Hydroxyapatite microsphere-containing composite solution for injection as well as preparation method and application thereof

Abstract

The invention relates to the technical field of biomedical materials, in particular to a preparation method of a hydroxyapatite microsphere-containing composite solution for injection, which comprises the following steps: S1, adding a high-molecular polymer, a local anesthetic and nutritional ingredient dry powder into a buffer salt solution according to a certain proportion, and stirring until complete dissolution; s2, adding the hydroxyapatite microspheres into the non-crosslinking composite solution, and blending until the hydroxyapatite microspheres are uniformly dispersed; and S3, filling, centrifugally defoaming and carrying out moist heat sterilization to obtain the hydroxyapatite-containing composite solution for injection. The composite solution containing hydroxyapatite microspheres for injection is prepared by the preparation method. The composite solvent is applied to the fields of wrinkle filling and repairing and tissue engineering materials. The hydroxyapatite microsphere prepared by the method does not contain chemical cross-linking agent residues, is smooth in pushing, and can greatly improve the solid content of the hydroxyapatite microsphere, so that the safety, experience and repair effect of injection filling are improved.

Description

Technical Field

[0001] The invention relates to the technical field of biomedical materials, and in particular to a composite solution containing hydroxyapatite microspheres for injection, a preparation method and application thereof. Background Art

[0002] Hydroxyapatite is the main component of human and animal bones and is the most stable phase of calcium phosphate. Due to its good biocompatibility and collagen regeneration ability, hydroxyapatite has attracted extensive attention in the field of medical aesthetic injections. Its mechanism of action is mainly as follows: after injection, hydroxyapatite microspheres will recruit fibroblasts with a low-inflammatory stimulation effect, thereby inducing collagen regeneration.

[0003] Hydroxyapatite for medical aesthetic injection is mostly made of gel as a blending matrix, such as CN118178719A, which first obtains a mixed solution of hydroxyapatite and natural polymer materials, then adds a crosslinking agent, and repeatedly passes the mixed solution through an extrusion reactor for extrusion reaction. After the extrusion reaction, the hydroxyapatite composite hydrogel is prepared through a sieve. This method has uniform reaction and controllable conditions, and can avoid stratification, but the invention uses a chemical crosslinking agent, which has the potential toxicity problem of residues. Summary of the invention

[0004] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art, provide a composite solution containing hydroxyapatite microspheres for injection, a preparation method and its application, and solve the technical problem that the current hydroxyapatite microsphere solution uses a chemical cross-linking agent, resulting in the presence of potential toxic residues.

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

[0006] First aspect:

[0007] Provided is a method for preparing a composite solution containing hydroxyapatite microspheres for injection, comprising the following steps:

[0008] S1: preparing a non-cross-linked composite solution: adding a high molecular weight polymer, a local anesthetic, and a nutrient component dry powder to a buffered saline solution in a certain proportion, and stirring until completely dissolved;

[0009] S2: adding hydroxyapatite microspheres into the non-cross-linked composite solution and blending until uniformly dispersed;

[0010] S3: filling, centrifugal degassing, wet heat sterilization, and obtaining a hydroxyapatite-containing composite solution for injection.

[0011] Furthermore, the concentration of the non-crosslinked composite solution is 0.1 to 10%;

[0012] The mass ratio of the hydroxyapatite microspheres in the non-crosslinked composite solution is 0.1-70%, and the tap density is 0.5-2.0 g / cm 3 .

[0013] Furthermore, the high molecular polymer is one or more of sodium hyaluronate, collagen solution, cellulose, chitosan, silk fibroin, agarose, and gelatin;

[0014] The local anesthetic is one or more of lidocaine hydrochloride, procaine hydrochloride, tetracaine hydrochloride, ropivacaine hydrochloride, and bupivacaine hydrochloride;

[0015] The nutritional ingredients are one or more of amino acids, nicotinamide, nicotinamide adenine dinucleotide, polypeptides, proteins, polysaccharides, polyols, vitamins, and lipids.

[0016] Furthermore, the particle size of the hydroxyapatite microspheres is 1 to 100 μm.

[0017] Second aspect:

[0018] Provided is a composite solution containing hydroxyapatite microspheres for injection, characterized in that it is prepared by the above-mentioned preparation method;

[0019] The pH of the composite solution is 6.5-8.5, the osmotic pressure is 200-400 mOsmol / kg, and the shear viscosity is greater than 100000 mPa·s.

[0020] Furthermore, the pushing force of the composite solution is ≤10N.

[0021] Furthermore, the storage temperature of the composite solution is 2-30°C.

[0022] The third aspect:

[0023] Provided is the application of the above-mentioned composite solution containing hydroxyapatite microspheres for injection in the fields of wrinkle filling and repair and tissue engineering materials.

[0024] The beneficial effects of the present invention are:

[0025] The composite solution containing hydroxyapatite microspheres for injection of the present invention is in a non-crosslinked form, and there is no problem of crosslinking agent residue. A special parameter ratio is used to ensure that the hydroxyapatite microspheres can be stably dispersed in the non-crosslinked solution and do not settle during long-term storage. In addition, the non-crosslinked solution can significantly reduce the pushing force, increase the solid content of the hydroxyapatite microspheres, and better play the filling role.

[0026] The preparation method of the composite solution does not contain any chemical cross-linking agent residues, is smooth to push, and can greatly increase the solid content of hydroxyapatite microspheres, thereby improving the safety, experience and repair effect of injection filling.

[0027] The composite solution of the present invention blends hydroxyapatite microspheres with a high molecular polymer solution, so that the microspheres are uniformly suspended in the solution, and has high injection safety without introducing any chemical cross-linking agent or initiator;

[0028] The composite solution of the present invention has a pushing force of ≤10N in a prefilled syringe, which can significantly improve the feel of clinical injection.

[0029] The present invention uses a high molecular polymer solution as a matrix, which can greatly increase the solid content of hydroxyapatite microspheres and improve the clinical treatment effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0031] Figure 1 A schematic diagram of a composite solution containing hydroxyapatite microspheres being filled in a prefilled syringe;

[0032] Figure 2 This is a microscopic schematic diagram of the composite solution of Example 1;

[0033] Figure 3 is a microscopic schematic diagram of the composite solution of Example 4;

[0034] Figure 4 is a microscopic schematic diagram of the composite solution of Example 5;

[0035] Figure 5 The cell encapsulation effect of sodium hyaluronate containing hydroxyapatite microspheres after subcutaneous injection into mice in Example 1;

[0036] Figure 6 This is a bar graph of cell survival rate when sodium hyaluronate containing hydroxyapatite microspheres is co-cultured with cells in Example 1. DETAILED DESCRIPTION

[0037] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution of the present invention will be clearly and completely described below in conjunction with the accompanying drawings. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0038] As used herein, the phrases "in one embodiment," "according to one embodiment," "in some embodiments," and the like generally refer to the fact that the particular feature, structure, or characteristic following the phrase may be included in at least one embodiment of the present disclosure. Therefore, a particular feature, structure, or characteristic may be included in more than one embodiment of the present disclosure, so that these phrases do not necessarily refer to the same embodiment. As used herein, the terms "example," "exemplary," and the like are used to "serve as an example, instance, or illustration." Any implementation, aspect, or design described herein as "example" or "exemplary" is not necessarily to be construed as preferred or superior to other implementations, aspects, or designs. On the contrary, the use of the terms "example," "exemplary," and the like is intended to present concepts in a concrete manner.

[0039] Herein, example embodiments of the present disclosure will be described in more detail with reference to the accompanying drawings. As used herein, expressions such as "at least one of..." modify the entire list of elements when following a list of elements, rather than modifying individual elements in the list. For example, the expression "at least one of a, b, and c" should be understood to include only a, only b, only c, both a and b, both a and c, both b and c, or all of a, b, and c.

[0040] The terms used herein are only used to describe specific exemplary configurations and are not intended to be limited. As used herein, the singular articles "one", "an" and "the" may also be intended to include plural forms, unless it is clearly indicated above that this is not the case. The terms "comprise", "include" and "have" are inclusive, and therefore specify the presence of features, steps, operations, elements and / or components, but do not exclude the presence or addition of one or more other features, steps, operations, elements, components and / or combinations thereof. The method steps, processes and operations described herein should not be interpreted as necessarily requiring them to be performed in the specific order discussed or shown, unless specifically identified as an execution order. Additional or alternative steps may be adopted.

[0041] Some embodiments of the present invention are described in detail below in conjunction with the accompanying drawings. In the absence of conflict, the following embodiments and features in the embodiments can be combined with each other.

[0042] The present disclosure provides a method for preparing a composite solution containing hydroxyapatite microspheres for injection, comprising the following steps:

[0043] S1: preparing a non-cross-linked composite solution: adding a high molecular weight polymer, a local anesthetic, and a nutrient component dry powder to a buffered saline solution in a certain proportion, and stirring until completely dissolved;

[0044] S2: adding hydroxyapatite microspheres into the non-cross-linked composite solution and blending until uniformly dispersed;

[0045] S3: filling, centrifugal degassing, wet heat sterilization, and obtaining a hydroxyapatite-containing composite solution for injection.

[0046] In some embodiments, specifically, the concentration of the non-cross-linked composite solution is 0.1-10%; the mass ratio of the hydroxyapatite microspheres in the non-cross-linked composite solution is 0.1-70%, and the tap density is 0.5-2.0 g / cm3.

[0047] In some embodiments, specifically, the high molecular polymer is one or more of sodium hyaluronate, collagen solution, cellulose, chitosan, silk fibroin, agarose, and gelatin;

[0048] The local anesthetic is one or more of lidocaine hydrochloride, procaine hydrochloride, tetracaine hydrochloride, ropivacaine hydrochloride, and bupivacaine hydrochloride;

[0049] The nutritional ingredients are one or more of amino acids, nicotinamide, nicotinamide adenine dinucleotide, polypeptides, proteins, polysaccharides, polyols, vitamins, and lipids.

[0050] In some embodiments, specifically, the particle size of the hydroxyapatite microspheres is 1 to 100 μm.

[0051] In some embodiments, specifically, the sterilization method of the composite solution containing hydroxyapatite microspheres for injection is moist heat sterilization or ethylene oxide sterilization, wherein moist heat sterilization is preferred.

[0052] The disclosed embodiment also provides a composite solution containing hydroxyapatite microspheres for injection, which is prepared by the above-mentioned preparation method;

[0053] The pH of the composite solution is 6.5-8.5, the osmotic pressure is 200-400 mOsmol / kg, and the shear viscosity is greater than 100000 mPa·s.

[0054] In some embodiments, specifically, the pushing force of the composite solution is ≤10N.

[0055] In some embodiments, specifically, the storage temperature of the composite solution is 2-30°C.

[0056] The disclosed embodiments also provide applications of a composite solution containing hydroxyapatite microspheres for injection in the fields of wrinkle filling and repair and tissue engineering materials.

[0057] The present invention is described below through several embodiments: It should be noted that the description order of the following embodiments is not intended to limit the preferred order of the embodiments of the present application. In the following embodiments, the description of each embodiment has its own emphasis. For parts that are not described in detail in a certain embodiment, please refer to the relevant description of other embodiments.

[0058] Example 1

[0059] A method for preparing a composite solution containing hydroxyapatite microspheres for injection is as follows:

[0060] (1) Dissolve 30 mg of lidocaine hydrochloride, 10 mg of amino acid and 2% sodium hyaluronate in 10 mL of phosphate buffer;

[0061] (2) 60% of hydroxyapatite microspheres are added to the sodium hyaluronate buffer solution and stirred and blended, wherein the particle size of the hydroxyapatite microspheres is 30 μm and the tap density of the hydroxyapatite microspheres is 0.5 g / cm 3 ;

[0062] (3) After mixing, the blended system is filled into a prefilled syringe and sterilized by high-pressure steam heat sterilization (125° C., 3 min);

[0063] (4) The sterilized sample was centrifuged at 3000 rpm for 1 min to remove bubbles, thereby obtaining a sodium hyaluronate composite solution containing hydroxyapatite microspheres.

[0064] The sample test results showed that the pushing force was 10N, the pH was 6.5, the osmotic pressure was 355mOsmol / kg, and the shear viscosity was 1500000mPa·s; the sample was stored at 2°C.

[0065] like Figure 1 As shown, the schematic diagram of the composite solution being filled into the prefilled syringe shows that the composite solution is uniformly distributed in off-white color;

[0066] like Figure 2 As shown, the composite solution containing hydroxyapatite microspheres prepared in Example 1 can be observed as spherical particles under a microscope, the particle size of the particles is about 30 μm and is evenly distributed in the high molecular polymer solution;

[0067] like Figure 5 As shown, the composite solution containing hydroxyapatite microspheres prepared in Example 1, after being injected subcutaneously into mice, can effectively recruit cells to wrap the microspheres, thereby promoting the production of collagen in the body, thereby effectively repairing wrinkles and depressions.

[0068] like Figure 6 As shown, the cell survival rates of the composite solution containing hydroxyapatite microspheres prepared in Example 1 after co-culture with cells for 1 day and 3 days were both greater than 90%, indicating that the hydroxyapatite microspheres have good biocompatibility with cells.

[0069] Example 2

[0070] A method for preparing a composite solution containing hydroxyapatite microspheres for injection is as follows:

[0071] (1) Add 30 mg of lidocaine hydrochloride, 10 mg of vitamins, 5 mg of nicotinamide, and 0.1% carboxymethyl cellulose to 10 mL of sodium chloride solution and dissolve;

[0072] (2) Add 0.1% hydroxyapatite microspheres into the carboxymethyl cellulose solution and stir and blend, wherein the particle size of the hydroxyapatite microspheres is 100 μm and the tap density of the hydroxyapatite microspheres is 1.0 g / cm 3 ;

[0073] (3) After mixing, the blended system is filled into a prefilled syringe and sterilized by high-pressure steam heat sterilization (121° C., 15 min);

[0074] (4) The sterilized sample was centrifuged at 3000 rpm for 1 min to remove bubbles, thereby obtaining a collagen composite solution containing hydroxyapatite microspheres.

[0075] The sample test results showed that the pushing force was 3N, the pH was 8.5, the osmotic pressure was 400mOsmol / kg, and the shear viscosity was 100000mPa·s; the sample was stored at 4°C.

[0076] Example 3

[0077] (1) 30 mg of bupivacaine hydrochloride, 10 mg of polypeptide and 5% carboxymethyl chitosan were added to 10 mL of sodium chloride solution and dissolved;

[0078] (2) Add 5% hydroxyapatite microspheres into the carboxymethyl chitosan solution and stir and blend, wherein the particle size of the hydroxyapatite microspheres is 1 μm, and the tap density of the hydroxyapatite microspheres is 1.4 g / cm 3 ;

[0079] (3) After mixing, the blended system is filled into a prefilled syringe and sterilized by high-pressure steam heat sterilization (115°C, 30 min);

[0080] (4) The sterilized sample was centrifuged at 3000 rpm for 1 min to remove bubbles, thereby obtaining a carboxymethyl chitosan composite solution containing hydroxyapatite microspheres.

[0081] The sample test results showed that the pushing force was 4N, the pH was 7.5, the osmotic pressure was 200mOsmol / kg, and the shear viscosity was 300000mPa·s; the sample was stored at 25°C.

[0082] Example 4

[0083] (1) Add 20 mg of polyol, 10 mg of amino acid and 4% carboxymethyl cellulose into 10 mL of sodium chloride solution and dissolve;

[0084] (2) 70% of hydroxyapatite microspheres were added to the carboxymethyl cellulose solution for three-way blending, wherein the particle size of the hydroxyapatite microspheres was 15 μm, and the tap density of the hydroxyapatite microspheres was 2.0 g / cm 3 ;

[0085] (3) After the mixing is completed, the blended system is filled into a prefilled syringe and sterilized with ethylene oxide;

[0086] (4) The sterilized sample was centrifuged at 3000 rpm for 1 min to remove bubbles, thereby obtaining a carboxymethyl cellulose composite solution containing hydroxyapatite microspheres.

[0087] The sample test results showed that the pushing force was 8N, the pH was 8.2, the osmotic pressure was 260mOsmol / kg, and the shear viscosity was 1300000mPa·s; the sample was stored at 30°C.

[0088] like Figure 3 As shown, in the composite solution containing hydroxyapatite microspheres prepared in Example 4, spherical particles can be observed under a microscope. The particle size of the particles is about 15 μm and is uniformly distributed in the high molecular polymer solution.

[0089] Example 5

[0090] (1) Add 30 mg of lidocaine hydrochloride, 30 mg of polysaccharide, 10 mg of protein and 3% sodium hyaluronate into 10 mL of sodium chloride solution and dissolve;

[0091] (2) 50% hydroxyapatite microspheres were added to the sodium hyaluronate solution for double-pass blending, wherein the particle size of the hydroxyapatite microspheres was 45 μm and the tap density of the hydroxyapatite microspheres was 1.6 g / cm 3 ;

[0092] (3) After mixing, the blended system is filled into a prefilled syringe and sterilized by high-pressure steam heat sterilization (130° C., 3 min);

[0093] (4) The sterilized sample was centrifuged at 3000 rpm for 1 min to remove bubbles, thereby obtaining a polyvinyl alcohol composite solution containing hydroxyapatite microspheres.

[0094] The sample test results showed that the pushing force was 7N, the pH was 8.1, the osmotic pressure was 320mOsmol / kg, and the shear viscosity was 1200000mPa·s; the sample was stored at 8°C.

[0095] like Figure 4 As shown, in the composite solution containing hydroxyapatite microspheres prepared in Example 5, spherical particles can be observed under a microscope. The particle size of the particles is about 45 μm and they are evenly distributed in the high molecular polymer solution.

[0096] Example 6

[0097] (1) Add 30 mg of lidocaine hydrochloride, 20 mg of polysaccharide, 10 mg of protein and 1% sodium hyaluronate into 10 mL of sodium chloride solution and dissolve;

[0098] (2) 10% hydroxyapatite microspheres were added to the sodium hyaluronate solution for double-pass blending, wherein the particle size of the hydroxyapatite microspheres was 60 μm and the tap density of the hydroxyapatite microspheres was 1.0 g / cm 3 ;

[0099] (3) After mixing, the blended system is filled into a prefilled syringe and sterilized by high-pressure steam heat sterilization (121° C., 15 min);

[0100] (4) The sterilized sample was centrifuged at 3000 rpm for 1 min to remove bubbles, thereby obtaining a sodium hyaluronate composite solution containing hydroxyapatite microspheres.

[0101] The sample test results showed that the pushing force was 5N, the pH was 7.5, the osmotic pressure was 300mOsmol / kg, and the shear viscosity was 1000000mPa·s; the sample was stored at 15°C.

[0102] Example 7

[0103] (1) Add 20 mg of lidocaine hydrochloride, 10 mg of polysaccharide, 5 mg of protein and 10% sodium hyaluronate into 10 mL of sodium chloride solution and dissolve;

[0104] (2) 1% hydroxyapatite microspheres were added to the sodium hyaluronate solution for double-pass blending, wherein the particle size of the hydroxyapatite microspheres was 25 μm and the tap density of the hydroxyapatite microspheres was 1.0 g / cm 3 ;

[0105] (3) After mixing, the blended system is filled into a prefilled syringe and sterilized by high-pressure steam heat sterilization (121° C., 15 min);

[0106] (4) The sterilized sample was centrifuged at 3000 rpm for 1 min to remove bubbles, thereby obtaining a sodium hyaluronate composite solution containing hydroxyapatite microspheres.

[0107] The sample test results showed that the pushing force was 9N, the pH was 7.5, the osmotic pressure was 300mOsmol / kg, and the shear viscosity was 1400000mPa·s; the sample was stored at 15°C.

[0108] In summary, the hydroxyapatite microspheres for injection of the present invention creatively blend hydroxyapatite microspheres and a high molecular polymer solution, and the composite solution system is uniform, has a small pushing force, and has high biosafety. After being injected subcutaneously into mice, it can promote collagen regeneration and has a good filling and repairing effect.

[0109] The various devices selected in this application (components whose specific structures are not described) are all universal standard parts or components known to technical personnel in this field, and their structures and principles can be known to technical personnel through technical manuals or through conventional experimental methods.

[0110] In the description of the embodiments of the present invention, unless otherwise clearly specified and limited, the terms "installed", "connected", and "connected" should be understood in a broad sense, for example, it can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection; it can be a direct connection or an indirect connection through an intermediate medium, or it can be the internal communication of two components. For ordinary technicians in this field, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0111] In the description of the present invention, it should be noted that the terms "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer", etc., indicating the orientation or positional relationship, are based on the orientation or positional relationship shown in the drawings, and are only for the convenience of describing the present invention and simplifying the description, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be understood as limiting the present invention. In addition, the terms "first", "second", and "third" are used for descriptive purposes only, and cannot be understood as indicating or implying relative importance.

[0112] In the several embodiments provided in the present application, it should be understood that the disclosed systems, devices and methods can be implemented in other ways. The device embodiments described above are merely schematic. For example, the division of the units is only a logical function division. There may be other division methods in actual implementation. For example, multiple units or components can be combined or integrated into another system, or some features can be ignored or not executed. Another point is that the mutual coupling or direct coupling or communication connection shown or discussed can be through some communication interfaces, and the indirect coupling or communication connection of devices or units can be electrical, mechanical or other forms.

[0113] The units described as separate components may or may not be physically separated, and the components shown as units may or may not be physical units, that is, they may be located in one place or distributed on multiple network units. Some or all of the units may be selected according to actual needs to achieve the purpose of the solution of this embodiment.

[0114] In addition, each functional unit in each embodiment of the present invention may be integrated into one processing unit, or each unit may exist physically separately, or two or more units may be integrated into one unit.

[0115] 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 method for preparing a composite solution containing hydroxyapatite microspheres for injection, characterized in that: The steps include: S1: preparing a non-cross-linked composite solution: adding a high molecular weight polymer, a local anesthetic, and a nutrient component dry powder to a buffered saline solution in a certain proportion, and stirring until completely dissolved; S2: adding hydroxyapatite microspheres into the non-cross-linked composite solution and blending until uniformly dispersed; S3: filling, centrifugal degassing, wet heat sterilization, and obtaining a hydroxyapatite-containing composite solution for injection.

2. The method for preparing the composite solution containing hydroxyapatite microspheres for injection according to claim 1, characterized in that: The concentration of the non-crosslinked composite solution is 0.1 to 10%; The mass ratio of the hydroxyapatite microspheres in the non-crosslinked composite solution is 0.1-70%, and the tap density is 0.5-2.0 g / cm 3 .

3. The method for preparing the composite solution containing hydroxyapatite microspheres for injection according to claim 1, characterized in that: The high molecular polymer is one or more of sodium hyaluronate, collagen solution, cellulose, chitosan, silk fibroin, agarose, and gelatin; The local anesthetic is one or more of lidocaine hydrochloride, procaine hydrochloride, tetracaine hydrochloride, ropivacaine hydrochloride, and bupivacaine hydrochloride; The nutritional ingredients are one or more of amino acids, nicotinamide, nicotinamide adenine dinucleotide, polypeptides, proteins, polysaccharides, polyols, vitamins, and lipids.

4. The method for preparing the composite solution containing hydroxyapatite microspheres for injection according to claim 1, characterized in that: The particle size of the hydroxyapatite microspheres is 1 to 100 μm.

5. A composite solution containing hydroxyapatite microspheres for injection, characterized in that: Prepared by the preparation method according to any one of claims 1 to 4; The pH of the composite solution is 6.5-8.5, the osmotic pressure is 200-400 mOsmol / kg, and the shear viscosity is greater than 100000 mPa·s.

6. The composite solution containing hydroxyapatite microspheres for injection according to claim 5, characterized in that: The pushing force of the composite solution is ≤10N.

7. The composite solution containing hydroxyapatite microspheres for injection according to claim 5, characterized in that: The storage temperature of the composite solution is 2-30°C.

8. Use of the composite solution containing hydroxyapatite microspheres for injection as claimed in claim 5 in the fields of wrinkle filling and repair and tissue engineering materials.

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