CN1446589A - Medicine controlled functional cement with calcium phosphate being as framework and its preparation method - Google Patents
Medicine controlled functional cement with calcium phosphate being as framework and its preparation method Download PDFInfo
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Abstract
A calcium phosphate cement with the function of controlling medicine release for repairing dysostosis, treating osteomyelitis and preventing infection and recurrence of osteoma is prepared from porous calcium phosphate cement and medicine capsules containing antibacterial medicine, antineoplastic medicine, anti-flammatory antalgic medicine, antituberculosis, etc. Its advantages are slow medicines releasing, and high curative effect.
Description
Technical field
The invention belongs to biomedical materials field, relate to a kind of be used for hard tissue repair hold concurrently the controlled release medicine carrying calcium phosphate bone cement and the application thereof of Drug therapy.
Background technology
The bone that causes owing to reasons such as wound, tumors is damaged to be the thorny problem of clinical treatment.For a long time, the method of autologous bone transplanting in conjunction with homogeneous allogenic bone transplantation mainly adopted in the reparation that bone is damaged, but two kinds of methods all have shortcoming separately: from the body bone restricted number of being originated, and get osseous surgery and have 10% surgery complication at least, need the creeping substitution process of long period after the implantation; Allograph bone exists in various degree immune rejection and potential source of disease to propagate dangerous.The synthetic substitution material then can be avoided the defective of biogenic repair materials, is a kind of comparatively ideal bone impairment renovation material.
The aseptic condition of implant site is the prerequisite and the key of bone grafting success.Clinical research shows: infect if treat implant site, then therapeutic effect is not good, and especially for the big-and-middle-sized operation of orthopaedics (as spinal operation etc.), in case infect, its harm will be catastrophic; In addition, because of osteoma excision back tumor cell may not clean up, the local transfer taken place, thereby it is not thorough to make that simple biomaterial is used for the treatment of bone defect repair, so that has a relapse.Based on this, medicines such as anticancer or antiinflammatory are introduced in the biomaterial, make material when filling reparation, also have the effect of further Drug therapy.Therefore, the research of drug-loaded biological material and use noticeablely especially, development in recent years is rapid, at present in clinical research and use relate to more have following several:
Buchholz in 1970 and Engelbrecht have reported that at first bone cement (PMMA) full hip plasty postoperative infection of treatment and the effect of using the medicine carrying gentamycin are remarkable; First has reported that the strain of application gentamycin medicine treats chronic osteomyelitis and obtained certain curative effect Klemm in 1974; Yet find that there is the explosion type release effects in vivo in medicine, the drug effect cycle is short and easily cause the side effect of whole body series.Document (Salvati E A, Callaghen JJ, Brause B D, Klein R F, Small RD.Clin Orthop, 1986,207:83～94) also reported polymethyl methacrylate (PMMA) bone cement is combined the infection that is used for target administration treatment bone and deep soft tissue and obtained obvious curative effects with antibiotic.But along with basic research further deeply and the further expansion of clinical practice, find that there are many shortcomings in the PMMA drug-loading system: histocompatibility is poor, the strong heat release of solidification process causes easily that surrounding tissue is burnt and downright bad, monomer is toxic to human body, material is not degraded, long-term foreign body exists and (or proposes one by one during treatment in vivo, patient is very painful), drug release is incomplete etc., make therapeutic outcome be difficult to comply with one's wishes, application is restricted, yet the design of this functional material is to be worth using for reference.
(Sun Wei opens etc. document, the West China pharmaceutical journal, 1997, vol14 (3), p172-174) reported the artificial bone of porous hydroxyapatite pottery (HAP) as the pharmaceutical carrier preparation, experiment finds that medicine carrying HAP artificial bone has tangible medicament slow release therapeutical effect in the bone repair process.But find that material fragility is big, elastic strength difference and absorb difficulty in vivo, easily cause the bone dissolving.Medicine soaks rear surface absorption by the Porous HAP pottery simultaneously, and adsorbance is few, and slow-release time is not long in vivo.
As fully visible, good pharmaceutical carrier and the effective complex method between medicine and bioabsorbable carrier material be the drug-loaded biological material dual purpose that really reaches bone defect repair and Drug therapy, realize medicament-carried continuing, the key of stable and high-efficiency sustained-release.
Summary of the invention
The technical issues that need to address of the present invention are to disclose a kind of drug controlled-releasing function self-curable calcium phosphate bone cement, to overcome the above-mentioned defective that prior art (as pharmaceutical carrier, medicine and carrier complex method etc.) exists, satisfy the needs of chronic osteomyelitis, therapentic part infection mitigation, tumor recurrence prevention etc.
The invention still further relates to the application clinically of described drug-loaded artificial bone.
Design of the present invention is such:
Calcium phosphate bone cement (CPC) is a kind of novel bone renovating material, by several calcium phosphate form (Chow, US 5525148,5545254,1996), can be under human body environment and temperature solidify voluntarily, accurately plastotype and biodegradation, and finally be converted into hydroxyapatite.CPC is as present unique hard tissue repairing material that can solidify and produce regeneration effect voluntarily, unification with its high-biocompatibility, biodegradable and any plastic properties, obtain the attention of international material circle and medical circle, become one of research focus of current biomaterial.Experiment in vitro shows that (Huang Yue, East China University of Science's master thesis, 1999) CPC is feasible as pharmaceutical carrier.The present invention utilizes CPC embedding microencapsulation medicament, form medicine carrying calcium phosphate bone cement firming body, avoid treating the recurrence that implant site infects or the debridement of prophylaxis of tumours cell does not thoroughly cause, by parameters such as control microcapsule wall material thickness, medicament contg, firming body porosity, solid-to-liquid ratios, realize calcium phosphate bone cement fixed point controllable sustained-release anti-cancer anti-inflammation medicine, give material and have the double effects of filling reparation and treatment concurrently.The present invention utilizes medicine carrying porous calcium phosphate bone cement firming body microcapsule wall material to have the medicine carrying calcium phosphate bone cement that certain degradability prepares the controllable sustained-release function in body fluid (or simulated body fluid), and drug microcapsule is embedded in the calcium phosphate bone cement powder equably.When porous calcium phosphate bone cement solidifies, drug microcapsule occupies the segment space of porous firming body, thereby form an independently unit, behind the implant into body, continue to flow erosion and infiltration through body fluid, microcapsule wall material is constantly degraded, the medicine capsule-core is subjected to microcapsule wall material thickness, medicament contg, the firming body porosity, parameter influences such as solid-to-liquid ratio are fixed a point controlled one-level slow release behind the porous firming body, then the porous microstructure by firming body realizes the secondary controllable sustained-release, make material when repairing, have the antitumor recurrence, the anti-inflammation and sterilization effect is used for the infection mitigation of results in treatment of chronic osteomyelitis and implant site.
The detailed technical scheme of the present invention is as described below:
The said medicine carrying calcium phosphate bone cement with controllable sustained-release function of the present invention mainly is made up of the drug microcapsule of porous calcium phosphate bone cement and treatment effective dose, and preferred ratio is:
Porous calcium phosphate bone cement: drug microcapsule=100: (0.5～20), mass ratio;
Said porous calcium phosphate bone cement is made of by a certain percentage calcium phosphate bone cement powder (CPC) and pore former, can be by (Liu Changsheng, ZL98110645.5) disclosed method preparation.Wherein: said CPC powder is by the blended according to a certain percentage mixture of several synthos, can be by (US5525148, US5545254) disclosed method preparation can be a kind of in tricalcium phosphate (α type or β type), the tetracalcium phosphate or both mixture; A kind of in OCP, dalcium biphosphate, hydroxyapatite, the fluor-apatite or their mixture.
Said pore former can be in nontoxic slightly soluble salt, acid salt and basic salt, the nontoxic macromolecule of solubility or the nontoxic surfactant one or more.
Said drug microcapsule is for adopting the embedding thing of pharmaceutically acceptable wall material embedding capsule-core (medicine), wherein:
Said capsule-core (medicine) comprises antimicrobial drug (as tobramycin, vancomycin, safe energy, Ceftriaxone, pipemidic acid, cephalo-type, metronidazole etc.), antineoplastic agent (as methotrexate, amycin, fluorouracil, flutamide, lomustine etc.), anti-anti-inflammatory analgesic (as naproxen sodium, NSC-145688, indometacin etc.), antitubercular agent (as rifampicin) and the mixture of two or more medicine under no incompatibility situation; The ratio of wall material and described medicine is: 1: 1～1: 20;
Said wall material comprises a kind of in soluble starch, hydroxypropyl cellulose, ethyl cellulose, gelatin or the chitosan etc., is good with ethyl cellulose;
Said microcapsule can adopt interface coacervation, in-situ method, polymerization, spray drying method, solvent evaporated method to be prepared, and is good with solvent evaporated method.
The said bone cement of the present invention is prepared as follows and uses:
Wall material and capsule-core are pressed the wall material: capsule-core=1: (1～20), the ratio of mass ratio, adopt solvent evaporated method to be prepared into the drug microcapsule that particle diameter is 100～400 μ m, porous calcium phosphate bone cement powder and this microcapsule of with diameter being 5～20 μ m again are with porous calcium phosphate bone cement: drug microcapsule=100: (0.5～20) (mass ratio) mixes embedding, promptly obtains the porous medicine carrying calcium phosphate bone cement with controllable sustained-release function.
As consolidation liquid, is ratio and its mix homogeneously of (1.5: 1～5: 1) in solid-to-liquid ratio with normal saline or other saline solution, can implant; Said other saline solution is that concentration is the aqueous phosphatic of 7～25wt%.
Said wall material comprises soluble starch, hydroxypropyl cellulose, ethyl cellulose, gelatin, chitosan etc., is good with ethyl cellulose;
Said capsule-core comprises that (medicine) comprises antimicrobial drug (as tobramycin, vancomycin, safe energy, Ceftriaxone, pipemidic acid, cephalo-type, metronidazole etc.), antineoplastic agent (as methotrexate, amycin, fluorouracil, flutamide, lomustine etc.), anti-anti-inflammatory analgesic (as naproxen sodium, NSC-145688, indometacin etc.), antitubercular agent (as rifampicin) and the mixture of two or more medicine under no incompatibility situation;
The inventor has carried out external simulation test and clinic trial to the said controllable sustained-release medicine carrying of the present invention self-curable calcium phosphate bone cement:
Place 37 ℃, 100% humidity environment to solidify 48h the controlled release medicine carrying porous calcium phosphate bone cement of above-mentioned preparation, and then in simulated cushioned solution, soak, take a sample at interval with appropriate time, use the determined by ultraviolet spectrophotometry drug level, show that the medicine carrying porous calcium phosphate bone cement is comparatively sufficient in the degree of release in vitro medicine, discharge the soonest in 24 hours, in 6 weeks, keep effective levels of drugs always, 8 week the back discharge nearly 80%.
The first phase debridement second phase is used the controlled release medicine carrying porous calcium phosphate bone cement of above-mentioned preparation and treats chronic bacillus pyocyaneus osteomyelitis, the damaged 8cm * 4cm that reaches of bone.Use the 20gCPC powder and add vancomycin 0.5g, piperacillin 0.5g respectively, make oval granule, wrapped up 15 minutes, mix and implant damaged place with 40 ℃ of warm gauzes.Row flap art, drain, near-end connects vacuum extractor, and the appropriate not mycin of distal injection 80,000 units once a day, continue a week.Find that postoperative 2 all wound surface heal fully, the visible a small amount of callus of postoperative X-ray film check in 3 months generates.Postoperative bone graft healing in a year is good, and focus does not recur.Postoperative was followed the tracks of 1 year, did not recur sign as yet, can think clinical cure.
The said controllable sustained-release medicine carrying of the present invention self-curable calcium phosphate bone cement has very significant advantage:
After drug microcapsuleization, heterogeneous compound with porous calcium phosphate bone cement again, reduced or remitted medicine to the solidified influence of CPC, prolonged the time of drug-loading system release active drug concentration.By controlling parameters such as microcapsule wall material kind and thickness, medicament contg, firming body porosity, solid-to-liquid ratio, realize the medicine carrying calcium phosphate bone cement controlled secondary slow release (degradability of wall material intrinsic structures shape realizes the secondary slow release that one-level slow release and firming body microcosmic loose structure are realized) of fixing a point, feasible not only bone repair of medicine carrying calcium phosphate bone cement firming body of preparing, and the double purpose that reaches treatment, be used for the prevention of recurrence behind results in treatment of chronic osteomyelitis, implant site infection mitigation and the tumor resection.Simultaneously, formed micropore helps growing into of osseous tissue behind the drug microcapsule slow release, the degraded of accelerated material, and the quickly-healing of promotion bone is a kind of human body hard tissue repair materials of new generation of excellent performance.
Description of drawings
Fig. 1 is medicine carrying calcium phosphate bone cement drug release figure.
The specific embodiment
Further illustrate content of the present invention below in conjunction with embodiment, but these embodiment do not limit protection scope of the present invention.
Embodiment 1
Claim 50mg ethyl cellulose, under water bath condition, be dissolved in acetone, treat that it dissolves fully after, add the 100mg tobramycin, after stirring, pour the liquid paraffin that 2g contains class of 8ml department 80 into, in 60 ℃ of following recirculated water constant temperature, stirring, sucking filtration, washing, oven dry promptly makes the tobramycin microcapsule.
Weighing pore former (200～350 μ m) 0.1g, calcium hydrogen phosphate, tetracalcium phosphate, the particle diameter that hydroxyapatite is formed is less than the CPC powder 3g of 20 μ m, add the tobramycin microcapsule for preparing simultaneously, in mortar, be uniformly dispersed, add the 1.2g normal saline, evenly become walk with the mediation of dentistry modulation cutter, place 37 ℃, solidify 48h in 100% humidity environment, and then in simulated cushioned solution, soak, take a sample at interval with appropriate time, with determined by ultraviolet spectrophotometry tobramycin concentration, show that the medicine carrying porous calcium phosphate bone cement is comparatively sufficient in the degree of release in vitro medicine, discharge the fastest in 24 hours, in 6 weeks, keep effective levels of drugs, 8 week back releases nearly 80% always.
Embodiment 2
Claim ethyl cellulose 50mg, under water bath condition, be dissolved in acetone, treat that it dissolves fully after, add the 100mg naproxen sodium, after stirring, pour the liquid paraffin that 2g contains class of 8ml department 80 into, in 60 ℃ of following recirculated water constant temperature, stirring, sucking filtration, washing, oven dry promptly makes the naproxen sodium microcapsule.Weighing pore former (200～350 μ m) 0.1g, calcium hydrogen phosphate, tetracalcium phosphate, the particle diameter that hydroxyapatite is formed is less than the CPC powder 3g of 20 μ m, add the naproxen sodium microcapsule for preparing simultaneously, in mortar, be uniformly dispersed, add the 1.2g normal saline, evenly become walk with the mediation of dentistry modulation cutter, place 37 ℃, solidify 48h in 100% humidity environment, and then in simulated cushioned solution, soak, take a sample at interval with appropriate time, with determined by ultraviolet spectrophotometry naproxen sodium concentration, show that the medicine carrying porous calcium phosphate bone cement is comparatively sufficient in the degree of release in vitro medicine, discharge the fastest in 24 hours, in 6 weeks, keep effective levels of drugs, 8 week back releases nearly 80% always.
Embodiment 3
Claim ethyl cellulose 50mg, under water bath condition, be dissolved in acetone, treat that it dissolves fully after, add the 100mg rifampicin, after stirring, pour the liquid paraffin that 2g contains class of 8ml department 80 into, in 60 ℃ of following recirculated water constant temperature, stirring, sucking filtration, washing, oven dry promptly makes the rifampicin microcapsule.Weighing pore former (200～350 μ m) 0.1g, calcium hydrogen phosphate, tetracalcium phosphate, the particle diameter that hydroxyapatite is formed is less than the CPC powder 3g of 20 μ m, add the rifampicin microcapsule for preparing simultaneously, in mortar, be uniformly dispersed, add the 1.2g normal saline, evenly become walk with the mediation of dentistry modulation cutter, place 37 ℃, solidify 48h in 100% humidity environment, and then in simulated cushioned solution, soak, take a sample at interval with appropriate time, with determined by ultraviolet spectrophotometry rifampicin concentration, show that the medicine carrying porous calcium phosphate bone cement is comparatively sufficient in the degree of release in vitro medicine, discharge the fastest in 24 hours, in 6 weeks, keep effective levels of drugs, 8 week back releases nearly 80% always.
Embodiment 4
Claim ethyl cellulose 50mg, under water bath condition, be dissolved in acetone, treat that it dissolves fully after, add the 100mg amycin, after stirring, pour the liquid paraffin that 2g contains class of 8ml department 80 into, in 60 ℃ of following recirculated water constant temperature, stirring, sucking filtration, washing, oven dry promptly makes the amycin microcapsule.Weighing pore former (200～350 μ m) 0.1g, calcium hydrogen phosphate, tetracalcium phosphate, the particle diameter that hydroxyapatite is formed is less than the CPC powder 3g of 20 μ m, add the amycin microcapsule for preparing simultaneously, in mortar, be uniformly dispersed, add the 1.2g normal saline, evenly become walk with the mediation of dentistry modulation cutter, place 37 ℃, solidify 48h in 100% humidity environment, and then in simulated cushioned solution, soak, take a sample at interval with appropriate time, use the determined by ultraviolet spectrophotometry doxorubicin concentration, show that the medicine carrying porous calcium phosphate bone cement is comparatively sufficient in the degree of release in vitro medicine, discharge the fastest in 24 hours, in 6 weeks, keep effective levels of drugs, 8 week back releases nearly 90% always.
Embodiment 5
Claim ethyl cellulose 50mg, under water bath condition, be dissolved in acetone, after treating that it dissolves fully, add 50mg tobramycin and 50mg vancomycin, after stirring, pour the liquid paraffin that 2g contains class of 8ml department 80 into, in 60 ℃ of following recirculated water constant temperature, stirring, sucking filtration, washing, oven dry promptly makes the combination drug microcapsule.Weighing pore former (200～350 μ m) 0.1g, calcium hydrogen phosphate, tetracalcium phosphate, the particle diameter that hydroxyapatite is formed is less than the CPC powder 3g of 20 μ m, add the combination drug microcapsule for preparing simultaneously, in mortar, be uniformly dispersed, add the 1.2g normal saline, evenly become walk with the mediation of dentistry modulation cutter, place 37 ℃, solidify 48h in 100% humidity environment, and then in simulated cushioned solution, soak, take a sample at interval with appropriate time, with determined by ultraviolet spectrophotometry combination drug concentration, show that the medicine carrying porous calcium phosphate bone cement is comparatively sufficient in the degree of release in vitro medicine, discharge the fastest in 24 hours, in 6 weeks, keep effective levels of drugs, 8 week back releases nearly 85% always.
Embodiment 6
Claim chitosan 30mg, be dissolved in 0.1% glacial acetic acid, treat that it dissolves fully after, add the 10mg amycin, after stirring, pour the liquid paraffin that 2g contains class of 8ml department 80 into, in 60 ℃ of following recirculated water constant temperature, stirring, sucking filtration, washing, oven dry promptly makes the amycin microcapsule.Weighing pore former (200～350 μ m) 0.1g, calcium hydrogen phosphate, tetracalcium phosphate, the particle diameter that hydroxyapatite is formed is less than the CPC powder 3g of 20 μ m, add the amycin microcapsule for preparing simultaneously, in mortar, be uniformly dispersed, add the 1.2g normal saline, evenly become walk with the mediation of dentistry modulation cutter, place 37 ℃, solidify 48h in 100% humidity environment, and then in simulated cushioned solution, soak, take a sample at interval with appropriate time, use the determined by ultraviolet spectrophotometry doxorubicin concentration, show that the medicine carrying porous calcium phosphate bone cement is comparatively sufficient in the degree of release in vitro medicine, discharge the fastest in 24 hours, in 6 weeks, keep effective levels of drugs, 8 week back releases nearly 80% always.
Embodiment 7
Claim chitosan 30mg, be dissolved in 0.1% glacial acetic acid, treat that it dissolves fully after, add the 100mg rifampicin, after stirring, pour the liquid paraffin that 2g contains class of 8ml department 80 into, in 60 ℃ of following recirculated water constant temperature, stirring, sucking filtration, washing, oven dry promptly makes the rifampicin microcapsule.Weighing pore former (200～350 μ m) 0.1g, calcium hydrogen phosphate, tetracalcium phosphate, the particle diameter that hydroxyapatite is formed is less than the CPC powder 3g of 20 μ m, add the rifampicin microcapsule for preparing simultaneously, in mortar, be uniformly dispersed, add the 1.2g normal saline, evenly become walk with the mediation of dentistry modulation cutter, place 37 ℃, solidify 48h in the 100% apparent degree environment, and then in simulated cushioned body lotion, soak, take a sample at interval with appropriate time, with determined by ultraviolet spectrophotometry rifampicin concentration, show that the medicine carrying porous calcium phosphate bone cement is comparatively sufficient in the degree of release in vitro medicine, discharge the fastest in 24 hours, in 6 weeks, keep effective levels of drugs, 8 week back releases nearly 80% always.
Embodiment 8
Claim 30mg chitosan, be dissolved in 0.1% glacial acetic acid, treat that it dissolves fully after, add the 100mg tobramycin, after stirring, pour the liquid paraffin that 2g contains class of 8ml department 80 into, recirculated water constant temperature, stirring, sucking filtration, washing under 60C, oven dry promptly makes the tobramycin microcapsule.
Weighing pore former (200～350 μ m) 0.1g, calcium hydrogen phosphate, tetracalcium phosphate, the particle diameter that hydroxyapatite is formed is less than the CPC powder 3g of 20 μ m, add the tobramycin microcapsule for preparing simultaneously, in mortar, be uniformly dispersed, add the 1.2g normal saline, evenly become walk with the mediation of dentistry modulation cutter, place 37 ℃, solidify 48h in 100% humidity environment, and then in simulated cushioned solution, soak, take a sample at interval with appropriate time, with determined by ultraviolet spectrophotometry tobramycin concentration, show that the medicine carrying porous calcium phosphate bone cement is comparatively sufficient in the degree of release in vitro medicine, discharge the fastest in 24 hours, in 6 weeks, keep effective levels of drugs, 8 week back releases nearly 80% always.As shown in Figure 1.
Embodiment 9
Claim chitosan 30mg, be dissolved in 0.1% glacial acetic acid, treat that it dissolves fully after, add the 100mg naproxen sodium, after stirring, pour the liquid paraffin that 2g contains class of 8ml department 80 into, in 60 ℃ of following recirculated water constant temperature, stirring, sucking filtration, washing, oven dry promptly makes the naproxen sodium microcapsule.Weighing pore former (200～350 μ m) 0.1g, calcium hydrogen phosphate, tetracalcium phosphate, the particle diameter that hydroxyapatite is formed is less than the CPC powder 3g of 20 μ m, add the naproxen sodium microcapsule for preparing simultaneously, in mortar, be uniformly dispersed, add the 1.2g normal saline, evenly become walk with the mediation of dentistry modulation cutter, place 37 ℃, solidify 48h in 100% humidity environment, and then in simulated cushioned solution, soak, take a sample at interval with appropriate time, with determined by ultraviolet spectrophotometry naproxen sodium concentration, show that the medicine carrying porous calcium phosphate bone cement is comparatively sufficient in the degree of release in vitro medicine, discharge the fastest in 24 hours, in 6 weeks, keep effective levels of drugs, 8 week back releases nearly 80% always.
Embodiment 10
Claim chitosan 30mg, be dissolved in 0.1% glacial acetic acid, after treating that it dissolves fully, add multiple amycin of 10mg and 50mg vancomycin, after stirring, pour the liquid paraffin that 2g contains class of 8ml department 80 into, in 60 ℃ of following recirculated water constant temperature, stirring, sucking filtration, washing, oven dry promptly makes the combination drug microcapsule.Weighing pore former (200～350 μ m) 0.1g, calcium hydrogen phosphate, tetracalcium phosphate, the particle diameter that hydroxyapatite is formed is less than the CPC powder 3g of 20 μ m, add the combination drug microcapsule for preparing simultaneously, in mortar, be uniformly dispersed, add the 1.2g normal saline, evenly become walk with the mediation of dentistry modulation cutter, place 37 ℃, solidify 48h in 100% humidity environment, and then in simulated cushioned solution, soak, take a sample at interval with appropriate time, with determined by ultraviolet spectrophotometry combination drug concentration, show that the medicine carrying porous calcium phosphate bone cement is comparatively sufficient in the degree of release in vitro medicine, discharge the fastest in 24 hours, in 6 weeks, keep effective levels of drugs, 8 week back releases nearly 80% always.
The foregoing description has reduced the influence of medicine to the CPC solidification process after showing medicine carrying self-curable calcium phosphate bone cement Chinese medicine micro encapsulation, has prolonged pharmaceutical release time.The calcium phosphate bone cement firming body of preparing can not only be used for the damaged filling reparation of bone, and sustainable slow releasing pharmaceutical, reaches the terrible purpose of further system, and prevention and the recurrence behind the bone tumour resection infected as results in treatment of chronic osteomyelitis, implant site prevent.Formed micropore helps growing into of osseous tissue after containing medicine microcapsule slow release simultaneously, the degraded of accelerated material, and the quickly-healing of promotion bone is a kind of human body hard tissue repair materials of new generation of excellent performance.
Claims (13)
1. the active artificial bone of drug controlled-releasing function is characterized in that mainly being made up of the drug microcapsule of porous calcium phosphate bone cement and treatment effective dose.
2. artificial bone according to claim 1 is characterized in that porous calcium phosphate bone cement: drug microcapsule=100: (0.5～20), mass ratio;
3. artificial bone according to claim 2 is characterized in that said porous calcium phosphate bone cement comprises calcium phosphate bone cement powder and pore former.
4. artificial bone according to claim 3 is characterized in that said calcium phosphate bone cement powder is a kind of in tricalcium phosphate (α type or β type), the tetracalcium phosphate or both mixture; A kind of in OCP, dalcium biphosphate, hydroxyapatite, the fluor-apatite or their mixture.
5. artificial bone according to claim 3 is characterized in that said pore former is one or more in nontoxic slightly soluble salt, acid salt and basic salt, solubility non-toxic organic thing or the nontoxic surfactant.
6. according to each described artificial bone of claim 1～5, it is characterized in that said drug microcapsule is for adopting the embedding thing of pharmaceutically acceptable wall material embedding capsule-core (medicine).
7. artificial bone according to claim 6 is characterized in that the ratio of wall material and described medicine is: 1: 1～1: 20.
8. artificial bone according to claim 6 is characterized in that said capsule-core (medicine) comprises antimicrobial drug, antineoplastic agent, anti-anti-inflammatory analgesic or antitubercular agent and the mixture of two or more medicine under no incompatibility situation.
9. artificial bone according to claim 6 is characterized in that said wall material comprises a kind of in soluble starch, hydroxypropyl cellulose, ethyl cellulose, gelatin or the chitosan series.
10. artificial bone according to claim 8, it is characterized in that, antimicrobial drug is tobramycin, vancomycin, safe energy, Ceftriaxone, pipemidic acid, cephalo-type or metronidazole etc., antineoplastic agent is methotrexate, amycin, fluorouracil, flutamide or lomustine, anti-anti-inflammatory analgesic is naproxen sodium, NSC-145688 or indometacin, and antitubercular agent is a rifampicin.
11. preparation method according to the described artificial bone of claim 1～10, it is characterized in that, wall material and capsule-core are pressed the wall material: capsule-core=1: (1～20), the ratio of mass ratio, adopt solvent evaporated method to be prepared into the drug microcapsule that particle diameter is 100～400 μ m, porous calcium phosphate bone cement powder and this microcapsule of with diameter being 5～20 μ m again are with porous calcium phosphate bone cement: drug microcapsule=100: (0.5～20) (mass ratio) mixes embedding, promptly obtains the porous medicine carrying calcium phosphate bone cement with controllable sustained-release function.
12. the application according to the described artificial bone of claim 1～10 is characterized in that, as consolidation liquid, is ratio and its mix homogeneously of (1.5: 1～5: 1) in solid-to-liquid ratio with normal saline or other saline solution, can implant.
13. the application of artificial bone according to claim 12 is characterized in that, said other saline solution is that concentration is the aqueous phosphatic of 7～25wt%.
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