Porous microsphere composite sodium hyaluronate gel and preparation method thereof

Abstract

The invention relates to the technical field of biological medicine, in particular to porous microsphere composite sodium hyaluronate gel and a preparation method thereof. The preparation method comprises the following steps: preparing porous hydroxyapatite microspheres by using a spray drying method, physically mixing the porous hydroxyapatite microspheres with a sodium hyaluronate solution, adding the mixture into polysaccharide polymer gel, uniformly dispersing the porous microspheres in the gel, performing vacuum filling in a pre-filling syringe, and performing high-pressure steam sterilization to obtain the porous hydroxyapatite hydrogel. The composite sodium hyaluronate gel containing the porous microspheres is obtained. The sodium hyaluronate is of a non-crosslinking type, the safety problem caused by residues of a chemical crosslinking agent is avoided, and the effects of immediate filling and collagen regeneration promoting are achieved by introducing the active material porous microspheres. The filling effect of the prepared gel can last for 12-18 months, and the gel can be safely degraded, can be prepared on a large scale and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to a porous microsphere composite sodium hyaluronate gel and a preparation method thereof. Background Art

[0002] Hyaluronic acid is a natural straight-chain polysaccharide existing in human and animal tissues. It is mainly distributed in the vitreous body, joints, umbilical cord, skin and other parts of the human body. Hyaluronic acid has good physical and chemical properties and biological activity such as water retention, lubricity, viscoelasticity, biodegradability and biocompatibility. Due to cost and safety issues, hyaluronic acid has replaced collagen as the mainstream material. However, hyaluronic acid products have the following defects: 1. The cost is high, and one injection costs thousands to tens of thousands of yuan. 2. The maintenance time is short. It is basically degraded and absorbed in the body in about 6 months. Consumers need to re-inject, which increases the burden and pain of consumers. 3. It only has the effect of filling and tissue volume increase on the face, and cannot promote the synthesis of its own collagen, and cannot remove oxygen free radicals in the subcutaneous tissue of the face. 4. The bleeding of the injection product at the injection point of the skin is not considered, especially for hemophilia users, because the product itself has no hemostatic function. If bleeding problems occur, it will be life-threatening. 5. The cross-linking agent in hyaluronic acid can cause inflammation, skin allergies and other phenomena.

[0003] As the main component of human bones, hydroxyapatite has excellent biocompatibility and is a commonly used bone tissue engineering material. Hydroxyapatite microspheres can be used as human body filling materials, often used in facial filling, fat atrophy filling, etc. After hydroxyapatite is injected into the human body, it will form a human cell growth scaffold in the body, which not only provides a platform for cell growth, but also stimulates the body to accelerate the generation of filling cells, thereby forming a long-term filling effect.

[0004] Chinese patent CN117323471A uses hydroxyapatite to prolong the effect of hyaluronic acid. In order to overcome the problem of rapid degradation of hyaluronic acid, hydroxyapatite and other ingredients are added to prolong the effect of hyaluronic acid. However, the residue of the chemical cross-linking agent used may cause inflammation, allergies and other adverse reactions.

[0005] At present, the disclosed technical information related to injectable facial fillers for cosmetic surgery all revolve around technical issues such as prolonging the degradation time of hyaluronic acid and promoting collagen self-synthesis. The present invention is a new type of injectable gel that integrates antibacterial, anti-inflammatory, antioxidant, hemostatic functions and long-lasting effects. Summary of the invention

[0006] In order to achieve the above object, the present invention provides the following technical solutions:

[0007] The first aspect of the present invention provides a porous microsphere composite sodium hyaluronate gel, which comprises the following mass fractions: 1-30% porous hydroxyapatite microspheres; 1-3% sodium hyaluronate solution; 0.5-4% polysaccharide polymer; 0.5-1.5% glycerol; 1-5% mannitol; 0.1-0.2% L-carnosine; 0.01-0.05% platelet-rich plasma; 0-0.4% anesthetic; and the rest is aqueous solution for injection.

[0008] Furthermore, the particle size of the porous hydroxyapatite microspheres ranges from 5 μm to 50 μm.

[0009] Furthermore, the porous hydroxyapatite microspheres have a particle size range of 10 μm-30 μm.

[0010] Furthermore, the concentration of the sodium hyaluronate solution is 10-30 mg / ml, and the molecular weight is 1-3 million Da.

[0011] Furthermore, the concentration of the sodium hyaluronate solution is 10 mg / ml and the molecular weight is 200,000-1,000,000 Da.

[0012] Furthermore, the polysaccharide polymer is one of sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose.

[0013] Furthermore, the polysaccharide polymer is sodium carboxymethyl cellulose.

[0014] Furthermore, the anesthetic is one of lidocaine, procaine, bupivacaine, and ropivacaine.

[0015] Furthermore, the anesthetic is lidocaine.

[0016] The second aspect of the present invention provides a method for preparing the porous microsphere composite sodium hyaluronate gel, comprising the following steps:

[0017] S1, preparation of porous hydroxyapatite microspheres using spray drying method;

[0018] S2, physically mixing the porous hydroxyapatite microspheres prepared in S1 with the sodium hyaluronate solution to obtain a mixture;

[0019] S3, adding the mixture described in S2 to a uniformly swollen polysaccharide polymer gel, wherein the polysaccharide polymer gel is obtained by fully and uniformly swelling sodium carboxymethyl cellulose, glycerol, mannitol, L-carnosine, platelet-rich plasma and an aqueous solution for injection in a constant temperature oscillator, so that the porous hydroxyapatite microspheres are uniformly dispersed in the polysaccharide polymer gel, vacuum-filling the mixture in a prefilled syringe, and sterilizing the mixture with high-pressure steam to obtain a porous microsphere-containing composite sodium hyaluronate gel.

[0020] Beneficial effects of the present invention:

[0021] The present invention is based on hyaluronic acid and combined with porous hydroxyapatite microspheres as an active material, which can not only play an instant filling role, but also promote tissue regeneration. The L-carnosine in the porous microsphere composite sodium hyaluronate gel provided by the present invention plays an antioxidant role, inhibits the degradation of non-cross-linked sodium hyaluronate by free radicals, increases its degradation time to ensure the growth of its own cells and the production of structural substances after injection into the skin tissue, and plays a filling, shaping and other effects. At the same time, it can be maintained in the body for a long time and can be safely degraded; mannitol in the porous microsphere composite sodium hyaluronate gel component, as a polyol compound, has excellent moisturizing, anti-inflammatory, antibacterial and permeability characteristics, and mannitol also has significant anti-inflammatory and antibacterial effects. When the skin is damaged or stimulated by external factors, mannitol can respond quickly, inhibit inflammatory reactions, and relieve skin discomfort. Its antibacterial properties can resist the invasion of harmful microorganisms and protect the skin from infection. The platelet-rich plasma (PRP) added to the porous microsphere composite sodium hyaluronate gel is rich in various growth factors and cytokines, which helps tissue repair, angiogenesis, anti-inflammation, and promote collagen synthesis.

[0022] (1) The sodium hyaluronate of the present invention is non-cross-linked, thus avoiding the safety issues caused by the residual chemical cross-linking agent;

[0023] (2) By introducing active material porous microspheres, it plays an immediate role in filling and promoting collagen regeneration;

[0024] (3) L-carnosine has an antioxidant effect and can effectively inhibit the degradation of sodium hyaluronate by free radicals;

[0025] (4) The gel filling effect prepared by the present invention can last for 12 to 18 months and can be safely degraded;

[0026] (5) The gel prepared by the present invention has antibacterial, anti-inflammatory, antioxidant and hemostatic functions, and the process is simple, can be prepared in large quantities, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is a scanning electron microscope (SEM) image of the hydroxyapatite microspheres of the present invention.

[0028] Figure 2 for Figure 1 Partial enlargement.

[0029] Figure 3 The porous microsphere composite sodium hyaluronate gel product is prepared in implementation 1.

[0030] Figure 4 The porous microsphere composite sodium hyaluronate gel product is prepared in Implementation 2. DETAILED DESCRIPTION

[0031] The specific implementation modes of the present invention are described below so that those skilled in the art can understand the present invention. However, it should be clear that the present invention is not limited to the scope of the specific implementation modes. For those of ordinary skill in the art, as long as various changes are within the spirit and scope of the present invention as defined and determined by the attached claims, these changes are obvious, and all inventions and creations utilizing the concept of the present invention are protected.

[0032] Embodiment 1:

[0033] S1. Preparation of porous hydroxyapatite microspheres

[0034] (1) preparing a hydroxyapatite suspension: preparing a hydroxyapatite aqueous solution with a mass concentration of 30%, placing it in a planetary ball mill for 20 minutes to obtain a hydroxyapatite suspension;

[0035] (2) preparing a 7% NH4HCO3 solution;

[0036] (3) adding the NH4HCO3 solution of step (2) into the hydroxyapatite suspension of step (1) at a mass ratio of 1:1, and stirring and mixing to obtain a mixed solution;

[0037] (4) subjecting the mixed solution obtained in step (3) to centrifugal spray drying and calcination to obtain hydroxyapatite porous microspheres;

[0038] (5) Use machine sieving method to collect microspheres within the target particle size range of 10-30 μm.

[0039] S2. 1 g of porous hydroxyapatite microspheres and 1 g of sodium hyaluronate solution were homogenized in a high-speed homogenizer for 1 min to obtain a mixed system;

[0040] S3. 3 g of sodium carboxymethyl cellulose, 0.5 g of glycerol, 1.5 g of mannitol, 0.2 g of L-carnosine, 0.03 g of platelet-rich plasma, 0 g of lidocaine, and 92.77 g of an aqueous solution for injection were fully swollen and uniformly dissolved in a thermostatic oscillator to obtain a polysaccharide polymer gel;

[0041] S4. The mixed system of S2 is added to the polysaccharide polymer gel of S3, and stirred evenly under vacuum to obtain a gel mixture;

[0042] S5. Fill 1 ml of the gel-like mixture stirred evenly in step S4 into a prefilled syringe, and sterilize it by high-pressure steam at 121° C. for 15-30 min to obtain the porous microsphere composite sodium hyaluronate gel.

[0043] Embodiment 2:

[0044] S1. Preparation of porous hydroxyapatite microspheres

[0045] (1) preparing a hydroxyapatite suspension: preparing a hydroxyapatite aqueous solution with a mass concentration of 30%, placing it in a planetary ball mill for 10 minutes to obtain a hydroxyapatite suspension;

[0046] (2) preparing a 7% NH4HCO3 solution;

[0047] (3) adding the NH4HCO3 solution of step (2) into the hydroxyapatite suspension of step (1) at a mass ratio of 1:1, and stirring and mixing to obtain a mixed solution;

[0048] (4) subjecting the mixed solution obtained in step (3) to centrifugal spray drying and calcination to obtain hydroxyapatite porous microspheres;

[0049] (5) Use machine sieving method to collect microspheres within the target particle size range of 20-30 μm.

[0050] S2. 20 g of porous hydroxyapatite microspheres and 3 g of sodium hyaluronate solution were homogenized in a high-speed homogenizer for 2 min to obtain a mixed system;

[0051] S3. 3.5 g of sodium carboxymethyl cellulose, 0.5 g of glycerol, 1.5 g of mannitol, 0.2 g of L-carnosine, 0.03 g of platelet-rich plasma (PRP), 0.03 g of lidocaine, and 71.24 g of an aqueous solution for injection were fully swollen and uniformly dissolved in a constant temperature oscillator to obtain a polysaccharide polymer gel;

[0052] S4. The mixed system of S2 is added to the polysaccharide polymer gel of S3, and stirred evenly under vacuum to obtain a gel mixture;

[0053] S5. Fill 1 ml of the gel-like mixture stirred evenly in step S4 into a prefilled syringe, and sterilize it by high-pressure steam at 121° C. for 15-30 min to obtain the porous microsphere composite sodium hyaluronate gel.

[0054] The present invention uses specific embodiments to illustrate the principles and implementation methods of the present invention. The description of the above embodiments is only used to help understand the method of the present invention and its core idea. At the same time, for those skilled in the art, according to the idea of ​​the present invention, there will be changes in the scope of the specific implementation methods. In summary, the content of this specification should not be understood as limiting the present invention.

Claims

1. A porous microsphere composite sodium hyaluronate gel, characterized in that: The invention comprises the following mass fractions: porous hydroxyapatite microspheres 1-30%; sodium hyaluronate solution 1-3%; polysaccharide polymer 0.5-4%; glycerol 0.5-1.5%; mannitol 1-5%; L-carnosine 0.1-0.2%; platelet-rich plasma 0.01-0.05%; anesthetic 0-0.4%; the rest is aqueous solution for injection.

2. The porous microsphere composite sodium hyaluronate gel according to claim 1, characterized in that: The particle size of the porous hydroxyapatite microspheres ranges from 5 μm to 50 μm.

3. The porous microsphere composite sodium hyaluronate gel according to claim 2, characterized in that: The particle size of the porous hydroxyapatite microspheres ranges from 10 μm to 30 μm.

4. The porous microsphere composite sodium hyaluronate gel according to claim 1, characterized in that: The concentration of the sodium hyaluronate solution is 10-30 mg / ml, and the molecular weight is 1-3 million Da.

5. The porous microsphere composite sodium hyaluronate gel according to claim 4, characterized in that: The concentration of the sodium hyaluronate solution is 10 mg / ml, and the molecular weight is 200,000-1,000,000 Da.

6. The porous microsphere composite sodium hyaluronate gel according to claim 1, characterized in that: The polysaccharide polymer is one of sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose.

7. The porous microsphere composite sodium hyaluronate gel according to claim 6, characterized in that: The polysaccharide polymer is sodium carboxymethyl cellulose.

8. The porous microsphere composite sodium hyaluronate gel according to claim 1, characterized in that: The anesthetic is one of lidocaine, procaine, bupivacaine, and ropivacaine.

9. The porous microsphere composite sodium hyaluronate gel according to claim 8, characterized in that: The anesthetic is lidocaine.

10. A method for preparing the porous microsphere composite sodium hyaluronate gel according to any one of claims 1 to 9, characterized in that: The steps include: S1, preparation of porous hydroxyapatite microspheres using spray drying method; S2, physically mixing the porous hydroxyapatite microspheres prepared in S1 with the sodium hyaluronate solution to obtain a mixture; S3, adding the mixture described in S2 to a uniformly swollen polysaccharide polymer gel, wherein the polysaccharide polymer gel is obtained by fully and uniformly swelling sodium carboxymethyl cellulose, glycerol, mannitol, L-carnosine, platelet-rich plasma and an aqueous solution for injection in a constant temperature oscillator, so that the porous hydroxyapatite microspheres are uniformly dispersed in the polysaccharide polymer gel, vacuum-filling the mixture in a prefilled syringe, and sterilizing the mixture with high-pressure steam to obtain a porous microsphere-containing composite sodium hyaluronate gel.

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