CN107840897A - It is a kind of to be used to treat hyaluronic acid magnesium salts of osteoarthritis and its preparation method and application - Google Patents
It is a kind of to be used to treat hyaluronic acid magnesium salts of osteoarthritis and its preparation method and application Download PDFInfo
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- CN107840897A CN107840897A CN201710825949.9A CN201710825949A CN107840897A CN 107840897 A CN107840897 A CN 107840897A CN 201710825949 A CN201710825949 A CN 201710825949A CN 107840897 A CN107840897 A CN 107840897A
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- hyaluronic acid
- pharmaceutical composition
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- magnesium
- osteoarthritis
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
Abstract
The invention discloses a kind of hyaluronic acid magnesium salts for being used to treat osteoarthritis and its preparation method and application.The preparation process of hyaluronic acid magnesium provided by the invention is：After magnesium salt solution to be made an addition to appropriate aqueous solution of sodium hyaluronate, it is allowed to precipitate, so as to obtain the associated matter of hyaluronic acid and magnesium ion.Find after tested, medicine hyaluronic acid magnesium of the present invention has the function that preferably to alleviate cartilage degeneration compared to Sodium Hyaluronate, so as to reach the purpose of preferably treatment osteoarthritis.
Description
Technical field
The present invention relates to a kind of medicine for treating osteoarthritis and preparation method thereof, is specifically that one kind is used to treat Bones and joints
Scorching hyaluronic acid magnesium salts and its preparation method and application.
Technical background
Osteoarthritis (Osteoarthritis, OA) is one kind with cartilage degeneration, Subchondral bone sclerosis and spur shape
As the joint degenerative disease of main feature, and mainly faced as it using movable posterior joint pain, limitation of activity and dysarthrasis
Bed performance, often involves weight-bearing joints.China's epidemiological investigation shows that OA illness rate exceedes in over-65s crowd
50%, there is a certain degree of limitation of movement in about 80% OA patient, 25% OA patient's daily life is significantly affected, and
The annual expense for being used to treat OA or up to 150,000,000,000 yuan.In more than the 50 years old crowd in the U.S., OA disability rate occupies all diseases
In second, be only second to angiocardiopathy.With the increase of global aging populations and population of being obese, OA illness rate is also
It will further improve.At present, there is no both at home and abroad treatment OA active drug, for early metaphase OA treatment can only often play it is slow
Solve pain and improve the effect of function.Due to OA patient be mostly the elderly, be often accompanied by other systemic diseases, as digestive system with
And disease of cardiovascular system, and OA first-line treatment medicine (remission) such as non-steroid anti-inflammatory drug (Non-steroidal
Antiinflammatory drugs, NSAIDs) use easily cause the increase of gastrointestinal side effect and cardiovascular event risk,
It would therefore be highly desirable to explore the safely and effectively medicine for early metaphase OA patient.
Hyaluronic acid (Hyaluronic acid, HA) is a kind of acid mucopolysaccharide, is widely present in human connective tissue
In extracellular matrix.HA plays important physiological function with its unique molecular structure and physicochemical property in body, such as lubricates
Joint, adjust the permeability of vascular wall and promote wound healing etc..Previously research shows, HA in the knuckle synovia of OA patient
Molecular weight and concentration reduce, the viscoplasticity of joint fluid decline (Balazs et al., J Rheumatol Suppl, 1993,39:3‐
9；Dahl et al., Ann Rheum Dis, 1985,44:817‐822).From the seventies in last century, joint cavity injection hyaluronic acid
Sodium is used for research and the existing many decades history of clinical practice for treating OA.It is saturating as a kind of local treatment mode, joint cavity injection
Bright matter acid sodium compares the maximum advantages of oral drug therapy OA and is that the whole bodies such as intestines and stomach and cardiovascular side effects can be avoided
Property adverse reaction, newest evidence-based medical show joint cavity injection hyaluronic acid preparation and placebo contrast will not increase
Incidence (Bannuru et al., the Osteoarthritis Cartilage, 2016, Epub ahead of of adverse events
print).Nowadays Sodium Hyaluronate has been widely used in OA treatment.Various products are included (as an example)
(HA purified according to EP 138572B1 by rooster comb),(Hylan G-F20, i.e., it is crosslinked with formaldehyde and divinyl sulfone
HA, as described in patent US 4713448) and(MW is 620 to 1200KDa HA).However, newest evidence-based medicine EBM
Evidence shows that the effect of joint cavity injection Sodium Hyaluronate is imprecise, and three big OA guides of internal authority are transparent to joint cavity injection
Matter acid sodium hold do not recommend attitude (Hochberg et al., Arthritis Care Res (Hoboken), 2012,64:465‐
474；McAlindon et al., Osteoarthritis Cartilage, 2014,22:363‐388；Brown et al., J Am
Acad Orthop Surg, 2013,21:577‐579).Therefore, exploitation for early metaphase OA patient curative effect more precisely or more effectively
Medicine be particularly important.
Magnesium ion (Magnesium2+, Mg) and it is the second abundant, extracellular 4th abundant cation in human body cell, as
The coenzyme of internal more than 300 kinds of enzymes, during the synthesis of the energetic supersession of body, nucleic acid and protein and inflammatory and immune response etc.
Play an important role.In recent years, Mg has been obtained for confirming to the inhibitory action and its molecular mechanism of articular cartilage inflammation.
There is zoopery to prove, the drug-induced arthritis of OA rats can effectively be mitigated by giving oral Mg therapeutic scheme, be mitigated
Arthroncus degree, and also have good therapeutic effect to arthroncus when non-steroid anti-inflammatory drug is administered together, and pass through
Detect blood concentration to find, Mg does not have the concentration for changing non-steroid anti-inflammatory drug in serum, may infer that Mg does not have an impact
The antiinflammatory action of non-steroid anti-inflammatory drug, but effect (Nagai et al., the Biol Pharm played by other approach
Bull, 2007,30：1934‐1937).In addition, there is research to confirm that to OA rat articulars intracavitary injection magnesium sulfate joint can be adjusted
Cartilage metabolism, delay OA progress (Lee et al., Osteoarthr and Cartilage, 2009,17：1485‐1493).Except this
Outside, Mg is also proved to play an important role in pain of alleviation, Saving cortilage cartilage and suppression abnormal mineralization etc.
(Fioravanti et al., Int J Biometeorol, 2014,58：79‐86；Pfister et al., Antimicrob Agents
Ch, 2007,51：1022‐1027；Calo et al., Am J Nephrol, 2000,20：347‐350).Therefore, Mg uses as medicine
In OA auxiliary treatment will be that OA prevention and treatments are benefited our pursuits.
The content of the invention
It is contemplated that overcome the deficiencies in the prior art, there is provided it is a kind of be used for treat osteoarthritis hyaluronic acid magnesium salts and
Its preparation method and application.
In order to achieve the above object, technical scheme provided by the invention is：
It is described to be used to treat shown in the structure such as formula (I) of the hyaluronic acid magnesium salts of osteoarthritis：
The preparation method of above-mentioned hyaluronic acid magnesium salts comprises the following steps：
(1) compound concentration is 50-70mg/mL, preferably 60mg/mL magnesium acetate solution；
(2) ethanol is added into magnesium acetate solution, 35-45 DEG C, preferably 40 DEG C are heated to after stirring；The acetic acid
The volume ratio of magnesium solution and ethanol is 1:25 to 1:15, preferably 1:20；
(3) Sodium Hyaluronate is added into the magnesium acetate solution for add ethanol, at 35-45 DEG C, under the conditions of preferably 40 DEG C
55-65min, preferably 60min are reacted, reaction stands 15min, centrifugation, obtains A sediments after terminating；The magnesium acetate and hyalomitome
The weight ratio of sour sodium is 1:2 to 1:1, preferably 3:5；
(4) A sediments are added into the ethanol (ratio 1 of sediment A and ethanol:In 2-10), centrifuged again after stirring, obtain B and sink
Starch；B sediments are pressed into step (4) repeatedly, preferably 5 times, obtain final sediment；
(5) after final sediment is dried in vacuo, hyaluronic acid magnesium is produced；Electedly, vacuum drying temperature is 60 DEG C.
Above-mentioned hyaluronic acid magnesium salts can be used for preparing treatment osteoarthritis drugs.The drug regimen of the treatment osteoarthritis
In thing in addition to hyaluronic acid magnesium is key component, also contain and be used to strengthening the molecule of extracellular matrix, for example, collagen or
The weight ratio of glycosaminoglycan, the hyaluronic acid magnesium and the molecule of enhancing extracellular matrix is 1:0.2 to 1:1；The treatment bone
In arthritic pharmaceutical composition in addition to hyaluronic acid magnesium is key component, also containing pharmacology and/or bioactive substance,
Such as growth factor, hormone and/or vitamin, the weight ratio of the hyaluronic acid magnesium and pharmacology and/or bioactive substance
For 1:0.2 to 1:1.In addition, also containing excipient in the pharmaceutical composition of the treatment osteoarthritis, pharmaceutical composition is made
Any formulation.Hyaluronic acid magnesium and excipient weight ratio are 1 in pharmaceutical composition:10 to 1:100.
The invention will be further described below：
The magnesium salts of present invention synthesis hyaluronic acid, is configured to be applied to joint cavity injection and the formulation of other local applications,
Treatment applied to osteoarthritis.It is reducing cartilage matrix degraded, reduces the cartilage surface degree of wear and is delaying cartilage degeneration
In be effective, and by its effect compared with Sodium Hyaluronate, clearly demonstrate the pharmacological action of hyaluronic acid magnesium and be better than hyalomitome
Sour sodium.Hyaluronic acid magnesium prepared by the present invention and other one or more pharmaceutically useful carrier/excipients can be prepared into treatment
The pharmaceutical composition of osteoarthritis is treated, is preferably suitable to the liquid of local application and semi-solid medicinal forms such as solution, solidifying
Jelly, creme or transdermal patch；Particularly preferably it is suitable to the form such as solution and gel of intra-articular injection.Medicinal forms are also
Can be made up of following form, some or all of which component is dried forms (as lyophilized), before use with the aqueous solution or its
The solvent that he is adapted to prepares it again.
The preparation can use known excipient such as adhesive, disintegrant, filler, stabilizer, diluent and
Toner is prepared by method known in the field.They also include using known suitable polymer in pharmaceutical technology to prepare
Sustained release or sustained release preparation.
For preparing the liquid form suitable for injection, preferably water is as solvent.
If desired, it is possible to by hyaluronic acid magnesium and other molecules that can be used for strengthening extracellular matrix, such as glue
Former albumen or glycosaminoglycan joint, or with other pharmacology and/or bioactive substance such as growth factor, hormone and/or dimension
Raw element joint.
The medicine hyaluronic acid magnesium of the present invention is improved using magnesium ion to traditional OA medicine, makes full use of magnesium
The cartilage protection effect of ion, makes magnesium and hyaluronic acid cooperate with the protective effect played to joint.Experiment in vitro shows：Hyalomitome
Sour magnesium is for cartilage cell's no cytotoxicity.Experiment in vivo proves：Compared to Sodium Hyaluronate, hyaluronic acid magnesium energy higher degree
Ground reduces cartilage matrix degraded and delays cartilage degeneration.Available for treating osteoarthritis, including traumatic arthritis and age phase
Close degenerative osteoarthritis.
In a word, the present invention can combine to form hyaluronic acid magnesium using magnesium ion with oxygen containing donors in HA, so as to change
Good traditional OA medicine Sodium Hyaluronate, so as to reach more effective treatment OA possibility.
Brief description of the drawings
Fig. 1 is that cartilaginous tissue improves Mankin pathological score statistical results；
Fig. 2 is the Rat Right knee joint section fast green coloration result of sarranine.
Embodiment
Embodiment 1 prepares hyaluronic acid magnesium
1st, 300mg magnesium acetates are taken, are allowed to be dissolved completely in 5ml distilled water.
2nd, put into the magnesium acetate solution in 100mL ethanol, stir well even, heated to make up to 40 DEG C.
3rd, in stirring, 500mg Sodium Hyaluronates is added, are reacted 60 minutes under 40 DEG C of temperature conditionss.
4th, after reaction terminates, 15 minutes are stood, incline supernatant, centrifugation, obtains sediment.
5th, taking precipitate, 90% (v/v) ethanol of 5 times of quality of sediment is added, stirred 10 minutes, after standing 15 minutes,
Centrifugation, obtains sediment.
6th, step 5 being repeated 5 times, gained sediment is dried in vacuo at 60 DEG C, obtains hyaluronic acid magnesium 450mg,
Yield (%)=450/500=90% of hyaluronic acid magnesium.Structure such as formula (I)：
Vitro Cytotoxicity Evaluation of the hyaluronic acid magnesium of embodiment 2 for cartilage cell
1 experiment material and method
1.1 medicines and reagent
Hyaluronic acid magnesium, Sodium Hyaluronate, physiological saline
Cell Counting Kit (CCK-8 kits)
1.2 cell
Mouse cartilage cell
1.3 experimental method
1.3.1 take the logarithm the Mouse cartilage cell of phase growth, be inoculated in 5000/ hole cell in 96 well culture plates, per hole
The μ l of volume about 100, in 5%CO2, 37 DEG C of incubator culture about 24h to cell length to individual layer.Then, inhale and abandon supernatant in hole, use
Phosphate buffer (PBS) is washed 1~2 time, adds complete medium (DMEM/F12+10% hyclones) and various concentrations medicine obtains
A series of concentration liquids (100 μ l) arrived, are divided into 5 groups, and every group sets 3 multiple holes.Cell plates are continued to be placed in incubator and are incubated
48h.It is grouped as follows：
1) 5ng/ml hyaluronic acids magnesium group；2) 2.5ng/ml hyaluronic acids magnesium group；3) 5ng/ml Sodium Hyaluronates group；4)
2.5ng/ml Sodium Hyaluronate groups；5) control group：Physiological saline.
1.3.2 the μ l of CCK-8 reagents 10 are added per hole, 4h is incubated in incubator.450nm wavelength is selected, is examined in enzyme linked immunological
Survey on instrument and determine each hole OD values, record result.Calculate the OD averages of each group.Increased using the OD averages of control group as l00% cells
Value rate, the cell proliferation rate of each drug concentration group are obtained according to following formula：P%=each groups OD averages/control group OD averages ×
100%.Then cytotoxicity is evaluated according to cell proliferation rate, cytotoxicity rating scale is shown in Table 1.
The cell of table 1 breeds percentage and the corresponding relation of cytotoxicity grade
2. experimental result
The each group cell proliferation rate of different pharmaceutical concentration is shown in Table 2
The each group cell proliferation rate of the different pharmaceutical concentration of table 2
Experimental result is shown：Hyaluronic acid magnesium and Sodium Hyaluronate are without cartilage cell's toxicity.
It is prepared by the hyaluronic acid magnesium joint cavity injection liquid of embodiment 3
Under normal temperature, the hyaluronic acid magnesium physiological saline solution that will be synthesized by embodiment 1, and respective concentration 1% is diluted to,
After 0.22 μm of membrane filtration, embedding, sterilizing, inspection and packaging, you can.
The zoopery checking of the hyaluronic acid magnesium of embodiment 4 treatment osteoarthritis curative effect
1 experiment material and method
1.1 medicines and reagent
The hyaluronic acid magnesium of gained is prepared in embodiment 3
Sodium Hyaluronate (0.1ml, Zhengda Furuida Pharmaceutical Co., Ltd., Shandong)
Physiological saline
1.2 experimental animal
Bull Sprague-Dawley (SD) rat
1.3 experimental method
1.3.1 operation modeling
Knee OA models are built by the right medial collateral ligament of row, anterior cruciate ligament-transection art and medial meniscus resection.
The model, which has been verified, can induce knee osteoarthritis, represent the good example of experimental degenerative osteoarthritis, can be used for
Pharmacological evaluation is carried out to the medicine surveyed.
1.3.2 packet and medication
Take RANDOMIZED BLOCK DESIGN that rat is randomly divided into 3 groups according to body weight after modeling：
1) joint cavity injection physiological saline group, joint cavity injection physiological saline 0.1ml is given within postoperative 6 days, once in a week, even
It is continuous 5 weeks；
2) joint cavity injection Sodium Hyaluronate group, give within postoperative 6 days joint cavity injection 1000ug Sodium Hyaluronates (0.1ml,
Zhengda Furuida Pharmaceutical Co., Ltd., Shandong), once in a week, continuous 5 weeks；
3) joint cavity injection hyaluronic acid magnesium group, give within postoperative 6 days joint cavity injection 1000ug hyaluronic acids magnesium (0.1ml,
It is made according to preparation method in embodiment 3), once in a week, continuous 5 weeks.
Postoperative 1 week each group rat, which starts to be run on a treadmill, (1.0km/h, 20min/d, every 2 days 1 time, continues 5
Week).
1.3.3 evaluation method
Take within postoperative 6th week right side knee cartilage preparation of specimen pathological section, the fast green dyeing of row sarranine, using improvement
Mankin scorings (table 3) are assessed each group rat knee joints cartilage degeneration degree.This method can wear to cartilage surface, be soft
Bone cell proliferation, cartilage matrix degraded carry out overall merit, react the degree of degeneration of cartilage.The higher reaction cartilage degeneration journey of scoring
Degree is heavier.
Table 3：Improve Mankin scorings
2. experimental result
Each group Rat Right knee joint Mankin appraisal results such as table 4.
Table 4：Cartilaginous tissue improves Mankin pathological scores
Statistical analysis shows that joint cavity injection Sodium Hyaluronate group and the right knee joint Mankin scorings of Sodium Hyaluronate magnesium are equal
Reduced compared with physiological saline group, difference has statistical significance (P ＜ 0.05)；Joint cavity injection hyaluronic acid magnesium group Mankin scores
Less than Sodium Hyaluronate group (P=0.064).
Result above shows that the hyaluronic acid magnesium that gained is prepared in embodiment 3 is softer with preferably alleviating than Sodium Hyaluronate
The effect of bone regression.Therefore, it is better than traditional OA medicine the effect of medicine hyaluronic acid magnesium of the invention treatment osteoarthritis
Sodium Hyaluronate.
Claims (10)
- A kind of 1. hyaluronic acid magnesium salts for being used to treat osteoarthritis, it is characterised in that the structure such as formula of the hyaluronic acid magnesium (I) shown in：
- 2. the preparation method of hyaluronic acid magnesium salts as claimed in claim 1, it is characterised in that methods described comprises the following steps：(1) compound concentration is 50-70mg/mL magnesium acetate solution；(2) ethanol is added into magnesium acetate solution, 35-45 DEG C are heated to after stirring；The magnesium acetate solution and ethanol Volume ratio is 1:25 to 1:15；(3) Sodium Hyaluronate is added into the magnesium acetate solution for add ethanol, under the conditions of 35-45 DEG C react 55- 65min, reaction is stood after terminating, centrifugation, obtains A sediments；The weight ratio of the magnesium acetate and Sodium Hyaluronate is 1:2 to 1:1；(4) A sediments are added in ethanol, is centrifuged again after stirring, obtain B sediments；B sediments are pressed into step (4) repeatedly, Obtain final sediment；(5) after final sediment is dried in vacuo, hyaluronic acid magnesium is produced.
- 3. hyaluronic acid magnesium salts as claimed in claim 1 is preparing the application in treating osteoarthritis drugs.
- 4. a kind of pharmaceutical composition for treating osteoarthritis, it is characterised in that described pharmaceutical composition contains described in claim 1 Hyaluronic acid magnesium.
- 5. pharmaceutical composition as claimed in claim 4, it is characterised in that also contain in described pharmaceutical composition and be used to strengthen carefully The molecule of extracellular matrix；The weight ratio of the hyaluronic acid magnesium and the molecule of enhancing extracellular matrix is 1:0.2 to 1:1.
- 6. pharmaceutical composition as claimed in claim 5, it is characterised in that the molecule for being used to strengthen extracellular matrix includes Collagen or glycosaminoglycan.
- 7. pharmaceutical composition as claimed in claim 4, it is characterised in that in described pharmaceutical composition also containing pharmacology and/ Or bioactive substance；The hyaluronic acid magnesium is 1 with the weight ratio of pharmacology and/or bioactive substance:0.2 to 1:1.
- 8. pharmaceutical composition as claimed in claim 7, it is characterised in that the pharmacology and/or bioactive substance include Growth factor, hormone and/or vitamin.
- 9. the pharmaceutical composition as described in any one of claim 4 to 8, it is characterised in that also contain in described pharmaceutical composition Excipient.
- 10. pharmaceutical composition as claimed in claim 9, it is characterised in that hyaluronic acid magnesium is with assigning in described pharmaceutical composition Shape agent weight ratio is 1:10 to 1:100.
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Cited By (1)
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| CN108383927A (en) * | 2018-04-11 | 2018-08-10 | 南方科技大学 | chondroitin sulfate magnesium and preparation method thereof |
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| CN108383927B (en) * | 2018-04-11 | 2021-06-08 | 南方科技大学 | Chondroitin sulfate magnesium and preparation method thereof |
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