CN101700228A - Preparation method of amino polysaccharide Aspirin composite nanometer particles - Google Patents
Preparation method of amino polysaccharide Aspirin composite nanometer particles Download PDFInfo
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- CN101700228A CN101700228A CN200910128089A CN200910128089A CN101700228A CN 101700228 A CN101700228 A CN 101700228A CN 200910128089 A CN200910128089 A CN 200910128089A CN 200910128089 A CN200910128089 A CN 200910128089A CN 101700228 A CN101700228 A CN 101700228A
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- aspirin
- aminopolysaccharide
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- amino polysaccharide
- composite nanometer
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- 229960001138 acetylsalicylic acid Drugs 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000002131 composite material Substances 0.000 title claims abstract description 7
- 229920001282 polysaccharide Polymers 0.000 title claims abstract description 7
- 239000005017 polysaccharide Substances 0.000 title claims abstract description 7
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 title abstract description 28
- 239000002245 particle Substances 0.000 title abstract description 6
- 150000004676 glycans Chemical class 0.000 title abstract 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 title abstract 3
- 238000000034 method Methods 0.000 claims abstract description 9
- -1 amino polysaccharide Chemical class 0.000 claims abstract description 8
- 238000004132 cross linking Methods 0.000 claims abstract description 5
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- 238000003381 deacetylation reaction Methods 0.000 claims description 6
- 235000019832 sodium triphosphate Nutrition 0.000 claims description 4
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 claims description 3
- 235000013923 monosodium glutamate Nutrition 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 3
- 229940073490 sodium glutamate Drugs 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical group O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 2
- 235000011152 sodium sulphate Nutrition 0.000 claims description 2
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- 150000001875 compounds Chemical class 0.000 abstract 1
- 230000002349 favourable effect Effects 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 241001597008 Nomeidae Species 0.000 description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000008901 benefit Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229920001661 Chitosan Polymers 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 3
- 206010000891 acute myocardial infarction Diseases 0.000 description 3
- 208000025870 aspirin resistance Diseases 0.000 description 3
- 230000003292 diminished effect Effects 0.000 description 3
- 238000004945 emulsification Methods 0.000 description 3
- 150000002333 glycines Chemical class 0.000 description 3
- 239000004531 microgranule Substances 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 241000195649 Chlorella <Chlorellales> Species 0.000 description 1
- 241000238424 Crustacea Species 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- NWGKJDSIEKMTRX-MDZDMXLPSA-N Sorbitan oleate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OCC(O)C1OCC(O)C1O NWGKJDSIEKMTRX-MDZDMXLPSA-N 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 238000013176 antiplatelet therapy Methods 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000010382 chemical cross-linking Methods 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
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- 229920000642 polymer Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
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- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of amino polysaccharide Aspirin composite nanometer particles, comprising the following steps: dissolving amino polysaccharide derivates; mixing the dissolved amino polysaccharide derivates with Aspirin bulk pharmaceutical chemicals; pouring the mixture into disperse phase solution, adding emulsifier, crosslinker and other solutions, and controlling reaction temperature, system PH value, stirring rate and curing time to obtain the amino polysaccharide Aspirin composite nanometer particles. The prominent characteristics of the invention are that: the technical method has convenient operation, simple, convenient and stable technology and very rich raw material sources and the like; the important meaning of the invention is that a compound crosslinking method is adopted in the preparation of the composite nanometer particles; the materials adopted in the invention is safe and has no toxic effect, favorable biocompatibility, biodegradability and the like; and the invention is expected to develop ideal drugs for preventing and curing angiocardiopathy, and has good research and developmental application prospects, thus the technology of the invention has good economic development potentiality.
Description
Technical field: the preparation method that the invention belongs to a kind of aminopolysaccharide in new drug development field-aspirin complex nanoparticle
Background technology: acute myocardial infarction (AMI) is all very high with the incidence and mortality of thrombotic disease, the medicine of this type of disease of research control is attracted attention by common people. find aspirin (Aspirin from the sixties in 20th century, Asp) the significant antiplatelet aggregative activity of tool, promptly be used for treatment and the prevention of AMI the seventies, Study of evidence based medicine proof aspirin is prevention and treatment apoplexy, angina pectoris, heart infarction, alzheimer disease, the active drug of diseases such as migraine, it can reduce the heart, thrombosis such as brain and peripheral blood vessel and thromboembolism incident reach 25%, yet oral Asp conventional tablet, medicine discharges rapidly at gastric, local concentration is too high, to gastrointestinal tract mucous stimulation arranged, especially the patient compliance of taking medicine for a long time for needs is relatively poor, clinical enteric coatel tablets commonly used can alleviate gastric mucosa injury, but do not reduce the digestive tract hemorrhage incidence rate, thereby seriously hindered the more extensive use of Asp. in addition, in recent years many experimental studies have found that, although the patient who has takes routine dose even heavy dose of aspirin, but still can not suppress the generation and the platelet aggregation of thromboxane fully, especially to having among the symptom arterial thrombus patient, aspirin can not stop at least 75% serious vascular events generation, promptly produce and be called aspirin resistance (aspirin resistance, AR) or aspirin failure (aspirin failire) phenomenon, for this reason, attempted number of research projects both at home and abroad, be intended to improve the character of aspirin, especially in recent years the research of this respect report is more, its research basic point concentrate on Asp under traditional slow-release material release characteristics research or with aspirin and small-molecule substance salify, ester, but only limit in vitro study mostly, clinical data is insufficient, practical application effect does not still have final conclusion. and the countermeasure for AR has bibliographical information to strengthen the generation that aspirin dose can reduce part A R, but because the hemorrhage and gastrointestinal reaction of secondary, often cause treatment to be ended. in recent years again clopidogrel and aspirin are share, how also disputable as for curative effect. therefore, take which kind of measure to improve the clinical efficacy of aspirin so far, reduce untoward reaction, enlarge its range of application, overcome the AR phenomenon and be still one of focus of the world of medicine's research.
The generation and the aspirin bioavailability that show AR on evidence, platelet function, too many levels factors vary such as receptor gene polymorphism are relevant, because the whole world has a large amount of patients to rely on the Antiplatelet therapy of aspirin, so the research about aspirin resistance has caused extensive concern, its counter-measure is except that adopt strengthening drug dose or two kinds of antiplatelet drug use in conjunction, and development of new aspirin alternative medicine is the better selection of prevention and treatment AR cardiovascular patient as early as possible.
Aminopolysaccharide (chitosan; Chi) be from insecticide; the chitin deacetylation derivative that extracts in Crustacean skeleton and fungal cell wall and some chlorellas; chemical constitution is the glucosamine polymer; because its source is abundant; nontoxic to human body; advantages such as good biocompatibility and degradability; extremely countries in the world study of pharmacy personnel's attractes attention. and with sugar and derivant thereof is that group carries out chemical modification to lead compound and can improve drug effect; reduce toxic and side effects; and having obtained the approval of Chinese scholars with the collaborative resistant effect of prodrug performance. the present invention adopts Study of New Method to prepare aminopolysaccharide-aspirin complex nanoparticle; inside and outside looking into new authentication state, there is not roughly the same report; this research is for improving AR cardiovascular disease prevention effect; reduce untoward reaction and provide new manufacturing technology, have huge social benefit and economic benefit for developing ideal novel aspirin alternative medicine.
Summary of the invention: it is the method that main carrier auxiliary material prepares aminopolysaccharide-aspirin complex nanoparticle with the aminopolysaccharide derivant that the purpose of this invention provides a kind of, to remedy the deficiency of prior art.
It is raw material that the present invention adopts aminopolysaccharide (chitosan) derivant and aspirin, its concrete grammar is earlier the aminopolysaccharide derivant to be dissolved, after under stirring condition, aminopolysaccharide derivative solution and aspirin crude drug being mixed, be poured in the decentralized photo solution, and to wherein adding solution such as emulsifying agent, cross-linking agent, by control reaction temperature, system acid-base value, mixing speed and hardening time, promptly obtain the mixed liquor of aminopolysaccharide-aspirin complex nanoparticle, solvent and emulsifying agent, with its separation, drying obtains solid product of the present invention at last.
The present invention has easy to operate, the easy advantage such as stable and cheap for manufacturing cost of preparing technique process. the present invention has extensive applicability to raw material, all chitin derivants with free amine group all can be suitable for. therefore, raw material sources of the present invention are very extensive. and significance of the present invention also is to have adopted in the preparation of complex nanoparticle the method for composite crosslinking, the result makes microgranule fine and close more, performance is more stable. and the material safety that the present invention adopts has no side effect, has excellent biological compatibility, biodegradability, characteristics such as filming performance is good. the present invention is expected to develop the ideal medicament of class treatment and prevention AR cardiovascular disease, have good research and development application prospect. therefore, this invention technology has fine economic development potentiality.
The specific embodiment: it is raw material that the present invention adopts aminopolysaccharide (chitosan) derivant, dissolving earlier obtains the solution of aminopolysaccharide derivant, the concentration of aminopolysaccharide derivative solution is 4%-12%, can use the deacetylation scope is 50%-98%, molecular weight is 20,000Da-2,000, the aminopolysaccharide of 00Da and derivant thereof, the addition of aspirin is 0.1-6 a times of aminopolysaccharide, under stirring condition, aminopolysaccharide derivative solution and aspirin crude drug are mixed, be poured in organic decentralized photo, mixeding liquid volume can be the 1/6-1/24 of organic decentralized photo, to wherein adding emulsifying agent and control mixing speed, temperature, system acid-base value and mixing time, promptly obtain aminopolysaccharide-aspirin complex nanoparticle, the mixed liquor of solvent and Emulsion is at last with its separation, drying obtains solid product aminopolysaccharide-aspirin complex nanoparticle.
The acid-base value of aminopolysaccharide-aspirin complex nanoparticle solution can be pH 1-12, mixing speed can be 1000-10000rpm, in order to reduce the diameter of particle mixing speed can be 8000-20000rpm, mixing time can be 0.5-10 hour, reaction temperature can be 5-60 ℃, solidify in order to quicken microgranule, solidification temperature can be reduced to 6-10 ℃.
Consider facile hydrolysis in the aspirin water, the complex Nanoparticulate formulations is easy to occur the prominent phenomenon of releasing of medicine, adopt chemical cross-linking agent microgranule to be solidified as 30% glutaraldehyde and 5% sodium tripolyphosphate use in conjunction, cross-linking agent also can be formaldehyde, sodium glutamate, wherein the two of sodium sulfate, and the degree of cross linking can be 1: 3-1: 5; The reagent of employed adjusting pH can be 10% ammonium bicarbonate, also can be sodium hydroxide, ammonia, potassium hydroxide, hydrochloric acid, acetic acid; Employed decentralized photo can be a toluene, also can be paraffin oil, Oleum Ricini, refining Oleum Glycines; Employed emulsifying agent can be a Tween 80, also can be span, sodium lauryl sulphate.
Aminopolysaccharide-aspirin complex nanoparticle that filtration or centrifugation obtain just obtains particle product by 20-45 ℃ of drying.
Aminopolysaccharide derivant of the present invention can comprise part deacetylation chitin, whole deacetylation chitin (being aminopolysaccharide), carboxymethylamino polyose, hydroxyethylamino polysaccharide, hydroxypropyl aminopolysaccharide, aminopolysaccharide doped quaternary ammonium salt, polyvinyl alcohol graft copolymerized aminopolysaccharide etc.
The specific embodiment is given an example:
Embodiment 1
Aspirin is joined in the polyvinyl alcohol graft copolymerized aminopolysaccharide solution behind the mix homogeneously, under stirring condition, splash in 50 ℃ of refining Oleum Glycines that contain tween, with 7000r/min high-speed stirred 3h, then at 40 ℃ of ultrasonic emulsification 40min, treat that temperature drops to 30 ℃, also add the multiple crosslinking agent curing that formaldehyde and sodium glutamate are formed in the impouring ether immediately, the washing of filtration under diminished pressure ether, fling to refining Oleum Glycines and ether, dry under the room temperature, promptly get buff aminopolysaccharide-aspirin complex nanoparticle.
Embodiment 2
Aspirin is joined in the aminopolysaccharide solution behind the mix homogeneously, under stirring condition, splash in 40 ℃ of toluene that contain sodium lauryl sulphate, with 5000r/min high-speed stirred 1h, then at 25 ℃ of ultrasonic emulsification 20min, regulate pH, treat that temperature reduces to 15 ℃, also add the multiple crosslinking agent curing that formaldehyde and sodium tripolyphosphate are formed in the impouring ether immediately, the washing of filtration under diminished pressure ether, fling to toluene and ether, add the gradient ethanol dehydration, drying at room temperature promptly gets light yellow aminopolysaccharide-aspirin complex nanoparticle.
Embodiment 3
Aspirin is joined in the aminopolysaccharide doped quaternary ammonium salt solution behind the mix homogeneously, under stirring condition, splash in 30 ℃ of Oleum Ricini that contain sorbester p17, with 6000r/min high-speed stirred 2h, at 15 ℃ of ultrasonic emulsification 30min, treat that temperature drops to 10 ℃ then, also add the multiple crosslinking agent curing that glutaraldehyde and sodium tripolyphosphate are formed in the impouring ether immediately, the washing of filtration under diminished pressure ether, fling to Oleum Ricini and ether, the room temperature vacuum drying promptly gets buff aminopolysaccharide-aspirin complex nanoparticle.
Claims (5)
1. the preparation method of aminopolysaccharide-aspirin complex nanoparticle.
2. the preparation method of a kind of aminopolysaccharide according to claim 1-aspirin complex nanoparticle, what its preparation method adopted is complex coacervation.
3. the preparation method of a kind of aminopolysaccharide according to claim 1-aspirin complex nanoparticle has adopted the method for composite crosslinking in the preparation of its complex nanoparticle.
4. the preparation method of a kind of aminopolysaccharide according to claim 1-aspirin complex nanoparticle, its described aminopolysaccharide comprise part deacetylation chitin, whole deacetylation chitin (being aminopolysaccharide), carboxymethylamino polyose, hydroxyethylamino polysaccharide, hydroxypropyl aminopolysaccharide, aminopolysaccharide doped quaternary ammonium salt, polyvinyl alcohol graft copolymerized aminopolysaccharide etc.
5. adopted the method for composite crosslinking in the complex nanoparticle preparation according to claim 3, its cross-linking agent is formaldehyde, glutaraldehyde, sodium tripolyphosphate, sodium glutamate, wherein the two of sodium sulfate.
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| CN200910128089A CN101700228A (en) | 2009-03-19 | 2009-03-19 | Preparation method of amino polysaccharide Aspirin composite nanometer particles |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104431369A (en) * | 2014-12-17 | 2015-03-25 | 宁夏伊品生物科技股份有限公司 | Rumen-protected lysine feed |
| CN104472877A (en) * | 2014-12-17 | 2015-04-01 | 宁夏伊品生物科技股份有限公司 | Preparation process of L-lysine product |
-
2009
- 2009-03-19 CN CN200910128089A patent/CN101700228A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104431369A (en) * | 2014-12-17 | 2015-03-25 | 宁夏伊品生物科技股份有限公司 | Rumen-protected lysine feed |
| CN104472877A (en) * | 2014-12-17 | 2015-04-01 | 宁夏伊品生物科技股份有限公司 | Preparation process of L-lysine product |
| CN104431369B (en) * | 2014-12-17 | 2017-05-24 | 宁夏伊品生物科技股份有限公司 | Rumen-protected lysine feed |
| CN104472877B (en) * | 2014-12-17 | 2017-07-18 | 宁夏伊品生物科技股份有限公司 | The preparation technology of L lysine products |
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