CN1618434A - Biological polysaccharide micro-capsule, prepn. method and application thereof - Google Patents
Biological polysaccharide micro-capsule, prepn. method and application thereof Download PDFInfo
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- CN1618434A CN1618434A CN 200310108684 CN200310108684A CN1618434A CN 1618434 A CN1618434 A CN 1618434A CN 200310108684 CN200310108684 CN 200310108684 CN 200310108684 A CN200310108684 A CN 200310108684A CN 1618434 A CN1618434 A CN 1618434A
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Abstract
A biological polyose microcapsule used as the carrier for preparing medicine or vaccine is prepared from the aqueous solution of biologic polyose and the aqueous solution of metallic salt through respectively adding them to the organic solvent containing surfactant, adding mineral oil, stirring to respectively obtain their suspension, respectively ultrasonic emulsifying on ice bath, mixing them together, centrifugal layering to obtain water phase, dewatering and washing.
Description
Technical field
The present invention relates to the materialogy field, relate more specifically to biological polyoses microcapsule and its production and application.
Background technology
Along with the development of bio-engineering research, will constantly there be newtype drug to occur, for human health provides more disease treatment means.Meanwhile, the development of bio-pharmaceutical and novel method of treatment is also had higher requirement to the development of administering mode.
Common biological polyoses has sodium alginate, Gellan glue (gellan gum), pectin, pectic acid, carrageenan, agar and agarose etc., and they all have by monosaccharide and connect formed chain structure.Wherein agar and agarose are thermosol (Thermal gel), can along with temperature raise and dissolve, along with temperature reduces and solidifies; Sodium alginate, pectin, pectic acid and carrageenan aqueous solution then have weak polyelectrolyte character, and owing to its specific structure, can combine with some metal ion and solidify; Depend on sodium ions content, Gellan glue can have above two specific characters respectively.
Sodium alginate has excellent biological compatibility, has therefore used for many years as the biological implantation material, is mainly used in the microcapsule (Franklin Lim, US Patent Number 4,391,909,1983) that preparation is embedded with islets of langerhans or cell.Thereby the aquation sodium alginate can crosslinked curing after reacting with bivalent metal ion such as alkaline-earth metal ions.The typical alginate capsule preparation method thereof comprises sessile drop method, static sessile drop method and atomization, makes the sodium alginate drop enter CaCl
2Solution, form diameter 1-2 millimeter respectively and (see Bing Q.Shen etc., Calcium alginateimmobilized hybridomas grown using a fluidized-bed perfusion system with a protein-free medium, Cytotechnology 14:109-117,1994), 50-200 micron (F.Lim and A.M.Sun, Microencapsulated islets as bioartificial endocrine pancreas, Science 210:908-910,1980) and several microns to 1 millimeter capsule (see Chinese patent application number 00801292, be used for the treatment of the micro-capsuled pheochromocyte of bull adrenal medulla as medicine of pain).Because above-mentioned alginate capsule is oversize, is not suitable for use in the intravascular drug carrier, also is not suitable for use in vaccine carrier.Do not see the capsular report of relevant preparation diameter biological polyoses below 1 micron as yet.
Therefore, this area presses for the new good biocompatibility that has, the microcapsule that particle diameter is little.
The invention summary
Therefore, it is good to the purpose of this invention is to provide a kind of biocompatibility, the biological polyoses microcapsule that particle diameter is little.
Another object of the present invention provides the method for making and the application of described biological polyoses microcapsule.
One aspect of the present invention provides a kind of preparation method of biological polyoses microcapsule, comprises the following steps:
A) 0.8-3% biological polyoses aqueous solution and 20-1000mM aqueous metal salt are added respectively in the organic solvent that is dissolved with surfactant, add mineral oil, mix, identical up to oil phase with water density, form biological polyoses water/oil suspension and metal saline/oil suspension, wherein said biological polyoses is selected from alginate (being preferably sodium alginate, potassium alginate), Gellan glue, pectin, pectic acid, carrageenan; Described slaine is selected from the water soluble salt that following metal ion forms: K
+, Ca
+ 2, Ba
+ 2, Sr
+ 2, Cu
+ 2, Fe
+ 2, Fe
+ 3, Al
+ 3Or its combination;
B) biological polyoses water/oil suspension and the metal saline/oil suspension that step a) is obtained used ultrasonic emulsification respectively on ice bath, forms stable biological polyoses water/oil emulsion and metal saline/oil emulsion;
C) at 4-35 ℃ of blend step b) the biological polyoses emulsion that obtains and slaine emulsion 5-60 minute, form reactant mixture;
D), obtain water to the centrifugal layering of the reactant mixture of step c);
E) product dehydration, surfactant and oil phase substance are removed in washing then, obtain biological polyoses microcapsule.
In the preference of the present invention aspect this, if biological polyoses is alginate (being preferably sodium alginate, potassium alginate), Gellan glue, pectin, pectic acid, described slaine is selected from: CaCl
2, BaCl
2, SrCl
2Or its mixture.
In the present invention's another preference aspect this, if biological polyoses is a carrageenan, described slaine metal ion is K
+Ion, concentration are 40-500mM.
In the present invention another embodiment aspect this, surfactant is Span 65, or surfactant is nonionic surfactant, and surfactant concentration is 5-50mg/ml; Described organic solvent is selected from dichloromethane, chloroform.
In the embodiment of the present invention aspect this, the dehydration in the step e) is carried out with dehydrated alcohol, and washing is to use washed with dichloromethane earlier, uses absolute ethanol washing then.
In the embodiment of the present invention aspect this, also comprise step:
F) biological polyoses microcapsule that step e) is obtained is put into the buffer (being preferably 2-N morpholino ethyl sulfonic acid solution) of pH4.5-6.2, with contain water solublity diamine compound (being preferably ethylenediamine), water-soluble carbodiimide (1-ethyl-3-dimethylaminopropyl carbodiimide hydrochloride, EDAC, be called EDC again), the pH of N-hydroxy thiosuccinimide (NHS) is that the solution (being preferably 2-N-morpholino ethyl sulfonic acid solution (MES)) of 4-6.9 mixes, wherein the biological polyoses microcapsule dry weight is 1 gram with the ratio of diamine compound: the 0.1-0.6 mM, 10-50 ℃ of following lucifuge and mixed 10-30 hour, remove metal ion with the metal ion chelation agent solution-treated that is selected from ethylenediaminetetraacetic acid or citric acid then, thereby obtain metal ion content and be lower than 5%, preferably be lower than 2%, most preferably be lower than 1% biological polyoses microcapsule.
Another aspect of the present invention provides the biological polyoses microcapsule with above-mentioned method preparation, and this capsule contains the biological polyoses of 50-90% weight, and capsular diameter is at 50-1000, preferably at 50-900, more preferably between the 50-800 nanometer.
In the embodiment of the present invention aspect this, biological polyoses is selected from alginate, is preferably sodium alginate, potassium alginate, or Gellan glue, pectin, pectic acid, carrageenan.
The purposes that also has an aspect that above-mentioned biological polyoses microcapsule is provided of the present invention, this microcapsule is used to prepare intravascular administration, oral administration, intramuscular injection or hypodermic medicine or vaccine as pharmaceutical carrier.
Of the present invention also have an aspect that a kind of drug microparticles is provided, and it comprises above-mentioned biological polyoses microcapsule and the active constituents of medicine that is embedded in, is adsorbed in and/or be coupled to described biological polyoses microcapsule.Term wherein used herein " active constituents of medicine " comprises curative active component, for example various medicines known in the art, for example hemoglobin, thrombin, insulin or the like also comprise preventative active component, for example antibody, immunogenic composition, vaccine etc.
The accompanying drawing summary
Fig. 1 has shown the diameter Distribution of the calcium alginate capsule of nano of embodiment 1 preparation.
Fig. 2 has shown that clear-headed Sprague Dawley rat blood kinetics is replied experimental result among the embodiment 5.
Fig. 3 has shown clear-headed Sprague Dawley rat blood chemical analysis results among the embodiment 5.Hurdle, a left side is the result of test group, and right hurdle is the result of matched group.Wherein " ALT (SGPT) " is meant alanine aminotransferase (serum glutamic pyruvic transaminase); " ALT (SGOT) " is meant alanine aminotransferase (serum glutamic oxalacetic transaminase); " CPK (CK) " is meant creatine phosphokinase (creatine kinase); " MG " refers to milligram, and " DL " is hundred milliliters, and " GM " is gram, and " IU " is iu, and " MEQ " is milliequivalent, and " U " is unit.
Fig. 4 has shown clear-headed Sprague Dawley rat serum cell counting result among the embodiment 5.Wherein " FL " is meant ounce fluid ounce, and " FG " is meant liquid measure gram (Fluid gram).
The specific embodiment
The inventor has realized the nanorize of biological polyoses microcapsule first by improving ultrasonic and emulsifying technology.
Organic solvent in the step of the present invention (a) can adopt polar solvent, for example dichloromethane, chloroform etc.Mineral oil can be petroleum ether or liquefied hydrocarbon, adds to mix, and is identical with water density up to oil phase, promptly can not form layering.The ultrasonic generating means of available routine in the step b), for example Misonic ultrasonic generator etc.Ultransonic intensity and time can be depended on the circumstances by persons skilled in the art, as long as form the emulsion of " stablizing ".The emulsion of " stablizing " is meant in the emulsion that obtains does not significantly reunite, and can not produce precipitation or reunion after placement yet.
After the reaction at room temperature, produce phase transformation in the step c), solid matter appears in aqueous phase originally, thereby can carry out centrifugalize, and can not merge as drop again.
Biological polyoses of the present invention is selected from sodium alginate, pectin, pectic acid and carrageenan etc.The characteristics of these biological polyoses are to have a plurality of free carboxyls along its sugar chain, and when running into metal ion, gel can be drawn close, form to polysaccharide chain by ionic bond mutually.The capsular particle diameter of biological polyoses that the present invention forms is nano level, and is more much smaller than the microcapsule of present use.Therefore it can be used as endovascular pharmaceutical carrier, does not stop up blood capillary or produces the phenomenon of cohesion and human body is worked the mischief and can not produce owing to particle diameter is excessive, can be used as the carrier of vaccine.In addition, owing to use the biological polyoses preparation, having the good compatibility with human body, is nontoxic.The preferred non-ionic surface active agent that uses is Span 65 among the present invention.This surfactant can be dissolved in organic solvents such as dichloromethane, chloroform.Other non-ionic surface active agent also can use, and for example Span 85.
Microcapsule of the present invention can forever be preserved in alcoholic solution, also can be suspended in the solution and preserve at 4 ℃, and the time was 1 year, still keeps stable, and flocculation or decomposing phenomenon do not occur.This solution can wherein can add 2mM CaCl with conventional normal saline solution
2With 10mM HEPES (pH 7.2-7.4), to keep ionic equilibrium and acid-base balance.
Metal ion polyoses capsule of the present invention can react with organic cross-linking reagent easily, for example uses diamine compound (best is ethylenediamine) to replace metal ion and combines with carboxyl.The amino chemical compound with carboxyl coupling connection of used mediation is preferably water-soluble carbodiimide, most preferably is 1-ethyl-3-dimethylaminopropyl carbodiimide hydrochloride (EDAC or title EDC).These water-soluble carbodiimide chemical compounds are well known by persons skilled in the art, also can obtain from merchandise resources, for example Sigma company etc.This capsule that obtains also has little, the nontoxic advantage of particle diameter, can be used as drug administration carrier.
Administration as herein described can be used for number of ways, for example oral, intravascular injection, intramuscular injection, subcutaneous injection etc.
The particle diameter of biological polyoses microcapsule of the present invention has reached 1000 nanometers first, and preferred 900,800 nanometers are following even reach 200 nanometers.Such microcapsule can artery-clogging, has the character of better transmission active constituents of medicine, can be engulfed by immunocyte (for example huge have a liking for cell) yet.In operation, the mixing ratio of biological polyoses microcapsule and active component can determine that according to actual operating position its mixing ratio is generally 1: 99-99: 1 by those skilled in the art.
Hereinafter provide embodiment to further illustrate the present invention.These examples are not in order to limit the scope of the invention.
Embodiment 1: Preparation of Calcium Alginate Microcapsule
(1) get two 50 ml polypropylene centrifuge tubes, each claims 400 milligrams of nonionic surfactant Span65, is dissolved in respectively in 16.6 milliliters of dichloromethane.Add 2 milliliters of sodium alginate soln and 2 milliliters of 120mM CaCl that are dissolved in 10mM HEPES buffer (pH7.4) respectively
2Solution (contain 10mM HEPES, pH 7.4) adds mineral oil again, mixes gently, and is identical with water density up to oil phase;
(2) centrifuge tube is put on the ice bath, utilizes ultrasound wave (Misonic, 1/4 inch) sodium alginate soln and CaCl
2Solution difference emulsifying 4 minutes;
(3) with sodium alginate emulsion and CaCl
2Emulsion mixed in beaker, reacts 5 minutes, finished phase transformation;
(4) after reaction is finished, with reactant mean transferred to 4 50 a ml polypropylene centrifuge tube, add dichloromethane to 50 milliliter more respectively, mix, rotating speed 1700RPM is centrifugal 5 minutes then, and water is shifted out from the top, incorporates 50 ml polypropylene centrifuge tubes into;
(5) add dehydrated alcohol, utilize ultrasound wave capsules disperse, centrifugal, remove ethanol;
(6) add 16 milliliters of dichloromethane, utilize ultrasound wave, add 32 milliliters of dichloromethane again, mixed then 1700RPM centrifugal 5 minutes, remove dichloromethane capsules disperse;
(7) repeat (6);
(8) add 16 milliliters of dehydrated alcohol, utilize ultrasound wave, add 32 milliliters of dehydrated alcohol again, mixed then 1700RPM centrifugal 5 minutes, remove ethanol capsules disperse;
(9) add 10 milliliters of 2mM CaCl
2Solution utilizes ultrasound wave with capsules disperse, adds 40 milliliters of 120mM CaCl again
2Solution mixed then 1700RPM centrifugal 5 minutes, removed supernatant;
(10) capsule is suspended in again 25 milliliters of pH, 7.4 142mM NaCl solution and (contains 2mM CaCl
2With 10mM HEPES), do grading analysis and microscopic examination.The NICOMP system of Particle Sizing Systems company is adopted in grading analysis, analysis result as shown in Figure 1, all capsule diameter below 1000 nanometers, about 250 nanometers of average diameter.
Embodiment 2: the preparation of alginic acid barium microcapsule
(1) get two 50 ml polypropylene centrifuge tubes, each claims 400 milligrams of nonionic surfactant Span65, is dissolved in respectively in 16.6 milliliters of dichloromethane.Add 2 milliliters of sodium alginate soln and 2 milliliters of 100mM BaCl that are dissolved in 10mM HEPES buffer (pH7.4) respectively
2Solution (contain 10mM HEPES, pH 7.4) adds mineral oil again, mixes gently, and is identical with water density up to oil phase;
(2) centrifuge tube is put on ice, utilizes ultrasound wave (Misonic, 1/4 inch) sodium alginate soln and BaCl
2Solution difference emulsifying 4 minutes;
(3) with sodium alginate emulsion and BaCl
2Emulsion mixed in beaker, reacts 5 minutes, finished phase transformation;
(4) after reaction was finished, mean transferred to 4 50 a ml polypropylene centrifuge tube added dichloromethane to 50 milliliter again, mixed then 1700RPM centrifugal 5 minutes, and water is shifted out from the top, incorporated 50 ml polypropylene centrifuge tubes into;
(5) add 16 milliliters of dehydrated alcohol, utilize ultrasound wave, add 32 milliliters of dehydrated alcohol again, mixed then 1700RPM centrifugal 5 minutes, remove dehydrated alcohol capsules disperse;
(6) add 16 milliliters of dichloromethane, utilize ultrasound wave, add 32 milliliters of dichloromethane again, mixed then 1700RPM centrifugal 5 minutes, remove dichloromethane capsules disperse;
(7) repeat (6);
(8) add 16 milliliters of dehydrated alcohol, utilize ultrasound wave, add 32 milliliters of dehydrated alcohol again, mixed then 1700RPM centrifugal 5 minutes, remove ethanol capsules disperse;
(9) add 10 milliliters of 2mM CaCl
2Solution utilizes ultrasound wave with capsules disperse, adds 40 milliliters of 100mM BaCl again
2Solution mixed then 1700RPM centrifugal 5 minutes, removed supernatant;
(10) capsule is suspended in again 25 milliliters 142mM NaCl solution and (contains 2mM CaCl
2And 10mMHEPES, pH 7.4), microscopic examination, visible capsule is dispersity, not reunion or crosslinked.
Embodiment 3: the preparation of the crosslinked alginate microcapsule of ethylenediamine
Use diamine compound that the crosslinked alginate microcapsule of alkaline-earth metal ions is organic crosslinked, re-use chelating agen bonded ion remaval.
(1) 200 milligrams of (dry weight) calcium alginate microcapsules are put into 50 ml polypropylene centrifuge tubes, centrifugal, remove supernatant;
(2) 25mM MES (the 2-N-morpholino ethyl sulfonic acid) buffer of 45 milliliters of pH 6.5 of adding (contains 20mM CaCl
2With 108mM NaCl), utilize ultrasound wave with capsules disperse, centrifugal, remove supernatant;
(3) repeat (2);
(4) add the ethylenediamine (2HCl, pH is transferred to 6.5) that 62.5 microlitre 1M are dissolved in MES, mix;
(5) divide 800 milligrams of EDAC of another name and NHS, be dissolved in 5 milliliters of 20mM MES solution rapidly, mix with the alginic acid capsule, hybrid reaction is 18.5 hours at ambient temperature;
(6) add 5 milliliters of 2mM CaCl
2Solution and 20 milliliters of 120mM CaCl
2Solution mixes, and is centrifugal, removes supernatant;
(7) add 5 milliliters of 2mM CaCl
2Solution utilizes ultrasound wave with capsules disperse, adds 40 milliliters of dehydrated alcohol, mixes, and is centrifugal, removes supernatant;
(8) repeat (7);
(9) add citric acid or EDTA solution, remove Ca
+ 2
Embodiment 4: the chemical coupling thing of hemoglobin and alginate microcapsule
(1) 200 milligrams of (dry weight) calcium alginate microcapsules are put into 50 ml polypropylene centrifuge tubes, centrifugal, remove supernatant;
(2) add 45 milliliters of pH 6.5 25mM MES buffer and (contain 20mM CaCl
2And 108mMNaCl), utilize ultrasound wave with capsules disperse, centrifugal, remove supernatant;
(3) repeat (2);
(4) add the human hemoglobin (pH 6.5) that 62.5 microlitres 3% are dissolved in MES, mix;
(5) divide 800 milligrams of EDAC of another name and NHS, be dissolved in 5 milliliters of 20mM MES solution rapidly, mix with the calcium alginate capsule, hybrid reaction is 18 hours at ambient temperature;
(6) with in reactant transfer to the 10 ten thousand MWCO bag filters, in 4 ℃ of phosphate buffers, dialyse, remove free hemoglobin.
Embodiment 5: the hematodinamics of calcium alginate microcapsule in clear-headed rat replied experiment
Be averaged 6 of body weight 80 gram Sprague Dawley rats.Calcium alginate microcapsule (is contained 2mM CaCl at 142mMNaCl solution
2With 10mM HEPES, pH 7.4) in be diluted to every milliliter 12 milligrams (dry weight), to 5 milliliters of the intravenous injections (60 milligrams of dry weights) respectively of 4 experimental rats, to 2 control rats respectively 5 milliliters of 142mM NaCl of intravenous injection solution (contain 2mM CaCl
2With 10mM HEPES, pH 7.4), and monitor arterial pressure (Arterial pressure), cardiac output (Cardiac output), heart rate (Heartrate), total peripheral resistance (Total peripheral resistance) (as shown in Figure 2) in real time.And blood sample carried out biochemical analysis (as shown in Figure 3 and Figure 4).Experimental result proves, between test rat and the control rats aspect hematodinamics, hematochemistry and hemocyte no significant difference.After testing, also no significant difference of respiratory frequency, body temperature and body weight.
The hematodinamics of the link coupled alginic acid microcapsule of embodiment 6 hemoglobin in clear-headed rat replied experiment
Alginic acid microcapsule in the link coupled alginic acid microcapsule of the hemoglobin alternate embodiment 5 that is obtained with embodiment 4, with independent hemoglobin buffer soln in contrast, method according to embodiment 5 is carried out administration, and monitors arterial pressure (Arterial pressure), cardiac output (Cardiac output), heart rate (Heartrate), total peripheral resistance (Total peripheral resistance) in real time.Experimental result proves that the test rat all has obvious rising with respect to control rats on cardiac output, body temperature and body weight, and its vigor increases.Therefore, played significantly better effect than the method for routine with biological polyoses microcapsule really as carrier transportation hemoglobin.
Claims (10)
1, a kind of preparation method of biological polyoses microcapsule is characterized in that, comprises the following steps:
A) 0.8-3% biological polyoses aqueous solution and 20-1000mM aqueous metal salt are added respectively in the organic solvent that is dissolved with surfactant, add mineral oil, mix, identical up to oil phase with water density, form biological polyoses water/oil suspension and metal saline/oil suspension respectively, wherein said biological polyoses is selected from alginate, Gellan glue, pectin, pectic acid, carrageenan; Described slaine is selected from the water soluble salt that following metal ion forms: K
+, Ca
+ 2, Ba
+ 2, Sr
+ 2, Cu
+ 2, Fe
+ 2, Fe
+ 3, Al
+ 3Or its combination;
B) biological polyoses water/oil suspension and the metal saline/oil suspension that step a) is obtained used ultrasonic emulsification respectively on ice bath, forms stable biological polyoses water/oil emulsion and metal saline/oil emulsion;
C) at 4-35 ℃ of blend step b) the biological polyoses emulsion that obtains and slaine emulsion 5-60 minute, form reactant mixture;
D), obtain water to the centrifugal layering of the reactant mixture of step c);
E) product dehydration, surfactant and oil phase substance are removed in washing then, obtain biological polyoses microcapsule.
2, the method for claim 1 is characterized in that, if biological polyoses is alginate, Gellan glue, pectin, pectic acid, described slaine is selected from: CaCl
2, BaCl
2, SrCl
2Or its mixture.
3. the method for claim 1 is characterized in that, if biological polyoses is a carrageenan, described slaine metal ion is K
+Ion, concentration are 40-500mM.
4. the method for claim 1 is characterized in that, described surfactant is Span 65, or surfactant is nonionic surfactant, and surfactant concentration is 5-50mg/ml; Described organic solvent is selected from dichloromethane, chloroform.
5. the method for claim 1 is characterized in that, the dehydration in the step e) is carried out with dehydrated alcohol, and washing is to use washed with dichloromethane earlier, uses absolute ethanol washing then.
6. the method for claim 1 is characterized in that, also comprises step:
F) biological polyoses microcapsule that step e) is obtained is put into the buffer of pH4.5-6.2, with the pH that contains water solublity diamine compound, water-soluble carbodiimide, N-hydroxy thiosuccinimide is that the buffer of 4-6.9 mixes, wherein the biological polyoses microcapsule dry weight is 1 gram with the ratio of diamine compound: the 0.1-0.6 mM, 10-50 ℃ of following lucifuge and mixed 10-30 hour, remove metal ion with the metal ion chelation agent solution-treated that is selected from ethylenediaminetetraacetic acid or citric acid then, be lower than 5% biological polyoses microcapsule thereby obtain metal ion content.
7. with the biological polyoses microcapsule of the described method preparation of claim 1, it is characterized in that this capsule contains the biological polyoses of 50-90% weight, and capsular diameter is between the 50-1000 nanometer.
8. microcapsule as claimed in claim 7 is characterized in that, described biological polyoses is selected from alginate, Gellan glue, pectin, pectic acid, carrageenan.
9. the purposes of biological polyoses microcapsule as claimed in claim 7 is characterized in that, this microcapsule is used to prepare intravascular administration, oral administration, intramuscular injection or hypodermic medicine or vaccine as pharmaceutical carrier.
10. a drug microparticles is characterized in that, it comprises described biological polyoses microcapsule of claim 7 and the active constituents of medicine that is embedded in, is adsorbed in and/or be coupled to described biological polyoses microcapsule.
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|---|---|---|---|
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102133433A (en) * | 2011-03-09 | 2011-07-27 | 中国人民解放军军事医学科学院基础医学研究所 | Injectable cardiac muscular tissue engineering product and preparation method thereof |
| CN101314035B (en) * | 2008-06-30 | 2011-09-07 | 沈炳谦 | Uses of biological polyoses microcapsule |
| CN102771688A (en) * | 2011-05-13 | 2012-11-14 | 富曼实（上海）商贸有限公司 | Edible liquid-filled polysaccharide capsule |
| CN103305497A (en) * | 2013-05-31 | 2013-09-18 | 东北农业大学 | Immobilized enzyme microcapsule for repairing organic contamination soil and preparation method thereof |
| GB2539006A (en) * | 2015-06-03 | 2016-12-07 | Ewos Innovation As | Functional feed |
| WO2016195509A1 (en) * | 2015-06-03 | 2016-12-08 | Ewos Innovation As | Oral delivery system for bioactive agents |
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2003
- 2003-11-19 CN CN 200310108684 patent/CN1268346C/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101314035B (en) * | 2008-06-30 | 2011-09-07 | 沈炳谦 | Uses of biological polyoses microcapsule |
| CN102133433A (en) * | 2011-03-09 | 2011-07-27 | 中国人民解放军军事医学科学院基础医学研究所 | Injectable cardiac muscular tissue engineering product and preparation method thereof |
| CN102133433B (en) * | 2011-03-09 | 2013-12-18 | 中国人民解放军军事医学科学院基础医学研究所 | Injectable cardiac muscular tissue engineering product and preparation method thereof |
| CN102771688A (en) * | 2011-05-13 | 2012-11-14 | 富曼实（上海）商贸有限公司 | Edible liquid-filled polysaccharide capsule |
| CN103305497A (en) * | 2013-05-31 | 2013-09-18 | 东北农业大学 | Immobilized enzyme microcapsule for repairing organic contamination soil and preparation method thereof |
| CN103305497B (en) * | 2013-05-31 | 2015-02-04 | 东北农业大学 | Immobilized enzyme microcapsule for repairing organic contamination soil and preparation method thereof |
| GB2539006A (en) * | 2015-06-03 | 2016-12-07 | Ewos Innovation As | Functional feed |
| WO2016195509A1 (en) * | 2015-06-03 | 2016-12-08 | Ewos Innovation As | Oral delivery system for bioactive agents |
| CN108076627A (en) * | 2015-06-03 | 2018-05-25 | Ewos创新股份有限公司 | For the oral delivery systems of bioactivator |
| CN108076627B (en) * | 2015-06-03 | 2021-05-25 | Ewos创新股份有限公司 | Oral delivery system for bioactive agents |
| EP3881835A1 (en) * | 2015-06-03 | 2021-09-22 | Ewos Innovation AS | Oral delivery system for bioactive agents |
| US11844863B2 (en) | 2015-06-03 | 2023-12-19 | Ewos Innovation As | Oral delivery system for bioactive agents |
| CN110961057A (en) * | 2020-01-16 | 2020-04-07 | 江苏罗格斯生物科技有限公司 | Green biological hydrogel conveying system and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| CN1268346C (en) | 2006-08-09 |
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