JPH0543720B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention provides gelatin, cyclodextrin,
The present invention relates to a process for the preparation of gelatin/cyclodextrin copolymers, which comprises reacting with derivatives thereof or water-soluble cyclodextrin polymers. (Prior Art) Gelatin is used in large quantities in the food industry, pharmaceutical industry, photochemical industry, and the like. In order to improve the physicochemical properties, chemical properties, mechanical properties, etc. of gelatin, appropriate functional groups thereof such as amino groups, carboxyl groups, hydroxyl groups, etc. are reacted with various reactants. For example, the amino groups of gelatin can be combined with organic acyl halides or acid anhydrides (e.g. benzenesulfonyl chloride, acetic anhydride, etc.), isothiocyanates, activated halogen-containing organic compounds (e.g. benzoyl bromide, haloacetic acid or sym
-chloro derivatives of triazines, pyrimidines, pyrazines, etc.) or epoxies. Additionally, carboxyl groups can be esterified. Additionally, hydroxy groups can be modified by formation of sulfate esters or acylation in anhydrous solvents. All of these reactions are discussed in detail in the literature [AGWard and A.
Courts), Gelatin Chemistry and Technology, Academic Press, London, 1977, pp. 212-223].
Some methods of gelatin modification consist of graft copolymerization of acrylic monomers, such as acrylic amide, methacrylic amide, acrylic acid, methacrylic acid, methyl methacrylate, butyl acrylate, in an aqueous medium, and peroxysulfuric acid. It is carried out in the presence of initiators such as salts, benzoyl peroxide, acetyl peroxide, perborates, etc.
Croome, J. Phot. Sci.), vol. 30, p. 181, 1982]. So far, cyclodextrins and their derivatives have not been utilized for such modification of gelatin. Cyclodextrins are cyclic, non-reducing oligosaccharides with α-D-
It consists of glucopyranose units and is particularly well known for its ability to form inclusion complexes [J. Szejtli, Cyclodextrins and their Inclusion Complexes, Akdemiai Kiado, Budapest, 1982 Year〕.
The production of α-, β- and γ-cyclodextrins, each consisting of 6, 7 and 8 glucopyranose units, is carried out by enzymatic degradation of starch. Many cyclodextrins contain esters, esters, nitrogen-, sulfur- or halogen-containing compounds,
It is synthesized as an acid derivative etc. [Sudiejitori, supra, pp. 81-89]. The reactivity of the primary and secondary alcoholic hydroxy groups present in the cyclodextrin molecule allows the production of water-soluble polymers of moderate molecular weight. According to one of these methods, unsaturated derivatives are prepared from polymerizable cyclodextrins and polymerized either themselves or with cyclodextrin-free monomers [J.
Polym.Sci.Letter), vol. 13, p. 357, 1975]. According to another method, a cyclodextrin molecule is coupled with a suitable bifunctional reactant, such as diepoxies, epichlorohydrin, etc., without the use of a crosslinking agent to form a linear or branched water-soluble polymer. [Hungarian Patent Specification No. 180597,
1982], or producing ionic-substituted water-soluble cyclodextrin polymers [see Hungarian Patent Specification No. 191101, 1983]. Water-soluble cyclodextrin polymers can also be prepared using polymerizable cyclodextrin monomer derivatives (e.g., cyclodextrin-acrylic esters) as starting materials or by coupling cyclodextrins to other polymers. See Sujiegitori, supra, pp. 81-91]. No literature describes the binding of cyclodextrin or its derivatives to gelatin. (Objective and Summary of the Invention) An object of the present invention is to provide a method for producing a water-soluble copolymer formed by combining gelatin and cyclodextrin. The present invention is based on the finding that the chemical reaction between cyclodextrins or derivatives thereof and gelatin can be realized through the use of suitable crosslinking agents. Furthermore, the present invention provides that the chemical properties of the resulting polymer,
It is based on the finding that physicochemical and mechanical properties can be controlled by the gelatin:cyclodextrin ratio in gelatin modified with cyclodextrin or its derivatives. The conjugation of gelatin and cyclodextrin or its derivatives can be accomplished in two ways: (1) by reacting a substituted or unsubstituted cyclodextrin with gelatin using a cross-linking agent, or (2) by reacting a water-soluble cyclodextrin polymer. This can be achieved by reacting gelatin with a crosslinking agent. That is, according to a specific example of the production method of the present invention, in producing a gelatin/cyclodextrin polymer, 1 g of gelatin, 1.5 to 15 mmol of epichlorohydrin, and the formula []: 0.1 to 2.5 mmol of diglycidyl ether represented by or formula []: [In the formula, m is an integer of 1 to 6. ] Or formula []: [wherein R represents hydrogen or alkyl having 1 to 5 carbon atoms, and Y represents chlorine, bromine, amino or alkoxy having 1 to 4 carbon atoms, such as methoxy, ethoxy or n- or isopropoxy. ] 0.1 to 2.5 mmol of a crosslinking agent represented by the formula (when using a compound of the formula [], an initiator is optionally used) and the formula []: CD-(OQX)m [wherein, CD is α-, β - or γ-cyclodextrin molecule, Q is -(CH ₂ ) m-, X is hydrogen,
It means carboxy, amino, _-NR2 , hydroxy or _-SO3H . m is the same as above. R ₂ is the same as described below. ] Substituted or unsubstituted cyclodextone represented by
0.05-3.0 mmol or formula []: [In the formula, CD is the same as above. R ¹ is a bridge attached to the cyclodextrin molecule via an ether bond in the polymer chain, R ² is hydrogen or the same as R ³ , R ³ is hydroxy, -CD-R ⁴ a , OR ⁵ , O(CH ₂ )mOR ⁵ ,
(OCH ₂ CH ₂ ) mOR ⁵ , NR ₂ or −NH (CH ₂ )
m-COOH, _R4 is ^-R1・^R2 ,

[Formula] or the same as R ⁵ , R ⁵ is hydrogen or -(CH ₂ ) m-
COOH or _H2N- ( _CH2 )m-, where a is 0 to 1 more than the original number of hydroxys in the cyclodextrin.
A smaller integer, p means 0 or an integer at least 2 less than the original number of hydroxys in the cyclodextrin, m as defined above, n an integer from 2 to 12. ] Water-soluble cyclodextrin polymer shown by
React 0.1-20g. Alternatively, 1.0 mmol of cyclodextrin and 0.2 of a compound of formula []: X'-( _CH2 )m-COOH
~2.0 mmol [wherein, X' is chlorine or bromine, m
is the same as above. ], formula []: H ₂ N-(CH ₂ )m-
0.2 to 2.0 mmol of COOH compound [where m is the same as above. ] or 0.2 to 2.0 mmol of a compound of the formula []: R ₂ =N-R ⁶ [wherein R is the same as above]. R ⁶
means hydrogen, -( _CH2 )mCl or -( _CH2 )mBr. ] each, 0.03 to 3.5 g of gelatin, and 5 to 15 mmol of epichlorohydrin, formula []
1.0 to 5.0 mmol of diglycidyl ether of formula [] or 1.0 to 5.0 mmol of a crosslinking agent of formula [] (when using a compound of formula [], an initiator is optionally used) are reacted. In the two methods of the invention, reaction by-products and water may be removed, if desired. DETAILED DESCRIPTION OF THE INVENTION Both line gelatin, which has a low isoelectric point, and gelatin, which is produced by an acid process and has a high isoelectric point, can be used in the process of the invention. In addition to α-, β- and γ-cyclodextrin monomers, substituted derivatives containing groups such as carboxymethyl, diethylaminoethyl, dimethyl, trimethyl, hydroxypropyl, sulfopropyl or sulfobutyl, as well as water-soluble cyclodextrin monomers. Polymers (e.g. unsaturated α
-, β- and γ-cyclodextrin polymers) or water-soluble cyclodextrin polymers containing carboxymethyl, diethylaminoethyl or carboxypropyl-γ-amino groups separately or simultaneously can also be used in the process of the invention. can. The following types of compounds can be used instead of monomers before binding with gelatin: halogenated carboxylic acids such as chloroacetic acid, bromoacetic acid or chloropropionic acid; amino acids such as β-aminopropionic acid, γ
- such as aminobutyric acid; alkylamines such as dimethylamine, diethylamine, dibutylamine; alkylaminoethyl chlorides such as diethylaminoethyl chloride; In addition to epichlorohydrin and diglycidyl ether, analogs of diglycidyl ether, such as ethylene, butylene diglycidyl ether,
Also unsaturated carboxylic acid chlorides and esters, such as methacryloyl chloride, methyl methacrylate, can also be used as crosslinking agents. Calcium persulfate, hydrogen peroxide, benzoyl peroxide, etc. can be used, for example, as initiators. In the method of the invention, the reaction product can be obtained in solution or solid form. As desired,
Chloride ions and low molecular weight products can be removed from the crude reaction mixture, for example by passing them through an ion exchange column or by dialysis. The solid product can be obtained from a previously deionized solution or a solution containing by-products of the reaction by precipitation with a solvent such as alcohol, acetone, etc. Due to the high gelatin content, gelable copolymers can be purified by water washing after grinding the gel. Each of the crosslinking agents mentioned above participates in the reaction with amino and/or carboxy groups of gelatin. A method of observing the binding reaction process consists of acid/base titration of the ionizable groups of gelatin, which allows the amount of reacted groups to be determined [P.
Lanza and I Mazey, Annali Dei
Chimila (P.Lanza and Mazzei, Annli di
Chimica), vol. 53, p. 1833, 1963]. The binding of gelatin and cyclodextrin by the crosslinking agent can be monitored by measuring the optical rotation. This includes solutions containing mechanical mixtures of gelatin and cyclodextrin or cyclodextrin polymers in various proportions (curve 1 in Figure 1).
a and 2a) are copolymers made from gelatin and cyclodexrin in the same proportions (curve 1b
and 2b), it is based on the fact that it exhibits a lower negative specific rotation compared to 2b). In Figure 1, 1a: mixture, 1b: copolymer (both containing 80% by weight gelatin and 20% by weight cyclodextrin), 2a: mixture, 2
b: means a copolymer (both containing 20% by weight of gelatin and 80% by weight of cyclodextrin). This phenomenon appears to be related to the fact that a certain proportion of the gelatin molecules formed in the copolymer have lost the ability to isomerize at the proline-hydroxyproline peptide bond. The properties of the copolymers obtained by reaction of gelatin, crosslinker and cyclodextrin depend inter alia on the gelatin:cyclodextrin ratio. When the amount of cyclodextrin calculated as a monomer is large compared to gelatin, its solubility increases rapidly and even a 50% solution can be prepared at room temperature. That is, the water solubility of the copolymer is higher than that of each starting material. Conversely, products capable of reversible sol-gel transition can be obtained by increasing the gelatin proportion. The copolymers exhibit the ability to form inclusion complexes in both cases. In summary, the method of the present invention provides the following advantages. (1) Water-soluble polymers that are useful in the formation of inclusion complexes or capable of reversible sol-gel transitions can be produced. (2) Cyclodextrin-containing polymers can be produced that have very high solubility in water compared to commonly used cyclodextrin polymers. (3) The physical properties of the copolymer obtained by the method of the present invention are very good compared to gelatin. (Examples) Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto. In the examples below, CD is an abbreviation for cyclodextrin. Example 1 0.013 mol of β-CD is added to 100 ml of a 10% gelatin solution (isoelectric point (IEP) = 4.8) which has been adjusted to pH 10.5 by addition of 40% sodium hydroxide solution, then epichlorohydride Add 0.13 mol of phosphorus to the solution at temperature
It was added dropwise while maintaining the temperature below 60°C. reaction mixture
After stirring at 60°C for 1 hour and cooling, the pH was adjusted to 6.5 by adding 10% hydrochloric acid. The solution was evaporated under reduced pressure to 1/3 of its original volume. The product was precipitated with alcohol, washed and dried. Example 2 The method described in Example 1 was repeated. However, β
-CD was replaced with γ-CD, and 0.16 mol of epichlorohydrin was added. Example 3 The method described in Example 1 was repeated. However, β
-CD was replaced with 0.010 mol of α-CD and 0.10 mol of epichlorohydrin was added. Example 4 The method described in Example 1 was repeated. However, β
- 0.005 mol of CD and 0.10 mol of epichlorohydrin were used. Example 5 The method described in Example 1 was repeated. However, β
- 0.005 mol of CD and 0.05 mol of epichlorohydrin were used. Example 6 The PH value of 100 ml of a 10% gelatin solution with a high isoelectric point (IEP = 8.2) was adjusted to 10 by the addition of 40% sodium hydroxide solution and then 20% β-CD
100 ml of a polymer (hereinafter referred to as β-CDP) solution (containing 56% CD) was added dropwise, and then 0.015 mol of epichlorohydrin was added dropwise. reaction mixture
Stirred at 58° C. for 45 minutes and then processed as described in Example 1 to obtain the product. Example 7 The method described in Example 6 was repeated. However, 10
% carboxymethyl-β-cyclodextrin
100 ml of polymer (hereinafter referred to as CM-β-CDP) solution (containing 59% CD) was used. Example 8 The method described in Example 7 was repeated. However, 0.050 mol of epichlorohydrin was used. Example 9 The method described in Example 7 was repeated. However, 0.015 mol of epichlorohydrin and CM−β−
CDP (containing 59% CD) was used. Example 10 The method described in Example 6 was repeated. However, 10
% diethylamino-β-cyclodextrin polymer (hereinafter referred to as DEA-β-CDP) solution (containing 59% CD) was used in place of CDP. Example 11 0.013 mol of diglycidyl ether (DGE) was added to 100 ml of a 10% gelatin solution with low isoelectric point (IEP = 4.8) at 55°C with stirring, and then
Stirring was continued for 30 minutes. Then 0.012 mol of β-CD was added, the pH value was adjusted to 11 by addition of 40% sodium hydroxide solution and the mixture was stirred at 60° C. for 1 hour. After neutralizing the solution with 10% hydrochloric acid,
The solution was evaporated under reduced pressure to 1/3 of the original volume.
I made it. After cooling, the precipitated yellow substance was dissolved in distilled water, precipitated with alcohol, filtered, and dried. Example 12 The method described in Example 11 was repeated. However, α
-CD was used in place of β-CD. Example 13 The method described in Example 11 was repeated. However, γ
-CD was used in place of β-CD. Example 14 The method described in Example 11 was repeated. however,
DGE 0.0065 mol, sulfobutyl-β-cyclodextrin (hereinafter referred to as SB-β-CDP) 7.62 g
and gelatin with a high isoelectric point (IEP=8.2), the PH value of the reaction mixture was adjusted to 8.5 by addition of 40% sodium hydroxide solution. Example 15 The method described in Example 14 was repeated. However, pentakis(carboxymethyl)-β-cyclodextrin (hereinafter referred to as PCM-β-CD)8.54
g was used in place of SB-β-CD. Example 16 10 g of gelatin (IEP=4.8) was swollen and then dissolved in 150 ml of distilled water. In this solution, DGE0.003
10 mol and the solution at 40 °C at its own pH.
Stir for a minute. At the same time, 0.015 mol of β-CD was introduced into 50 ml of distilled water and dissolved by addition of 40% sodium hydroxide solution. The alkaline β-CD solution was poured into the gelatin solution over a period of 5 minutes, then the temperature was increased to 55°C and then to 60°C, and after stirring at the same temperature for 1 hour, the reaction mixture was stored overnight. Adjust the pH value to 6.5 by adding 10% hydrochloric acid,
The solution was then evaporated under reduced pressure to half the volume. After precipitation with alcohol, the resulting solid was washed and dried. Example 17 The method described in Example 16 was repeated. however,
0.015 mol of DGE was used. Example 18 The method described in Example 16 was repeated. However, β
-Instead of CD, CM-β-CDP (contains 55% CD)
30.9 g were dissolved in 100 ml of water by addition of 40% sodium hydroxide solution. Example 19 The method described in Example 18 was repeated. however,
0.015 mol of DGE was used. Example 20 The method described in Example 16 was repeated. However, β
-Instead of CD, CM-β-CDP (contains 59% CD)
57.7 g were dissolved in 150 ml of water by addition of 40% sodium hydroxide solution. It also has a high isoelectric point (IEP
= 8.2) gelatin was used. Example 21 The method described in Example 20 was repeated. however,
0.025 mol of DGE was used. Example 22 The method described in Example 20 was repeated. However, 5 g of gelatin with a high isoelectric point was used. Example 23 The method described in Example 16 was repeated. however,
Instead of DGE, 0.015 mol of butylene diglycidyl ether (hereinafter referred to as BDE) (compound of formula [] where m is 4) was used. Example 24 The method described in Example 23 was repeated. however,
0.050 mol BDE and 0.025 mol β-CD were used. Example 25 The method described in Example 16 was repeated. However, 5
% gelatin solution, 45 g CM-β-CDP containing 0.015 mol BDE (instead of DGE) and 57% CD
(instead of β-CD) was dissolved in 150 ml of water by addition of 40% sodium hydroxide solution. Example 26 The method described in Example 25 was repeated. However, 10
% gelatin solution 100ml, CD57% containing CM-β-
25 g of CDP and 0.022 mol of BDE were used. Example 27 The method described in Example 25 was repeated. However, a 10% gelatin solution with a high isoelectric point (IEP8.2)
100ml, 5g of CM-β-CDP containing 57% CD and
0.015 mol of BDE was used. Example 28 The method described in Example 25 was repeated. However, 10
% gelatin solution 100ml, CD57% containing CM-β-
1 g of CDP and 0.025 mol of BDE were used. Example 29 0.018 mol of β-CD in 10% inert gelatin solution
100 mol at 40 °C and the pH value of the solution was adjusted to 10.5 by addition of 40% sodium hydroxide solution.
The temperature was then increased to 58°C and the methacryloyl
0.025 mole of chloride (compound of formula [ ] where R is CH ₃ and Y is Cl) was added with stirring. The mixture was stirred for a further 30 minutes at the same temperature, then the reaction mixture was cooled to 40° C. and the solid product was precipitated out by addition of acetone, washed and dried. Example 30 The method described in Example 29 was repeated. However, 1
8 ml of % calcium persulfate solution was also added to the gelatin solution. Example 31 The method described in Example 29 was repeated. However, β
-CD instead of γ-CD and high isoelectric point (IEP)
= 8.2) and the PH value of the reaction mixture was adjusted to 8.5 by addition of sodium hydroxide solution. Example 32 100ml of 10% CM-β-CDP solution containing 57% CD
% inert gelatin solution. temperature
Adjust to 60℃ and add methacryloyl chloride.
0.025 mol was added dropwise with stirring and stirring continued for 30 minutes. After cooling to 40°C, the solid product was precipitated with acetone, washed and dried. Example 33 The method described in Example 32 was repeated. However, 5
% inert gelatin solution and 0.005 moles of methacryloyl chloride. Example 34 The method described in Example 32 was repeated. However, 1
% inert gelatin solution 100ml, 20% CM-β-
100 ml of CDP solution and 0.001 mol of methacryloyl chloride were used. Example 35 0.018 mol of β-CD dissolved in 30 ml of 6% sodium hydroxide solution at room temperature in 3.42 g of chloroacetic acid
(0.036 mol) with stirring. After stirring for an additional 20 minutes, 30 ml of 6% sodium hydroxide solution was added dropwise again. The temperature was increased to 58°C and the mixture was stirred at the same temperature for 70 minutes. After addition of 50 ml of 3% inert gelatin solution, the pH value was adjusted to 10.5 by addition of 20% sodium hydroxide solution, and while maintaining the temperature at 60 °C, 7 ml of BDE (0.045 mol) was added dropwise and stirred. was continued for an additional 30 minutes at the same temperature. Then, the pH value was adjusted to 6.5 by adding 10% hydrochloric acid.
The solution was evaporated to half the volume under reduced pressure, precipitated with acetone, and the solid product was washed and dried. Example 36 The method described in Example 35 was repeated. However, 0.342 g (0.0036 mol) of chloroacetic acid and 200 ml of 10% inert gelatin solution were used. Example 37 The method described in Example 35 was repeated. However, 12
% inert gelatin solution was used. Example 38 The method described in Example 35 was repeated. However, 1.026 g (0.0108 mol) of chloroacetic acid and 50 ml of 1% inert gelatin solution were used. Furthermore, 0.27 mol of epichlorohydrin was used instead of BDE. Example 39 The method described in Example 38 was repeated. However, 0.18 mol of epichlorohydrin was used. Example 40 The method described in Example 35 was repeated. However, 0.09 mol of epichlorohydrin and gelatin with a high isoelectric point (IEP=8.2) were used. Example 41 0.018 mol of β-CD in 20% sodium hydroxide solution
After dissolving in 45 ml, 0.035 mol of γ-aminobutyric acid was added, then the temperature was raised to 50°C and 50 ml of 3% inert gelatin solution was added. After adjusting the pH value to 10.5 with 40% sodium hydroxide solution, add 0.18 mol of epichlorohydrin with stirring and increase the temperature to maximum.
It was added dropwise while maintaining the temperature at 60°C. Reaction mixture at 60℃
The mixture was stirred for an additional hour, and then the pH value was adjusted to 6.5 by adding 10% hydrochloric acid. The solution was evaporated to half volume under reduced pressure. After precipitation with acetone, the solid product was washed and dried. Example 42 The method described in Example 41 was repeated. However, 0.13 mol of epichlorohydrin and 150 ml of a 10% inert gelatin solution were used. Example 43 The method described in Example 41 was repeated. However, 0.030 mol of diethylamine was used instead of γ-aminobutyric acid. Example 44 The method described in Example 43 was repeated. However, 0.020 mol of diethylamine and 200 ml of a 10% inert gelatin solution were used. Example 45 The method described in Example 35 was repeated. However, the addition of the sodium hydroxide solution was not repeated after the addition of the gelatin solution, and 0.045 mol of methacryloyl chloride was used instead of BDE. Example 46 The method described in Example 45 was repeated. However, 10
% inert gelatin solution and 0.018 moles of methacryloyl chloride were used. Example 47 The method described in Example 45 was repeated. However, 0.090 moles of methacryloyl chloride and high isoelectric point (IEP=8.2) gelatin were used. Example 48 The method described in Example 45 was repeated. However, 20
% gelatin solution and 0.018 mol of methacryloyl chloride were used. Example 49 The method described in Example 45 was repeated. However, 20
% inert gelatin solution and 0.018 moles of methacryloyl chloride were used. Example 50 The method described in Example 45 was repeated. However, 0.036 mol of diethylaminoethyl chloride hydrochloride was used instead of chloroacetic acid. (Discussion) Data regarding the products synthesized according to Examples 1 to 50 are summarized in Tables 1 and 2. In these tables, the specific rotation of the 1% solution measured at a wavelength of 220 nm is also shown. This can be evaluated using FIG. In this figure, CM-β-CD combined with various ratios of (1) β-cyclodextrin, (2) cyclodextrin polymer prepared using epichlorohydrin or (3) butylene diglycidyl ether. The specific optical rotation (λ=220 nm) is shown for a 1% solution prepared from a mixture of and gelatin. Comparing these values with the specific rotations observed at the corresponding cyclodextrin ratios for each example shown in Tables 1 and 2, the specific rotations of the products produced by the process of the invention are more + This evidences the fact that, without exception, a chemical reaction proceeded between the starting materials, resulting in a polymer that also contained gelatin as a component.

【table】

【table】 [Brief explanation of the drawing]

FIG. 1 is a graph showing the relationship between specific optical rotation and wavelength, and FIG. 2 is a graph showing the relationship between specific optical rotation and the ratio of cyclodextrin.

Claims (1)

[Claims] 1. In producing a gelatin/cyclodextrin copolymer, (a) gelatin and epichlorohydrin, formula []: Diglycidyl ether represented by the formula []: [In the formula, m means an integer of 1 to 6. ] Compound represented by or formula []: [In the formula, R means hydrogen or alkyl having 1 to 5 carbon atoms, and Y means chlorine, bromine, amino or alkoxy having 1 to 4 carbon atoms. ] A compound represented by the formula []: CD-(OQX)m [wherein, CD is an α-, β- or γ-cyclodextrin molecule, Q is -(CH ₂ )m-, and X is hydrogen or carboxy , amino, _-NR2 , hydroxy or _-SO3H . m and R are the same as above. ] Substituted or unsubstituted cyclodextone or formula [ ]: [In the formula, CD is the same as above. R ¹ is a bridge linking cyclodextrin molecules via an ether bond in the polymer chain, containing the crosslinker as a component, R ² is hydrogen or the same as R ³ , R ³ is hydroxy, -CD-R ⁴ a , OR ⁵ , O(CH ₂ )
mOR ⁵ , (OCH ₂ CH ₂ ) mOR ⁵ , NR ₂ or −
NH( _CH2 )m-COOH, _R4 is ^-R1・^R2 , [Formula] or the same as ^R5 , ^R5 is hydrogen or -( _CH2 )
m-COOH or _H2N- ( _CH2 )m-, R is the same as above, a is an integer from 0 to 1 less than the original number of hydroxy in the cyclodextrin, p is 0
or an integer at least 2 less than the original number of hydroxys in the cyclodextrin, where n is 2 to
means 12 integers. [In _the formula, X' is chlorine or bromine, m is the same as above. ], formula []: H ₂ N-(CH ₂ )m-COOH
A compound [where m is the same as above]. ], or a compound of the formula []: R ₂ =N-R ⁶ [wherein R is the same as above]. R ⁶ is hydrogen, −(CH ₂ )mCl or −
( _CH2 ) means mBr. ] with gelatin, epichlorohydrin, a diglycidyl ether of formula [] or a compound of formula [] or formula [], and then optionally removing by-products of the reaction and water in both methods. A manufacturing method characterized by removal. 2. Claim 1: Gelatin produced by the lime method and having a low isoelectric point and substituted or unsubstituted cyclodextrin of the formula [] are used as starting materials.
Manufacturing method described. 3. Claim 1: Gelatin produced by the lime method and having a low isoelectric point and a water-soluble cyclodextrin polymer of the formula [] are used as starting materials.
Manufacturing method described. 4. The process according to claim 1, wherein gelatin produced by an acid process and having a high isoelectric point and a substituted or unsubstituted cyclodextrin polymer of the formula [] are used as starting materials. 5. The process according to claim 1, wherein gelatin produced by an acid process and having a high isoelectric point and a water-soluble cyclodextrin polymer of the formula [] are used as starting materials.