WO2007034795A1 - Ϝ-polyglutamic acid crosslinked product and method for producing same - Google Patents

Ϝ-polyglutamic acid crosslinked product and method for producing same Download PDF

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Publication number
WO2007034795A1
WO2007034795A1 PCT/JP2006/318541 JP2006318541W WO2007034795A1 WO 2007034795 A1 WO2007034795 A1 WO 2007034795A1 JP 2006318541 W JP2006318541 W JP 2006318541W WO 2007034795 A1 WO2007034795 A1 WO 2007034795A1
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WIPO (PCT)
Prior art keywords
gel
poly
polyamine
glutamic acid
pga
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PCT/JP2006/318541
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French (fr)
Japanese (ja)
Inventor
Hiroshi Uyama
Tomomitsu Sewaki
Yasushi Osanai
Mie Iwamoto
Jae-Chul Choi
Chung Park
Moon-Hee Sung
Original Assignee
Genolac Bl Corporation
Bioleaders Corporation
Osaka University
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Priority to JP2007536498A priority Critical patent/JPWO2007034795A1/en
Publication of WO2007034795A1 publication Critical patent/WO2007034795A1/en

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/042—Gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/88—Polyamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/48—Polymers modified by chemical after-treatment

Definitions

  • the present invention is a polyamine crosslinked poly - a method of manufacturing a glutamic acid gel - I.
  • poly- ⁇ -dartamic acid hydrogel As a material for cosmetics and the like that is biodegradable and excellent in moisture retention, poly- ⁇ -dartamic acid hydrogel has attracted attention.
  • poly- ⁇ -dartamic acid is also referred to as “PGA”.
  • Patent Document 1 discloses a strain of the genus Bacillus that produces high molecular weight poly ⁇ -gnoretamic acid.
  • Patent Document 2 discloses poly ⁇ -gnoretamic acid having an average molecular weight of 5, OOOkDa or more.
  • JP-A-2005-179534 discloses a method for obtaining a poly ⁇ -gnoretamic acid hydrogel using polyglycidyl ether as a crosslinking agent.
  • Patent Document 3 allows a ring-opening reaction of glycidino ether without a catalyst, so that a relatively high temperature (eg 55 ° C) and a long time (eg 20 Time) and the high temperature causes the PGA to be easily decomposed.
  • a relatively high temperature eg 55 ° C
  • a long time eg 20 Time
  • Non-Patent Document 1 discloses a method of cross-linking poly- ⁇ -gnoretamic acid with a polyamine.
  • water-soluble carpositimide for example, 1 _ethyl _ 3 _ (3 dimethyl diamine
  • Disclosed is a method for obtaining poly_ ⁇ -glutamic acid hydrogels using minopropyl) monocarbodiimide hydrochloride).
  • water-soluble carbopositimide is also referred to as “WSC” (acronym for Water-Soluble Carbodiimide).
  • Non-Patent Document 1 has the following formulation and obtained in Table I on page 1892: The gel data is described.
  • PGA is polygnoretamic acid, 1, 3 -P
  • D is 1,3_propanediamin.
  • 1,3-PD is indicated by volume. 1, 3— It can be converted to weight using the specific gravity of PD (0.885 g / mL).
  • Non-Patent Document 1 has a drawback that a gel cannot be obtained when the amount of polyamine is small. For this reason, it is necessary to use a large amount of diamine to obtain a gel. If a large amount of jamin is used, the content of jamin in the gel obtained is inevitably increased. According to the data in Table 1 above, the No. 7 diamine mole fraction of 17% is the lowest.
  • Non-Patent Document 1 it is necessary to mix a large amount of diamine, and as a result, a gel having a high diamine content (for example, 17 mol% or more) is obtained. ) could only get. That is, in the non-patent document 1 method, low poly Amin content gels (e.g., 10 mole 0/0 or less) was a force, such can be obtained.
  • low poly Amin content gels e.g., 10 mole 0/0 or less
  • a gel having an excessively high polyamine content has a disadvantage that the degree of swelling is low. Specifically, in Table 1 above, the degree of swelling is only 834 times (No. 7) at the maximum. In general, it is known that a poly- ⁇ -glutamic acid gel should have a degree of swelling as high as possible in order to exhibit good moisturizing properties and the like. It was considered preferable to have a degree of swelling of 1000 times or more. For this reason, the degree of swelling shown in Table 1 above is not a desirable value for a poly ⁇ -glutamic acid gel, and a gel having a higher degree of swelling of the gel is desired.
  • the method of Non-Patent Document 1 has a drawback that the yield is extremely low. Specifically, when the ratio of the dry weight of the obtained gel to the sum of the weight of polyglutamic acid and the weight of polyamine used in the experiment of Table 1 is calculated as a yield, About 10% yield power S in the case of 5 S, No. 3, 4, 7, 8 and 9 yield is slightly, about: ⁇ ⁇ 3% Only it is. In Nos. 1, 2, and 6, the yield is 0% even before calculation. That is, in the method of Non-Patent Document 1, the yield is only about 10% at the maximum among various blends adjusted as shown in Table 1.
  • Non-Patent Document 1 has a very low yield, and is far from being practically used as an industrial production method.
  • PEI poly (ethyleneimine)
  • Patent Document 1 JP 2002-233391 A
  • Patent Document 2 International Publication WO2004-7593
  • Patent Document 3 Japanese Patent Laid-Open No. 2005-179534
  • Non-Patent Document 1 J. Appl. Polym. Sci. Vol. 65, pp. 1889— 1896, 1997, Poly (y—glutamic acid) Hydroge ⁇ Prepared from Microbial Poly (y—glut mic acid) and Alkane diamine with Water — Soluble Carbodiimide, Ku nioka et al.
  • the present invention is intended to solve the above problems, and provides a gel having a high degree of swelling, in which PGA is bridged with a small amount of polyamine, and obtaining the gel in high yield.
  • the purpose is to provide a method.
  • a method for producing poly_ ⁇ -gnoretamic acid gel comprising a step of cross-linking poly ( mono -glutamic acid) or a salt thereof with polyamine in the presence of water-soluble carpositimide and ⁇ ⁇ ⁇ ⁇ ⁇ -hydroxyimide. The method of inclusion.
  • poly one I - Gunoretamin acid is a poly _ .gamma.-glutamic acid gel crosslinked with a polyamine, in the dry gel, the sum of the number of moles a polyamine residue of glutamic acid residues Of these, a poly_ ⁇ -glutamic acid gel having a molar ratio of the number of moles of polyamine residues of 10 mol% or less.
  • the ratio power of the number of moles of polyamine residues in the dry gel is 3 mol% or less.
  • a gel in which PGA is crosslinked with polyamine in a very high yield According to the present invention, a gel having a low polyamine residue content, a low crosslinking density, and a high degree of swelling is provided.
  • Poly ⁇ -glutamic acid refers to a compound obtained by polymerizing D, L gnoretamic acid.
  • PGA can also be used in the present invention as its salt.
  • a sodium salt of PGA can be suitably used.
  • the molecular weight of PGA is not particularly limited. However, in terms of physical properties, the weight average molecule The amount is preferably 10,000 or more, more preferably 100,000 or more. More preferably, it is 500,000 or more, and more preferably 1 million or more, particularly preferably 1.5 million or more, particularly preferably 2 million or more. In addition, the weight average molecular weight is preferably 13 million or less, more preferably 10 million or less in view of difficulty in synthesis.
  • Patent Document 1 Japanese Patent Laid-Open No. 2002-233391 describes PGA having a weight average molecular weight of about 13 million, and this PGA can be suitably used in the present invention.
  • the PGA used in the present invention can be produced by any known production method. For example, the method described in Patent Document 1 above can be used.
  • polyamine refers to a compound having a plurality of amino groups.
  • the amino group may be a primary amino group (1NH) or a secondary amino group (1NH-). 1st grade
  • amino group is preferred.
  • the number of amino groups is not particularly limited, but in one preferred embodiment, there are two in the molecule (ie, diamine).
  • the polyamine is an alkylenediamine or polyethyleneimine.
  • the number of carbon atoms in the alkylenediamine is not particularly limited. Preferably, it is 2 or more
  • the alkylene group in the alkylenediamine may be either a straight chain or a branched chain. A straight chain is preferred.
  • preferable alkylene diamines include 1,2_ethylene diamine, 1,3_propylene diamine, 1,4_butane diamine, 1,5_heptane diamine, 1,6-hexane diamine and the like. Is mentioned.
  • Polyethyleneimine is a polymer obtained by polymerizing ethyleneimine, and any conventionally known polyethyleneimine can be used in the method of the present invention.
  • Grade 1 Min A secondary amine: A polymer containing tertiary amine in a ratio of 1: 2: 1.
  • the weight average molecular weight of polyethyleneimine is not particularly limited. Preferably, it is 100 or more, more preferably 200 or more, still more preferably 400 or more, even more preferably 500 or more, and most preferably 600 or more. Further, it is preferably 100,000 or less, more preferably 50,000 or less, further preferably 10,000 or less, and most preferably 5000 or less.
  • polyethyleneimine a commercially available polymer can be used as it is. Alternatively, it may be obtained by polymerization from ethyleneimine by a known method.
  • the amount of polyamine used is not particularly limited, but it may be blended so that the total of primary amino groups of the polyamine used is 0.0001 mol or more per 1 mol of glutamic acid residues in PGA. Preferred is 0.001 mol or more, more preferred 0.003 mol or more is more preferred, and particularly preferred is 0.005 monole or more.
  • the total number of primary amine groups of the polyamine used is preferably 1 mol or less with respect to 1 mol of glutamic acid residue in PGA, 0.2 mol or less is more preferable, and 0.1 mol or less is more preferable. Further preferred is 0.06 mol or less, particularly preferred is 0.04 mol or less.
  • the polyamine used is blended so that the weight of the polyamine used is 0.0002 g or more, more preferably 0.0002 g or more, and even more preferably 0.0005 g or more. Particularly preferably, it is not less than 0. OOlg. Also, it is preferable that the PGAlg is 0.25g or less. More preferably, 0.05g or less is more preferable. 0.25g or less is more preferable. 0.015g or less is more preferable. 0. Olg or less Is particularly preferred.
  • water-soluble carpositimide is used as the condensing agent.
  • water-soluble carpositimide is also referred to as WSC.
  • WSC water-soluble carpositimide
  • Specific examples of WSC that can be used in the present invention For example, 1-ethyl-3- (3-dimethylaminopropyl) monocarbodiimide or a salt thereof, 1-cyclohexyl 3- (2-morpholinoethyl) carbodiimido-metho-toluene sulfate or a salt thereof, and the like.
  • 1-Ethyl- 3 — ( 3 —Dimethylaminopropyl) carbodiimide hydrochloride (EDC) or 1-cyclohexyl _ 3_ (2-mono-reinoethyl) carbopositimide-meth _p-toluene sulfate (CMC) can be preferably used .
  • the amount of WSC used is not particularly limited, but 2 moles or more is preferred, 3 moles or more is more preferred, 6 moles or more is more preferred, 12 moles per mole of polyamine used. More than 24 moles are especially preferred.
  • 50 mol or less is preferable, 40 mol or less is more preferable, and 30 mol or less is more preferable.
  • the amount of WSC used is preferably determined based on the amount of polyamine.
  • the amount of dartamic acid in PGA is used as a guideline of the blending amount based on the amount of PGA. 0.001 mol or more is preferable with respect to 1 mol of the residue, 0.01 mol or more is more preferable 0.03 mol or more is more preferable 0.06 mol or more is particularly preferable. Further, 1 mol or less is preferable with respect to 1 mol of glutamic acid residues in PGA, 0.3 mol or less is more preferable, and 0.1 mol or less is more preferable.
  • this compound is represented by the following general formula.
  • R A and R B may be combined to form a ring structure.
  • a compound in which R A and RB are bonded to form a 5-membered ring with two carbons in R A and R B and an N-hydroxyimide group is preferred.
  • N-hydroxyimide is preferably water-soluble.
  • ⁇ -Hydroxyimide may be a commercially available reagent, or may be synthesized by a conventionally known synthesis method. For example, it may be synthesized by the method described in JP 2002-47270 A.
  • ⁇ -hydroxyimides ⁇ ⁇ ⁇ ⁇ ⁇ -hydroxysuccinimide is most preferable.
  • ⁇ -hydroxysuccinimide a commercially available reagent can be used as it is.
  • ⁇ -hydroxysuccinimide is also referred to as NHS.
  • the amount of ⁇ ⁇ ⁇ -hydroxyimide used is not particularly limited, but 2 mol or more is preferable, 3 mol or more is more preferable, and 6 mol or more is more preferable with respect to 1 mol of the polyamine used. More than 12 mol is more preferable. More than 24 mol is particularly preferable. Further, with respect to 1 mol of the polyamine used, 50 mol or less is preferable, 40 mol or less is more preferable, and 30 mol or less is more preferable.
  • the amount of ⁇ ⁇ ⁇ ⁇ ⁇ -hydroxyimide used is preferably equimolar to the amount of WSC used.
  • the amount of ⁇ -hydroxyimide used is preferably determined based on the amount of polyamine.
  • ⁇ 0.001 mol or more is preferable with respect to 1 mol of glutamic acid residue of 0.01 mol or less More preferable is 0.03 mol or more, and more preferable is 0.06 mol or more.
  • 1 mol or less is preferable with respect to 1 mol of glutamic acid residue in PGA, 0.3 mol or less is more preferable, and 0.1 mol or less is more preferable.
  • the solvent is not particularly limited. Preferably, it is water.
  • the method of the present invention is preferably carried out in a solvent using only the above materials. However, in addition to each of the above materials, an appropriate amount of a known additive or the like may be blended as necessary.
  • condensing agents other than WSC and NHS condensation aids, catalysts, fillers, colorants (pigments or dyes), reinforcing agents (for example, fibers), antioxidants, release agents
  • a solvent, a thickener and the like can be added depending on the application.
  • the conditions for the crosslinking reaction are not particularly limited. It may be warmed at room temperature. However, if the temperature is too low, the curing reaction takes a very long time, so heating is preferred. Specifically, the temperature during the crosslinking reaction is preferably 10 ° C or higher, more preferably 15 ° C or higher, and further preferably 20 ° C or higher. Also, it is preferably 100 ° C or lower, more preferably 50 ° C or lower. If it is too high, the PGA will break down. Therefore, it is preferable to carry out at around room temperature.
  • the pH in the crosslinking reaction is not particularly limited, but is preferably 6 or more, more preferably 7 or more. Further, it is preferably 11 or less, more preferably 10 or less.
  • a gel in which PGA is cross-linked is obtained.
  • the order in which the materials are charged is not particularly limited, and all materials may be charged at once, or the materials may be charged in any order.
  • the WSC is charged last. . That is, it is preferable in terms of yield to add WSC after preparing a reaction solution containing PGA, polyamine and N-hydroxyimide.
  • Time from the addition of N-hydroxyimide to the addition of WSC More preferably, it is 5 minutes or more, and more preferably 10 minutes or more. Further, it is preferably 3 hours or less, more preferably 1 hour or less, and further preferably 30 minutes or less.
  • the reaction time for the crosslinking reaction is preferably 5 minutes or more, more preferably 10 minutes or more, and further preferably 20 minutes or more in order to sufficiently perform the crosslinking reaction. It is preferably 30 minutes or more, particularly preferably 1 hour or more. However, in order to shorten the overall length of the process, it is preferably 5 days or less, more preferably 2 days or less, and even more preferably 1 day or less. More preferably, it is 12 hours or less. Particularly preferably, it is 6 hours or less.
  • reaction solution may be stirred or allowed to stand as necessary. Preferably, it is left still.
  • the gel obtained by the above-described method has a structure in which polyamine is crosslinked to PGA. WSC and N-hydroxyimide are substantially absent in the final gel.
  • the number of moles of polyamine residues is preferably 15% or less, more preferably 10% or less, relative to the sum of the number of moles of glutamic acid residues and the number of moles of polyamine residues. 5% or less is more preferable 3% or less is more preferable 1% or less is particularly preferable. And 0. ⁇ 01. More than / ⁇ is preferred 0. ⁇ 1. More than / ⁇ is more preferable 0. More than 1% is more preferable.
  • the gel obtained by the above-described method becomes a hydrogel form by water. It is possible to obtain a hydrogel product containing a necessary amount of water depending on the application.
  • the gel of the present invention exhibits an excellent degree of swelling.
  • immersed in distilled water for 2 days at room temperature It is possible to obtain a gel with a degree of gel swelling of 1000 times or more after being applied, and by appropriately adjusting the composition, it is 2000 times or more, 3000 times or more, 4000 times or more, 5000 times or more, 5500 times or more
  • a gel having a degree of swelling of 6000 times or more can be produced.
  • the higher the degree of swelling the better.
  • the hydrogel of the present invention is expected to be applied in a wide range of fields.
  • the cosmetic field it can be used as a moisturizer or moisturizer.
  • it is used as a soil modifier, seed coating agent, moisture retention agent for plant cultivation, animal compost fixative, compost additive, and additive for faeces and urine.
  • Doing power S In the civil engineering field, water treatment sludge can be used as sewage sludge, water conditioning agent for river sewer sludge, solidifying agent, modifier, coagulant, or soil for reservoir.
  • the medical and hygiene field it can be used as an absorbent for blood, body fluids, disposable diapers and tambons, or as a deodorant or controlled release drug carrier.
  • bioengineering it can be used as a medium substrate for culturing microorganisms, plant cells, or animal cells, or as a fixing material for bioreactors.
  • the crosslinking reaction was allowed to proceed sufficiently (one day), and then immersed in 2 L of distilled water. The gel was swollen while being exchanged. The gel swelling degree and the gel yield were measured by lyophilizing the gel from which the crosslinking agent was removed by swelling (one day).
  • the gel swelling degree and gel yield were 6620 times and 92%, respectively, when immersed in distilled water for 2 days to achieve sufficient swelling.
  • the gelation time time until elasticity and viscosity crossover over obtained from viscoelasticity measurement was 7.8 minutes, and the gel elastic modulus in steady state G 'was 130Pa.
  • the initial elastic modulus E is obtained from the result of the compression test and is 1.9 kPa.
  • the composition of the obtained gel naturally had a blending ratio of PGA and 1,3-PD in the starting material of about
  • the gel composition is considered as it is.
  • the 1,3-PD residue in the gel is about 1%.
  • Example 1 a gel having a low crosslinker density that cannot be obtained by the technique of Non-Patent Document 1 was obtained in Example 1.
  • a gel cross-linked product was prepared using PGA having a weight average molecular weight of 500,000 instead of PGA having a molecular weight of 2 million in Example 1. As a result, the gel swelling degree and the gel yield were 2 respectively.
  • Non-Patent Document 1 As explained in the background section above, the yield in Non-Patent Document 1 was only about several percent to 10%. Compared to this prior art, the gel yield of 97% in Example 1 above and 79% in Example 1A are very unpredictable from the prior art, very high yields. It is understood that
  • Non-patent Document 1 when the amount of 1,3-PD added is small, a gel cannot be obtained. Specifically, for example, for PGAl OOmg 1, 3—? When 0 was added to 10/1 1 ⁇ (about 9 ⁇ , about 9 parts by weight with respect to 100 parts by weight of PGA), a gel could not be obtained. That is, the yield is 0%. On the other hand, in Example 1 and Example 1A above, gels were obtained in yields of 97% and 79% in a composition in which only 1 part by weight of 1,3-PD was added to 100 parts by weight of PGA. This is nothing but to evaluate the surprisingly high yield.
  • Example 1 a gel cross-linked product was prepared using PGA having a weight average molecular weight of 5 million instead of PGA having a molecular weight of 2 million. As a result, a good gel cross-linked product was obtained.
  • the gel swelling degree and the gel yield were measured by freeze-drying the gel from which the cross-linking agent had been removed by S-junction, and they were 2400 times and 95%, respectively.
  • the gelation time obtained from the viscoelasticity measurement was 7.7 minutes, and the gel elasticity in a steady state.
  • the rate G ' was 590Pa.
  • the initial elastic modulus E is obtained from the result of the compression test and is 2.6 kPa.
  • the Gelich time time until the elastic modulus and the viscosity crossover obtained from viscoelasticity measurement was 11 minutes, and the gel elastic modulus G ′ in the steady state was 52 Pa.
  • the initial elastic modulus E was obtained and was 0.24 kPa.
  • the molecular weight of PGA is a weight average molecular weight.
  • Cross-linking agent 1, 3-PD a) Use a sample left for a sufficient time (about 1 day) after the start of the crosslinking reaction. After confirming that there was no frequency dependence when measuring the elasticity, we measured with a rheometer using a frequency of 1 Hz.
  • the Gerich time can be controlled by the amount of the crosslinking agent.
  • the gelling time is more influenced by the amount of the crosslinking agent than the PGA molecular weight.
  • Comparative Example 1 the experiment was performed in the same manner as in Comparative Example 1, except that the pH of the reaction solution was adjusted to 6. Since WSC is known to have high activity at about pH 6, the pH was adjusted. As a result, the viscosity of the reaction solution increased, but no cross-linked product was obtained, and the yield was 0. /. It was.
  • the gel time obtained from viscoelasticity measurement (time until the elastic modulus and the viscosity crossover) is 2.6 minutes, and the gel in a steady state
  • the elastic modulus G ′ was 400 Pa.
  • the initial elastic modulus E is obtained from the result of the compression test, and 2.3 kPa
  • the total amount of water contained in the PGA cross-linked product was 5 mL.
  • the gelation time obtained from viscoelasticity measurement time until the elastic modulus and the viscosity crossover
  • the gel elastic modulus G in the steady state G 'Was 200Pa was 2.3 minutes, and the gel elastic modulus G in the steady state G 'Was 200Pa.
  • the total amount of water contained in the PGA cross-linked product was 5 mL.
  • the Gelich time (time until the elastic modulus and the viscosity crossover) obtained from the viscoelasticity measurement was 11 minutes, and the gel elastic modulus G ′ in the steady state was 39 Pa. Met.
  • the gelation time obtained from viscoelasticity measurement (time until the elastic modulus and the viscosity crossover) is 4.0 minutes, and the gel elastic modulus G in the steady state G 'Was 52Pa. From the result of the compression test, the initial elastic modulus E was obtained and was 1.5 kPa.
  • the degree of swelling of the obtained gel was 2000 times.
  • the gelation time obtained by measuring viscoelasticity time until the elastic modulus and the viscosity crossover
  • the gel elastic modulus in the steady state G ' was l lOOPa.
  • the initial elastic modulus E was obtained, which was 6.4 kPa.
  • PEI weight average molecular weight: 600, 1800, 10000
  • the molecular weight of one monomer unit of polyethyleneimine is 44.
  • Comparative Example 3 the experiment was performed in the same manner as Comparative Example 3 except that the pH of the reaction solution was adjusted to 6. Since WSC is known to have high activity at about pH 6, the pH was adjusted. As a result, the viscosity of the reaction solution increased, but no cross-linked product was obtained, and the yield was 0%.
  • N-hydroxyimide N-hydroxyimide (NHS in the above examples) as a crosslinking activation aid in addition to WSC as a crosslinking activator, a gel composed of PGA crosslinked rapidly with PEI could be prepared.
  • the gel of the present invention has an excellent degree of swelling, it can be used effectively in applications where conventionally known hydrogels have been used. For example, it is expected to be applied in the field of cosmetics because of its excellent moisture retention. In addition, its high water absorption rate is expected to be applied in the field of sanitary products.

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Abstract

Disclosed is a biodegradable poly-Ϝ-glutamic acid gel which is excellent in swelling degree and moisture retention. A poly-Ϝ-glutamic acid hydrogel can be obtained with an extremely high yield by using a water-soluble carbodiimide (such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and an N-hydroxyimide (such as an N-hydroxysuccinimide) as a condensing agent and a condensation assistant when a poly-Ϝ-glutamic acid is crosslinked with a polyamine. In particular, a biodegradable poly-Ϝ-glutamic acid hydrogel having excellent swelling degree can be obtained by using a poly-Ϝ-glutamic acid having a molecular weight of not less than 1,000,000 as the raw material.

Description

明 細 書  Specification
γ 一ポリグルタミン酸架橋物及びその製造方法 技術分野  γ-monopolyglutamic acid cross-linked product and method for producing the same
[0001] 本発明は、ポリアミン架橋ポリ— Ί—グルタミン酸ゲルの製造方法に関する。 [0001] The present invention is a polyamine crosslinked poly - a method of manufacturing a glutamic acid gel - I.
背景技術  Background art
[0002] 生分解性を有し、かつ保湿性等に優れた化粧品等の材料として、ポリ— Ί—ダルタ ミン酸ヒドロゲルが注目されている。以下、本明細書中において、ポリ一 γ—ダルタミ ン酸を「PGA」とも記載する。 As a material for cosmetics and the like that is biodegradable and excellent in moisture retention, poly- Ί -dartamic acid hydrogel has attracted attention. Hereinafter, in the present specification, poly-γ-dartamic acid is also referred to as “PGA”.
[0003] 特開 2002— 233391号公報（特許文献 1)は、高分子量のポリ γーグノレタミン酸 を生産するバチルス属菌株を開示する。 [0003] Japanese Patent Application Laid-Open No. 2002-233391 (Patent Document 1) discloses a strain of the genus Bacillus that produces high molecular weight polyγ-gnoretamic acid.
[0004] 国際公開 WO2004— 7593号公報（特許文献 2)は、平均分子量が 5, OOOkDa以 上のポリ γーグノレタミン酸を開示する。 [0004] International Publication No. WO2004-7593 (Patent Document 2) discloses poly γ-gnoretamic acid having an average molecular weight of 5, OOOkDa or more.
[0005] 特開 2005— 179534号公報（特許文献 3)は、ポリグリシジルエーテルを架橋剤と して用いてポリ γーグノレタミン酸ヒドロゲルを得る方法を開示する。 [0005] JP-A-2005-179534 (Patent Document 3) discloses a method for obtaining a polyγ-gnoretamic acid hydrogel using polyglycidyl ether as a crosslinking agent.
[0006] しかし、特許文献 3に記載された方法は、触媒なしでグリシジノレエーテルの開環反 応を行わせるため、比較的高い温度（例えば、 55°C)および長時間（例えば、 20時 間）を必要とし、その高温のために PGAが分解しやすいという欠点がある。 [0006] However, the method described in Patent Document 3 allows a ring-opening reaction of glycidino ether without a catalyst, so that a relatively high temperature (eg 55 ° C) and a long time (eg 20 Time) and the high temperature causes the PGA to be easily decomposed.
[0007]  [0007]
また、 Kuniokaら（非特許文献 1)は、ポリ— γ—グノレタミン酸をポリアミンで架橋す る方法を開示し、縮合剤として、水溶性カルポジイミド (例えば、 1 _ェチル _ 3 _ (3 —ジメチルァミノプロピル）一カルポジイミド 塩酸塩）を用いて、ポリ _ γ—グルタミン 酸ヒドロゲルを得る方法を開示する。なお、本願明細書中では、水溶性カルポジイミド を「WSC」（Water— Soluble Carbodiimideの頭文字)とも記載する。  Kunioka et al. (Non-Patent Document 1) discloses a method of cross-linking poly-γ-gnoretamic acid with a polyamine. As a condensing agent, water-soluble carpositimide (for example, 1 _ethyl _ 3 _ (3 dimethyl diamine) is disclosed. Disclosed is a method for obtaining poly_γ-glutamic acid hydrogels using minopropyl) monocarbodiimide hydrochloride). In the present specification, water-soluble carbopositimide is also referred to as “WSC” (acronym for Water-Soluble Carbodiimide).
[0008] しかし、この方法は、非常に収率が低いという欠点があった。また、ポリアミン含有量 の高いゲルしか得られないという欠点があった。さらに、ゲルの膨潤度が低ぐヒドロ ゲルとして使用する際の保湿性などに劣るという欠点があった。  [0008] However, this method has a drawback that the yield is very low. In addition, there is a drawback that only gels with a high polyamine content can be obtained. Furthermore, there is a drawback that the moisture retention property is poor when used as a hydrogel with a low degree of gel swelling.
[0009] 具体的には、非特許文献 1は、その 1892頁の Table Iに以下の配合および得られ たゲルのデータを記載する。 [0009] Specifically, Non-Patent Document 1 has the following formulation and obtained in Table I on page 1892: The gel data is described.
[0010] なお、非特許文献 1の Table Iには、配合番号および PGA (ポリグノレタミン酸）の配 合量の欄が存在しないが、説明の便宜上、以下の表においては、配合番号および P[0010] In Table I of Non-Patent Document 1, there are no columns for the blending number and the amount of PGA (polygnoretamic acid), but for the convenience of explanation, in the following table, the blending number and the P
GAの量の欄を追加して記載する。表中、 PGAとはポリグノレタミン酸であり、 1 , 3 -PAdd an additional column for GA amount. In the table, PGA is polygnoretamic acid, 1, 3 -P
Dは、 1 , 3 _プロパンジァミンである。 D is 1,3_propanediamin.
[0011] [表 1] [0011] [Table 1]
Figure imgf000003_0001
注（1)：非特許文献 1の表 I中には PGAの量は記載されていないが、表の下の脚注 に lOOmgの PGAが使用されたことが記載されている。
Figure imgf000003_0001
Note (1): Although the amount of PGA is not described in Table I of Non-Patent Document 1, it is described in the footnote below the table that lOOmg of PGA was used.
(2)：非特許文献 1の表 I中においては「Dry Gel Weight」と記載されている。  (2): In Table I of Non-Patent Document 1, “Dry Gel Weight” is described.
(3)：非特許文献 1の表 I中においては「Specific Water Contendと記載されて いる。  (3): In Table I of Non-Patent Document 1, “Specific Water Contend” is described.
(4)：非特許文献 1の表 I中にぉレ、ては「glu」と記載されてレ、る。  (4): In Table I of Non-Patent Document 1, it is written as “glu”.
(5)：非特許文献 1の表 I中においては「1 , 3— PD」と記載されている。  (5): In Table I of Non-Patent Document 1, “1, 3—PD” is described.
(6)：上記表中、 1 , 3— PDの配合量は体積で示されている。 1 , 3— PDの比重（0. 8 85g/mL)を用いて重量に換算することが可能である。  (6): In the above table, the amount of 1,3-PD is indicated by volume. 1, 3— It can be converted to weight using the specific gravity of PD (0.885 g / mL).
[0012] 上記表 1の No. 4および Νο· 6〜Νο· 9を比較すると、この方法では、ポリアミンモ ル分率が少なレ、ゲルを製造することができなレ、ことが理解される。  [0012] Comparing No. 4 and Νο · 6 to Νο · 9 in Table 1 above, it is understood that this method has a low polyamine mole fraction and cannot produce a gel. .
[0013] すなわち、 No. 4および No. 8〜No. 9の配合では、ポリアミンを多量に配合してお り、 2. 5〜6. 5mgのゲルが得られている力 ポリアミンの量を減少させた No. 6では 、乾燥ゲルの収量が 0になってしまっている。つまり、非特許文献 1の方法では、ポリ ァミンの量が少ない場合にはゲルを得ることができないという欠点がある。このため、 ゲルを得るためには、多量のジァミンを使用する必要がある。そして、多量のジァミン を使用すると、必然的に、得られるゲル中のジァミン含有量が多くなる。上記表 1中の データによれば、 No. 7のジァミンモル分率 17%が最低である。 [0013] That is, in the combination of No. 4 and No. 8 to No. 9, a large amount of polyamine is blended, and the force to obtain 2.5 to 6.5 mg of gel is reduced. In the case of No. 6 The yield of the dried gel has become zero. That is, the method of Non-Patent Document 1 has a drawback that a gel cannot be obtained when the amount of polyamine is small. For this reason, it is necessary to use a large amount of diamine to obtain a gel. If a large amount of jamin is used, the content of jamin in the gel obtained is inevitably increased. According to the data in Table 1 above, the No. 7 diamine mole fraction of 17% is the lowest.
[0014] このように、非特許文献 1の方法においては、多量のジァミンを配合する必要があり 、そして、その結果、得られるゲルとしては、ジァミン含有率の高いゲル (例えば、 17 モル％以上）しか得ることができなかった。すなわち、非特許文献 1の方法では、ポリ ァミン含有率の低いゲル (例えば、 10モル0 /0以下）を得ることができな力 た。 [0014] Thus, in the method of Non-Patent Document 1, it is necessary to mix a large amount of diamine, and as a result, a gel having a high diamine content (for example, 17 mol% or more) is obtained. ) Could only get. That is, in the non-patent document 1 method, low poly Amin content gels (e.g., 10 mole 0/0 or less) was a force, such can be obtained.
[0015] そして、ポリアミン含有率が高すぎるゲルは、膨潤度が低いという欠点を有する。具 体的には、上記表 1では、膨潤度が最大でも 834倍 (No. 7)にしかならない。一般に 、ポリ— γ—グルタミン酸ゲルは、良好な保湿性などの性能を発揮するためには、で きるだけ高い膨潤度を有するべきであることが知られており、具体的には、例えば、約 1000倍以上の膨潤度を有することが好ましいと考えられていた。このため、上記表 1 に示された膨潤度は、ポリ γ グルタミン酸ゲルとして望ましい値とはいえず、より 高レヽ膨潤度を有するゲルが望まれてレ、た。  [0015] A gel having an excessively high polyamine content has a disadvantage that the degree of swelling is low. Specifically, in Table 1 above, the degree of swelling is only 834 times (No. 7) at the maximum. In general, it is known that a poly-γ-glutamic acid gel should have a degree of swelling as high as possible in order to exhibit good moisturizing properties and the like. It was considered preferable to have a degree of swelling of 1000 times or more. For this reason, the degree of swelling shown in Table 1 above is not a desirable value for a polyγ-glutamic acid gel, and a gel having a higher degree of swelling of the gel is desired.
[0016] また、そもそも、非特許文献 1の方法においては、収率が極めて低いという欠点があ る。具体的には、上記表 1の実験において用いられた、ポリグルタミン酸の重量とポリ ァミンの重量との和に対する、得られたゲルの乾燥重量の比率を収率として計算する と、表 1の No. 5の酉己合にぉレヽて、約 10%の収率力 S得られる力 S、 No. 3、 4、 7、 8、 9 では、収率はわずかに、約：!〜 3%程度でしかない。そして、 No. 1、 2、 6では、計算 するまでもなぐ収率は 0%である。すなわち、非特許文献 1の方法では、その収率は 、表 1に示されたように各種配合を調整した中の最大でも約 10%にしかならないので ある。  [0016] In the first place, the method of Non-Patent Document 1 has a drawback that the yield is extremely low. Specifically, when the ratio of the dry weight of the obtained gel to the sum of the weight of polyglutamic acid and the weight of polyamine used in the experiment of Table 1 is calculated as a yield, About 10% yield power S in the case of 5 S, No. 3, 4, 7, 8 and 9 yield is slightly, about: ~ ~ 3% Only it is. In Nos. 1, 2, and 6, the yield is 0% even before calculation. That is, in the method of Non-Patent Document 1, the yield is only about 10% at the maximum among various blends adjusted as shown in Table 1.
[0017] このように、非特許文献 1の方法は、極めて収率が低いために、工業的製法として 実用化するには程遠いものであった。  [0017] As described above, the method of Non-Patent Document 1 has a very low yield, and is far from being practically used as an industrial production method.
[0018] また、上述したように、従来からポリアミンを架橋剤に用いることは試みられていたが[0018] As described above, conventionally, attempts have been made to use polyamines as crosslinking agents.
、ポリマーを架橋剤として用いることは考えられていなかった。特に、カチオン性のポ リマーであるポリ（エチレンィミン）（本明細書中で「PEI」と略す）は、ァニオン性のポリ マーである PGAとがポリイオンコンプレックスを形成して不溶化しやすいことが知られ ていたので、 PEIを PGAの架橋剤として用いることができるとは、考えられていなかつ た。 The use of a polymer as a crosslinking agent has not been considered. In particular, cationic po It was known that poly (ethyleneimine) (abbreviated as “PEI” in this specification), which is a remer, is easily insolubilized by forming a polyion complex with PGA, which is an anionic polymer. It was not thought that it could be used as a cross-linking agent for PGA.
特許文献 1 :特開 2002— 233391号公報  Patent Document 1: JP 2002-233391 A
特許文献 2 :国際公開 WO2004— 7593号公報  Patent Document 2: International Publication WO2004-7593
特許文献 3 :特開 2005— 179534号公報  Patent Document 3: Japanese Patent Laid-Open No. 2005-179534
非特許文献 1 :J. Appl. Polym. Sci. Vol. 65, pp. 1889— 1896， 1997, Poly ( y—glutamic acid) Hydroge丄 Prepared from Microbial Poly ( y— gluta mic acid) and Alkane diamine with Water— Soluble Carbodiimide、 Ku niokaら  Non-Patent Document 1: J. Appl. Polym. Sci. Vol. 65, pp. 1889— 1896, 1997, Poly (y—glutamic acid) Hydroge 丄 Prepared from Microbial Poly (y—glut mic acid) and Alkane diamine with Water — Soluble Carbodiimide, Ku nioka et al.
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0019] 本発明は、上記問題点の解決を意図するものであり、 PGAが少量のポリアミンで架 橋された、高い膨潤度を有するゲルを提供すること、およびそのゲルを高い収率で得 る方法を提供することを目的とする。 [0019] The present invention is intended to solve the above problems, and provides a gel having a high degree of swelling, in which PGA is bridged with a small amount of polyamine, and obtaining the gel in high yield. The purpose is to provide a method.
課題を解決するための手段  Means for solving the problem
[0020] 本発明者らは、鋭意研究を重ねた結果、特定の縮合補助剤を用いる方法を採用す ることによって上記課題が解決されることを見出し、これに基づいて本発明を完成さ せた。 [0020] As a result of extensive research, the present inventors have found that the above problem can be solved by adopting a method using a specific condensation aid, and based on this, the present invention has been completed. It was.
[0021] 具体的には、本発明によれば、以下の方法およびゲルが提供される。  Specifically, according to the present invention, the following method and gel are provided.
[0022] (1) ポリ _ γ—グノレタミン酸ゲルの製造方法であって、水溶性カルポジイミドおよ び Ν—ヒドロキシイミドの存在下で、ポリ一 Ί—グルタミン酸またはその塩をポリアミン で架橋する工程を包含する、方法。 [0022] (1) A method for producing poly_γ-gnoretamic acid gel, comprising a step of cross-linking poly ( mono -glutamic acid) or a salt thereof with polyamine in the presence of water-soluble carpositimide and ヒ ド ロ キ シ -hydroxyimide. The method of inclusion.
[0023] (2) 前記 Ν—ヒドロキシイミドが Ν—ヒドロキシコハク酸イミドである、上記項 1に記 載の方法。 [0023] (2) The method according to item 1, wherein the Ν-hydroxyimide is Ν-hydroxysuccinimide.
[0024] (3) 前記ポリ— y—グノレタミン酸またはその塩の重量平均分子量力 100万以上 である、上記項 1に記載の方法。 [0025] (4) 前記水溶性カルポジイミドカ S、 1ーェチルー 3—（3 ジメチルァミノプロピ ノレ）—カルポジイミド 塩酸塩である、上記項 1に記載の方法。 [0024] (3) The method according to item 1, wherein the poly-y-gnoretamic acid or a salt thereof has a weight average molecular weight of 1 million or more. [0025] (4) The method according to item 1 above, wherein the water-soluble carposimidica S, 1-ethyl-3- (3 dimethylaminopropinole) -carposimido hydrochloride is used.
[0026] (5) 前記ポリアミン力 アルキレンジァミンまたはポリ（エチレンィミン）である、上記 項 1に記載の方法。 [0026] (5) The method according to item 1, wherein the polyamine force is an alkylenediamine or poly (ethyleneimine).
[0027] (6) 前記ポリアミン力 炭素数 2〜8のアルキレンジァミンである、上記項 1に記載 の方法。  [0027] (6) The method according to item 1, wherein the polyamine strength is alkylenediamine having 2 to 8 carbon atoms.
[0028] (7) 前記ポリアミン力 重量平均分子量 100〜20000のポリ（エチレンィミン）であ る、上記項 1に記載の方法。  [0028] (7) The method according to item 1, wherein the polyamine force is poly (ethyleneimine) having a weight average molecular weight of 100 to 20000.
[0029] (8) 前記ポリアミン力 1， 3_プロパンジァミンである、上記項 1に記載の方法。 [0029] (8) The method according to item 1, wherein the polyamine force is 1,3_propanediamine.
[0030] (9) ポリ一 Ί—グノレタミン酸がポリアミンで架橋されたポリ _ γ—グルタミン酸ゲル であって、乾燥ゲル中の、グルタミン酸残基のモル数とポリアミン残基のモル数との和 のうちの、ポリアミン残基のモル数の比率力 10モル％以下である、ポリ _ γ—グル タミン酸ゲル。 [0030] (9) poly one I - Gunoretamin acid is a poly _ .gamma.-glutamic acid gel crosslinked with a polyamine, in the dry gel, the sum of the number of moles a polyamine residue of glutamic acid residues Of these, a poly_γ-glutamic acid gel having a molar ratio of the number of moles of polyamine residues of 10 mol% or less.
[0031] (10) 前記乾燥ゲル中の、ポリアミン残基のモル数の比率力 3モル％以下である [0031] (10) The ratio power of the number of moles of polyamine residues in the dry gel is 3 mol% or less.
、上記項 9に記載のポリ γ グルタミン酸ゲル。 10. The poly γ-glutamic acid gel according to item 9 above.
[0032] (11) ポリ γ—グルタミン酸がポリ（エチレンィミン）で架橋されたポリ— γ—ダル タミン酸ゲル。 [0032] (11) A poly-γ-dalamic acid gel in which polyγ-glutamic acid is crosslinked with poly (ethyleneimine).
発明の効果  The invention's effect
[0033] 本発明によれば、非常に高い収率で PGAをポリアミンで架橋したゲルが提供される 。本発明によれば、ポリアミン残基含有量が少なぐ架橋密度が低ぐ膨潤度が高い ゲルが提供される。  [0033] According to the present invention, there is provided a gel in which PGA is crosslinked with polyamine in a very high yield. According to the present invention, a gel having a low polyamine residue content, a low crosslinking density, and a high degree of swelling is provided.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0034] 以下、本発明を詳細に説明する。 [0034] Hereinafter, the present invention will be described in detail.
[0035] (PGA) [0035] (PGA)
ポリ γ グルタミン酸 (PGA)は、 D, L グノレタミン酸が重合されて得られる化合 物をいう。 PGAは、また、その塩として本発明に用いることもできる。例えば、 PGAの ナトリウム塩が好適に使用可能である。  Polyγ-glutamic acid (PGA) refers to a compound obtained by polymerizing D, L gnoretamic acid. PGA can also be used in the present invention as its salt. For example, a sodium salt of PGA can be suitably used.
[0036] PGAの分子量は、特に限定されなレ、。ただし、物性などの点から、重量平均分子 量 1万以上であることが好ましぐ 10万以上であることがより好ましい。さらに好ましく は、 50万以上であり、レ、つそう好ましくは 100万以上であり、ひときわ好ましくは 150 万以上であり、特に好ましくは 200万以上である。また、合成の困難性などの点で、 重量平均分子量 1300万以下であることが好ましぐ 1000万以下であることがより好 ましい。 [0036] The molecular weight of PGA is not particularly limited. However, in terms of physical properties, the weight average molecule The amount is preferably 10,000 or more, more preferably 100,000 or more. More preferably, it is 500,000 or more, and more preferably 1 million or more, particularly preferably 1.5 million or more, particularly preferably 2 million or more. In addition, the weight average molecular weight is preferably 13 million or less, more preferably 10 million or less in view of difficulty in synthesis.
[0037] 例えば、上記特許文献 1 (特開 2002— 233391号公報）には、重量平均分子量約 1300万の PGAが記載されており、この PGAを好適に本発明に使用することができ る。  For example, Patent Document 1 (Japanese Patent Laid-Open No. 2002-233391) describes PGA having a weight average molecular weight of about 13 million, and this PGA can be suitably used in the present invention.
[0038] また、上記特許文献 1の従来の技術欄に記載されているように、従来から、分子量 1 0万〜 200万の PGAが汎用されており、この分子量範囲の PGAを本発明に用いるこ とも可能である。  [0038] Further, as described in the conventional technical column of Patent Document 1, a PGA having a molecular weight of 100,000 to 2,000,000 has been conventionally used, and a PGA having this molecular weight range is used in the present invention. This is also possible.
[0039] 本発明に用いる PGAは、任意の公知の製造方法で製造され得る。例えば、上記特 許文献 1に記載された方法などが使用可能である。  [0039] The PGA used in the present invention can be produced by any known production method. For example, the method described in Patent Document 1 above can be used.
[0040] (ポリアミン） [0040] (Polyamine)
本願明細書において、ポリアミンとは、アミノ基を複数有する化合物を言う。アミノ基 は 1級ァミノ基（一NH )であってもよぐ 2級ァミノ基（一 NH— )であってもよレヽ。 1級  In the present specification, polyamine refers to a compound having a plurality of amino groups. The amino group may be a primary amino group (1NH) or a secondary amino group (1NH-). 1st grade
2  2
ァミノ基が好ましい。ァミノ基の数は、特に限定されないが、 1つの好ましい実施形態 では分子内に 2つ（すなわち、ジァミン)である。  An amino group is preferred. The number of amino groups is not particularly limited, but in one preferred embodiment, there are two in the molecule (ie, diamine).
[0041] 好ましくは、ポリアミンは、アルキレンジァミンまたはポリエチレンィミンである。 [0041] Preferably, the polyamine is an alkylenediamine or polyethyleneimine.
[0042] アルキレンジァミンにおける炭素数は特に限定されない。好ましくは、 2以上である[0042] The number of carbon atoms in the alkylenediamine is not particularly limited. Preferably, it is 2 or more
。また、好ましくは 10以下であり、より好ましくは、 8以下であり、さらに好ましくは、 6以 下である。またアルキレンジァミン中のアルキレン基は、直鎖であってもよぐ分岐鎖 であってもよレ、。直鎖であることが好ましい。 . Further, it is preferably 10 or less, more preferably 8 or less, and further preferably 6 or less. The alkylene group in the alkylenediamine may be either a straight chain or a branched chain. A straight chain is preferred.
[0043] 具体的には、好ましいアルキレンジァミンとしては、 1， 2_エチレンジァミン、 1 , 3_ プロピレンジァミン、 1， 4_ブタンジァミン、 1 , 5 _ヘプタンジァミン、 1， 6—へキサン ジァミンなどが挙げられる。 Specifically, preferable alkylene diamines include 1,2_ethylene diamine, 1,3_propylene diamine, 1,4_butane diamine, 1,5_heptane diamine, 1,6-hexane diamine and the like. Is mentioned.
[0044] ポリエチレンイミンは、エチレンイミンを重合して得られるポリマーであって、従来公 知の任意のポリエチレンィミンが本発明の方法に使用可能である。好ましくは、 1級ァ ミン： 2級ァミン： 3級ァミンが 1： 2 : 1で含まれるポリマーである。 [0044] Polyethyleneimine is a polymer obtained by polymerizing ethyleneimine, and any conventionally known polyethyleneimine can be used in the method of the present invention. Preferably, Grade 1 Min: A secondary amine: A polymer containing tertiary amine in a ratio of 1: 2: 1.
[0045] ポリエチレンィミンの重量平均分子量は、特に限定されない。好ましくは、 100以上 であり、より好ましくは、 200以上であり、さらに好ましくは、 400以上であり、いっそう 好ましくは、 500以上であり、最も好ましくは、 600以上である。また、好ましくは 10万 以下であり、より好ましくは、 5万以下であり、さらに好ましくは 1万以下であり、最も好 ましくは 5000以下である。  [0045] The weight average molecular weight of polyethyleneimine is not particularly limited. Preferably, it is 100 or more, more preferably 200 or more, still more preferably 400 or more, even more preferably 500 or more, and most preferably 600 or more. Further, it is preferably 100,000 or less, more preferably 50,000 or less, further preferably 10,000 or less, and most preferably 5000 or less.
[0046] ポリエチレンィミンとしては、市販されているポリマーをそのまま使用することができ る。あるいは、公知の方法によりエチレンィミンから重合して得てもよい。  [0046] As polyethyleneimine, a commercially available polymer can be used as it is. Alternatively, it may be obtained by polymerization from ethyleneimine by a known method.
[0047] ポリアミンの使用量は、特に限定されないが、 PGA中のグルタミン酸残基 1モルに 対して、用いるポリアミンの 1級ァミノ基の合計が 0. 0001モル以上となるように配合さ れることが好ましぐ 0. 001モル以上がより好ましぐ 0. 003モル以上がさらに好まし く、特に好ましくは 0. 005モノレ以上である。また、 PGA中のグルタミン酸残基 1モル に対して、用いるポリアミンの 1級ァミノ基の合計が 1モル以下となることが好ましぐ 0 . 2モル以下がより好ましぐ 0. 1モル以下がさらに好ましぐ 0. 06モル以下がいっそ う好ましく、 0. 04モル以下が特に好ましい。  [0047] The amount of polyamine used is not particularly limited, but it may be blended so that the total of primary amino groups of the polyamine used is 0.0001 mol or more per 1 mol of glutamic acid residues in PGA. Preferred is 0.001 mol or more, more preferred 0.003 mol or more is more preferred, and particularly preferred is 0.005 monole or more. In addition, the total number of primary amine groups of the polyamine used is preferably 1 mol or less with respect to 1 mol of glutamic acid residue in PGA, 0.2 mol or less is more preferable, and 0.1 mol or less is more preferable. Further preferred is 0.06 mol or less, particularly preferred is 0.04 mol or less.
[0048] 重量基準では、 PGAlgに対して、用いるポリアミンの重量が 0· 00002g以上となる ように配合されることが好ましぐ 0. 0002g以上がより好ましぐ 0. 0005g以上がさら に好ましく、特に好ましくは 0. OOlg以上である。また、 PGAlgに対して、 0. 25g以 下となることが好ましぐ 0. 05g以下がより好ましぐ 0. 25g以下がさらに好ましぐ 0. 015g以下がいっそう好ましぐ 0. Olg以下が特に好ましい。  [0048] On a weight basis, it is preferable that the polyamine used is blended so that the weight of the polyamine used is 0.0002 g or more, more preferably 0.0002 g or more, and even more preferably 0.0005 g or more. Particularly preferably, it is not less than 0. OOlg. Also, it is preferable that the PGAlg is 0.25g or less. More preferably, 0.05g or less is more preferable. 0.25g or less is more preferable. 0.015g or less is more preferable. 0. Olg or less Is particularly preferred.
[0049] 用いるポリアミンの量が多すぎる場合には、架橋密度が高くなりやすぐ膨潤度の低 レ、 PGAゲルが得られやすい。用いるポリアミンの量が少なすぎる場合には、架橋密 度が低くなりやすぐゲルの状態が得られにくくなる可能性がある。  [0049] When the amount of polyamine used is too large, the crosslink density becomes high and the swelling degree is low, and a PGA gel is easily obtained. If the amount of polyamine used is too small, the crosslink density may be lowered and it may be difficult to obtain a gel state immediately.
[0050] (水溶性カルポジイミド）  [0050] (Water-soluble carpositimide)
本発明の方法においては、縮合剤として、水溶性カルポジイミドを用いる。本願明 細書において、水溶性力ノレポジイミドとは、分子内にカルポジイミド基（_N = C = N 一）を有する化合物であって、水溶性を有する化合物をいう。なお、本願明細書中で は、水溶性カルポジイミドを WSCとも記載する。本発明に使用可能な WSCの具体例 としては、例えば、 1ーェチルー 3—（3—ジメチルァミノプロピル）一カルポジイミドま たはその塩、 1—シクロへキシル 3— (2—モルホリノエチル）カルボジイミドーメト一 p トルエン硫酸またはその塩などが挙げられる。 1—ェチル— 3— (3—ジメチルアミ ノプロピル）カルボジイミド塩酸塩（EDC)、または 1—シクロへキシル _ 3_ (2—モノレ ホリノエチル)カルポジイミド—メト _p—トルエン硫酸塩 (CMC)が好ましく使用可能 である。 In the method of the present invention, water-soluble carpositimide is used as the condensing agent. In the specification of the present application, the water-soluble force-repositimide means a compound having a carpositimide group (_N = C = N 1) in the molecule and having water solubility. In the present specification, water-soluble carpositimide is also referred to as WSC. Specific examples of WSC that can be used in the present invention For example, 1-ethyl-3- (3-dimethylaminopropyl) monocarbodiimide or a salt thereof, 1-cyclohexyl 3- (2-morpholinoethyl) carbodiimido-metho-toluene sulfate or a salt thereof, and the like. Can be mentioned. 1-Ethyl- 3 — ( 3 —Dimethylaminopropyl) carbodiimide hydrochloride (EDC) or 1-cyclohexyl _ 3_ (2-mono-reinoethyl) carbopositimide-meth _p-toluene sulfate (CMC) can be preferably used .
[0051] WSCの使用量は、特に限定されないが、使用されるポリアミン 1モルに対して、 2モ ル以上が好ましぐ 3モル以上がより好ましぐ 6モル以上がさらに好ましぐ 12モル以 上がいつそう好ましぐ 24モル以上が特に好ましレ、。また、使用されるポリアミン 1モル に対して、 50モル以下が好ましぐ 40モル以下がより好ましぐ 30モル以下がさらに 好ましい。  [0051] The amount of WSC used is not particularly limited, but 2 moles or more is preferred, 3 moles or more is more preferred, 6 moles or more is more preferred, 12 moles per mole of polyamine used. More than 24 moles are especially preferred. In addition, with respect to 1 mol of the polyamine used, 50 mol or less is preferable, 40 mol or less is more preferable, and 30 mol or less is more preferable.
[0052] また、 WSCの使用量は、上述したとおり、ポリアミンの量を基準として決定すること が好ましいが、 PGAの量を基準とした場合の配合量の目安としては、 PGA中のダル タミン酸残基 1モルに対して、 0. 001モル以上が好ましぐ 0. 01モル以上がより好ま しぐ 0. 03モル以上がさらに好ましぐ 0. 06モル以上が特に好ましい。また、 PGA 中のグルタミン酸残基 1モルに対して、 1モル以下が好ましぐ 0. 3モル以下がより好 ましく、 0. 1モル以下がさらに好ましい。  [0052] Further, as described above, the amount of WSC used is preferably determined based on the amount of polyamine. However, as a guideline of the blending amount based on the amount of PGA, the amount of dartamic acid in PGA is used. 0.001 mol or more is preferable with respect to 1 mol of the residue, 0.01 mol or more is more preferable 0.03 mol or more is more preferable 0.06 mol or more is particularly preferable. Further, 1 mol or less is preferable with respect to 1 mol of glutamic acid residues in PGA, 0.3 mol or less is more preferable, and 0.1 mol or less is more preferable.
[0053] (N ヒドロキシイミド）  [0053] (N-hydroxyimide)
本発明の方法に用いる N ヒドロキシイミドは、分子内に N ヒドロキシイミド基： (C = 0) (N-OH) (C = 0)  The N hydroxyimide used in the method of the present invention has an N hydroxyimide group in the molecule: (C = 0) (N-OH) (C = 0)
を有する化合物である。すなわち、この化合物は、以下の一般式で表される。  It is a compound which has this. That is, this compound is represented by the following general formula.
RA- (C = 0) - (N-OH) - (C = 0) -RB R A- (C = 0)-(N-OH)-(C = 0) -R B
ここで、 RAおよび RBが結合することにより、環構造が形成されてもよい。 RAおよび R Bが結合して RAおよび RB中の 2つの炭素と N—ヒドロキシイミド基とで 5員環を形成し た化合物が好ましい。また、 N-ヒドロキシイミドは、水溶性であることが好ましい。 Here, R A and R B may be combined to form a ring structure. A compound in which R A and RB are bonded to form a 5-membered ring with two carbons in R A and R B and an N-hydroxyimide group is preferred. N-hydroxyimide is preferably water-soluble.
[0054] 本発明に使用可能な N—ヒドロキシイミドの具体例としては、以下の化合物が例示 される： [0054] Specific examples of N-hydroxyimide that can be used in the present invention include the following compounds:
N—ヒドロキシコハク酸イミド、 N—ヒドロキシマレイン酸イミド、 N-hydroxysuccinimide, N-hydroxymaleimide
N—ヒドロキシへキサヒドロフタル酸イミド、  N-hydroxyhexahydrophthalic imide,
N, Ν' ージヒドロキシシクロへキサンテトラカルボン酸イミド、  N, Ν'-dihydroxycyclohexanetetracarboxylic imide,
Ν—ヒドロキシフタル酸イミド、  Ν-hydroxyphthalimide
Ν—ヒドロキシテトラブロモフタル酸イミド、  Ν-hydroxytetrabromophthalimide,
Ν—ヒドロキシへット酸イミド、 Ν-Hydroxyhetacid imide,
Ν—ヒドロキシハイミック酸イミド、  Ν—Hydroxyhymic acid imide,
Ν—ヒドロキシトリメリット酸イミド、  Ν-hydroxytrimellitic acid imide,
Ν, N' —ジヒドロキシピロメリット酸イミド、  Ν, N '— Dihydroxypyromellitic imide,
N， N' —ジヒドロキシナフタレンテトラカルボン酸イミド  N, N '—Dihydroxynaphthalenetetracarboxylic imide
Ν—ヒドロキシイミドは、市販の試薬をそのまま使用することが可能であり、また、従 来公知の合成方法により合成してもよレヽ。例えば、特開 2002— 47270号方法に記 載の方法で合成してもよい。  Ν-Hydroxyimide may be a commercially available reagent, or may be synthesized by a conventionally known synthesis method. For example, it may be synthesized by the method described in JP 2002-47270 A.
[0055] Ν—ヒドロキシイミドの中でも、 Ν—ヒドロキシコハク酸イミドが最も好ましい。 [0055] Among Ν-hydroxyimides, ヒ ド ロ キ シ -hydroxysuccinimide is most preferable.
[0056] Ν—ヒドロキシコハク酸イミドとしては、市販されている試薬などをそのまま使用する こと力 Sできる。なお、本明細書中においては、 Ν—ヒドロキシコハク酸イミドを NHSとも いう。 [0056] As Ν-hydroxysuccinimide, a commercially available reagent can be used as it is. In the present specification, Ν-hydroxysuccinimide is also referred to as NHS.
[0057] Ν—ヒドロキシイミドの使用量は、特に限定されないが、使用されるポリアミン 1モル に対して、 2モル以上が好ましぐ 3モル以上がより好ましぐ 6モル以上がさらに好ま しぐ 12モル以上がいっそう好ましぐ 24モル以上が特に好ましい。また、使用される ポリアミン 1モルに対して、 50モル以下が好ましぐ 40モル以下がより好ましぐ 30モ ル以下がさらに好ましい。  [0057] The amount of イ ミ ド -hydroxyimide used is not particularly limited, but 2 mol or more is preferable, 3 mol or more is more preferable, and 6 mol or more is more preferable with respect to 1 mol of the polyamine used. More than 12 mol is more preferable. More than 24 mol is particularly preferable. Further, with respect to 1 mol of the polyamine used, 50 mol or less is preferable, 40 mol or less is more preferable, and 30 mol or less is more preferable.
[0058] また、 Ν—ヒドロキシイミドの使用量は、使用される WSCの量と等モルとすることが好 ましい。  [0058] In addition, the amount of ヒ ド ロ キ シ -hydroxyimide used is preferably equimolar to the amount of WSC used.
[0059] また、 Ν—ヒドロキシイミドの使用量は、上述したとおり、ポリアミンの量を基準として 決定することが好ましいが、 PGAの量を基準とした場合の配合量の目安としては、 Ρ GA中のグルタミン酸残基 1モルに対して、 0. 001モル以上が好ましぐ 0. 01モル以 上がより好ましぐ 0. 03モル以上がより好ましぐ 0. 06モル以上が特に好ましい。ま た、 PGA中のグルタミン酸残基 1モルに対して、 1モル以下が好ましぐ 0. 3モル以 下がより好ましぐ 0. 1モル以下がより好ましい。 [0059] Further, as described above, the amount of Ν-hydroxyimide used is preferably determined based on the amount of polyamine. However, as a guideline of the blending amount based on the amount of PGA, 中0.001 mol or more is preferable with respect to 1 mol of glutamic acid residue of 0.01 mol or less More preferable is 0.03 mol or more, and more preferable is 0.06 mol or more. In addition, 1 mol or less is preferable with respect to 1 mol of glutamic acid residue in PGA, 0.3 mol or less is more preferable, and 0.1 mol or less is more preferable.
[0060] (溶媒） [0060] (Solvent)
本発明の方法においては、溶媒は特に限定されなレ、。好ましくは、水である。  In the method of the present invention, the solvent is not particularly limited. Preferably, it is water.
[0061] (その他の成分） [0061] (Other ingredients)
本発明の方法は、好ましくは、上記の各材料のみを用いて溶媒中で行われる。しか し、上記の各材料に加えて、必要に応じて、公知の添加剤等を適当量を配合しても よい。  The method of the present invention is preferably carried out in a solvent using only the above materials. However, in addition to each of the above materials, an appropriate amount of a known additive or the like may be blended as necessary.
[0062] 具体的には、たとえば、 WSCおよび NHS以外の縮合剤、縮合補助剤、触媒、充填 材、着色料 (顔料または染料)、補強剤 (例えば、繊維)、酸化防止剤、離型剤、溶媒 、増粘剤などを用途に応じて添加することができる。  [0062] Specifically, for example, condensing agents other than WSC and NHS, condensation aids, catalysts, fillers, colorants (pigments or dyes), reinforcing agents (for example, fibers), antioxidants, release agents A solvent, a thickener and the like can be added depending on the application.
[0063] (架橋反応条件）  [0063] (Crosslinking reaction conditions)
架橋反応の条件は特に限定されない。室温でもよぐ加温してもよい。ただし、温度 が低すぎる場合には、硬化反応に極めて長時間を有するので、加熱を行うことが好ま しい。架橋反応の際の温度は、具体的には、好ましくは、 10°C以上であり、より好まし くは、 15°C以上であり、さらに好ましくは、 20°C以上である。また、好ましくは、 100°C 以下であり、より好ましくは、 50°C以下である。高すぎる場合には、 PGAが分解しや すレ、。従って室温付近で行うことが好ましい。  The conditions for the crosslinking reaction are not particularly limited. It may be warmed at room temperature. However, if the temperature is too low, the curing reaction takes a very long time, so heating is preferred. Specifically, the temperature during the crosslinking reaction is preferably 10 ° C or higher, more preferably 15 ° C or higher, and further preferably 20 ° C or higher. Also, it is preferably 100 ° C or lower, more preferably 50 ° C or lower. If it is too high, the PGA will break down. Therefore, it is preferable to carry out at around room temperature.
[0064] 架橋反応の際の pHは特に限定されないが、好ましくは 6以上であり、より好ましくは 7以上である。また、好ましくは 11以下であり、より好ましくは 10以下である。  [0064] The pH in the crosslinking reaction is not particularly limited, but is preferably 6 or more, more preferably 7 or more. Further, it is preferably 11 or less, more preferably 10 or less.
[0065] (手順）  [0065] (Procedure)
上述した各反応材料（PGA、ポリアミン、 WSCおよび N—ヒドロキシイミド）を溶媒中 で架橋反応させることにより、 PGAが架橋したゲルが得られる。各材料の投入順序は 特に限定されず、すべての材料を一度に投入してもよぐ各材料を任意の順序で投 入してもょレ、が、好ましくは、 WSCの投入を最後に行う。すなわち、 PGA、ポリアミン および N—ヒドロキシイミドを含む反応溶液を調製した後に WSCを添加することが、 収率の点で好ましレ、。 N—ヒドロキシイミドの添加の後、 WSCを添加するまでの時間 を 1分以上とすることが好ましぐより好ましくは、 5分以上であり、さらに好ましくは 10 分以上である。また、好ましくは 3時間以下であり、より好ましくは 1時間以下であり、さ らに好ましくは 30分以下である。 By cross-linking the above-mentioned reaction materials (PGA, polyamine, WSC and N-hydroxyimide) in a solvent, a gel in which PGA is cross-linked is obtained. The order in which the materials are charged is not particularly limited, and all materials may be charged at once, or the materials may be charged in any order. Preferably, the WSC is charged last. . That is, it is preferable in terms of yield to add WSC after preparing a reaction solution containing PGA, polyamine and N-hydroxyimide. Time from the addition of N-hydroxyimide to the addition of WSC More preferably, it is 5 minutes or more, and more preferably 10 minutes or more. Further, it is preferably 3 hours or less, more preferably 1 hour or less, and further preferably 30 minutes or less.
[0066] 反応材料がすべて投入されると、架橋反応がスタートする。架橋反応の際の反応時 間は、架橋反応を十分に行うためには、好ましくは、 5分間以上であり、より好ましくは 、 10分間以上であり、さらに好ましくは、 20分間以上であり、レ、つそう好ましくは、 30 分間以上であり、特に好ましくは、 1時間以上である。ただし、プロセス全体の長さを 短縮するためには、好ましくは、 5日以下であり、より好ましくは、 2日以下であり、さら に好ましくは、 1日以下である。レ、つそう好ましくは、 12時間以下である。特に好ましく は、 6時間以下である。 [0066] When all of the reaction materials are charged, the crosslinking reaction starts. The reaction time for the crosslinking reaction is preferably 5 minutes or more, more preferably 10 minutes or more, and further preferably 20 minutes or more in order to sufficiently perform the crosslinking reaction. It is preferably 30 minutes or more, particularly preferably 1 hour or more. However, in order to shorten the overall length of the process, it is preferably 5 days or less, more preferably 2 days or less, and even more preferably 1 day or less. More preferably, it is 12 hours or less. Particularly preferably, it is 6 hours or less.
[0067] 架橋反応の際には、必要に応じて、反応溶液を攪拌してもよぐ静置しておいてもよ レ、。好ましくは、静置しておく。  [0067] During the cross-linking reaction, the reaction solution may be stirred or allowed to stand as necessary. Preferably, it is left still.
[0068] 架橋反応に充分な時間が経過した後、反応溶液中にゲルが得られる。この反応溶 液を水（好ましくは蒸留水）で洗うことにより、反応溶液中の WSCおよび N—ヒドロキ シイミドが除去され、 PGAがポリアミンで架橋されたゲルが得られる。  [0068] After a sufficient time for the crosslinking reaction has elapsed, a gel is obtained in the reaction solution. By washing this reaction solution with water (preferably distilled water), WSC and N-hydroxyimide in the reaction solution are removed, and a gel in which PGA is crosslinked with polyamine is obtained.
[0069] (生成物）  [0069] (Product)
上述した方法により得られたゲルは、 PGAにポリアミンが架橋した構造を有する。 WSCおよび N—ヒドロキシイミドは、最終的に得られるゲル中には実質的に存在しな レ、。得られるゲル中の、ポリアミン残基のモル数は、グルタミン酸残基のモル数とポリ ァミン残基のモル数との和に対して、 15%以下とすることが好ましぐ 10%以下がより 好ましぐ 5%以下がさらに好ましぐ 3%以下がいっそう好ましぐ 1 %以下が特に好 ましレ、。また、 0. Ο01。/ο以上が好ましぐ 0. Ο1。/ο以上がより好ましぐ 0. 1%以上が さらに好ましレ、。  The gel obtained by the above-described method has a structure in which polyamine is crosslinked to PGA. WSC and N-hydroxyimide are substantially absent in the final gel. In the obtained gel, the number of moles of polyamine residues is preferably 15% or less, more preferably 10% or less, relative to the sum of the number of moles of glutamic acid residues and the number of moles of polyamine residues. 5% or less is more preferable 3% or less is more preferable 1% or less is particularly preferable. And 0. Ο01. More than / ο is preferred 0. Ο1. More than / ο is more preferable 0. More than 1% is more preferable.
[0070] (ヒドロゲルの製造）  [0070] (Production of hydrogel)
上述した方法により得られたゲルは、水をカ卩えることにより、ヒドロゲルの形態になる 。用途に応じて必要量の水を含ませたヒドロゲル製品とすることが可能である。  The gel obtained by the above-described method becomes a hydrogel form by water. It is possible to obtain a hydrogel product containing a necessary amount of water depending on the application.
[0071] (性能）  [0071] (Performance)
本発明のゲルは、優れた膨潤度を示す。例えば、室温で 2日間、蒸留水中に浸漬 させた後のゲル膨潤度が 1000倍以上のゲルを得ることが可能であり、配合を適宜調 整することにより、 2000倍以上、 3000倍以上、 4000倍以上、 5000倍以上、 5500 倍以上または 6000倍以上の膨潤度を有するゲルが製造され得る。膨潤度は高けれ ば高いほど好ましいが、具体的には、例えば、 6500倍程度まで、あるいは 7000倍 程度までの膨潤度のゲルを得ることが可能である。 The gel of the present invention exhibits an excellent degree of swelling. For example, immersed in distilled water for 2 days at room temperature It is possible to obtain a gel with a degree of gel swelling of 1000 times or more after being applied, and by appropriately adjusting the composition, it is 2000 times or more, 3000 times or more, 4000 times or more, 5000 times or more, 5500 times or more A gel having a degree of swelling of 6000 times or more can be produced. The higher the degree of swelling, the better. However, specifically, for example, it is possible to obtain a gel having a degree of swelling of up to about 6500 times or up to about 7000 times.
[0072] (用途） [0072] (Application)
本発明のヒドロゲルは、幅広い分野における応用が期待される。例えば、化粧品分 野では、モイスチヤライザ一や保湿剤として使用することができる。農業用品や園芸 用品の分野では、土壌改質剤、種子被覆剤、植物栽培用の水分保持剤、動物の堆 肥用の固定剤、コンポスト添加剤、糞便や尿などに用いる加失剤として使用すること 力 Sできる。土木工事分野においては、水処理スラッジゃ下水スラッジ、河川下水道ス ラッジ用の水コンディショニング剤、固化剤、改質剤、凝固剤、あるいは貯水池用の 土壌として使用することができる。医療'衛生分野では血液や体液、紙おむつ、タン ボン用の吸収剤として、あるいはデオドラントや放出制御薬剤担体として使用すること ができる。バイオエンジニアリング分野では、微生物、植物細胞、または動物細胞を 培養するための培地基材として、あるいはバイオリアクターのための固定材として使 用すること力 Sできる。  The hydrogel of the present invention is expected to be applied in a wide range of fields. For example, in the cosmetic field, it can be used as a moisturizer or moisturizer. In the field of agricultural and horticultural supplies, it is used as a soil modifier, seed coating agent, moisture retention agent for plant cultivation, animal compost fixative, compost additive, and additive for faeces and urine. Doing power S. In the civil engineering field, water treatment sludge can be used as sewage sludge, water conditioning agent for river sewer sludge, solidifying agent, modifier, coagulant, or soil for reservoir. In the medical and hygiene field, it can be used as an absorbent for blood, body fluids, disposable diapers and tambons, or as a deodorant or controlled release drug carrier. In the field of bioengineering, it can be used as a medium substrate for culturing microorganisms, plant cells, or animal cells, or as a fixing material for bioreactors.
実施例  Example
[0073] (実施例:!〜 4 : 1 , 3— PDを架橋剤に用いた PGA架橋物の調製）  [0073] (Examples:! To 4: 1, 3-—Preparation of a PGA crosslinked product using PD as a crosslinking agent)
以下に、 1 , 3_プロピレンジァミンを用いた実施例を説明する。  Hereinafter, examples using 1,3_propylenediamine will be described.
[0074] (実施例 1) [Example 1]
水 3mLに 0. 453gの PGAのナトリウム塩（PGANa)および 120 z Lの 1 , 3— PD水 溶液 [0. 1853g/l0mL ( = 0. 25mmol/mL) ] ( = 2. 2236mg相当）を入れ、ゆ つくりと 30分程度攪拌することで溶解させ、そこへ lmLの水に溶解させた 0. 0207g の NHSを添カロした。 15分経過後、 0. 88mLの水に溶角军させた 0. 0346gの WSCを 添加することで PGA架橋物を調製した。なお、 PGA架橋物に含まれる水の全量を 5 mLとした。  Add 0.353 g of PGA sodium salt (PGANa) and 120 zL of 1,3—PD water solution [0.1853 g / l0mL (= 0.25 mmol / mL)] (= 2.2236 mg equivalent) to 3 mL of water Then, it was dissolved by stirring for about 30 minutes, and 0.0207 g of NHS dissolved in 1 mL of water was added thereto. After 15 minutes, a PGA cross-linked product was prepared by adding 0.0346 g of WSC that had been dissolved in 0.88 mL of water. The total amount of water contained in the cross-linked PGA was 5 mL.
[0075] 架橋反応を十分に進行させた（一日間）後、 2Lの蒸留水に浸漬させ、途中で水の 交換をしながらゲルを膨潤させた。 （一日間)膨潤により架橋剤が除去された状態の ゲルを凍結乾燥することで、ゲル膨潤度およびゲル収率を測定したところ、それぞれ[0075] The crosslinking reaction was allowed to proceed sufficiently (one day), and then immersed in 2 L of distilled water. The gel was swollen while being exchanged. The gel swelling degree and the gel yield were measured by lyophilizing the gel from which the crosslinking agent was removed by swelling (one day).
780倍および 97%であった。また、十分な膨潤を行うために蒸留水中に 2日間浸漬 させた場合のゲル膨潤度およびゲル収率はそれぞれ 6620倍および 92%であった。 また、得られたゲルの物性評価を行った結果、粘弾性測定より求めたゲル化時間（弾 性率と粘性率がクロスオーバーするまでの時間）は 7. 8分、定常状態のゲル弾性率 G 'は 130Paであった。圧縮試験の結果からは初期弾性率 Eが求まり、 1. 9kPaであ 780 times and 97%. The gel swelling degree and gel yield were 6620 times and 92%, respectively, when immersed in distilled water for 2 days to achieve sufficient swelling. In addition, as a result of evaluating the physical properties of the obtained gel, the gelation time (time until elasticity and viscosity crossover over) obtained from viscoelasticity measurement was 7.8 minutes, and the gel elastic modulus in steady state G 'was 130Pa. The initial elastic modulus E is obtained from the result of the compression test and is 1.9 kPa.
0  0
つた。  I got it.
[0076] 上述したとおり、ほぼ 100%に近い収率でゲルが得られたことから、得られたゲルの 組成は、当然に、出発原料中の PGAおよび 1 , 3— PDの配合比がほぼそのままゲル の組成になっていると考えられる。すなわち、ゲル中の 1， 3— PD残基は、約 1 %であ ること力 S理角军される。  [0076] As described above, since the gel was obtained with a yield of almost 100%, the composition of the obtained gel naturally had a blending ratio of PGA and 1,3-PD in the starting material of about The gel composition is considered as it is. In other words, it is assumed that the 1,3-PD residue in the gel is about 1%.
[0077] すなわち、非特許文献 1の技術では得ることが不可能な架橋剤密度の低いゲルが 実施例 1におレ、て得られたことがわかった。  That is, it was found that a gel having a low crosslinker density that cannot be obtained by the technique of Non-Patent Document 1 was obtained in Example 1.
[0078] (実施例 1A) [0078] (Example 1A)
実施例 1における分子量 200万の PGAの代わりに重量平均分子量 50万の PGAを 用いてゲル架橋物を調製した。その結果、ゲル膨潤度およびゲル収率はそれぞれ 2 A gel cross-linked product was prepared using PGA having a weight average molecular weight of 500,000 instead of PGA having a molecular weight of 2 million in Example 1. As a result, the gel swelling degree and the gel yield were 2 respectively.
440倍および 79%であった。 440 times and 79%.
[0079] (実施例 1A' ) [0079] (Example 1A ')
実施例 1Aにおいて、 1 , 3— PD水溶液の配合量を 240 /i L ( =4. 4472mg相当） に変更し、それ以外は実施例 1Aと同様に実験を行った。その結果、良好なゲル架 橋物が得られた。  In Example 1A, the amount of 1,3-PD aqueous solution was changed to 240 / i L (= 4.4472 mg equivalent), and the experiment was performed in the same manner as in Example 1A except that. As a result, a good gel bridge was obtained.
[0080] 上記背景技術の項に説明したとおり、非特許文献 1における収率は、数％〜10% 程度に過ぎなかったのである。この従来技術と比較すれば、上記実施例 1における 9 7%というゲル収率、および実施例 1Aにおける 79%というゲル収率は、従来技術か らとても予想され得なレ、、極めて高い収率であることが理解される。  [0080] As explained in the background section above, the yield in Non-Patent Document 1 was only about several percent to 10%. Compared to this prior art, the gel yield of 97% in Example 1 above and 79% in Example 1A are very unpredictable from the prior art, very high yields. It is understood that
[0081] しかも、そもそも、非特許文献 1においては、 1 , 3— PDの添カ卩量が少ない場合には 、ゲルを得ることはできなかったのである。具体的には、例えば、 PGAl OOmgに対し て、 1 , 3—？0を10 /1 1^ (約9 ^、 PGA100重量部に対して約 9重量部）添加した場 合に、ゲルを得ることはできなかったのである。すなわち、収率は 0%である。他方、 上記実施例 1および実施例 1Aにおいては、 PGA100重量部に対して 1 , 3— PDを わずか 1重量部添カ卩した配合において 97%および 79%の収率でゲルが得られてお り、これは驚くべき高収率であると評価する以外にはない。 In addition, in Non-patent Document 1, when the amount of 1,3-PD added is small, a gel cannot be obtained. Specifically, for example, for PGAl OOmg 1, 3—? When 0 was added to 10/1 1 ^ (about 9 ^, about 9 parts by weight with respect to 100 parts by weight of PGA), a gel could not be obtained. That is, the yield is 0%. On the other hand, in Example 1 and Example 1A above, gels were obtained in yields of 97% and 79% in a composition in which only 1 part by weight of 1,3-PD was added to 100 parts by weight of PGA. This is nothing but to evaluate the surprisingly high yield.
[0082] (実施例 1 B)  [0082] (Example 1 B)
実施例 1におレ、て、分子量： 200万の PGAの代わりに重量平均分子量 500万の P GAを用いてゲル架橋物を調製した。その結果、良好なゲル架橋物が得られた。  In Example 1, a gel cross-linked product was prepared using PGA having a weight average molecular weight of 5 million instead of PGA having a molecular weight of 2 million. As a result, a good gel cross-linked product was obtained.
[0083] (実施例 1 B ' )  [0083] (Example 1 B ')
実施例 1Bにおいて、 1， 3— PD水溶液の配合量を 240 ( = 4. 4472mg相当） に変更し、それ以外は実施例 1Bと同様に実験を行った。その結果、良好なゲル架橋 物が得られた。  In Example 1B, the amount of the 1,3-PD aqueous solution was changed to 240 (= 4.4472 mg equivalent), and the experiment was performed in the same manner as in Example 1B except that. As a result, a good gel crosslinked product was obtained.
[0084] (実施例 2)  [0084] (Example 2)
水 3mLに 0. 453gの PGANa [分子量： 200万]および実施例 1での 120 Lの代 わりに 240 /i Lの 1, 3— PD水溶液 [0. 1853g/10mL ( = 0. 25mmol/mL) ] (= 4. 4472mg相当）を入れ、室温でゆっくりと 30分程度攪拌することで溶解させ、そこ へ lmLの水に溶角军させた 0. 0207gの NHSを添カロした。 15分経過後、 0. 76mLの 水に溶解させた 0. 0346gの WSCを添加することで PGA架橋物を調製した。なお、 PGA架橋物に含まれる水の全量を 5mLとした。架橋反応を十分に進行させた（一日 間）後、 2Lの蒸留水に浸漬させ、途中で水の交換をしながらゲルを十分に膨潤させ た。 (2日間) S彭潤により架橋剤が除去された状態のゲルを凍結乾燥することで、ゲル 膨潤度およびゲル収率を測定したところ、それぞれ 2400倍および 95%であった。ま た、得られたゲルの物性評価を行った結果、粘弾性測定より求めたゲル化時間（弾 性率と粘性率がクロスオーバーするまでの時間）は 7. 7分、定常状態のゲル弾性率 G'は 590Paであった。圧縮試験の結果からは初期弾性率 Eが求まり、 2. 6kPaであ  0.453 g of PGANa [molecular weight: 2 million] in 3 mL of water and 240 / i L of 1,3-PD aqueous solution instead of 120 L in Example 1 [0.1853 g / 10 mL (= 0.25 mmol / mL) ] (= 4.4 4472 mg equivalent) was added and dissolved by slowly stirring at room temperature for about 30 minutes, and 0.0207 g of NHS dissolved in 1 mL of water was added thereto. After 15 minutes, a PGA cross-linked product was prepared by adding 0.0346 g WSC dissolved in 0.76 mL water. The total amount of water contained in the PGA cross-linked product was 5 mL. After allowing the crosslinking reaction to proceed sufficiently (for one day), it was immersed in 2 L of distilled water, and the gel was sufficiently swollen while exchanging water along the way. (2 days) The gel swelling degree and the gel yield were measured by freeze-drying the gel from which the cross-linking agent had been removed by S-junction, and they were 2400 times and 95%, respectively. In addition, as a result of evaluating the physical properties of the obtained gel, the gelation time obtained from the viscoelasticity measurement (time until the elasticity and viscosity crossover) was 7.7 minutes, and the gel elasticity in a steady state. The rate G 'was 590Pa. The initial elastic modulus E is obtained from the result of the compression test and is 2.6 kPa.
0  0
つた。  I got it.
[0085] (実施例 3)  [0085] (Example 3)
水 3mLに 0. 453gの PGANa [分子量： 200万]および実施例 1での 120 x Lの代 わりに 60 /i Lの 1, 3— PD水溶液 [0. 1853g/10mL ( = 0. 25mmol/mL) ] (= 1 . 1118mg相当）を入れ、室温でゆっくりと 30分程度攪拌することで溶解させ、そこへ lmLの水に溶角军させた 0. 0207gの NHSを添カロした。 15分経過後、 0. 76mLの水 に溶解させた 0. 0346gの WSCを添カ卩することで PGA架橋物を調製した。また、得 られたゲルの物性評価を行った結果、粘弾性測定より求めたゲルィヒ時間（弾性率と 粘性率がクロスオーバーするまでの時間）は 11分、定常状態のゲル弾性率 G'は 52 Paであった。圧縮試験の結果からは初期弾性率 Eが求まり、 0. 24kPaであった。 0.45 g of PGANa [molecular weight: 2 million] in 3 mL of water and the amount of 120 x L in Example 1 Instead, add 60 / i L of 1,3-PD aqueous solution [0.18553g / 10mL (= 0.25mmol / mL)] (= 1.1118mg equivalent) and dissolve it by slowly stirring for 30 minutes at room temperature. Then, 0.0207 g of NHS dissolved in 1 mL of water was added thereto. After 15 minutes, a PGA cross-linked product was prepared by adding 0.0346 g of WSC dissolved in 0.76 mL of water. In addition, as a result of evaluating the physical properties of the obtained gel, the Gelich time (time until the elastic modulus and the viscosity crossover) obtained from viscoelasticity measurement was 11 minutes, and the gel elastic modulus G ′ in the steady state was 52 Pa. From the result of the compression test, the initial elastic modulus E was obtained and was 0.24 kPa.
0  0
[0086] (実施例 4)  [0086] (Example 4)
水 3mLに 0. 453gの PGANa [分子量： 200万]および実施例 1での 120 しの代ゎり（こ30 しの1， 3— PD水溶 f夜 [0. 1853g/l0mL ( = 0. 25mmol/m L) ] ( = 0. 5559mg相当）を入れ、室温でゆっくりと 30分程度攪拌することで溶解さ せ、そこへ lmLの水に溶角军させた 0. 0207gの NHSを添カロした。 15分経過後、 0. 7 6mLの水に溶解させた 0. 0346gの WSCを添加することで PGA架橋物を調製した。 また、得られたゲルの物性評価を行った結果、粘弾性測定より求めたゲル化時間（弾 性率と粘性率がクロスオーバーするまでの時間）は 16分、定常状態のゲル弾性率 G 'は 20Paであった。  0.45 g of PGANa [molecular weight: 2 million] in 3 mL of water and 120 substitutions in Example 1 (30, 1, 3- PD aqueous solution at night [0. 1853 g / l0 mL (= 0.25 mmol / m L)] (= 0.5559 mg equivalent) was added, dissolved by slowly stirring at room temperature for about 30 minutes, and 0.0207 g of NHS dissolved in 1 mL of water was added thereto. After 15 minutes, PGA cross-linked product was prepared by adding 0.0346 g WSC dissolved in 0.7 6 mL water, and physical properties of the obtained gel were evaluated. The determined gel time (time until elasticity and viscosity crossover) was 16 minutes, and the gel elastic modulus G ′ in the steady state was 20 Pa.
[0087] 上記実施例:!〜 4の配合を以下の表に示す。  [0087] Formulations of the above examples:! To 4 are shown in the following table.
[0088] [表 2] [0088] [Table 2]
調製条件 Preparation conditions
Figure imgf000017_0001
a) 0. 01853g/mL ( = 0. 25mmolZmU水溶液を調製の上、添加した。
Figure imgf000017_0001
a) 0.01853 g / mL (= 0.25 mmol ZmU aqueous solution was prepared and added.
b) c)水溶液とした上で添加することで、全量が反応に関与するようにした。  b) c) The solution was added in the form of an aqueous solution so that the entire amount was involved in the reaction.
d) 溶媒の全量  d) Total amount of solvent
* ) PGANaのモル数はモノマーユニット換算。  *) The number of moles of PGANa is in terms of monomer units.
[0089] PGAの分子量は、重量平均分子量である。 [0089] The molecular weight of PGA is a weight average molecular weight.
[0090] 上述したとおり、特段の pH調節の作業を行わなかったが、ゲルの調製を再現性よく 且つ収率良く行うことが可能であった。  [0090] As described above, no particular pH adjustment work was performed, but it was possible to prepare the gel with good reproducibility and high yield.
[0091] 以下の表に、上記実施例 1 1Aおよび 1Bのゲルィヒ時間、弾性率等の測定結果を 示す [0091] The following table shows the measurement results of Examples 1 1A and 1B, such as the Gerich time and the elastic modulus.
[0092] [表 3] 1 , 3-POを架橋剤に用いた高分子量 PGA架橋物の物性 PGA分子量の影響 [0092] [Table 3] Properties of high molecular weight PGA crosslinked products using 1, 3-PO as crosslinker Effect of PGA molecular weight
架橋剤： 1 , 3-PD
Figure imgf000018_0001
a)架橋反応開始後、十分な時間（1日程度)放置したものをサンプルとして使用。弾 性率測定の際に周波数依存がないことを確認の上、 1Hzの周波数を用いてレオメー ターにより測定した。 Cross-linking agent: 1, 3-PD
Figure imgf000018_0001
a) Use a sample left for a sufficient time (about 1 day) after the start of the crosslinking reaction. After confirming that there was no frequency dependence when measuring the elasticity, we measured with a rheometer using a frequency of 1 Hz.
[0093]  [0093]
(考察）  (Discussion)
上記実験結果から、以下のことが理解される。  The following can be understood from the above experimental results.
[0094] 架橋剤量により、ゲルィヒ時間の制御が可能である。 [0094] The Gerich time can be controlled by the amount of the crosslinking agent.
[0095] ゲルィ匕時間に対しては PGA分子量よりも架橋剤量の影響が大きい。 [0095] The gelling time is more influenced by the amount of the crosslinking agent than the PGA molecular weight.
[0096] 弾性率測定結果より、架橋剤量および PGA分子量の増加に伴った架橋物強度の 上昇が確認された（すなわち、同じ架橋物強度のためには、高分子量 PGAを用いれ ば架橋剤濃度を低下させることが出来る)。 [0096] From the results of the elastic modulus measurement, it was confirmed that the strength of the cross-linked product increased as the amount of the cross-linking agent and the PGA molecular weight increased. Can be reduced).
[0097] 圧縮試験結果より導いた初期弾性率の変化はレオメーターを用いて測定した粘弾 性測定結果と高レ、相同性を示した。 [0097] The change in the initial elastic modulus derived from the compression test result showed high resemblance with the viscoelasticity measurement result measured using a rheometer.
[0098] (比較例 1) [0098] (Comparative Example 1)
NHSを添加しなかった以外は実施例 1と同様に実験を行った。しかし、架橋物は得 られず、収率は 0%であった。  The experiment was performed in the same manner as in Example 1 except that NHS was not added. However, no cross-linked product was obtained, and the yield was 0%.
[0099] (比較例 2) [0099] (Comparative Example 2)
比較例 1において、反応液の pHを 6に調整した以外は、比較例 1と同様に実験を 行った。 WSCは pH約 6程度で活性が高くなることが知られているため、 pHを調節し た。その結果、反応溶液の粘度は上昇したが、架橋物は得られず、収率は 0。 /。であ つた。  In Comparative Example 1, the experiment was performed in the same manner as in Comparative Example 1, except that the pH of the reaction solution was adjusted to 6. Since WSC is known to have high activity at about pH 6, the pH was adjusted. As a result, the viscosity of the reaction solution increased, but no cross-linked product was obtained, and the yield was 0. /. It was.
[0100] (実施例 5〜9 : PEIを架橋剤に用いた高分子量 PGA架橋物の調製）  [0100] (Examples 5 to 9: Preparation of crosslinked high molecular weight PGA using PEI as a crosslinking agent)
以下に、ポリ（エチレンィミン)を用いた実施例を説明する。 [0101] (実施例 5) Hereinafter, examples using poly (ethyleneimine) will be described. [0101] (Example 5)
水 3mLに 0· 453gの PGANa (重量平均分子量： 200万）および 120 /i Lの ΡΕΙ ( 重量平均分子量: 600、和光純薬工業株式会社製、試薬グレード)水溶液 [0. 88g /l 0mL ( = 0. 25mmol/mL) ] ( = 2. 64mg相当）（PGAモノマーユニット換算に 対して 0. 25mol%の PEI)を入れ、ゆっくりと 30分程度攪拌することで溶解させ、そこ へ lmLの水に溶角军させた 0. 0207gの NHSを添カロした。 15分経過後、 0. 88mLの 水に溶解させた 0. 0346gの WSCを添加することで PGA架橋物を調製した。なお、 PGA架橋物に含まれる水の全量を 5mLとした。  0 · 453g of PGANa (weight average molecular weight: 2 million) and 120 / i L of 重量 (weight average molecular weight: 600, manufactured by Wako Pure Chemical Industries, Ltd., reagent grade) in 3 mL of water [0. 88 g / l 0 mL ( = 0.25 mmol / mL)] (= 2.64 mg equivalent) (0.25 mol% PEI in terms of PGA monomer unit), dissolve slowly by stirring for about 30 minutes, and then add 1 mL water Then, 0.0207 g of NHS that had been melted into the melt was added. After 15 minutes, a PGA cross-linked product was prepared by adding 0.0346 g WSC dissolved in 0.88 mL water. The total amount of water contained in the PGA cross-linked product was 5 mL.
[0102] また、得られたゲルの物性評価を行った結果、粘弾性測定より求めたゲルィ匕時間（ 弾性率と粘性率がクロスオーバーするまでの時間）は 2. 6分、定常状態のゲル弾性 率 G 'は 400Paであった。圧縮試験の結果からは初期弾性率 Eが求まり、 2. 3kPa  [0102] In addition, as a result of evaluating the physical properties of the obtained gel, the gel time obtained from viscoelasticity measurement (time until the elastic modulus and the viscosity crossover) is 2.6 minutes, and the gel in a steady state The elastic modulus G ′ was 400 Pa. The initial elastic modulus E is obtained from the result of the compression test, and 2.3 kPa
0  0
であった。  Met.
[0103] (実施例 6)  [0103] (Example 6)
水 3mLに 0· 453gの PGANa [重量平均分子量： 200万]および 120 /i Lの PEI ( 重量平均分子量： 1800、和光純薬工業株式会社製、試薬グレード)水溶液 [0. 88g /10mL ( = 0. 25mmol/mL) ] ( = 2. 64mg相当）（PGAモノマーユニット換算に 対して 0. 25mol%の PEI)を入れ、ゆっくりと 30分程度攪拌することで溶解させ、そこ へ lmLの水に溶角军させた 0. 0207gの NHSを添カロした。 15分経過後、 0. 88mLの 水に溶解させた 0. 0346gの WSCを添加することで PGA架橋物を調製した。なお、 PGA架橋物に含まれる水の全量を 5mLとした。また、得られたゲルの物性評価を行 つた結果、粘弾性測定より求めたゲル化時間（弾性率と粘性率がクロスオーバーする までの時間）は 2. 3分、定常状態のゲル弾性率 G 'は 200Paであった。  0 · 453g of PGANa [weight average molecular weight: 2 million] and 120 / i L of PEI (weight average molecular weight: 1800, manufactured by Wako Pure Chemical Industries, Ltd., reagent grade) in 3 mL of water [0.88g / 10mL (= 0. 25mmol / mL)] (= 2.64mg equivalent) (0.25mol% PEI in terms of PGA monomer unit), dissolve slowly by stirring for about 30 minutes, and add to 1mL water Add 0.020g NHS that had been melted. After 15 minutes, a PGA cross-linked product was prepared by adding 0.0346 g WSC dissolved in 0.88 mL water. The total amount of water contained in the PGA cross-linked product was 5 mL. In addition, as a result of evaluating the physical properties of the obtained gel, the gelation time obtained from viscoelasticity measurement (time until the elastic modulus and the viscosity crossover) was 2.3 minutes, and the gel elastic modulus G in the steady state G 'Was 200Pa.
[0104] (実施例 7)  [Example 7]
水 3mLに 0. 453gの PGANa [重量平均分子量： 200万]および 120 z Lの PEI ( 重量平均分子量： 10000、和光純薬工業株式会社製、試薬グレード)水溶液 [0. 88 g/l OmL ( = 0. 25mmol/mL) ] ( = 2. 64mg相当）（PGAモノマーユニット換算 に対して 0. 25mol%の PEI)を入れ、ゆっくりと 30分程度攪拌することで溶解させ、 そこへ lmLの水に溶角军させた 0. 0207gの NHSを添カロした。 15分経過後、 0. 88m Lの水に溶解させた 0· 0346gの WSCを添加することで PGA架橋物を調製した。な お、 PGA架橋物に含まれる水の全量を 5mLとした。また、得られたゲルの物性評価 を行った結果、粘弾性測定より求めたゲルィヒ時間（弾性率と粘性率がクロスオーバー するまでの時間）は 11分、定常状態のゲル弾性率 G'は 39Paであった。 0.43 g of PGANa [weight average molecular weight: 2 million] and 120 zL of PEI (weight average molecular weight: 10,000, manufactured by Wako Pure Chemical Industries, Ltd., reagent grade) in 3 mL of water [0.88 g / l OmL ( = 0.25 mmol / mL)] (= 2.64 mg equivalent) (0.25 mol% PEI with respect to PGA monomer unit conversion), dissolve slowly by stirring for about 30 minutes, and then add lmL water Then, 0.0207 g of NHS that had been melted into the melt was added. After 15 minutes, 0.8m A PGA cross-linked product was prepared by adding 0 · 0346 g WSC dissolved in L water. The total amount of water contained in the PGA cross-linked product was 5 mL. In addition, as a result of evaluating the physical properties of the obtained gel, the Gelich time (time until the elastic modulus and the viscosity crossover) obtained from the viscoelasticity measurement was 11 minutes, and the gel elastic modulus G ′ in the steady state was 39 Pa. Met.
[0105] (実施例 8) [Example 8]
水 3mLに 0. 453gの PGANa [分子量： 200万]および 60 μ Lの ΡΕΙ (重量平均分 子量： 600)水溶液 [0. 88g/l0mL ( = 0. 25mmol/mL) ] (= 1. 32mg相当）（P GAモノマーユニット換算に対して 0. 125mol%の PEI)を入れ、ゆっくりと 30分程度 攪拌することで溶解させ、そこへ lmLの水に溶解させた 0. 0207gの NHSを添加し た。 15分経過後、 0. 88mLの水に溶解させた 0. 0346gの WSCを添加することで P GA架橋物を調製した。なお、 PGA架橋物に含まれる水の全量を 5mLとした。また、 得られたゲルの物性評価を行った結果、粘弾性測定より求めたゲル化時間（弾性率 と粘性率がクロスオーバーするまでの時間）は 4. 0分、定常状態のゲル弾性率 G'は 52Paであった。圧縮試験の結果からは初期弾性率 Eが求まり、 1. 5kPaであった。  In 3 mL of water, 0.453 g of PGANa [molecular weight: 2 million] and 60 μL of) (weight average molecular weight: 600) aqueous solution [0.88 g / l0 mL (= 0.25 mmol / mL)] (= 1.32 mg Equivalent) (0.125 mol% PEI with respect to PGA monomer unit) was added, dissolved by slowly stirring for about 30 minutes, and then added 0.0207 g NHS dissolved in 1 mL water. It was. After 15 minutes, a PGA cross-linked product was prepared by adding 0.0346 g of WSC dissolved in 0.88 mL of water. The total amount of water contained in the PGA cross-linked product was 5 mL. In addition, as a result of evaluating the physical properties of the obtained gel, the gelation time obtained from viscoelasticity measurement (time until the elastic modulus and the viscosity crossover) is 4.0 minutes, and the gel elastic modulus G in the steady state G 'Was 52Pa. From the result of the compression test, the initial elastic modulus E was obtained and was 1.5 kPa.
0  0
[0106] (実施例 9)  [Example 9]
水 3mLに 0· 453gの PGANa [分子量： 200万]および 240 μ Lの PEI (重量平均 分子量： 600)水溶液 [0· 88g/10mL ( = 0. 25mmol/mL) ] ( = 5. 28mg相当）（ PGAモノマーユニット換算に対して 0· 5mol%の PEI)を入れ、ゆっくりと 30分程度 攪拌することで溶解させ、そこへ lmLの水に溶解させた 0. 0207gの NHSを添カロし た。 15分経過後、 0. 88mLの水に溶解させた 0. 0346gの WSCを添加することで P GA架橋物を調製した。なお、 PGA架橋物に含まれる水の全量を 5mLとした。得ら れたゲルの膨潤度は 2000倍であった。また、得られたゲルの物性評価を行った結 果、粘弾性測定より求めたゲル化時間（弾性率と粘性率がクロスオーバーするまでの 時間）は 1. 8分、定常状態のゲル弾性率 G'は l lOOPaであった。圧縮試験の結果 からは初期弾性率 Eが求まり、 6. 4kPaであった。  Water 3mL 0 · 453g PGANa [Molecular weight: 2 million] and 240 μL PEI (weight average molecular weight: 600) aqueous solution [0 · 88g / 10mL (= 0.25mmol / mL)] (= 5.28mg equivalent) (0.5 mol% PEI relative to PGA monomer unit) was added and dissolved by slowly stirring for about 30 minutes, and 0.0207 g NHS dissolved in 1 mL water was added thereto. After 15 minutes, a PGA cross-linked product was prepared by adding 0.0346 g of WSC dissolved in 0.88 mL of water. The total amount of water contained in the PGA cross-linked product was 5 mL. The degree of swelling of the obtained gel was 2000 times. In addition, as a result of evaluating the physical properties of the obtained gel, the gelation time obtained by measuring viscoelasticity (time until the elastic modulus and the viscosity crossover) is 1.8 minutes, and the gel elastic modulus in the steady state G 'was l lOOPa. From the result of the compression test, the initial elastic modulus E was obtained, which was 6.4 kPa.
0  0
[0107] 上記実施例 5〜9の配合を以下の表に示す。  [0107] The formulations of Examples 5 to 9 are shown in the following table.
[0108] [表 4] 調製条件 [0108] [Table 4] Preparation conditions
Figure imgf000021_0001
調製条件
Figure imgf000021_0001
Preparation conditions
架橋剤： PEI (重量平均分子量： 600, 1800, 10000) Crosslinking agent: PEI (weight average molecular weight: 600, 1800, 10000)
PGAの重量平均分子量： 200万 Weight average molecular weight of PGA: 2 million
a) ポリエチレンィミンの 1モノマーユニットの分子量は 44。ポリエチレンイミン中、一 級ァミン：二級アミン：三級アミン= 1 : 2 : 1の比率で含まれてレ、る。一級ァミンが 2個含 まれる繰り返し単位をユニットとすると、 8個のモノマーユニットからなる 1ユニット中に 2個の一級ァミンが含まれる計算になり、 1ユニットの分子量は 352となる。この計算 方法により、他のジァミン類との比較および PEIの分子量の影響を検討することが可 肯 となった。 a) The molecular weight of one monomer unit of polyethyleneimine is 44. Polyethyleneimine contains primary amine: secondary amine: tertiary amine = 1: 2: 1. If the unit is a repeating unit containing two primary amines, one unit consisting of eight monomer units is calculated to contain two primary amines, and the molecular weight of one unit is 352. This calculation method proved to be effective in comparing with other diamines and examining the effect of the molecular weight of PEI.
b)， c) 水溶液とした上で添加することで、全量が反応に関与するようにした。 b), c) By adding it as an aqueous solution, the whole amount was involved in the reaction.
d) 溶媒の全量 d) Total amount of solvent
* ) PGANaのモル数はモノマーユニット換算  *) Number of moles of PGANa in terms of monomer units
[表 5] [Table 5]
P E Iを架橋剤に用いた高分子量 P G A架橋物の物性  Physical properties of high molecular weight PGA cross-linked products using PEI as a crosslinking agent
架橋剤： PE I PGA分子量： 200万  Crosslinker: PE I PGA Molecular weight: 2 million
Figure imgf000021_0002
a)レオメーターを用いて貯蔵弾性率 (弾性率 'の値と損失弾性率 (粘性率) G' 'の 値を測定し、液体 (G'く G' ' )が架橋反応の進行に伴って G' >G' ' (固体）となるま での時間をゲル化時間とした。 （測定不能領域は、各サンプルともおよそ 30分程度で あった）
Figure imgf000021_0002
a) Storage elastic modulus (value of elastic modulus' and loss elastic modulus (viscosity) G '' using a rheometer The value was measured, and the time until the liquid (G ′ and G ′ ′) became G ′> G ′ ′ (solid) as the crosslinking reaction progressed was defined as the gelation time. (The non-measurable area was about 30 minutes for each sample)
b)架橋反応開始後、十分な時間（1日程度)放置したものをサンプルとして使用。弾 性率測定の際に周波数依存がないことを確認の上、 1Hzの周波数を用いてレオメー ターにより測定した。  b) Use a sample that has been left for a sufficient amount of time (about 1 day) after the start of the crosslinking reaction. After confirming that there was no frequency dependence when measuring the elasticity, we measured with a rheometer using a frequency of 1 Hz.
c)作製したゲルを用いて圧縮試験により測定を行った。  c) Measurement was performed by a compression test using the prepared gel.
[0110] (比較例 3) [0110] (Comparative Example 3)
NHSを添加しなかった以外は実施例 5と同様に実験を行った。しかし、架橋物は得 られず、収率は 0%であった。  The experiment was performed in the same manner as in Example 5 except that NHS was not added. However, no cross-linked product was obtained, and the yield was 0%.
[0111] (比較例 4) [0111] (Comparative Example 4)
比較例 3において、反応液の pHを 6に調整した以外は、比較例 3と同様に実験を 行った。 WSCは pH約 6程度で活性が高くなることが知られているため、 pHを調節し た。その結果、反応溶液の粘度は上昇したが、架橋物は得られず、収率は 0%であ つに。  In Comparative Example 3, the experiment was performed in the same manner as Comparative Example 3 except that the pH of the reaction solution was adjusted to 6. Since WSC is known to have high activity at about pH 6, the pH was adjusted. As a result, the viscosity of the reaction solution increased, but no cross-linked product was obtained, and the yield was 0%.
[0112] (考察） [0112] (Discussion)
架橋活性化剤である WSCのほかに架橋活性化補助剤である N—ヒドロキシイミド（ 上記実施例では NHS)を用いることにより、迅速に PEIで架橋された PGAからなるゲ ルを調製できた。  By using N-hydroxyimide (NHS in the above examples) as a crosslinking activation aid in addition to WSC as a crosslinking activator, a gel composed of PGA crosslinked rapidly with PEI could be prepared.
[0113] 架橋剤としての PEIの分子量が大きい場合には、架橋物強度は低下する傾向にあ ることが上記結果から理解される。従って、強度の高い架橋物が所望される場合には 、低めの分子量のポリアミンを架橋剤として用いることが有利であることが理解される  [0113] It is understood from the above results that when the molecular weight of PEI as a crosslinking agent is large, the strength of the crosslinked product tends to decrease. Therefore, it is understood that it is advantageous to use a lower molecular weight polyamine as a crosslinking agent when a high-strength crosslinked product is desired.
[0114] 以上のように、本発明の好ましい実施形態を用いて本発明を例示してきたが、本発 明は、この実施形態に限定して解釈されるべきものではない。本発明は、特許請求 の範囲によってのみその範囲が解釈されるべきであることが理解される。当業者は、 本発明の具体的な好ましい実施形態の記載および技術常識に基づいて、特許請求 の範囲に等価な範囲を理解することができる。本明細書において引用した特許、特 許出願および文献は、その内容自体が具体的に本明細書に記載されているのと同 様にその内容が本明細書に対する参考として援用されるべきであることが理解される 産業上の利用可能性 [0114] As described above, the present invention has been illustrated using the preferred embodiment of the present invention, but the present invention should not be construed as being limited to this embodiment. It is understood that the scope of the present invention should be construed only by the claims. Those skilled in the art can understand the scope equivalent to the claims based on the description of the specific preferred embodiments of the present invention and the common general technical knowledge. Patents and patents cited in this specification It is understood that license applications and documents should be incorporated by reference into this specification as if the contents themselves were specifically described in this specification. possibility
本発明のゲルは、膨潤度に優れることから、従来公知のヒドロゲルが用いられてい た用途に有効に使用することができる。例えば、保湿性に優れることから、化粧品等 の分野において応用が期待される。また、吸水率が高いことから、衛生用品等の分 野において応用が期待される。  Since the gel of the present invention has an excellent degree of swelling, it can be used effectively in applications where conventionally known hydrogels have been used. For example, it is expected to be applied in the field of cosmetics because of its excellent moisture retention. In addition, its high water absorption rate is expected to be applied in the field of sanitary products.

Claims

請求の範囲 The scope of the claims
[I] ポリ― Ί—グルタミン酸ゲルの製造方法であって、水溶性カルポジイミドおよび Ν—ヒ ドロキシイミドの存在下で、ポリ _ γ—グルタミン酸またはその塩をポリアミンで架橋す る工程を包含する、方法。 [I] A method for producing a poly- Ί -glutamic acid gel, comprising a step of crosslinking poly_γ-glutamic acid or a salt thereof with a polyamine in the presence of water-soluble carpositimide and Ν-hydroxyimide.
[2] 前記 Ν—ヒドロキシイミドが Ν—ヒドロキシコハク酸イミドである、請求項 1に記載の方 法。  [2] The method according to claim 1, wherein the Ν-hydroxyimide is Ν-hydroxysuccinimide.
[3] 前記ポリ γ グルタミン酸またはその塩の重量平均分子量力 100万以上である、 請求項 1に記載の方法。  [3] The method according to claim 1, wherein the polyγ-glutamic acid or a salt thereof has a weight average molecular weight of 1 million or more.
[4] 前記水溶性カルポジイミドカ 1ーェチルー 3—（3—ジメチルァミノプロピル） カル ポジイミド 塩酸塩である、請求項 1に記載の方法。 [4] The method according to claim 1, wherein the water-soluble carpositimide carbonate 1-ethyl-3- (3-dimethylaminopropyl) carpositimide hydrochloride is used.
[5] 前記ポリアミンが、アルキレンジァミンまたはポリ（エチレンィミン）である、請求項 1に 記載の方法。 5. The method according to claim 1, wherein the polyamine is an alkylene diamine or poly (ethylene imine).
[6] 前記ポリアミン力 炭素数 2〜8のアルキレンジァミンである、請求項 1に記載の方法。  [6] The method according to [1], wherein the polyamine force is an alkylenediamine having 2 to 8 carbon atoms.
[7] 前記ポリアミン力 重量平均分子量 100〜20000のポリ（エチレンィミン）である、請 求項 1に記載の方法。 [7] The method according to claim 1, wherein the polyamine force is poly (ethyleneimine) having a weight average molecular weight of 100 to 20,000.
[8] 前記ポリアミン力 1 , 3 _プロパンジァミンである、請求項 1に記載の方法。 8. The method according to claim 1, wherein the polyamine force is 1,3_propanediamine.
[9] ポリ一 Ί—グルタミン酸がポリアミンで架橋されたポリ一 Ί—グノレタミン酸ゲルであつ て、乾燥ゲル中の、グルタミン酸残基のモル数とポリアミン残基のモル数との和のうち の、ポリアミン残基のモル数の比率力 10モル0 /0以下である、ポリ _ γ—グルタミン 酸ゲル。 [9] poly one I - glutamic acid is a poly one I crosslinked with a polyamine - shall apply in Gunoretamin acid gel, in the dry gel, of the sum of the number of moles a polyamine residue of glutamic acid residues, ratio force 10 moles of moles of polyamine residues is 0/0 or less, poly _ .gamma. glutamic acid gel.
[10] 前記乾燥ゲル中の、ポリアミン残基のモル数の比率力 S、 3モル％以下である、請求項 9に記載のポリ _ γ—グルタミン酸ゲル。  [10] The poly_γ-glutamic acid gel according to [9], wherein the ratio power S of the number of moles of polyamine residues in the dry gel is 3 mol% or less.
[II] ポリ一 Ί—グルタミン酸がポリ（エチレンィミン）で架橋されたポリ一 Ί—グルタミン酸 ゲル。 [II] poly one I - glutamic acid crosslinked with poly (Echirenimin) poly one I - glutamic acid gel.
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