A kind of implant filling material of hydroxyapatite composite microsphere and preparation method thereof

Abstract

The present invention relates to the field of biomedical engineering, and in particular to an implant filling material of hydroxyapatite composite microspheres and a preparation method thereof; the implant filling material includes a matrix, and hydroxyapatite microspheres with carboxymethyl chitosan filling pores dispersed in the matrix; the matrix includes a hydrogel solute; the mass ratio of the hydroxyapatite microspheres with carboxymethyl chitosan filling pores to the matrix is ​​in the range of 1:(1-4). The present invention introduces hydroxyapatite microspheres with carboxymethyl chitosan filling pores. After the carboxymethyl chitosan is decomposed, the regenerated collagen fibers are interspersed in the matrix degradation site and the pores of the hydroxyapatite microspheres, thereby strengthening the anchoring of the hydroxyapatite microspheres and preventing the displacement of the filler. After the basic skeleton constructed by the regenerated collagen fibers, the hydroxyapatite microspheres gradually dissolve and decompose into calcium ions and phosphates, further enhancing the firming effect of the skin.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedical engineering, and in particular to an implant filling material of hydroxyapatite composite microspheres and a preparation method thereof. Background Art

[0002] As people's anti-aging awareness increases, injectable filling materials have become an indispensable part of cosmetic medicine.

[0003] At present, the mainstream injection materials for light medical beauty are hyaluronic acid, botulinum toxin, exogenous collagen and other materials, which are mainly used for filling plasticity, thereby eliminating facial wrinkles and anti-aging. After the injection of such materials, as the injected materials gradually degrade, the filling effect gradually dissipates, and the filling effect is poor in durability, requiring repeated periodic injections, which only treats the symptoms but not the root cause. Summary of the invention

[0004] The technical problem to be solved by the present invention is that the filling effect of existing implant filling materials has poor durability.

[0005] The technical solution adopted by the present invention to solve its technical problem is:

[0006] A hydroxyapatite composite microsphere implant filling material comprises a matrix and hydroxyapatite microspheres with carboxymethyl chitosan filling pores dispersed in the matrix; the matrix comprises a hydrogel solute; the mass ratio of the hydroxyapatite microspheres with carboxymethyl chitosan filling pores to the matrix is ​​in the range of 1:(1-4).

[0007] Optionally, the particle size of the hydroxyapatite microspheres with pores filled with carboxymethyl chitosan is in the range of 25-45 μm.

[0008] Optionally, the hydrogel solute is selected from at least one of carboxymethyl chitosan, sodium carboxymethyl cellulose, and sodium hyaluronate.

[0009] Another object of the present invention is to provide a method for preparing the implant filling material of the hydroxyapatite composite microspheres as described above, comprising the following steps:

[0010] S1: using phosphoric acid and calcium hydroxide as raw materials to prepare hydroxyapatite precipitation;

[0011] S2: drying and crushing the hydroxyapatite precipitate, and then sintering the obtained powder at 100° C.-200° C. to obtain sintered hydroxyapatite;

[0012] S3: immersing the sintered hydroxyapatite in a carboxymethyl chitosan solution, pre-freezing at (-20)°C to (-40)°C, and then freeze-drying at (-30)°C to (-80)°C to obtain a freeze-dried product;

[0013] S4: crushing and grinding the freeze-dried product, and then screening it through an ultrasonic vibration screen to obtain hydroxyapatite microspheres with pores filled with carboxymethyl chitosan;

[0014] S5: mixing the hydroxyapatite microspheres with pores filled with carboxymethyl chitosan with a matrix to obtain an implant filling material of hydroxyapatite composite microspheres.

[0015] Optionally, the hydroxyapatite precipitate in step S1 is a needle / rod-shaped hydroxyapatite precipitate.

[0016] Optionally, step S1 includes: preparing phosphoric acid and calcium hydroxide into solutions respectively, mixing and stirring the two solutions at a calcium-phosphorus ratio of 1.66-1.71, adding potassium sulfate as an electrolyte, and then performing electrochemical precipitation to obtain hydroxyapatite precipitate.

[0017] Optionally, the mass fraction of the carboxymethyl chitosan solution in step S3 is 2%-5%.

[0018] Optionally, the moisture content of the freeze-dried product in step S3 is in the range of 3%-5%.

[0019] Optionally, the matrix in step S5 is prepared according to the following method: after mixing the hydrogel solute with water, glycerol is added to obtain the matrix.

[0020] Optionally, the mass ratio of the hydrogel solute, the water, and the glycerol is (0.5-5):(40-75):(1-10).

[0021] The beneficial effects of the present invention are:

[0022] The implant filling material of hydroxyapatite composite microspheres provided by the present invention can stabilize the distribution of microspheres after injection by introducing hydroxyapatite microspheres with pores filled with carboxymethyl chitosan. After the decomposition of carboxymethyl chitosan, the regenerated collagen fibers are interspersed in the matrix degradation sites and the pores of the hydroxyapatite microspheres, strengthening the anchoring of the hydroxyapatite microspheres and preventing the displacement of the filler. After the basic skeleton constructed by the regenerated collagen fibers, the hydroxyapatite microspheres gradually dissolve, and their submicron particles are released and finally decomposed into calcium ions and phosphates, stimulating the production of collagen and elastin, and further enhancing the skin's firming effect by promoting the growth of fibroblasts, thereby being able to extend the filling duration while improving the filling effect. DETAILED DESCRIPTION

[0023] The present invention is now further described in detail. The embodiments described below are exemplary and intended to be used to explain the present invention, but cannot be understood as limiting the present invention. All other embodiments obtained by ordinary technicians in this field without creative work based on the embodiments of the present invention belong to the scope of protection of the present invention.

[0024] In order to solve the problem of poor durability of the filling effect of implantable filling materials in the prior art, the present invention provides an implantable filling material of hydroxyapatite composite microspheres, comprising a matrix, and hydroxyapatite microspheres with carboxymethyl chitosan filling pores dispersed in the matrix; wherein the matrix comprises a hydrogel solute; and the mass ratio of the hydroxyapatite microspheres with carboxymethyl chitosan filling pores to the matrix is ​​in the range of 1:(1-4).

[0025] The implantable filling material of the hydroxyapatite composite microsphere can be filled by subcutaneous injection; the hydroxyapatite microspheres with carboxymethyl chitosan filling the pores in the filling material are evenly dispersed in the injection material after injection, and the gaps form a mesh structure of the hydrogel material. As the hydrogel decomposes, the regenerated collagen fibers fill the space of the original hydrogel to form a collagen fiber skeleton. The pores in the hydroxyapatite microspheres are filled with carboxymethyl chitosan, which can form a stable structure with the matrix when injected into the body. After decomposition, the regenerated collagen fibers can pass through the pores when growing, making the collagen fiber skeleton more stable. The decomposition products of hydroxyapatite are calcium ions and phosphates, which can stimulate the production of collagen and elastin and promote the growth of fibroblasts. The hydroxyapatite microspheres with pores decompose faster and have a shorter treatment cycle than general hydroxyapatite filling materials.

[0026] The hydroxyapatite composite microsphere implant filling material is an injectable regenerative filling material, which can be used for injection into facial depressions or sagging areas, while promoting the regeneration of the body's own collagen fibers, thereby achieving long-term remodeling, firming, beauty and anti-aging effects.

[0027] The implant filling material of hydroxyapatite composite microspheres provided by the present invention can stabilize the distribution of microspheres after injection by introducing hydroxyapatite microspheres with pores filled with carboxymethyl chitosan. After the decomposition of carboxymethyl chitosan, the regenerated collagen fibers are interspersed in the matrix degradation sites and the pores of the hydroxyapatite microspheres, strengthening the anchoring of the hydroxyapatite microspheres and preventing the displacement of the filler. After the basic skeleton constructed by the regenerated collagen fibers, the hydroxyapatite microspheres gradually dissolve, and their submicron particles are released and finally decomposed into calcium ions and phosphates, stimulating the production of collagen and elastin, and further enhancing the skin's firming effect by promoting the growth of fibroblasts, thereby being able to extend the filling duration while improving the filling effect.

[0028] To ensure the filling effect, the particle size of the hydroxyapatite microspheres whose pores are filled with carboxymethyl chitosan is preferably in the range of 25-45 μm.

[0029] In the present invention, the preferred hydrogel solute is at least one selected from carboxymethyl chitosan, sodium carboxymethyl cellulose, and sodium hyaluronate.

[0030] When the hydroxyapatite composite microsphere implant filling material provided by the present invention is used, the filling material and 2% lidocaine are mixed in a ratio of 6.5:1 (volume ratio), and injected into subcutaneous depressions or sagging skin areas at multiple points using a syringe, preferably with an injection volume of no more than 1.5 ml per treatment.

[0031] Another object of the present invention is to provide a method for preparing the implant filling material of the hydroxyapatite composite microspheres as described above, the preparation method comprising the following steps:

[0032] S1: using phosphoric acid and calcium hydroxide as raw materials to prepare hydroxyapatite precipitation;

[0033] S2: drying and crushing the hydroxyapatite precipitate, and then sintering the obtained powder at 100° C.-200° C. to obtain sintered hydroxyapatite;

[0034] S3: immersing the sintered hydroxyapatite in a carboxymethyl chitosan solution, pre-freezing at (-20)°C to (-40)°C, and then freeze-drying at (-30)°C to (-80)°C to obtain a freeze-dried product;

[0035] S4: crushing and grinding the freeze-dried product, and then screening it through an ultrasonic vibration screen to obtain hydroxyapatite microspheres with pores filled with carboxymethyl chitosan;

[0036] S5: The hydroxyapatite microspheres with pores filled with carboxymethyl chitosan are mixed with a matrix to obtain an implant filling material of hydroxyapatite composite microspheres.

[0037] The preparation method of the implantable filling material of hydroxyapatite composite microspheres provided by the present invention has a simple preparation process; the prepared implantable filling material of hydroxyapatite composite microspheres can stabilize the distribution of microspheres after injection by introducing hydroxyapatite microspheres with pores filled with carboxymethyl chitosan. After the decomposition of carboxymethyl chitosan, the regenerated collagen fibers are interspersed in the matrix degradation site and the pores of the hydroxyapatite microspheres, strengthening the anchoring of the hydroxyapatite microspheres and preventing the displacement of the filler. After the basic skeleton constructed by the regenerated collagen fibers, the hydroxyapatite microspheres gradually dissolve, and their submicron particles are released, and finally decomposed into calcium ions and phosphates, stimulating the production of collagen and elastin, and by promoting the growth of fibroblasts, the skin's firming effect is further enhanced, thereby being able to extend the filling duration while improving the filling effect.

[0038] In order to better stimulate the production of collagen and elastin, the hydroxyapatite precipitate in step S1 of the present invention is preferably a needle / rod-shaped hydroxyapatite precipitate.

[0039] Specifically, in order to obtain needle / rod-shaped hydroxyapatite precipitates, the preferred step S1 of the present invention includes: phosphoric acid and calcium hydroxide are respectively configured into solutions, preferably the mass fraction of phosphoric acid in the phosphoric acid solution is (0.3-0.6)%, and the mass fraction of calcium hydroxide in the calcium hydroxide solution is (0.10-0.17)%, and then the two solutions are mixed and stirred at a calcium-phosphorus ratio of 1.66-1.71, potassium sulfate (preferably the mass ratio of potassium sulfate to calcium hydroxide is (3-5:1)) is added as an electrolyte, and then electrochemical precipitation is performed, and needle / rod-shaped hydroxyapatite precipitates are obtained by adjusting the stirring speed; the preferred stirring speed is 200-500r / min, and the preferred size of the needle / rod-shaped hydroxyapatite precipitate is 20nm-60nm.

[0040] The preferred step S2 of the present invention is carried out as follows: the hydroxyapatite precipitate is placed in an oven and dried at 60°C, then placed in a pulverizer and crushed into powder, the powder is spread in a container, placed in a muffle furnace and sintered at 1000-1200°C for 3 hours, and cooled to room temperature to obtain sintered hydroxyapatite.

[0041] Furthermore, in the preferred embodiment of the present invention, the mass fraction of the carboxymethyl chitosan solution in step S3 is 2%-5%; and the water content of the freeze-dried finished product in step S3 is in the range of 3%-5%.

[0042] Specifically, the present invention preferably performs step S3 as follows: immersing the sintered hydroxyapatite into a carboxymethyl chitosan solution, precooling at (-20)°C-(-40)°C for 2-4 hours, placing in a freeze dryer at (-30)°C-(-80)°C for freeze drying for 10-15 hours, controlling the water content at 3%-5%, and obtaining a freeze-dried product.

[0043] The matrix in the preferred step S5 of the present invention is prepared as follows: after mixing the hydrogel solute with water, preferably sterile water for injection, glycerol is added to obtain the matrix. The specific preparation process can be operated as follows: the hydrogel solute is uniformly mixed with sterile water for injection, the solute is fully dissolved by a stirrer, and then glycerol is added to obtain the matrix.

[0044] Specifically, the preferred step S5 can be performed as follows: the hydroxyapatite microspheres with pores filled with carboxymethyl chitosan and the matrix are placed in a container at a mass ratio of 1: (1-4) and stirred for 0.5-2 hours, and the hydroxyapatite microspheres with pores filled with carboxymethyl chitosan are evenly dispersed in the matrix to obtain an injectable regenerative filling material, that is, an implant filling material of hydroxyapatite composite microspheres.

[0045] Existing filling materials are prone to inflammatory reactions in the early stage after injection, causing discomfort to the human body; in the filling material provided by the present invention, the hydrogel solute and sterilized water for injection form a hydrogel to fill the subcutaneous depression, and the active ingredient of carboxymethyl chitosan can also reduce the inflammatory reaction after injection. The addition of glycerol increases the viscosity of the injection solution, making the injection solution more stable, and the apatite microspheres and hydrogel are not easy to produce solid-liquid separation, so as to ensure that the injection material is not easily deformed by force after being injected subcutaneously.

[0046] In order to take into account both the filling effect and the durability of the filling effect, the preferred mass ratio of the hydrogel solute, water, and glycerol in the matrix of the present invention is (0.5-5): (40-75): (1-10).

[0047] The present invention injects the filling material including the hydrogel solute into the subcutaneous tissue, which can achieve the effect of immediate filling of the skin in the concave or sagging area. At the same time, the matrix has analgesic and anti-inflammatory effects to deal with the discomfort that may be caused by the filling material when it first enters the body. Subsequently, the matrix material degrades and promotes the regeneration of collagen fibers. The basic skeleton constructed by the regenerated collagen fibers forms a mesh structure to fill the concave area.

[0048] In summary, the present invention provides a composite injectable medical beauty regeneration filler, which achieves the filling effect after injection, and the matrix has analgesic and anti-inflammatory effects, greatly improving the discomfort that may be caused by the filling material entering and exiting the body. As the matrix material degrades, the regeneration of its own collagen fibers is promoted to replace the injected matrix material, so that the injection effect can be maintained for a long time without the need for multiple injections.

[0049] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, specific embodiments of the present invention are described in detail below.

[0050] Example 1

[0051] This embodiment provides a method for preparing an implant filling material of hydroxyapatite composite microspheres, the preparation method comprising the following steps:

[0052] S1: Phosphoric acid and calcium hydroxide are respectively prepared into solutions, wherein the mass fraction of phosphoric acid in the phosphoric acid solution is 0.4%, and the mass fraction of calcium hydroxide in the calcium hydroxide solution is 0.13%; the two solutions are then mixed and stirred at a calcium-phosphorus ratio of 1.7, potassium sulfate (the mass ratio of potassium sulfate to calcium hydroxide is (4:1)) is added as an electrolyte, and electrochemical precipitation is performed, and the stirring speed is adjusted to 300 r / min to obtain needle / rod-shaped hydroxyapatite precipitation;

[0053] S2: Put the hydroxyapatite precipitate into an oven and dry it at 60°C, then put it into a grinder and grind it into powder. Spread the powder into a container, put it into a muffle furnace and sinter it at 1100°C for 3 hours, and cool it to room temperature to obtain sintered hydroxyapatite.

[0054] S3: immersing the sintered hydroxyapatite into a carboxymethyl chitosan solution (carboxymethyl chitosan mass fraction is 3%), precooling at -30°C for 3 hours, placing in a freeze dryer at -60°C for 12 hours, controlling the water content at 4%, and obtaining a freeze-dried product;

[0055] S4: crushing and grinding the freeze-dried product, and then screening it through an ultrasonic vibration screen to obtain hydroxyapatite microspheres filled with carboxymethyl chitosan with a particle size of 25-45 μm;

[0056] S5: putting the hydroxyapatite microspheres filled with carboxymethyl chitosan and the matrix in a mass ratio of 3:7 into a container and stirring for 1.5 hours, the hydroxyapatite microspheres filled with carboxymethyl chitosan are evenly dispersed in the matrix, and an implant filling material of hydroxyapatite composite microspheres is obtained;

[0057] The matrix was prepared as follows:

[0058] The carboxymethyl chitosan and sterile water for injection are mixed evenly, and after the solute is fully dissolved by a blender, glycerol is added to obtain a matrix; wherein the mass ratio of the carboxymethyl chitosan, the sterile water for injection and the glycerol is 1.5:62.5:6.

[0059] Take 6.5 ml of hydroxyapatite composite microsphere implant filling material, add 1 ml of 2% lidocaine by mass, mix evenly, draw 1.5 ml with a syringe, and inject it subcutaneously to the user.

[0060] Example 2

[0061] The difference between this embodiment and embodiment 1 is that in step S5, the mass ratio of the hydroxyapatite microspheres in which the pores are filled with carboxymethyl chitosan to the matrix is ​​1:1.

[0062] Example 3

[0063] The difference between this embodiment and embodiment 1 is that in step S5, the mass ratio of the hydroxyapatite microspheres in which the pores are filled with carboxymethyl chitosan to the matrix is ​​1:4.

[0064] Based on the above ideal embodiments of the present invention, the relevant staff can make various changes and modifications without departing from the technical concept of the present invention through the above description. The technical scope of the present invention is not limited to the contents of the specification, and its technical scope must be determined according to the scope of the claims.

Claims

1. A hydroxyapatite composite microsphere implant filling material, characterized in that: It comprises a matrix, and hydroxyapatite microspheres with pores filled by carboxymethyl chitosan dispersed in the matrix; the matrix comprises a hydrogel solute; the mass ratio of the hydroxyapatite microspheres with pores filled by carboxymethyl chitosan to the matrix is ​​in the range of 1:(1-4); The implant filling material of the hydroxyapatite composite microspheres is prepared according to the following method: S1: using phosphoric acid and calcium hydroxide as raw materials to prepare hydroxyapatite precipitation; S2: drying and crushing the hydroxyapatite precipitate, and then sintering the obtained powder at 100° C.-200° C. to obtain sintered hydroxyapatite; S3: immersing the sintered hydroxyapatite in a carboxymethyl chitosan solution, pre-freezing at (-20)°C to (-40)°C, and then freeze-drying at (-30)°C to (-80)°C to obtain a freeze-dried product; S4: crushing and grinding the freeze-dried product, and then screening it through an ultrasonic vibration screen to obtain hydroxyapatite microspheres with carboxymethyl chitosan filled pores; S5: mixing the hydroxyapatite microspheres with pores filled with carboxymethyl chitosan with a matrix to obtain an implant filling material of hydroxyapatite composite microspheres.

2. The implant filling material of hydroxyapatite composite microspheres according to claim 1, characterized in that: The particle size of the hydroxyapatite microspheres with pores filled with carboxymethyl chitosan is in the range of 25-45 μm.

3. The implant filling material of hydroxyapatite composite microspheres according to claim 1, characterized in that: The hydrogel solute is selected from at least one of carboxymethyl chitosan, sodium carboxymethyl cellulose and sodium hyaluronate.

4. The implant filling material of hydroxyapatite composite microspheres according to claim 1, characterized in that: The hydroxyapatite precipitate described in step S1 is a needle / rod-shaped hydroxyapatite precipitate.

5. The implant filling material of hydroxyapatite composite microspheres according to claim 4, characterized in that: Step S1 includes: preparing phosphoric acid and calcium hydroxide into solutions respectively, mixing and stirring the two solutions at a calcium-phosphorus ratio of 1.66-1.71, adding potassium sulfate as an electrolyte, and then performing electrochemical precipitation to obtain hydroxyapatite precipitate.

6. The implant filling material of hydroxyapatite composite microspheres according to claim 1, characterized in that: The mass fraction of the carboxymethyl chitosan solution in step S3 is 2%-5%.

7. The implant filling material of hydroxyapatite composite microspheres according to claim 1, characterized in that: The moisture content of the freeze-dried product in step S3 is in the range of 3%-5%.

8. The implant filling material of hydroxyapatite composite microspheres according to any one of claims 1 to 7, characterized in that: The matrix in step S5 is prepared as follows: after mixing the hydrogel solute with water, glycerol is added to obtain the matrix.

9. The implant filling material of hydroxyapatite composite microspheres according to claim 8, characterized in that: The mass ratio of the hydrogel solute, the water and the glycerol is (0.5-5):(40-75):(1-10).