CN102551927A - Embedded type graded drug release three-dimensional rack and preparation method thereof - Google Patents
Embedded type graded drug release three-dimensional rack and preparation method thereof Download PDFInfo
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- CN102551927A CN102551927A CN2011103861672A CN201110386167A CN102551927A CN 102551927 A CN102551927 A CN 102551927A CN 2011103861672 A CN2011103861672 A CN 2011103861672A CN 201110386167 A CN201110386167 A CN 201110386167A CN 102551927 A CN102551927 A CN 102551927A
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Abstract
The invention relates to an embedded type graded drug release three-dimensional rack and a preparation method of the rack. A rack inner-layer shaped body with high porosity is wrapped by a rack outer-layer shaped body with low porosity to form an embedded bi-layer structural rack. The classes of drugs carried by the inner layer and the outer layer of the rack are different. The graded distribution of drug classes and the graded distribution of rack microstructures are realized in the same rack, thereby obtaining the embedded two-graded drug release artificial rack. The preparation process of the multi-graded drug release rack comprises the three steps, namely, (1) freeze-forming of the drug carrying rack inner-layer shaped body; (2) freeze-forming of the drug carrying rack outer-layer wrapping shaped body; and (3) drying the embedded rack in a low temperature and vacuum. In the embedded multi-layer rack prepared in the invention, the content of calcium phosphate and the drug classes in a composite slurry used in each layer of the rack are respectively different; the degradation rate of the rack is related to the solid content of solid phase; as the solid content of the slurry is different, the degradation rate of the prepared rack is different; and the release rate of the drug is influenced by the rack degradation.
Description
Technical field
The present invention relates to a kind of three-dimensional artificial bone scaffold of field of tissue engineering technology and preparation method thereof, particularly a kind of embedded classification release degradable three-dimensional rack and preparation method thereof.
Background technology
The defect repair of bone, particularly big section bone reparation are exactly the research focus of clinical medical thorny problem and field of tissue engineering technology all the time.At present, transplanting in the body is the bone restorative procedure of using always, mainly contains: autologous bone transplanting, but material is limited, and it is limited to originate; Homogeneous allogenic bone transplantation, not only material source is limited and the high risk that infects arranged.Therefore, artificial bone scaffold has caused field of tissue engineering technology correlational study personnel's extensive concern, and begin to design, preparation and using artificial bone support as the three-dimensional of tissue culture and be used for tissue repair.
For avoiding second operation, generally select the Biodegradable material of good biocompatibility to prepare support.Common degradation material has two big types: organic Biodegradable material, like polylactic acid PLA, lactic-co-glycolic acid PLGA etc.; Inorganic Biodegradable material is like hydroxyapatite, calcium phosphate etc.Wherein, the contact surface compatibility of organic Biodegradable material and body is poor, and it is acid that the hydrolyzate of embedded material is, and is prone to cause the local inflammation reaction, and it is newborn to suppress tissue.The good hydrophilic property of inorganic Biodegradable material, its hydrolyzate is soluble in body fluid, and reaction can not cause inflammation.Therefore, laboratory often selects for use inorganic Biodegradable material to prepare three-dimensional rack.Calcium phosphate is kind of a common inorganic Biodegradable material; Chemical constituent is consistent with the main component of the inorganic salt of bone; Biocompatibility and bone conductibility are good, and the hydrophilic of material surface is better than organic Biodegradable material, help the adhesion of cell and the propagation of irritation cell.The hydrolyzate of calcium phosphate is phosphate anion and the calcium ion that is soluble in body fluid, and reaction can not cause inflammation.
The stem cell that the bone reconstruction starts from support after implanting is raised and breeds; Then, stem cell is divided into skeletonization and hematopoietic cell under the stimulation of the bio signal factor in vivo; The deposition of a large amount of osteocyte, hematopoietic cell are invaded the inner capillary tube that forms of three-dimensional rack.Wherein, blood vessel intrusion three-dimensional rack is the successful sign of bone reparation.In the osteanagenesis process, need the bio signal factor to stimulate cellular proliferation, the inducing cell differentiation.Usually, the concentration of the bio signal factor in body fluid of body defect is low excessively, can not satisfy the requirement to drug level of process of reconstruction.Therefore, need use external pharmaceutical agent, auxiliary treatment.
It is required that common oral dispenser, intravenous injection dispenser need the strong dose thing could satisfy reparation, and medicine uses this type medicine can produce toxic and side effects usually with other histoorgans in the circulation arrival body of body fluid and blood in a large number.Therefore, common application method medicine effectively utilizes interest rate low, expense height and toxic side effect.Drug release carrier is to be purpose with the targeting dispenser, and the bioavailability of maximization medicine is optimized the curative effect of medicine, reduces the toxic and side effects of medicine to organism.As far back as five sixties of 19th-century; Just having research worker that drug release is applied to the bone defect repair rebuilds; Obtain effective drug level keeping the requirement of normal structure reparation through the targeting dispenser, reduce drug waste and reduce the toxic and side effects of organism drug dose.
Medicine carrying mode common in the three-dimensional rack has: (1) uniform mixing type: base material and medicine uniform mixing postforming support.(2) drip absorbent-type: with the solvent of uniform mixing medicine, be written into support with the mode that drips absorption, medicine is distributed in rack surface for several kinds.(3) soak type: support is immersed in the solvent of uniform mixing medicine, makes medicine along with solvent penetrates into internal stent, etc.Uniform mixing type medicine carrying, support medicine carrying kind is single, and the inhomogeneous and gradient that can't realize medicine of drug distribution is written into and distributes.Soak type or drip the absorbent-type medicine carrying, support implant that the medicine at initial stage is prominent to be released phenomenon and can lose high amount of drug, and residual drug dosage can not be kept normally carrying out of follow-up reparation.The common drug of bone defect repair belongs to polypeptide protein class and ammonia compounds of group more, in soda acid, high temperature and high light environment, is prone to decompose, and needs storage and operation in the environment of low-temperature dark.
Summary of the invention
The objective of the invention is to defective, a kind of embedded classification release three-dimensional rack and preparation method thereof is provided to the prior art existence.Adhesion, propagation and differentiation that this classification release three-dimensional rack is a cell provide the place, and most important is that the targeting classification discharges medicine.Through the degraded of control support and the drug loading of support, make medicine spread, dissolve and discharge with the degraded of support, for each stage of bone reparation provides effective drug level, improve the effective rate of utilization of medicine, reduce the toxic and side effects of medicine to organism.
For achieving the above object; Design of the present invention is: design a kind of embedded classification release three-dimensional rack structure; And use the cold drying embedded support that has been shaped: will mix in the medicine calcium phosphate slurry injection model, successively, the cold drying Embedded carried stent that is shaped step by step.Wherein, the slurry concentration that injects when being shaped each layer support is different, has made the support of Concentraton gradient; Uniform mixing medicine in the slurry of each layer support, the Gradient distribution of formation medicine.
The present invention includes two parts: the preparation of embedded classification release degradable three-dimensional rack structure Design and support.The contemplated methods of supporting structure design is: use the support internal layer of the high freezing shaping of slurry parcel low-solid content slurry of solid content, the secondary cold drying forms the support of embedded double-deck structure.Supporting structure distributes shown in accompanying drawing 1; The internal layer solid content of slurry is lower than outer solid content of slurry; Therefore the porosity of lyophilization after-poppet internal layer is higher than the outer field porosity of support; The drug dose that evenly is written into the support internal layer is higher than outer drug dose, realizes that unitary system medium-height trestle microstructure and drug level distribute in gradient, obtain embedded two-stage medicine carrying three-dimensional rack.Embedded classification release biomimetic scaffolds structure of the present invention is prone to expand to multistage embedded carried stent, three grades of embedded supporting structure scattergrams shown in accompanying drawing 2.The mould that uses among the present invention (accompanying drawing 3: small size profile minus and accompanying drawing 4: large scale profile minus); Use the physical model (accompanying drawing 5) that this embedded thought obtains support: the arc wall profile of small size minus embeds in the large scale profile minus, and the support that two kinds of minus are formed separately is different two cylinders greatly once of diameter height.
The laboratory compound method of the calcium phosphate slurry of preparation support: at first, grinder grinds calcium phosphate; Then, the material of the grinding acquisition calcium phosphate powder that sieves; At last, powder and distilled water uniform mixing are made the calcium phosphate slurry.Calcium phosphate content among the present invention in the internal layer support slurry is 10% ± 0.5%, and surplus is a distilled water; The calcium phosphate content of outer support slurry is 20% ± 0.5%, and surplus is a distilled water.Before the support preparation, medicine is evenly sneaked into respectively in the slurry, promptly obtain mixing the calcium orthophosphate base slurry of medicine.
The preparation of support divides three phases: phase I, the even medicine carrying shape of the internal layer base of the embedded classification release three-dimensional rack that is shaped.At first, medicine D1 is evenly sneaked in the slurry of calcium phosphate content 10% ± 0.5%, will mix the medicine slurry and inject the small size minus; Then, in-10 ℃ ± 0.5 ℃ environment, remove mould behind precooling 12h ± 0.5h, evenly be written into the support internal layer shape base (accompanying drawing 6) of medicine D1.Second stage, the skin parcel shape base of the embedded classification release three-dimensional rack that is shaped.At first, the internal layer carried stent shape base in the phase I is put into large scale minus (accompanying drawing 7); Then the slurry with uniform mixing medicine D2 injects minus, and medicine D2 is different with the kind of medicine D1, and calcium phosphate content is 20% ± 0.5% in the slurry; De-bubble in-10 ℃ ± 0.5 ℃ vacuum environment is then removed mould behind precooling 12h ± 0.5h in-20 ℃ ± 0.5 ℃ environment, evenly be loaded with the embedded release three-dimensional rack shape base of medicine D1 and medicine D2.Phase III, embedded two-stage release three-dimensional rack shape base is put into-30 ℃ ± 0.5 ℃ vacuum environment, finish-drying 36h ± 0.5h obtains the biodegradable calcium orthophosphate base three-dimensional rack of embedded two-stage release (Fig. 8).
The diffusion of medicine, dissolving and release receive scaffold degradation speed, factor affecting such as interior microscopic pattern and medicine carrying concentration.The internal stent microstructure mainly receives the influence of substrate slurry solid content and precooling temperature two aspects, and the brace aperture rate that the high solids content slurry is shaped is lower than the support that the low-solid content slurry is shaped.The support of the freezing shaping of high pre-freeze temperature, its inner aperture is greater than the freezing shaping internal stent of low pre-freeze temperature aperture.The degradation rate of support is relevant with substrate slurry solid content, and its degradation rate of the support that different solid content slurries are shaped is different.Therefore, the embedded hierarchy release three-dimensional rack for preparing among the present invention: through the technological parameter of control support preparation, the amount of being written into of medicine between substrate slurry solid content and shelf layer and the layer is controlled three-dimensional carried stent classification and is discharged medicine.
According to above-mentioned design, technical scheme of the present invention is following:
A kind of embedded classification release three-dimensional rack is made up of internal layer shape base (1) and outer field parcel shape base (2), it is characterized in that:
1), internal layer shape base (1) is for evenly sneaking into the calcium phosphate shape base of medicine D1, this shape base prepares the slurry of usefulness: the content of calcium phosphate is 10% ± 0.5%, the content of medicine D1 is 0.0017, surplus is a distilled water;
2), outer parcel shape base (2) is for evenly sneaking into the calcium phosphate shape base of medicine D2; Its Chinese medicine D2 is and the different types of medicine of medicine D1; The slurry that this shape base prepares usefulness is: the content of calcium phosphate is 20% ± 0.5%, and the content of medicine D2 is 0.0085, and surplus is a distilled water;
3), the quality g of said medicament contg=drug quality mg/ biotic experiment biopsy sample.
A kind of embedded classification release three-dimensional rack, by internal layer shape base (1), the parcel shape base (3) in middle level and outer shape base (2) constitute, and it is characterized in that:
1), internal layer shape base (1) is for evenly sneaking into the calcium phosphate shape base of medicine D1, this shape base prepares the slurry of usefulness: the content of calcium phosphate is 10% ± 0.5%, the content of medicine D1 is 0.0020, surplus is a distilled water;
2), middle level shape base (3) is for evenly sneaking into the calcium phosphate shape base of medicine D2, medicine D2 is and the different types of medicine of medicine D1 that the slurry that this shape base prepares usefulness is: the content of calcium phosphate is 20% ± 0.5%, the content of medicine D2 is 0.0017, surplus is a distilled water;
3), outer parcel shape base (2) is for evenly sneaking into the calcium phosphate shape base of medicine D3; Its Chinese medicine D3 is and medicine D1 and the different types of medicine of medicine D2; The slurry that this shape base prepares usefulness is: the content of calcium phosphate is 30% ± 0.5%, and the content of medicine D3 is 0.0085, and surplus is a distilled water;
4), the quality g of said medicament contg=drug quality mg/ biotic experiment biopsy sample.
A kind of method for preparing of embedded classification release three-dimensional rack is used to prepare by internal layer shape base and the support that outer parcel shape base constitutes, and it is characterized in that step of preparation process is following:
1), the freezing shaping of internal layer shape base (1): at first calcium phosphate is ground and be screened into powder, be mixed with the calcium phosphate slurry of drug D1 by following weight proportioning; Calcium phosphate 10% ± 0.5%, medicine D1 content is 0.0017, surplus is a distilled water, medicament contg=drug quality mg/ biotic experiment biopsy sample quality g; Then inject the small size minus to this slurry, vacuum leaves standstill de-bubble; Remove the minus profile after minus being put into-10 ℃ ± 0.5 ℃ environment precooling 12h ± 0.5h, obtain being loaded with the support internal layer shape base (1) of medicine D1, place low temperature environment to preserve;
2), the freezing shaping of outer parcel shape base (2): the support internal layer shape base (1) that obtains in the step 1) is embedded in the big minus profile inner chamber; Then calcium phosphate is ground and is screened into powder; Be mixed with the calcium phosphate slurry of drug D1 by following weight proportioning: calcium phosphate 20% ± 0.5%; Medicine D2 content 0.0085, surplus are distilled water, medicament contg=drug quality mg/ biotic experiment biopsy sample quality g; The calcium phosphate slurry of drug D2 is injected big minus, and-10 ℃ ± 0.5 ℃ vacuum leaves standstill de-bubble; Remove the minus profile after then minus being put into-20 ℃ ± 0.5 ℃ environment precooling 12h ± 0.5h, form the outer parcel of support shape base (2), obtain the release three-dimensional rack shape base of embedded double-layer structure;
3), vacuum lyophilization makes embedded two-stage release support: with step 2) in the two-layer carried stent shape base that obtains put into freezer dryer; Lyophilization 36h ± 0.5h in-30 ℃ ± 0.5 ℃ vacuum environment obtains the biodegradable three-dimensional rack of embedded two-stage release calcium orthophosphate base.
A kind of embedded classification release three-dimensional rack and preparation method thereof is used to prepare by internal layer, middle level and the outer support that constitutes, and it is characterized in that step of preparation process is following:
1), the freezing shaping of internal layer shape base (1): at first calcium phosphate is ground and be screened into powder; Be mixed with the calcium phosphate slurry of drug D1 by following weight proportioning: calcium phosphate 10% ± 0.5%; Medicine D1 content 0.0020; Surplus is a distilled water, medicament contg=drug quality mg/ biotic experiment biopsy sample quality g; Then inject the small size minus to slurry, vacuum leaves standstill de-bubble; Remove the minus profile after minus being put into-10 ℃ ± 0.5 ℃ environment precooling 12h ± 0.5h, obtain being loaded with the support internal layer shape base SD1 of medicine D1, place low temperature environment to preserve;
2), the freezing shaping of middle level shape base (3): the internal layer shape base (1) that obtains in the step 1) is embedded in the big minus profile inner chamber; Then calcium phosphate is ground and is screened into powder; Be mixed with the calcium phosphate slurry of drug D2 by following weight proportioning: calcium phosphate 20% ± 0.5%; Medicine D2 content 0.0017, surplus are distilled water, medicament contg=drug quality mg/ biotic experiment biopsy sample quality g; The calcium orthophosphate base slurry of drug D2 is injected minus, and-10 ℃ ± 0.5 ℃ vacuum leaves standstill de-bubble; Remove the minus profile after then minus being put into-20 ℃ ± 0.5 ℃ environment precooling 12h ± 0.5h, form the middle level shape base (3) of coated stent internal layer shape base;
The middle level shape base (3) of the wrapping inner layer shape base (1) that obtains 3), the freezing shaping of outer parcel shape base (2): with step 2) embeds in the minus profile inner chamber; Then calcium phosphate is ground and is screened into powder; Be mixed with the calcium phosphate slurry of drug D3 by following weight proportioning: calcium phosphate 30% ± 0.5%; Medicine D3 content 0.0085, surplus are distilled water, medicament contg=drug quality mg/ biotic experiment biopsy sample quality g; The calcium orthophosphate base slurry of drug D3 is injected big minus, and-10 ℃ ± 0.5 ℃ vacuum leaves standstill de-bubble; Remove the minus profile after then minus being put into-20 ℃ ± 0.5 ℃ environment precooling 12h ± 0.5h, form the skin parcel shape base (2) of support, obtain the release three-dimensional rack shape base of embedded three-decker;
4), vacuum lyophilization makes embedded two-stage release support: three layers of carried stent shape base that obtain in the step 3) are put into freezer dryer; Lyophilization 42h ± 0.5h in-30 ℃ ± 0.5 ℃ vacuum environment obtains the biodegradable three-dimensional rack of embedded two-stage release calcium orthophosphate base.
The present invention compared with prior art; It has following conspicuous outstanding characteristics and significant advantage: the internal layer solid content of slurry is less than outer solid content of slurry; The substrate slurry of adjacent two layers shelf-like base exists a solid content poor; Be shaped the step by step internal layer and outer parcel of embedded classification release three-dimensional rack are evenly sneaked into different types of medicine in the different slurry of solid content.The structure (accompanying drawing 1) of the embedded two-stage release biomimetic scaffolds that lyophilization makes is an outstanding feature of the present invention, uses this thought, can expand the release thing support (accompanying drawing 2) that this structure obtains the embedded multi-layer structure on this basis.
Inject the slurry of uniform mixing medicine among the present invention stage by stage, blended drug kinds difference of each stage can realize that maybe drug concentrations gradient of the same race is written into, through adjustment slurry concentration and precooling temperature, and control internal stent form and scaffold degradation speed.This embedded hierarchy release three-dimensional rack has following characteristic: the Gradient distribution on (1) backing substrate slurry concentration, and radially the support internal layer is loose outer closely knit; (2) be written into medicine of the same race, the internal layer drug level is higher than outer drug level, realizes the Gradient distribution of drug level; (3) be written into multiple medicine simultaneously in the same support, realize the Gradient distribution of drug kinds.This embedded hierarchy release three-dimensional rack can satisfy bone and repair the demand of each stage to drug kinds and dosage; And can the be shaped porous support of bionical thing bone structure of the proportioning through adjustment substrate slurry is realized regulation and control scaffold degradation speed and drug release.
Description of drawings
Fig. 1 is the radial structure scattergram of embedded two-stage release support of the present invention;
Fig. 2 is the radial structure scattergram of embedded multistage drug release support of the present invention;
The small size minus appearance profile mould of Fig. 3 for using among the present invention;
The large scale minus appearance profile mould of Fig. 4 for using among the present invention;
Fig. 5 is an embedded classification release supporting structure physical model of the present invention;
Fig. 6 utilizes the internal layer shape base of the support that the small size minus makes for the inventive method;
Fig. 7 puts into the large scale minus for the internal layer shape base of support of the present invention;
The embedded two-stage release three-dimensional rack that Fig. 8 makes for the inventive method.
The specific embodiment
The preferred embodiments of the present invention are described with reference to the accompanying drawings as follows:
Embodiment one:Referring to Fig. 1, this embedded classification release three-dimensional rack is made up of internal layer shape base (1) and outer field parcel shape base (2), it is characterized in that:
1), internal layer shape base (1) is for evenly sneaking into the calcium phosphate shape base of medicine D1, this shape base prepares the slurry of usefulness: the content of calcium phosphate is 10% ± 0.5%, the content of medicine D1 is 0.0017, surplus is a distilled water;
2), outer parcel shape base (2) is for evenly sneaking into the calcium phosphate shape base of medicine D2; Its Chinese medicine D2 is and the different types of medicine of medicine D1; The slurry that this shape base prepares usefulness is: the content of calcium phosphate is 20% ± 0.5%, and the content of medicine D2 is 0.0085, and surplus is a distilled water;
3), the quality g of said medicament contg=drug quality mg/ biotic experiment biopsy sample.
The step of preparation process of this support is following:
1), the freezing shaping of internal layer shape base (1): at first calcium phosphate is ground and be screened into powder, be mixed with the calcium phosphate slurry of drug D1 by following weight proportioning; Calcium phosphate 10% ± 0.5%, medicine D1 content is 0.0017, surplus is a distilled water, medicament contg=drug quality mg/ biotic experiment biopsy sample quality g; Then inject the small size minus to this slurry, vacuum leaves standstill de-bubble; Remove the minus profile after minus being put into-10 ℃ ± 0.5 ℃ environment precooling 12h ± 0.5h, obtain being loaded with the support internal layer shape base (1) of medicine D1, place low temperature environment to preserve;
2), the freezing shaping of outer parcel shape base (2): the support internal layer shape base (1) that obtains in the step 1) is embedded in the big minus profile inner chamber; Then calcium phosphate is ground and is screened into powder; Be mixed with the calcium phosphate slurry of drug D1 by following weight proportioning: calcium phosphate 20% ± 0.5%; Medicine D2 content 0.0085, surplus are distilled water, medicament contg=drug quality mg/ biotic experiment biopsy sample quality g; The calcium phosphate slurry of drug D2 is injected big minus, and-10 ℃ ± 0.5 ℃ vacuum leaves standstill de-bubble; Remove the minus profile after then minus being put into-20 ℃ ± 0.5 ℃ environment precooling 12h ± 0.5h, form the outer parcel of support shape base (2), obtain the release three-dimensional rack shape base of embedded double-layer structure;
3), vacuum lyophilization makes embedded two-stage release support: with step 2) in the two-layer carried stent shape base that obtains put into freezer dryer; Lyophilization 36h ± 0.5h in-30 ℃ ± 0.5 ℃ vacuum environment obtains the biodegradable three-dimensional rack of embedded two-stage release calcium orthophosphate base.
Embodiment two:Referring to Fig. 2, this embedded classification release three-dimensional rack, by internal layer shape base (1), the parcel shape base (3) in middle level and outer shape base (2) constitute, and it is characterized in that:
1), internal layer shape base (1) is for evenly sneaking into the calcium phosphate shape base of medicine D1, this shape base prepares the slurry of usefulness: the content of calcium phosphate is 10% ± 0.5%, the content of medicine D1 is 0.0020, surplus is a distilled water;
2), middle level shape base (3) is for evenly sneaking into the calcium phosphate shape base of medicine D2, medicine D2 is and the different types of medicine of medicine D1 that the slurry that this shape base prepares usefulness is: the content of calcium phosphate is 20% ± 0.5%, the content of medicine D2 is 0.0017, surplus is a distilled water;
3), outer parcel shape base (2) is for evenly sneaking into the calcium phosphate shape base of medicine D3; Its Chinese medicine D3 is and medicine D1 and the different types of medicine of medicine D2; The slurry that this shape base prepares usefulness is: the content of calcium phosphate is 30% ± 0.5%, and the content of medicine D3 is 0.0085, and surplus is a distilled water;
4), the quality g of said medicament contg=drug quality mg/ biotic experiment biopsy sample.
The step of preparation process of this support is following:
1), the freezing shaping of internal layer shape base (1): at first calcium phosphate is ground and be screened into powder; Be mixed with the calcium phosphate slurry of drug D1 by following weight proportioning: calcium phosphate 10% ± 0.5%; Medicine D1 content 0.0020; Surplus is a distilled water, medicament contg=drug quality mg/ biotic experiment biopsy sample quality g; Then inject the small size minus to slurry, vacuum leaves standstill de-bubble; Remove the minus profile after minus being put into-10 ℃ ± 0.5 ℃ environment precooling 12h ± 0.5h, obtain being loaded with the support internal layer shape base SD1 of medicine D1, place low temperature environment to preserve;
2), the freezing shaping of middle level shape base (3): the internal layer shape base (1) that obtains in the step 1) is embedded in the big minus profile inner chamber; Then calcium phosphate is ground and is screened into powder; Be mixed with the calcium phosphate slurry of drug D2 by following weight proportioning: calcium phosphate 20% ± 0.5%; Medicine D2 content 0.0017, surplus are distilled water, medicament contg=drug quality mg/ biotic experiment biopsy sample quality g; The calcium orthophosphate base slurry of drug D2 is injected minus, and-10 ℃ ± 0.5 ℃ vacuum leaves standstill de-bubble; Remove the minus profile after then minus being put into-20 ℃ ± 0.5 ℃ environment precooling 12h ± 0.5h, form the middle level shape base (3) of coated stent internal layer shape base;
The middle level shape base (3) of the wrapping inner layer shape base (1) that obtains 3), the freezing shaping of outer parcel shape base (2): with step 2) embeds in the minus profile inner chamber; Then calcium phosphate is ground and is screened into powder; Be mixed with the calcium phosphate slurry of drug D3 by following weight proportioning: calcium phosphate 30% ± 0.5%; Medicine D3 content 0.0085, surplus are distilled water, medicament contg=drug quality mg/ biotic experiment biopsy sample quality g; The calcium orthophosphate base slurry of drug D3 is injected big minus, and-10 ℃ ± 0.5 ℃ vacuum leaves standstill de-bubble; Remove the minus profile after then minus being put into-20 ℃ ± 0.5 ℃ environment precooling 12h ± 0.5h, form the skin parcel shape base (2) of support, obtain the release three-dimensional rack shape base of embedded three-decker;
4), vacuum lyophilization makes embedded two-stage release support: three layers of carried stent shape base that obtain in the step 3) are put into freezer dryer; Lyophilization 42h ± 0.5h in-30 ℃ ± 0.5 ℃ vacuum environment obtains the biodegradable three-dimensional rack of embedded two-stage release calcium orthophosphate base.
Embodiment three:Present embodiment and embodiment one are basic identical, and medicine D1 is a deferoxamine, and medicine D2 is micromolecular compound OIC-006, and the step of preparation process of this support is following:
The first, use the internal layer shape base SD1 of small size minus (Fig. 3) shaping carried stent: at first, be the slurry that 10% ± 0.5% slurry uniform mixing obtains the internal layer support with hypoxia-mimicking chemical compound deferoxamine (medicine D1) that promotes skeletonization and calcium phosphate content.Then, internal layer support slurry is injected the small size minus, in-10 ℃ ± 0.5 ℃ environment, remove mould behind precooling minus 12h ± 0.5h, obtain sealing the support internal layer shape base SD1 (Fig. 6) of deferoxamine;
The second, the support internal layer shape base SD1 that will in the first step, obtain puts into large scale minus (Fig. 4), with micromolecular compound OIC-006 and calcium phosphate content is behind 20% ± 0.5% the slurry mix homogeneously, to inject the minus (Fig. 7) that is placed with support internal layer shape base SD1.Leave standstill froth breaking through-10 ℃ ± 0.5 ℃ cryogenic vacuum, remove mould in-20 ℃ ± 0.5 ℃ environment behind precooling minus 12h ± 0.5h, the support skin that has been shaped wraps up shape base SD2, obtains sealing the two-layer configuration shelf-like base of deferoxamine and two kinds of medicines of OIC-006;
The 3rd; The two-layer configuration shelf-like base that obtains in second one is put into freezer dryer; In-30 ℃ ± 0.5 ℃ cryogenic vacuum environment, heat 36h ± 0.5h, make the liquid phase finish-drying support that volatilizees fully, obtain the embedded biodegradable three-dimensional rack of two-stage release calcium orthophosphate base (Fig. 8); The drug kinds that is written in support internal layer and the skin is different, forms the carried stent that evenly is written into the variety classes medicine in the same support.
Claims (4)
1. an embedded classification release three-dimensional rack is made up of internal layer shape base (1) and outer field parcel shape base (2), it is characterized in that:
A. internal layer shape base (1) is for evenly sneaking into the calcium phosphate shape base of medicine D1, and this shape base prepares the slurry of usefulness: the content of calcium phosphate is 10% ± 0.5%, and the content of medicine D1 is 0.0017, and surplus is a distilled water;
B. outer parcel shape base (2) is for evenly sneaking into the calcium phosphate shape base of medicine D2; Its Chinese medicine D2 is and the different types of medicine of medicine D1; The slurry that this shape base prepares usefulness is: the content of calcium phosphate is 20% ± 0.5%, and the content of medicine D2 is 0.0085, and surplus is a distilled water;
The quality g of c. said medicament contg=drug quality mg/ biotic experiment biopsy sample.
2. embedded classification release three-dimensional rack, by internal layer shape base (1), the parcel shape base (3) in middle level and outer shape base (2) constitute, and it is characterized in that:
A. internal layer shape base (1) is for evenly sneaking into the calcium phosphate shape base of medicine D1, and this shape base prepares the slurry of usefulness: the content of calcium phosphate is 10% ± 0.5%, and the content of medicine D1 is 0.0020, and surplus is a distilled water;
B. middle level shape base (3) is for evenly sneaking into the calcium phosphate shape base of medicine D2, and medicine D2 is and the different types of medicine of medicine D1 that the slurry that this shape base prepares usefulness is: the content of calcium phosphate is 20% ± 0.5%, and the content of medicine D2 is 0.0017, and surplus is a distilled water;
C. outer parcel shape base (2) is for evenly sneaking into the calcium phosphate shape base of medicine D3; Its Chinese medicine D3 is and medicine D1 and the different types of medicine of medicine D2; The slurry that this shape base prepares usefulness is: the content of calcium phosphate is 30% ± 0.5%, and the content of medicine D3 is 0.0085, and surplus is a distilled water;
The quality g of d. said medicament contg=drug quality mg/ biotic experiment biopsy sample.
3. embedded classification release three-dimensional rack and preparation method thereof, the step of preparation process that is used to prepare embedded classification release three-dimensional rack according to claim 1 is following:
A. the freezing shaping of internal layer shape base (1): at first calcium phosphate is ground and be screened into powder, be mixed with the calcium phosphate slurry of drug D1 by following weight proportioning; Calcium phosphate 10% ± 0.5%, medicine D1 content is 0.0017, surplus is a distilled water, medicament contg=drug quality mg/ biotic experiment biopsy sample quality g; Then inject the small size minus to this slurry, vacuum leaves standstill de-bubble; Remove the minus profile after minus being put into-10 ℃ ± 0.5 ℃ environment precooling 12h ± 0.5h, obtain being loaded with the support internal layer shape base (1) of medicine D1, place low temperature environment to preserve;
B. the freezing shaping of outer parcel shape base (2): the support internal layer shape base (1) that obtains among the step a is embedded in the big minus profile inner chamber; Then calcium phosphate is ground and is screened into powder; Be mixed with the calcium phosphate slurry of drug D1 by following weight proportioning: calcium phosphate 20% ± 0.5%; Medicine D2 content 0.0085, surplus are distilled water, medicament contg=drug quality mg/ biotic experiment biopsy sample quality g; The calcium phosphate slurry of drug D2 is injected big minus, and-10 ℃ ± 0.5 ℃ vacuum leaves standstill de-bubble; Remove the minus profile after then minus being put into-20 ℃ ± 0.5 ℃ environment precooling 12h ± 0.5h, form the outer parcel of support shape base (2), obtain the release three-dimensional rack shape base of embedded double-layer structure;
C. vacuum lyophilization makes embedded two-stage release support: the two-layer carried stent shape base that obtains among the step b is put into freezer dryer; Lyophilization 36h ± 0.5h in-30 ℃ ± 0.5 ℃ vacuum environment obtains the biodegradable three-dimensional rack of embedded two-stage release calcium orthophosphate base.
4. embedded classification release three-dimensional rack and preparation method thereof is used to prepare embedded classification release three-dimensional rack according to claim 2, it is characterized in that step of preparation process is following:
A. the freezing shaping of internal layer shape base (1): at first calcium phosphate is ground and be screened into powder; Be mixed with the calcium phosphate slurry of drug D1 by following weight proportioning: calcium phosphate 10% ± 0.5%; Medicine D1 content 0.0020; Surplus is a distilled water, medicament contg=drug quality mg/ biotic experiment biopsy sample quality g; Then inject the small size minus to slurry, vacuum leaves standstill de-bubble; Remove the minus profile after minus being put into-10 ℃ ± 0.5 ℃ environment precooling 12h ± 0.5h, obtain being loaded with the support internal layer shape base SD1 of medicine D1, place low temperature environment to preserve;
B. the freezing shaping of middle level shape base (3): the internal layer shape base (1) that obtains among the step a is embedded in the big minus profile inner chamber; Then calcium phosphate is ground and is screened into powder; Be mixed with the calcium phosphate slurry of drug D2 by following weight proportioning: calcium phosphate 20% ± 0.5%; Medicine D2 content 0.0017, surplus are distilled water, medicament contg=drug quality mg/ biotic experiment biopsy sample quality g; The calcium orthophosphate base slurry of drug D2 is injected minus, and-10 ℃ ± 0.5 ℃ vacuum leaves standstill de-bubble; Remove the minus profile after then minus being put into-20 ℃ ± 0.5 ℃ environment precooling 12h ± 0.5h, form the middle level shape base (3) of coated stent internal layer shape base;
C. the freezing shaping of outer parcel shape base (2): the middle level shape base (3) of the wrapping inner layer shape base (1) that obtains among the step b is embedded in the minus profile inner chamber; Then calcium phosphate is ground and is screened into powder; Be mixed with the calcium phosphate slurry of drug D3 by following weight proportioning: calcium phosphate 30% ± 0.5%; Medicine D3 content 0.0085, surplus are distilled water, medicament contg=drug quality mg/ biotic experiment biopsy sample quality g; The calcium orthophosphate base slurry of drug D3 is injected big minus, and-10 ℃ ± 0.5 ℃ vacuum leaves standstill de-bubble; Remove the minus profile after then minus being put into-20 ℃ ± 0.5 ℃ environment precooling 12h ± 0.5h, form the skin parcel shape base (2) of support, obtain the release three-dimensional rack shape base of embedded three-decker;
D. vacuum lyophilization makes embedded two-stage release support: three layers of carried stent shape base that obtain among the step c are put into freezer dryer; Lyophilization 42h ± 0.5h in-30 ℃ ± 0.5 ℃ vacuum environment obtains the biodegradable three-dimensional rack of embedded two-stage release calcium orthophosphate base.
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