WATER SOLUBLE MICROFLAKE THROUGH AIR-GAP AND PROCESS THEREFORE

Abstract: Disclosed is a multi-layered, air-gap sheet of chitosan with a regular lamellar structure, which retains drug for a prolonged period of time and makes drug distributed uniformly therethroughout. In the lamellar structure chitosan thin films 1-50 mu m thick are layered at such regular gaps of 1-10,000 mu m in the direction perpendicular or horizontal to the surface of the sheet or slanting against the surface of the sheet that drugs can be homogeneously dispersed throughout the sheet. It is a novel form which can be effectively used as a clinical-pathological agent with high coatability onto skin, maximizing the medicinal efficacy of chitosan. The sheet of the present invention is highly suitable for use as a chitosan source for a broad spectrum of applications because it can be readily dissolved in water owing to its large surface area.

Description: WATER SOLUBLE MICROFLAKE THROUGH AIR-GAP AND PROCESS THEREFORE BACKGROUND OF THE INVENTION 1. Field of the invention The present invention relates to chitosan microflakes which are greatly improved in coatability onto the skin. Also, the present invention relates to a multi-layered, air- gap sheet of chitosan, which can prolong the retention time of drugs therein and allow the uniform distribution of the drug therethroughout . In addition, the present invention is concerned with methods for preparing such a chitosan microflake and a multi-layered, air-gap sheet of chitosan. 2. Description of the Prior Art Chitin is quantitatively found in the shells of crustaceans, such as crabs and shrimps, and insects, and in the cell walls of fungi, mushrooms and bacteria, and along with potassium carbonate, proteins, lipids, and pigments, serves to comprise the main structure of the shells and exoskeletons of various animals. Next to cellulose, chitin is the polysaccharide most produced in the world, with as much as ten billion tons of chitin and its derivatives estimated to be produced by living organisms each year. In spite of its abundance in nature, chitin has not been effectively utilized because of its low solubility in aqueous solutions. Owing to this problem, chitin is difficult to form into fibers or films and thus, has found limited applications. In an effort to overcome this problem, chitin was converted into chitosan which is soluble in aqueous acid solutions. A deacetylation technique is generally used for the conversion of chitin into chitosan. Industrially, chitosan, which is water-soluble, is more extensively used than chitin, which is non-water soluble. Derived from chitin, chitosan, which is an aminopolysaccharide represented by the following chemical formula 1, is known as being bio-friendly, i.e., non-toxic and biodegradable. In addition, chitosan was found to have effective biological activities for use in, for example, cell fusing, tissue culturing and hemorrhage stopping, and biological properties such as antibacterial activity and biocompatibility. Also, physiological functions associated with chitosan include reduction of blood cholesterol and sugar levels, activation of intestinal metabolism, anticancer activity through immunological enhancement, improvement of liver activity, and counteractivity against heavy metal poisoning. Chemical Formula 1 At first, chitin and chitosan were used as coagulants to recover useful materials from the wastewater of food factories. In recent times, numerous applications of chitin and chitosan have been found in a broad spectrum of industries, including food, pharmaceutical and medicine, bioengineering, cosmetic, agricultural, chemical engineering, and environmental industries . Thus far, wastes from crustaceans, such as crabs and shrimps, have been used as main sources for chitin. In the future, chitin is expected to be obtained from krill. With respect to the production of chitosan, particular attention is paid to fungi because they are found to contain chitosan as well as chitin in their cell walls. Thus, if culture and extraction methods from fungi are developed to ensure the production of the useful polysaccharides, their sources will be expanded. U.S. Pat. No. 3,533,940 discloses a method for preparing chitosan from chitin, along with its application to fibers and films. For possible applications, the prepared chitosan is dissolved in aqueous organic solutions. In U.S. Pat. No. 4,699,135, it is disclosed that chitin is dissolved in polar solvents such as lithium chloride- containing dimethyl acetate amide to produce chitin fibers . Also, disclosed is the production of chitosan staples from a solution of chitosan in an aqueous acetic acid solution. U.S. Pat. No. 5,900,479 describes the production of films and fibers of water-insoluble chitin using an aqueous organic acid solution of chitosan. U. S. Pat. No. 4,286,087 introduced a process of making chitin powder by treating particulate chitin at an elevated temperature with phosphoric acid diluted with a lower aliphatic alcohol, separating the treated chitin and subjecting same to shearing in an inert liquid medium until a uniform dispersion is obtained, thereafter separating the sheared chitin and drying and grinding same to a fine powder. In addition to these, many other techniques for utilizing chitin or chitosan as raw materials in producing films and fibers are disclosed. In addition, active research has been directed to the production of biocompatible, hygienic products suitable for use in clinical medicine fields and to their possible applications. As4 a result, various relevant techniques are developed and disclosed at present. For example, the applicability and superior functionalities of chitin, chitosan and derivatives thereof as materials for use in wound healing agents, artificial skins, pharmaceuticals, blood coagulants, artificial kidney membranes, biodegradable sutures, antibacterial agents, etc. are described in Dynesh et al . (Rev. Macromol . Chem. Phys . , C40(l), 69-83 (2000)). Another research result can be referred to Maryefan et al. (ILEE Engineering In Medicine and Biology November/December, 1999) , reporting that bedcovers with a coating of chitosan have the medicinal effects of preventing the formation of cicatrices and facilitating wound healing. (?) Lithbethylem et al . (Pharmaceutcial Research, Vol. 15, No. 9, 1998) , reported that, thanks to its characteristic properties of non-toxicity and biocompatibility, chitosan has numerous applications in the pharmaceutical industry, including binders for drug, wetting agents, gel, films, emulsifying agents, coating agents, microcapsules, bio-adhesives, official preparations, vaccine derivatives, gene derivatives, etc., adding that active research was directed to a broad spectrum of applications of chitosan. A research result published by Wang, K. R. et al . (Journal of Biomedical Materials Research, V. 53, N. 1, 8-17, 2000) discloses that a wound dressing comprising chitin and chitosan acetate, when being applied to second degree burns, prevented the accumulation of wound exudates owing to the high moisture permeability of chitosan, as well as preventing the secondary infection owing to the antibacterial activity of chitosan. U. S. Pat. No. 5,836,970 relates to wound dressings comprising a mixture having effective amounts of chitosan and alginate, both of which can be provided in the form of a powder, film, or gel, asserting that the wound dressings have the ability to accelerate wound healing. U.S. Pat. Nos. 3,632,754 and 3,914,413 teach that chitin has the effect of facilitating wound healing and can be physiologically solubilized by virtue of its hydrolysis by lysozyme . In both European Pat. No. EP0089152 and Japanese Pat. No. 86141373, there is disclosed that composite films prepared from chitin and keratin or collagen are used as wound protectives. With such physiologically effective advantages, chitin and chitosan have been utilized in a variety of commercialized products. For example, health foods manufactured by Choito-Bios Company and Acona Company, both of Germany, are known to utilize chitin and chitosan. Wella Company, Italy, uses hydrolyzed chitosan in hair protection produts . Other examples of commercialized chitin and/or chitosan products include the diet food Evalson R of Nihon Kayaku, Japan, CM-chitin (a skin protective) of Ichimarn Farukosu, Japan, chitin non-woven fabric, and chitin fiber for use as biodegradable surgical suture of Yunichika Japan, chitosan-collagen material for use as artificial skin of Katakurachkkarin, Japan, etc. Although recognizing chitin or chitosan as a body- adaptable material, however, clinical applications of chitin and chitosan are still in their initial stages. No conventional techniques relate to effective forms of chitosan, with which chitosan can exert its benefits maximally while being applied for various purposes. Conventional chitosan products are usually in forms of films, non-woven fabrics, or foaming sheets with simple exposed or closed space in cross section view. Therefore, high retention capability and uniform distribution of drugs cannot be expected in such a structure at all . The possibility for an advanced form of chitosan shape was suggested by Kenziokuyoma et al . (Macromolecular 1997, 30, 5849-5855) , based on the theory that hydrated chitosan molecules are able to form a two-dimensional structure during crystallization. Sonyasalmon et al . (Gout-Ilal of Polymer Sci. Part B: Polymer Physics, Vol. 33, 1007-1014 (1995)) concluded that only one-dimensionally structured fibers are possible. As described above, there are many techniques for applying chitin and chitosan for medicinal purposes . However, most of the conventional techniques only suggest the availability of chitin or chitosan as biocompatible materials, but failed to provide suggestions for their commercialization. Further, nowhere is mentioned the preparation of chitin and chitosan in forms which can be properly applied for various clinical-pathological treatments with maximal functionality. Skins of the body assume various forms, depending on body regions. With exercise, skin differs from one body region to another in physical properties such as extent of extension and contraction. For these reasons, there is a strong requirement for a novel form of chitosan, which is greatly improved in close adherence to the skin. Because conventional chitosan applications for skin are in the form of powders, films, sponge or sheets, an extreme limitation is imposed on their uses. For instance, chitosan powders are difficult to uniformly apply onto a wounded dermal region. A large quantity of chitosan powder is required to cover a wounded dermal region. Another disadvantage of chitosan powder is that chitosan powder is too small in contact area with the dermal region to sufficiently exert its medicinal effect . Also, chitosan powder is poor in close adherence. As for chitosan films, sponge or sheets, they suffer from disadvantages of having difficulty in closely adhering to skins and being extremely limited in size. Furthermore, it is expected that they are not able to maintain close adherence to the skin, which continuously conducts movements such as extension and contraction. SUMMARY OF THE INVENTION Therefore, it is an object of the present invention to overcome the above problems encountered in prior arts and to provide a method for preparing chitosan into microflake forms which are exceptionally improved in close adherence to the skin. It is another object of the present invention to provide chitosan microflakes which have very high coatability onto the skin, thereby improving the medicinal efficacies of highly pure chitosan, including wound healing, sterilization, prevention or suppression of cicatrix formation, and recuperation from wounds, upon being applied to external traumas such as skin wounds, surgically operated regions, and burns . It is a further object of the present invention to provide a multi-layered, air-gap sheet of chitosan with such a regular, three-dimensional structure in which drug can be retained for a long period of time and distributed uniformly. The chitosan microflakes of the present invention are manufactured by dissolving chitosan in a weak acidic, aqueous organic acid solution to give a chitosan solution, extracting chitosan from the solution, and solidifying the chitosan into anisotropic microflakes which have widths ten fold greater than thickness. When being applied onto skin, the chitosan microflakes of the present invention form a mosaic plane, thereby exhibiting greatly improved coatability onto the skin. In addition, the chitosan microflakes adhere so well to the skin as to maximize their medicinal function. The chitosan microflake structures provided according to the present invention, which are novel forms which have not been manufactured before the present invention, can be effectively used as clinical-pathological agents with high coatability onto skin and maximize the medicinal efficacy of chitosan. Consisting of a plurality of thin films of chitosan, the multi-layered, air-gap sheet of the present invention has such a lamella structure in which the chitosan thin films are spaced at regular distance intervals from each other in the direction perpendicular, horizontal, or oblique to the sheet surface. Therefore, drugs can be uniformly distributed throughout this structure in addition to residing for a long period of time therein. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a schematic view showing a structure of a chitosan microflake according to the present invention; Fig. 2 gives photographs showing chitosan microflakes at a magnification of 60 times (left) and at a magnification of 6,000 times (right); Fig. 3 is a scanning electron microphotograph (SEM) of a freeze-dried chitosan microflake, magnified by 200 times, showing a lamella structure of chitosan of high purity. Fig. 4 shows multi-layered, air-gap structures of chitosan sheets, in which chitosan thin films are laminated at regular space intervals in perpendicular, horizontal and slanting directions, respectively. Fig. 4a shows a lamella structure of a chitosan sheet having a plurality of chitosan thin films layered in the direction perpendicular (a) to the surface of the sheet with the thin films being spaced with regular distance intervals (b) therebetween. Fig. 4b shows a lamellar structure of a chitosan sheet having a plurality of chitosan thin films layered in the slanting direction (a) against the surface of the sheet with the thin films being spaced with regular distance intervals (b) therebetween. Fig. 4c shows a lamella structure of a chitosan sheet having a plurality of chitosan thin films layered in the direction horizontal (c) to the surface of the sheet with the thin films being spaced with regular distance intervals (b) therebetween. Fig. 5 is an electron microphotograph, taken of a longitudinal cross-section of a multi-layered, air-gap sheet consisting of chitosan thin films, showing a lamellar structure in which the thin films, each 5-10 μm thick, are layered at distance intervals of 20-120 μm in the direction perpendicular to the surface of the sheet. Fig. 6 is an electron microphotograph, taken of a longitudinal cross-section of a multi-layered, air-gap sheet consisting of chitosan thin films, showing a lamellar structure in which the thin films, each 5-10 μm thick, are layered at distance intervals of 20-120 μm in the slanting direction against the surface of the sheet . Fig. 7 is an electron microphotograph, taken of a longitudinal cross-section of a multi-layered, air-gap sheet consisting of chitosan thin films, showing a lamellar structure in which the thin films, each 5-10 μm thick, are layered at distance intervals of 60-360 μm in the direction horizontal to the surface of the sheet. Fig. 8 is an electron microphotograph, taken of a longitudinal cross-section of a multi-layered, air-gap sheet consisting of chitosan thin films, showing a lamellar structure in which the thin films, each 5-10 μm thick, are layered at distance intervals of 50-220 μm in both the directions perpendicular and horizontal to the surface of the sheet . DETAILED DESCRIPTION OF THE INVENTION In one embodiment, the present invention contemplates a novel form of chitosan, which is greatly improved in coatability onto skin and maximizes the medicinal efficacy of chitosan. The novel form is found to be microflakes in accordance with the present invention. The microflakes are prepared by dissolving chitosan in a weak-acidic solvent in a particular weight ratio, freeze-drying the solution, extracting the dried chitosan into porous chitosan films, and pulverizing the films into microflakes in which the width is at least 10 times greater than thickness. Suitable in the present invention are chitosan which ranges in polymerization degree from 10 to 100,000 and in deacetylation degree from 60 to 99 %. More preferable is chitosan which ranges in polymerization degree from 100 to 10,000 and in deacetylation degree from 70 to 95 %. Any solvent may be used if it is selected from aqueous acidic solutions, aqueous inorganic salt solutions and organic solvents . To obtain an aqueous acidic solution available in the present invention, water is added with 0.1-20 wt% of an acid which is selected from the group consisting of organic acids such as acetic acid, lactic acid, formic acid, glycolic acid, acrylic acid, propionic acid, succinic acid, oxalic acid, ascorbic acid, gluconic acid, tartaric acid, maleic acid, citric acid, glutamic acid, and mixtures thereof. Available inorganic salt solutions contain an inorganic salt at an amount of 10-70 wt% in water. The inorganic salt is selected from the group consisting of sodium thioisocyanate, zinc chloride, calcium chloride, sodium chloride, potassium chloride, lithium chloride, and mixtures thereof . In the selected solvent, chitosan is dissolved at 0.5- 30 wt% to give a chitosan solution which is then subjected to freeze-drying and pulverization to produce chitosan microflakes . In another embodiment, the present invention pertains to a multi-layered, air-gap sheet of chitosan with a regular lamellar structure, which retains drug for a prolonged period of time and makes drug distributed uniformly therethroughout . In the lamellar structure, chitosan thin films are layered at such regular gaps in the direction perpendicular or horizontal to the surface of the sheet or slanting against the surface of the sheet that drugs can be homogeneously dispersed throughout the sheet. Therefore, the sheet of the present invention is exceptionally improved in drug retention and distribution. For the preparation of the lamellar sheet of the present invention, chitosan is first dissolved in a weak-acidic solvent. The resulting chitosan solution is freeze-dried, followed by extracting the dried chitosan into thin chitosan films with a thickness of 1 to 50 μm. In this regard, when the chitosan solution is aged for 1 to 30 days at -5 °C to 50 °C, there is formed the environment under which molecular chains of chitosan are potentially arranged in a plane so as to form thin films, as inferred from the crystal structure (structure formula 2) disclosed by Kenziokuyo a (Macromolecular, supra) . During this procedure, the chitosan films are layered at an angle of 0° to 180° to the sheet surface with regular gaps of 1 to 10,000 μm. With this structure, the chitosan sheet of the present invention shows high air and water permeability,, drug delivery rate, and water solubility. Therefore, the lamellar, air-gap chitosan sheet of the present invention shows novel three-dimensional structures suitable for use in medical applications. For instance, the chitosan sheet of the present invention, when being used as a wound dressing, can effectively remove wound exudates, as well as affording good ventilation to the wound thanks to its good air permeability, and effectively apply drugs to the wound. In the course of the solidification and extraction of chitosan from the chitosan solution by a variety of methods, including freeze drying, thermal drying, and vacuum drying, the chitosan microflake and the multi-layered, air-gap sheet can be obtained. In connection to the preparation of the microflake and the sheet, the chitosan solution is preferably freeze-dried. Generally, freeze-drying can be achieved by freezing a material and drying the material through direct sublimation under high vacuum without undergoing a liquid phase. Over ordinary drying techniques, the freeze-drying technique has the advantage of producing higher quality products. In addition, freeze-dried products are characterized in that they are of slightly porous lamellar structures. In the present invention, the freeze-drying is carried out in three steps: pre-freezing, sublimation-drying, and dehydration- drying. Because of its a great influence on the final product, the freezing temperature of the pre-freezing must be carefully controlled. In the present invention, the chitosan solution is pre-frozen at a temperature ranging from -10 °C to -60 °C and more preferably at a temperature ranging from -35 °C to -40 °C. In the sublimation-drying step, the frozen chitosan solution is deprived of the free solvent which corresponds to 50 wt% to 90 wt% of the total solvent present in the frozen chitosan solution. In this regard, heating and sublimating processes are repeated at regular time intervals while the latter is conducted at a temperature from -10 °C to -60 °C for 10 min to 2 hours under a pressure of 100 Torr to 0.1 Torr. In the dehydration-drying step, the combined solvent which is present at an amount of 10 to 50 wt% of the total solvent in the sublimated chitosan solution is removed. To this end, heating is conducted such that all calories are consumed for the sublimation phase transition from the frozen phase. Therefore, the moisture is gradually removed from the top of the frozen phase while a porous structure of a chitosan film appears. As the sublimation boundary travels downward, the porous lamellar structure becomes larger. At last, the frozen phase disappears while a water- soluble, multi-layered sheet of chitosan is obtained in which the chitosan films are arranged at regular space intervals in the direction perpendicular or horizontal to the surface of the sheet, or slanting against the surface of the sheet . Afterwards, the multi-layered air-gap sheet of chitosan (porous chitosan film) is freeze-pulverized at a temperature of 0 °C to -60 °C, followed by passing the pulverized chitosan film through a sieve of 10-100 meshes to give highly pure microflakes which have widths at least ten fold larger than the necessary thickness . With reference to Fig. 1, there is a schematic view of a chitosan microflake whose width is ten or more times as great as its thickness. When using a thermal drying method, it is possible to prepare multi-layered air-gap sheets of chitosan by drying the chitosan solution at 50 to 200 °C. As for vacuum drying, it is conducted at 50 to 200 °C under 0.1 to 100 torr to dry the chitosan solution to give layered, air-gap sheets. In the multi-layered, air-gap sheet of chitosan, thin films, each ranging, in thickness, from 1 to 50 μm, are layered with space intervals of 1 to 10,000 μm. Composed of 30-95 % by weight of chitosan, 3-50 % by weight of an organic acid, and 2-25 % by weight of water, the multi- layered, air-gap sheet of chitosan ranges in bulk density from 0.01 to 1.0 g/cm 3 and more preferably from 0.05 to 0.5 g/cm 3 . Defined as a proportion of the total volume minus the volume of the films to the total volume of the sheet, a void volume ratio was measured to be between 99 % and 20 % in the sheet . A better understanding of the present invention may be obtained in light of the following examples which are set forth to illustrate, but are not to be construed to limit the present invention. Preparation of Chitosan Microflake EXAMPLE 1 1. Preparation of Chitosan Solution In 95 g of an aqueous 3 wt% lactic acid solution was dissolved 5 g of chitosan which was 116 cps in viscosity with a deacetylation degree of 94 % to give a transparent solution. Incubation at 30 °C for 3 days afforded the condition under which the molecular chains of chitosan could be arranged in a plane so as to form thin films. 2. Pre-Freezing Treatment The chitosan solution thus obtained was placed in a container of a freeze-drier and frozen at as low as -50 °C. 3. Freeze Drying The pre-frozen chitosan solution was subjected to freeze-drying at a pressure of 0.1 Torr for 2 hours while the temperature was changed from -5 °C to 50 °C. The morphologies of the chitosan microflakes thus obtained are shown in the full-size microphotographs of Fig. 2. As seen in Fig. 2, the microflakes have wide lamellar structures whose widths are greater than the thickness . The left microphotograph shows aggregated chitosan microflakes at a magnification of 60 times while the right microphotograph further magnifies a portion of the left microphotograph at 100 times and thus, shows a chitosan microflake in a total magnification power of 6,000 times. Turning to Fig. 3, there is an SEM of a freeze-dried chitosan microflake, magnified by 200 times. As demonstrated in the electron microphotograph, the chitosan microflake has a lamellar structure. Production of Chitosan Microflakes Using an electrical pulverizer, the freeze-dried, highly pure, porous chitosan film was pulverized at -30 °C for 10 min to produce chitosan microflakes in which the width was at least ten fold larger than the thickness . EXAMPLES 2 TO 5 Properties of Microflakes According to Viscosities of Chitosan The same procedure of Example 1 was conducted with the exception that 3 g of each of chitosans which had viscosities of 11.6, 116, 370, and 1,446 cps, respectively, all being deacetylated at 94 %, and an aqueous 5 wt% lactic acid solution were used, so as to form chitosan microflakes in which the width was at least ten fold larger than the thickness . . Ten chitosan microflakes selected randomly from each of Examples 2 to 5 were measured for dimension and their average values are given in Table 1, below. TABLE 1 Property of Chitosan Microflake EXAMPLES 6 TO 10 Properties of Microflakes According to Concentrations of Chitosan Solution In aqueous 3 wt% lactic acid solutions, chitosan which had a viscosity of 116 cps with a deacetylation degree of 94% was dissolved at amounts of 1, 2, 3, 4 and 5 wt%, respectively, and from these chitosan solutions, chitosan microflakes were prepared in the same manner as in Example I . Microphotographic analysis showed that the microflakes had widths ten or more times as large as their thickness. Ten chitosan microflakes selected randomly from each of Examples 6 to 10 were measured for dimension and their average values are given in Table 2, below. TABLE 2 EXAMPLES 11 TO 13 Properties of Chitosan Microflakes According to Pre-Freezing Temperatures Chitosan microflakes were prepared in a manner similar to that of Example 1 with the exception that the pre- freezing temperatures were set to be -30 °C, -40 °C and -50 °C, respectively. The properties of the microflakes according to the pre-freezing temperatures are given in Table 3, below. TABLE 3 Preparation of Chitosan Air-Gap Sheet with Layered, Lamellar Structure While the temperature was changed from -5 °C to 50 °C at 0.1 Torr, the chitosan solution pre-dried in Example 1 was subjected to sublimation-drying and dehydration-drying, to produce chitosan air-gap sheets with layered, lamellar structures . EXAMPLE 14 TO 17 Properties of Microflakes According to Chitosan Viscosities The same procedure of Example 1 was conducted with the exception that 3 g of each of chitosans which had viscosities of 11.6, 116, 370, and 1,446 cps, respectively, all being deacetylated at 94 %, and an aqueous 5 wt% lactic acid solution were used, so as to form chitosan air-gap sheets which were from 7.5 to 15 μm in thickness with spacings of 100 to 200 μm between lamella layers. Ten chitosan, air-gap sheets selected randomly from each of Examples 14 to 17 were measured for dimension and their average values are given in Table 4, below. TABLE 4 Property of Chitosan Microflake EXAMPLE 18 TO 22 Properties of Layered, Air-Gap Sheets of Chitosan According to Concentration of Chitosan Solution In aqueous 3 wt% lactic acid solutions, chitosan which had a viscosity of 116 cps with a deacetylation degree of 94% was dissolved at amounts of 1, 2, 3, 4 and 5 wt%, respectively, and from these chitosan solutions, multi- layered air-gap sheets of chitosan were prepared in the same manner as in Example I . Ten chitosan microflakes selected randomly from each of Examples 14 to 17 were measured for dimension and their average values are given in Table 5, below. TABLE 5 EXAMPLES 23 TO 25 Properties of Layered, Air-Gap Sheets of Chitosan According to Pre-Freezing Temperatures Multi-layered, air-gap sheets of chitosan were prepared in a manner similar to that of Example 1 with the exception that the pre-freezing temperatures were set to be -30 °C, -40 °C and -50 °C, respectively. The properties of the sheets according to the pre-freezing temperatures are given in Table 6, below. TABLE 6 Having numerous applications in various industries, including the food industry, the medical industry, the cosmetic industry, the agricultural industry, the chemical engineering industry, the environmental industry, etc., the multi-layered, air-gap sheets of chitosan of the present invention have a complex three-dimensional morphology quite different from those of fibers, films, powders and the like, which prior arts suggest . With such a novel three- dimensional structure, therefore, the lamellar, air-gap sheet of the present invention is suitable particularly for use in medical applications, including wound healing agents, artificial skins, pharmaceuticals, blood coagulants, artificial kidney membranes, antibacterial agents, etc., thanks to its significantly increased surface area and air and moisture permeability. For instance, the chitosan sheet of the present invention, when being used as a wound dressing, can effectively remove wound exudates, as well as affording good ventilation to the wound. In particular, the sheet has such a structure in which thin films are layered at regular gaps as to homogeneously distribute drugs therethroughout, thereby prolonging the drug retention time. In the pharmaceutical industry, a material is required to form a moldable solution in order to be used as binders for drug, wetting agents, gel, films, emulsifying agents, coating agents, microcapsules, and bio-adhesives . In this aspect, the multi-layered, air-gap sheets of the present invention is highly suitable for use as a chitosan source for a broad spectrum of applications because it can be readily dissolved in water owing to its large surface area. The present invention has been described in an illustrative manner, and it is to be understood that the terminology used is intended to be in the nature of description rather than of limitation. Many modifications and variations of the present invention are possible in light of the above teachings. Therefore, it is to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.

Claims: What is claimed is: 1. A chitosan microflake, which has a plate structure ranging, in thickness, from 0.1 to 10 μm and, in width, from 2 to 2000 μm with a deacetylation degree of 60 to 90 % and a viscosity average molecular weight of 1,000 to 1,000,000 g/mol . 2. A method for manufacturing a chitosan microflake, comprising the steps of: dissolving chitosan at a concentration of 0.5 to 30 % by weight in an organic solvent to give a chitosan solution; incubating the chitosan solution at -5 to 50 °C for 1 to 30 days; freeze-drying the chitosan solution; and pulverizing the freeze-dried chitosan solution to afford a plate structure of a chitosan microflake, which ranges, in thickness, from 0.1 to 10 μm and, in width, from 2 to 2, 000 μm. 3. The method as set forth in claim 2 , wherein the organic acid is selected from the group consisting of acetic acid, lactic acid, formic acid, glycolic acid, acrylic acid, propionic acid, succinic acid, ascorbic acid, glyconic acid, tartaric acid, maleic acid, citric acid, glutamic acid, and mixtures thereof . 4. A multi-layered, air-gap sheet of chitosan, which comprises 30-95 % by weight of chitosan, 3-50 % by weight of an organic solvent, and 2-25 % by weight of water and has a void volume ratio of 20 to 99 % with a lamellar structure in which chitosan thin films with a thickness of 1 to 50 μm are layered at regular gap intervals of 1 to 10,000 μm at an angle or angles of 0 to 180° to the surface of the sheet, said chitosan having a deacetylation degree of 60 to 99 % and a polymerization degree of 10 to 100,000. 5. The multi-layered, air gap sheet as set forth in claim 1, wherein the chitosan thin films are layered in the direction perpendicular or horizontal to the surface of the sheet or slanting against the surface of the sheet, or in two-dimensional patterns of any two of the perpendicular, horizontal and slanting directions. 6. A method for manufacturing a multi-layered, air-gap sheet of chitosan, comprising the steps of: dissolving chitosan at a concentration of 0.5 to 30 % by weight in an organic solvent to give a chitosan solution; incubating the chitosan solution at -5 to 50 °C for 1 to 30 days; and drying the chitosan solution by a thermal-, vacuum- or freeze-drying process. 7. The method as set forth in claim 6, wherein the freeze-drying process has cycles of pre-freeze drying at -10 °C to -60 °C and sublimating at 50 to 100 °C at regular time intervals for 10 min to 2 hours under a pressure of 100 Torr to 0.1 Torr. 8. The method as set forth in claim 2 , wherein the organic acid is selected from the group consisting of acetic acid, lactic acid, formic acid, glycolic acid, acrylic acid, propionic acid, succinic acid, ascorbic acid, glyconic acid, tartaric acid, maleic acid, citric acid, glutamic acid, and mixtures thereof .

Inventors: KIM MIN-JO, KIM WON-KI, PARK BONG-KUK, SON TAE-WON, YOO HYUN-OH, KIM, MIN-JO, KIM, WON-KI, PARK, BONG-KUK, SON, TAE-WON, YOO, HYUN-OH
Applicants: IBECKS TECHNOLOGIES CO LTD, IBECKS TECHNOLOGIES CO. LTD
Application year: 2001
Main classification: A61K9
IPC codes: A61K9, A61K47, C08B37