A composite material for injection and its uses

Abstract

The present invention relates to an injectable composite material and its uses, an injection containing the injectable composite material, and a method for enhancing the suspension stability of polymer microspheres in water. In the present invention, a water-agarose system is used to achieve good dispersion of polymer microspheres and prevent their aggregation and sedimentation. The products of the present invention are used in the field of medical aesthetics, can be injected into the dermis and / or subcutaneous tissue to fill and increase tissue volume, correct structural defects such as asymmetry, contour deformity and volume defect, and can also be used to improve the skin condition.

Description

Technical Field

[0001] The present invention relates to the fields of medical aesthetics and biomedical technologies, and particularly relates to an injectable composite material for injection into the dermis and subcutaneous tissue, and more particularly to an injectable composite material containing polymer microspheres and agarose. Background Art

[0002] The aging of the human body is manifested as an increase in wrinkles on the skin. From the perspectives of dermatology and physiology, the following changes occur: the epidermal thickness decreases, and epidermal and dermal cells decrease; the total thickness of the dermis also decreases with skin aging, the cells decrease, the synthesis of collagen and glycosaminoglycans slows down, and elastin degrades; with skin aging, the size of hyaluronic acid polymers decreases. Among various plastic surgery and aesthetic techniques, injection aesthetic techniques are the main means, which achieve the purpose of correcting wrinkles by injecting biological materials or synthetic materials into the dermis or subcutaneous tissue.

[0003] In the early stage, commonly used injection materials were non-absorbable polymer materials, such as polymethyl methacrylate. Since it cannot be decomposed or absorbed by tissues in the human body, it is easy to form cysts, may move in position, and there is also a risk of stimulating autoimmune disorders. Absorbable materials mainly include collagen, hyaluronic acid, polylactic acid, etc. Among them, after collagen injection, the skin elasticity and appearance are better, but it is not from the recipient himself, and heterologous proteins may cause allergic reactions, such as local skin erythema, swelling, sclerosis, itching and even ulceration, and severe cases may present systemic symptoms. In addition, collagen will be completely absorbed and degraded within a few months after injection and needs to be reinjected. Hyaluronic acid, that is, hyaluronic acid, is absorbed within a few weeks after injection of uncrosslinked hyaluronic acid. Therefore, most of them are crosslinked physically or chemically to increase the molecular weight. Due to the presence of crosslinking agents, the adverse reaction rate is relatively high.

[0004] Therefore, an alternative strategy is to use polymer microspheres such as polylactic acid and polycaprolactone, which can stimulate the proliferation of subcutaneous tissue and the production of collagen at the injection site, and thus can produce long-term wrinkle removal effects. The main problem with injectable polymer microspheres is that since polymer microspheres are generally hydrophobic, they have a high surface free energy when dispersed in water, are in an unstable state, and have a different density from the isotonic solution for injection, so they are very likely to settle. The resulting problem is that it is difficult to make an injection solution for long-term storage, and the reconstitution of lyophilized powder for injection is cumbersome. To solve the sedimentation problem, the commonly used methods in the chemical field are: (1) reducing the particle size, which is not feasible in the aesthetic medicine field, as too small particles may diffuse in the body or enter the blood vessels, causing danger, and at the same time are more likely to be phagocytosed by macrophages and lose their function; (2) hydrophilically modifying the particle surface or adding surfactants to reduce the surface free energy, but the injection safety of the modification or addition of surfactants is difficult to guarantee; (3) increasing the viscosity of the system; (4) reducing the density difference between the solid and the liquid. The prior art generally adds thickeners / suspending agents such as sodium carboxymethylcellulose and sodium hyaluronate to make a suspension or gel to suspend the microspheres, such as Patent US2016 / 0038635 Al, CN104258470A, CN110787319A, CN113730652A. After the carrier gel gradually degrades, the solid microspheres will come into contact with the surrounding tissues and stimulate the secretion of collagen, thereby filling the voids left after the gel degradation, see J Cosmet LaserTher2015, 17(2): 99-101. By using this method, the viscosity of the dispersant can be increased and the density difference between the solid and the liquid can be reduced at the same time. Some such products have been approved for marketing in many countries. For example, the US FDA approved the product Sculptra of Sanofi-Aventis in 2004, which is mainly used to treat facial lipoatrophy in HIV patients. In 2009, the FDA approved Sculptra Aesthetic for the treatment of mild to severe nasolabial fold contour defects and other facial wrinkles. The main component of both is poly-L-lactic acid, and sodium carboxymethylcellulose (CMC) is used as a suspending agent. In 2021, the NMPA approved the poly-L-lactic acid product of Changchun Sunbiom Biomat Co., Ltd. The thickener / suspending agent is also sodium carboxymethylcellulose, which is reconstituted with normal saline before injection into the affected area. Such products claim that poly-L-lactic acid can stimulate the regeneration of collagen in the skin while degrading. In 2021, "Evelis" of East China Medicine was approved. The main component of this product is polycaprolactone, and sodium carboxymethylcellulose is used as a thickener / suspending agent. However, the current methods have obvious bottlenecks in improving the suspension stability. To improve the stability, it is necessary to increase the concentration of the thickener hyaluronic acid or CMC. During this process, the system gradually changes from a suspension to a colloid until the viscosity is too high to be manually injected through a syringe.Even when a high concentration of hyaluronic acid or thickening agent is added, microsphere sedimentation and aggregation still occur during use, resulting in non-uniform samples and clogging of the needle. If the injector applies excessive force to push, it is easy to have an excessive local injection volume, causing subcutaneous nodules and bulges. This phenomenon is more obvious when using a fine needle. In recent years, "hydropin needles" have emerged for problems such as dry skin, enlarged pores, skin laxity, and fine wrinkles. They use 30G - 32G (the inner diameter of a 32G needle is 110μm) or finer microneedles to precisely inject active ingredients into the dermis layer. They can hydrate the skin or inject hyaluronic acid to improve skin luster in the short term. However, limited by the above technical problems, it is difficult to apply microspheres to hydropin needles, so long-term effects cannot be achieved.

[0005] Agarose is a natural polysaccharide extracted from seaweed. It is composed of alternating 1,3-linked β-D-galactose and 1,4-linked 3,6-anhydro-L-galactose, and has hydrophilicity, electrical neutrality, chemical stability, and easy moldability. Its aqueous solution has the characteristic of forming a hydrogel at low temperature. It is rich in resources and low in cost. Agarose is mostly used as a raw material for detecting the molecular weights of macromolecules such as proteins and nucleic acids in the field of life sciences, such as agarose gel electrophoresis, which utilizes its ability to form a natural reticular porous structure and electrical neutrality at high concentrations.

[0006] Research shows that agarose has good biosecurity and tissue compatibility, can be biodegradable, has a controllable degradation period, is easy to be compatible or grafted with other materials, and can change and adjust the properties of composite materials as needed. Chinese Patent CN110279888A discloses a preparation method of an injectable agarose gel, which physically mixes agarose and non-crosslinked hyaluronic acid for filling injection. Chinese Patent CN101134784A discloses an agarose and hyaluronic acid graft and its preparation method and application, and the prepared graft is used as a carrier for targeted drugs, which can slowly release drugs. Chinese Patent CN110392584A discloses the preparation of a high-concentration agarose hydrogel by crosslinking, which can be used for wound care, orthopedic surgery, skin filling, etc. More similar reports can be found in documents such as US9579418B2, US2021 / 0268144A1, WO2016154277A1, US2021 / 0138112A1, etc. However, the above documents do not record the combined use of agarose and microspheres. Summary of the Invention

[0007] In view of the above problems, the inventor studied the characteristics of various materials at different concentrations under different temperature conditions and different process conditions through experiments, and found that agarose can be dispersed into colloidal particles in water, preventing the aggregation and sedimentation of polymer microspheres, and having a unique suspension effect on polymer microspheres, thus solving this problem. According to the existing technology records and animal experiments, agarose gel can be used for filling injections, and there is no significant risk of toxic side effects. The inventor tried to add different concentrations of agarose in water and unexpectedly found that the suspension with a lower agarose content, although not in the common gel form, can still better stabilize the suspension system and prevent the sedimentation and aggregation of microspheres (see Figure 1 -2). Further physical property tests and animal experiments showed that this new composite material is suitable for injection into the dermis or / and subcutaneous tissue, especially suitable for the medical aesthetic field. Among them, when the contents of agarose and polymer microspheres are higher, it is more viscous and suitable for subcutaneous tissue injection; when the water content is higher, it has better fluidity and can pass through finer needles, and is suitable for use as a hydrating needle for dermal injection.

[0008] Based on this, the present invention provides a composite material for injection, which is an aqueous suspension containing water, agarose and polymer microspheres, and the agarose and polymer microspheres are dispersed in water to form a suspension. The content of agarose in the composite material for injection is 0.01% - 1.5%, preferably 0.05% - 1.2%; the suspension is the polymer microspheres, and the content is 0.2% - 20%, preferably 0.5% - 15%.

[0009] The polymer microspheres of the present invention are polymer materials that can be used for injection into the dermis and / or subcutaneous tissue in medicine. For example: one or more of poly-L-lactic acid (PLLA), poly-D-lactic acid (PDLA), poly-DL-lactic acid (PDLLA), polyvinyl alcohol (PVA), polycaprolactone (PCL), polydioxanone (PDO), polytrimethylene carbonate (P-TMC), polyethylene glycol (PEG) block copolymers. The above polyethylene glycol block copolymers can be a mixture of one or more of diblock copolymers or / and triblock copolymers. As an example, other blocks in the copolymer can be selected from polylactic acid and polycaprolactone.

[0010] The above polymer microspheres have a weight average molecular weight of 5 - 200 KDa, preferably 8 - 100 KDa. The above polymer microspheres have an average particle size of 1 - 100 μm, preferably 3 - 80 μm. In practice, the particles of some polymers are not regular spheres, but as long as the molecular weight or particle size falls within the above range and is suitable for injection, they still belong to the polymer microspheres described in the present invention.

[0011] The present invention also provides a preparation method of the above composite material, which at least includes the following steps:

[0012] (1) Preparation of agarose matrix:

[0013] Dissolve agarose in water by heating and stir to prepare a water-agarose matrix;

[0014] (2) Blend the water-agarose matrix with polymer microspheres.

[0015] Since agarose has the property that its solubility increases with increasing temperature, conditions above room temperature are favorable for dissolution. Considering the convenience of operation, in practice, it is generally heated to 40 - 95 °C, and the specific temperature can be adjusted according to the amount of agarose used and the desired dissolution rate. It is easily understood by those skilled in the art that a higher temperature results in faster dissolution.

[0016] The blending process is as follows: stir and mix the water-agarose matrix with polymer microspheres evenly. After the suspension cools down, it can be directly used for injection or dispensed into appropriate containers.

[0017] Furthermore, to ensure the need for injection, after step (1) is stirred evenly, it is sterilized, and the polymer microspheres used are also sterilized. The sterilization method can be autoclaving or other methods. The mixing and dispensing in step (2) are both required to be aseptic operations. It is also possible to select terminal sterilization after primary packaging according to the characteristics of the polymer material.

[0018] The present invention also provides the above-mentioned composite material for injection, which is used for injection into the dermis and / or subcutaneous tissue, and produces at least one of the following effects: (1) filling to increase tissue volume, (2) correcting structural defects, (3) improving the skin condition. The structural defects include asymmetry, contour deformity, volume defect, and other defects affecting the aesthetic appearance of the structure.

[0019] The present invention further provides an injection, which contains the above-mentioned composite material for injection. Optionally, it may further include pharmaceutically acceptable excipients. Typical examples of the pharmaceutically acceptable excipients are inorganic salts, sugars, and antioxidants for adjusting osmotic pressure and pH. Further, the injection is a water suspension.

[0020] The excipients can be added in appropriate amounts at appropriate steps according to the needs of the preparation. For example, to add sodium chloride, it can be directly used as a sodium chloride aqueous solution in step (1), or sodium chloride can be added when adding agarose, or when adding polymer microspheres, or after the suspension is formed.

[0021] As a type of injection, it is a dermal injection. Preferred examples can be injected using a 30G - 32G needle. Reducing the particle size and dosage of the polymer microspheres also allows for the use of a finer needle. The dermal injection contains the above-mentioned composite material for injection. In the injection, the preferred molecular weight of the polymer microspheres is 5 - 100KDa, the average particle size is preferably 1 - 60μm, the content of the polymer microspheres is preferably 0.2% - 10%, and the agarose content is preferably 0.01% - 0.5%.

[0022] As another type of injection, it is a subcutaneous tissue injection. It contains the above-mentioned composite material for injection. In the injection, the preferred molecular weight of the polymer microspheres is 10 - 200KDa, the average particle size is preferably 5 - 100μm, the content of the polymer microspheres is preferably 1.5% - 20%, and the agarose content is preferably 0.1% - 1.5%.

[0023] The present invention also provides the application of the above-mentioned composite material for injection and injection in the injection of the dermal layer and / or subcutaneous tissue of humans or other mammals for medical aesthetic or medical therapeutic purposes.

[0024] The present invention also provides a method for enhancing the suspension stability of polymer microspheres in water, which is characterized in that the water contains 0.01% - 1.5% of agarose.

[0025] The "aqueous suspension" referred to in the present invention means that the main component of the liquid phase in the suspension is water.

[0026] The "for injection" referred to in the present invention means for injection into humans or other mammals.

[0027] The suspension referred to in the present invention means that the polymer microspheres are suspended and dispersed in a liquid phase with fluidity. As the concentration increases, the system gradually becomes viscous and exhibits certain gel properties, but as long as it still has liquid fluidity and can be used for injection, it still belongs to the category of the suspension referred to in the present invention.

[0028] The percentage contents mentioned in the present invention are all mass percentages unless otherwise specified.

[0029] The suspension stability referred to in the present invention refers to the property of the microspheres to resist sedimentation and agglomeration. The enhancement of the suspension stability means slowing down the agglomeration and / or sedimentation rate of the polymer microspheres in the injection.

[0030] The polymer microspheres described in the present invention can be directly commercially available microspheres that meet the requirements, or can be prepared on-site using methods in the prior art. The preparation method can be at least one of the emulsion-solvent evaporation method, spray drying method, and pulverization method, and the emulsion-solvent evaporation method is preferred. The specific exemplary emulsion-solvent evaporation method is as follows: A polymer with a weight-average molecular weight of 5 - 200 KDa (which can be selected according to product requirements) is dissolved in an organic solvent, and the solution is added dropwise to an aqueous solution of a water-soluble emulsifier under stirring; then the solvent is evaporated by stirring at room temperature, and after sieving and suction filtration, the filter cake is dried to obtain polymer microspheres with different particle size specifications. The organic solvents are chloroform, tetrahydrofuran, ethyl acetate, acetone, ethanol, trifluoroethanol, etc., and trifluoroethanol is preferred; the water-soluble emulsifier is polyvinyl alcohol, Tween-80, and polyvinyl alcohol is preferred. By using the above method, poly(L-lactic acid) microspheres, polycaprolactone microspheres, poly(dl-lactic acid) microspheres, polyvinyl alcohol microspheres, poly(trimethylene carbonate) microspheres, etc. can be prepared. Different specifications of polymer microspheres can be obtained by adjusting the types and concentrations of the organic solvent and the water-soluble emulsifier. This is a conventional technique in the field of polymer chemistry and will not be elaborated here.

[0031] The technical solution of the present invention has the following advantages:

[0032] The products of the present invention can be used for injection into the dermis and / or subcutaneous tissue to fill and increase tissue volume, correct structural defects such as asymmetry, contour deformity, and volume deficiency, and can also be used to improve the skin condition.

[0033] The present invention uniformly disperses polymer microspheres in the honeycomb structure of a low-concentration agarose framework to form a uniform microsphere suspension. The microspheres in the prepared suspension can maintain a uniformly suspended state for a long time, and there is no need to repeatedly shake and mix during use, which facilitates the use of doctors and improves the problems caused by hydrophobic aggregation of polymer microspheres, such as product non-uniformity, needle clogging, and uneven injection. Moreover, while ensuring suspension stability, it also maintains a low viscosity, which is beneficial for the injector to more precisely control the injection site and dosage. The dermal injection dosage form can pass through a 30G, 32G or finer needle, and can be used for the dermal injection of a skin booster needle, which can have a long-term effect and is also beneficial for reducing the pain of patients.

[0034] As a macromolecular polysaccharide, agarose has good biocompatibility, does not stimulate immune reactions, and will not enter blood vessels to form thrombi. Agarose can be slowly degraded in the body, and the degradation time is longer than that of sodium hyaluronate and sodium carboxymethylcellulose. The microspheres released during the degradation process can stimulate collagen production to maintain a long-term effect. Therefore, it is possible to achieve a longer action time and a more natural skin state without crosslinking. Description of the Drawings

[0035] 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.

[0036] Figure 1 This is a scanning electron microscope image of the product of Example 4.

[0037] Figure 2 This is a comparison chart of the products of Example 3 (A) of the present invention and Comparative Example 1 (B) in Physical Property Test 1 after being placed for 24 hours.

[0038] Figure 3 This is a graph showing the trend of absorbance changes measured in physical property test 2.

[0039] Figure 4 A comparison chart of the push force measured in physical property test 3.

[0040] Figure 5 This is a photo of the rabbit skin after being injected with the hyaluronic acid injection made from the product of Example 4 in Test Example 1.

[0041] Figure 6 This is a photo of the rabbit skin after injection of the product of Example 8 in Test Example 2.

[0042] Figure 7 This is a photo of the rabbit skin in Test Example 2 three months after injection of the product in Example 8. DETAILED DESCRIPTION

[0043] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. 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.

[0044] Example 1

[0045] Disperse 0.01% agarose in water, heat and dissolve, and sterilize by high pressure steam at 121°C for 15 minutes to obtain an agarose suspension with good fluidity;

[0046] 0.2% sterilized PLLA-PEG microspheres with an average particle size of 1 μm and a weight average molecular weight of 5 KDa were added to the agarose suspension during stirring, mixed, stirred evenly, and dispensed into prefilled syringes.

[0047] Examples 2-8 were prepared in a similar manner to Example 1, with the agarose content adjusted, and the types, particle sizes, molecular weights, and contents of the microspheres being different. In Example 9, physiological saline was used instead of water, and in Example 10, a 0.5% glucose solution was used instead of water.

[0048] Comparative Example 1: Referring to Example 3, agarose was not added, and 2% CMC was used instead.

[0049] Comparative Example 2: Referring to Example 4, agarose was not added, and 2% hyaluronic acid was used instead.

[0050] The parameters of Examples 1-10 and the comparative examples are shown in Table 1 below. The electron microscopy scanning image of the product of Example 4 is as Figure 1 shown. It can be seen from the figure that the polymer microspheres are uniformly dispersed in the honeycomb structure of the low-concentration agarose framework.

[0051] Table 1: Preparation of Injectable Composite Materials

[0052]

[0053]

[0054] Physical Property Test 1: Observe the sedimentation situation after standing for 24 hours

[0055] After standing for 24 hours to observe the sedimentation situation, the products of Examples 1-10 all showed excellent stability, while sedimentation occurred in Comparative Examples 1 and 2. As Figure 2 shown, compared with Comparative Example 1, the solution product of Example 3 remained suspended after standing for 24 hours, while obvious stratification occurred in Comparative Example 1, with clear liquid appearing on the upper layer. Comparative Example 2 was similar to Comparative Example 1. Adding osmotic pressure regulators in Examples 9 and 10 had no effect on the suspension stability.

[0056] Physical Property Test 2: Absorbance

[0057] Take two groups of test tubes, divide them into groups A and B and number them. Add 5 ml of the product of Example 3 to group A and 5 ml of the product of Comparative Example 1 to group B. Measure the absorbance of the upper liquid at the time of preparation, after standing for 12 hours, 24 hours, 36 hours, and 48 hours respectively. The trend chart is shown in Figure 3 ; and the stability of the sample of Example 3 was investigated for 6 months. It can be seen from the experimental results that the suspension stability of Example 3 is good, and the absorbance basically does not change, indicating that the product of the present invention can be stored for a long time in this form, and there is no need for on-site preparation in practical applications, which has obvious advantages.

[0058] Physical Property Test 3: Pushing Force Test.

[0059] Take the products of Example 3 and Comparative Example 1. After standing for 24 hours, install a 30G needle and measure using a texture analyzer.

[0060] As Figure 4 shown, in Example 3, the product mixed with agarose was evenly mixed without needle clogging, and the pushing force could be detected normally. In Comparative Example 1, sedimentation occurred in the product, resulting in needle clogging. After pressurization, local over-injection occurred. When continuing to push, the pushing force exceeded the load, indicating that the needle was blocked.

[0061] The following combines animal test examples to illustrate its effects. The animals used in the test were white rabbits (rabbits).

[0062] Test Example 1:

[0063] Experimental method: Each dosage was 2 mL, using a 31G nine-row needle, and 0.02 mL per point was injected into the dermis of rabbits.

[0064] Experimental results: Compared with the sample without added agarose, when the product of the present invention (Examples 1-5) was injected into the dermis, the solution was evenly distributed without needle clogging, the needle did not need to be replaced, and the injection process was smooth. The overall injection site did not turn red, the skin had slight protrusions, and there was no swelling. Taking the product of Example 4 injected into the dermis of rabbits as an example, it can be seen Figure 5 , and the protrusions gradually disappeared starting from the next day. It was proved that the product could be used for hydrodermabrasion injection.

[0065] The products of Comparative Examples 1 and 2 could not pass through the 31G needle smoothly, so no comparison was made.

[0066] Test Example 2:

[0067] Experimental method: Each dosage was 1 mL, using a 27G needle, and 0.2 mL per point was injected subcutaneously into rabbits at a total of 4 points.

[0068] Experimental results: Compared with the sample without added agarose, when the product of the present invention (Examples 5-10) was injected subcutaneously, there was no needle clogging phenomenon, and the shape of the swelling was relatively smooth. Taking the product of Example 8 injected subcutaneously into rabbits as an example, it was observed that the skin was slightly reddened after injection, with a relatively large swelling ( Figure 6 ), and after 3 months, the swelling was observed to be round and normal ( Figure 7 ), and after 12 months, the swelling flattened, and the skin became thick when gently pressed.

[0069] Obviously, the above examples are merely illustrations given for clarity and are not limitations on the implementation manners. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation manners here. And the obvious changes or modifications derived therefrom are still within the protection scope of the present invention.

Claims

1. A composite material for injection, which is an aqueous suspension of agarose and polymer microspheres. The content of agarose in the suspension is 0.01% - 0.15%. The components of the polymer microspheres are one or more of poly(L-lactic acid), poly(D-lactic acid), poly(DL-lactic acid), polyvinyl alcohol, polycaprolactone, polydioxanone, poly(trimethylene carbonate), and poly(ethylene glycol) block copolymer. The poly(ethylene glycol) block copolymer is a mixture of one or more of diblock copolymers or / and triblock copolymers.

2. The composite material for injection according to claim 1, wherein The composite material for injection is a suspension formed by dispersing agarose and polymer microspheres in water, and the content of agarose in the suspension is 0.05% - 0.15%.

3. The composite material for injection according to claim 1, wherein The polymer microspheres have a weight-average molecular weight of 5 - 200 KDa.

4. The composite material for injection according to claim 3, wherein The polymer microspheres have a weight-average molecular weight of 8 - 100 KDa.

5. The composite material for injection according to claim 1, characterized in that, The polymer microspheres have an average particle size of 1 - 100 μm.

6. The composite material for injection according to claim 5, characterized in that, The polymer microspheres have an average particle size of 3 - 80 μm.

7. The composite material for injection according to claim 1, characterized in that, The content of the polymer microspheres is 0.2% - 20%.

8. The composite material for injection according to claim 7, characterized in that, The content of the polymer microspheres is 0.5% - 15%.

9. The composite material for injection according to any one of claims 1 - 8 is used for intradermal and / or subcutaneous injection, and produces at least one of the following effects: (1) filling to increase tissue volume, (2) correcting structural defects, (3) improving skin condition. The structural defects include asymmetry, contour deformity, volume defect, and other defects affecting the aesthetic appearance of the structure.

10. A method for preparing the composite material for injection according to any one of claims 1-9, characterized in that, It at least includes the following steps: (1) Preparation of agarose matrix: Dissolve agarose in water by heating and stir to prepare a water-agarose matrix. (2) Blend the water-agarose matrix with polymer microspheres.

11. An injection, which contains the composite material for injection according to any one of claims 1 - 9. Optionally, it further includes pharmaceutically acceptable excipients, and the excipients are selected from inorganic salts, saccharides for adjusting osmotic pressure and pH, and antioxidants.

12. The injection according to claim 11, characterized in that: The injection is an intradermal injection, wherein the molecular weight of the polymer microspheres is 5 - 100 KDa, the average particle size is 1 - 60 μm, the content of the polymer microspheres is 0.2% - 10%, and the content of agarose is 0.01% - 0.15%.

13. The injection according to claim 11, characterized in that: The injection is a subcutaneous injection. The molecular weight of the polymer microspheres is 10 - 200 KDa, the average particle size is 5 - 100 μm, the content of the polymer microspheres is 1.5% - 20%, and the content of agarose is 0.1% - 0.15%.

14. A method for enhancing the suspension stability of polymer microspheres in water, characterized in that, Make the water contain 0.01% - 0.15% of agarose. The polymer microspheres have a weight-average molecular weight of 5 - 200 KDa and / or an average particle size of 1 - 100 μm. The components of the polymer microspheres are one or more of poly(L-lactic acid), poly(D-lactic acid), poly(DL-lactic acid), polyvinyl alcohol, polycaprolactone, polydioxanone, poly(trimethylene carbonate), and poly(ethylene glycol) block copolymer. The poly(ethylene glycol) block copolymer is a mixture of one or more of diblock copolymers or / and triblock copolymers.

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