GB2224507A

GB2224507A - Gelatin/cyclodextrin copolymers

Info

Publication number: GB2224507A
Application number: GB8910114A
Authority: GB
Inventors: Miklos Szucs; Judit Csaplaros
Original assignee: FORTE FOTOKEMIAI IPAR
Current assignee: FORTE FOTOKEMIAI IPAR
Priority date: 1988-05-03
Filing date: 1989-05-03
Publication date: 1990-05-09
Anticipated expiration: 2009-05-03
Also published as: HUT50198A; JPH0215100A; HU203899B; GB8910114D0; JPH0543720B2; DE3914428A1; GB2224507B

Description

1 1 A i 2224507 $0 PROCESS FOR THE PREPARAI i014 OF GELA 1

Il'E/Cyi--',ODEXTRIN POL YME RS '1 The invention relates to a process for the preparation o'L geiatin- /cyclodextrin polymers by reacting gelatine with cyclod--xtrine or derivatives thereof or with water-soluble cyclodextrin polymers..

Gelatine is used in large amounts in the food, pharmaceutical and photochemical industry. For improving or modifying its physicochemical, chemical and mechanical properties, its functional groups, e.g. the amino, carboxyl or hydroxyl groups may be reacted with various reactants. The amino groups can be reacted with organic acyl halides or acid anhydrides (e.g. benzenesulfonyl chloride, acetic acid anhydride), or with isothiocyanates, or organic compounds containing an activated halogen atom (e.g. benzoyl bromide, a haloacetic acid, or chloro derivatives of s-triazines, pyrimidiras or pyrazines,) or with epoxides. The carboxyl groups can be esterified, and the hydroxyl groups can be modified by sulfate ester formation or by acylation in anhydrous media. All these reactions are discussed in detail in the literature, (e.g. A.G. Ward and A. Courts: The Science and Technology of Gelatin, Academic Press, London, 1977, pages 212 to 223).

One specific method of modifying gelatine comprises the copolymerization (grafting) with acrylic monomers which is i 5.

2 realized by using, inter alia, acrylic acid amide, methacrylic acid amide, acrylic acid, metnacrylic acid, metnyi ffietnacryia-Lu, butyl acrylate in aqueous media, in the presence of an initiaL,c..-, e- a peroxysuLitate, benzoyl peroxide, acety'! peroxide or a perborate, /_'R. J. Croome: J. Phot. Sci. 30, 181 (1982)7 Currently however, cyclodextrin and its derivatives have not yet been utilized for the modification of gelatines.

Cyclodextrins are cyclic, non-reducing oligosaccharids built up from a(--D-glucopyra nose units through 1,4-glucoside bonds, which are knot-in for their ability to form inclusion complexes (J. Szejtli: Cyclodextrins and their Inclusion Complexes, Akad6miai Kiad6, Budapest, 1982).

The preparation of and 6 cyclodextrins consisting of 6,7 and 8 glucopyranose units respectively, is accomplished by the enzymatic decomposition of starch.

A high number of cyclodextrins have been synthetized such as: ethers, esters, compounds containing nitrogen, sulfur or halogenatom or atoms, and acid derivatives (see: Szejtli, ibid(pages 81 to 89). The reactivity of the primary and secondary alcoholic hydroxyl groups present in the cyclodextrin molecules makesit possible to prepare water-soluble polymers with a medium average molecular weight. According to one of these methods describe-i above, ar. unsaturated cyclodextrin derivative is prepared from cyclodextrin which is capable of polymerization and this is then polymerized with itself 1 1 4 lo - 3 c- wi t h a rono mer- not con t a inin g cv cl c) de v trin P Sci. Letters, 13 357 (197527. According to an other method, cyclodextrin molecules are linked with suitable bifunctional reactants, e.g. diepoxides or epichlorohydrin, to i..,ater-soluble pol,meric products containing or branched chains without crosslinking /Hungarian patent specification No. 180,597 (1982)7 or to water -soluble cyclodextrin polymers substituted by ionic groups Hungarian patent specification No. 191,101 (1983)7

Water-soluble cyclodextrin polymers can also be prepared by using polymerizable cyclodextrin monomer derivatives, e.g. a cyclodextrin-acrylic ester, as starting substances or by linking cyclodextrin to another suitable polymer (Szejtli, ibid, pages 88 to 91).

The linking of cyclodextrins and their derivatives with gelatine has not up till now been described in the literature.

We have therefore sought to prepare a water-soluble copolymer combining the properties of gelatine and cyclodextrin or its derivatives.

We have now realized that it is possible to cause a chemical reaction between cyclodextrin or its derivatives and gelatine by using a suitable linking agent.

We have also realized that the chemical, physicochemical and mechanical characteristics of the polymer product thus formed can be regulated 4 54194.301 by varying the gelatins/eyclodextrin ratio.

According to the invention, the linking of gelatine with cyclc--2--xtrin or its derivatives can be achieved primarily in two ways, i.e.: either 1) by reacting cyclodextrin or a substituted cyclodextrin with gelatine and a linking agent; or 2) by reacting a water-soluble cyclodextrin polymer with gelatine and a linking agent.

According to one embodiment of the invention, we provide a process for the preparation of a gelatin/cyclodextrin polymer which comprises either a) reacting, per gram of gelatin, 1.5 to 15 mmol of epichlorohydrin or 0.1 to 2.5 mmol of a diglycidyl ether of formula (I) is CH2-CH-CH2- 0 -CH2-CH -CH2 \ 0 / \ 0 / (I) or a linking agent of general formula (II) or (III), CH2- CH- CH 2_ 0 -(CH2)rT- O-C- H2-CH-CH2 0 0 CH27=C-C=0 1 1 R Y wherein represents a hydrogen atom or a Cl-, alkyl group; Y represents a chlorine or bromine atom, or an amino or C.-4 alkoxy group such as methoxy, ethoxy, n- or isopropoxy group; m is an integer from 1 to 6; and 0.05 to 3.0 mmol of cyclodextrin or a substituted cyclodextrin of general formula (IV), CD(OCtX)M (ii) (III) (IV) wherein Q represents a -(CH2),,- group in which m is as defined above; X represents a hydrogen atom or a carboxyl, amino, NR2, hydroxyl or SO,H CD represents an a, p- or V-cyclodextrin molecule; and m is as defined above or 0.1 to 20 g of a watersoluble cyclodextrin polymer of general formula (V), 2 3 R qCD- Rl-R 1 n (V) p.R4 wherein CD is as defined above; R' represents a bridging group linking the cyclodextrin molecules used through an ether linkage in the polymeric chain, which contains the linking agent as a constituent; R 2 represents a hydrogen atom or is identical with R 3; 3 represents a hydroxyl, -CD.aR 4, OR5, O(CH2),0Rs. (OCH2CH2),OR-5, NR2 or -NH(CH2)m COOH group; 4 represents a -Rl.R2 or --[-- R'-CD-Rl group or p - 13 R.5 n is identical with R5; represents a hydrogen atom or a - (CH2),-COOH, or H2N- (CH2)._ group; is an integer from 2 to 12; p is zero or at least 2 units less than the original number of hydroxyl groups in the cyclodextrin used; and is an integer from zero up to an integer less by 1 unit than the original number of hydroxyl groups in cyclodextrin; with gelatin: or b) reacting, per mmol of cyclodextrin, 0.2 to 2.0 mmol of a compound of general formula (VI), or (VII), or 6 (VIII) X'- (CH2)m_ COOH H2N -(CH2)m COOH R2= N - R6 1 (VI) (Vii) wherein m and R2 are as def ined above; R 6 represents a hydrogen atom or a -(CH2)MC' or - (CH2),Br group; X1 is chlorine or bromine; 0.03 to 3.5 g of gelatin and 5 to 15 mmol of epichlorohydrin or 1.0 to 5.0 mmol of a diglycidyl ether of formula (I) or a linking agent of the general formula (II) or (III) with cyclodextrin.

In both processes according to the invention, any side products of the reaction and the water may be removed, if necessary or desired.

If it is desired to use a compound of general formula (III) in the above processes, an initiator may be used.

Lime gelatines with a low isoelectric point and gelatines with a high isoelectric point prepared by the acid process may both be used in the processes according to the invention.

In addition to a-, P- and -y-cyclodextrin monomers, 1 lO 1 their substituted derivatives containing e.g. carboxymethyl, diethylaminoethyl, dimethyl, trimethyl, hydroxypropyl, sulfopropyl or sulfobutyl moieties, or Water-SCI-LU,-j-2C cyclodextrin polymers, e.g. unsubstituted C - ' i- 0 r f-cyclodextrin polymers, or water-solubllee cvc lodextrin polymers containing carboxymethyl, diethylamino ethyl or carboxypropyl- Ir- amino groups separately or simultaneously,can also be used in the processes according to the invention.

Before linking with the gelatine, the following compound types may for example be used for substituting the monomer; halogenated carboxylic acids such as chloroacetic acid, bromoacetic acid or chloropropionic acid amino acids such as P-aminopropionic acid, r- aminobutyric acid; alkylamines such as dimethylamine, diethylamine, dibutylamine; or alkylaminoethyl chlorides such as diethylaminoethyl chloride.

In addition to epichlorohydrin and diglycidyl ether, the homologues of diglycidyl ether such as ethylene or butylene diglycidyl ether as well as unsaturated carboxylic acid chlorides and esters, e.g. methacryloyl chloride or methyl methacrylate may also be used as linking agents.

Potassium persulfate, hydrogen peroxide, benzoyl peroxide, inter alia, may be used as initiators.

In the processes of the invention, the reaction product can be obtained either in the form of a solution or as a solid.

k_ 0 8 - If desired, chloride ions and products with a lower molecular,weight may be removed from the crude reaction mixture by e.g. passing them through an ion exchange column or by dialysis. A solid product of the invention can be obtained by precipitation with a solvent, e.g. alcohol or acetone from solution, which is either previously deicnized or contains the side products of the reaction. Copolymers, which can be transformed to a gel due to their sufficient gelatine content, can be purified by washing with water after crushing the gel.

Each of the linking agents listed above goes into reacts with the amino and/or carboxyl groups of gelatine.

A method for observing the process of the linking reaction consists in the use of acid-base titration of the ionizing groups of gelatine, whereby the amount of groups that have entered the reaction at any one time can be determined /-P. Lanza and I. Mazzei: Annali di Chimica 53, 1833 (1963)7 The linking of gelatine with cyclodextrin through the linking agent can be followed by measuring the optical rotation (see Figure 1). This is based on the fact that the solution containing a mechanical mixture of various ratios of gelatine and cyclodextrin or cyclodextrin polymer (c.urves la and 2b) shows a more negative specific optical rotatory power than the copolymer according to the invention prepared with the same ratio of gelatine to cyclodextrin (curves lb and 2b).

The following explanation 0 is for the Cur.'les In fLg-:- 1: a: mixture; lu: copoly,-.,EL; both contain 80 % by mass of gelatine and 20 % by mass of cyclodextrin; 2a: mixture; 2b: copolymer; both contain % by mass of gelatine and 80 % by mass of cyclodexLrin.

This phenomenon may be connected with the fact that a certain proportion of the gelatine molecules in the copolymer product lose their isomerization at the proline-hydroxyproline peptide bonds.

The properties of a copolymer obtained from the reaction between gelatine, a linking agent and a cyclodextrin depend heavily on the gelatine/cyclodextrin ratio. When cyclodextrin calculated for the monomer is predominant as compared to gelatine, the solubility sharply increases and an aqueous solution of up to 50 % can be prepared at room temperature, i.e. the water-solubility of the copolymer is higher than that of any of the individual starting substances. Oppositely, a product capable of a reversible sol-gel transformation is obtained by an increase in the gelatine proportion. The copolymers possess an inclusion complex-forming character in both cases.

We therefore provide the following advantages which can be achieved by using theprocesses according to the invention.

1) A watersoluble polymer can be prepared which is useful for inclusion complex formation and capable of reversible sol-gel transformation.

2) A cyclodextrin-containing polymer can be prepared with a higher water-solubility than that of known cyclodextrin polymers.

3) The physical characteristics of a copolymer obtained by the processes according to the invention are more favourable than those of gelatine.

The process according to the invention is illustrated in detail by the following non-limiting Examples. (Cyclodextrin is abbreviated to "CO" in the Examples.) Example 1

0.013 mol of P-CD is added to 100 ml of 10 % gelatine solution with a low isoelectric point (IEP) (IEP = 4.8) previously adjusted to a pH value of 10.5 by adding 40 % sodium hydroxide solution. 0.13 Mol of epichlorohydrin is added dropwise to the solution while the temperature is maintained below 60 0 C. Then the reaction mixture is stirred at 60 oC for 1 hour, and after cooling down the pH value is adjusted to 6.5 by the addition of 10% hydrochloric acid. The solution is evaporated to a third of its oriqinal volume under reduced pressure. After precipitating with alcohol, the product is washed and dried.

Example 2

The process described in Example 1 is followed,except that CD is used instead of VCD and 0.16 mol of epichlorohydrin is added.

Example 3

The process described in Example 1 is followed, 11 J except that 0.010 mol of C_CD is used instead of -CD and 0.10 mol of epichlorohydrin is added.

Example 4

The process described in Example 1 is followed, except that 0.005 mol =1 P-CC and 0.10 mol oi' epichlorohydrin are used.

Example 5

The process described in Example 1 is followed, except that 0.005 mol of CD and 0.05 mol of epichlorohydri are used.

Example 6

The pH value of 100 ml of 10 % gelatine solution with a high isoelectric point (IEP = 8.2) is adjusted to by adding 40 % sodium hydroxide solution. Then 100 ml of a 20 %P-CD polymer (hereinafter abbreviated:PCDP) (containing 56 % of CD) solution and 0.015 mol of epichlorohydrin are added dropwise. The reaction mixture is stirred at 58 OC for 45 minutes and then treated and worked up as described in Example 1.

Example 7

The process described in Example 6 is followed, except that 100 inl of 10 % carboxymethyl- P-cyclodextrin polymer solution (hereinafter abbreviated: CM-P -CDP) containing 59 of CP)are used.

Example 8

The process described in Example 7 is followed, except that 0.050 mol of epichlorohydrin is used.

12 Example 9

The Process described in Evample 7 is followed, eycent that 0.015 mol of epichlorohydrin and 1.0 g of CM- CDP (containing 59 % of CO) are used.

Example 10

The process described in Example 6 is followed, except that 100 ml of 10 % diethylami no- Vcyclodextrin polymer (hereinafter abbreviated: DEA- p COP) (containing 59 % of CD) solution are used instead of the CDP Example 11

0.013 mol of diglycidyl ether (hereinafter abbreviated: DGE) is added to 100 ml of 10 % gelatine solution with a low isoelectric point ( IEP = 4. 8) at 55 OC under stirring, and the stirring is continued for 30 minutes. Thereafter, 0.012 mol of k CO is added, the pH value is adjusted to 11 by 40 % sodium hydroxide solution and the mixture is stirred at 60 0 C for 1 hour. After neutralizing the solution,by the addition of 10% hydrochloric acid, it is evaporated to a third of its original volume under reduced pressure. After cooling down, the precipitated yellow mass is dissolved in distilled water, precipitated by alcohol, filtered and dried.

Example 12 k The process described in Example 11 is followed, except that c,-CD is used instead of Co.

Example 13

The process described in Example 11 is followed, except Q 0 0 that r- CD is used instead of CD.

Example 14

The process described in Example 11 is followed, except that 0.0065 mol of DGE, 7.62 g of sulfobutyl- cyclodextrin (hereinafter abbreviated: SB-PCO) and a gelatine with a high i.soelectric point (IEP = 8.2) are used and the pH value of the reaction mixture is adjusted to 8.5 by using 40% sodium hydroxide solution.

Example 15

The process described in Example 14 is followed, except that 8.54 g of pentakis(carboxymethyl)- P -cyclodextrin (hereinafter abbreviated: PCM-P CD) are used instead of SB- Co.

Example 16 g of gelatine (IEP = 4.8) are swollen and then dissolved in 150 ml of distilled water. To this solution 0.003 mol of DGE are added and the solution is stirred at its own pH at 40 0 C for 10 minutes. Simultaneously, 0.015 mol of s- CO is introduced into 50 ml of distilled water and dissolved by adding sufficient 40% sodium hydroxide solution. The alkaline CO solution is aedxqith the gelatine solution during 5 minutes, then the temperature is raised to 55 to 60 0 C and after stirring for 1 hour at the same temperature, the reaction mixture is stored overnight. The pH value is adjusted to 6.5 by using 10% hydrochloric acid, then the solution is evaporated to half the volume under reduced pressure. After t -z precipitating with alcohol, tne solid product obtained is washed and dried.

Example 17

The process described in Example 16 is follo.wed, except that 0.015 mol of DGE is used.

Example 18

The process described in Example 16 is followed, except that, instead of CO, 30.9 g of CM--COP (containing 55 % of CD) are dissolved in 100 ml of water by adding 40 % sodium hydroxide solution.

Example 19

The process described in Example 18 is followed, except that 0.015 mol of DGE is used.

Example 20

The process described in Example 16 is followed, except that, instead of CD, 57.7 g of CM-P-COP (containing 59 % of CD) are dissolved in 150 ml of water by adding 40 % sodium hydroxide solution and a gelatine with a high isoelectric point (IEP = 8.2) is used.

Example 21

The process described in Example 20 is followed, except-that 0.025 mol of DGE is used.

Example 22

The process described in Example 20 is followed, except that 5 g of gelatine with a high isoelectric point are used.

- Example 23

The process described in Example 16 is follot..,ed, except that, instead of DGE, 0.015 mol of butylene didglycidyl ether ( hereinafter abbreviated: BOE) /-a of general formula (II) wherein m is 4) is used.

Example 24

The process described in Example 23 is followed, except that 0.050 mol of BDE and 0.025 mol ofP-CO are used.

Example 25

The process described in Example 16 is followed, except that 100 ml of 5 % gelatine solution, 0.015 mol of BOE instead of DGE and instead of P-CO, 45 9 of CM -COP (containing 57 % of CD) dissolved in 150 ml of water by adding 40 % sodium hydroxide soluiion are used.

Example 26

The process described in Example 25 is followed, except that 100 ml of a 10 % gelatine solution, 25 g of CM- -COP (containing 5 7 % of CO) and 0. 022 mol of BDE are used.

Example 27

The process described in Example 25 is followed, except that 100 ml of 10_% gelatine solution with a high isoelectric point (IEP = 8.2), 5 g of CM- P -CDP (containing 57 % of CD) and 0.015 mol of BDE are used.

Example 28 The process described in Example 25 is followed, ? 5 - 16 excep-, that 166 m! oi' 10 % gelatine solution, 1 g of CM-P -COP (containing 57 % of CD) and 0.025 mol of BDE are used.

Example 29

After adding 0.018 mol of -CO to 100 mol of % inert gelatine solution at 40 OC, the pH value of the solution is adjusted to 10.5 by adding 40 % sodium hydroxide solution, then the temperature is increased to 58 0 C and 0.025 mol of methacryloyl chloride /-a compound of general formula (III), wherein R is CH3 and Y is C17 is added under stirring. The mixture is stirred for additional 30 minutes at the same temperature, then the reaction mixture is cooled to 40 0 C, the solid product is precipitated by adding acetone, washed and dried.

Example 30

The process described in Example 29 is followed, except that 8 ml of 1 % potassium persulfate solution are also added to the gelatine solution.

Example 31

The process described in Example 29 is followed, except that IT- CD instead of -CD and a gelatine with a high isoelectric point (IEP = 8.2) are used and the pH value of the reaction mixture is adjusted to 8.5 by adding sodium hydroxide solution.

Example 32 100 ml of 10 % CM- P -COP solution (containing 57 % of Q lO CD) are added to 100 ml of 10 % inert gelatine solution.

The temperature is adjusted to 60 0 C, 0.025 mol of methacrycloyl chloride is added dropwise under stirring, then the stirring is continued 30 r.--nutes. After cooling to 40 C the solid product is precipitated by acetone, washed and dried.

Example 33

The process described in Example 32 is followed, except that 100 ml of 5 % inert gelatine solution and 0.005 mol of methacryloyl chloride are used.

Example 34

The process described in Example 32 is followed, except that 100 ml of 1 % inert gelatine solution, 100 ml of 20 % CM--COP solution and 0.001 mol of methacryoyl chloride are used.

Example 35

0.018 mol. of CD is added at room temperature to 3.42 g (0.036 mol.) of chloroacetic acid dissolved in 30 ml of 6 % sodium hydroxide solution under stirring. After stirring for additional 20 minutes, 30 ml of 6 % sodium hydroxide solution are added again dropwise, the temperature is increased to 58 OC and the mixture is stirred at the same temperature for 70 minutes. Then, after adding 50 ml of 3 % inert gelatine solution, the pH value is adjusted to 10.5 by adding 20 % sodium hydroxide solution and, while maintaining the temperature at 60 OC, 7 ml 18 (0.045 mole) of BDE are added dropwise and the stirring is continued at the same temperature for additional 30 minutes.

Thereafter, the pH value is adjusted to 6.5 by adding % hydrochloric acid, the solution is evaporated to its half volume under reduced pressure and after precipitating by acetone, the solid product is was.hed and dried.

Example 36

The process described in Example 35 is followed, except that 0.342 9 (0. 0036 mol) of chloroacetic acid and 200 ml of 10 % inert gelatine solution are used.

Example 37

The process described in Example 35 is followed, except that 300 ml of 12 % inert gela+ine solution are used.

Example 38

The process described in Example 35 is followed, except that 1.026 9 (0. 0108 mol) of chloroacetic acid, 50 mI of 1 % inert gelatine solution and, instead of BOE, 0.27 mol of epichlorohydrin are used.

Example 39 -

The process described in Example 38 is followed, except that 0.18 mol of epichlorohydrin is used.

Example 40

The process described in Example 35 is followed, except that 0.09 mol of epichlorohydrin and a gelatine with a high isoelectric point (IEP = 8.2) are used.

lo 1 1 i lo - 19 Example 41

After dissn vi nn n ni P,1 nf G-Pn 51 45 1 nf 1 - % sodium hydroxide solution, 0.035 mol of 'r-aminobutyric acid is added, then the temperature is increased to 50 OC and 50 ml of 3 % inert gelatine solution are added. After adjusting the pH value to 10.5 by 40 % sodium hydroxide solution, 0.18 mol of epichlorohydrin is added dropwise under stirring while the temperature is maintained at 60 OC as a maximum. The reaction mixture is stirred at 60 0 C for anadditionall hour, then the pH value is adjusted to 6.5 by adding 10 % hydrochloric acid and the solution is evaporated to its half volume under reduced pressure. After precipitating by acetone, the solid product is washed and dried.

Example 42

The process described in Example 41 is followed, except that 150 ml of 10 % inert gelatine solution and 0.13 mol of epichlorohydrin are used.

Example 43

The process described in Example 41 is followed, except that 0.030 mol of diethylamine are used instead of f-aminobutyric acid.

Example 44

The process described in Example 43 is followed except that 0.020 mol of diethylamine and 200 ml of 10 inert gelatine solution are used.

0 Example 45 The Process described in Example 35 is followed, c,.ce,,t that the addition of sodium hydroxide solution is r- not repeated after adding the gelatine solution and 0.045 mol of methacryloyl chloride is used instead of BDE.

Examnle 46 The process described in Example 45 is followed, except that 200 ml of 10 % inert gelatine solution and 0.018 mol of methacryloyl chloride are used.

Example 47

The process described in Example 45 is followed, except that 0.090 mol of methacryloyl chloride and a gelatine with a high isoelectric point (IEP = 8.2) are used.

Example 48

The process described in Example 45 is followed, except that 200 ml of 20 % gelatine solution and 0.018 mol of methacryloyl chloride are used.

Example 49

The process described in Example 45 is followed, except that 320 ml of 20 % inert gelatine solution and 0.018 mol of methacryloyl chloride are used.

Example 50

The process described in Example 45 is followed, except that 0.036 mol of diethylaminoethyl chloride hydrochloride are used instead of chloroacetic acid.

The data relating to the products synthetized according to Examples 1 to 50 are summarized in Tables 1 and 2 where the specific optical rotatory power values 1-c,7 of 1 % solutions measured at a wave length of 220 nm are also shown. These can be evaluated by caiparirotl-sn w-l the data in Figire 2. In this Figze 2, the [o%:] values at^,\ = 220 nn of 1 % solution prepared from the mixtures of various ratios of P- cyclodextrin (1), cyclodextrin polymer prepared with epichlorohydrin (2), or CIA- -CD linked with butylene diglycidyl ether (3) and gelatine are illustrated.

On the comparison of these values to the specific optical rotatory power values observed with the corresponding cyclodextrin ratios of the Examples shown in the Tables, it can be stated that the /-b/- 7 values of the products prepared according to the invention are without exception more positive, indicating that the chemical reaction has proceeded between the starting substances to give a polymer also containing gelatine as constituent.

1 Table 1

Data relating to Examples 1 to 34 (reactants calculated for 1 g of gelatine) Example Linking agent No.

k mmol Cyclodextrin of Name 9 linking agent mm Ol CD ratio c- =22u % by mass 1 Epichlorohydrin 13 -CD 1.3 59.6 - 8 2 15 T-CO 1.3 62.8 + 30 3 10 c--CD 1.0 49.3 + 80 4 10 -CD 0.5 36.2 - 200 5 P-CD 0.5 36.2 - 900 6 1.5 PWP 2.0 66.6 + 420 7 1.5 CM--COP.1,0 50.0 + 100 8 5 CM--CDP 1.0 50.0 + 210 9 1.5 CM-P-CDP 0.1. 9.1 - 1800 1.5 DEA--COP 1.0 50.0 + 165 11 Diglycidyl ether 1.3 -CD 1.2 57.7 - 27 12 1.3 dI-CO 1.2 53.8 - 20 13 1.3 f--CD 1.2 60.9 + 50 14 0.65 SB-P-CD 0.6 43.2 - 110 0.65 PCM- -CD 0.7 46.0 - 200 16 0.3 -CD 1.5 63.0 + 210 17- 1.5 -CD 1.5 63.0 + 290 18 0.3 CM+WP 3.0 75.5 + 400 19 1.5 CM-P-CDP 3.0 75.5 + 600 0.3 CM-P-COP 5.8 85.2 + 800 q 23 Table 1 (cont.) Example Linking agent mnibl of Cyclodextrin linking Nante g n, ITIO agent CD ratio /-c, 7 A =22G % by mass 21 2.5 CM--COP 5.8 85.2 + 860 22 5.0 CM--COP 11.5 92.0 + 960 23 Butylene diglycidyl ether 1. 5 P-CD 1.5 63.0 + 100 24 5.0 -CO 2.5 73.9 + 450 3.0 CM--CDP 9.0 90.0 + 1200 26 2.2 CM--CDP 2.5 71.4 + 400 27 1.5 CM-P-COP 0.5 33.3 250 28 2.5 CM--CDP 0.1 9.0 1000 29 Methacryloyl chloride 2.5 -CO 1.B 67.1 + 350 2.5 P-CD 1.6 67.1 + 420 31 2.5 t-CD 1.8 70.0 + 600 32 2.5 CM-P-WP 1.0 50.0 + 800 33 1.0 CM--CDP 2.0 66.7 + 1000 34 1.0 CM-P-COP 20.0 95.2 + 1800 24 Table 2

Oata relating to Examples 35 to 50 (reactants calculated for 1 mmol of P-cyclodextrin) Example Linking agent mmol Substituting Gelatine CO /& 7, =220 NO. agent 9 ratio % by G1355 Butylene diglycidyl ether 2.5 C hloroacetic acid 0.083 93.2 1350 36 2-5 1.111 50.6 400 37 2.5 2.0 36.2 100 38 Epichlorohydrin 115.0 0.083 9 3. 2 + 1600 39 io. 13 O.OU3 93.2 1530 4 0 5.0 0.083 9 3. -2 1450 J 41 10.0 -Aminobutyric acid 0.083 93.2 1500 42 7.0 0.830 57.8 + 430 43 10.0 Ethylamine 0.083 93.2 + 14.00 44 10.0 1.111 50.6 + 870 Methacrylyol chloride 2.5 Chloroacetic acid 0.083 93.2 + 1050 46 1.0 1-111 50.6 - 200 47 5.0 1.111 50.6 - 100 48 1.0 2.222 33.8 - 500 49 1.0 3.55 24.2 - 950 2.5 Diethylaminoethyl chloride 0.083 93.2 + 1150 1

Claims

1. Process for the preparation of a gelatin/cyclodextrin polymer which comprises either a) reacting, per gram of gelatin, 1.5 to 15 mmol of epichlorohydrin or 0.1 to 2.5 rmol of a diglycidyl ether of formula (I) -CH2-CH-CH2- 0 -CH2-CH -CH2 \ 0 / \ 0 / or a linking agent of general formula (II) or (III), is CH2- CH - CH 2- 0-02)m O-CH2-CH-CH2 \ 0 / - \ 0 / CH2= C-C--0 1 1 R Y- wherein R Y represents a hydrogen atom or a C1-5 alkyl group; represents a chlorine or bromine atom, or an amino or Cj-, alkoxy group such as methoxy, ethoxy, n- or isopropoxy group; M. is an integer from 1 to 6; and 0.05 to 3.0 mmol of cyclodextrin or a substituted cyclodextrin of general formula (IV), CD- (OQX)rn (IV) wherein represents a -(CH2)m- group in which m is as defined above; x represents a hydrogen atom or a carboxyl, amino, NR2, hydroxyl or S03H group; CD represents an a, fl- or 7-cyclodextrin molecule; and m is as defined above or 0.1 to 20 g of a water- (I) G I) (III) t j.

26 soluble cyclodextrin polymer of general formula (V), R2fCD-Rll-R3 1 n (V) P.R4 wherein CD is as defined above; R' represents a bridging group linking the cyclodextrin molecules used through an ether linkage in the polymeric chain, which contains the linking agent as a constituent; R2 represents a hydrogen atom or is identical with R3; 3 represents a hydroxyl, -CD.aR 4, ORS, 0 (CH2) ORS (OCH2CH2 -5, NR2 or -NH (CH COOH group; ) OR 2) m 4 represents a -Rl.R2 or --[-- R'-CD-Rl group or 1 3 p.R R 5 n p a b) of a (VIII) X'- (CH2)M-.;- COOH H2N -(CH2), COOH R2= N - R6 is identical with R5; represents a hydrogen atom or a -(CH2),-COOH, or H2N- (CH.) - group; is an integer from 2 to 12; is zero or at least 2 units less than the original number of hydroxyl groups in the cyclodextrin used; and is an integer from zero up t- an integer less by 1 unit than the original number of hydroxyl groups in cyclodextrin; with gelatin: or reacting, per mmol of cyclodextrin, 0.2 to 2.0 mmol compound of general formula (VI), or (VII), or (VI) (VII) (VIII) 27 wherein m and R 2 are as defined above; R 6 represents a hydrogen atom or a -(CH2)mCl or - (CH2),Br group; X1 is chlorine or bromine; 0.03 to 3.5 g of gelatin and 5 to 15 mmol of epichlorohydrin or 1.0 to 5.0 mmol of a diglycidyl ether of formula (I) or a linking agent of the general formula (11) or (III) with cyclodextrin, and when necessary or desired, removing the side products of the reaction and the water in both processes.

2. A process as claimed in claim 1, which comprises using a gelatine prepared by the lime process and having a low isoelectric point as well as cyclodextrin or a substituted cyclodextrin of formula (IV), as starting materials.

3. A process as claimed in claim 1, which comprises using a gelatine prepared by the lime process and having a low isoelectric point as well as a water-soluble cyclodextrin polymer of general formula (V) as starting materials.

4. A process as claimed in claim 1, which comprises using a gelatine prepared by the acid process and having a high isoelectric point as well as cyclodextrin or a substituted cyclodextrin of general formula (IV) as starting materials.

5. A process as claimed in claim 1, which comprises using a gelatine prepared by the acid process and having a high isoelectric point as well as a water-soluble cyclodextrin polymer of the general formula (V) as starting materials.

# It 28

6. A process as claimed in any preceding claim wherein if a linking agent of general formula III is used, an initiator is used.

7. A cyclodextrin/gelatin polymer which comprises gelatin and cyclodextrin or a derivative thereof crosslinked by a linking agent of epichlorohydrine or of formula (I) or (II) or (III) as defined in claim 1 above.

is

8. A cyclodextrin/gelatin polymer substantially as hereinbefore described.

9. A cyclodextrin/gelatin polymer substantially as hereinbefore described with reference to any of the Examples.

10. A process as claimed in claim 1 substantially as hereinbefore described and with reference to the 20 Examples.

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