CN1248679C - Water soluble microflake through air gap and process thereof - Google Patents
Water soluble microflake through air gap and process thereof Download PDFInfo
- Publication number
- CN1248679C CN1248679C CNB018128831A CN01812883A CN1248679C CN 1248679 C CN1248679 C CN 1248679C CN B018128831 A CNB018128831 A CN B018128831A CN 01812883 A CN01812883 A CN 01812883A CN 1248679 C CN1248679 C CN 1248679C
- Authority
- CN
- China
- Prior art keywords
- chitosan
- acid
- drying
- microflakes
- thin slice
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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 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
Background of invention
1. the technology of the present invention field
The present invention relates to that coating performance has the big improved chitosan microflakes of root on skin.The present invention also relates to a kind of chitosan multilamellar space sheet, it can prolong the time of staying of its Chinese medicine and make medicine uniform distribution on the whole.In addition, the present invention relates to prepare the method for such chitosan microflakes and chitosan multilamellar space sheet.
2. prior art
Find that chitin is present in the shell of Crustaceans in a large number, the cell wall of Eriocheir sinensis and shrimp, insecticide and fungus, mushroom and antibacterial for example, it and potassium carbonate, protein, lipoid and pigment constitute the primary structure of multiple animal ectoskeleton and shell.Be only second to cellulose, chitin is the maximum polysaccharide of output in the world, estimates that annual biologic artifact produces 10,000,000,000 tons chitin and derivant thereof.
Although very abundant at occurring in nature, because the low solubility in aqueous solution, chitin is not effectively utilized.Because this problem, chitin is difficult to form fiber and thin film, only finds limited application.In order to attempt to overcome this problem, chitin is changed into the chitosan that dissolves in acidic aqueous solution.Common use is taken off the acetyl technology and is changed chitin into chitosan.In industry, the use of water-soluble chitosan is much more extensive than water-fast chitin.
Derived from chitinous chitosan is aminopolysaccharide by the representative of following chemical formula 1, and known have a biocompatibility, that is to say avirulence and biodegradable.In addition, find that chitosan has effective biological activity, can be used for for example cell fusion, tissue culture and hemostasis, and biological property for example antibacterial activity and biocompatibility.In addition, the physiological function relevant with chitosan comprises minimizing blood cholesterol levels and blood sugar level, activates the metabolism of intestinal, by the active anticancer of enhancing immunity, improves the toxic effect of activity and the reduction heavy metal of liver.
At first, chitin and chitosan are used as from the coagulating agent of the useful raw material of waste water reclamation of bakery and confectionery.Recently, have been found that the multiple application of chitin and chitosan, comprise food, pharmacy and medicine, biological engineering, cosmetics, agricultural, Chemical Engineering and environment-industry in multiple industry.
In addition, Crustaceans is the waste product of shrimp and Eriocheir sinensis for example, as chitinous main source.In the future, chitin is expected to obtain from krill.Consider the production of chitosan, pay particular attention to fungus, because in the cell wall of fungus, found chitin and chitosan.Therefore, if developed from fungus the method for cultivating and extracting to guarantee the preparation of useful polysaccharide, their source will be expanded.
U.S. Patent number 3,533,940 disclose and have a kind ofly prepared the method for chitosan and the application on fiber and thin film from chitin.For possible application, the chitosan for preparing is dissolved in the aqueous organopolysiloxane.At U.S. Patent number 4,669, in 135, disclose chitin has been dissolved in the dimethyl acetic acid esteramides that for example contains lithium chloride in the polar solvent, with the preparation chitin fiber.The method for preparing the chitosan fiber from the solution of chitosan acetic acid aqueous solution is also disclosed.U.S. Patent number 5,900,479 disclose the method for using the chitosan aqueous solutions of organic acids to prepare water soluble chitin fiber and thin film.United States Patent (USP) 4,286,087 discloses a kind of method for preparing the chitin powder, by under the temperature that improves, handling chitin granules with the phosphoric acid of lower aliphatic alcohols dilution, the chitin of separating treatment, and in inert liquid medium, shear until homodisperse, separate chitin and the drying and grinding sheared subsequently and obtain fine powder.
In addition, many other technology are also disclosed to utilize chitin or chitosan as raw materials in producing films and fiber.In addition, activity research has been directly used in preparation and has been applicable to the biocompatible health product of clinical medicine fields and possible application.As a result, develop at present and disclose multiple correlation technique.
For example, at (Rev.Macromol.Chem.Phys. such as Dynesh, C40 (1), chitin, chitosan and its derivant are used for Wound-healing agent, artificial skin, medicine, blood clotting agent, artificial kidney barrier film, biodegradation stitching thread and antibacterial etc. as raw material application and excellent functionality are disclosed 69-83,2000).Another result of study is (ILEE Engineering in Medicine and Biology, November/December, 1999) such as Maryefan, discloses the bedcover that covers chitosan and has had medicinal efficacy, prevents to form cicatrix and promotes wound healing.
(the Pharmaceutcial Research of Lithbethylem etc., Vol.15, No.9,1998), disclose because avirulence and biocompatible performance feature, chitosan has multiple application at pharmaceutical industries, comprises medical binding agent, wetting agent, gel, thin film, emulsifying agent, coating reagent, microcapsule, biological adhesive, medicinal (official) preparation, vaccine derivant, gene derivative etc., and activity research in addition points to the wide spectrum purposes of chitosan.
Wang, (Journal of Biomedical Materials Research such as K.R., V.53, N.1,8-17,2000) result of study of publishing discloses a kind of wound dressing that comprises chitin and chitosan acetate, when being used for second degree burn, because the high-moisture penetrance of chitosan has prevented gathering of Wound exudate, and because the chitosan antibacterial activity has been avoided superinfection.
U.S. Patent number 5,836,970 relate to the wound dressing that comprises a kind of mixture, and this mixture has the chitosan and the alginate of effective dose, and the two all exists with powder, thin film or gel form, declares that wound dressing has the ability that promotes wound healing.
U.S. Patent number 3,632,754 and 3,914,413 disclose the chitin with promotion wound healing effect, can carry out physiology's dissolving by the effect of lysozyme hydrolysis.
Disclose from the laminated film of chitin and keratin or collagen preparation at european patent number 0089152 and Japanese Patent No. 86141373, be used for Wound protection.
Consider the advantage of physiologic effect, chitin and chitosan have been used for multiple commercial product.For example the health food of the Choito-Bios Company of known Germany and Acona Company manufacturing has used chitin and chitosan; gondola wellaCompany has used the chitosan of hydrolysis in hair products; the business-like example of other chitins and/or chitosan products comprises the nutraceutical Evalson R of the Nihon Kayaku of Japan; the Ichimarn Farukosu CM-chitin (a kind of skin care product) of Japan; the chitin nonwoven fabric of Japan Yunichika and as the chitin fiber of biodegradable surgical sewing thread and Japanese Katakurachkkarin as artificial skin chitosan-collagen-based materials etc.
Although think that chitin or chitosan are a kind of biological adaptation materials, yet the clinical practice of chitin and chitosan remained in the starting stage.Traditional method does not relate to the effective form of chitosan, and under this form, chitosan can be brought into play its advantage to greatest extent when being used for various objectives.The form of traditional chitosan products is thin film, non-woven fabrics or at cross section single face plastic foamboard that expose or enclosed space normally.Therefore in such structure, can not look to the medicine can uniform distribution and have high holdup capacity at all.(Macromolecular 1997,30,5849-5855) wait the probability that proposes new chitosan form, and according to this theory, the chitosan molecule of hydration can form two-dimensional structure when crystallization for Kenziokuyoma.It may only be the fiber of one-dimentional structure that Sonyasalmon etc. (Gout-Ilal ofPolymer Sci.Part B:Polymer Physics, Vol.33,1007-1014 (1995)) sum up.
As mentioned above, have and many chitin and chitosan are used for medicinal purpose technology.Yet most of traditional method only proposes chitin or the chitosan availability as biocompatible material, but fails to make its commercialization.In addition, do not mention a kind of chitin and chitosan that can suitably be applied to various clinical-pathology treatment and have the maximum function form of preparation.
Body skin presents different forms, depends on region.During motion, the skin in a zone of health is different from another regional physical property, the scope that for example prolongs and shrink.Owing to these reasons, the chitosan of a kind of new model of intensive needs improves having greatly aspect the close adhesion of skin.Because the form of traditional chitosan that is used for skin is powder, thin film, spongy or lamellar, limited their purposes greatly.
For example, chitosan power is difficult to be coated onto equably on the injured skin area.A large amount of chitosan powers need be covered injured skin area.To such an extent as to be the contact area of chitosan power and skin area too little can not fully produce drug effect for another shortcoming of chitosan power.In addition, chitosan power lacks airtight bonding force.As for chitosan films, spongy or lamellar, have be difficult to closely bonding and with skin in restricted shortcoming aspect the size.And then, can expect them when carrying out serial movement, for example prolong and can not keep close cohesive with skin when shrinking.
Summary of the invention
Therefore the present invention seeks to overcome the problem that above-mentioned prior art runs into and a kind of method for preparing the chitosan of meagre form is provided, this chitosan has improved the close cohesive with skin especially.
Another object of the present invention provides a kind of very chitosan microflakes of high-coverage that has on skin, therefore improve the medicinal usefulness of high-purity chitosan, comprise that wound healing, sterilization stop or suppress the formation and the wound recovery of cicatrix, are applied to wound for example skin wound, surgical operation and burn.
Another object of the present invention provides a kind of multilamellar chitosan space sheet with regular three dimensional structure, and its Chinese medicine can keep long period and distributed uniform.
Preparing chitosan microflakes of the present invention is by chitosan being dissolved in the moisture organic acid soln of a kind of faintly acid to obtain chitosan soln, from this solution, extract chitosan, and making anisotropic meagre of chitosan solidify out into, its width is ten times of thickness.
In the time of on being applied to skin, chitosan microflakes of the present invention forms speckle shape plane, demonstrates the covering performance that has greatly improved on skin.And the cohesive of this chitosan microflakes and skin is so good, has maximally utilised the medicinal function of chitosan.
The structure of chitosan microflakes provided by the invention is the new model that did not produce before the present invention, can be used as clinical pathology reagent effectively, has high coating performance and reach the maximum medicinal efficacy of chitosan on skin..
By the plural layers that chitosan is formed, multilamellar of the present invention space sheet has such laminated structure, and wherein chitosan films is each other vertical, parallel or favour the sheet surface direction and be spaced with the distance of rule.Therefore, medicine can be in total uniform distribution and keeping the long period.
Particularly, the present invention relates to:
1. a chitosan microflakes has slab construction, and thickness is 0.1 to 10 μ m, width 2 to 2000 μ m, and width is at least 10 times of thickness, deacetylation 60 to 99%, and the degree of polymerization is 100 to 10,000.
2. method for preparing chitosan microflakes may further comprise the steps:
Is 0.5 to 30wt% to be dissolved in the organic acid that comprises 0.1-20 weight % acid, to obtain chitosan soln chitosan with concentration;
Under-5 to 50 ℃ with chitosan soln heat insulating culture 1 to 30 day;
By heated drying, vacuum drying or freeze-drying method drying chitosan solution; With
Pulverize exsiccant chitosan soln to obtain the slab construction of chitosan microflakes, its thickness range is 0.1 to 10 μ m, and width is 2 to 2,000 μ m, and width is at least 10 times of thickness.
3. the 2nd method, wherein freeze-drying method has following circulation: carrying out the precooling drying under-10 ℃ to-60 ℃ and in 100 holders to the pressure of 0.1 holder, with the interval of rule in 50-100 ℃ of distillation 10 minutes to 2 hours.
4. the 2nd method, wherein the heated drying method is carried out under 50～200 ℃.
5. the 2nd method, wherein vacuum drying method carries out under 50 to 200 ℃ and 0.1 to 100 holder.
6. the 2nd method, wherein organic acid is selected from acetic acid, lactic acid, formic acid, hydroxyacetic acid, acrylic acid, propanoic acid, succinic acid, ascorbic acid, gluconic acid, tartaric acid, maleic acid, citric acid, glutamic acid and its mixture.
7. chitosan multilamellar space thin slice, have the layer structure that the voidage rate is 20%-99%, wherein chitosan films thickness is 1-50 μ m, becomes 0 to 180 ℃ of angle with 1 to 10 with the chitosan sheet surface, the spacing rule layered arrangement of 000 μ m
Wherein chitosan films comprises 30 to 95 weight % chitosans, and 3 to 50 weight % comprise the organic acid and the 2-25 weight % water of 0.1-20 weight % acid,
Wherein the deacetylation of chitosan is 60 to 99%, and the degree of polymerization is 10 to 100,000.
8. the 7th multilamellar space thin slice, wherein chitosan films perpendicular to or be parallel to sheet surface or favour layered arrangement on the direction of sheet surface, perhaps arrange with the two-dimensional model of any both direction in vertical, parallel and the incline direction.
9. method for preparing chitosan multilamellar space thin slice may further comprise the steps:
Is 0.5 to 30wt% to be dissolved in the organic acid that comprises 0.1-20 weight % acid, to obtain chitosan soln chitosan with concentration;
Under-5 to 50 ℃ with chitosan soln heat insulating culture 1 to 30 day; With
By heated drying, vacuum drying or freeze-drying method drying chitosan solution.
10. the 9th method, wherein freeze-drying method has following circulation: carrying out the precooling drying under-10 ℃ to-60 ℃ and in 100 holders to the pressure of 0.1 holder, with the interval of rule in 50-100 ℃ of distillation 10 minutes to 2 hours.
11. the 9th method, wherein the heated drying method is carried out under 50～200 ℃.
12. the 9th method, wherein vacuum drying method 50 to 200 ℃ and 0.1 to 100 the holder under carry out.
13. the 9th method, wherein organic acid is selected from acetic acid, lactic acid, formic acid, hydroxyacetic acid, acrylic acid, propanoic acid, succinic acid, ascorbic acid, gluconic acid, tartaric acid, maleic acid, citric acid, glutamic acid and its mixture.
Brief Description Of Drawings
Fig. 1 is a chitosan microflakes sketch map of the present invention.
Fig. 2 provides chitosan microflakes and amplifies 60 times of (left side) photos and amplify 6,000 times photo (the right).
Fig. 3 is the scanning electron microscopy sheet (SEM) of cryodesiccated chitosan microflakes, has amplified 200 times, demonstrates the laminated structure of high-purity chitosan.
Fig. 4 has shown the multilamellar gap structure of chitosan thin slice, and wherein chitosan films is in vertical, the parallel and regular respectively laminated thin plate at interval of incline direction.Fig. 4 a has shown the laminated structure of chitosan thin slice, has a plurality of chitosan films perpendicular to (a) sheet surface direction, and rule interval (b).Fig. 4 b has shown the laminated structure of chitosan thin slice, has a plurality of chitosan films and favours (a) sheet surface, and rule interval (b).Fig. 4 c has shown the laminated structure of chitosan thin slice, has a plurality of chitosan films and is parallel to (c) sheet surface, and rule interval (b).
Fig. 5 is that the electron microscopic picture of the multilamellar space thin slice that is made of chitosan films is a longitudinal sectional drawing, demonstrates lamellar structure, and wherein each film thickness is 5-10 μ m, every layer of 20-120 μ m at interval on perpendicular to the sheet surface direction.
Fig. 6 is the fixed longitudinal sectional drawing of electron microscopic picture of the multilamellar space thin slice that is made of chitosan films, demonstrates laminated structure, and wherein each film thickness is 5-10 μ m, and every layer is favouring on the sheet surface direction 20-120 μ m at interval.
Fig. 7 is that the electron microscopic picture of the multilamellar space thin slice that is made of chitosan films is a longitudinal sectional drawing, demonstrates laminated structure, and wherein each film thickness is 5-10 μ m, and every layer is being parallel on the direction of sheet surface 60-360 μ m at interval.
Fig. 8 is that the electron microscopic picture of the multilamellar space thin slice that is made of chitosan films is a longitudinal sectional drawing, demonstrate laminated structure, wherein each film thickness is 5-10 μ m, every layer be parallel to and perpendicular to the direction of sheet surface on 50-220 μ m at interval.
Detailed Description Of The Invention
In one embodiment, the present invention is a kind of chitosan of new model, greatly improved it on skin covering performance and utilize the medicinal usefulness of chitosan to greatest extent.The new model of finding is meagre of the present invention.By chitosan is dissolved in the faintly acid solvent with specific weight ratio, freeze-drying solution, extracting exsiccant chitosan becomes porous chitosan films, and thin-film grinding is become meagre, and wherein width is 10 times of thickness at least.
The degree of polymerization that is applicable to chitosan of the present invention is 10 to 100,000, and deacetylation is 60 to 99%.More preferably the degree of polymerization of chitosan is 100 to 10,000, and deacetylation is 70 to 95%.Can use and be selected from aqueous acid solution, contain any solvent of aqueous inorganic salt solution and organic solvent.
In order to obtain aqueous acid solution of the present invention, add the acid of 0.1-20wt% in water, this acid is selected from organic acid for example acetic acid, lactic acid, formic acid, hydroxyacetic acid, acrylic acid, propanoic acid, succinic acid, oxalic acid, ascorbic acid, gluconic acid, tartaric acid, maleic acid, citric acid, glutamic acid and its mixture.
Available inorganic salt solution inorganic salt content in water is 10-70wt%.Inorganic salt is selected from isothiocyanic acid sodium, zinc chloride, calcium chloride, sodium chloride, potassium chloride, lithium chloride and its mixture.
In selected solvent, dissolving 0.5-30wt% chitosan obtains chitosan soln, with its process lyophilization and grinding, obtains chitosan microflakes then.
In another embodiment, the present invention relates to a kind of chitosan multilamellar space thin slice with regular layer structure, it keeps the medicine long period and makes the medicine uniform distribution.In layer structure, chitosan films perpendicular to or be parallel to sheet surface or favour on the direction of sheet surface the stratiform rule at interval, medicine can be in thin slice uniform distribution.Therefore, thin slice of the present invention has improved the medicine reservation especially and has distributed.In order to prepare laminar sheet of the present invention, at first chitosan is dissolved in the weak acid solvent, with the chitosan soln lyophilization that obtains, extract exsiccant chitosan subsequently and make it become the chitosan films that thickness is 1-50 μ m.Thus, when-5 ℃ under 50 ℃ with the chitosan soln ripening in the time of 1-30 days, make that under such environment the strand of chitosan may be with planar alignment, thereby formation thin film, as the disclosed crystalline texture of Kenziokuyoma (Macromolecular, the same) (structural formula 2).
In this process, chitosan films becomes 0 ° of-180 ° of angle to become stratiform, regular spaces 1-10,000 μ m with sheet surface.In this structure, chitosan thin slice of the present invention demonstrates high ventilative water permeability, drug delivery rate and water solublity.
Therefore, the present invention is the novel three-dimensional structure that is applicable to the stratiform space thin slice of medical applications.Chitosan thin slice for example of the present invention can effectively be removed the wound overflow when when the wound dressing, and because its good breathability makes wound to take a breath preferably, and can be effectively with medicinal application to wound.
When from chitosan soln, solidifying and extracting chitosan, can pass through several different methods, comprise lyophilization, heated drying and vacuum drying, can make multilamellar space thin slice and chitosan microflakes.Consider preparation meagre and thin slice, preferably chitosan soln is carried out lyophilization.
Usually can by do not destroy liquid phase directly under fine vacuum the freezing and dry matter of distillation carry out lyophilization.Compare with common dry technology, Freeze Drying Technique has the advantage that produces high quality of products.In addition, being characterized as of lyophilisation product has the micropore layer structure.In the present invention, lyophilization divided for three steps carried out: precooling, sublimation drying and dehydrate.
Since to the tremendous influence of final products, the essential careful control of the cryogenic temperature of precooling.In the present invention, chitosan soln precooling temperature range is-10 ℃ to-60 ℃, more preferably-35 ℃ to-40 ℃.
In the sublimation drying step, refrigerated chitosan soln loses free solvent, and it is equivalent to the 50wt% to 90wt% of whole solvents in the freezing chitosan soln.Therefore, repeat heating and sublimation process with the interval of rule, the latter is to carry out 10 minutes to 2 hours under 100 holders are held in the palm to 0.1 at-10 ℃ to-60 ℃ and pressure.
In the dehydrate step, removed the whole solvents 10 to 50wt% of back chitosan soln that are equivalent to distil in conjunction with solvent.For this reason, during heating net quantity of heat from the freezing distillation phase of delivering to according to legend.Therefore, when the loose structure of chitosan films occurred, moisture was removed from freezing phase top gradually.When sublimation boundary developed downwards, it is big that porous laminated structure becomes.At last, freezingly disappear mutually, obtain water solublity multilamellar chitosan thin slice, wherein chitosan films is with perpendicular or parallel sheet surface, and perhaps the direction rule that tilts with sheet surface is spaced.
Afterwards, under 0 ℃ to 60 ℃, freezing and pulverizing is carried out in chitosan multilamellar space thin slice (porous chitosan films), the chitosan films of order pulverizing obtains highly purified meagre by 10-100 purpose sieve then, and its width is 10 times of thickness at least.
With reference to figure 1, it is the sketch map of chitosan microflakes, and wherein width is 10 times of thickness or bigger.
When using the heated drying method, can be by preparing chitosan multilamellar space thin slice at 50 to 200 ℃ of dry chitosans.Vacuum drying be 50 to 200 ℃ and 0.1 to 100 the holder under carry out, drying chitosan solution obtains multilamellar space thin slice.
In the thin film of chitosan multilamellar space, each film thickness scope is 1-50 μ m, layered arrangement is 1-10 at interval, 000 μ m, be made of 30-95wt% chitosan, 3-50wt% organic acid and 2-25wt% water, the bulk density of chitosan multilamellar space thin slice is 0.01-1.0g/cm
3, 0.05-0.5g/cm more preferably
3
Being defined as the ratio that cumulative volume deducts thin film volume and thin slice cumulative volume is the voidage rate, is the 99%-20% of thin slice after measured.
Can better understand the present invention by the following embodiment of exemplifying, but should not be construed as limitation of the invention.
The preparation chitosan microflakes
1. preparation chitosan soln
Dissolving 5g viscosity is that 116cps, deacetylation are 94% chitosan in the 3wt% of 95g lactic acid aqueous solution, obtains clear solution.30 ℃ of following heat insulating culture 3 days, the chitosan strand can planar alignment under this condition, thereby forms thin film.
2. precooling is handled
The chitosan soln that obtains is placed in the container of freezer dryer, and freezing down at-50 ℃.
3. lyophilization
Under 0.1 backing pressure power the precooling chitosan soln is carried out lyophilization in 2 hours, temperature range is-5 ℃ to 50 ℃.
The form of the chitosan microflakes that obtains thus is shown in the full-scale displaing micro picture of Fig. 2.As Fig. 2 finding, meagre has wide layer structure, and its width is greater than thickness.The displaing micro picture on the left side has shown the accumulative chitosan microflakes of having amplified 60 times, and the right has further been amplified 100 times with the part of left side displaing micro picture is micro-, therefore amounts to chitosan microflakes has been amplified 6,000 times.
Fig. 3 is the SEM figure of lyophilization chitosan microflakes, has amplified 200 times.Shown in electron micrograph, chitosan microflakes has layer structure.
The preparation of chitosan microflakes
Use electronic flour mill, cryodesiccated high-purity porous chitosan films was pulverized 10 minutes down at-30 ℃, make chitosan microflakes, its width is 10 times of thickness at least.
Embodiment 2-5
Meagre piece performance corresponding to chitosan viscosity
Carry out the process identical with embodiment 1, except the viscosity of every part of 3g chitosan is respectively 11.6,116,370 and 1,446cps, deacetylation are 94%, used the lactic acid aqueous solution of 5wt%, obtaining width is the chitosan microflakes of 10 times of thickness at least.
Select 10 chitosan microflakes measurement sizes separately at random from embodiment 2 to 5 respectively, meansigma methods is listed in following table 1.
Table 1
The chitosan microflakes performance
| The chitosan performance | The embodiment numbering | |||
| 2 | 3 | 4 | 5 | |
| Chitosan viscosity (cps) | 116 | 116 | 370 | 1146 |
| Meagre average thickness | 1.1μm | 1.3μm | 1.3μm | 2μm |
| Meagre mean breadth | 11.2μm | 42μm | 49μm | 63μm |
Embodiment 6-10
Meagre piece performance corresponding to chitosan soln concentration
In the lactic acid aqueous solution of 3wt%, dissolve respectively 1,2,3,4 and the viscosity of 5wt% be that 116cps and deacetylation are 94% chitosan.From these chitosan solns, use the mode identical to prepare meagre with embodiment 1, the width that microscopic image analysis demonstration is meagre is more than 10 times or 10 times of thickness.
Select 10 chitosan microflakes measurement sizes separately at random from embodiment 6 to 10 respectively, meansigma methods is listed in following table 2.
Table 2
| The chitosan performance | The embodiment numbering | ||||
| 6 | 7 | 8 | 9 | 10 | |
| Chitosan concentration | 1wt％ | 2wt％ | 3wt％ | 4wt％ | 5wt％ |
| Meagre average thickness | 0.8μm | 1.2μm | 1.3μm | 3μm | 5.3μm |
| Meagre mean breadth | 10.2μm | 44μm | 42μm | 330μm | 610μm |
Embodiment 11-13
Chitosan microflakes performance corresponding to the precooling temperature
Use mode similar to Example 1 to prepare chitosan microflakes, except the precooling temperature is made as-30 ℃ ,-40 ℃ and-50 ℃ respectively.List in down tabulation 3 corresponding to the chitosan microflakes performance of precooling temperature.
Table 3
| Performance and condition | The embodiment numbering | ||
| 11 | 12 | 13 | |
| The precooling temperature | 30℃ | 40℃ | 50℃ |
| The chitosan microflakes average thickness | 0.9μm | 1.1μm | 1.1μm |
| The chitosan microflakes mean breadth | 41μm | 41μm | 42μm |
Chitosan space preparation of sections with stratified layer structure
When temperature be-5 ℃ to 50 ℃ and 0.1 the holder under, the pre-dried chitosan soln among the embodiment 1 is carried out sublimation drying and dehydrate, the preparation have stratified layer structure chitosan space thin slice.
Embodiment 14 to 17
Meagre piece performance corresponding to chitosan viscosity
Carry out the process identical with embodiment 1, except the viscosity of every part of 3g chitosan is respectively 11.6,116,370 and 1,446cps, deacetylation all is 94%, used the lactic acid aqueous solution of 5wt%, forming chitosan space sheet thickness thus is 7.5 to 15 μ m, interlamellar spacing 100 to 200 μ m.
Select 10 chitosan space thin slice measurement sizes separately at random from embodiment 14 to 17, meansigma methods is listed in following table 4.
Table 4
The chitosan microflakes performance
| The chitosan performance | The embodiment numbering | |||
| 14 | 15 | 16 | 17 | |
| Chitosan viscosity (cps) | 11.6μm | 116cps | 370cps | 1146cps |
| Average film thickness | 7.5μm | 7.7μm | 8.8μm | 10μm |
| Average thin film spacing | 89μm | 99μm | 134μm | 144μm |
Embodiment 18-22
Chitosan stratiform space thin slice performance corresponding to chitosan soln concentration
In the lactic acid aqueous solution of 3wt%, dissolve respectively 1,2,3,4 and the viscosity of 5wt% be that 116cps and deacetylation are 94% chitosan.From these chitosan solns, use the mode identical to prepare chitosan stratiform space thin slice with embodiment 1.Select 10 chitosan microflakes measurement sizes separately at random from embodiment 18-22, meansigma methods is listed in following table 5.
Table 5
| The chitosan performance | The embodiment numbering | ||||
| 18 | 19 | 20 | 21 | 22 | |
| Chitosan concentration | 1wt％ | 2wt％ | 3wt％ | 4wt％ | 5wt％ |
| Meagre average thickness | 7.1μm | 7.7μm | 7.7μm | 14μm | 11μm |
| Average thin film spacing | 65μm | 85μm | 99μm | 98μm | 98μm |
Embodiment 23-25
Chitosan stratiform space thin slice corresponding to the precooling temperature
Use mode similar to Example 1 to prepare chitosan stratiform space thin slice, except the precooling temperature is made as-30 ℃ ,-40 ℃ and-50 ℃ respectively.List in down tabulation 6 corresponding to the chitosan microflakes performance of precooling temperature.
Table 6
| Performance and condition | The embodiment numbering | ||
| 23 | 24 | 25 | |
| The precooling temperature | 30℃ | 40℃ | 50℃ |
| Average film thickness | 14μm | 11μm | 11.5μm |
| Average thin film spacing | 140μm | 110μm | 112μm |
The multilamellar space thin slice of chitosan of the present invention has multiple application in many industry, comprise food industry, medical industry, cosmetics industry, agricultural, chemical engineering science industry and environment-industry etc., it has the complex three-dimensional form, and is very different with existing fiber, thin film, powder and analog.Because surface area and ventilative water permeability that this novel three-dimensional structure and it significantly increase, stratiform of the present invention space thin slice is specially adapted to medical application, comprises Wound-healing agent, artificial skin, medicament, blood clotting agent, artificial kidney barrier film, antibacterial etc.For example, when chitosan thin slice of the present invention is used as wound dressing, can effectively remove the wound overflow, and because its good breathability makes wound to take a breath preferably.Particularly flake structure is a thin film regular gap layered arrangement, makes the medicine uniform distribution wherein, has prolonged the medicine time of staying.
In pharmaceutical industries, require material to form moldable solution so that as medicinal adhesive, wetting agent, gel, thin film, emulsifying agent, coating reagent, microcapsule and biological adhesive.In this respect, multilamellar of the present invention space thin slice extremely is suitable for use as the chitosan source that wide spectrum is used, because its high surface area, it is water-soluble easily.
The present invention to be exemplifying mode explanation, and is appreciated that term used herein should be its original implication rather than limit implication.In the above teachings, can make numerous modifications and variations to the present invention.Therefore, it should be understood that within appended claims scope of the present invention, can be different from foregoing description and put into practice.
Claims (13)
1. a chitosan microflakes has slab construction, and thickness is 0.1 to 10 μ m, width 2 to 2000 μ m, and width is at least 10 times of thickness, deacetylation 60 to 99%, and the degree of polymerization is 100 to 10,000.
2. method for preparing chitosan microflakes may further comprise the steps:
Is 0.5 to 30wt% to be dissolved in the organic acid that comprises 0.1-20 weight % acid, to obtain chitosan soln chitosan with concentration;
Under-5 to 50 ℃ with chitosan soln heat insulating culture 1 to 30 day;
By heated drying, vacuum drying or freeze-drying method drying chitosan solution; With
Pulverize exsiccant chitosan soln to obtain the slab construction of chitosan microflakes, its thickness range is 0.1 to 10 μ m, and width is 2 to 2,000 μ m, and width is at least 10 times of thickness.
3. the method for claim 2, wherein freeze-drying method has following circulation: carrying out the precooling drying under-10 ℃ to-60 ℃ and in 100 holders to the pressure of 0.1 holder, with the interval of rule in 50-100 ℃ of distillation 10 minutes to 2 hours.
4. the method for claim 2, wherein the heated drying method is carried out under 50～200 ℃.
5. the method for claim 2, wherein vacuum drying method carries out under 50 to 200 ℃ and 0.1 to 100 holder.
6. the method for claim 2, wherein organic acid is selected from acetic acid, lactic acid, formic acid, hydroxyacetic acid, acrylic acid, propanoic acid, succinic acid, ascorbic acid, gluconic acid, tartaric acid, maleic acid, citric acid, glutamic acid and its mixture.
7. chitosan multilamellar space thin slice, have the layer structure that the voidage rate is 20%-99%, wherein chitosan films thickness is 1-50 μ m, becomes 0 to 180 ° of angle with 1 to 10 with the chitosan sheet surface, the spacing rule layered arrangement of 000 μ m
Wherein chitosan films comprises 30 to 95 weight % chitosans, and 3 to 50 weight % comprise the organic acid and the 2-25 weight % water of 0.1-20 weight % acid,
Wherein the deacetylation of chitosan is 60 to 99%, and the degree of polymerization is 10 to 100,000.
8. the multilamellar space thin slice of claim 7, wherein chitosan films perpendicular to or be parallel to sheet surface or favour layered arrangement on the direction of sheet surface, perhaps arrange with the two-dimensional model of any both direction in vertical, parallel and the incline direction.
9. method for preparing chitosan multilamellar space thin slice may further comprise the steps:
Is 0.5 to 30wt% to be dissolved in the organic acid that comprises 0.1-20 weight % acid, to obtain chitosan soln chitosan with concentration;
Under-5 to 50 ℃ with chitosan soln heat insulating culture 1 to 30 day; With
By heated drying, vacuum drying or freeze-drying method drying chitosan solution.
10. the method for claim 9, wherein freeze-drying method has following circulation: carrying out the precooling drying under-10 ℃ to-60 ℃ and in 100 holders to the pressure of 0.1 holder, with the interval of rule in 50-100 ℃ of distillation 10 minutes to 2 hours.
11. the method for claim 9, wherein the heated drying method is carried out under 50～200 ℃.
12. the method for claim 9, wherein vacuum drying method 50 to 200 ℃ and 0.1 to 100 the holder under carry out.
13. the method for claim 9, wherein organic acid is selected from acetic acid, lactic acid, formic acid, hydroxyacetic acid, acrylic acid, propanoic acid, succinic acid, ascorbic acid, gluconic acid, tartaric acid, maleic acid, citric acid, glutamic acid and its mixture.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR2000/41075 | 2000-07-18 | ||
| KR1020000041075A KR100315381B1 (en) | 2000-07-18 | 2000-07-18 | Chitosan microflake and method of manufacturing them |
| KR1020000061106A KR100324164B1 (en) | 2000-10-17 | 2000-10-17 | Layered air-gap sheet of chitosan and process therefor |
| KR2000/61106 | 2000-10-17 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1443063A CN1443063A (en) | 2003-09-17 |
| CN1248679C true CN1248679C (en) | 2006-04-05 |
Family
ID=26638223
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB018128831A Expired - Fee Related CN1248679C (en) | 2000-07-18 | 2001-03-19 | Water soluble microflake through air gap and process thereof |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1313446A4 (en) |
| JP (1) | JP2004503671A (en) |
| CN (1) | CN1248679C (en) |
| AU (1) | AU2001244756A1 (en) |
| WO (1) | WO2002005783A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007300812A (en) * | 2006-05-09 | 2007-11-22 | Yoshiaki Takada | Method for producing rice processed food |
| CN101812743B (en) * | 2010-05-10 | 2012-10-17 | 山东华兴海慈新材料有限公司 | Spinning solution for industrially producing pure chitosan fiber and preparation method thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0780921B2 (en) * | 1987-01-23 | 1995-08-30 | ダイセル化学工業株式会社 | Microcrystalline chitosan and method for producing the same |
| JPH02261838A (en) * | 1989-04-03 | 1990-10-24 | Sumitomo Cement Co Ltd | Preparation of porous chitosan material |
| JP2996356B2 (en) * | 1990-12-26 | 1999-12-27 | 岩瀬コスフア株式会社 | Amorphous flaky chitosan powder, method for producing the same, and finished cosmetics incorporating the same |
| DE19932075A1 (en) * | 1999-07-12 | 2001-01-18 | Cognis Deutschland Gmbh | Crosslinker-free preparations |
-
2001
- 2001-03-19 CN CNB018128831A patent/CN1248679C/en not_active Expired - Fee Related
- 2001-03-19 AU AU2001244756A patent/AU2001244756A1/en not_active Abandoned
- 2001-03-19 WO PCT/KR2001/000432 patent/WO2002005783A1/en not_active Application Discontinuation
- 2001-03-19 EP EP01917879A patent/EP1313446A4/en not_active Withdrawn
- 2001-03-19 JP JP2002511716A patent/JP2004503671A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| AU2001244756A1 (en) | 2002-01-30 |
| EP1313446A4 (en) | 2007-05-30 |
| JP2004503671A (en) | 2004-02-05 |
| WO2002005783A1 (en) | 2002-01-24 |
| CN1443063A (en) | 2003-09-17 |
| EP1313446A1 (en) | 2003-05-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Yu et al. | Transdermal delivery of insulin with bioceramic composite microneedles fabricated by gelatin and hydroxyapatite | |
| US20090130186A1 (en) | Wound dressing assemblies, systems, and methods formed from hydrophilic polymer sponge structures such as chitosan and incorporating silver nanoparticles | |
| Alven et al. | Fabrication of hybrid nanofibers from biopolymers and poly (Vinyl alcohol)/poly (ε-caprolactone) for wound dressing applications | |
| US20050181027A1 (en) | Chitosan-containing wound dressings | |
| KR100324164B1 (en) | Layered air-gap sheet of chitosan and process therefor | |
| Liu et al. | Recent progress of electrospun herbal medicine nanofibers | |
| CN1340079A (en) | Freeze-dried agent containing paramylon, production and utilization thereof | |
| CN101249077A (en) | Preparation of degradable pollutant polyalcohol stephanoporate microballoons and uses thereof | |
| CN111945301B (en) | Membrane for releasing nitric oxide based on near-infrared response, preparation method and application | |
| Morganti et al. | Chitin nanofibrils for biomimetic products: nanoparticles and nanocomposite chitosan films in health care | |
| Duan et al. | Polymeric nanofibers for drug delivery applications: a recent review | |
| Teaima et al. | Synthesis of biocompatible and environmentally nanofibrous mats loaded with moxifloxacin as a model drug for biomedical applications | |
| JP2004261456A (en) | Porous calcium phosphate polymer hydrogel complex with penetration, its manufacturing method and artificial bone or chemical slowly releasing body using it | |
| Constantino et al. | Biomaterials based on organic polymers and layered double hydroxides nanocomposites: Drug delivery and tissue engineering | |
| CN1248679C (en) | Water soluble microflake through air gap and process thereof | |
| US6444797B1 (en) | Chitosan microflake and method of manufacturing the same | |
| KR20110027949A (en) | Nanofiber sheet with core-shell structure | |
| Pal et al. | Chitosan: as highly potential biopolymer obtainable in several advance drug delivery systems including biomedical applications | |
| CN1720989A (en) | Sustained release microsphere of epidermal growth factor, its preparation method and application | |
| Metwally et al. | Bioinspired 3D-printed scaffold embedding DDAB-nano ZnO/nanofibrous microspheres for regenerative diabetic wound healing | |
| Azad et al. | Chitin-and chitosan-based nanomaterials for therapeutic applications | |
| Badar et al. | Chitin-based nanomaterials | |
| Anand et al. | Biomaterial-based nanofibers for drug delivery applications | |
| CN114786738A (en) | 3D patterned fibrous material for local delivery of nucleic acids and method of making same | |
| WO2015049656A2 (en) | Suspensions and materials comprising complexes of chitin nanofibrils with metals |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |