CN113730652A - Mixed gel for injection and preparation method and application thereof - Google Patents

Abstract

The invention provides a mixed gel for injection and a preparation method and application thereof, wherein the mixed gel for injection comprises a gel matrix and polyhydroxyalkanoate microspheres, the polyhydroxyalkanoate microspheres have a molecular weight of 50000-500000 daltons, an average particle size of 30-50 microns, and a mass fraction of the polyhydroxyalkanoate microspheres in the mixed gel is 15-30%. The PHA microspheres with specific molecular weight and average particle size are mixed with the gel matrix to form a mixed gel which has good filling effect and can maintain mechanical properties in the degradation process, and after the mixed gel is injected into the dermis layer of the skin, the mixed gel can stimulate collagen proliferation, activate the skin, effectively and gradually smooth wrinkles, realize the remodeling of the skin contour and realize the long-term filling effect, and in addition, the degradation product 3-hydroxybutyric acid is a natural energy source of human cells, can promote the growth of fiber cells, promote the regeneration of collagen and make the beauty filling effect more obvious.

Description

Mixed gel for injection and preparation method and application thereof

Technical Field

The invention relates to the technical field of medical and aesthetic materials, in particular to a mixed gel for injection and a preparation method and application thereof.

Background

In recent years, with the rapid development of medical and cosmetic technologies, injectable gels have attracted much attention to the effects of minimally invasive treatment or cosmetic filling at the injection site.

At present, the gel for injection in the market mainly comprises Hyaluronic Acid (HA) and salt thereof, the hyaluronic acid is an acidic mucopolysaccharide macromolecular substance widely existing in human and animal connective tissues, the hyaluronic acid gel is injected into a dermal fold dent or a part needing to be plump in a filling manner, the effects of removing wrinkles and modifying the face can be achieved, and the gel HAs the potential of replacing collagen, placental peptide and botulism. However, hyaluronic acid is easily diffused in the body and degraded by enzymes in body tissues, so that it has a short residence time, and requires many injections for long-term beauty, which is time-consuming and labor-consuming.

In order to overcome the defects, researchers provide that maleylation aldehyde group hyaluronic acid and hydrazide group hyaluronic acid are prepared respectively, and then an auxiliary agent is added to prepare the target hyaluronic acid. Although the hyaluronic acid obtained by the method has obviously prolonged in-vivo retention time, the preparation method is too complicated and is not beneficial to popularization and application. Researchers also propose that polylactic acid microspheres are added into the hyaluronic acid gel, but the polylactic acid has a high hydrolysis rate and is unstable, microspheres may collapse or be adhered after being mixed with the hydrogel, the in vivo effective period is short, and the degradation product of the polylactic acid is lactic acid which is acidic and is easy to generate inflammation and form granuloma.

Disclosure of Invention

Aiming at the problems in the prior art, the invention provides a mixed gel for injection and a preparation method and application thereof.

In a first aspect, the present invention provides a mixed gel for injection, comprising a gel matrix and polyhydroxyalkanoate microspheres (i.e., PHA microspheres, hereinafter all abbreviated as PHA microspheres), wherein the molecular weight of the PHA microspheres is 50000 to 500000 dalton, the average particle size is 30 to 50 microns, and the mass fraction in the mixed gel is 15 to 30%.

The research of the invention finds that the PHA microspheres have excellent biocompatibility and small stimulation to subcutaneous tissues, the PHA microspheres with specific molecular weight and average particle size are mixed with a gel matrix to form a mixed gel with good filling effect, the mechanical property can be maintained in the degradation process, and the mixed gel can stimulate collagen proliferation after being injected into the dermis layer of the skin, activate the skin, effectively and gradually smooth wrinkles, realize the remodeling of the skin contour and realize the long-term filling effect.

Further, the PHA microspheres of the present invention include, but are not limited to, one or more of polyhydroxybutyrate microspheres (PHB microspheres), polyhydroxybutyrate-valerate microspheres (PHBV microspheres), polyhydroxybutyrate-hexanoate copolyester microspheres (PHBHHx microspheres), and poly-3-hydroxybutyrate/4-hydroxybutyrate copolymer microspheres (P34HB microspheres).

Further, the gel matrix is formed by dispersing gel molecules in a dispersion medium, and the elastic modulus of the gel matrix is 700Pa, the viscous modulus is 50-200Pa and the dynamic viscosity is 5-15 Pa.S.

Wherein the gel molecules can be one or more of cross-linked hyaluronic acid, chitosan and derivatives thereof, cellulose and derivatives thereof, sodium alginate, amino acid and collagen;

the dispersion medium is water, sodium chloride solution, phosphate buffer solution or glucose solution.

In a preferred embodiment of the invention, the gel matrix is obtained by swelling and balancing crosslinked hyaluronic acid in a sodium chloride solution or a phosphate buffer solution with the osmotic pressure of 270-350 mOsmol/L and the pH of 6.5-7.5; wherein the molecular weight of the hyaluronic acid is 100000-3000000, and the cross-linking agent is PEG-NHS active ester, divinyl sulfone or 1, 4-butanediol diglycidyl ether. Preferably, the cross-linking agent is a PEG-NHS active ester.

Further, to meet the actual need, the mixed gel for injection may further comprise one or more active ingredients of amino acids, nucleic acids, polypeptides, vitamins, mannitol, niacinamide, and local anesthetics.

In a second aspect, the present invention provides a method for preparing the above-mentioned mixed gel for injection.

The method provided by the invention comprises the following steps: mixing the PHA microspheres with a gel matrix, filling, and sterilizing for 15-35 minutes by using high-pressure steam at the temperature of 115-125 ℃. Wherein, the filling can be directly filled into a pre-filled and sealed injector, thereby being convenient for injection use.

The preparation process of the invention is easy to control, the operation steps are less, and the product quality is stable.

In the technical scheme, the PHA microspheres can be prepared by a solvent emulsification and volatilization method. The preparation method comprises the following steps: adding PHA into the oil phase for dissolving, then dropwise adding the PHA into a solution containing 0.05-1 wt% of a surfactant, stirring at normal temperature to completely solidify the solvent volatile microspheres, adding a large amount of deionized water, standing and separating for 3-5 times, removing the residual surfactant, and freeze-drying for 16-24 hours.

In a third aspect, the invention provides a modified mixed gel for injection, which comprises a gel matrix and PHA derivative microspheres, wherein the molecular weight of the PHA derivative microspheres is 50000-500000 daltons, the average particle size is 30-50 microns, and the mass fraction in the mixed gel is 15-30%.

Wherein, the selectable range of the gel matrix is the same as the selectable range of the gel matrix in the mixed gel for injection.

The PHA derivative comprises a blend or copolymer of PHA and one or more of protein, aliphatic polyether, polyamino acid and natural polysaccharide. Wherein the copolymer includes a block copolymer and a graft copolymer. The molar ratio of PHA to derivative group in PHA derivative is 1:20-19: 1.

Wherein the molecular weight of the protein is 1000-;

the molecular weight of the aliphatic polyether is 1000-10000 dalton, and the aliphatic polyether comprises but is not limited to polyethylene glycol, polypropylene glycol, polyethylene glycol and polypropylene glycol copolymer;

the molecular weight of the polyamino acid is 1000-100000 daltons, and the polyamino acid comprises but is not limited to amino acids such as polyarginine, polyglycine, polyaspartic acid, polylysine and the like;

the molecular weight of the natural polysaccharide is 1000-100000 daltons, and the natural polysaccharide comprises but is not limited to sodium hyaluronate, chitosan and derivatives thereof, cellulose and derivatives thereof, sodium alginate and the like.

The research of the invention finds that the mixed gel obtained by mixing the PHA microspheres and the gel matrix occasionally has the phenomena of difficult injection and pain caused by uneven dispersion and agglomeration, so the invention further develops the mixed gel obtained by mixing the PHA derivative microspheres and the gel matrix, namely, the PHA derivative microspheres are obtained by modifying the PHA microspheres and adding hydrophilic groups, so that the PHA derivative microspheres are dispersed more uniformly in the gel matrix, the product is more uniform and fine and is easy to inject, and meanwhile, degradation products of the hydrophilic groups of the PHA derivative, such as amino acid, polypeptide and the like, can provide required molecules and energy for protein formation.

Preferably, the PHA derivative microspheres are one or more of PHA-polyethylene glycol microspheres, PHA-collagen microspheres and PHA-polylysine microspheres.

In a preferred embodiment of the invention, the PHA derivative microspheres are P34 HB-collagen-microspheres with a molecular weight of 110000 to 120000 daltons, wherein the molar ratio of P34HB to polylysine is 1:20 to 19: 1.

The preparation method of the modified mixed gel for injection comprises the following steps: mixing the PHA derivative microspheres with a gel matrix, filling, and sterilizing for 15-35 minutes by using high-pressure steam at the temperature of 115-125 ℃.

The preparation method of the PHA derivative microspheres comprises the steps of firstly preparing the PHA derivative and then preparing the PHA derivative microspheres by the same solvent emulsification and volatilization method.

In a fourth aspect, the present invention provides the use of any one of the above-mentioned mixed gels for injection or any one of the above-mentioned modified mixed gels for injection in the preparation of a filler in the medical or cosmetic field.

The invention provides a mixed gel for injection and a preparation method and application thereof, the PHA microspheres with specific molecular weight and average particle size are mixed with a gel matrix to form the mixed gel which has good filling effect, can maintain mechanical property in the degradation process, can stimulate collagen proliferation after being injected into the dermis layer of the skin, enables the skin to be activated, effectively and gradually smoothes wrinkles, realizes the remodeling of the skin contour, and realizes the effect of long-term filling, in addition, the degradation product 3-hydroxybutyric acid is the natural energy source of human cells, can promote the growth of fiber cells, promotes the regeneration of collagen, enables the cosmetic filling effect to be more obvious, compared with polylactic acid, the degradation product generates lactic acid, and has better biocompatibility.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are a part of the embodiments of the present invention, but not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The raw materials and auxiliary materials used in the following examples are commercially available unless otherwise specified.

Example 1

This example provides a hyaluronic acid mixed gel containing P34HB microspheres for injection, which is prepared as follows:

dissolving 5g of P34HB with molecular weight of 100000 in an organic solvent dichloromethane, dissolving at 60 ℃ for 30min, adding into a 1% polyvinyl alcohol (PVA) aqueous solution, stirring at a constant speed for 4h, heating to remove an organic reagent, adding a large amount of purified water, washing for three times to remove PVA, filtering to collect a filter cake, freeze-drying at a low temperature for 24h, and screening out P34HB microspheres with the particle size of 30-50 microns.

Dissolving 0.4g of hyaluronic acid in 2ml of water for injection, adding 0.2ml of 20% sodium hydroxide solution, adding 10 microliters of 1, 4-butanediol diglycidyl ether, adding 1M hydrochloric acid to adjust the pH value and the PBS to swell and adjust the osmotic pressure after crosslinking is finished for 24 hours, and filtering by using a screen to obtain the gel with the mass fraction of the sodium hyaluronate of 20%.

Adding the prepared 20g of microspheres into 100g of sodium hyaluronate gel, mixing uniformly, filling into a disposable syringe, and performing steam sterilization at 121 ℃ for 15min to obtain the hyaluronic acid mixed gel containing P34HB microspheres for injection.

Example 2

This example provides a hyaluronic acid mixed gel containing P34HB-PEG microspheres for injection, which is prepared by the following steps:

dissolving 5g of copolymer P34HB-PEG (molar ratio is 4:1) with molecular weight of 100000 in an organic solvent of dichloromethane, then adding the mixture into 1% polyvinyl alcohol (PVA) aqueous solution, stirring at constant speed for 4h, heating to remove an organic reagent, adding a large amount of purified water, washing for three times to remove PVA, filtering to collect a filter cake, freeze-drying at low temperature for 24h, and screening out P34HB-PEG microspheres with the particle size of 30-50 microns.

Dissolving 0.4g of hyaluronic acid in 2ml of water for injection, adding 0.2ml of 20% sodium hydroxide solution, adding 10 microliters of 1, 4-butanediol diglycidyl ether, adding 1M hydrochloric acid to adjust the pH value and the PBS to swell and adjust the osmotic pressure after crosslinking is finished for 24 hours, and filtering by using a screen to obtain the gel with the mass fraction of the sodium hyaluronate of 20%.

Adding the prepared 20g of microspheres into 100g of sodium hyaluronate gel, mixing uniformly, filling into a disposable syringe, and performing steam sterilization at 121 ℃ for 15min to obtain the hyaluronic acid mixed gel containing P34HB-PEG microspheres for injection.

Example 3

The present embodiment provides a hyaluronic acid mixed gel containing P34 HB-collagen microspheres for injection, which is prepared by the following steps:

dissolving 5g of copolymer P34 HB-collagen (the molar ratio is 4:1) with the molecular weight of 120000 in an organic solvent dichloromethane, then adding the mixture into 1% polyvinyl alcohol (PVA) aqueous solution, stirring at a constant speed for 4h, heating to remove an organic reagent, adding a large amount of purified water, washing for three times to remove the PVA, filtering to collect a filter cake, freeze-drying at a low temperature for 24h, and screening out P34 HB-collagen microspheres with the particle size of 30-50 microns.

Dissolving 0.4g of hyaluronic acid in 2ml of water for injection, adding 0.2ml of 20% sodium hydroxide solution, adding 10 microliters of 1, 4-butanediol diglycidyl ether, adding 1M hydrochloric acid to adjust the pH value and the PBS to swell and adjust the osmotic pressure after crosslinking is finished for 24 hours, and filtering by using a screen to obtain the gel with the mass fraction of the sodium hyaluronate of 20%.

Adding the prepared 20g of microspheres into 100g of sodium hyaluronate gel, uniformly mixing, filling into a disposable syringe, and performing steam sterilization at 121 ℃ for 15min to obtain the hyaluronic acid mixed gel containing the P34 HB-collagen microspheres for injection.

Example 4

This example provides a hyaluronic acid mixed gel containing P34 HB-polylysine microspheres for injection, which is prepared as follows:

dissolving 5g of copolymer P34 HB-polylysine with the molecular weight of 110000 (the molar ratio is 4:1) in an organic solvent of dichloromethane, then adding the mixture into 1% polyvinyl alcohol (PVA) aqueous solution, stirring at a constant speed for 4 hours, heating to remove an organic reagent, adding a large amount of purified water, washing for three times to remove PVA, filtering to collect a filter cake, freeze-drying at a low temperature for 24 hours, and screening out P34 HB-polylysine microspheres with the particle size of 30-50 micrometers.

Dissolving 0.4g of hyaluronic acid in 2ml of water for injection, adding 0.2ml of 20% sodium hydroxide solution, adding 10 microliters of 1, 4-butanediol diglycidyl ether, adding 1M hydrochloric acid to adjust the pH value and the PBS to swell and adjust the osmotic pressure after crosslinking is finished for 24 hours, and filtering by using a screen to obtain the gel with the mass fraction of the sodium hyaluronate of 20%.

Adding the prepared 20g of microspheres into 100g of sodium hyaluronate gel, uniformly mixing, filling into a disposable syringe, and performing steam sterilization at 121 ℃ for 15min to obtain the hyaluronic acid mixed gel containing P34 HB-polylysine microspheres for injection.

Comparative example 1

The comparative example provides a hyaluronic acid mixed gel containing PLLA-PEG microspheres for injection, and the preparation method comprises the following steps:

dissolving 5g of copolymer PLLA-PEG (molar ratio is 4:1) with molecular weight of 110000 in an organic solvent dichloromethane, then adding the mixture into 1% polyvinyl alcohol (PVA) aqueous solution, stirring at constant speed for 4h, heating to remove an organic reagent, adding a large amount of purified water, washing for three times to remove PVA, filtering to collect a filter cake, freeze-drying at low temperature for 24h, and screening out PLLA-PEG microspheres with the particle size of 30-50 microns.

Dissolving 0.4g of hyaluronic acid in 2ml of water for injection, adding 0.2ml of 20% sodium hydroxide solution, adding 10 microliters of 1, 4-butanediol diglycidyl ether, adding 1M hydrochloric acid to adjust the pH value and the PBS to swell and adjust the osmotic pressure after crosslinking is finished for 24 hours, and filtering by using a screen to obtain the gel with the mass fraction of the sodium hyaluronate of 20%.

Adding the prepared 20g of microspheres into 100g of sodium hyaluronate gel, mixing uniformly, filling into a disposable syringe, and performing steam sterilization at 121 ℃ for 15min to obtain the hyaluronic acid mixed gel containing PLLA-PEG microspheres for injection.

Comparative example 2

The comparative example provides a hyaluronic acid mixed gel containing PLLA microspheres for injection, and the preparation method comprises the following steps:

dissolving 5g of PLLA with the molecular weight of 110000 in an organic solvent dichloromethane, then adding the solution into a 1% polyvinyl alcohol (PVA) aqueous solution, uniformly stirring for 4h, heating to remove an organic reagent, adding a large amount of purified water, washing for three times to remove the PVA, filtering to collect a filter cake, freeze-drying for 24h at a low temperature, and screening out PLLA microspheres with the particle size of 30-50 microns.

Dissolving 0.4g of hyaluronic acid in 2ml of water for injection, adding 0.2ml of 20% sodium hydroxide solution, adding 10 microliters of 1, 4-butanediol diglycidyl ether, adding 1M hydrochloric acid to adjust the pH value and the PBS to swell and adjust the osmotic pressure after crosslinking is finished for 24 hours, and filtering by using a screen to obtain the gel with the mass fraction of the sodium hyaluronate of 20%.

Adding the prepared 20g of microspheres into 100g of sodium hyaluronate gel, uniformly mixing, filling into a disposable syringe, and performing steam sterilization at 121 ℃ for 15min to obtain the hyaluronic acid mixed gel containing PLLA microspheres for injection.

Test example 1 gel Performance test

The mixed gels obtained in examples 1 to 4 and comparative examples 1 to 2 were subjected to pH, osmotic pressure test and rheology test, respectively, and the results are shown in table 1, which are in accordance with the range of normal values of human body.

Wherein, the rheology test is as follows: the dynamic viscosity of the gel was measured at 25 ℃ and the elastic modulus and viscous modulus of the gel were measured at 37 ℃ using a rotational rheometer.

TABLE 1 gel Performance test results for each of the mixed gels

Test example 2 degradability

And (3) placing the gel with equal mass into a container, adding sodium hyaluronate enzyme solution with equal concentration and equal volume, observing and recording the complete degradation time of the gel at 37 ℃, and detecting the pH value of each solution after complete degradation. The results are shown in Table 2.

TABLE 2 degradation test results for each of the mixed gels

	Example 1	Example 2	Example 3	Example 4	Comparative example 1	Comparative example 2
							Degradation time/min	240	230	250	240	150	160
pH	7.3	7.1	7.4	7.3	5.8	5.7

The result shows that the mixed gel containing PHA microspheres has longer complete degradation time, can be continuously filled for a longer time, does not change the pH value after degradation, and has better biocompatibility compared with the mixed gel containing PLLA microspheres which can generate lactic acid to change the local pH value in the degradation process.

Test example 3 thrust test

The thrust test using the 27G needle resulted in the results shown in Table 3, and the modified microsphere gel containing hydrophilic groups (examples 2-4 and comparative example 1) had lower thrust and uniform and stable thrust, indicating that the microspheres and gel were uniformly dispersed and free of agglomeration.

TABLE 3 thrust test results for each mixed gel

	Example 1	Example 2	Example 3	Example 4	Comparative example 1	Comparative example 2
							Maximum thrust/N	15	10	9	11	12	16

Test example 4 MTT method for detecting cell proliferation Rate

The mouse fibroblast cell suspension (cell density approximately 2X 10) was seeded in 96-well plates⁴one/mL), the 96-well plate was pre-incubated in an incubator (5% CO at 37 ℃)₂Under the conditions of (a). Mouse fibroblast broth containing serum was added to each well and an equal amount of the mixed gel of the example was added to the designated wells. To each well 10. mu.L of MTT solution was added and incubated for 1h in an incubator. The supernatant was removed and dissolved in dimethyl sulfoxide. The optical density value (OD value) at 540nm was determined with a microplate reader. Cell viability was calculated assuming a blank cell viability of 100% and the others were compared. The results are shown in Table 4.

TABLE 4 cell proliferation Rate test results for each mixed gel

Example 1

Example 2

Example 3

Example 4

Comparative example 1

Comparative example 2

1 day

99％

101％

102％

100％

100％

98％

5 days

130％

135％

147％

140％

115％

110％

10 days

160％

180％

240％

210％

84％

79％

Therefore, PHA degradation products can provide energy for cells, lactic acid generated by degradation of polylactic acid has larger stimulation to the cells, and mixed gel containing PHA microspheres can obviously promote cell proliferation for a long time compared with the gel containing polylactic acid microspheres.

Test example 5 subcutaneous implantation test

0.5ml of each mixed gel of examples 1-4 and comparative examples 1-2 was implanted under the skin of rats, and the 6 groups of mixed gels had significant filling effect after implantation and no red swelling appeared. After the hyaluronic acid gel is implanted for 2 months, as the hyaluronic acid gel begins to slowly degrade, the number of the fibrocytes begins to increase, the number of the inflammatory cells of the comparative examples 1-2 is more than that of the inflammatory cells of the examples 1-4, the inflammatory cells are implanted for 6 months, the samples of the examples 1-4 are completely wrapped by fibrous connective tissues to form fixed space occupation, the surrounding tissues have no abnormal change, and the long-term filling effect is achieved, but the nodular lesions partially appear in the comparative examples 1-2 to form granuloma, and the PHA microsphere mixed gel shows better biocompatibility.

In summary, the product of the invention is uniform, fine, easy to inject, pyrogen-free, better in biocompatibility, longer in vivo retention time, good in plasticity, less in side effect, obvious in wrinkle eliminating effect, and suitable for medical and beauty filling preparations.

Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.

Claims (10)

1. The mixed gel for injection is characterized by comprising a gel matrix and polyhydroxyalkanoate microspheres, wherein the polyhydroxyalkanoate microspheres have the molecular weight of 50000-500000 daltons, the average particle size of 30-50 microns, and the mass fraction of the polyhydroxyalkanoate microspheres in the mixed gel is 15-30%.

2. The hybrid gel for injection as claimed in claim 1, wherein the polyhydroxyalkanoate microspheres are one or more of polyhydroxybutyrate microspheres, hydroxybutyrate-valerate microspheres, hydroxybutyrate-hexanoate copolyester microspheres, and poly 3-hydroxybutyrate/4-hydroxybutyrate copolymer microspheres.

3. The hybrid gel for injection as claimed in claim 1 or 2, wherein the gel matrix is formed by dispersing gel molecules in a dispersion medium, and the gel matrix has an elastic modulus of 100-700Pa, a viscous modulus of 50-200Pa and a dynamic viscosity of 5-15 Pa-S.

4. The hybrid gel for injection as claimed in claim 3, wherein the gel molecules comprise one or more of cross-linked hyaluronic acid, chitosan and its derivatives, cellulose and its derivatives, sodium alginate, amino acids, collagen;

the dispersion medium is water, sodium chloride solution, phosphate buffer solution or glucose solution.

5. The mixed gel for injection as claimed in claim 4, wherein the gel matrix is obtained by swelling and balancing crosslinked hyaluronic acid in sodium chloride solution or phosphate buffer solution with osmotic pressure of 270-350 mOsmol/L and pH of 6.5-7.5; wherein the molecular weight of the hyaluronic acid is 100000-3000000, and the cross-linking agent is PEG-NHS active ester, divinyl sulfone or 1, 4-butanediol diglycidyl ether.

6. The method for preparing a mixed gel for injection according to any one of claims 1 to 5, comprising: mixing the polyhydroxyalkanoate microspheres with the gel matrix, filling, and sterilizing for 15-35 minutes by using high-pressure steam at the temperature of 115-125 ℃.

7. The modified mixed gel for injection is characterized by comprising a gel matrix and polyhydroxyalkanoate derivative microspheres, wherein the molecular weight of the polyhydroxyalkanoate derivative microspheres is 50000-500000 daltons, the average particle size is 30-50 microns, and the mass fraction of the polyhydroxyalkanoate derivative microspheres in the mixed gel is 15-30%.

8. The modified hybrid gel for injection according to claim 7, wherein the polyhydroxyalkanoate derivative comprises a blend or copolymer of polyhydroxyalkanoate with one or more of proteins, aliphatic polyethers, polyamino acids, natural polysaccharides; the gel matrix is the same as the gel matrix in any one of claims 1-5;

preferably, the polyhydroxyalkanoate derivative microspheres are one or more of polyhydroxyalkanoate-polyethylene glycol microspheres, polyhydroxyalkanoate-collagen microspheres and polyhydroxyalkanoate-polylysine microspheres.

9. The modified mixed gel for injection as claimed in claim 8, wherein the polyhydroxyalkanoate derivative microspheres are P34 HB-collagen microspheres, the molecular weight thereof is 110000 to 120000 daltons, and the molar ratio of P34HB to collagen is 1:20 to 19: 1.

10. Use of the mixed gel for injection according to any one of claims 1 to 5 or the modified mixed gel for injection according to any one of claims 7 to 9 for the preparation of a filler for medical or cosmetic applications.