CN104288842A - Injectable bone joint lubricating material and preparation method thereof - Google Patents
Injectable bone joint lubricating material and preparation method thereof Download PDFInfo
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- CN104288842A CN104288842A CN201310305955.3A CN201310305955A CN104288842A CN 104288842 A CN104288842 A CN 104288842A CN 201310305955 A CN201310305955 A CN 201310305955A CN 104288842 A CN104288842 A CN 104288842A
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- nanocrystal cellulose
- bone joint
- hyalomitome
- injectable bone
- acid
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Abstract
The invention discloses an injectable bone joint lubricating material and a preparation method thereof. The injectable bone joint lubricating material includes nanocrystal cellulose and a hyaluronic acid substance. The hyaluronic acid substance can be hyaluronic acid or a water soluble salt of hyaluronic acid. The injectable bone joint lubricating material provided by the invention has the advantages of easy injection, long local action time, strong plasticity, and good biocompatibility.
Description
Technical field
The present invention relates to a kind of osteoarthrosis lubriation material and preparation method thereof, particularly relate to a kind of injectable bone joint lubrication material and preparation method thereof.
Background technology
Osteoarthritis shows as articular cartilage degeneration, and has new bone formation with periarticular under cartilage.Pain increases the weight of when load-bearing, articular cartilage wearing and tearing and disappearing, hyperosteogeny and cause joint deformity; Time movable, there is friction sound in joint, local tenderness and joint mild swelling.
There are some researches prove, joint disease and synovial fluid viscoelasticity reduce closely related, exogenous hyaluronic acid HA to the therapeutical effect of osteoarthritis mainly based on the raising to synovial fluid viscoelasticity.When exogenous HA exists for a long time in articular cavity, rely on self repair of cartilaginous tissue, osteoarthritis is fully recovered.HA product in the past due to metabolism very fast, need multiple injection, multiple injection turn increases the chance of irritant reaction and infection.
Therefore, in the urgent need to a kind of osteoarthrosis lubriation material extending action time, to reduce accretion rate, reduce frequency injection.
Summary of the invention
In order to overcome the defect of prior art, present inventor, to this has been further investigation, finds that the osteoarthrosis lubriation material comprising nanocrystal cellulose and hyalomitome acid can realize above-mentioned purpose.
The invention provides a kind of injectable bone joint lubrication material, this injectable bone joint lubrication material comprises nanocrystal cellulose and hyalomitome acid.Hyalomitome acid of the present invention can be hyaluronic acid or hyaluronic water soluble salt.
In the present invention, the mass ratio of nanocrystal cellulose and hyalomitome acid can be 200:1 ~ 15:1, is preferably 100:1 ~ 18:1; Be more preferably 50:1 ~ 20:1.
In the present invention, the diameter of described nanocrystal cellulose can be 10 ~ 100nm.Preferably, the diameter of nanocrystal cellulose is 30 ~ 80nm, is more preferably 50 ~ 60nm.The length of described nanocrystal cellulose can be 150 ~ 300nm, is preferably 180 ~ 250nm, is more preferably 200 ~ 220nm.The degree of polymerization of described nanocrystal cellulose is 160-180, is preferably 165-175, is more preferably 170-173.Length and the diameter of nanocrystal fiber of the present invention are measured by atomic force microscope; The degree of polymerization of nanocrystal fiber is measured by viscosimetry.
In the present invention, hyalomitome acids thing comprises hyaluronic acid or hyaluronic water soluble salt.Hyaluronic water soluble salt comprises hyaluronate sodium, potassium hyaluronate.Preferably, described hyalomitome acid can be hyaluronate sodium.The relative molecular mass of described hyaluronate sodium is about 1.0 × 10
6~ 2.0 × 10
6da, is preferably 1.2 × 10
6~ 1.8 × 10
6da, most preferably is 1.5 × 10
6~ 1.6 × 10
6da.Size exclusion chromatography (SEC) is adopted to measure the relative molecular mass of hyaluronate sodium.
The present invention also provides the preparation method of above-mentioned injectable bone joint lubrication material, nanocrystal cellulose, hyalomitome acid is mixed under the existence of disperse medium.In the present invention, described hyalomitome acid is hyaluronic acid or hyaluronic water soluble salt.In the present invention, described hyalomitome acid is preferably hyaluronate sodium.
Preparation method of the present invention, comprises following concrete steps:
(1) nanocrystal cellulose, hyalomitome acid are scattered in disperse medium respectively to form nanocrystal cellulose solution, hyalomitome acids substance solution;
(2) by described nanocrystal cellulose solution and described hyalomitome acids substance solution mix homogeneously to form mixed liquor;
(3) described mixed liquor is obtained colloidal materials through homogenizer process;
(4) described colloidal materials is removed bubble, irradiation sterilization.
In the present invention, nanocrystal cellulose can be obtained through acid hydrolysis, homogenizer process and lyophilization by the Plant fiber in cotton, numb or timber paddle board.The deionized water solution of homogenizer process nanocrystal cellulose is to improve its dispersibility.
According to preparation method of the present invention, in step (1), nanocrystal cellulose, hyalomitome acid are scattered in disperse medium respectively to form nanocrystal cellulose solution, hyalomitome acids substance solution.The mode of dispersion can carry out stirring for stirring arm or homogenizer carries out dynamically mixing.In the present invention, described disperse medium can be deionized water, distilled water or aqueous solution.Preferably, described disperse medium is injection normal saline.In nanocrystal cellulose solution, the content of nanocrystal cellulose is 0.5 ~ 10wt%, is preferably 1 ~ 8wt%, is more preferably 3 ~ 4wt%.At hyalomitome acids substance solution, the content of hyalomitome acid is 0.01 ~ 0.1wt%, is preferably 0.02 ~ 0.08wt%, is more preferably 0.05 ~ 0.06wt%.
According to preparation method of the present invention, in step (2), by described nanocrystal cellulose solution and described hyalomitome acids substance solution mix homogeneously to form mixed liquor.The mixed proportion of the two is not particularly limited, and such as, the volume ratio of described nanocrystal cellulose solution and described hyalomitome acids substance solution can be 10:1 ~ 1:10, is preferably 5:1 ~ 1:5; Be more preferably 1:2 ~ 2:1.Most preferably, by described nanocrystal cellulose solution and described hyalomitome acids substance solution equal-volume (1:1) mix homogeneously to form mixed liquor.
According to preparation method of the present invention, in step (3), described mixed liquor is obtained colloidal materials through homogenizer process.The effect of homogenizer be mixed liquor mixing evenly, to promote the physical bond of nanocrystal cellulose and hyalomitome acid, thus form stable colloidal materials.The present invention adopt homogenizer be this area routine use those, repeat no more here.
In step of the present invention (4), colloidal materials is removed bubble through centrifuge process.The rotating speed of centrifuge of the present invention can be 1000 ~ 10000r/min, is more preferably 5000 ~ 8000r/min.Centrifugation time can be 10 ~ 30min, is preferably 15 ~ 20min.In step of the present invention (4), cobalt-60 is adopted to carry out irradiation sterilization.Cobalt-60 irradiation sterilization intensity can be 10 ~ 30kGy, is preferably 20 ~ 25kGy.Irradiation time is 10 ~ 30 minutes, is preferably 15 ~ 20 minutes.
Injectable bone joint lubrication material of the present invention is easy to injection, the local action time is long, plasticity is strong, good biocompatibility.In addition, the present invention adopts nanocrystal cellulose to be combined with hyalomitome acid and forms colloidal materials, as injectable bone joint lubrication material, effectively can extend the action time of lubriation material, slow down between osteoarthrosis due to fricative pain
Accompanying drawing explanation
Fig. 1 observes to the implantation region of rat skin lower injection injectable bone joint lubrication material (embodiment 1) after the 1st week, and (A) is matched group, and (B) represents experimental group.
Fig. 2 observes to the implantation region of rat skin lower injection injectable bone joint lubrication material (embodiment 1) after the 3rd week, and (A) is matched group, and (B) represents experimental group.
Fig. 3 observes to the implantation region of rat skin lower injection injectable bone joint lubrication material (embodiment 1) after the 5th week, and (A) is matched group, and (B) represents experimental group.
Detailed description of the invention
Below in conjunction with specific embodiment, set forth the present invention further.Be interpreted as, these embodiments are only not used in for illustration of the present invention and limit the scope of the invention.In addition be interpreted as, after having read content of the present invention, the various change that those skilled in the art can make the present invention or amendment, these equivalent form of values have still belonged to the scope that the present patent application appended claims limits.In the present invention, " % " represents weight percentage " wt% ", " part " expression " weight portion ", unless specifically stated otherwise.
The raw material used in following examples, is described as follows:
nanocrystal cellulose:length is 200nm, and diameter is 50nm, and the degree of polymerization is 160-180.Nanocrystal cellulose NCC used is that in cotton, fiber crops and timber paddle board, Plant fiber obtains through acid hydrolysis.Concrete preparation method is as follows:
Get 500g refined cotton linter and be dipped in 25 DEG C, in 55% aqueous sulfuric acid of 5000mL, 2.5h is vibrated by ultrasonic continuous, scrape off the impurity floating on liquid level, pour in 10000mL distilled water at once, stop hydrolysis, use nylon filtering cloth impurity screening, leave standstill 6h, upper strata of inclining contains acid solution body, by ceramic post sintering funnel elimination acid solution, add distilled water diluting sample, pH=7 is neutralized to 0.05% sodium hydrate aqueous solution, settle out NCC-I, incline supernatant liquid, move in the cellulose acetate sheets of 0.22 μm, aperture and filter, add deionized water wash to salt-free, again through washing with acetone and dehydration, room temperature in vacuo is dry, pulverize, sieve and obtain the present invention's nanocrystal cellulose powder body used.
Length and the diameter of nanocrystal fiber of the present invention are measured by atomic force microscope, test concentrations: 0.1%; Test pattern: tapping-mode.The degree of polymerization of nanocrystal fiber of the present invention is measured by viscosimetry.
hyaluronate sodium (Topical grade): come from biological engineering company limited of Shandong Novartis, relative molecular mass is about 1.5 × 10
6da.Size exclusion chromatography (SEC) is adopted to measure the relative molecular mass of hyaluronate sodium.Chromatographic condition is: chromatographic column TSK GMPW
xL(7.8mm × 300mm, 13 μm); Mobile phase, city sodium chloride 11.69g, Hydrazoic acid,sodium salt 0.2g, add 1000mL distilled water and dissolve, be the sodium chloride solution of 0.2mol/L, 0.22 μm of membrane filtration, stand-by; Flow velocity 0.6mL/min, column temperature 35 DEG C, sample size 500uL.
injection normal saline:sodium chloride concentration is 0.9%.
Irradiation sterilization in following examples, ultrasonic, centrifugal, vacuum treated operating condition are as follows:
Irradiation sterilization condition: cobalt-60 irradiation sterilization intensity is 25kGy, irradiation time 15min.
Centrifugal condition: the swept volume of centrifuge is 0.3L, rotating speed 5000r/min, separating factor 1400W
2r/g, processing time 20min.
The model of high pressure homogenizer is GJZJ-50; Working environment: pressure 20 ~ 40MPa.
Embodiment 1
With injection normal saline dispersing nanocrystals cellulose and hyaluronate sodium respectively.The content of the nanocrystal cellulose in the normal saline solution of nanocrystal cellulose is 1.0wt%; In the normal saline solution of hyaluronate sodium, the content of hyaluronate sodium is 0.05wt%.By each for the normal saline solution of the normal saline solution of nanocrystal cellulose, hyaluronate sodium 20mL, equal-volume mixes, and through high pressure homogenizer process 15min, obtains stable colloidal materials.Utilize the bubble in centrifuge process removal finished product, and carry out irradiation sterilization with cobalt-60 pairs of finished products.
Embodiment 2 ~ 8
Except the nanocrystal cellulose content in the normal saline solution of nanocrystal cellulose is adjusted to 2wt%, 3wt%, 4wt%, 5wt%, 6wt%, 7wt% and 8wt%, other conditions are identical with embodiment 1, obtain injectable bone joint lubrication material.
Testing example
The injectable bone joint lubrication material of embodiment 1-8 is labeled as A, B, C, D, E, F, G, H respectively, separately has a normal saline to be labeled as I.144 wistar rats are divided into 9 groups at random, each side design a circular injection zone at 9 groups of rat backs, 1-8 group random injection injectable bone joint lubrication material, the 9th group of injecting normal saline, and it is also random for often organizing the material injected.Put to death animals respectively at the 1st week, 3 weeks, 5 weeks and label taking basis, carry out naked eyes and histological observation.
Test result is as follows:
Inflammatory reaction: have no obvious rejection in implantation region, when 1 week, the skin of A, B, C, D, E, F, G, H group all rats injection site is slightly red and swollen, without oozing out, I group has no obvious inflammatory reaction, when 3 weeks, the skin of all rat injection sites is all without the inflammatory reaction such as red and swollen, to ooze out, the surrounding materials in 1-5 week has no obvious fibrous capsule and is formed
Collagenation amount: 1-5 week, A, B, C, D, E, F, G, H group rat compares P<0.05 difference with I group statistical significance, the collagen content of A, B, C, D, E, F, G, H group rat injection site increases gradually along with the increase of time and the increase of nanocrystal cellulose, after being increased to mobile degree, reduce on the contrary, C, D group collagen content is maximum.
Above-mentioned test result shows, the colloidal materials containing nanocrystal cellulose and hyaluronate sodium has good histocompatibility, nontoxic, nonirritant, absorbs slow and can promote collagen secretion, being expected to become a kind of novel injectable bone joint lubrication material.
Claims (10)
1. an injectable bone joint lubrication material, is characterized in that, this injectable bone joint lubrication material comprises nanocrystal cellulose and hyalomitome acid; Described hyalomitome acid is hyaluronic acid or hyaluronic water soluble salt.
2. injectable bone joint lubrication material according to claim 1, is characterized in that, the mass ratio of nanocrystal cellulose and hyalomitome acid is 200:1 ~ 15:1.
3. injectable bone joint lubrication material according to claim 1, is characterized in that, the diameter of described nanocrystal cellulose is 10 ~ 100nm, and length is 150 ~ 300nm.
4. injectable bone joint lubrication material according to claim 3, is characterized in that, the degree of polymerization of described nanocrystal cellulose is 160-180.
5. injectable bone joint lubrication material according to claim 1, is characterized in that, described hyalomitome acid is hyaluronate sodium.
6. injectable bone joint lubrication material according to claim 5, is characterized in that, the relative molecular mass of described hyaluronate sodium is 1.0 × 10
6~ 2.0 × 10
6da.
7. the preparation method of the injectable bone joint lubrication material according to any one of claim 1 ~ 6, is characterized in that, nanocrystal cellulose, hyalomitome acid is mixed under the existence of disperse medium.
8. preparation method according to claim 7, is characterized in that, comprises following concrete steps:
(1) nanocrystal cellulose, hyalomitome acid are scattered in disperse medium respectively to form nanocrystal cellulose solution, hyalomitome acids substance solution;
(2) by described nanocrystal cellulose solution and described hyalomitome acids substance solution mix homogeneously to form mixed liquor;
(3) described mixed liquor is obtained colloidal materials through homogenizer process;
(4) described colloidal materials is removed bubble, then irradiation sterilization.
9. preparation method according to claim 8, it is characterized in that: in step (1), the content of the nanocrystal cellulose in described nanocrystal cellulose solution is 0.5 ~ 10wt%, and the content of the hyalomitome acid in hyalomitome acids substance solution is 0.01 ~ 0.1wt%; In step (2), by described nanocrystal cellulose solution and described hyalomitome acids substance solution equal-volume mix homogeneously to form mixed liquor; In step (4), colloidal materials is removed bubble through centrifuge process, then carries out irradiation sterilization with cobalt-60.
10. the preparation method according to any one of claim 7 ~ 9, is characterized in that, described hyalomitome acid is hyaluronate sodium; Described disperse medium is injection normal saline.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107149688A (en) * | 2017-04-27 | 2017-09-12 | 南京华开生物科技有限公司 | The sterile production method of hyalomitome acids product |
| CN113004563A (en) * | 2021-03-19 | 2021-06-22 | 常州大学 | Lubricating film material of hyaluronic acid modified cellulose and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107149688A (en) * | 2017-04-27 | 2017-09-12 | 南京华开生物科技有限公司 | The sterile production method of hyalomitome acids product |
| CN113004563A (en) * | 2021-03-19 | 2021-06-22 | 常州大学 | Lubricating film material of hyaluronic acid modified cellulose and preparation method thereof |
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