Human soft tissue filling material and method for preparing the same
By combining cross-linked zinc hyaluronic acid gel with bioglass and hydroxyapatite, a filler material with slow degradation and good antibacterial properties was prepared, which solved the problems of easy displacement and poor antibacterial properties of existing sodium hyaluronic acid gel, reduced the number of injections, and lowered medical costs.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- HEBEI YOUGU BIOTECHNOLOGY CO LTD
- Filing Date
- 2023-06-02
- Publication Date
- 2026-06-26
AI Technical Summary
Existing soft tissue filler materials, such as sodium hyaluronate gel, have problems such as poor antibacterial properties, rapid degradation, and easy displacement, which leads to the need for repeated injections, increasing patients' medical expenses and time costs.
Human soft tissue filler materials are prepared by combining cross-linked zinc hyaluronic acid gel with materials such as bioglass and hydroxyapatite through a specific process. This process includes the preparation of cross-linked zinc hyaluronic acid gel and bioglass. After mixing, a filler material with excellent biocompatibility and antibacterial properties is formed.
It achieves a filling effect with slow degradation, good antibacterial properties, and minimal displacement, reducing the number of injections, lowering medical costs, and extending the duration of the filling effect.
Smart Images
Figure BDA0004263881160000081 
Figure BDA0004263881160000091
Abstract
Description
Technical Field
[0001] This invention belongs to the field of biomaterials technology, specifically relating to a human soft tissue filling material and its preparation method. Background Technology
[0002] Among soft tissue fillers, the main types are silicone and expanded polytetrafluoroethylene (ePTFE), as well as hyaluronic acid and fat. Hyaluronic acid is quite common in the cosmetic industry, primarily containing sodium hyaluronate. It is generally used as a filler and has good gelling properties. However, sodium hyaluronate gel not only has poor antibacterial properties but also degrades rapidly, is prone to displacement, and cannot maintain its filling effect well, requiring repeated injections. This increases the cost of medical procedures for patients and wastes a significant amount of time for both medical staff and patients. Summary of the Invention
[0003] The purpose of this invention is to overcome the shortcomings of the prior art and provide a human soft tissue filling material with slow degradation rate, good antibacterial and biocompatibility, and low displacement, as well as its preparation method.
[0004] This invention provides the following technical solution:
[0005] In a first aspect, a human soft tissue filling material is provided, comprising the following components in parts by weight: 45-75 parts of cross-linked zinc hyaluronic acid gel, 30-50 parts of bioglass, 5-15 parts of hydroxyapatite, 0.5-5 parts of glycerin, 0.1-0.25 parts of lidocaine hydrochloride, and 0.1-0.7 parts of dexamethasone.
[0006] Furthermore, the bioglass comprises the following components in parts by weight: 50-55 parts silicon dioxide, 12-15 parts sodium bicarbonate, 18-22 parts calcium oxide, 6-8 parts calcium phosphate, 9.5-12 parts magnesium carbonate, and 14.8-20.5 parts potassium carbonate.
[0007] In a second aspect, a method for preparing the human soft tissue filling material described in the first aspect is provided, comprising the following steps:
[0008] pH was adjusted by adding an acid-base regulator to the zinc hyaluronic acid solution, and then a cross-linking agent was added. The solution was heated and kept at a certain temperature, and then cooled to room temperature to obtain crude cross-linked zinc hyaluronic acid gel. The crude cross-linked zinc hyaluronic acid gel was purified, granulated, packaged, and sterilized to obtain cross-linked zinc hyaluronic acid gel.
[0009] Silica, sodium bicarbonate, calcium oxide, calcium phosphate, magnesium carbonate and potassium carbonate are mixed evenly in a weight ratio, heated and kept at a temperature in stages, then poured into deionized water for quenching, dried and ball-milled in stages, and sieved to separate particles of different particle sizes. The particles of each size are mixed in proportion to obtain bioglass.
[0010] Cross-linked zinc hyaluronic acid gel, bioglass, hydroxyapatite, glycerin, lidocaine hydrochloride, and dexamethasone were mixed in proportions by weight to obtain a human soft tissue filling material.
[0011] Furthermore, the specific preparation method of the cross-linked zinc hyaluronic acid gel includes: mixing zinc hyaluronic acid powder with physiological saline to obtain a zinc hyaluronic acid solution; adding an acid-base regulator to the zinc hyaluronic acid solution to adjust the pH value of the solution to 7.8-10.2, then adding a cross-linking agent, stirring and heating to 70-85℃, keeping it at that temperature for 12-20h, and then cooling to room temperature to obtain crude cross-linked zinc hyaluronic acid gel; purifying the crude cross-linked zinc hyaluronic acid gel with phosphate buffer for 18-72h, and finally granulating, dispensing, and moist heat sterilizing to obtain the final product.
[0012] Furthermore, the mass ratio of the zinc hyaluronic acid powder to physiological saline is 1:(22-25).
[0013] Furthermore, the acid-base regulator includes one or more of sodium hydroxide, potassium hydroxide, sodium citrate, triethanolamine, hydrochloric acid, citric acid, acetic acid, and carbonic acid.
[0014] Furthermore, the crosslinking agent includes one of butylene glycol glycidyl ether, divinyl sulfone, oxalic acid dihydrazide, carbodiimide, and glycidyl methacrylate.
[0015] Furthermore, the phosphate buffer solution includes ammonium dihydrogen phosphate or diammonium hydrogen phosphate.
[0016] Furthermore, the specific method for staged heating and heat preservation includes: heating to 550℃ and holding for 30 minutes, continuing to heat to 850℃ and holding for 45 minutes, then heating to 1200℃ and holding for 24 minutes, and finally heating to 1450-1520℃ and holding for 60 minutes.
[0017] Furthermore, after the grading ball milling, particles with particle sizes of 1-20μm, 20-120μm, 120-350μm and 350-550μm are screened out, and the four are mixed in a mass ratio of (25-40):(20-30):(15-35):(5-30).
[0018] Compared with the prior art, the beneficial effects of the present invention are:
[0019] (1) The human soft tissue filling material provided by the present invention includes cross-linked zinc hyaluronic acid gel, which has the characteristics of slow degradation and does not require repeated injections. The zinc ions contained therein have antibacterial and anti-inflammatory effects and are crucial for the normal development of various cells and the natural and acquired immune functions, such as neutrophils, natural killer cells, macrophages, T cells, etc.
[0020] (2) The human soft tissue filling material provided by the present invention includes bioglass and hydroxyapatite, which can be used as a filling material for human bone defects. It is also currently an active material that can be used for both hard tissue repair and soft tissue repair. Bioglass is an inorganic silicate material containing potassium and magnesium, which has excellent mechanical properties, biocompatibility and antibacterial properties. When it is mixed with cross-linked zinc hyaluronic acid gel and implanted into human soft tissue, the shaping time of the soft tissue after filling can be greatly extended. At the same time, because bioglass and hydroxyapatite are powder particles, they are more likely to provide support and are less prone to displacement.
[0021] (3) The preparation method of human soft tissue filling material provided by the present invention is simple, easy to operate, low in cost, and conducive to promotion and use. Detailed Implementation
[0022] The following embodiments are only used to illustrate the technical solutions of the present invention more clearly, and should not be used to limit the scope of protection of the present invention.
[0023] Example 1
[0024] This embodiment provides a human soft tissue filling material, the preparation method of which is as follows:
[0025] Step 1: Preparation of cross-linked zinc hyaluronic acid gel.
[0026] Zinc hyaluronic acid powder and physiological saline were mixed evenly at a mass ratio of 1:22 to obtain a zinc hyaluronic acid solution. Sodium hydroxide was added to the zinc hyaluronic acid solution to adjust the pH to 10, and then butylene glycol glycidyl ether was added. The mixture was stirred and heated to 70°C, kept at this temperature for 20 hours, and then cooled to room temperature to obtain a crude cross-linked zinc hyaluronic acid gel. The crude cross-linked zinc hyaluronic acid gel was purified for 20 hours using ammonium dihydrogen phosphate buffer. Finally, the product was granulated, dispensed, and sterilized by moist heat to obtain the cross-linked zinc hyaluronic acid gel.
[0027] Step 2: Preparation of bioglass.
[0028] 50 parts of silicon dioxide, 12 parts of sodium bicarbonate, 18 parts of calcium oxide, 6 parts of calcium phosphate, 9.5 parts of magnesium carbonate, and 14.8 parts of potassium carbonate were mixed evenly and added to a crucible. The mixture was heated to 550℃ and held for 30 min, then heated to 850℃ and held for 45 min, then heated to 1200℃ and held for 24 min, and finally heated to 1450℃ and held for 60 min. The mixture was then poured into deionized water for quenching, dried, and then ball-milled in stages. Particles with diameters of 1-20 μm, 20-120 μm, 120-350 μm, and 350-550 μm were sieved out. The four components were then mixed in a mass ratio of 25:30:15:30 to obtain bioglass.
[0029] Step 3: Preparation of human soft tissue filling materials.
[0030] A mixture of 45 parts cross-linked zinc hyaluronic acid gel, 30 parts bioglass, 15 parts hydroxyapatite, 0.5 parts glycerin, 0.1 parts lidocaine hydrochloride, and 0.1 parts dexamethasone was prepared to obtain a human soft tissue filling material.
[0031] Example 2
[0032] This embodiment provides a human soft tissue filling material, the preparation method of which is as follows:
[0033] Step 1: Preparation of cross-linked zinc hyaluronic acid gel.
[0034] Zinc hyaluronic acid powder and physiological saline were mixed evenly at a mass ratio of 1:23 to obtain a zinc hyaluronic acid solution. Potassium hydroxide was added to the zinc hyaluronic acid solution to adjust the pH to 9, and then divinyl sulfone was added. The mixture was stirred and heated to 85°C, kept at this temperature for 12 hours, and then cooled to room temperature to obtain a crude cross-linked zinc hyaluronic acid gel. The crude cross-linked zinc hyaluronic acid gel was purified for 72 hours using diammonium hydrogen phosphate buffer. Finally, the product was granulated, dispensed, and sterilized by moist heat to obtain the cross-linked zinc hyaluronic acid gel.
[0035] Step 2: Preparation of bioglass.
[0036] 53 parts of silicon dioxide, 13 parts of sodium bicarbonate, 20 parts of calcium oxide, 7 parts of calcium phosphate, 11 parts of magnesium carbonate, and 18 parts of potassium carbonate were mixed evenly and added to a crucible. The mixture was heated to 550℃ and held for 30 min, then heated to 850℃ and held for 45 min, then heated to 1200℃ and held for 24 min, and finally heated to 1500℃ and held for 60 min. The mixture was then poured into deionized water for quenching, dried, and ball-milled to separate particles with diameters of 1-20 μm, 20-120 μm, 120-350 μm, and 350-550 μm. The four components were then mixed in a mass ratio of 40:20:35:5 to obtain bioglass.
[0037] Step 3: Preparation of human soft tissue filling materials.
[0038] A mixture of 50 parts cross-linked zinc hyaluronic acid gel, 37 parts bioglass, 8 parts hydroxyapatite, 3 parts glycerin, 0.2 parts lidocaine hydrochloride, and 0.3 parts dexamethasone was prepared to obtain a human soft tissue filling material.
[0039] Example 3
[0040] This embodiment provides a human soft tissue filling material, the preparation method of which is as follows:
[0041] Step 1: Preparation of cross-linked zinc hyaluronic acid gel.
[0042] Zinc hyaluronic acid powder and physiological saline were mixed evenly at a mass ratio of 1:23 to obtain a zinc hyaluronic acid solution. Sodium citrate was added to the zinc hyaluronic acid solution to adjust the pH to 7.8, and then oxalic acid dihydrazide was added. The mixture was stirred and heated to 75°C, kept at this temperature for 14 hours, and then cooled to room temperature to obtain a crude cross-linked zinc hyaluronic acid gel. The crude cross-linked zinc hyaluronic acid gel was purified for 36 hours using ammonium dihydrogen phosphate or diammonium hydrogen phosphate. Finally, the product was granulated, packaged, and sterilized by moist heat to obtain the cross-linked zinc hyaluronic acid gel.
[0043] Step 2: Preparation of bioglass.
[0044] 53 parts of silicon dioxide, 14 parts of sodium bicarbonate, 20 parts of calcium oxide, 7 parts of calcium phosphate, 10 parts of magnesium carbonate, and 18 parts of potassium carbonate were mixed evenly and added to a crucible. The mixture was heated to 550℃ and held for 30 min, then heated to 850℃ and held for 45 min, then heated to 1200℃ and held for 24 min, and finally heated to 1500℃ and held for 60 min. The mixture was then poured into deionized water for quenching, dried, and ball-milled to separate particles with diameters of 1-20 μm, 20-120 μm, 120-350 μm, and 350-550 μm. The four components were then mixed in a mass ratio of 30:25:25:20 to obtain bioglass.
[0045] Step 3: Preparation of human soft tissue filling materials.
[0046] A mixture of 63 parts cross-linked zinc hyaluronic acid gel, 42 parts bioglass, 10 parts hydroxyapatite, 3.5 parts glycerin, 0.15 parts lidocaine hydrochloride, and 0.4 parts dexamethasone was prepared to obtain a human soft tissue filling material.
[0047] Example 4
[0048] This embodiment provides a human soft tissue filling material, the preparation method of which is as follows:
[0049] Step 1: Preparation of cross-linked zinc hyaluronic acid gel.
[0050] Zinc hyaluronic acid powder and physiological saline were mixed evenly at a mass ratio of 1:25 to obtain a zinc hyaluronic acid solution. Sodium hydroxide was added to the zinc hyaluronic acid solution to adjust the pH value to 8.5, and then carbodiimide was added. The mixture was stirred and heated to 80°C, kept at this temperature for 16 hours, and then cooled to room temperature to obtain a crude cross-linked zinc hyaluronic acid gel. The crude cross-linked zinc hyaluronic acid gel was purified for 48 hours using (ammonium dihydrogen phosphate or diammonium hydrogen phosphate). Finally, the product was granulated, packaged, and sterilized by moist heat to obtain the cross-linked zinc hyaluronic acid gel.
[0051] Step 2: Preparation of bioglass.
[0052] 55 parts of silicon dioxide, 15 parts of sodium bicarbonate, 22 parts of calcium oxide, 8 parts of calcium phosphate, 12 parts of magnesium carbonate, and 20.5 parts of potassium carbonate were mixed evenly and added to a crucible. The mixture was heated to 550℃ and held for 30 min, then heated to 850℃ and held for 45 min, then heated to 1200℃ and held for 24 min, and finally heated to 1520℃ and held for 60 min. The mixture was then poured into deionized water for quenching, dried, and then ball-milled in stages. Particles with diameters of 1-20 μm, 20-120 μm, 120-350 μm, and 350-550 μm were sieved out. The four components were then mixed in a mass ratio of 35:28:18:20 to obtain bioglass.
[0053] Step 3: Preparation of human soft tissue filling materials.
[0054] A human soft tissue filling material was obtained by mixing 75 parts of cross-linked zinc hyaluronic acid gel, 50 parts of bioglass, 5 parts of hydroxyapatite, 5 parts of glycerin, 0.25 parts of lidocaine hydrochloride, and 0.7 parts of dexamethasone.
[0055] Comparative Example 1
[0056] Sodium hyaluronate powder and physiological saline were mixed evenly at a mass ratio of 1:23 to obtain a sodium hyaluronate solution. Potassium hydroxide was added to the sodium hyaluronate solution to adjust the pH to 9, and then divinyl sulfone was added. The mixture was stirred and heated to 85°C, kept at this temperature for 12 hours, and then cooled to room temperature to obtain a crude cross-linked sodium hyaluronate gel. The crude cross-linked sodium hyaluronate gel was purified using diammonium hydrogen phosphate buffer for 72 hours. Finally, it was granulated, dispensed, and sterilized by moist heat to obtain the cross-linked sodium hyaluronate gel, which is used as a soft tissue filler material for human bodies.
[0057] Comparative Example 2
[0058] Cross-linked sodium hyaluronate gel was prepared according to the method in Comparative Example 1. 50 parts of cross-linked sodium hyaluronate gel, 3 parts of glycerin, 0.2 parts of lidocaine hydrochloride and 0.3 parts of dexamethasone were mixed and used as a soft tissue filler for human body.
[0059] Performance Comparison
[0060] 1. Antibacterial properties.
[0061] Antibacterial tests were conducted using *Escherichia coli* and *Staphylococcus aureus* on the human soft tissue filling materials prepared in Examples 1-4 and Comparative Examples 1-2, as well as the control sample (silica powder, which has no antibacterial effect and does not affect the determination of experimental results). The initial inoculation count of *Escherichia coli* was 3.5 × 10⁻⁶ colonies. 4 The initial inoculation count of Staphylococcus aureus was 4.2 × 10⁻⁶ CFU / mL. 4 The cfu / mL count was determined by incubation at 37℃ for 18 hours, followed by viable cell count. The results are shown in Table 1 below.
[0062] Table 1 Results of antibacterial test
[0063]
[0064]
[0065] As shown in Table 1, compared with Comparative Examples 1-2, the human soft tissue filling materials prepared in Examples 1-4 of the present invention have good antibacterial properties.
[0066] 2. Degradation performance.
[0067] The human soft tissue filling materials prepared in Examples 1-4 and Comparative Examples 1-2 were placed in a hyaluronidase solution of the same concentration (30 U / mL) for accelerated degradation. The degradation rate was calculated after a certain period of time, and the results are shown in Table 2 below.
[0068] Table 2 Degradation rate results
[0069] sample Degradation rate (%) in 12 hours 24h degradation rate (%) Degradation rate (%) after 48 hours Example 1 4.4 5.5 7.1 Example 2 4.3 5.3 7.8 Example 3 3.9 4.9 7.6 Example 4 4.2 5.3 8.0 Comparative Example 1 7.9 8.7 11 Comparative Example 2 8.1 9.6 12
[0070] As shown in Table 2, compared with Comparative Examples 1-2, the human soft tissue filling materials prepared in Examples 1-4 of the present invention degrade more slowly, so they are less prone to deformation and displacement after use and do not require repeated injections.
[0071] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the technical principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. A human soft tissue filling material, characterized in that, It includes the following components in parts by weight: 45-75 parts cross-linked zinc hyaluronic acid gel, 30-50 parts bioglass, 5-15 parts hydroxyapatite, 0.5-5 parts glycerin, 0.1-0.25 parts lidocaine hydrochloride, and 0.1-0.7 parts dexamethasone. The bioglass comprises the following components in parts by weight: 50-55 parts silicon dioxide, 12-15 parts sodium bicarbonate, 18-22 parts calcium oxide, 6-8 parts calcium phosphate, 9.5-12 parts magnesium carbonate, and 14.8-20.5 parts potassium carbonate. The preparation method of the bioglass includes: mixing silicon dioxide, sodium bicarbonate, calcium oxide, calcium phosphate, magnesium carbonate and potassium carbonate in a weight ratio, heating and keeping at a temperature in stages, quenching in deionized water, drying, ball milling in stages, sieving out particles of different particle sizes, mixing particles of different sizes in a ratio to obtain bioglass. The specific method for graded heating and heat preservation includes: heating to 550℃ and holding for 30 minutes, continuing to heat to 850℃ and holding for 45 minutes, then heating to 1200℃ and holding for 24 minutes, and finally heating to 1450-1520℃ and holding for 60 minutes. After the grading ball milling, particles with particle sizes of 1-20μm, 20-120μm, 120-350μm and 350-550μm are sieved out, and the four particles are mixed in a mass ratio of (25-40):(20-30):(15-35):(5-30).
2. A method for preparing the human soft tissue filling material according to claim 1, characterized in that, Includes the following steps: pH was adjusted by adding an acid-base regulator to the zinc hyaluronic acid solution, and then a cross-linking agent was added. The solution was heated and kept at a certain temperature, and then cooled to room temperature to obtain crude cross-linked zinc hyaluronic acid gel. The crude cross-linked zinc hyaluronic acid gel was purified, granulated, packaged, and sterilized to obtain cross-linked zinc hyaluronic acid gel. Silica, sodium bicarbonate, calcium oxide, calcium phosphate, magnesium carbonate and potassium carbonate are mixed evenly in a weight ratio, heated and kept at a temperature in stages, then poured into deionized water for quenching, dried and ball-milled in stages, and sieved to separate particles of different particle sizes. The particles of each size are mixed in proportion to obtain bioglass. Cross-linked zinc hyaluronic acid gel, bioglass, hydroxyapatite, glycerin, lidocaine hydrochloride, and dexamethasone were mixed in proportions by weight to obtain a human soft tissue filling material.
3. The method for preparing human soft tissue filling material according to claim 2, characterized in that, The specific preparation method of the cross-linked zinc hyaluronic acid gel includes: mixing zinc hyaluronic acid powder with physiological saline to obtain a zinc hyaluronic acid solution; adding an acid-base regulator to the zinc hyaluronic acid solution to adjust the pH value of the solution to 7.8-10.2, then adding a cross-linking agent, stirring and heating to 70-85℃, keeping it at this temperature for 12-20h, and then cooling to room temperature to obtain crude cross-linked zinc hyaluronic acid gel; purifying the crude cross-linked zinc hyaluronic acid gel with phosphate buffer for 18-72h, and finally granulating, dispensing, and sterilizing by moist heat to obtain the final product.
4. The method for preparing the human soft tissue filling material according to claim 3, characterized in that, The mass ratio of zinc hyaluronic acid powder to physiological saline is 1:(22-25).
5. The method for preparing human soft tissue filling material according to claim 2, characterized in that, The acid-base regulator includes one or more of sodium hydroxide, potassium hydroxide, sodium citrate, triethanolamine, hydrochloric acid, citric acid, acetic acid, and carbonic acid.
6. The method for preparing human soft tissue filling material according to claim 2, characterized in that, The crosslinking agent includes one of butylene glycol glycidyl ether, divinyl sulfone, oxalic acid dihydrazide, and carbodiimide.
7. The method for preparing the human soft tissue filling material according to claim 3, characterized in that, The phosphate buffer solution includes ammonium dihydrogen phosphate or diammonium hydrogen phosphate.