine diacrylamine, glutaraldehyde, Epicholorohydrin, the linking agent that contains 1,2 diol structure, the linking agent that contains functional peptides and proteinaceous linking agent.
Said linear polysaccharide base polymer is sodium alginate, chitosan, chitosan hydrochloride, cm-chitosan, N, N, a kind of in N-trimethyl chitin and the cross-linking products thereof.
The linking agent of said crosslinked linear polysaccharide base polymer is a kind of in formaldehyde, acetaldehyde, glutaraldehyde, genipin and the calcium chloride.The ratio of preferred genipin or glutaraldehyde and chitosan and derivative thereof was at 1: 10.The ratio of preferred calcium chloride and sodium alginate was at 1: 5.
Interpenetrating network polymer type super porous aquogel of the present invention, its mean pore size are 50 μ m to 4000 μ m.Preferred mean pore size is 100 μ m to 800 μ m.Because the existence of a large amount of holes and they are interconnected with one another, so the time that this swelling behavior is very fast and it reaches swelling equilibrium is also very short.The swelling ratio of interpenetrating network polymer type super porous aquogel of the present invention is 5 to 1000, and the time that reaches swelling equilibrium is 1 second to 2 hours.
Interpenetrating network polymer type super porous aquogel of the present invention, its preparation method is as follows:
(1) at least a ethylenic unsaturation monomer, a kind of polyene cross-linking agent, a kind of linear polysaccharide base polymer and a kind of pore forming material are mixed, form the semi-interpenetrating network polymer Superporous hydrogels under the room temperature;
(2) above-mentioned semi-interpenetrating network polymer Superporous hydrogels is placed cross-linking agent solution, placed 0.5～8 hour, form full interpenetrating network polymer type super porous aquogel.
Wherein the ratio of linear polysaccharide base polymer and cross-linked polymer (being formed by at least a ethylenic unsaturation monomer and polyene cross-linking agent polymerization) is in 0.05: 100 to 40: 100 scope.The consumption of linear polysaccharide base polymer is too big, it all can not be covered in the polymkeric substance in polymerization process, has the partial linear polysaccharide polymer that gelling does not take place.Said ethylenic unsaturation monomer is a vinylformic acid, methacrylic acid, the vinylformic acid salt, the methacrylic acid salt, esters of acrylic acid, methyl acrylic ester, the salt of acrylate or acids, the salt of methacrylic ester or acids, acrylic acid amides, the amides of methacrylic acid, acrylic acid N-alkylamide, the N-alkylamide of methacrylic acid, the salt of acrylic acid N-alkylamide and acids, the salt and the acids of the N-alkylamide of methacrylic acid, the N-vinyl pyrrolidone, acrylamide, acrylamide derivative, Methacrylamide, in the methacrylamide derivatives one or more.
Usually used ethylenic unsaturation monomer is one or more in acrylamide, N-N-isopropylacrylamide, 2-hydroxyethyl meth acrylate, 2-hydroxypropylmethyl acrylate, N-vinyl pyrrolidone, vinylformic acid, 2-acrylamide-2-methyl isophthalic acid-propanesulfonic acid, the 3-sulfopropyl-vinylformic acid sylvite.
Said linking agent is N, N-methylene radical-bisacrylamide, two (methyl) vinylformic acid glycol ester, piperazine diacrylamine, glutaraldehyde, Epicholorohydrin, the linking agent that contains 1,2 diol structure, the linking agent that contains functional peptides and proteinaceous linking agent.Its consumption is that linking agent and monomeric ratio are in 0.01: 100 to 10: 100 scope.Preferred cross-linking agents and monomeric ratio were at 1: 100.Crosslinker concentration is too high, causes that the swollen interpenetrating network polymer type super porous aquogel becomes frangible, causes the reduction of swelling ratio.Otherwise the concentration of linking agent is too low, causes interpenetrating network polymer type super porous aquogel to become more soft frangible.
Said polysaccharide polymer is sodium alginate, chitosan, chitosan hydrochloride, cm-chitosan, N, N, a kind of in N-trimethyl chitin and the cross-linking products thereof.
The linking agent of said linear polysaccharide base polymer is a kind of in formaldehyde, acetaldehyde, glutaraldehyde, genipin and the calcium chloride.Wherein formaldehyde, acetaldehyde, glutaraldehyde and genipin are used for chitosan and derivative thereof, and calcium chloride is used for sodium alginate.The ratio of genipin or glutaraldehyde and chitosan and derivative thereof is in 1: 100 to 50: 100 scope.The ratio of preferred genipin or glutaraldehyde and chitosan and derivative thereof was at 1: 10.Genipin or glutaraldehyde concentration are too high, cause that the swollen interpenetrating net polymer becomes more crisp and frangible, cause swelling ratio to reduce, and physical strength reduces.Otherwise the concentration of genipin or glutaraldehyde is too low, and it is more soft frangible that interpenetrating network polymer type super porous aquogel becomes.The ratio of calcium chloride and sodium alginate is in 1: 100 to 100: 100 scope.The ratio of preferred calcium chloride and sodium alginate was at 1: 5.Calcium chloride concentration is too high, causes that the swollen interpenetrating net polymer becomes frangible, and swelling ratio reduces, and physical strength reduces.Otherwise the concentration of calcium chloride is too low, and it is more soft frangible that interpenetrating network polymer type super porous aquogel becomes.
Said pore forming material be supercarbonate, carbonate one or more or from outer importing bubble.One or more of wherein commonly used is sodium bicarbonate, yellow soda ash and lime carbonate.Sodium bicarbonate preferably.
In the aforesaid method, can add entry or suds-stabilizing agent in polymerization with before bubbling.
In the aforesaid method, can add initiator and catalyzer earlier in polymerization with before bubbling.
Two necessary conditions that form Superporous hydrogels are polymerization and foaming.In order to prepare the homogeneous phase interpenetrating network polymer type super porous aquogel, polymerization and foaming should take place simultaneously.Because bubbling process is short and very difficult stabilise bubbles is longer than several minutes, for catching the bubble in the polymer network, when bubble stabilizes gelling must take place.
Blistered method is varied, the chemistry or the mechanical means such as expansion of gas dissolved when comprising volatilization, chemical reaction, the release of pressure of thermolysis, mechanical shaking, the low-boiling point liquid of chemical reagent.The size in the consumption decision bubble aperture of pore forming material and the porosity of interpenetrating network polymer type super porous aquogel.After bubble produces, stable in gelatinization process for making it, need to use suds-stabilizing agent, it comes stable foam by reducing film-aerosphere surface tension and increasing film viscosity.The ideal suds-stabilizing agent should be the beginning of foam stabilization to gelatinization process.Poloxamer (Pluronic F127) is a kind of suds-stabilizing agent preferably, and the time of its stable foam is longer.But its consumption has certain requirement, and foam stabilization effect preferably can not be provided very little, and surpasses a certain amount of effect that does not reach stable foam equally.In general, its consumption is 0.1～1.2% (W/W) of monomer weight.Preferred consumption is 0.5% (W/W) of monomer weight.
Among the present invention, when having acid to exist, select for use sodium bicarbonate to prepare interpenetrating network polymer type super porous aquogel, because sodium bicarbonate-acid system has the advantage that other gas injection technology does not have as pore forming material.Its safe, cheap, easy use, and allow the artificial amount of controlling the gas that forms the foamy time and in polymerization process, import.
Can reach fast gelation by control monomer (kind and concentration), initiator (kind and concentration), temperature and solvent.Common water miscible acrylate, methacrylate and acrylamide gelling are very fast, and therefore, preferred above-mentioned monomer prepares interpenetrating network polymer type super porous aquogel.
The preferred ammonium persulphate that uses is as initiator, and N,N,N (TMEDA) is as catalyzer, but initiator and catalyst consumption remarkably influenced polymeric speed.Usually, the concentration of the concentration of ammonium persulphate and N,N,N is respectively 0.1～5% (W/W) of monomer weight.The concentration of preferred ammonium persulphate and the concentration of N,N,N are respectively 2% (W/W) of monomer weight.
The swelling ratio of interpenetrating network polymer type super porous aquogel of the present invention and the measuring method of density are as follows:
The mensuration of swelling ratio: swelling ratio is defined as Q=(Ws-Wd)/Wd, and wherein Ws is the weight of the interpenetrating network polymer type super porous aquogel after the swelling, and Wd is the weight of the interpenetrating network polymer type super porous aquogel done.The dried interpenetrating network polymer type super porous aquogel of at first weighing obtains Wd, and sample is placed excessive distilled water, regularly takes out with the container of band screen cloth, removes remainder water in the screen cloth, weighs then, obtains Ws, can try to achieve swelling ratio Q.
The mensuration of density: density is d=Wd/Vd, and wherein Wd is the weight of dried interpenetrating network polymer type super porous aquogel, and Vd is the volume of interpenetrating network polymer type super porous aquogel.Wherein Vd utilizes the solvent replacing method to record, and soon interpenetrating network polymer type super porous aquogel places and records diameter and cylindrical test tube height, that normal hexane is housed, learns Vd by the variation of height, thus the density of trying to achieve.
Externally press down enzyme test: make 1.2mgml respectively
-1Trypsin solution and 1.6mgml
-1Chymetin PBS solution.In the Erlenmeyer flask that is added with 10ml PBS, add 100 μ l trypsin solutions or 100 μ l Chymetin solution respectively, the IPN-SPH that adds 200mg chitosan-containing and derivative thereof or sodium alginate then, make it abundant swelling and absorb protein enzyme solution, in above-mentioned solution, add 10ml 100 μ gml behind the 30min
-1Insulin solutions, make sample solution.Adding proteolytic ferment but not adding IPN-SPH is the insulin solutions positive control, does not add the negative contrast of insulin solutions of proteolytic ferment and IPN-SPH.37 ℃, 150rpm vibrate above-mentioned sample solution and reference substance solution, the 100 μ l that take a sample during 60min add 150 μ l trifluoroacetic acid solution (pH1.8) enzymolysis reaction in the sample.Through 12, the centrifugal 10min of 000rpm gets supernatant liquor and injects liquid chromatograph, measures insulin content.
The density of table 1 IPN-SPH, swelling ratio, swelling time (n=3)
| Embodiment | Density (g/cm 3) | Swelling ratio | The swelling equilibrium time (min) |
| 1 | 0.65±0.04 | 127±7 | 15 |
| 2 | 0.64±.0.05 | 126±6 | 15 |
| 3 | 0.72±0.03 | 104±6 | 10 |
| 4 | 0.71±0.05 | 95±4 | 10 |
| 5 | 0.76±0.01 | 140±8 | 15 |
| 6 | 0.69±0.02 | 113±5 | 15 |
| 7 | 0.65±0.05 | 135±9 | 20 |
| 8 | 0.76±0.08 | 89±6 | 45 |
| 9 | 0.78±0.05 | 80±5 | 60 |
| 10 | 0.82±0.06 | 105±6 | 15 |
| 11 | 0.86±0.04 | 100±8 | 20 |
| 12 | 0.84±0.03 | 106±4 | 20 |
| 13 | 0.72±0.05 | 93±4 | 30 |
| 14 | 0.76±0.03 | 120±7 | 20 |
| 15 | 0.82±0.06 | 128±7 | 20 |
| 16 | 0.80±0.04 | 83±4 | 30 |
| 17 | 0.68±0.05 | 79±5 | 20 |
The enzyme effect that presses down of table 2 IPN-SPH
| Embodiment | Regular Insulin residual quantity (%) |
| 1 | 85 |
| 2 | 87 |
| 3 | 84 |
| 4 | 88 |
| 5 | 86 |
| 6 | 90 |
| 7 | 84 |
| 8 | 86 |
| 9 | 86 |
| Positive control | 25 |
| Negative control | 97 |
The invention has the advantages that:
(1) chitosan that is added and derivative thereof have quick swollen characteristics, and the interpenetrating net polymer that itself and Superporous hydrogels form still has quick swollen characteristic;
(2) introducing of chitosan and derivative thereof and sodium alginate interpenetrating(polymer)networks makes the physical strength of this interpenetrating net polymer improve, and helps the raising of drug loading;
(3) introducing of chitosan and derivative thereof and sodium alginate interpenetrating(polymer)networks makes the physical strength of this interpenetrating net polymer improve, and helps improving medicine-feeding part drug concentrations gradient, increases the diffusing capacity of medicine;
(4) adding of chitosan and derivative thereof and sodium alginate makes this interpenetrating network polymer type super porous aquogel have tight ligation of the epithelial cell of opening and proteolytic enzyme restraining effect, helps the oral administration of protein and peptide medicine.
Description of drawings
Accompanying drawing 1 rat is oral to be loaded with blood sugar decreasing effect figure behind the IPN-SPH enteric coated capsule of Regular Insulin
Embodiment
Poly-(acrylic acid-acrylamide) IPN-SPH of embodiment 1 chitosan-containing
(add following ingredients: the AM of 300 μ l 50% (acrylamide) successively among the 40mm * 25mm) at tall regular weighing bottle; The AA of 200 μ l 50% (vinylformic acid); The BIS of 100 μ l 2.5% (N, N '-methylene radical-bisacrylamide); 300 μ l DDW (distilled water); The Pluronic of 30 μ l 10%
F127 (PF127, poloxamer); The APS of 25 μ l 20% (ammonium persulphate); The TEMED of 25 μ l 20% (N,N,N); The chitosan of 300 μ l 4% (with the dissolving of 2% acetate).After adding every kind of composition, the concussion mixing solutions.Gelling adding in preceding 2 minutes 120mg sodium bicarbonate, vortex vibration are taking place.With the Superporous hydrogels polymkeric substance of above-mentioned chitosan-containing contain the HCl/ dehydrated alcohol of 1% glutaraldehyde (3: 7, place 2h in v/v), can obtain poly-(acrylic acid-acrylamide) IPN-SPH of chitosan-containing.
Poly-(acrylic acid-acrylamide) IPN-SPH of embodiment 2 chitosan-containing hydrochlorides
(add following ingredients: the AM of 300 μ l 50% (acrylamide) successively among the 40mm * 25mm) at tall regular weighing bottle; The AA of 200 μ l 50% (vinylformic acid); The BIS of 100 μ l 2.5% (N, N '-methylene radical-bisacrylamide); 300 μ l DDW (distilled water); The Pluronic of 30 μ l 10%
F127 (PF127, poloxamer); The APS of 25 μ l 20% (ammonium persulphate); The TEMED of 25 μ l 20% (N,N,N); The chitosan hydrochloride of 300 μ l 4%.After adding every kind of composition, vortex mixed solution.Gelling adding in preceding 2 minutes 120mg sodium bicarbonate, vortex vibration are taking place.With the Superporous hydrogels polymkeric substance of above-mentioned chitosan-containing hydrochloride contain the HCl/ dehydrated alcohol of 1% glutaraldehyde (3: 7, place 2h in v/v), can obtain poly-(acrylic acid-acrylamide) IPN-SPH of chitosan-containing hydrochloride.
Poly-(acrylic acid-acrylamide) IPN-SPH of embodiment 3 chitosan-containing trimethyl quaternary ammonium salts (TMC)
(add following ingredients: the AM of 300 μ l 50% (acrylamide) successively among the 40mm * 25mm) at tall regular weighing bottle; The AA of 200 μ l 50% (vinylformic acid); The BIS of 100 μ l 2.5% (N, N '-methylene radical-bisacrylamide); 300 μ l DDW (distilled water); The Pluronic of 30 μ l 10%
F127 (PF127, poloxamer); The APS of 25 μ l 20% (ammonium persulphate); The TEMED of 25 μ l 20% (N,N,N); The TMC of 300 μ l 8%.After adding every kind of composition, vortex mixed solution.Gelling adding in preceding 2 minutes 120mg sodium bicarbonate, vortex vibration are taking place.With the Superporous hydrogels polymkeric substance of the above-mentioned TMC of containing contain the HCl/ dehydrated alcohol of 1% glutaraldehyde (3: 7, place 4h in v/v), can obtain poly-(acrylic acid-acrylamide) IPN-SPH of chitosan-containing trimethyl quaternary ammonium salt (TMC).
Poly-(acrylic acid-acrylamide) IPN-SPH of embodiment 4 chitosan-containing trimethyl quaternary ammonium salts (TMC)
(add following ingredients: the AM of 300 μ l 50% (acrylamide) successively among the 40mm * 25mm) at tall regular weighing bottle; The AA of 200 μ l 50% (vinylformic acid); The BIS of 100 μ l 2.5% (N, N '-methylene radical-bisacrylamide); 300 μ l DDW (distilled water); The Pluronic of 30 μ l 10%
F127 (PF127, poloxamer); The APS of 25 μ l 20% (ammonium persulphate); The TEMED of 25 μ l 20% (N,N,N); The TMC of 300 μ l 16%.After adding every kind of composition, vortex mixed solution.Gelling adding in preceding 2 minutes 120mg sodium bicarbonate, vortex vibration are taking place.With the Superporous hydrogels polymkeric substance of the above-mentioned TMC of containing contain the HCl/ dehydrated alcohol of 1% glutaraldehyde (3: 7, place 8h in v/v), can obtain poly-(acrylic acid-acrylamide) IPN-SPH of chitosan-containing trimethyl quaternary ammonium salt (TMC).
Embodiment 5 contains poly-(acrylic acid-acrylamide) IPN-SPH of cm-chitosan (CMC)
(add following ingredients: the AM of 300 μ l 50% (acrylamide) successively among the 40mm * 25mm) at tall regular weighing bottle; The AA of 200 μ l 50% (vinylformic acid); The BIS of 100 μ l 2.5% (N, N '-methylene radical-bisacrylamide); 300 μ l DDW (distilled water); The Pluronic of 30 μ l 10%
F127 (PF127, poloxamer); The APS of 25 μ l 20% (ammonium persulphate); The TEMED of 25 μ l 20% (N,N,N); The CMC of 600 μ l 4%.After adding every kind of composition, vortex mixed solution.Gelling adding in preceding 2 minutes 120mg sodium bicarbonate, vortex vibration are taking place.With the Superporous hydrogels polymkeric substance of the above-mentioned CMC of containing contain the HCl/ dehydrated alcohol of 1% glutaraldehyde (3: 7, place 2h in v/v), can obtain containing poly-(acrylic acid-acrylamide) IPN-SPH of cm-chitosan (CMC).
Embodiment 6 contains poly-(acrylic acid-acrylamide) IPN-SPH of cm-chitosan (CMC)
(add following ingredients: the AM of 300 μ l 50% (acrylamide) successively among the 40mm * 25mm) at tall regular weighing bottle; The AA of 200 μ l 50% (vinylformic acid); The BIS of 100 μ l 2.5% (N, N '-methylene radical-bisacrylamide); 300 μ l DDW (distilled water); The Pluronic of 30 μ l 10%
F127 (PF127, poloxamer); The APS of 25 μ l 20% (ammonium persulphate); The TEMED of 25 μ l 20% (N,N,N); The CMC of 600 μ l 8%.After adding every kind of composition, vortex mixed solution.Gelling adding in preceding 2 minutes 120mg sodium bicarbonate, vortex vibration are taking place.With the Superporous hydrogels polymkeric substance of the above-mentioned CMC of containing contain the HCl/ dehydrated alcohol of 1% glutaraldehyde (3: 7, place 4h in v/v), can obtain containing poly-(acrylic acid-acrylamide) IPN-SPH of cm-chitosan (CMC).
Embodiment 7 contains poly-(acrylic acid-acrylamide) IPN-SPH of sodium alginate (SA)
(add following ingredients: the AM of 300 μ l 50% (acrylamide) successively among the 40mm * 25mm) at tall regular weighing bottle; The AA of 200 μ l 50% (vinylformic acid); The BIS of 100 μ l 2.5% (N, N '-methylene radical-bisacrylamide); 300 μ l DDW (distilled water); The Pluronic of 30 μ l 10%
F127 (PF127, poloxamer); The APS of 25 μ l 20% (ammonium persulphate); The TEMED of 25 μ l 20% (N,N,N); The SA of 300 μ l 4%.After adding every kind of composition, vortex mixed solution.Gelling adding in preceding 2 minutes 120mg sodium bicarbonate, vortex vibration are taking place.The Superporous hydrogels polymkeric substance of the above-mentioned SA of containing is being contained 1%CaCl
2The HCl/ dehydrated alcohol (3: 7, place 0.5h in v/v), can obtain containing poly-(acrylic acid-acrylamide) IPN-SPH of sodium alginate (SA).
Embodiment 8 contains poly-(acrylic acid-acrylamide) IPN-SPH of sodium alginate (SA)
(add following ingredients: the AM of 300 μ l 50% (acrylamide) successively among the 40mm * 25mm) at tall regular weighing bottle; The AA of 200 μ l 50% (vinylformic acid); The BIS of 100 μ l 2.5% (N, N '-methylene radical-bisacrylamide); 300 μ l DDW (distilled water); The Pluronic of 30 μ l 10%
F127 (PF127, poloxamer); The APS of 25 μ l 20% (ammonium persulphate); The TEMED of 25 μ l 20% (N,N,N); The SA of 300 μ l 8%.After adding every kind of composition, vortex mixed solution.Gelling adding in preceding 2 minutes 120mg sodium bicarbonate, vortex vibration are taking place.The Superporous hydrogels polymkeric substance of the above-mentioned SA of containing is being contained 1%CaCl
2The HCl/ dehydrated alcohol (3: 7, place 2h in v/v), can obtain containing poly-(acrylic acid-acrylamide) IPN-SPH of sodium alginate (SA).
Embodiment 9 contains poly-(acrylic acid-acrylamide) IPN-SPH of sodium alginate (SA)
(add following ingredients: the AM of 300 μ l 50% (acrylamide) successively among the 40mm * 25mm) at tall regular weighing bottle; The AA of 200 μ l 50% (vinylformic acid); The BIS of 100 μ l 2.5% (N, N '-methylene radical-bisacrylamide); 300 μ l DDW (distilled water); The Pluronic of 30 μ l 10%
F127 (PF127, poloxamer); The APS of 25 μ l 20% (ammonium persulphate); The TEMED of 25 μ l 20% (N,N,N); The SA of 450 μ l 8%.After adding every kind of composition, vortex mixed solution.Gelling adding in preceding 2 minutes 120mg sodium bicarbonate, vortex vibration are taking place.The Superporous hydrogels polymkeric substance of the above-mentioned SA of containing is being contained 1%CaCl
2The HCl/ dehydrated alcohol (3: 7, place 4h in v/v), can obtain containing poly-(acrylic acid-acrylamide) IPN-SPH of sodium alginate (SA).
Embodiment 10 contains poly-(acrylamide-acrylicacid 3-sulphur propyl ester sylvite) IPN-SPH of sodium alginate (SA)
(add following ingredients: the AM of 300 μ l 50% (acrylamide) successively among the 40mm * 25mm) at tall regular weighing bottle; The SPAK of 200 μ l 50% (vinylformic acid 3-sulphur propyl ester sylvite); The BIS of 100 μ l 2.5% (N, N '-methylene radical-bisacrylamide); The Pluronic of 30 μ l 10%
F127 (PF127, poloxamer); The APS of 25 μ l 20% (ammonium persulphate); The TEMED of 25 μ l 20% (N,N,N); The SA of 450 μ l 8%.After adding every kind of composition, vortex mixed solution.Gelling adding in preceding 2 minutes 120mg sodium bicarbonate, vortex vibration are taking place.The Superporous hydrogels polymkeric substance of the above-mentioned SA of containing is being contained 1%CaCl
2The HCl/ dehydrated alcohol (3: 7, place 4h in v/v), can obtain containing poly-(acrylamide-acrylicacid 3-sulphur propyl ester sylvite) IPN-SPH of sodium alginate (SA).
Embodiment 11 contains poly-(acrylamide-acrylicacid 3-sulphur propyl ester sylvite) IPN-SPH of cm-chitosan (CMC)
(add following ingredients: the AM of 300 μ l 50% (acrylamide) successively among the 40mm * 25mm) at tall regular weighing bottle; The SPAK of 200 μ l 50% (vinylformic acid 3-sulphur propyl ester sylvite); The BIS of 100 μ l 2.5% (N, N '-methylene radical-bisacrylamide); The Pluronic of 30 μ l 10%
F127 (PF127, poloxamer); The APS of 25 μ l 20% (ammonium persulphate); The TEMED of 25 μ l 20% (N,N,N); The CMC of 600 μ l 8%.After adding every kind of composition, vortex mixed solution.Gelling adding in preceding 2 minutes 120mg sodium bicarbonate, vortex vibration are taking place.With the Superporous hydrogels polymkeric substance of the above-mentioned CMC of containing contain the HCl/ dehydrated alcohol of 1% glutaraldehyde (3: 7, place 4h in v/v), can obtain containing poly-(acrylamide-acrylicacid 3-sulphur propyl ester sylvite) IPN-SPH of cm-chitosan (CMC).
(acrylamide-acrylicacid 3-sulphur propyl ester sylvite) IPN-SPH of embodiment 12 chitosan-containing trimethyl quaternary ammonium salts (TMC)
(add following ingredients: the AM of 300 μ l 50% (acrylamide) successively among the 40mm * 25mm) at tall regular weighing bottle; The AA of 200 μ l 50% (vinylformic acid); The BIS of 100 μ l 2.5% (N, N '-methylene radical-bisacrylamide); 300 μ l DDW (distilled water); The Pluronic of 30 μ l 10%
F127 (PF127, poloxamer); The APS of 25 μ l 20% (ammonium persulphate); The TEMED of 25 μ l 20% (N,N,N); The TMC of 300 μ l 16%.After adding every kind of composition, vortex mixed solution.Gelling adding in preceding 2 minutes 120mg sodium bicarbonate, vortex vibration are taking place.With the Superporous hydrogels polymkeric substance of the above-mentioned TMC of containing contain the HCl/ dehydrated alcohol of 1% glutaraldehyde (3: 7, place 8h in v/v), can obtain (acrylamide-acrylicacid 3-sulphur propyl ester sylvite) IPN-SPH of chitosan-containing trimethyl quaternary ammonium salt (TMC).
Embodiment 13 contains poly-(N-N-isopropylacrylamide-methacrylic acid) IPN-SPH of sodium alginate (SA)
(add following ingredients: the NIPAM of 300 μ l 50% (N-isopropylacrylamide) successively among the 40mm * 25mm) at tall regular weighing bottle; The MAA of 200 μ l 50% (methacrylic acid); The BIS of 100 μ l 2.5% (N, N '-methylene radical-bisacrylamide); The Pluronic of 30 μ l 10%
F127 (PF127, poloxamer); The APS of 25 μ l 20% (ammonium persulphate); The TEMED of 25 μ l20% (N,N,N); The SA of 450 μ l 8%.After adding every kind of composition, vortex mixed solution.Gelling adding in preceding 2 minutes 120mg sodium bicarbonate, vortex vibration are taking place.The Superporous hydrogels polymkeric substance of the above-mentioned SA of containing is being contained 1%CaCl
2The HCl/ dehydrated alcohol (3: 7, place 4h in v/v), can obtain containing poly-(N-N-isopropylacrylamide-methacrylic acid) IPN-SPH of sodium alginate (SA).
Poly-(N-N-isopropylacrylamide-methacrylic acid) IPN-SPH of embodiment 14 chitosan-containing trimethyl quaternary ammonium salts (TMC)
(add following ingredients: the NIPAM of 300 μ l 50% (N-isopropylacrylamide) successively among the 40mm * 25mm) at tall regular weighing bottle; The MAA of 200 μ l 50% (methacrylic acid); The BIS of 100 μ l 2.5% (N, N '-methylene radical-bisacrylamide); 300 μ l DDW (distilled water); The Pluronic of 30 μ l 10%
F127 (PF127, poloxamer); The APS of 25 μ l 20% (ammonium persulphate); The TEMED of 25 μ l 20% (N,N,N); The TMC of 300 μ l 16%.After adding every kind of composition, vortex mixed solution.Gelling adding in preceding 2 minutes 120mg sodium bicarbonate, vortex vibration are taking place.With the Superporous hydrogels polymkeric substance of the above-mentioned TMC of containing contain the HCl/ dehydrated alcohol of 1% glutaraldehyde (3: 7, place 8h in v/v), can obtain poly-(N-N-isopropylacrylamide-methacrylic acid) IPN-SPH of chitosan-containing trimethyl quaternary ammonium salt (TMC).
Embodiment 15 contains poly-(N-N-isopropylacrylamide-methacrylic acid) IPN-SPH of cm-chitosan (CMC)
(add following ingredients: the NIPAM of 300 μ l 50% (N-isopropylacrylamide) successively among the 40mm * 25mm) at tall regular weighing bottle; The MAA of 200 μ l 50% (methacrylic acid); The BIS of 100 μ l 2.5% (N, N '-methylene radical-bisacrylamide); 300 μ l DDW (distilled water); The Pluronic of 30 μ l 10%
F127 (PF127, poloxamer); The APS of 25 μ l 20% (ammonium persulphate); The TEMED of 25 μ l 20% (N,N,N); The CMC of 600 μ l 8%.After adding every kind of composition, vortex mixed solution.Gelling adding in preceding 2 minutes 120mg sodium bicarbonate, vortex vibration are taking place.With the Superporous hydrogels polymkeric substance of the above-mentioned CMC of containing contain the HCl/ dehydrated alcohol of 1% glutaraldehyde (3: 7, place 4h in v/v), can obtain containing poly-(N-N-isopropylacrylamide-methacrylic acid) IPN-SPH of cm-chitosan (CMC).
Embodiment 16 contains the 2-hydroxyethyl meth acrylate IPN-SPH of sodium alginate (SA)
(add following ingredients among the 40mm * 25mm) successively: 300 μ l 2-hydroxyethyl meth acrylates at tall regular weighing bottle; 60 μ l 2.5%Bis; 60 μ l 10%Pluronic F127; Vortex mixed; 60 ℃ of insulations add the ammonium persulphate of 20 μ l 20%; The SA of 450 μ l 8%; 20 μ l 15%TEMED.After adding every kind of composition, gelling adding in preceding 2 minutes 50mg sodium bicarbonate, vortex vibration are taking place in vortex mixed solution.The Superporous hydrogels polymkeric substance of the above-mentioned SA of containing is being contained 1%CaCl
2The HCl/ dehydrated alcohol (3: 7, place 4h in v/v), can obtain containing the 2-hydroxyethyl meth acrylate IPN-SPH of sodium alginate (SA).
Embodiment 17 contains the poly N-vinyl pyrrolidone IPN-SPH of sodium alginate (SA)
(add following ingredients among the 40mm * 25mm) successively: 500 μ l N-vinyl pyrrolidones at tall regular weighing bottle; 200 μ l 2.5%Bis; 100 μ l DDW (distilled water); 50 μ l 10%Pluronic F127; 20 μ lAA; The APS of 20 μ l 20%; The SA of 450 μ l 8%; 20 μ l 15%TEMED.After adding every kind of composition, vortex mixed solution.85 ℃ of water-baths add 50 μ l 10%V545 after 2 minutes.Gelling adding in preceding 2 minutes 50mg sodium bicarbonate, vortex vibration are taking place.85 ℃ were reacted 5 minutes.The Superporous hydrogels polymkeric substance of the above-mentioned SA of containing is being contained 1%CaCl
2The HCl/ dehydrated alcohol (3: 7, place 4h in v/v), can obtain containing the poly N-vinyl pyrrolidone IPN-SPH of sodium alginate (SA).
Embodiment 18 oral insulin drug delivery systems
Regular Insulin at first with the HCl dissolving of 0.1N, adds the solution that water makes 2mg/ml; Take out 15ml, embodiment 4 gained samples are added wherein; After treating that it absorbs insulin solutions fully, under the room temperature dry 2 days, pack into promptly for the rat enteric coated capsule.
Normal SD rat oral gavage gives insulin solutions and is loaded with IPN-SPH (embodiment 4) enteric coated capsule of Regular Insulin, dosage is 100U/kg, get blood 0.2ml respectively at 0.5,1,1.5,2,3,4,5,6,8 hour tail vein, after treating blood coagulation, 12, centrifugal 4 minutes of 000rpm gets serum 20ul, the determination of glucose oxidase blood glucose value.The results are shown in accompanying drawing 1.After rat oral gavage is loaded with the IPN-SPH enteric coated capsule of Regular Insulin as seen from the figure, produce hypoglycemic activity.
Claims (21)
1, a kind of interpenetrating network polymer type super porous aquogel, it is characterized in that containing two kinds of polymkeric substance, a kind of is to form cross-linked polymer by at least a ethylenic unsaturation monomer and polyene cross-linking agent polymerization, another kind is the cross-linked polysaccharides base polymer that linear polysaccharide base polymer and linking agent polymerization form, and has inierpeneirating network structure and super vesicular structure; Wherein, the ratio of linear polysaccharide base polymer and cross-linked polymer was at 0.05: 100 to 40: 100, the monomeric ratio of polyene cross-linking agent and ethylenic unsaturation was at 0.01: 100 to 10: 100, and the part by weight that is used for linear polysaccharide base polymer polymeric linking agent and linear polysaccharide base polymer is in 1: 100 to 100: 100 scope.
2, interpenetrating network polymer type super porous aquogel according to claim 1 is characterized in that said ethylenic unsaturation monomer is a vinylformic acid, methacrylic acid, the vinylformic acid salt, the methacrylic acid salt, esters of acrylic acid, methyl acrylic ester, the salt of acrylate or acids, the salt of methacrylic ester or acids, acrylic acid amides, the amides of methacrylic acid, acrylic acid N-alkylamide, the N-alkylamide of methacrylic acid, the salt of acrylic acid N-alkylamide and acids, the salt and the acids of the N-alkylamide of methacrylic acid, the N-vinyl pyrrolidone, acrylamide, acrylamide derivative, Methacrylamide, in the methacrylamide derivatives one or more.
3, interpenetrating network polymer type super porous aquogel according to claim 2 is characterized in that used ethylenic unsaturation monomer is one or more in acrylamide, N-N-isopropylacrylamide, 2-hydroxyethyl meth acrylate, 2-hydroxypropylmethyl acrylate, N-vinyl pyrrolidone, vinylformic acid, 2-acrylamide-2-methyl isophthalic acid-propanesulfonic acid, the 3-sulfopropyl-vinylformic acid sylvite.
4, interpenetrating network polymer type super porous aquogel according to claim 1, it is characterized in that used polyene cross-linking agent is N, N-methylene radical-bisacrylamide, two (methyl) vinylformic acid glycol ester, piperazine diacrylamine, glutaraldehyde, Epicholorohydrin, the linking agent that contains 1,2 diol structure, the linking agent that contains functional peptides and proteinaceous linking agent.
5, interpenetrating network polymer type super porous aquogel according to claim 1, it is characterized in that used linear polysaccharide base polymer is sodium alginate, chitosan, chitosan hydrochloride, cm-chitosan, N, N, a kind of in N-trimethyl chitin and the cross-linking products thereof.
6, interpenetrating network polymer type super porous aquogel according to claim 1, the linking agent that it is characterized in that crosslinked linear polysaccharide base polymer are a kind of in formaldehyde, acetaldehyde, glutaraldehyde, genipin and the calcium chloride.
7, interpenetrating network polymer type super porous aquogel according to claim 6, the weight ratio that it is characterized in that genipin or glutaraldehyde and chitosan and derivative thereof is 1: 10.
8, interpenetrating network polymer type super porous aquogel according to claim 6, the ratio that it is characterized in that calcium chloride and sodium alginate was at 1: 5.
9,, it is characterized in that its mean pore size is 50 μ m to 4000 μ m according to the described interpenetrating network polymer type super porous aquogel of claim 1-8.
10, interpenetrating network polymer type super porous aquogel according to claim 9 is characterized in that its mean pore size is 100 μ m to 800 μ m.
11, interpenetrating network polymer type super porous aquogel according to claim 1 is characterized in that its swelling ratio is 5 to 1000, and the time that reaches swelling equilibrium is 1 second to 2 hours.
12, a kind of preparation method of interpenetrating network polymer type super porous aquogel is characterized in that preparing as follows:
(1) at least a ethylenic unsaturation monomer, a kind of polyene cross-linking agent, a kind of linear polysaccharide base polymer and a kind of pore forming material are mixed, form the semi-interpenetrating network polymer Superporous hydrogels under the room temperature;
(2) above-mentioned semi-interpenetrating network polymer Superporous hydrogels is placed cross-linking agent solution, placed 0.5～8 hour, form full interpenetrating network polymer type super porous aquogel;
Wherein, the ratio of linear polysaccharide base polymer and cross-linked polymer was at 0.05: 100 to 40: 100, the monomeric ratio of polyene cross-linking agent and ethylenic unsaturation was at 0.01: 100 to 10: 100, and the part by weight that is used for linear polysaccharide base polymer polymeric linking agent and linear polysaccharide base polymer is in 1: 100 to 100: 100 scope.
13, the preparation method of interpenetrating network polymer type super porous aquogel according to claim 12 is characterized in that said ethylenic unsaturation monomer is a vinylformic acid, methacrylic acid, the vinylformic acid salt, the methacrylic acid salt, esters of acrylic acid, methyl acrylic ester, the salt of acrylate or acids, the salt of methacrylic ester or acids, acrylic acid amides, the amides of methacrylic acid, acrylic acid N-alkylamide, the N-alkylamide of methacrylic acid, the salt of acrylic acid N-alkylamide and acids, the salt and the acids of the N-alkylamide of methacrylic acid, the N-vinyl pyrrolidone, acrylamide, acrylamide derivative, Methacrylamide, in the methacrylamide derivatives one or more.
14, the preparation method of interpenetrating network polymer type super porous aquogel according to claim 13 is characterized in that used ethylenic unsaturation monomer is one or more in acrylamide, N-N-isopropylacrylamide, 2-hydroxyethyl meth acrylate, 2-hydroxypropylmethyl acrylate, N-vinyl pyrrolidone, vinylformic acid, 2-acrylamide-2-methyl isophthalic acid-propanesulfonic acid, the 3-sulfopropyl-vinylformic acid sylvite.
15, the preparation method of interpenetrating network polymer type super porous aquogel according to claim 12, it is characterized in that used linking agent is N, N-methylene radical-bisacrylamide, two (methyl) vinylformic acid glycol ester, piperazine diacrylamine, glutaraldehyde, Epicholorohydrin, the linking agent that contains 1,2 diol structure, the linking agent that contains functional peptides and proteinaceous linking agent.
16, the preparation method of interpenetrating network polymer type super porous aquogel according to claim 12, it is characterized in that used linear polysaccharide base polymer is sodium alginate, chitosan, chitosan hydrochloride, cm-chitosan, N, N, a kind of in N-trimethyl chitin and the cross-linking products thereof.
17, the preparation method of interpenetrating network polymer type super porous aquogel according to claim 12, the linking agent that it is characterized in that crosslinked linear polysaccharide base polymer is a kind of in formaldehyde, acetaldehyde, glutaraldehyde, genipin and the calcium chloride.
18, the preparation method of interpenetrating network polymer type super porous aquogel according to claim 12, it is characterized in that said pore forming material be supercarbonate, carbonate one or more or from outer importing bubble.
19, the preparation method of interpenetrating network polymer type super porous aquogel according to claim 12 is characterized in that adding entry or suds-stabilizing agent in mixture before polymerization and bubbling.
20, the preparation method of interpenetrating network polymer type super porous aquogel according to claim 12 is characterized in that adding initiator and catalyzer in mixture before polymerization and bubbling.
21, each the application of interpenetrating network polymer type super porous aquogel in the protein and peptide oral administration system among the claim 1-11.
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