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Methods for producing modified microcrystalline chitosan and uses thereforRelated Patent Categories: Chemistry: Molecular Biology And Microbiology, Micro-organism, Tissue Cell Culture Or Enzyme Using Process To Synthesize A Desired Chemical Compound Or Composition, Preparing Compound Containing Saccharide Radical, N-glycosideMethods for producing modified microcrystalline chitosan and uses therefor description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070087415, Methods for producing modified microcrystalline chitosan and uses therefor. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The invention concerns a method to produce modified microcrystalline chitosan and uses thereof. BACKGROUND OF THE INVENTION [0002] Polish Patent No 125 995 and A journal of Applied Polymer Science vol. 33 p. 177, 1987 teach a method, to produce a chitosan with a developed internal surface in a batch process in which the chitosan is periodically precipitated from its solutions in aqueous organic or inorganic acids or their salts by means of hydroxides of alkali metals. The mixture is vigorously stirred. The precipitated chitosan in suspension form is washed with water several times. The well-known method produces chitosan with a developed internal surface with an out-put of 70-90% of theoretical values. The batch process requires at least 12-24 hours for a production cycle. The single batches of the product lack homogeneity. The product tends to degrade and its sorption capacity is rather poor, due to insufficient development of the inner surface. Polish Patent 164 247 and Finnish Patent FI 83 426 teach continuous methods to produce microcrystalline chitosan MCCh). A solution of chitosan in aqueous acids and/or their salts is introduced to a reactor along with an aqueous hydroxide solution of alkali metals and/or their salts until microcrystalline chitosan is formed at pH.gtoreq.7. Simultaneously, the microcrystalline alkaline suspension of chitosan is continuously removed from the reactor. The alkaline solution may also be introduced directly to the recirculation system. Limitations of the process are: out-put below 90%, average agglomerate size above 1 .mu.m and water retention value below 5000%. [0003] Water retention value is an indication of the development of the inner surface. Another drawback of these processes is that it is not possible to control the molecular, and super molecular and morphological structure of the generated chitosan. The continuous process causes a substantial decrease of the average molecular weight of the generated MCCh as result of intensive degradation processes. [0004] Polish Patent Application P 340 132 and the International Application WO 01/87 988 teach a method to produce modified microcrystalline chitosan. According to the disclosed process, a chitosan solution in aqueous solutions of acids and/or their salts with the polymer concentration not lower than 0.001 wt % is neutralized with aqueous hydroxides and/or their salts with a concentration in the range of 0.01-20% at intensive agitation with a rotary speed 10-1000 rpm to attain pH in the range 5.0-6.9; the chitosan salt is thereby converted into its gel form. The gel is homogenized at agitation speed in the range of 100-5000 rpm for not shorter than 10 seconds. Next, still with agitation 100-5000 rpm, the gel is alkalized with aqueous hydroxides in the concentration of 0.01-20 wt % to pH not lower than 6.9. The produced gel-like microcrystalline chitosan suspension is purified, possibly concentrated and dried according to known procedures. This method does not enable production of a modified microcrystalline chitosan with controlled molecular, super-molecular and morphological structure and assumed properties, particularly biological ones. [0005] The invention also concerns a chitosan-calcium complex and a method to produce the complex. The sorption of metal ions by chitosan in its solid state or in aqueous organic and inorganic acid solutions in is well-known from following publications: journals-International Journal of Biological Macromolecules, v. 9, p. 109, 1987, "Carbohydrate Polymer", v. 8, p. 1-21, 1988, v. 11, p. 205-307, 1989; "Talanta", v. 16, p. 1571-1579, 1969; "Carbohydrate Polymers", v. 36, p. 267-276, 1998 and monographs "Chitin Chemistry", Mac Millan Press Ltd, Great Britain, 1992, p. 222-225 and "Advances in Chitin Science", v. V, Universitat Potsdam, Germany, 2000, p. 202-205. [0006] The amount of bound calcium (II) ions is insignificant compared to other alkali metals and amounts to only 0.4-0.8.times.10.sup.-3 mol/gr of chitosan. Soluble derivatives of chitosan demonstrate a better ability to bind calcium II ions notably carboxymethylchitosan, carboxybenzylchitosan, (N)methylchitosan phosphoniate. Complexes of these derivatives with calcium II ions do not dissolve in water. Unknown are chitosan complexes with calcium (II) ions able to dissolve in water or to produce thermally stable suspensions. SUMMARY OF THE INVENTION [0007] The present invention addresses these and other issues. [0008] Thus, according to one aspect, the present invention relates to methods for preparing modified microcrystalline chitosan by degrading chitosan in an aqueous acidic solution under conditions to achieve a desired molecular weight range and polydispersity. Then, the aqueous acidic solution is alkalized at vigorous agitation said acidic aqueous solution of chitosan with an aqueous base to form a solution having chitosan concentration of about 0.01-20 wt % and a pH of at least about 7.0. Microcrystalline chitosan can then be precipitated from this solution. [0009] In another aspect, methods of the invention relate to techniques for preparing modified microcrystalline chitosan by first alkalizing at vigorous agitation an acidic aqueous solution of chitosan with an aqueous base to form a solution having chitosan concentration of about 0.01-20 wt % and a pH of at least about 7.0. The dissolved chitosan in this solution is then degraded under conditions to achieve a desired molecular weight range and polydispersity. The microcrystalline chitosan product can then be precipitated. [0010] The present invention also relates to a chitosan-calcium (II) complex containing calcium (II) ions bound to microcrystalline chitosan prepared according to methods of the invention. These inventive complexes contain .gtoreq.0.01 wt % chitosan having an average molecular weight .gtoreq.10 kD, a polydispersity .gtoreq.2.0, deacetylation degree .gtoreq.65% and wherein said complex has a water retention value .gtoreq.300%, pH .gtoreq.7.1 and a calcium (II) ion content .gtoreq.0.1 wt % relative to chitosan. [0011] In other aspects, the present invention also provides methods to produce a chitosan-calcium complex from a suspension of microcrystalline chitosan prepared according to methods of the invention. These suspensions can be mixed with >0.01 wt % calcium (J1) salt to form the inventive complexes of the invention. DESCRIPTION OF THE INVENTION [0012] Unlike in conventional techniques, methods for producing microcrystalline chitosan, according to the invention, precipitate the chitosan from its aqueous acidic solutions using aqueous hydroxides and/or their salts. According to these methods, chitosan with a concentration in aqueous solution of at least 0.001 wt % (preferably 0.1-2% wt %) is first degraded in a controlled way to attain an assumed average molecular weight and polydispersity degree. The chitosan under intensive agitation with rotary speed below 40,000 rpm is next alkalized with aqueous hydroxides and/or their salts with concentration in the range of 0.01-20 wt % to pH not lower than 7.0. The precipitated modified microcrystalline chitosan is purified and possibly concentrated and dried according to known methods. [0013] The chitosan according to this invention is subjected to degradation by enzymatic, hydrolytic or oxidative treatment. [0014] In enzymatic degradation, enzymes such as cellulases, chitanases or xylanases are used at a temperature not lower than 20.degree. C., preferably 30-60.degree. C. The degradation lasts 1 minute to 100 hours at enzyme activity not lower than 0.01 units/cm.sup.3. The enzymes remaining after the treatment are deactivated at a temperature not lower than 70.degree. C. [0015] The hydrolytic degradation is run at a temperature not lower than 20.degree. C., preferably 40-80.degree. C., lasting 1 minute to 100 hours, preferably in the presence of strong acids such as hydrochloric acid or chloroacetic acid in an amount not lower than 0.001 wt % on chitosan. [0016] The oxidative degradation according to the invention is conducted with oxidizing agents like hydrogen peroxide or sodium perborate in an amount not lower than 0.001 wt %, preferably 0.01-0.5% on chitosan, not shorter than 1 minute at a temperature not lower than 20.degree. C., preferably 30-60.degree. C. The method to produce modified microcrystalline chitosan, according to the invention consists also in that the chitosan, whose concentration in the aqueous acid solution is not lower than 0.001 wt %, preferably 0.1-2 wt % is intensely agitated with rotary speed not exceeding 10 000 rpm, alkalized to pH not lower than 7.0 with aqueous hydroxide solutions and/or their salts with 0.01-20 wt % concentration. The microcrystalline chitosan, precipitated from the solution, is next subjected to a controlled degradation to attain the assumed average molecular weight and polydispersity degree. The produced modified microcrystalline chitosan is purified and optionally concentrated and dried in a classical way. [0017] Microcrystalline chitosan obtained, according to the invention, is subjected to either enzymatic or oxidative degradation. The enzymatic degradation of the microcrystalline chitosan uses enzymes active in neutral and/or alkaline media like cellulases at temperatures not lower than 20.degree. C., preferably 30-60.degree. C. for 1 minute to 100 hours at pH not lower than 7.0 with the enzymes activity not lower than 0.01 units/cm.sup.3. The enzymes remaining after the degradation are deactivated at a temperature beyond 70.degree. C. The oxidative degradation of the microcrystalline chitosan is conducted with the use of oxidizing agents like hydrogen peroxide or sodium perborate in the amount of at least 0.001 wt %, preferably 0.01-0.5 wt % on chitosan during not shorter than 1 minute at a temperature not lower than 20.degree. C., preferably 30-60.degree. C. [0018] According to the invention, an aqueous solution of chitosan in acetic acid, lactic acid, citric acid or hydrochloric acid is used at pH not higher than 6.9. Aqueous solutions of sodium-, potassium- or ammonium hydroxide or/and the corresponding salts like sodium, potassium or ammonium carbonate are used during alkalization. The production of the microcrystalline chitosan, according to the invention can be run batch-wise or continuously. [0019] According to the invention, modified microcrystalline chitosan is produced with an assumed, controlled molecular, supermolecular and morphological structure following enzymatic, hydrolytic or oxidative degradation of the chitosan macromolecules, dissolved in aqueous acids in the course of the manufacture or the enzymatic or oxidative degradation of the microcrystalline chitosan precipitated from its solution. The enzymatic degradation enables production of microcrystalline chitosan with a relatively lower average molecular weight and polydispersity degree. In addition, the applied enzymes affect other properties of the microcrystalline chitosan like water retention value, size of molecules and crystallinity index. The hydrolytic degradation, particularly in the presence of strong acids, enables production of obtaining polymers with lowered average molecular weight and increased polydispersity. The modified microcrystalline chitosan, obtained according to the invention, is characterized by a wide spectrum of the average molecular weight compared to the initial chitosan. [0020] The controlled degradation of chitosan in a homogeneous medium, prior to the manufacture of the microcrystalline chitosan, allows structural adaptation to the optimum conditions of the agglomeration. Thanks to the modification of the chitosan at this stage, the obtained microcrystalline chitosan is characterized by assumed physical-, chemical-, useful- and biological properties particularly bioactivity, biodegradability and biocompatibility. The degradation of the microcrystalline chitosan in the form of agglomerates according to the invention runs in a heterogeneous phase and enables a controlled modification of the chitosan structure, mainly the biodegradation of low molecular weight fractions, altering of morphological structure and widening the range of its properties like water retention value, porosity, sorption ability and biological activity. The degradation process, run this way, is simultaneously controlled by the diffusion of the enzymes or the oxidizing agent to the structure of the agglomerates. The assumed structure of the modified microcrystalline chitosan profoundly affects many of its properties like biodegradability, bioactivity, porosity, adhesion and miscibility with other polymers and stability. An advantage of the method of the invention is to produce modified microcrystalline chitosan with assumed properties in the forms of suspension, paste and powder according to the envisaged application. 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