CA2092513A1

CA2092513A1 - N-substituted chitosan derivatives, process for their preparation and the use thereof

Info

Publication number: CA2092513A1
Application number: CA002092513A
Authority: CA
Inventors: Dieter Lohmann; Donald R. Randell
Original assignee: Ciba Geigy AG
Current assignee: BASF Schweiz AG
Priority date: 1992-03-27
Filing date: 1993-03-25
Publication date: 1993-09-28
Also published as: DE59306229D1; KR930019700A; AU3551193A; KR100257092B1; JPH0641202A; EP0563013B1; EP0563013A2; BR9301334A; ATE152132T1; MX9301732A; AU658986B2; EP0563013A3

Abstract

N-Substituted chitosan derivatives, process for their preparation and the use thereof Abstract of the Disclosure Chitosan derivatives having structural units of formula I, II and III in random distribution

Description

N-Substituted chitosan derivatives. pr~cess ~or thelr preparation and the use thereof The present invention relates to chitosan derivatives the amino groups of which are substituted by hydroxyacyl that carries a carboxylic acid, phosphonic acid or sul~onic acid group, or the esters and salts thereof, to a process for their preparation by react~ng a chitosan with a 4- or ~membe~ed lactone or a 4-membered sultone that carries sulfonic acid ester, phosphonic acid ester or carboxylic acid ester or CC13 ~OUpS, and subsequently hydrolysing CCI3 groups, if desired converting ester groups into acid groups and acid groups thereafter into salts, and tO the use ~hereof for preventing the adherence to and/or formation of solid coats on inorganic or organic substrates, as well as to the use thereof as humectants for s~n and mucous membranes.

Chitosan derivatives which ca~y carboxyaLI~yl-substitu~d amino gTOUpS are disclosed in DE-A-2 222 733. They are prepared by reacting chitosan with a cyclic anhydri~e such as succinic anhydride. Hydroxyi-substituted anhydrides are not mentioned and even excluded in the description of ~he synthesis. These chitosan derivatives may be used as chelating agents, detergents, and ~s additives for cosmetic or phannaceutical compositions.

SulfopIopyl derivatives of chitosan that are obtained by reacting chitosan with 1,3-propanesultone are disclosed in DE-A-3 432 227. These derivatives are used as additives for cosmetis compositions.

K. Kurita et al., in Polymer Journal 22, No. 5, pages 429434 (199û), descnbe the reaction of chitosan with ~-butyrolactone t~ prepare ~-hydr~xybutanoyl-sllbstituted chitosan derivatives. E. Loubaki et al. in Eur. Polym. J, 25, No. 4, pages 379 -84 (1989) describe a similar modification of chitosan with ~B-propiolactone and ~gluconolactone.

Chitosan derivatives the N-,substituent of which carries hydroxyl groups and acid groups, and which are thereby capable of salt forma~on, are not yet known in the art. It has now been ~ound that such chitosan denvatives are obtained in good yield and quality by using instead of inert lactones those carrying an activadng group in o~-position to the ring oxygen atom. They are suitable for many u~lities as substitute ~or hyaluronic acid.

In one of its aspects the inveneion relates to oligome.ric and polymeric chitosan derivatives containing structural units of fonnulae I, II and m ill random dis~ibution CH20R1 CH20Rl CH20Rl ~O~ H~O~o H~~ro \~NH/ ~ ~H
Z--R2- X H NHR3 H ~3NH3Ye I) (m), wherein the substituents Rl are each independently of one another H or ehe :radical -ZR2-X, R3 is H or acetyl, Y is the anion O-7.-R2-X, and (a) Z is -CO- or -SO2-, X is -C02H, -CH2CO2H or -CII2PO(OH)2, and R2 iS
-CHR4CR5(OH~-, R4 is -H, -OH, Cl C4aLkoxy or Cl-C4aLk~YI, and Rs is H or Cl-C4aLlcyl, or (b) Z is -CO-, X is -CO2H, and E~2 iS -~6-(~7-CH~O~I)- or -CHR8-CHRg-CHRlo-CH(OH3-, R6, R7, R8 and Rlo are each independently of one anoeher -H, -OH, Cl-C4al1yl or Cl-C4alko~sy, and Rg is -H, -OH, Cl-~4aLkyl, Cl-C4aL~coxy or -CO2H, and the esters and salts thereof, which chitosan denvatives contain a total of at least 2 stmctural units and, based on 1 mol of the chitosan derivative, 30 to 100 % molar o~
structural units of formula I, 60 to 0 % molar of structural units of formula II, and 30 to O % molar of struct~al lmits of foImula m, and the sum of the molar percentages is 100%.

In preferred embodiment of the invention, the chitosan derivative contains a total of at least 4 structural units, oligomers preferal~ly containing 4 to 50, most pre~erably 6 to 30, s~uctural units. Polymeric chitosan derivatives may typically contain up to 10 000, preferably up to 8000 and, most preferably, up to 5000, s~ctural units.

In a further prefe~red embodiment of the invention, the chitosan delivative contains 50 to 100 % molar of structural u:nits of formula I, S0 to 0 % molar of structural units of formula II, and 20 to 0 % molar of structl~l units of folmula m, the sum of the molar ,, .

r~ 3 2 i~

percentages being 100 %. Most preferably, the chitosan deriva~ive contains 60 tolQO % molar of structural units of formula I, 40 to O % molaT of structural units of forrnula II, and 10 to O % molar of s~lctural units of formula m, the sum of the molar percentages being 100 %.

Z in definition (a) of the structural units I, II and m is preferably -CO- and X is preferably -CO2H or -CH2P~(OH)2, or ~ is -SO2- and X is -CO2H.

R4 to Rlo as aLIcyl may be methyl, ethyl, n- or isopropyl or n-, iso- or tert-butyl. Preferably R4 to Rlo as alkyl are methyl or ethyl.

R4 to Rlo as aLIcoxy may be methoxy, ethoxy, propoxy or butoxy. Preferably R4 to Rlo as aLkoxy are methoxy.

R4 and R6 to Rlo are preferably H, OH, methyl or methoxy and Rs is H or methyl.

Typical examples of R2 are -C~2CH(OH)-, -CH2C(CH3)(0H)-, -OEI(OH)CEI(r)H)-, -CH(CH3)CH(OH)-, -CH(OCH3)C~(0~I)-, -CH2CH2CH(C)H)-, -OEI(OH)CH2CH(O~I)-, -CH(OH)OEI(OH)CH(OH)-, -CH(CH3)~H2CH(OH)-, -CH2C~H(OH)CH(OH)-, -CH(OCH3)CH(OH)CH(OH)-, -CH2CH(OCH3)CH(OH)-, -CH2CH2CH2CH(OH)-, -CH2CH2CH(OH)CH(O~l)-,-CH2CH(OH)CH(OH)CH(OH)-, -CH2CH(COOH)C~I2CH~OH)-, -CH2CH(OH)CH(CH3)CH(OH)- iand -CH2CH(OH)CH(OC~13)CH(O~I)-. Most preferably R2 iS -CH2CH(OH)- i~md -CH2C(OEI3)(0H)-.

The carboxylic acid and phosphonic acid group can be estenfied, ~pically with analiphatic, cycloaliphatic, araliphatic or aromatic alcohol which contains 1 to 30, 1 to 20 and, most preferably, 1 to 12, carbon atoms. Representative examples of such alcohols are alkanols such as me~hanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, nonanol, decanol, undecanol, dodecanol, tetradecanol, octadecanol; po-lyoxaaLlcanols such as ethylene g,lycol monome~yl ether or monoethyl ether, diethylene monomethyl ether or monoethyl ether, oligoethylene glycols or oligopropylene glycols or copolymers thereof containing a total of up to 20, preferably of up to 12, monomer units;
cycloaLlcanols such as cyclopentanol and cyclohexanol; benzyl alcohol and Cl-cl2alkyl-substiblted benzyl alcohols; phenol and Cl-CI2alkyl-substituted phenols.

The carboxylic acid and phosphonic acid groups may also be in salt ~orm. They may be metals of the main and subsidiary groups of the Periodic System of the elements, typically the metals of the third, fourth and fifth main group and the subsidiary groups of the Periodic System of the chemical elements. Particulalrly suitable metals are Li, Na, K, Mg, Ca,Sr,Ba,B,Al,Ga,In,Sn,Pb,Sb,Bi,Cu,Ag,Au,Zn,~d,Hg,Sc,Y,La,Ti,~r,Hf,V, Nb, Ta, Cr, Mo, W, Fe, Co, Ni, Ru, lRh, Pd, Os, k, Pt and ~he lanthanide metals Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, HO, Er, Tm, Yb and Lu. When using polyvalent metals, the corresponding cations can act as crosslinkers of the oligomer and polymer chains.
Preferred metals are the alkali metals and aLkaline earth metals. The salts may also be in the form of amine salts, conveniently of ammonium salts or salts of prim2ry, secondary or tertiary amines which pre~erably contain 1 to 20 and, most preFerably, 1 to 12, carbon atoms, or of salts of polyamines containing primary, secondary andlor tertiary amino groups and, preferably, 2 to 20, most preferably, 2 to 16, carbon atoms, or of salts of a polymer containing amino groups in structural repeating units.

Typical examples of amines are: methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylan~ine, n-propylamine, isopropylamine, di-n-propylamine, diisopropylamine, tri-n-propylamine, triisopropylamine, n-butylamine, di-n-butylarnine, tri-n-butylamine, hexylan~ine, dodecylamine, octadecylamin, icosylamine, morpholinw, N-methylmorpholine, piperidine, N-methylpiperidine, aniline, N-methylaniline, N-dimethylaniline, pyridin, pyrimidine, ethanolamine, die~hanolamine and triethanolamine.

Typical examples of polyarnines are: ethylenediamine, N,N'-dimethyle~hylenediarnine, diethylenetriamine, triethylenetetramine, 1,3-diaminopropane, 1,3-dimethylaminopropane, 1,4-diaminobutane, piperazine, phenylenediamine, naph~hylenediamine, 4,4'-diaminodiphenyl, 4,4'-diaminodiphenyl e~her, 4,4'-diaminodipherlyl thioether and 4,4'-diaminodiphenylmethane.

Typical examples of polymers containing amino groups are poly(aminosaccharides) such as chitosan itself and polygalactosamine, albumin or polyethylenimine, low molecular polyamides ca~rying amino end groups and aminoaL~cylated polyacrylamides or polyme-thacrylamides.

The chitosan derivatives can be prepared in sirnple manner by reacting chitosan with ~-, y-or ~-lactones or ~B-sultones which contain an esterified carboxyl group or a CCI3 group in - s -~-position to the ring oxygen atom, and subsequently hydrolysi:ng the CC13 group and, if desired, conver~ng the ester groups into acid groups and the acid groups into salts.

In another of its aspects, the invention relates to a process for the preparation ~f the novel chitosan derivatives containing a total of at least 2 structural units of formulae I, II and III
in random distribution, which process comprises reacting a chitosan containing a total of at least ? structural Imits of formulae IV and V in random distnbution, -aV), ~-(V), wherein R3 is acetyl or H, and said chitosan contains 30 to 100 % molar of structural units of formula IV and 70 to 0 % molar of structural units of forrnula V, based on 1 mol of chitosan, in the presence of an inert solvent, with at least 30 % molar of a lactone of formula VI, VIl or YIII, based on said chitosan, x~ ~R4 R7~_~R6 R~R8 1--11 X/~O~O XlO~o wherein R4, R5, R6, R7, R8, Rg and Rlo have the mear~ings previously assigned to them, 2;
is =CO or =SO2, Xl is -CC13, -CO2Rll, -cH2cr)2Rll or -c~2Po(oRll)2~ X2 is -ct32Rll, and Rll is the radical of an alcohol of l to 20 carbon atoms which lacks the hydroxyl group, and hydrolysing the resultant chitosan derivatives, wherein Xl is -CU3, under alkaline condidons to form the corresponding carboxylic acid salts, if desired conver~ng the carboxylic acid salts ancl esters into the colTesponding acids and the acids into salts.
By adjusting the pH of the reaction mixture, the carboxylic acid salts can be conver~ed into the coIresponding acids,, which are also isolated as such.

Surprisingly, the inventive process makes it possible for the ~lrSt dme to prepare N-acylated chitosans containing acid and hydrs~xyl groups in the N-acyl group.
Particularly advantageous is the use of the ,B-lactones and ,B-sl1ltones which contain CCl3 groups, as these CCl3 groups can be converted in sirnple manner into the carboxyl group.
The reaction leads under mild conditions to high chemical conve~sions such that even complete substitutions at the NH2 group of the chitosan can be achieved and side-reactions substantiaUy avoided.

In yet another of its aspects, the invention relates to ~he intermediate chitosan derivaeives containing structural units of formulae IX and X in random distribution, ~0_ (IX) (X) wheIein the Rl2 substituents are each independently of the other H or ehe radical -ZR2-X3, 1;~3 is H or acetyl, Z is -CO- or -SO2-, X3 is -CCl3, and R2 is -CHR4CRs(OH)-, R4 is -H, -OH, Cl-C4aLtcoxy or Cl-C4allyl, and Rs is H or Cl-C4aLlcyl, which chi~osan derivative contains a total of at least 2 structural units and, based on l mol of s~ud chitosan derivative, 30 to l00 % molar of structural units of formula IX and 70 to 0 % molar of structural units of ~ormula X.

Rl2 is preferably H, and X3 is preferably -CCl3. Z is preferably -CO-. R2, R4 and Rs have the preferred meanings previously assigned to them. Most preferably R2 represents the radicals -CH2CEI(OH)- and CH2C(C~I33(0H)-. With respect to the number of s~uctural units and the content of structural units, reference is made to the preferences stated previously concerning the novel chitosan acids, esters and acid salts.

It has been found useful to activate the commercially available chitosan before the reaction by dissolving the chitosan in e.g, dilute acetic acid, removing undissolved constituents by filtration ancl then neutralising with a dilute aqueous base, conveniendy NaOH, until the pH is c. 8-9, so that the chitosan again precipitates. The salts are removed 7 t'lJ ii ~

by known methods, typically by washing off or dialysis. The product can then be hyroextracted by repeated centrifugation with a non-solvent, conveniently an ether such as dioxane, to give products with water contents of c. 3 to 10 % by weight which are highly swollen and have a high reactivity. Depending on the reaction conditions and on the water content of the chitosan used, it is possible during the reacdon by hydrolysis to obtain hydroxycarboxylic acids which lead to chitosan derivatives containing structural units of formula III by salt for~nation. The reaction can, however, be completely suppressed by rnild conditions, so that it is also possible to obtain chitosan derivatives which do not contain structural units of formula m. Under drastic ~action conditions7 and given a high water and acetyl group content of the chitosan, it is possible to obtain highly swellable gels as final products which arç readily crosslinked.

In the course of the reaction a limited reaction of the free hydroxyl groups with the lactones can also take place; but this reaction can be substantially suppressed by ~he choice of reaction conditions. Chitosan derivatives wherein R1 is hydrogen in the structural units of formulae I, II and m are preferred.

The amount of structural units of formula II will depend on the one hand on the content of acetyl groups in the cl~itosan and, on the other, on the reactivity of the lactones used and on the degree of substitution which is attainable. Commercially available chitosans can contain up to 70 % mvlar of acetyl group containing s~uctural units of formula V.

Oligomeric chitosans can be typically obtained by hydrolytic degradation of the polymers, for example with a dllute mineral acid such as hydrochloric acid. The mixtures of oligomers obtained are then neutralised with e.g. NaOH and freed firom salts and low molecular constituents by ultra~lltration through a membrane. The resultant mixtures of oligomers can be used as obtained or fracdonated beforehand in known manner.
Oligomeric chitosans can also be obtained by deacetylation of chitosan oligomers, for example deacetylated chitobiose or chitohexaose, which are also commercially available.

The lactones suitable for use in the practice of this invention are known, some being commercially available or obtainable by known methods.

The inventive process may be calTied out by dissolving or suspending the chitosan in a solvent and then adding the solution or suspension to a solution of the lactone. This step is preferably carried out at room temperature. Afterwards, the reacdon mixture is s~rred at f~ U

room or eleYated temperature and the reaction is allowed to go to completion. The reaction can be calTied out in the temperature range from 0 tO 150C, preferably frorn 10 to 120C
and, most preferably, ~om 20 tO 100C.

The reaction is conveniently carried out excluding moisture, ~or exam~le humidity or water in solvents. In general, the process is conveniently carried out in a dry inert gas atmosphcre, typically a rare gas (helium or argon) or nitrogen.

Suitable solvents are typically polar aprotic solvents which can be used singly or as rnixtures of at least two or more solvents and in which are the chitosan dissolves or swells.
The solvents can also be used as suspension agents. Exemplary of such solvents are ethers (dibutyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether), halogenated hydrocarbons (methylene chloride, chloroform, 1,2-dichloroethane, 1,1,1-tri chloroethane, 1,1,2,2-tetrachloroethane), N-aLkylated carboxan~ides and lac~ams ~N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, tetramethylurea, hexamethylphosphoric triamide, N-methylpyrrolidone, N-acetylpyrrolidone, N-methylcaprolactam), sulfoxides (dimethyl sulfoxide), sulfones (dimethyl sulfone, diethyl sulfone, trimethylene sulfone, tetramethylene sulfone), substituted benzenes (benzonitlile, chlorobenzene, o-dichlorobenzene, 1,2,~tri-chlorobenzene, nitrobenzene), nitriles (acetonitrile, propionitrile). Also suitable are aroma-tic-aliphatic ethers such as methyl or ethyl phenyl ether, and ke~ones such as acetone, methyl ethyl ketone, methyl propyl ketone, dipropyl ketone, dibutyl ketone and methyl isobutyl ketone.

A group of preferred solvents comprises cyclic ethers, N-aLkylated acid amides and lactams, sulfoxides and sulfones.

The reaction products can be isolated and purified either by known processes or subsequently hydrolysed direct andlor converted into salts.

The reaction products contz~ining CCl3 groups are conveniently hydrolysed wi~ aqueous alkali metal bases, typically KOH or NaOH, and, depending on the adjustment o~ the pH
after the reaction, the acids or their sodium or potassium salts can be isolated in per se known manner.

L-~ ~ r~

The novel esters can likewise, as described above, be hydrolysed with aqueous alkali metal bases to the acids or converted into the salts. Novel esters, for example benzyl ester, can also be converted catalytically with hydrogen in the presence of a noble metal catalyst into the desired carboxylic acids. It is further possible to convert the ester group into a readily hydrolysable group, for example with trimethylbromosilane, and then to Temove this group by hydrolysis to forrn carboxylic acid groups.

The preparatdon of salts from the novel chitosan acids or their aLkali metal salts can be carried out in per se known manner by reacdon with metal salts of e.g. mineral acids or carboxylic acids in aqueous solution, in which case - especially when using polyvalent metal salts - the chitosan salts form insoluble polyelectrolyte gels. Suitable metals are those previously cited. Suitable metal salts are typically oxides, hydro7~ides, fluorides, chlorides, bromides, sulfates, nitrites, nitrates, phosphites, phosphates, ~ormates and acetates.

The preparation of salts from the novel chitosan acids and ammonia, mono- or polyamines or polymeric polyamines can be calTied out in ~he same manner. Water-insoluble polyelectrolyte gels are also obtained when using polyamines or polymeric polyamines.

The novel chitosan derivatives can be isolated by known methods, typically filtration, whereas soluble products can be precipitated beforehand by addition of non-solvents or by adjusting the pH. The products can be isolated by dialysis or by passage over ion exchange resins. For purification, the products can be washed and then dned, but without a complete drying being necessary, and the purified products may have water contents of up to c. 40 % by weight and more. The products can also be milled to powders. Lyophilisadon is particularly useful, as buLlcy and cottonwool-like products are obtained which are especially readily soluble and very reac~ve.

The novel chitosan deriva~ves are solid products which are readily soluble or highly swellable in aqueous or aqueous-aLkaline media or in polar organic solvents. The free acids or their salts with non-toxic cations are physiologically acceptable and biodegradable. The products are suitable for a wide range of utili~ies.

The novel chitosan derivatives, especially the salts and acids, are polyampholytes with film-forming and chelating properties also in the presence of alkaline ear~h metal ions.
Owing to their pronounced chelating action for heavy metal ions even in low 2 ~ 3 concentrations, the products can be used for removing such cations from contallunat~d water, for example for removing iron or copper ions from mains water. In addition, they can be used as chelating agents in the food industry, the pharmaceutical industry and the textile industry, as well as ,detergents singly or in conjunction with cationic, anionic or neutral detergents.

The novel chitosan derivatives have a sorprisingly good complexing ac~on for metal ions, whereby the precipitation of polymeric metal salts, especially in the case of polyvalent cations, can be favourably influenced or prevented. Furthermore, they have a modulating action in crystallisation processes, especially on the formation of seed crystals, their growth and the morphology of the resultant crystals and their size distribotions, as well as on the aggregation and adhesion properties. They are therefore suitable for water treatment to prevent the formation of deposits in water-conducting systems (water treatment plants), for exarnple on the walls of containers, membranes or conduits. They can also be used for the pretreatment of textiles, conveniently cotton. The novel chitosan derivatives also prevent the formation of deposits of inorganic and/or organic components. They are therefore also suitable for use as additives for dental care products for the prevention of dental plaque, as well as additives for detergent formulations.

The invention fi~her relates to a process for the prevention of the adherence to andfor formation of solid deposits on inorganic or organic substrates, which comprises add;ng to a fluid or a composition that is in contact with an inorganic or organic substrate at least one of the novel chitosans, but preferably 0.01 to 20 % by weight, most preferably 0.1 to 10 % by weight.

The novel chitosan derivatives have film-forming properties. The evaporation of aqueous solutions leads to the folmation of transparent, solid and water-containing films which are permeable to air and moisture. By vir~ue of this property and their hydropectic action, they are also suitable for use as humectants for the skin or mucous membranes in cosmetic and pharmaceutical compositions, as agents for maintaining articular mobility (lubricant action simlar to that of hyaluronic acid), and for surgical dressings. Typical cosmeticformulations are skin and hair care products and deodorants. The novel chitosan derivatives, especially gels made therefrom and also the esters, are fur~er suitable ~or the preparation of compositions with controlled release of the chemical agent over aprolonged period.

h ~ 5 ~ 3 The novel chitosan derivatives also have a viscosity increasing and dispersing action in aqueous solutions. They are thus suitable for use as additiv~s in suspensi~ns, emulsions and aqueous solutions, for example in the manufacLure of foodstu~fs or active sobstance concentrations as well as in dye and pigment forrouLltions.

I he novel chitosan derivatives can also have biocidal activity, typically bacteriostatic, fungistatic or algicidic activity.

Especially preferred, and a further object of the invention, is the use of the novel chitosan derivatives, preferably the acids or alkali metal salts, for preventing the adhesion to and/or formation of solid deposits on inorganic or organic substrates. The deposits, which often have a crusty consistency, may be composed of inorganic and/or organic components, typically salts and polymers, also of biological origin. The substrates may be inorganic andlor organic materials or biologlcal materials, for example glass, ceramics, metals and alloys, natural or synthetic plastic materials, paper, textiles, leather or vegetable or animal organs or tissues. Yet a further object of the invention is the use of the novel chitosan derivatives as humectants ~or the skin or mucous membranes.

It has also surprisingly been ~ound that the novel chitosan derivatives can be crosslinked with polyepoxides to give products which are swellable, but insoluble~ in water with good mechanical properties.

The invention filrther relates to crosslinlced chitosan derivatives obtainable by reaction of novel chitosan derivatives with at least one polyepoxide that con~ains on ave~age at least two epoxy groups in the molecule.

Suitable polyepoxides are typically glycidyl compounds containing on average two epoxy groups in the molecule. Particularly suitable glycidyl compounds a~e those having two glycidyl groups bonded to a hetero atom ~e.g. sulfur, preferably oxygen or nitrogen), J~-methylglycidyl groups or 2,3-epoxycyclopentyl groups. Typical examples are preferably bis(2,3-epoxycyclopentyl) ether; diglycidyl ethers of polyhydric aliphadc alcohols, typically 1,4-butanediol, or polyaLkylene glycols such as polypropylene glycols; diglycidyl ethers of cycloaliphadc pol~yols such as 2,2-bis(4-hydroxycyclohexyl)p~opane; diglycidyl ethers of polyhydric phenols such as resorcinol, bis(p-hydro~yphenyl)methane, 2,2-bis(p-hydroxyphenyl)propane (=diomethane), 2,2-bis(4'-hydroxy-3',5'-dibromophen-yl)propane, 1,3-bis(p-hydroxyphenyl)ethane; bis(B-methylglycidyl) ethers of the above - 12 - ~ 3 l ~3 dihydric alcohols or dihydric phenols; diglycidyl esters of dicarboxylic acids such as phtha]ic acid, terephthalic acid, ~4-tetrahydrophthallc acid and hexahydrophthalic acid, N,N-diglycidyl derivatives of primary amines and amides and heterocyclic nitrogen bases that carry hVO N-atoms, and N,N'-digiycidyl derivatives of disecondary diamides and diamines, including N,N-diglycidylaniline, N,N-diglycidyltoluitline, N,N-diglycidyl-p-aminophenyl methyl ether, N,N'-dime-thyl-N,N'-diglycidylbis(p-aminophenyl)methane; N',N"-diglycidyl-N-phenylisocyanurate;
N,N'-diglycidylethylene urea; N,N'-diglycidyl-5,5-climethylhydantoin, N,N'-di-glycidyl-5-isopIopylhydantoin, N,N-methylenebis(~;~',N'-diglycidyl-5,5-dimethylhytlan-toin), 1,3-bis(N-glycidyl-5,5-dimethylhydantoin)-2-hydroxypropane; N,N'-diglycidyl-5,S-dimethyl-6-isopropyl-S,~dihydrouracil, ~iglycidylisocyanurate.

Preferred epoxides are those that are soluble in strongly polar solvents and, more particularly, those that are soluble in wa~er.

A preferred group of polyepoxides comprises glycidylated aliphatic diols and poly-oxaalkyIene diols, novolaks, hydantoins, aminophenols, bisphenols and aromatic diarnines or cycloaliphatic epoxy compounds. Particularly preferred polyepoxides are glycidylated aliphatic diols and polyoxaaLkylene diols, cresol novolaks, diglycidyl ethers of bisphe-nol A and bisphenol F, or rnixtures thereof.

Particularly prefeIred a~ water-soluble glyridyl aliphatic diols and polyoxaalkylenediols, as the rnixing with the novel chitosan derivatives can be calTied out in simple manner in aqueous systems.

To prepare novel crosslinked products it is also possible to use in addition cu~ing accelcrators. Typical examples of curing accelerators are 3-ethyl-4-methylimidazole, triamylammonium phenolate); mono- or polyphenols (phenol, diomethane, salicylic acid);
and phosphoric acid. Curing accelerators and catalysts are normally used in an amount of 0.1 to 10 % by weight, based on the polyepoxide.

The amount of polyepoxide will depend mainly on the desired degree of crosslinking and the properties associated therewith. Advantageously up to SO %, preferably up to 35 %
and, most preferably, up to 25 %, of the stluctural units of the novel chitosans are crosslinked.

The preparation of the crosslinked derivatives can be carried out in a manner known per se~ conveniently by rnixing the components together with an optional solvent or suspension agent which is then removed by heating. The mixture can be thermally crosslinked, typically by heating to 50-200C.

The crosslinked chitosan derivatives are particularly suitable for the preparation of water swellable and mechanical stable moulded articles, such that shaping can be combined with the preparation. It is thus possible to prepare f;lms and foils which can be used as membranes or surgical dressings, or to make capsules or encapsulations for chcrnical agents the release of which to the environrnent is delayed and continuous.
The following Examples illustrate the invention in more detail.
A) Preparation of inte~mediates Example A1. Reacdon of a chitosan with R(-)-4-trichloromethyl-2-oxetanone.
a) Activation of the chitosan To activate the chitosan, a commercial product (~luka: average molecular weight M ~ 75 000, acetyl group CQntent 4.5 %) is dissolved in 5 % acetic acid and undissolved constituents are removed by filtration. The product is precipi~ated again by addition of 2 N sodium hydroxide solution to the fil~ate until the pH is 8-9. The swollen white product is freed from salts by repeated centrifugation, decantation and resuspension in distilled water or by dialysis of the aqueous suspension. Afterwards the product is dried by repeated centrifugation with dioxane up to a water content of 9.8 %. Titration of a lyophilised sample of this material with 0.1 N HC1, taking into account the water content of 9.8 %, gives a base content of 5.11 mes~/g. The dioxane-containing activated polymer gel is used for most of the subsequent reactions.

b) Reaction with R~2~-trichloromethy1-2-oxetanone 546.2 g of the chitosan gel (25 g of chitosan = 0.115 mol) are suspended in 500 rnl of dry N-methylpyrrolidone (NMP) with the addition of 25 g of LiCI and the suspension is added in increments at room temperature to a solution of 58.9 g of R(-)-4-(trichloromethyl)-2-oxetanone (0.310 mol) in 1 1 of NMP. The resultant suspension is stirred for 1 hour under nitrogen and excluding moisture in a sulfonation flask fitted with reflux condenser, blade 7 ~

stirrer and internal thermometer, then heated to 55C and kept at this temperature ~or 24 hours. After cooling, the clear gel obtained is precipitated, with efficient s~Ting, with S litres of acetone. T} e ~me suspension is ~lltered over a sintered suction filter and washed free of chloride with distilled wa~er. The product is suspended once more in methanol and again collected by ~lltra~don. A small sample is cautiously dried under vacuum and the ClJN ratio of elemental analysis is 3.06.

Examples A2-A10: The products listed in Table 1 are prepared in accordance with Example Al. In Examples A2 and A5 R-t~ichloromethyl-2-oxetanone is used. In Example A3 S- trichloromethyl-2-oxetanonine and in Example A4 R,S-4-trichloro-methyl-2-oxetanone is used; and in Examples A9 and A10 S-4-trichlorome-thyl-~methyl-2-oxetanone is used. The solvent is dirnethyl sul~oxid ~MSO) (Examples A2 to A4 100 ml, Examples A5 to A7 800 rnl, Example A8 400 rnl, Examples A9 and Alû 200 ml). The amount OI LiCl is ~ g (Examples A2 to A4), 40 g(Exarnples A~ to A7), 20 g (Example A8~, 10 g (Examples A9 and A10). Further particulars will be found in Table 1. In Example A9 the reaction time is 32 hours a~ 80C
and in Example A10 24 hours at 80C and 24 hours at 1û0C. In the last column ~he content of Cl and N is given in m eq/CCI3/g m eq N/g and in brackets the CVN rado.

2 ~ ~ 2 .~ 1 3 Table 1 ~x. Chitosan Amount of Degree of Cl/N content No. oxetanone subst. (%) A2 S.Og=0.031mol 11.7g=0.062mol 92 8.43/2,71 sigma; 6.3% acetyl ~3.11) A3 5.0g=0.031 mol 11.7 g=0.062mol lOS) 9.02/2.57 Fluka;M 2x106; (3.5 4,5% Ace~l A4 S.0 g=0.031 mol 11.7 g=0.062 mol 1~ 9.22/2.49 Fluka; M 2x106; (3.7) 45% acetyl A5 20 g--0.124 mol 47.10 g=0.248 mol 9S 8.09/2.48 Fluka; M 2x106; (3.26) 4.5% acetyl A6 20 ~,~.124 mol 47.10 g~.248 mol 94 8.47/~.50 Fluka; M 7.5x105; (3.38) 4 % acetyl A7 20 g=0.124 mol 47.10 g~.248 mol 97 8.26/2.49 Fluka;M 7x104; (3.31) 4.3 % ace~l A8 10 g=0.062 mol 23,6 g=0,124 mol 100 7~95/2,57 chitosan of Ex. A6, (3.01 activated A9 5.0 g=0.031 mol 12.6 g=0.062 mol 55 6.06/3.24 Fluka;M 2x106; (1.84) 4.5 % acetyl A10 S.0 g=0.031 mol 12.6 g=0.062 mol 61 4.94/2.99 of activated chitosan (1.65) acc. Ex. Al, but from dioxane lyophilised pC

Example A 11:
a) 20 g of chitosan ~luka, M 7.5x105) is partially de,graded with 1~0 ml of HCl (37%) at 75C over 75 rninutes to chitosan oligomers [A. Domard et. al., Int. J. Biol. Macromol. 11, 297 (1989~]. The mixture of oligomers obtained is neutralised to pH 8.5 with 2N NaOH
and freed from salts and very low molecular constituents by ultrafiltration through a membrane with a cut-off level of 1000. After Iyophilisation, a rnixture of oligomers having an average degree of polymerisadon of c. 6-20 is obtained.

b) 0.7 g (4.34x10-3 mol) of the dried mixture of oligomers is suspended in 15 ml of dry DMSO together with 750 mg of LiCl and the suspension is then added, with stirring, to a solution of 1.65 g (8.64x10-3 mol) of R,S-4-(tTichloromethyl)-2-oxetanone in 15 ml s)f DMSO containing 750 mg of LiCI. The mixture is stirred in an atmosphere of dry nitrogen for 3 hours at room temperature and then -for 10 hours at 50C. The oligomeric reaction product is precipita~ed with the lû-fold arnount by volume of dichloromethan. Piltration over a glass suction filter and washing off with CH2Cl2 and methanol until the filtrate is free from chloride, followed by vacuum drying, gives 950 mg ~f a brownish powdered product which has a Cl/N ratio of 1.52.

Exarnple A12: In accordance with the general procedure described in Exarnple Al 1, 150 mg (7.59x104 mol) of chitohexaose, prepared ~om cornrnercially available chitohexaose hexahydrochloride (lkara Chem. Ind. Tokyo) by neutralisation with tri-ethylarnine, are reacted in 10 ml of dry N-methylpyrrolidone with 2&8 mg (1.52x10-3 mol) of R(-)-4-trichloromethyl-2-oxetanone. Yield: 246 mg (theory 26S mg) of a beige product which is saponified direct (cf. Exarnples B3 and B4).

Exarnple A13: In accordance with the general procedure described in Example Al, 2.0 g (1.24x10-2 mol) of a chitosan product which contains 50 % of amino groups and 50 % of ace~lamino groups (chitin 50TM, Protan A/S, Norway)are reacted in N-methylpyrrolidone (80 ml) with the addition of 4 g of LiCl with 2.36 g (1.24x10-2 mol) OI
R(-)-4-(trichloromethyl)-2-l~xetanone. To bring the reaction to completion, the reaction mixture is sti~ed for 18 hours at 80C and for a further 8 hours at 105C, giving 1.88 g (59 % of theory) of a brownish beige powdered product which has a CVN ratio of 0.55, corresponding to a degree of substitution of 36.6 %.

Example A14: In acordance with the procedure described in Example Al, S g of chitosan -17- ~2~ S~;3 are activated and the dioxane-containing gel (69.1 g) is suspended in 100 ml of DMSO in which 5 g of LiCl has been dissolved. The suspension is added under N~ to a solution of 14 g (6.2x10-~ mol) of R,S-4-trichloromethyl-,B-sultone ~D. Borrrnann et. al., Chem. Ber.
99, 1245 (1966)] in 100 mL of dry DMSO and 5 g of LiCl and the mixture is stirred at room temperature. After 15 minutes the clear yellowish gel obtained is s~rred for 12 hours at room temperature. Afterwards the reaction mixtun~ is precipitated in 2 litres of acetone with vigorous stirring. For purification, the yellowish product is stirred twice in fresh ace-tone and then swollen in 200 mL of methanol and in ]L litre of water to ~emove LiCI. The product is filtered on a glass suction filter, washed free of chloride with water, IyophiLised, and the lyophilisate is dried under 104 mbar for 24 hours. Yield: 6.9 g (58 % of theory) of a pale yeLLow polymer powder with a ClIN ratio of 3.09 m and a C~IS ratio of 3.31 as found by elementaL analysis.

Example A15: In acordance with ~he general procedure described in ~xample A14, 2 g (1.24x10-2 mol) of chitin 50 in 80 ml of dry DMSO containing 4 g of LiCl are reacted with 2.79 g (1.24x10-2 moi) of trichloromethyl-,B-sultone. The reaction mix~lre is reacted for 24 hours at 50C and ~hen for 5 hours at 80C. Yield: 2.44 g of a white polymer which has a Cl~N ratio of 1.1.

B) Preparation of the chitosan derivatives Example B 1 The product of Example A1 is subjected direct and moist with methanol to s2ponification. This is done by suspending the product in 750 ml of water and adding a solution of 34.1 g of NaOH in '~54 rnl of water over 45 minutes while cooling with ice.
The viscous suspension so obtained is sdrred for a further 14 hours at 0-5C, then ~or another 8 hours at room temperature. Titration of the reaction mixture with lN HC1 shows that 3.2 equivalents of the base have reac~ed, i.e. the reaction is complete. The product solution is adjusted to pH 8.0 with 2N HCI and filtered on- a glass suction filter To remove inorganic salts, the solution is subjected to ultra~lltration and the chloride-free soludon is then lyophilised. The white, water-soluble product of stryopor-like consistency is dried under a high vacuum. Yielcl: 29.9 g (69.5 % of theory); water content 19.11 % by weight;
carboxyl content 3.57 m eq,/g (theory 3.61).

Example B2: To prepare the sodium salt, the calculated amount of 2N sodiurn hydroxide solution is added to a 3 % aqueous solution of the product obtained in E3xample B1. The solution is dialysed and then lyophilised, giving a quantitative yield of a white highly 2 ~ G~

porous product that is readily soluble in water.

Example B3: The saponification of the product of Example A12 with 5 equivalents of NaOH in aqueous suspension according to Example B 1 gives the sodium salt of c hitohexaose-hexamalamide in a yield of 135 mg (73 % of theory) after the product has been freed from salts in a dialysis tube with a cut-off level of M = 1~00 (Spec~apor No. 6).

Example B4: The corresponding hexacarboxylic acid is prepared from the salt of Example B3 by dissolving the sodium salt in 5 ml of water. The solution is acidi~led with 0. lN HCl to pH 3.0, followed by fresh dialysis as described in Example B3. Yield: 93 mg (77.5 % of theory) of a slighdy yellowish powder which has a carboxyl group content of 3.~2 m eq/g.

Example B5: In acordance with the general plocedure described in Example A14, 10.0 g (0.062 mol) of activated chitosan (138.2 g of dioxane-containing gel) are reacted in 400 ml of dry DMSO and 16 g of LiCI with 13.7 g (0.062 mol) of 4-(diethylphosphonomethyl)-2-oxetanone (J.G. Dingwall et. al., J. Chem. Soc., Perkin Trans I 1986, p. 20813. The reaction rnixture is stirred for 24 hours at 60C and then worked up, giving 7.5 g of a white polymer powder which has a P/N ratio of 0.12.

Example B6: In a 100 ml sulfonation flask equipped with stirrer, reflux condenser and thermometer, 3 g (0.0145 mol) of ben~yl 2-oxetanone-4-carbw~ylate are dissolved in 25 ml of dry dioxane. To this solution are added 2.31 g (0.0132 mol) of activated chitosan (according to Example A1; 33.1 g of dioxane-containing chitosan gel) at room temperature ~nd the reac~iion mix~ure is stirred for 18 hours. The reaction mixture is then heated for 8 hours to 60C and for a further 48 hours to 100C The consumption of ,B-lactone in the reaC1iOn mixture as an indication of the progress of the raection can be monitored by thin-layer chromatography on silica gel with toluene/ethyl acetate 1:1 as eluant. The reaction product is subsequently precipitated in ~00 ml of diethyl ether, collected by filtration and washed with 3x100 ml of diethyl ether. The product is suspended in 50 ml of dioxane and then lyophilised, and the lyophilisate is dried under 10-2 mbar for 24 hours over phosphorus pentoxide. Yield: 2.85 g (~8.8 % of theory) of a white polymer powder whic:h according to elemental analysis is substituted to a degree of 66.2 %.

d ~

Example B7: To remove the benzyl protective g;oup from the product of Example B6, 2 g of the product are dissolved in 100 ml of dry tet;ahydrofuran and, after addition of 40 mg of palladium acetate, hydrogenated at 50C and 50 bar hydrogen pressure for 21 hours~
~he catalyst is afterwards removed by filtration on a glass suction filter. The polymeric acid is extracted from the filter residue with 0.1N NaOH and combined with the filtrate, which is also adjusted to pH 8. After dialysis through a membrane with a cut-off level of 1000 and subsequent lyopnilisation there are obtaine~d 1.48 g (83 % of th~ory) of a white powder which is the sodium salt of the polymeric acid. No more signals of the benzyl group can be detected in tne lH-NMR spectrum of the polymer in DMSO-d6.

Example B8: In acordance with the general procedure described in Example B 1, the product of Example A14 is saponified with sodium hydroxide solution. This is done by adding a soluition of 2.85 g (r/'1.12x10-3 mol) of NaO~l in 23 ml of water to a suspension of S g (12.93x10-3 mol) of the product in 5 ml of water and stirling the rnixture for 2 hours, whereupon the suspension becomes a clear solution which is s~rred for a further 12 hours at 0-5C. Titration of the reaction mixture with 0. lN HCl snows that 3.o4 equivalents of sodium hydroxide have been consumed. For working up, the reaction mixture is freed from minor amolmts of gel by filtration on a glass suction filter, adjusted to pH 3.0 with 2N HCI solution while cooling with ice, and subseq~uen~ly dialysed against dis~led water through a membrane with an exclusion limit of 1000 Dal~on. The dialysate is lyophilised and the product is dried under 10-2 mbar for 24 hours. Titration of the yellowish polymer obtailled in 65.3 % yield (2.61 g) with 0.1 N NaOH shows a carboxyl group content of 1.67 m eq/g.

Examples B9-B17. In acordance with the general procedure described in Example Bl, the products listed in Table 2 are saponified with NaOH and the acids isolated.

Table 2 Exarnple Educt of Carboxyl group content No. Example No. ~m eq/g) B9 A2 2.8 B 10 A4 3.05 Bll A3 3.1 B12 A5 2.~
B13 A6 3.58 B 14 A7 3.36 B15 A8 3.65 (100 % of theory) B16 A9 1.73 (50 % of theory) B17 A13 0.98 (50 % of theory) Exa~8: Crosslinking of chitosan-mala~Dic ac;d with metal ions or polyamines to form hydrogels.
1 ml of a 3 % aqueous solution of the following reagents is added at room temperature to a 0.5 % aqueous solution (1 ml) of the sodium salt obtalned in ~xample B~. The crosslinking is indicated by the ~ormation of an insoluble precipitate in the form of a hydrogel:
Salt Consistency aluminium acetate white hydrogel - iron(III) nitrate yellow hydrogel polyethyleneimine white hydrogel chitosan C~13COOH white hydrogel albumin (from beef blood) white hydrogel Fxample B 19: TIiethanolamine salt of chitosan malamic acid.
400 mg (0.00144 mol) of the product of Example Bl a~e dissolved at room temperature in 100 ml of dis~lled water and undissolved constituents a~e removed by ISltration on a glass suction filter. Then 215 mg (û.00144 mol) of triethanol~mine are added dropwise to the cle~r solution. The viscous solution can be applied in a thin layer (1000 ~m) with a doctor knife to glass plates or polyester sheets and air d~ied. The thin, glass-clear films obtained bond well to glass, but can be easily removed from a polyester substrate.
Lyophilisation of the solution gives the triethanolamine salt of chitosan malamic acid in the form of a white, buL~cy powder which is readily soluble in water Example B20: Crosslinking of chitosan malamic acid with diepoxides to form hydrogel films.

4~

A solu~ion of 0.01 ml of the diglycidyl ether of 1,4-butane diol in 1 ml of water is added at room temperatu}e to 22 ml of a 0.3 % aqueous solution of the product of Example B2. The resultant clear solu~on is cast to a ~llm on a polyester substrate as described in Example Bl9. The film is dried to give a clear film which is crosslinked by heating for 3 hours to 100C and which can be hardened to a coating which is swellable, but no longer soluble, in water.

Example B21: Preparation of a polyelectrogel.
Equimolar amounts of a 0.024 molar aqueous soludon of a product of Fxample B2 and a 0.062 molar aqueous solution of the chitosanlacetic acid salt are mixed, with vigorous stirnng. The resultant precipitate is collected by filtration, washed with water until neutral and lyophilised. The bully polyelectrolyte powder is dried under 10-2 mbar for 24 hours. It contains solely chitosan and malic acid as components and, despite the sharp drying, has a residual water content of 14.8 % by weight. The product swells in water to a glass-clear and very bulky gel which is able to bind large amounts of water.

Example B22. The solution used in Example B21 is cast to a film and placed in a solution of chitosan acetate to give a water-insoluble polyelectrolyte ~llm. Tlle ~llm is glass-clear, strongly refractive and contains ~he 50- to 100-fold amount by volume of water. The ~llm has a hybrid structure in which solely the polyelectrolyte gel with chitosan as polymeric counterion is formed on the surface of the primary film of chitosan-malamic acid.

Laminate filrns of reverse structure with sirnilar properlies, namely with chitosan as primary film and chitosan-malamic acid as polymeric counterion, are prepared by the same procedure.

C) Use Examples Exarnple Cl: Crystallisation of sodium chloride under the influence of acid polysaccharides A solution of 204 g of sodium chloride in 600 ml of distilled water is filtered through a membrane ISlter and put into each of 6 glass beakers covered with a filter paper and provided with a blade stirrer. The stirring rate is adjusted to 30 rpm. Then to each of the 6 solutions is added 1 ml of a solution that contains 1 mg of one of the polysaccharides listed below. The concentration of polysaccharide in the crystallisation solution is thus 10 ppm. Then the solutions are stirred for 4 days at room temperature and afterwards the 2 ~

crystals obtained are isolated by ~lltration. Forrn, size, size distIibution, agglomeration and adhesion of the crystals are assessed by microscopy and scanning electron photomicrographs. The results are reported in Table 3.
Table 3 Polysaccharide Gystalformand '3ize distribution Adhesion size . _ hyaluronic acid cubes of broad range growth on glass different size, S ~ to 2 mm wall and mrn agglomerates stirrer irregular growth i-carrageenan as above, broad range growth on glass agglomerates S ~1 to 2 mm wall and and cubes of mm size stirrer x-carrageenan as above, broad range growth on glass agglomerates S ,u to 2 rr~n wall and and cubes of rnm size stirrer chondroitin- round less growth on glass 4-sulfate agglomerates heterogeneous walland of many single 30-300 llm s~rrer crystals, cube structure chitosan-mal- regular, well uniform no growth on amic acid formed ~win 50-100 ~,lm glass par~s acc. E~. B 1 to quadruplet aggregates of octahedron structure blanlc test cube broad range growth on agglomerates S ~L to 2 mm glass wall and of different size stirrer .~ , .

Example C2: Crystallisa~on of CalCiUIII carbonate under the influence of polysaccharides A saturated solution of calcium hydrogencarbonate is prepared by suspending 700 mg of CaC03 in 7QO ml of distilled water, introducing C02 until solution is almost complete, and filtration. The undissolved constituents are removed by filtration and the solution is put into each of 6 glass beakers as described in Example Cl and to each of which are added 10 ppm of the polysaccharides listed below. The solutions are heated for 1 hour to 8~85C and the CaC03 precipitates are evaluated as described in Example Cl.

Polysaccharide Cnstal form and Size distribution adhesion sl~e blank test a,o,gregates of 30-300 ~m hard crusts needles on some glass parts hyaluronic ac aggregates of 30-3001,lm hard crusts needles on some glass parts i-carrageenan aggregates of 30-300~,1m hard crusts needles on some glass parts x-carrageenan aggregates of 30-3QO~Lm hard CIUStS
needles on some glass parts chondroitin- grou th of 30-300~,1m hard crusts 4-sulfate needles aggregates on some glass parts chitosan-mal- amorphous 30-100 ~lm no crusts, amic acid plates 5-10 llm all in suspen-acc. ~x. Cl thic'k sion Example C3:
a) In accordance with the general procedure describe d in Example Cl, solutions having the following ion concentrations are prepared:

375 ppm Ca 220 ]ppm HCO3e 183 ppm Mg 85 ppm Co32~

After addition of 2 and 8 ppm respec~ively of a polysaccharide, the solutions are heated for 30 minutes to 70C and filtered after cooling. The uncrystallised calcium concentration in the filtrates is determined by atomic absorption analysis (or titration wi~h a 0.01 M
solution of ethylenediaminetetraacetic acid~ and expressed in percentage inhibition.

b~ In similar manner, the inhibi~ion of ~e barium sulfate concentration with different polysaccharides is determined by the standardised Downell test.

The test is callied out by starting from a solution which contains 8.9 ppm of Ba2~~, 20 000 ppm of Na(: 1 and 8 ppm of a polysaccharide. The solution is adjusted with acetate buffer to pH 5.5 and Icept a~ 25C. Then 270.5 ppm of so42- are added, precipitated BaSO4 is removed by filtration after 4 hours and, as described in a), ~he residual Ba2~ con-centration in the filtrates is determined.

The results of the inhibition of crystallisation are reported in Table 4.

Table 4 Polysaccharide Concentration in ppm Inhibition of crystallisa~ion (%) Ca/MgCO3 BaSO4 _ _ _ _ . _ i-c~rageenan 8 10 0 sodium 8 0 0 chondroitin-4-sulfate sodium 8 0 0 chondroitin-~sulfate x-carrageenan 8 8.6 0 xanthane 8 10.6 0 polygalactu- 8 20 0 ronic acid alginic acid 8 : 27.6 0 chitosan-mal- 2 14.6 24.8 amic acid acc.Ex.B2 chitosan-mal- 8 43.6 67.2 amic acid acc. Ex. B2 .

- : - .~ .

Claims

1. An oligomeric or polymeric chitosan derivative containing structural units of formulae I, II and m in random distribution (I) (II) (III), wherein the substituents R1 are each independently of one another H or the radical -Z-R2-X, R3 is H or acetyl, Y is the anion 0-7-R2-X, and (a) Z is -CO- or -SO2, X is -CO2H, -CH2CO2H or -CH2PO(OH)2, and R2 is -CHR4CR5(OH)-, R4 is -H, -OH, C1-C4alkoxy or C1-C4allyl, and R5 is H or C1-C4allyl, or (b) Z is -CO-, X is -CO2H, and R2 is -CHR6-CHR7-CH(OH)- or -CHR8-CHR9-CHR10-CH(OH)-, R6, R7, R8 and R10 are each independently of one another -H, -OH, C1-C4alkyl or C1-C4alkoxy, and R9 is -H, -OH, C1-C4allyl, C1-C4alkoxy or or an ester or a salt thereof, which chitosan derivative contains a total of at least

2 structural units and, based on 1 mol of the chitosan derivative, 30 to 100 % molar of structural units of formula I, 60 to 0 % molar of structural units of formula II, and 30 to 0 % molar of structural units of formula m, and the sum of the molar percentages is 100%.

2. A chitosan derivative according to claim 1, which contains a total of at least 4 structural units.

3. A chitosan derivative according to claim 1 which, as oligomer, contains 4 to 50 structural units.

4. A chitosan derivative according to claim 1 which, as oligomer, contains 6 to 30 structural units.

5. A chitosan derivative according to claim 1 which contains 50 to 100 % molar of structural units of formula I, 50 to 0 % molar of structural units of formula II, and 20 to 0 % molar of structural units of formula III, the sum of the molar percentages being 100%.

6. A chitosan derivative according to claim 5 which contains 60 to 100 % molar of structural units of formula I, 40 to 0 % molar of structural units of formula II, and 10 to 0 % molar of structural units of formula III, the sum of the molar percentages being 100%.

7. A chitosan derivative according to claim 1, wherein Z in definition (a) of the structural units I, II and III is -CO- and X is -CO2H or -CH2PO(OH)2, or Z is -SO2- and X is -CO2H.

8. A chitosan derivative according to claim 1, wherein R4 to R10 as alkyl is methyl, ethyl, n- or isopropyl or n-, iso- or tert-butyl.

9. A chitosan derivative according to claim 8, wherein R4 to R10 as alkyl are methyl or ethyl.

10. A chitosan derivative according to claim 1, wherein, R4 to R10 as alkoxy are methoxy, ethoxy, propoxy or butoxy.

11. A chitosan derivative according to claim 10, wherein R4 to R10 as alkoxy are methoxy.

12. A chitosan derivative according to claim 1, wherein R4 and R6 to R10 are preferably H, OH, methyl or methoxy, and R5 is H or methyl.

13. A chitosan derivative according to claim 1, wherein R2 is selected from the group consisting of -CH2CH(OH)-, -CH2C(CH3)(OH)-, -CH(OH)CH(OH)-, -CH(CH3)CH(OH)-, -CH(OCH3)CH(OH)-, -CH2CH2CH(OH)-, -CH(OH)CH2CH(OH)-, -CH(OH)CH(OH)CH(OH)-, -CH(CH3)CH2CH(OH)-, -CH2CH(OH)CH(OH)-, -CH(OCH3)CH(OH)CH(OH)-, -CH2CH(OCH3)CH(OH)-, -CH2CH2CH2CH(OH)-, -CH2OH2CH(OH)CH(OH)-, -CH2CH(OH)CH(OH)CH(OH)-, -CH2CH(COOH)CH2CH(OH)-, -CH2CH(OH)CH(CH3)CH(OH)- and -CH2CH(OH)CH(OCH3)CH(OH)-.

14. A chitosan derivative according to claim 13, wherein R2 is -CH2CH(OH)- or -CH2C(CH3)(OH)-.

15. A chitosan derivative according to claim 1, wherein the carboxylic acid and phosphonic acid groups as ester groups are esterified with an aliphatic, cycloaliphatic, araliphatic or aromatic alcohol which contains 1 to 30 carbon atoms.

16. A chitosan derivative according to claim 1, wherein the carboxylic acid and phosphonic acid groups in salt form are formed from a metal of the main and subsidiary groups of the Periodic System of the elements.

17. A chitosan derivative according to claim 16, wherein the metals are selected from the third, fourth and fifth main group and the subsidiary groups of the Periodic System of the chemical elements.

18. A chitosan derivative according to claim 1, wherein the carboxylic acid and phosphonic acid groups are in the form of ammonium salts or salts of primary, secondary or tertiary amines, or of salts of polyamines containing primary, secondary and/or tertiary amino groups, or of salts of a polymer containing amino groups in structural repeating units.

19. A process for the preparation of a chitosan derivative according to claim 1, which comprises containing a total of at least 2 structural units of formulae I, II and III in random distribution, which process comprises reacting a chitosan containing a total of at least 2 structural units of formulae IV and V in random distribution, (IV), (V), wherein R3 is acetyl or H, and said chitosan contains 30 to 100 % molar of structural units of formula IV and 70 to 0 % molar of structural units of formula V, based on 1 mol of chitosan, in the presence of an inert solvent, with at least 30 % molar of a lactone of formula VI, VII or VIII, based on said chitosan, (VI), (VII), (VIII), wherein R4, R5, R6, R7, R8, R9 and R10 have the meanings previously assigned to them, Z
is =CO or =SO2, X1 is -CCl3, -CO2R11, -CH2CO2R11 or -CH2PO(OR11)2, X2 is -CO2R11, and R11 is the radical of an alcohol of 1 to 20 carbon atoms which lacks the hydroxyl group, and hydrolysing the resultant chitosan derivative, wherein X1 is -CCl3, under alkaline conditions to form the corresponding carboxylic acid salt, if desired converting the carboxylic acid salt or ester into the corresponding acid and the acid into a salt.

20. A process according to claim 19, wherein the reaction is carried out in the temperature range from 0 to 150°C.

21. A process according to claim 20, wherein the reaction is carried out in the temperature range from 10 to 120°C.

22. A process according to claim 20, wherein the reaction is carried out in the temperature range from 20 to 100°C.

23. A process according to claim 19, wherein the solvent is selected from the group consisting of cyclic ethers, N-alkylated acid amides and lactams, sulfoxides and sulfones.

24. A process according to claim 19, wherein the reaction product containing CCl3 groups is hydrolysed with an aqueous alkali metal base.

25. A process according to claim 19, wherein the ester is hydrolysed with an aqueous alkali metal base to the acid or the benzyl ester to the acid.

26. A process according to claim 19, wherein the acid is converted with a metal salt, ammonia, a mono- or polyamine or a polymeric amine into a salt.

27. A chitosan derivative containing structural units of formulae IX and X in random distribution, (IX) (X) worin the R12 substituents are each independently of the other H or the radical -Z-R2-X3, R3 is H or acetyl, Z is -CO- or -SO2-, X3 is -CC13, and R2 is -CHR4CR5(OH)-, R4 is -H, -OH, C1-C4alkoxy or C1-C4alkyl, and R5 is H or C1-C4alkyl, which chitosan derivative contains a total of at least 2 structural units and, based on 1 mol of said chitosan derivative, 30 to 100 % molar of structural units of formula IX and 70 to 0 % molar of structural units of formula X.

28. A chitosan derivative according to claim 27, wherein R12 is H.

29. A chitosan derivative according to claim 27, wherein Z is -CO-.

30. A chitosan derivative according to claim 27, wherein R2 is -CH2CH(OH)- or CH2C(CH3)(OH)-.

31. A chitosan derivative according to claim 27 which contains a total of at least 4 structural units.

32. A chitosan derivative according to claim 31 which, as oligomer, contains 4 to 50 structural units.

33. A chitosan derivative according to claim 32 which, as oligomer, contains 6 to 30 structural units.

34. A chitosan derivative according to claim 27 which contains 50 to 100 % molar of structural units of formula XI 50 to 0 % molar of structural units of formula X.

35. A chitosan derivative according to claim 27 which contains 60 to 100 % molar of structural units of formula IX 40 to 0 % molar of structural units of formula X.

36. A crosslinked chitosan derivative obtainable by the reaction of a chitosan derivative as claimed in claim 1 with at least one polyepoxide which contains on average at least two epoxy groups in the molecule.

37. A crosslinked chitosan derivative according to claim 36, wherein the polyepoxide is selected from the group consisting of glycidylated aliphatic diols and poly-oxaalkylenediols, novolaks, hydantoins, aminophenols, bisphenols and aromatic diamines and cycloaliphatic epoxy compounds.

38. A crosslinked chitosan derivative according to claim 36, wherein the polyepoxide is selected from the group consisting of glycidylated aliphatic diols and poly-oxaalkylenediols.

39. A process for the prevention of the adherence to and/or formation of solid deposits on inorganic or organic substrates, which comprises adding to a fluid or a composition that is in contact with an inorganic or organic substrate an effective amount of a chitosan derivative as claimed in claim 1.

40. Use of a chitosan derivative as claimed in claim 1, especially an acid or alkali metal salt, for the prevention of the adherence to and/or formation of solid deposits on inorganic or organic substrates.

41. Use of a chitosan derivative as claimed in claim 1, especially an acid or alkali metal salt, as humectant for the skin or mucous membranes.