CN101401958B - Chitosan-hydroxyapatite composite spheroidal particle, producing method and apparatus thereof - Google Patents

Abstract

Translated fromChinese

本发明涉及一种壳聚糖-羟基磷灰石复合球形颗粒及其制备方法和装置。制备过程中先配制壳聚糖醋酸溶液，再在壳聚糖醋酸溶液中加入纳米羟基磷灰石粉末制备悬浮液，羟基磷灰石与壳聚糖的质量比为(6～1)：(1～5)。制备好的悬浮液从加料口加入储料罐，通过控制储料罐中的压力使其从导液管均匀流出，滴入保温容器内的冷凝液中冷凝，形成球形颗粒。冷凝后的球形颗粒先进行冷冻干燥，再用2.5％的戊二醛溶液交联处理，最后用无水乙醇清洗，得到壳聚糖-羟基磷灰石复合球形多孔颗粒材料。这种球形颗粒材料具有均一的粒径分布，内部含有大量的互通微孔，具有较高的比表面积，可在组织修复和药物缓释中得到应用。

The invention relates to a chitosan-hydroxyapatite composite spherical particle and a preparation method and device thereof. In the preparation process, chitosan acetic acid solution is first prepared, and then nano-hydroxyapatite powder is added to the chitosan acetic acid solution to prepare a suspension. The mass ratio of hydroxyapatite to chitosan is (6-1): (1 ~5). The prepared suspension is added to the storage tank from the feeding port, and the pressure in the storage tank is controlled to make it flow out from the catheter tube evenly, and drip into the condensate in the heat preservation container to condense to form spherical particles. The condensed spherical particles are first freeze-dried, then cross-linked with 2.5% glutaraldehyde solution, and finally washed with absolute ethanol to obtain chitosan-hydroxyapatite composite spherical porous particle materials. The spherical particle material has a uniform particle size distribution, contains a large number of interconnected micropores inside, and has a high specific surface area, and can be applied in tissue repair and drug sustained release.

Description

Chitosan-hydroxyapatite composite spheroidal particle and preparation method thereof and device

One, technical field

The invention belongs to a kind of technology of preparing that is applied to the spherical particle material of biomedical sector, be specifically related to a kind of chitosan-hydroxyapatite composite spheroidal particle and preparation method thereof and device.

Two, background technology

Prior art: chitin extensively is present in the cell wall of arthropodan shell such as shrimp, Eriocheir sinensis and insecticide and rudimentary plants such as bacterium, algae, is one of the abundantest biopolymer of occurring in nature, is a kind of very abundant natural regenerated resources.Chitosan be chitin take off the acetyl product, chitosan is nontoxic, good biocompatibility, biodegradable, in recent years, very noticeable in the research that can absorb aspects such as operation suture thread, hemostatic material, wound dressing material and artificial skin as natural medical polymer materials.Simultaneously, chitosan also is a kind of good hard tissue repairing material, can absorb in fracture also to be applied aspect immobilization material and the damaged packing material of bone.But because the mechanical property of chitosan is lower, its application in hard tissue repair is subjected to certain restriction.

Hydroxyapatite (Hydroxyapatite is called for short HA) is the main inorganic composition in vertebrates skeleton and the tooth, and in sclerotin, hydroxyapatite accounts for 60% greatly.The hydroxyapatite of synthetic has the inorganic constituents similar to body bone tissue, contain the necessary calcium of tissue and P elements, after implanting, under the effect of body fluid, calcium and the phosphorus material surface that can dissociate, absorbed by body tissue, and can be combined the tissue that growth makes new advances with skeleton tissue formation chemical bond.Therefore, hydroxylapatite ceramic is the excellent biological compatibility that has of generally acknowledging at present, and has bone and lure guided bone, i.e. biological activity.But the hydroxyapatite of synthetic exists with Powdered usually, because it lacks adhesive, operation is inconvenient in application, and molding is not good, and material is implanted normal generation the in back and is shifted and spills, and makes its application be subjected to certain limitation.If with chitosan and the compound preparation composite of hydroxyapatite, the good biocompatibility of existing natural macromolecular material and biodegradability have the good mechanical performance again, and the performance of material will obtain very big improvement.Chitosan-hydroxyapatite composite material also can be used for preparing the packing material of particle shape except being used for preparing the block body stephanoporate support.

Micro-sphere material has the unexistent excellent properties of a lot of irregular particles, as being difficult for causing stress concentration etc. after high flowability, high bulk density, difficult reunion, the filling.At present, reparation, the alveolar ridge of frontal resorption increase due to the filling, periodontal disease of root canal and exodontia nest, the filling of jawbone bone blister cavities, atrophic rhinitis's filling, mastoid cavity filling, shaping (as the nasus incurvus beauty treatment) reach in the damaged filling of bone with other position of skeleton, and the microsphere particle packing material is used widely.The polymer-matrix microsphere particle has multiple preparation method, and commonly used have emulsifying-chemical crosslink technique, emulsifying-solvent evaporated method and a spray drying method.The microsphere diameter distribution of using these method preparations is bigger, and packed density is big, and when being applied to tissue filling, intergranular hole is very few, is unfavorable for growing into of cambium.

Three, summary of the invention

The present invention is directed to above-mentioned technological deficiency, a kind of chitosan-hydroxyapatite composite spheroidal particle and preparation method thereof and device are provided, can prepare the chitosan-hydroxyapatite composite spheroidal particle with homogeneous particle diameter.

Technical scheme of the present invention is a kind of preparation method of chitosan-hydroxyapatite composite spheroidal particle, the particle diameter of described chitosan-hydroxyapatite composite spheroidal particle is φ 0.8～4mm, the granule body interior is that the aperture is less than the micropore of 150 μ m, intercommunication between the micropore, the porosity of chitosan-hydroxyl lime stone composite spheroidal particle is 75～92%, and the mass ratio of hydroxyapatite and chitosan is (6～1) in the granule: (1～5).

A kind of preparation method for preparing described chitosan-hydroxyapatite composite spheroidal particle, preparation process is:

The first step, taking by weighing 5～25% the chitosan that accounts for the solution gross mass, to be dissolved in mass concentration be to make chitosan-acetic acid solution in 1～5% the acetum, the mass ratio of pressing hydroxyapatite and chitosan is (6～1): (1～5) takes by weighing nanometer hydroxyapatite;

Second step added nanometer hydroxyapatite in the chitosan-acetic acid solution, fully stirred and obtained chitosan-hydroxyapatite suspension;

The 3rd step was the pipe of φ 0.5～3mm with second chitosan-hydroxyapatite suspension of preparing of step from caliber, evenly flowed out with the speed of 10～60/min, splashed into temperature for condensation in the-condensed fluid of (10～20) ℃, formed spheroidal particle; Described condensed fluid is dimethicone or vegetable oil.

The 4th step is with the condensed spherical particles separation of the 3rd step, lyophilization; It is cross-linking agent solution crosslinking Treatment 3～24h of 0.25～2.5% that spheroidal particle after the lyophilization is put into mass concentration, cleans with dehydrated alcohol then, obtains chitosan-hydroxyapatite composite spheroidal particle.Described cross-linking agent is any one in formaldehyde, glutaraldehyde, the Biformyl.

Adopt drop-condensation method of the present invention to prepare microsphere particle, the preparation facilities of chitosan-hydroxyapatite composite spheroidal particle mainly is made up of charge door, Pressure gauge, pressure-control valve, storage tank, flow control valve, catheter, condensed fluid and cool-bag.

The slurry for preparing adds storage tank from charge door, by the pressure in Pressure gauge and the pressure-control valve control storage tank, to guarantee that slurry evenly flows out from catheter.The slurry that flows out from catheter drips behind certain volume greatly mouth of pipe director, in dropping process, because that capillary effect forms is spherical, then enters the condensed fluid condensation in the cool-bag, forms spheroidal particle.According to the surface tension formula:

mg＝2πrσ

In the formula: m is drop mass; R is the extracapillary radius; σ is surface tension; G is acceleration of gravity.When density and viscosity one timing of chitosan solution, under the condition of no external interference, this method can be prepared the spheroidal particle of good sphericity, uniform particle diameter.

Beneficial effect: the present invention preparation obtain chitosan-hydroxyapatite composite spheroidal particle:

(1) contain a large amount of intercommunication micropores in the granule body interior, form the 3 D stereo network structure, this granule has higher specific surface area, is conducive to the flowing of tissue fluid of the adhesion of cell;

(2) chitosan particle has narrower particle size distribution, does not need to sieve the granular materials that processing can obtain having same particle size; The present invention be the slurry that will configure by splashing in the freezing in advance liquid, the surface tension of using liquid is condensed into a kind of process of spheroidal particle.According to the surface tension formula:

mg＝2πrσ

In the formula: m is drop mass; R is the extracapillary radius; σ is surface tension; G is acceleration of gravity.When density and viscosity one timing of slurry, under the condition of no external interference, this method can be prepared the microsphere particle of good sphericity, uniform particle diameter.

(3) because the narrow diameter distribution of the spheroidal particle of the present invention preparation, and the spherical granular material of same particle size can obtain largest inter-particle porosity after the filling, so when being applied to tissue filling, be conducive to growing into of cambium.

(4) granular materials is made up of chitosan and nanometer hydroxyapatite, has both possessed good degradation capability, has possessed biological activity again.

Four, description of drawings:

Fig. 1 spheroidal particle forming device sketch map.

Device mainly is made up of charge door 1, Pressure gauge 2, pressure-control valve 3, storage tank 4, flow control valve 5, catheter 6, condensed fluid 7 and cool-bag 8.

Fig. 2 is the photo of chitosan-hydroxyapatite composite spherical honeycombed grain.

Fig. 3 is the internal void photo of chitosan-hydroxyapatite composite spherical honeycombed grain.

Five, the specific embodiment:

Embodiment 1:

(1) taking by weighing the chitosan that accounts for solution gross mass 5%, to be dissolved in mass concentration be in 1% the acetum, to be mixed with chitosan-acetic acid solution, and the mass ratio by hydroxyapatite and chitosan is that 2:1 takes by weighing nanometer hydroxyapatite then;

(2) nanometer hydroxyapatite is added in the chitosan-acetic acid solution, fully stir and obtain chitosan-hydroxyapatite suspension;

(3) shown in Figure 1, chitosan-hydroxyapatite the suspension for preparing is added storage tank 4 from charge door 1, the pressure of controlling in the storage tanks 4 by Pressure gauge 2 and pressure-control valve 3 is 0.08MPa, to guarantee that chitosan-hydroxyapatite suspension is that the speed with 10/min evenly flows out the catheter 6 of φ 0.5mm from caliber, flow velocity can be controlled by flow control valve 5, solution splashes into condensation in the condensed fluid 7 in the cool-bag 8, the temperature of condensed fluid is-10 ℃, condensed fluid is vegetable oil, forms spheroidal particle;

(4) condensed microsphere separates, and handle 8h-5 ℃ temperature lyophilization, it is 0.25% glutaraldehyde solution crosslinking Treatment 3h that spheroidal particle after the lyophilization is put into mass concentration earlier, the reuse dehydrated alcohol cleans, obtain chitosan-hydroxyapatite composite spheroidal particle, as shown in Figure 2, the good sphericity of granule, uniform particle diameter, particle diameter are φ 0.8mm, as shown in Figure 3, the granule body interior is that the aperture is less than the micropore of 150 μ m, intercommunication between the micropore forms the 3 D stereo network structure, and porosity is 75%.

Embodiment 2:

(1) taking by weighing the chitosan that accounts for solution gross mass 15%, to be dissolved in mass concentration be to be mixed with chitosan-acetic acid solution in 3% the acetum, and the mass ratio by hydroxyapatite and chitosan is that 6:1 takes by weighing nanometer hydroxyapatite then;

(2) nanometer hydroxyapatite is added chitosan-acetic acid solution, fully stir and obtain chitosan-hydroxyapatite suspension;

(3) prepared suspension liquid adds storage tank 4 from charge door 1, the pressure of controlling in the storage tanks 4 by Pressure gauge 2 and pressure-control valve 3 is 0.5MPa, to guarantee that chitosan-hydroxyapatite suspension is that the speed with 60/min evenly flows out the catheter 6 of φ 3mm from caliber, flow velocity can be controlled by flow control valve 5, solution splashes into condensation in the condensed fluid 7 in the cool-bag 8, the temperature of condensed fluid is-20 ℃, and condensed fluid is dimethicone, forms spheroidal particle;

(4) condensed microsphere separates, and handle 14h-7 ℃ temperature lyophilization, it is 1.5% glyoxal solution crosslinking Treatment 14h that spheroidal particle after the lyophilization is put into mass concentration earlier, the reuse dehydrated alcohol cleans, obtain chitosan-hydroxyapatite composite spheroidal particle, particle diameter is φ 4mm, and the granule body interior is that the aperture is less than the micropore of 150 μ m, intercommunication between the micropore, porosity are 92%.

Embodiment 3:

(1) taking by weighing the chitosan that accounts for solution gross mass 25%, to be dissolved in mass concentration be that 5% acetum is made chitosan-acetic acid solution, is that 2:5 takes by weighing nanometer hydroxyapatite by the mass ratio of hydroxyapatite and chitosan;

(2) nanometer hydroxyapatite is added chitosan-acetic acid solution, fully stir and obtain suspension;

(3) prepared suspension liquid adds storage tank 4 from charge door 1, the pressure of controlling in the storage tanks 4 by Pressure gauge 2 and pressure-control valve 3 is 1.08MPa, to guarantee that chitosan-hydroxyapatite suspension is that the speed with 40/min evenly flows out the catheter 6 of φ 1.5mm from caliber, flow velocity can be controlled by flow control valve 5, solution splashes into condensation in the condensed fluid 7 in the cool-bag 8, the temperature of condensed fluid is-15 ℃, and condensed fluid is vegetable oil, forms spheroidal particle;

(4) condensed microsphere separates, and handle 24h-10 ℃ temperature lyophilization, it is 2.5% formalin crosslinking Treatment 24h that spheroidal particle after the lyophilization is put into mass concentration earlier, the reuse dehydrated alcohol cleans, obtain chitosan-hydroxyapatite composite spheroidal particle, particle diameter is φ 2mm, and the granule body interior is that the aperture is less than the micropore of 150 μ m, intercommunication between the micropore, porosity are 82%.

Claims (4)

1. a chitosan-hydroxyapatite composite spheroidal particle is characterized in that the particle diameter of described chitosan-hydroxyapatite composite spheroidal particle is

0.8～4mm, the granule body interior be the aperture less than the micropore of 150 μ m, intercommunication between the micropore, the porosity of chitosan-hydroxyapatite composite spheroidal particle is 75～92%, the mass ratio of hydroxyapatite and chitosan is (6～1) in the granule: (1～5).

2. preparation method for preparing the described chitosan-hydroxyapatite composite spheroidal particle of claim 1 is characterized in that preparation process is:

The first step, taking by weighing 5～25% the chitosan that accounts for the solution gross mass, to be dissolved in mass concentration be to make chitosan-acetic acid solution in 1～5% the acetum, be (6～1) by the mass ratio of hydroxyapatite and chitosan: (1～5) takes by weighing nanometer hydroxyapatite;

Second step added nanometer hydroxyapatite in the chitosan-acetic acid solution, fully stirred and obtained chitosan-hydroxyapatite suspension;

In the 3rd step, chitosan-hydroxyapatite suspension that second step was prepared from caliber is

0.5 the pipe of～3mm evenly flows out with the speed of 10～60/min, splashes into temperature for condensation in the-condensed fluid of (10～20) ℃, forms spheroidal particle;

The 4th step is with the condensed spherical particles separation of the 3rd step, lyophilization; It is cross-linking agent solution crosslinking Treatment 3～24h of 0.25%～2.5% that spheroidal particle after the lyophilization is put into mass concentration, cleans with dehydrated alcohol then, obtains chitosan-hydroxyapatite composite spheroidal particle.

3. the preparation method of chitosan-hydroxyapatite composite spheroidal particle as claimed in claim 2 is characterized in that, described condensed fluid is dimethicone or vegetable oil.

4. the preparation method of chitosan-hydroxyapatite composite spheroidal particle as claimed in claim 2 is characterized in that, described cross-linking agent is any one in formaldehyde, glutaraldehyde, the Biformyl.

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