CN101121044B - Bone-repairing material and preparing method thereof - Google Patents
Bone-repairing material and preparing method thereof Download PDFInfo
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- CN101121044B CN101121044B CN2006101043616A CN200610104361A CN101121044B CN 101121044 B CN101121044 B CN 101121044B CN 2006101043616 A CN2006101043616 A CN 2006101043616A CN 200610104361 A CN200610104361 A CN 200610104361A CN 101121044 B CN101121044 B CN 101121044B
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Abstract
The invention relates to a bone rehabilitating material and a preparation method of the material. The invention provides a bone rehabilitating material, the effective components of which are prepared by the following weights and portions of raw materials: 40 of a PLGA; 20 to 80 of a semi-hydrated calcium sulphate; 2 to 8 of a rifampicin. The invention also provides the preparation method of the bone rehabilitating material. The invention mixes and solidifies the semi-hydrated calcium sulphate, the PLGA, the rifampicin and a sodium chloride granule and digests the sodium chloride granule to make a novel multi-hole bone rehabilitating material with a function of anti-bacillus tuberculosis.
Description
Technical field
The present invention relates to a kind of bone renovating material and preparation method thereof.
Background technology
The current material that is used for bone disease treatment roughly can two classes:
The non-biodegradation type: comprise polyethylene, polypropylene, polyacrylate, aromatic polyester, polysiloxanes, polyformaldehyde etc., can stable for extended periods of time in biotic environment, do not degrade, crosslinked or physical abrasion etc., and have good physical and mechanical properties.
Biodegradation type: comprise polylactic acid, polycaprolactone, polyvinyl alcohol, linear aliphatic adoption ester etc., structural deterioration can take place under biotic environment for they and performance is changed in quality, its catabolite can be absorbed by body or is excreted by normal metabolic, and they are mainly used in drug release, send to carrier, bone renovating material, cytoskeleton material and impermanency implanting device.
Tuberculosis of bone and joint is the outer tuberculosis of common Secondary cases lung, accounts for all lungyly 3%, and wherein about half involves spinal column.As it is delay the diagnosis and treatment and to cause patient's lifelong disability, even dead.Spinal tuberculosis is as the most common form of tuberculosis of bone and joint, and is also in rising trend with increase lungy in recent years.Because spine node is endorsed and caused bone destruction, deformity of spine, even paraplegia, document statistics paraplegia or quadriplegia incidence rate are about 10%, if not treatment in time, with the serious harm health.At present to tuberculosis of bone and joint, especially behind the spinal tuberculosis focal cleaning, how to solve damaged, the local tuberculose focus abscess recurrence of the bone of bulk of focal cleaning postoperative and how to shorten course of treatment of antituberculotics or problem such as administering mode, still lack effective treatment means.
Summary of the invention
At at present to tuberculosis of bone and joint, especially behind the spinal tuberculosis focal cleaning, how to solve damaged, the local tuberculose focus abscess recurrence of the bone of bulk of focal cleaning postoperative and how to shorten course of treatment of antituberculotics or administering mode etc. lacks the problem of effective treatment means, the invention provides a kind of is the novel bone renovating material of carrier with PLGA (polylactic acid-polyglycolic acid copolymer), half-H 2 O calcium sulphate.
Technical scheme of the present invention is as follows:
The invention provides a kind of bone renovating material, its effective ingredient is formed by the feedstock production of following parts by weight:
PLGA 40; Half-H 2 O calcium sulphate 20-80; Rifampicin 2-8.
As prioritization scheme, bone renovating material provided by the present invention, its effective ingredient is formed by the feedstock production of following parts by weight:
PLGA40; Half-H 2 O calcium sulphate 40; Rifampicin 3-4.
As prioritization scheme further, bone renovating material provided by the present invention, its effective ingredient is formed by the feedstock production of following parts by weight:
PLGA40; Half-H 2 O calcium sulphate 40; Rifampicin 3.2.
As prioritization scheme, bone renovating material provided by the present invention, its preparation raw material also comprises the sodium chloride of 20-80 parts by weight.
Described half-H 2 O calcium sulphate is meant the powder of particle diameter below 80um; Described PLGA is meant that molecular weight is the PLGA of 3-10 ten thousand; Described sodium chloride is meant the sodium chloride crystal granule of 200-600um.
The present invention also provides the preparation method of above-mentioned bone renovating material, comprises the steps:
1) PLGA of described amount is joined is made into 15-25% solution in the chloroform, sealing and standing 10-14 hour;
2), join and fully stir the title mixture in the solution with rifampicin, half-H 2 O calcium sulphate, the sodium chloride of described amount;
3) with step 2) solvent flashing under the gained mixture room temperature, solidify;
4) step 3) gained cured article is soaked in the distilled water, treats that chloride ion wherein removes after drying fully.
As prioritization scheme, the preparation method of above-mentioned bone renovating material comprises the steps:
1) PLGA of described amount is joined is made into 20% solution in the chloroform, sealing and standing 12 hours;
2), join in the solution and fully stir with described amount rifampicin, half-H 2 O calcium sulphate, sodium chloride particle.In being uniformly distributed in solution, this moment, solution was gel;
3) with step 2) the gained mixture placed in the room temperature ventilated chamber volatilization 24 hours, solidifies voluntarily.Be cut into height and be 3 millimeters tablet;
4) the step 3) products obtained therefrom is immersed in the 100ml distilled water, changed distilled water 1 time in per 4 hours, the sodium chloride in material dissolves fully, in the soak till the no chloride ion;
5) material drying, sterilization, standby.
By the bone renovating material of method for preparing, the weight ratio of effective ingredient is:
PLGA: half-H 2 O calcium sulphate: rifampicin=40: 20-80: 2-8.
As prioritization scheme, by the bone renovating material of method for preparing, the weight ratio of effective ingredient is: PLGA: half-H 2 O calcium sulphate: rifampicin=40: 40: 3.2; Pore size is 190-310 μ m, and mean porosities is that (47.43 ± 0.34) %, average pore size are (250.86 ± 25.27) μ m.
The technique effect that the present invention realized is as follows:
The present invention is mixing cured with half-H 2 O calcium sulphate microgranule, PLGA, rifampicin, sodium chloride particle, again with the sodium chloride particle stripping, makes the novel porous bone repair material with anti-mycobacterium tuberculosis effect.
It is good that the raw material of bone renovating material provided by the present invention is formed with the biocompatibility and the Bioabsorbable of human body.Soak time is about three months fully, and infiltration rate is consistent with the formation speed of new bone.
Bone renovating material provided by the present invention can recover the form profile of bone mainly as the implant in space, stops soft tissue to be grown into, and growing into for blood vessel and osteoblast provides bone guided substrate.
PLGA (random copolymer (GA) of L-lactide (LLA) and Acetic acid, hydroxy-, bimol. cyclic ester) is one of maximum Biodegradable material of research at present, obtained drugs approved by FDA as operation suture thread, angiocarpy bracket controlled release drug coating, and the material of injection microcapsule, microsphere, implants etc.The rate of release of medicine can be by selecting different molecular weight, the active lactic acid copolymerization of different optical, and the polymerization ratio of LLA/GA is regulated.The end product of polylactic acid hydrolysis is water and CO2, and intermediate product lactic acid also is normal carbohydrate metabolism product in the body, thus nontoxic, the nonirritant of this polymer, and have good biocompatibility.Report mesenchymal stem cells MSCs (BMSCs) such as Cao Ying light can stick, breed, secrete extracellular matrix on PLGA, and can be divided into polygonal skeletonization like cell under the effect of osteogenic induction agent.But have following shortcoming: the acid degradation product that produces in degradation process as bone fracture internal fixation material produces non-infectious inflammation; It is poor to develop on the sheet, is unfavorable for problems such as clinical follow.Technical scheme provided by the present invention after adding 1: 1 half-H 2 O calcium sulphate, can make the acid degradation product obviously reduce, and also can develop on the X-ray sheet.
Use bone renovating material provided by the present invention, when treatment tuberculosis of bone and joint bone is damaged, both had lasting osteogenic ability, excellent biological compatibility, easily absorb simultaneously, replaced from the body bone gradually; Higher local antitubercular agent substrate concentration and long slow-release time are arranged simultaneously, reduce local abscess recurrence, reduce the complication of long-term oral anti-tuberculous drug thing.
Description of drawings
Fig. 1: product Electronic Speculum figure, the implant aperture is even, and is big or small between 190-310 μ m, EM * 35;
Fig. 2: microcosmic Electronic Speculum figure in the product hole, the microstructure of seeing in hole, EM * 2000.
The specific embodiment
Embodiment 1:
1 materials and methods
1.1 material
PLGA (85/15) is provided by Chengdu Organical Chemical Co., Ltd., Chinese Academy of Sciences, and relative molecular mass is 300000; The half-H 2 O calcium sulphate crystal is provided by Wright company; The rifampicin reference substance is given birth to worker's bio tech ltd by Qingdao and is provided.
1.2 method
1.2.1 the preparation of material
Half-H 2 O calcium sulphate: PLGA: sodium chloride: rifampicin=1: 1: 2: 0.08 (mass ratio), wherein half-H 2 O calcium sulphate and PLGA are slow-released carrier, and sodium chloride is porogen, and the sodium chloride crystal granular size is 180-250 μ m.Material ethane via epoxyethane is respectively disinfected, and carries out following processing in gnotobasis.
(1) organic solvent injection molding: by prescription quantitative PLGA is added the people in chloroform, abundant magnetic agitation is made into concentration and is 20% solution.Behind half-H 2 O calcium sulphate, sodium chloride and rifampicin mixing, join in the PLGA solution, fully stir, in rifampicin, half-H 2 O calcium sulphate and sodium chloride particle were dispersed in that PLGA is molten and cross, this moment, mixture was gel.With this mixture chloroform volatilization 12h in 37 ℃ of constant temperature air dry ovens, mixture solidifies voluntarily.
(2) solute extraction pore: the material after moulding is soaked in the 1000ml distilled water, and every 6h changes distilled water 1 time, and the sodium chloride in material dissolves fully, does not have in the soak till the chloride ion (drip silver nitrate reagent and do not produce precipitation).The material drying, oxirane disinfection (400mg/l, normal pressure 2 hours).The refrigerator sealing is preserved standby.
1.2.2 the Performance Detection of material
(1) detection of voidage: adopt Shi Guixin (Shi Guixin, king's body state, etc. polylactic acid and the preparation of polylactic acid-glycolic guanidine-acetic acid porous cell support and the sign of hole. functional polymer journal, 2001,14 (1): 7-11.) wait the hydrometer method of introducing, measure down at 25 ℃, select a density bottle for use, fill it up with dehydrated alcohol and weigh (M1), is quality in the sample immersion ethanol of Ws, evacuation is replaced the gas in the sample fully by ethanol, treat to claim quality (M2) after density bottle is mended full ethanol; To soak into alcoholic acid sample and take out, claim the quality (M3) of remaining ethanol and density bottle.By formula ε=(M2-M3-Ms)/(M1-M3) x100% calculates the porosity of material.
(2) detection in aperture: the section to material carries out electron-microscope scanning, gets 5 sample film makings arbitrarily, measures the aperture of hole on the photo one by one.
(3) stability of granule Chinese medicine: after the dissolving of rifampicin granular preparation, room temperature keeps in Dark Place, and checks the medicine stable case with spectrophotography, surveys its absorbance every 2 days, surveys altogether 3 times.Exsiccant slow-releasing granules is sealed in respectively in the vial, stored 3 months under the room temperature 20-25 ℃ of condition, survey medicament contg and absorbance and change.
1.2.3 date processing adopts the SPSS13.0 statistical software to analyze, the various performance parameters of material are directly asked arithmetic mean and standard deviation by sample value.
2 results
2.1 the outward appearance of material
Material appearance is cerise, and is cylindric, and quality is even and hard, rough surface, the naked eyes visible surface fine hole that gathers.
2.2 the Specifeca tion speeification of material
See under the ultramicroscope that section is the pore structure of comparison uniformity, its transverse section and vertical section basically identical, pore size are 190-310 μ m, and the micropore of visible a large amount of numerical aperture microns connects (as Fig. 1,2) mutually on the hole wall.Mean porosities is that (47.43 ± 0.34) %, aperture are (250.86 ± 25.27) μ m.Rifampicin concentration is almost constant in the material dissolves 6 days, illustrates that in preparation process rifampicin is stable.Slow-release material 3 months intensive amounts under 25 ℃ of conditions of room temperature are stable, can room temperature and refrigerator preservation.
Embodiment 2:
It is as follows that present embodiment is made proportioning raw materials that bone renovating material adopts:
PLGA: half-H 2 O calcium sulphate: sodium chloride particle: rifampicin=40: 20: 80: 2.
Described half-H 2 O calcium sulphate is meant the powder of particle diameter below 80um; Described PLGA is meant that molecular weight is the PLGA of 3-10 ten thousand; Described sodium chloride is meant the sodium chloride crystal granule of 200-600um.
The method that present embodiment is made bone renovating material is as follows:
1) PLGA of described amount is joined is made into 15-25% solution in the chloroform, sealing and standing 10-14 hour;
2), join and fully stir the title mixture in the solution with rifampicin, half-H 2 O calcium sulphate, the sodium chloride of described amount;
3) with step 2) solvent flashing under the gained mixture room temperature, solidify;
4) step 3) gained cured article is soaked in the distilled water, treats that chloride ion wherein removes after drying fully.
The effective ingredient weight ratio that the product that makes comprises is PLGA: half-H 2 O calcium sulphate: rifampicin=40: 20: 2; Pore size is 190-310 μ m, and mean porosities is that (47.43 ± 0.34) %, aperture are (250.86 ± 25.27) μ m.
The result of use checking of the bone renovating material of present embodiment preparation is as follows:
(1) detection of voidage: adopt Shi Guixin (Shi Guixin, king's body state, etc. polylactic acid and the preparation of polylactic acid-glycolic guanidine-acetic acid porous cell support and the sign of hole. functional polymer journal, 2001,14 (1): 7-11.) wait the hydrometer method of introducing, measure down at 25 ℃, select a density bottle for use, fill it up with dehydrated alcohol and weigh (M1), is quality in the sample immersion ethanol of Ws, evacuation is replaced the gas in the sample fully by ethanol, treat to claim quality (M2) after density bottle is mended full ethanol; To soak into alcoholic acid sample and take out, claim the quality (M3) of remaining ethanol and density bottle.By formula ε=(M2-M3-Ms)/(M1-M3) x100% calculates the porosity of material.
(2) detection in aperture: the section to material carries out electron-microscope scanning, gets 5 sample film makings arbitrarily, measures the aperture of hole on the photo one by one.
(3) stability of granule Chinese medicine: after the dissolving of rifampicin granular preparation, room temperature keeps in Dark Place, and checks the medicine stable case with spectrophotography, surveys its absorbance every 2 days, surveys altogether 3 times.Exsiccant slow-releasing granules is sealed in respectively in the vial, stored 3 months under the room temperature 20-25 ℃ of condition, survey medicament contg and absorbance and change.
Date processing adopts the SPSS13.0 statistical software to analyze, and the various performance parameters of material are directly asked arithmetic mean and standard deviation by sample value.
The outward appearance of material
Material appearance is cerise, and is cylindric, and quality is even and hard, rough surface, the naked eyes visible surface fine hole that gathers.
The Specifeca tion speeification of material
See under the ultramicroscope that section is the pore structure of comparison uniformity, its transverse section and vertical section basically identical, pore size are 190-310 μ m, and the micropore of visible a large amount of numerical aperture microns connects mutually on the hole wall.Mean porosities is that (47.43 ± 0.34) %, aperture are (250.86 ± 25.27) μ m.Rifampicin concentration is almost constant in the material dissolves 6 days, illustrates that in preparation process rifampicin is stable.Slow-release material 3 months intensive amounts under 25 ℃ of conditions of room temperature are stable, can room temperature and refrigerator preservation.
Embodiment 3:
It is as follows that present embodiment is made proportioning raw materials that bone renovating material adopts:
PLGA: half-H 2 O calcium sulphate: sodium chloride particle: rifampicin=40: 80: 20: 8.
Described half-H 2 O calcium sulphate is meant the powder of particle diameter below 80um; Described PLGA is meant that molecular weight is the PLGA of 3-10 ten thousand; Described sodium chloride is meant the sodium chloride crystal granule of 200-600um.
The method that present embodiment is made bone renovating material is as follows:
1) PLGA of described amount is joined is made into 20% solution in the chloroform, sealing and standing 12 hours;
2), join in the solution and fully stir with described amount rifampicin, half-H 2 O calcium sulphate, sodium chloride particle.In being uniformly distributed in solution, this moment, solution was gel;
3) with step 2) the gained mixture placed in the room temperature ventilated chamber volatilization 24 hours, solidifies voluntarily.Be cut into height and be 3 millimeters tablet;
4) the step 3) products obtained therefrom is immersed in the 100ml distilled water, changed distilled water 1 time in per 4 hours, the sodium chloride in material dissolves fully, in the soak till the no chloride ion;
5) material drying, sterilization, standby.
Making the effective ingredient weight ratio that product comprises is PLGA: half-H 2 O calcium sulphate: rifampicin=40: 80: 8; Pore size is 190-310 μ m, and mean porosities is that (47.43 ± 0.34) %, aperture are (250.86 ± 25.27) μ m.
The result of use checking of the bone renovating material of present embodiment preparation is as follows:
(1) detection of voidage: adopt Shi Guixin (Shi Guixin, king's body state, etc. polylactic acid and the preparation of polylactic acid-glycolic guanidine-acetic acid porous cell support and the sign of hole. functional polymer journal, 2001,14 (1): 7-11.) wait the hydrometer method of introducing, measure down at 25 ℃, select a density bottle for use, fill it up with dehydrated alcohol and weigh (M1), is quality in the sample immersion ethanol of Ws, evacuation is replaced the gas in the sample fully by ethanol, treat to claim quality (M2) after density bottle is mended full ethanol; To soak into alcoholic acid sample and take out, claim the quality (M3) of remaining ethanol and density bottle.By formula ε=(M2-M3-Ms)/(M1-M3) x100% calculates the porosity of material.
(2) detection in aperture: the section to material carries out electron-microscope scanning, gets 5 sample film makings arbitrarily, measures the aperture of hole on the photo one by one.
(3) stability of granule Chinese medicine: after the dissolving of rifampicin granular preparation, room temperature keeps in Dark Place, and checks the medicine stable case with spectrophotography, surveys its absorbance every 2 days, surveys altogether 3 times.Exsiccant slow-releasing granules is sealed in respectively in the vial, stored 3 months under the room temperature 20-25 ℃ of condition, survey medicament contg and absorbance and change.
Date processing adopts the SPSS13.0 statistical software to analyze, and the various performance parameters of material are directly asked arithmetic mean and standard deviation by sample value.
The outward appearance of material
Material appearance is cerise, and is cylindric, and quality is even and hard, rough surface, the naked eyes visible surface fine hole that gathers.
The Specifeca tion speeification of material
See under the ultramicroscope that section is the pore structure of comparison uniformity, its transverse section and vertical section basically identical, pore size are 190-310 μ m, and the micropore of visible a large amount of numerical aperture microns connects mutually on the hole wall.Mean porosities is that (47.43 ± 0.34) %, aperture are (250.86 ± 25.27) μ m.Rifampicin concentration is almost constant in the material dissolves 6 days, illustrates that in preparation process rifampicin is stable.Slow-release material 3 months intensive amounts under 25 ℃ of conditions of room temperature are stable, can room temperature and refrigerator preservation.
Embodiment 4:
It is as follows that present embodiment is made proportioning raw materials that bone renovating material adopts:
PLGA: half-H 2 O calcium sulphate: sodium chloride particle: rifampicin=40: 80: 80: 4.
Described half-H 2 O calcium sulphate is meant the powder of particle diameter below 80um; Described PLGA is meant that molecular weight is the PLGA of 3-10 ten thousand; Described sodium chloride is meant the sodium chloride crystal granule of 200-600um.
The method that present embodiment is made bone renovating material is as follows:
1) PLGA of described amount is joined is made into 20% solution in the chloroform, sealing and standing 12 hours;
2), join in the solution and fully stir with described amount rifampicin, half-H 2 O calcium sulphate, sodium chloride particle.In being uniformly distributed in solution, this moment, solution was gel;
3) with step 2) the gained mixture placed in the room temperature ventilated chamber volatilization 24 hours, solidifies voluntarily.Be cut into height and be 3 millimeters tablet;
4) the step 3) products obtained therefrom is immersed in the 100ml distilled water, changed distilled water 1 time in per 4 hours, the sodium chloride in material dissolves fully, in the soak till the no chloride ion;
5) material drying, sterilization, standby.
Making the effective ingredient weight ratio that product comprises is PLGA: half-H 2 O calcium sulphate: rifampicin=40: 80: 4; Pore size is 190-310 μ m, and mean porosities is that (47.43 ± 0.34) %, aperture are (250.86 ± 25.27) μ m.
The result of use checking of the bone renovating material of present embodiment preparation is as follows:
(1) detection of voidage: adopt Shi Guixin (Shi Guixin, king's body state, etc. polylactic acid and the preparation of polylactic acid-glycolic guanidine-acetic acid porous cell support and the sign of hole. functional polymer journal, 2001,14 (1): 7-11.) wait the hydrometer method of introducing, measure down at 25 ℃, select a density bottle for use, fill it up with dehydrated alcohol and weigh (M1), is quality in the sample immersion ethanol of Ws, evacuation is replaced the gas in the sample fully by ethanol, treat to claim quality (M2) after density bottle is mended full ethanol; To soak into alcoholic acid sample and take out, claim the quality (M3) of remaining ethanol and density bottle.By formula ε=(M2-M3-Ms)/(M1-M3) x100% calculates the porosity of material.
(2) detection in aperture: the section to material carries out electron-microscope scanning, gets 5 sample film makings arbitrarily, measures the aperture of hole on the photo one by one.
(3) stability of granule Chinese medicine: after the dissolving of rifampicin granular preparation, room temperature keeps in Dark Place, and checks the medicine stable case with spectrophotography, surveys its absorbance every 2 days, surveys altogether 3 times.Exsiccant slow-releasing granules is sealed in respectively in the vial, stored 3 months under the room temperature 20-25 ℃ of condition, survey medicament contg and absorbance and change.
Date processing adopts the SPSS13.0 statistical software to analyze, and the various performance parameters of material are directly asked arithmetic mean and standard deviation by sample value.
The outward appearance of material
Material appearance is cerise, and is cylindric, and quality is even and hard, rough surface, the naked eyes visible surface fine hole that gathers.
The Specifeca tion speeification of material
See under the ultramicroscope that section is the pore structure of comparison uniformity, its transverse section and vertical section basically identical, pore size are 190-310 μ m, and the micropore of visible a large amount of numerical aperture microns connects mutually on the hole wall.Mean porosities is that (47.43 ± 0.34) %, aperture are (250.86 ± 25.27) μ m.Rifampicin concentration is almost constant in the material dissolves 6 days, illustrates that in preparation process rifampicin is stable.Slow-release material 3 months intensive amounts under 25 ℃ of conditions of room temperature are stable, can room temperature and refrigerator preservation.
Embodiment 5:
It is as follows that present embodiment is made proportioning raw materials that bone renovating material adopts:
PLGA: half-H 2 O calcium sulphate: sodium chloride particle: rifampicin=40: 40: 80: 3.2.
Described half-H 2 O calcium sulphate is meant the powder of particle diameter below 80um; Described PLGA is meant that molecular weight is the PLGA of 3-10 ten thousand; Described sodium chloride is meant the sodium chloride crystal granule of 200-600um.
The method that present embodiment is made bone renovating material is as follows:
1) PLGA of described amount is joined is made into 20% solution in the chloroform, sealing and standing 12 hours;
2), join in the solution and fully stir with described amount rifampicin, half-H 2 O calcium sulphate, sodium chloride particle.In being uniformly distributed in solution, this moment, solution was gel;
3) with step 2) the gained mixture placed in the room temperature ventilated chamber volatilization 24 hours, solidifies voluntarily.Be cut into height and be 3 millimeters tablet;
4) the step 3) products obtained therefrom is immersed in the 100ml distilled water, changed distilled water 1 time in per 4 hours, the sodium chloride in material dissolves fully, in the soak till the no chloride ion;
5) material drying, sterilization, standby.
The weight ratio that makes the effective ingredient that product comprises is PLGA: half-H 2 O calcium sulphate: rifampicin=40: 40: 3.2; Pore size is 190-310 μ m, and mean porosities is that (47.43 ± 0.34) %, aperture are (250.86 ± 25.27) μ m.
The result of use checking of the bone renovating material of present embodiment preparation is as follows:
(1) detection of voidage: adopt Shi Guixin (Shi Guixin, king's body state, etc. polylactic acid and the preparation of polylactic acid-glycolic guanidine-acetic acid porous cell support and the sign of hole. functional polymer journal, 2001,14 (1): 7-11.) wait the hydrometer method of introducing, measure down at 25 ℃, select a density bottle for use, fill it up with dehydrated alcohol and weigh (M1), is quality in the sample immersion ethanol of Ws, evacuation is replaced the gas in the sample fully by ethanol, treat to claim quality (M2) after density bottle is mended full ethanol; To soak into alcoholic acid sample and take out, claim the quality (M3) of remaining ethanol and density bottle.By formula ε=(M2-M3-Ms)/(M1-M3) x100% calculates the porosity of material.
(2) detection in aperture: the section to material carries out electron-microscope scanning, gets 5 sample film makings arbitrarily, measures the aperture of hole on the photo one by one.
(3) stability of granule Chinese medicine: after the dissolving of rifampicin granular preparation, room temperature keeps in Dark Place, and checks the medicine stable case with spectrophotography, surveys its absorbance every 2 days, surveys altogether 3 times.Exsiccant slow-releasing granules is sealed in respectively in the vial, stored 3 months under the room temperature 20-25 ℃ of condition, survey medicament contg and absorbance and change.
Date processing adopts the SPSS13.0 statistical software to analyze, and the various performance parameters of material are directly asked arithmetic mean and standard deviation by sample value.
The outward appearance of material
Material appearance is cerise, and is cylindric, and quality is even and hard, rough surface, the naked eyes visible surface fine hole that gathers.
The Specifeca tion speeification of material
See under the ultramicroscope that section is the pore structure of comparison uniformity, its transverse section and vertical section basically identical, pore size are 190-310 μ m, and the micropore of visible a large amount of numerical aperture microns connects mutually on the hole wall.Mean porosities is that (47.43 ± 0.34) %, aperture are (250.86 ± 25.27) μ m.Rifampicin concentration is almost constant in the material dissolves 6 days, illustrates that in preparation process rifampicin is stable.Slow-release material 3 months intensive amounts under 25 ℃ of conditions of room temperature are stable, can room temperature and refrigerator preservation.
Embodiment 6:
It is as follows that present embodiment is made proportioning raw materials that bone renovating material adopts:
PLGA: half-H 2 O calcium sulphate: sodium chloride particle: rifampicin=40: 20: 20: 3.
Described half-H 2 O calcium sulphate is meant the powder of particle diameter below 80um; Described PLGA is meant that molecular weight is the PLGA of 3-10 ten thousand; Described sodium chloride is meant the sodium chloride crystal granule of 200-600um.
The method that present embodiment is made bone renovating material is as follows:
1) PLGA of described amount is joined is made into 20% solution in the chloroform, sealing and standing 12 hours;
2), join in the solution and fully stir with described amount rifampicin, half-H 2 O calcium sulphate, sodium chloride particle.In being uniformly distributed in solution, this moment, solution was gel;
3) with step 2) the gained mixture placed in the room temperature ventilated chamber volatilization 24 hours, solidifies voluntarily.Be cut into height and be 3 millimeters tablet;
4) the step 3) products obtained therefrom is immersed in the 100ml distilled water, changed distilled water 1 time in per 4 hours, the sodium chloride in material dissolves fully, in the soak till the no chloride ion;
5) material drying, sterilization, standby.
The weight ratio of the effective ingredient that obtained product comprises is PLGA: half-H 2 O calcium sulphate: rifampicin=40: 20: 3; Pore size is 190-310 μ m, and mean porosities is that (47.43 ± 0.34) %, aperture are (250.86 ± 25.27) μ m.
The result of use checking of the bone renovating material of present embodiment preparation is as follows:
(1) detection of voidage: adopt Shi Guixin (Shi Guixin, king's body state, etc. polylactic acid and the preparation of polylactic acid-glycolic guanidine-acetic acid porous cell support and the sign of hole. functional polymer journal, 2001,14 (1): 7-11.) wait the hydrometer method of introducing, measure down at 25 ℃, select a density bottle for use, fill it up with dehydrated alcohol and weigh (M1), is quality in the sample immersion ethanol of Ws, evacuation is replaced the gas in the sample fully by ethanol, treat to claim quality (M2) after density bottle is mended full ethanol; To soak into alcoholic acid sample and take out, claim the quality (M3) of remaining ethanol and density bottle.By formula ε=(M2-M3-Ms)/(M1-M3) x100% calculates the porosity of material.
(2) detection in aperture: the section to material carries out electron-microscope scanning, gets 5 sample film makings arbitrarily, measures the aperture of hole on the photo one by one.
(3) stability of granule Chinese medicine: after the dissolving of rifampicin granular preparation, room temperature keeps in Dark Place, and checks the medicine stable case with spectrophotography, surveys its absorbance every 2 days, surveys altogether 3 times.Exsiccant slow-releasing granules is sealed in respectively in the vial, stored 3 months under the room temperature 20-25 ℃ of condition, survey medicament contg and absorbance and change.
Date processing adopts the SPSS13.0 statistical software to analyze, and the various performance parameters of material are directly asked arithmetic mean and standard deviation by sample value.
The outward appearance of material
Material appearance is cerise, and is cylindric, and quality is even and hard, rough surface, the naked eyes visible surface fine hole that gathers.
The Specifeca tion speeification of material
See under the ultramicroscope that section is the pore structure of comparison uniformity, its transverse section and vertical section basically identical, pore size are 190-310 μ m, and the micropore of visible a large amount of numerical aperture microns connects mutually on the hole wall.Mean porosities is that (47.43 ± 0.34) %, aperture are (250.86 ± 25.27) μ m.Rifampicin concentration is almost constant in the material dissolves 6 days, illustrates that in preparation process rifampicin is stable.Slow-release material 3 months intensive amounts under 25 ℃ of conditions of room temperature are stable, can room temperature and refrigerator preservation.
In tuberculosis of bone and joint, the sickness rate of spinal tuberculosis is the highest, accounts for 50%, and harm is maximum.Evidence suggests that the trend that tuberculosis spreads in the whole world is controlled as yet fully, and popular this form that makes of AIDS is severe more.As pulmonary tuberculosis, also there is the trend of obvious rising in spinal tuberculosis sickness rate in recent years.
Can select preceding road or way of escape bone grafting behind the tuberculosis of bone and joint focal cleaning.Behind the focal cleaning, the bone deletion problem is very obvious.At present clinical method still commonly used is for taking from body ilium or rib, because ilium is mainly spongy bone, its comprcssive strength is limited.It is limited to originate from the body bone, and gets the bone complication, arbitrarily plastotype.Simultaneously, cause MOI, plant bone mass to absorb complication such as sinking because usually cause local recurrence, sinus tract to form with the clear factor such as not thorough of huge cold abscess or focus.
Therefore, the treatment of tuberculosis of bone and joint is as results in treatment of chronic osteomyelitis, and focal cleaning and the medication of secular system completely is to promote healing and eradicate the key that infects.The topical application antibiotic can be traced back to the thirties of eighties of last century the earliest.To the seventies, having occurred again with the bone cement is the antibiotic product of carrier topical application, carries out bone grafting again but need second operation to take out carrier.Occurred the degradable biological material afterwards as carrier of antibiotics, and avoided second operation to take out carrier, but often left over bigger cavity after the carrier absorption.Novel bone biologic material provides the antibiotic while of high local concentrations again, has the characteristic of bone conduction, has avoided operation taking-up carrier in theory again and has taken from body bone bone grafting.For this reason, some bone implant materials arise at the historic moment, as PMMA, and calcium phosphate bone cement, half-H 2 O calcium sulphate, Ca-P ceramic class or the like.At present, the half water half-H 2 O calcium sulphate crystalline solid that U.S. Wright company produces has the crystal structure of homogeneous, and the post-absorption rate stabilization that implants and new bone substitute speed and adapt.In addition, half-H 2 O calcium sulphate also has the ability of stimulation of bone growth.
PLGA is one of maximum slow releasing carrier of medication of research at present, has obtained the material of drugs approved by FDA as injection microcapsule, microsphere, implants etc.The rate of release of medicine can be by selecting different molecular weight, the active lactic acid copolymerization of different optical, and the polymerization ratio of lactide not of the same race and Acetic acid, hydroxy-, bimol. cyclic ester is regulated.The end product of polylactic acid hydrolysis is water and CO2, and intermediate product lactic acid also is normal carbohydrate metabolism product in the body, thus nontoxic, the nonirritant of this polymer, and have good biocompatibility.Cao Yingguang (Cao Yingguang, Wang Rong, Wang Huajun, Deng. the external experimentation of adhering to of mesenchymal stem cells MSCs and PLGA. clinical stomatology magazine, 2005,21 (4): 212-214.) etc. report mesenchymal stem cells MSCs (BMSCs) can stick, breed, secrete extracellular matrix on PLGA, and can be divided into polygonal skeletonization like cell under the effect of osteogenic induction agent.
Porous material surface more helps the cell pseudopodium than common material surface seeks connections with, and increases the thing active force between cellular layer and the base material.And help the transportation and the exchange of moisture, inorganic salt and other nutrient substance and products of cellular metabolism, thereby more help the normal growth and the physiological metabolism of cell.1993, Mikos (Mikos AG, Sarakinos G, Leite SM, et al.Laminated three-dimensional biodegradable foams for usein tissue engineering.Biomaterials JT-Biomaterials, 1993,14 (5): 323-30.) wait proposition solvent casting-salting out method to make the porous support, be after water solublity implant (as sodium chloride, sucrose crystal) and plastic material mix, solidify, to dissolve at aqueous solution.Chen Jianting (Liu Jinbiao, Chen Jianting. the development and the correlated performance thereof of nacreous layer/polylactic acid reorganization bone renovating material detect. No.1 Military Medical Univ.'s journal, 2002,22 (3): 236-238.) wait human polylactic acid, nacreous layer, the novel porous bone repair material material of sodium chloride crystal (perforating agent) development.Zooscopy shows to have excellent biological compatibility and bone conduction effect.The aperture of its inner vent hole allows fibrous tissue to grow into wherein when 5-40um; When 40-100um, allow non-mineralising osteoid tissue to grow into; When 150um, can for osseous tissue grow into provide ideal place (Zheng Yuehua, Hou Xiaomei. the progress of porous hydroxyapatite bioceramic. silicate circular, 1995 (3): 20.).Zoopery shows that the new bone growth requisite space should be greater than 100um, and pore size helps new bone growth most when 200-400um.The size of porosity is less to new osteoplastic influence with respect to the aperture, when porosity surpasses 30%, can be interconnected between the hole, the cambium inner each several part of can growing into from the bone renovating material surface, and mutually combine, obtain good interface in conjunction with (de GK.Bioceramics consistingof calcium phosphate salts.Biomaterials, 1980,1 (1): 47.).
In sum, the constituent good biocompatibility of this slow-release material, rifampicin is stable in the preparation process.The mean porosities of material (47.43～0.14) %, aperture (250.86～3.57) μ m meet the requirement of osteogenesis, help growing into and the circulation of body fluid of new bone.
Zoopery shows that the new bone growth requisite space should be greater than 100um, and pore size helps new bone growth most when 200-400um.The size of porosity is less to new osteoplastic influence with respect to the aperture, for the macropore of same apertures, and porosity 40% and 50%, new bone formation speed does not almost change.When porosity surpasses after 30%, can be interconnected between the hole, the cambium inner each several part of can growing into from the bone renovating material surface, and mutually combine, obtain the good interface combination.
Claims (4)
1. a bone renovating material is characterized in that, its effective ingredient is formed by the feedstock production of following parts by weight:
PLGA 40, half-H 2 O calcium sulphate 40, rifampicin 3.2, sodium chloride 80;
Wherein, described half-H 2 O calcium sulphate is meant the powder of particle diameter below 80um, and described PLGA is meant that molecular weight is 300000 PLGA, and described sodium chloride is meant the sodium chloride crystal granule of 180-250um.
2. the preparation method of the described bone renovating material of claim 1 is characterized in that, comprises the steps:
1) PLGA of described amount is joined is made into 15-25% solution in the chloroform, sealing and standing 10-14 hour;
2), join and fully stir into mixture in the solution with rifampicin, half-H 2 O calcium sulphate, the sodium chloride of described amount;
3) with step 2) solvent flashing under the gained mixture room temperature, solidify;
4) step 3) gained cured article is soaked in the distilled water, treats that chloride ion wherein removes after drying fully.
3. the preparation method of bone renovating material according to claim 2 is characterized in that, comprises the steps:
1) PLGA of described amount is joined is made into 20% solution in the chloroform, sealing and standing 12 hours;
2) with described amount rifampicin, half-H 2 O calcium sulphate, sodium chloride particle, join in the solution and fully stir, in being uniformly distributed in solution, this moment, solution was gel;
3) with step 2) the gained mixture placed in the room temperature ventilated chamber volatilization 24 hours, solidified voluntarily, was cut into height and is 3 millimeters tablet;
4) the step 3) products obtained therefrom is immersed in the 100ml distilled water, changed distilled water 1 time in per 4 hours, the sodium chloride in material dissolves fully, in the soak till the no chloride ion;
5) material drying, sterilization, standby.
4. by the bone renovating material of claim 2 or 3 described method preparations, it is characterized in that: the weight ratio of effective ingredient is: PLGA: half-H 2 O calcium sulphate: rifampicin=40: 40: 3.2; Pore size is 190-310 μ m, and mean porosities is that (47.43+0.34) %, average pore size are (250.86+25.27) μ m.
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