CN102552994A - Medical slow release material and preparation method thereof - Google Patents

Medical slow release material and preparation method thereof Download PDF

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Publication number
CN102552994A
CN102552994A CN2011104588108A CN201110458810A CN102552994A CN 102552994 A CN102552994 A CN 102552994A CN 2011104588108 A CN2011104588108 A CN 2011104588108A CN 201110458810 A CN201110458810 A CN 201110458810A CN 102552994 A CN102552994 A CN 102552994A
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microsphere
weeks
medicine
slow release
temperature sensitive
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CN102552994B (en
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谭荣伟
佘振定
王明波
刘伟强
张文强
李丽花
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Shenzhen Research Institute Tsinghua University
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Shenzhen Research Institute Tsinghua University
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Abstract

The invention relates to an injectable medical slow release material which is mainly formed by the mixing of pulse type releasing microspheres carrying drugs and a temperature sensitive polymer solution. The preparation method mainly comprises the steps of preparing the pulse type releasing microspheres carrying drugs; preparing the temperature sensitive polymer solution; and mixing the pulse type releasing microspheres carrying drugs with the temperature sensitive polymer solution, and stirring the mixture to be uniform to form a mixed solution. According to the invention, carrying factors or microspheres of drugs are uniformly dispersed in the solution of the temperature sensitive injectable carrier, and after the solution is injected to a treatment position, the material is solidified quickly and then degrades slowly to release drugs or factors, so as to prolong the active time of the factors in the body, and improve the controllability on factor release speed and factor release cycle, thereby realizing the combination of release of same or different drugs in desired locations and different time slots alternatively and the manner of minimally invasive treatments.

Description

A kind of medical slow release material and preparation method thereof
Technical field
The invention belongs to the bioactive materials field, refer in particular to injectable sustained-release material and preparation and method for using that a kind of temperature sensitive type carries microsphere.
Background technology
In China; Annual cause the patient of bone injury to reach 300 ~ 4,000,000 person-times because of vehicle accident and production safety accident; Add orthopaedic diseases such as bone tumor, bone tuberculosis, ischemic necrosis of femoral head; Caused the damaged patient of numerous bones, therefore, damaged a kind of serious disease and the social problem that influences the health of people life that become of bone.Perfect along with the raising of the aging of China's population, health of people consciousness and the consuming capacity and national medical system, the bone renovating material market demand of China sharply increases.From the body bone is ideal bone impairment renovation material, has increased new wound and the misery of patient but get the bone process, and originate limited, be difficult for mouldingly, be difficult to satisfy the requirement that big section bone is transplanted, more be unwell to juvenile patient; And there are the risk of immunological rejection, propagation source of disease and initiation operation sequela in allograph bone and bone xenograft, add the restriction of donor source, and the obstacle of medical ethics aspect, have limited it and have used clinically.
In order to satisfy clinical demand, in the last few years, the existing synthetic bone reparing biological material of kinds of artificial obtained extensive use clinically, and wherein the injectable bone repair materials is wherein most important one type.At first, the injectable bone repair materials can implant through the mode of injection, wound is little, has eliminated the relevant many complication of traditional bone transplant operation; Secondly, this bone material possesses good plasticity, the timbering material of the porous microstructure of in-situ solidifying, and formation in vivo, performance bone conduction effect; At last, material is slowly degraded in the back that implants, and is followed growing into of the new bone of host.In the last few years, along with the development of less invasive techniques, the injection aquagel material received people's attention gradually, its research and use increasingly extensive.Injection aquagel is strong except possessing plasticity, can fill various difform damaged and in-situ solidifyings, and the wound that causes is little; Can reduce outside patient's the advantages such as misery; Hydrogel is the bionical characteristic of type of possessing extracellular matrix also, and the three-dimensional aquation network structure of height helps the migration and the growth of cell in tissue regeneration and the wound healing process; The curing molding mild condition is particularly suitable for the carrier as protein and cell.Wherein, More and more receive the attention of researcher through the injectable type gel of temperature sensitive type phase transformation molding; Especially lower critical solution temperature (Lower Critical Solution Temperature, LCST) a little less than the hydrogel of body temperature, main cause is that this gellike is at room temperature for liquid; Under body temperature, just can solidify rapidly, condition of cure and simple to operate, be very suitable for being written into of cell or protein factor.
In the process of various orthopaedic disease treatments, need be used some medicines or the factor, but these medicines or factor half-life are short, very fast diluted and metabolism during topical application, its bioavailability is extremely low; Especially the medicine of protides such as some somatomedin, hormone, production cost is expensive, lets patient be difficult to bear, and has restricted the market expansion and the application of this series products.But prior art can't provide efficiently at present, the slow-released system of safety, Wicresoft.
Summary of the invention
Technical problem to be solved by this invention is: provide a kind of temperature sensitive type of Minimally Invasive Surgery that is applicable to carry the injectable sustained-release material of microsphere, to solve the technical barrier that in the prior art a spot of pharmaceutical agent is carried out safe and effective release.
For solving the problems of the technologies described above, the present invention adopts following technical scheme: a kind of medical slow release material mainly is to be mixed in the mixture that forms in the temperature sensitive type polymer solution by sustained-release micro-spheres; Said sustained-release micro-spheres is loaded with medicine, and forms the alternately microsphere of the pulsed slow release of release of identical or different medicine by the microsphere of different deenergized periods according to certain mixed together.
The mass concentration scope of said temperature sensitive type poly compound solution chamber relaxing the bowels with purgatives of warm nature is 1 ~ 20%, and this solution forms solid gel in the internal energy rapid curing of 31 ~ 36 ℃ scope; Said sustained-release micro-spheres mass and size specific concentration in amalgam is 0.01 ~ 10%.Preferably, said temperature sensitive type polymer solution is to be formed to dissolving fully by normal saline or phosphate buffer dissolving temperature sensitive type poly compound.Said temperature sensitive type poly compound is preferable over a kind of in poly-N-isopropyl acrylamide PNIPAAm, the grafted Polyethylene Glycol of PNIPAAm (PNIPAAm-g-PEG), the grafted chitosan of PNIPAAm (PNIPAAm-g-Ch), the grafted collagen of PNIPAAm (PNIPAAm-g-Col), the grafted hyaluronic acid of PNIPAAm (PNIPAAm-g-HA), the grafted chondroitin sulfate of PNIPAAm (PNIPAAm-g-CS), the grafted sodium alginate of the PNIPAAm temperature sensitive type polymer such as (PNIPAAm-g-Alg) and several kinds, and the molecular weight ranges of these polymer is at 5 ~ 50KDa.
Contained medicine is antibacterials and/or somatomedin; The content of medicine in microsphere accounts for 0.001 ~ 5% of microsphere gross mass; Said sustained-release micro-spheres mass and size specific concentration in mixture is 0.01 ~ 10%.Said antibacterials are selected from one or more in streptomycin, cefradine, gentamycin, acetylspiramycin, erythromycin, albomycin, amoxicillin, oxytetracycline, kanamycin, penicillin, metronidazole, danshensu, neomycin, ribostamycin, tetracycline, vancomycin, the azithromycin.Said somatomedin is selected from one or more in rhBMP-2, rhBMP-7, insulin-like growth factor-i, transforming growth factor-beta, VEGF, basic fibroblast growth factor, platelet derived growth factor or the active polypeptide etc.
Said microsphere raw material is selected from one or more in polylactic acid, polyglycolic acid or the lactic acid-ethanol copolymer, and contains lactic acid-ethanol copolymer at least; The molecular weight ranges of microsphere raw material is 1~200KDa.The lactic acid-ethanol copolymer molecular weight is 1 ~ 3KDa in microsphere, and accounts for the microsphere gross mass and reach 30% when above, and microsphere can be regulated in 1 ~ 2 week deenergized period.When the lactic acid-ethanol copolymer molecular weight greater than 3 KDa and less than 10KDa, and account for the microsphere gross mass and reach more than 50%, can regulate in 3 ~ 6 weeks deenergized period.When the lactic acid-ethanol copolymer molecular weight greater than 10KDa and less than 200 KDa, and the gross mass that accounts for microsphere is less than 50%, can regulate in 7 ~ 12 weeks deenergized period.
Said pulsed discharges microsphere and comprises that be 5 kinds of microspheres in 1 week, 2 weeks, 4 weeks, 8 weeks and 12 weeks deenergized period, and mass ratio is (1 ~ 10): (1 ~ 10): (1 ~ 10): (1 ~ 10): (1 ~ 10); Be that the contained medicine of microsphere in 1 week and 2 weeks is antibacterials deenergized period; Be that the contained medicine of microsphere in 4 weeks, 8 weeks and 12 weeks is a somatomedin deenergized period.
Medical slow release material of the present invention, it is an injection type.
Medical slow release preparation methods of the present invention may further comprise the steps:
1) pulsed of preparation medicine carrying thing discharges microsphere;
2) preparation temperature sensitive type polymer solution;
3) mixing: the medicine carrying pulsed of step 1) preparation is discharged microsphere and step 2) solution of preparation mixes, stirs, prepares the mixed solution of microsphere and polymer.
Further comprise step 4): solidifying, specifically is that the mixed solution of step 3 preparation is packed in the syringe, is expelled to therapentic part, and solidifies rapidly.
The technology of this step 1) further comprises:
At first with difference microsphere raw material and the said medicine difference wiring solution-forming of deenergized periods; Wherein the microsphere raw material is selected from one or more in polylactic acid, polyglycolic acid or the lactic acid-ethanol copolymer; And contain lactic acid-ethanol copolymer at least, the molecular weight ranges of microsphere raw material is 1~200KDa;
Produce the microsphere drop through the nebulizer atomizing; Obtain the different microsphere that is loaded with medicine deenergized period behind the volatile dry respectively: wherein; When the lactic acid-ethanol copolymer molecular weight is 1 ~ 3KDa, and accounts for the microsphere gross mass and reach 30% when above, obtain the microsphere that to regulate in 1 ~ 2 week deenergized period; When the lactic acid-ethanol copolymer molecular weight greater than 3 KDa and less than 10KDa, and account for the microsphere gross mass and reach more than 50%, obtain the microspheres that can regulate in 3 ~ 6 weeks deenergized period; When the lactic acid-ethanol copolymer molecular weight greater than 10KDa and less than 200KDa, and the gross mass that accounts for microsphere is less than 50%, obtains the microsphere that deenergized period can adjusting in 7 ~ 12 weeks;
Then, with the microspheres of different deenergized periods together, can form the microsphere of the pulsed slow release that identical or different medicine alternately discharges according to certain mixed.
Beneficial effect of the present invention is following: the present invention is on the basis of sustained-release micro-spheres and temperature sensitive type injectable gel, and a kind of temperature sensitive type of Minimally Invasive Surgery that is applicable to that makes carries the injectable sustained-release material of microsphere.It has pulse slow-releasing function, can realize the sustained release of different pharmaceutical in different time sections; Plasticity is good, degradable, can promote characteristics such as the damaged regeneration of bone, good stability, safety height.The shape and size bone that can be used for filling various complicacy is damaged, and the solidification temperature of material is in a liquid state under the room temperature between 31 ~ 36 ℃, can be at self-curing under the body temperature, and hardening time was at 3 ~ 15 minutes; Can keep due shape in defect repair in cycle, possess excellent biological compatibility simultaneously, can promote the regeneration of bone.
Further; The microsphere that the present invention will be carried the factor or medicine is dispersed in the solution of temperature sensitive type injectable carrier uniformly, be expelled to therapentic part after, material solidifies rapidly; Slowly degraded discharges the medicine or the factor then; With the elongation factor active time in vivo, improve factor rate of release and the controllability of deenergized period, realized identical or different medicine in the precalculated position, the alternately combination of release and minimally-invasive treatment means of different time sections.
The specific embodiment
In the process of various orthopaedic disease treatments, some medicines or the factor (like hBMP-2 or-7, i.e. rhBMP-2 or rhBMP-7) are very favourable to bone reparative regeneration and antibacterial therapy.
And microsphere is a kind of good slow release carrier, if can the degraded through microsphere of medicine or the factor progressively be discharged the safe and effective input that just can realize the medicine or the factor.But microsphere is difficult to be fixed on therapentic part, runs off easily and moves, and therefore also needs other materials to make it be fixed on therapentic part as carrier.In addition, microsphere is in case degraded is broken, and the medicine or the factor will discharge rapidly.
The present invention provides a kind of medical slow release material, mainly is to be mixed in the mixture that forms in the temperature sensitive type polymer solution by sustained-release micro-spheres.Said sustained-release micro-spheres is loaded with medicine, and forms the alternately microsphere of the pulsed slow release of release of identical or different medicine by the microsphere of different deenergized periods according to certain mixed together.The microsphere mixed proportion of different deenergized periods can be regulated and selects according to concrete needs, and for example, the mass ratio that the microsphere of different deenergized periods mixes each other is (1 ~ 10): (1 ~ 10).
The mass concentration scope of said temperature sensitive type poly compound solution chamber relaxing the bowels with purgatives of warm nature is 1 ~ 20%, and this solution forms solid gel in the internal energy rapid curing of 31 ~ 36 ℃ scope; Said sustained-release micro-spheres mass and size specific concentration in amalgam is 0.01 ~ 10%.Preferably, said temperature sensitive type polymer solution is to be formed to dissolving fully by normal saline or phosphate buffer dissolving temperature sensitive type poly compound.
Contained medicine is antibacterials and/or somatomedin; The content of medicine in microsphere accounts for 0.001 ~ 5% of microsphere gross mass; Said sustained-release micro-spheres mass and size specific concentration in mixture is 0.01 ~ 10%.Said antibacterials are selected from one or more in streptomycin, cefradine, gentamycin, acetylspiramycin, erythromycin, albomycin, amoxicillin, oxytetracycline, kanamycin, penicillin, metronidazole, danshensu, neomycin, ribostamycin, tetracycline, vancomycin, the azithromycin.Said somatomedin is selected from one or more in rhBMP-2, rhBMP-7, insulin-like growth factor-i, transforming growth factor-beta, VEGF, basic fibroblast growth factor, platelet derived growth factor or the active polypeptide etc.
Said microsphere raw material is selected from one or more in polylactic acid, polyglycolic acid or the lactic acid-ethanol copolymer, and contains lactic acid-ethanol copolymer at least; The molecular weight ranges of microsphere raw material is 1~200KDa.The lactic acid-ethanol copolymer molecular weight is 1 ~ 3 KDa in microsphere, and accounts for the microsphere gross mass and reach 30% when above, and microsphere can be regulated in 1 ~ 2 week deenergized period.When the lactic acid-ethanol copolymer molecular weight greater than 3KDa and less than 10KDa, and account for the microsphere gross mass and reach more than 50%, can regulate in 3 ~ 6 weeks deenergized period.When the lactic acid-ethanol copolymer molecular weight greater than 10KDa and less than 200KDa, and the gross mass that accounts for microsphere is less than 50%, can regulate in 7 ~ 12 weeks deenergized period.
The present invention combines the technology of preparing of temperature sensitive type injectable gel with the pulsed sustained-release micro-spheres, at first prepares the microsphere of pulsed slow release, with microsphere and pulsed microspheres solution mix homogeneously; The microsphere that is about to year factor or medicine is dispersed in the solution of temperature sensitive type injectable carrier uniformly; After being expelled to therapentic part, material solidifies rapidly, and slowly degraded discharges the medicine or the factor then; With elongation factor action time in vivo, improve factor rate of release and the controllability of deenergized period.
Temperature sensitive type of the present invention carries the injectable medical slow release preparation methods of microsphere, specifically mainly may further comprise the steps:
1) microsphere of preparation pulsed slow release ": prepare the different microsphere that is loaded with the medicine or factor deenergized period earlier; with the microspheres of different deenergized periods together, can form " microsphere of pulsed slow release " that identical or different medicine alternately discharges then according to certain mixed;
2) preparation temperature sensitive type polymer solution: at room temperature, adopt normal saline or phosphate buffer dissolving temperature sensitive type poly compound to dissolving fully;
3) mix: the mixed solution that " microsphere of pulsed slow release " and the solution of step 2 preparation of step 1 preparation is mixed, stirs, prepares microsphere and polymer.
This method for preparing can comprise step 4 further: solidifying, specifically is the mixed solution of step 3 preparation is packed in the syringe (syringe can clinical as required needs be designed to different syringe needles); Be expelled to therapentic part, also solidify rapidly.
In said the 1st step, according to the disclosed preparation bone growth factor-carrying microspheres technology of Chinese patent publication number CN101816634A.The microsphere raw material is selected from: polylactic acid (PLA), polyglycolic acid (PGA) or lactic acid-ethanol copolymer (PLGA).With microsphere raw material and some antibacterials or factor wiring solution-forming, produce the microsphere drop through the nebulizer atomizing, volatile dry obtains solid-state-microspherical.The method that medicine adds is identical with the method that protein factor adds.But, the molecular weight and the proportion of raw materials of polylactic acid (PLA), polyglycolic acid (PGA), lactic acid-ethanol copolymer (PLGA) in the microsphere raw material are adjusted and controlled in order to prepare the microsphere of different deenergized periods.At first, the molecular weight range of choice is 1~200KDa, and every kind of microsphere all contains PLGA raw material at least.When the PLGA molecular weight less than 3 KDa, and account for the microsphere gross mass and reach more than 30%, can regulate in 1 ~ 2 week deenergized period; When the PLGA molecular weight greater than 3KDa and less than 10 KDa, and account for the microsphere gross mass and reach more than 50%, can regulate in 3 ~ 6 weeks deenergized period; When the PLGA molecular weight greater than 10KDa and less than 200KDa, and account for the microsphere gross mass less than 50%, can regulate in 7 ~ 12 weeks deenergized period.More specifically, for example, be that the microsphere proportioning raw materials in 1 week is exactly that to adopt molecular weight be that PLGA and the molecular weight of 2 KDa is the PLA of 10KDa deenergized period, and PLGA quality branch accounts for 60% of microsphere gross mass, and the microsphere of preparing as stated above its deenergized period was 1 week.In like manner, according to said method can prepare the microsphere of various different deenergized periods respectively.
In specific embodiment, " pulsed release microsphere " is made up of 5 kinds of microspheres that are 1 week, 2 weeks, 4 weeks, 8 weeks and 12 weeks deenergized period, and mass ratio is (1 ~ 10): (1 ~ 10): (1 ~ 10): (1 ~ 10): (1 ~ 10); And medicine contained in the microsphere can be selected according to actual needs, and drug main will be selected from one of antibacterials and somatomedin the two or the two, and the content in microsphere accounts for 0.001 ~ 5% of microsphere gross mass.Antibacterials mainly are selected from one or more in streptomycin, cefradine, gentamycin, acetylspiramycin, erythromycin, albomycin, amoxicillin, oxytetracycline, kanamycin, penicillin, metronidazole, danshensu, neomycin, ribostamycin, tetracycline, vancomycin, the azithromycin.Somatomedin is selected from one or more in rhBMP-2, rhBMP-7, insulin-like growth factor-i (IGF-1), transforming growth factor-beta (TGF-β), VEGF (VEGF), basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF) or the active polypeptide etc.Be appreciated that the contained medicine of microsphere also can be according to concrete needs, select other medicine or factor of being suitable for, and be not limited to carry antibacterials and somatomedin.
In said the 2nd step; The temperature sensitive type poly compound is selected from a kind of in poly-N-isopropyl acrylamide (PNIPAAm), the grafted Polyethylene Glycol of PNIPAAm (PNIPAAm-g-PEG), the grafted chitosan of PNIPAAm (PNIPAAm-g-Ch), the grafted collagen of PNIPAAm (PNIPAAm-g-Col), the grafted hyaluronic acid of PNIPAAm (PNIPAAm-g-HA), the grafted chondroitin sulfate of PNIPAAm (PNIPAAm-g-CS), the grafted sodium alginate of the PNIPAAm temperature sensitive type polymer such as (PNIPAAm-g-Alg) and several kinds; The scope of the molecular weight of these polymer is at 5 ~ 50KDa; Mass volume ratio concentration range at the temperature sensitive type polymer solution under the room temperature is 1 ~ 20% (W/V); Its aqueous solution solidifies rapidly in 31 ~ 36 ℃ scope, forms solid gel.
In said the 3rd step, " pulsed release microsphere " mass volume ratio concentration range in solution is 0.01 ~ 10% (W/V).
In the described step 4,, the material direct injection fills and the damaged filling of various irregular bone but being used for the formed cavity of osteoporosis; When material is used for Subperiosteum ossification, need the certain normal saline of injection that the periosteum and the cortical bone of predetermined position are peeled off, inject this material then, when this method was used to raise alveolar bone bone amount, with respect to traditional bone grafting operation, wound was little, cost is low.
The microsphere that the present invention will be carried the factor or medicine is dispersed in the solution of temperature sensitive type injectable carrier uniformly; After being expelled to therapentic part; Material solidifies rapidly, and slowly degraded discharges the medicine or the factor then, with the elongation factor active time in vivo; Improve factor rate of release and the controllability of deenergized period, realized identical or different medicine in the precalculated position, the alternately combination of release and minimally-invasive treatment means of different time sections.
Further specify bone renovating material of the present invention below in conjunction with embodiment, but not as restriction of the present invention.
Embodiment 1
Temperature sensitive type carries the preparation and the method for using of the injectable sustained-release material of microsphere, specifically may further comprise the steps:
1) prepares 5 kinds of microspheres that be 1 week, 2 weeks, 4 weeks, 8 weeks and 12 weeks deenergized period; Then respectively together with the mixed of 1:1:1:1:1; Form " microsphere of pulsed slow release " that alternately discharge; Be that the contained medicine of microsphere in 1 week and 2 weeks is gentamycins deenergized period, accounts for 3% of microsphere gross mass, can play the effect of anti-inflammation in wound site; Be 3 kinds of contained pharmaceutical agent rhBMP-2 of microsphere in 4 weeks, 8 weeks and 12 weeks deenergized period, accounts for 0.005% of microsphere gross mass.
2) at room temperature, adopt phosphate buffer dissolving PNIPAAm-g-Ch,, prepare 5% PNIPAAm-g-Ch solution to dissolving fully;
3) " microsphere of pulsed slow release " of step 1 preparation and the solution that step 2 prepares are mixed, stir, prepare the mixed solution of microsphere and polymer, wherein the content of microsphere is 1% (W/V);
4) mixed solution of step 3 preparation is packed in the syringe by (syringe needle that syringe can be suitable for according to clinical needs design);
5) be expelled to predetermined therapentic part, can solidify rapidly.
Embodiment 2
Temperature sensitive type carries the preparation and the method for using of the injectable sustained-release material of microsphere, specifically may further comprise the steps:
1) prepares 5 kinds of microspheres that be 1 week, 2 weeks, 4 weeks, 8 weeks and 12 weeks deenergized period; Then respectively together with the mixed of 2:1:1:1:1; Form " microsphere of pulsed slow release " that alternately discharge; Be that the contained medicine of microsphere in 1 week and 2 weeks is respectively vancomycin and gentamycin deenergized period, accounts for 3% of microsphere gross mass respectively, can play the effect of anti-inflammation at the damaged severe infections of bone position; Be 3 kinds of contained pharmaceutical agent rhBMP-2 of microsphere in 4 weeks, 8 weeks and 12 weeks deenergized period, accounts for 0.008% of microsphere gross mass.
2) at room temperature, adopt phosphate buffer dissolving PNIPAAm-g-HA,, prepare 10% PNIPAAm-g-HA solution to dissolving fully;
3) " microsphere of pulsed slow release " of step 1 preparation and the solution that step 2 prepares are mixed, stir, prepare the mixed solution of microsphere and polymer, wherein the content of microsphere is 0.8% (W/V);
4) mixed solution of step 3 preparation is packed in the syringe (syringe also can the clinical as required syringe needle that needs design special);
5) be expelled to predetermined therapentic part, can solidify rapidly.
The material that above-mentioned embodiment is prepared is used for alveolar bone when raising, and can carefully be expelled to subperiosteum with biological saline earlier, and periosteum and cortical bone are peeled off; Form certain clearance; Inject material into this position then, material can solidify rapidly under the body temperature effect, after 2 months; The bone of alveolar bone increases, and raises 2 ~ 3mm.When this material is used for the damaged filling of irregular bone, be injected directly into damaged in, can be with whole damaged filling, material can solidify rapidly under the body temperature effect, promotes the damaged reparation of bone.
In a word, above instance utilizes sustained-release micro-spheres and temperature sensitive type injectable gel technology, and a kind of temperature sensitive type of Minimally Invasive Surgery that is applicable to that makes carries the injectable sustained-release material of microsphere.It has pulse slow-releasing function, can realize the sustained release of different pharmaceutical in different time sections; Plasticity is good, degradable, can promote characteristics such as the damaged regeneration of bone, good stability, safety height.Its shape and size bone that can be used for filling various complicacy is damaged, and the solidification temperature of material is in a liquid state under the room temperature between 31 ~ 36 ℃, can be at self-curing under the body temperature, and hardening time was at 3 ~ 15 minutes; Can keep due shape in defect repair in cycle, possess excellent biological compatibility simultaneously, can promote the regeneration of bone.

Claims (10)

1. a medical slow release material mainly is to be mixed in the mixture that forms in the temperature sensitive type polymer solution by sustained-release micro-spheres; Said sustained-release micro-spheres is loaded with medicine, and forms the alternately microsphere of the pulsed slow release of release of identical or different medicine by the microsphere of different deenergized periods according to certain mixed together.
2. medical slow release material as claimed in claim 1; It is characterized in that: said temperature sensitive type polymer solution is a kind of injectable carrier solution; Mass concentration scope at room temperature is 1 ~ 20%, and this solution solidifies rapidly in 31 ~ 36 ℃ scope ability, forms solid gel; Said temperature sensitive type polymer solution is to be formed to dissolving fully by normal saline or phosphate buffer dissolving temperature sensitive type poly compound; Said temperature sensitive type poly compound is selected from a kind of in poly-N-isopropyl acrylamide, the grafted Polyethylene Glycol of poly-N-isopropyl acrylamide, the grafted chitosan of poly-N-isopropyl acrylamide, the grafted collagen of poly-N-isopropyl acrylamide, the grafted hyaluronic acid of poly-N-isopropyl acrylamide, the grafted chondroitin sulfate of poly-N-isopropyl acrylamide, the grafted sodium alginate of poly-N-isopropyl acrylamide and several kinds, and the molecular weight ranges of these polymer is at 0.5 ~ 5KDa.
3. medical slow release material as claimed in claim 1 is characterized in that: contained medicine is antibacterials and/or somatomedin; The content of medicine in microsphere accounts for 0.001% ~ 5% of microsphere gross mass; Said sustained-release micro-spheres mass and size specific concentration in mixture is 0.01 ~ 10%.
4. medical slow release material as claimed in claim 3 is characterized in that: said antibacterials are selected from one or more in streptomycin, cefradine, gentamycin, acetylspiramycin, erythromycin, albomycin, amoxicillin, oxytetracycline, kanamycin, penicillin, metronidazole, danshensu, neomycin, ribostamycin, tetracycline, vancomycin, the azithromycin; Said somatomedin is selected from one or more in rhBMP-2, rhBMP-7, insulin-like growth factor-i, transforming growth factor-beta, VEGF, basic fibroblast growth factor, platelet derived growth factor or the active polypeptide etc.
5. medical slow release material as claimed in claim 1 is characterized in that: the microsphere raw material is selected from one or more in polylactic acid, polyglycolic acid or the lactic acid-ethanol copolymer, and contains lactic acid-ethanol copolymer at least; The molecular weight ranges of microsphere raw material is 1~200KDa; The lactic acid-ethanol copolymer molecular weight is 1 ~ 3KDa in microsphere, and accounts for the microsphere gross mass and reach 30% when above, and microsphere can be regulated in 1 ~ 2 week deenergized period; When the lactic acid-ethanol copolymer molecular weight greater than 3 KDa and less than 10 KDa, and account for the microsphere gross mass and reach more than 50%, can regulate in 3 ~ 6 weeks deenergized period; When the lactic acid-ethanol copolymer molecular weight greater than 10KDa and less than 200 KDa, and the gross mass that accounts for microsphere is less than 50%, can regulate in 7 ~ 12 weeks deenergized period.
6. medical slow release material as claimed in claim 1; It is characterized in that: said pulsed discharges microsphere and comprises that be 5 kinds of microspheres in 1 week, 2 weeks, 4 weeks, 8 weeks and 12 weeks deenergized period, and mass ratio is (1 ~ 10): (1 ~ 10): (1 ~ 10): (1 ~ 10): (1 ~ 10); Be that the contained medicine of microsphere in 1 week and 2 weeks is antibacterials deenergized period; Be that the contained medicine of microsphere in 4 weeks, 8 weeks and 12 weeks is a somatomedin deenergized period.
7. like each described medical slow release material among the claim 1-6, it is the injection-type dosage form.
8. like each described medical slow release material among the claim 1-7, its preparation method may further comprise the steps:
1) pulsed of preparation medicine carrying thing discharges microsphere;
2) preparation temperature sensitive type polymer solution;
3) mixing: the medicine carrying pulsed of step 1) preparation is discharged microsphere and step 2) solution of preparation mixes, stirs, prepares the mixed solution of microsphere and polymer.
9. medical slow release preparation methods as claimed in claim 8 is characterized in that: further comprise step 4): solidifying, specifically is that the mixed solution of step 3 preparation is packed in the syringe, is expelled to therapentic part, and solidifies rapidly.
10. medical slow release preparation methods as claimed in claim 8 is characterized in that: the technology of said step 1) further comprises:
At first prepare the microsphere raw material of different deenergized periods and respectively with said medicine wiring solution-forming; Wherein the microsphere raw material is selected from one or more in polylactic acid, polyglycolic acid or the lactic acid-ethanol copolymer; And contain lactic acid-ethanol copolymer at least, the molecular weight ranges of microsphere raw material is 1~200KDa;
Produce the microsphere drop through the nebulizer atomizing; Obtain the different microsphere that is loaded with medicine deenergized period behind the volatile dry respectively: wherein; When the lactic acid-ethanol copolymer molecular weight is 1 ~ 3KDa, and accounts for the microsphere gross mass and reach 30% when above, obtain the microsphere that to regulate in 1 ~ 2 week deenergized period; When the lactic acid-ethanol copolymer molecular weight greater than 3 KDa and less than 10KDa, and account for the microsphere gross mass and reach more than 50%, obtain the microspheres that can regulate in 3 ~ 6 weeks deenergized period; When the lactic acid-ethanol copolymer molecular weight greater than 10KDa and less than 200KDa, and the gross mass that accounts for microsphere is less than 50%, obtains the microsphere that deenergized period can adjusting in 7 ~ 12 weeks;
Then, with the microspheres of different deenergized periods together, can form the microsphere of the pulsed slow release that identical or different medicine alternately discharges according to certain mixed.
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