CN114177352B

CN114177352B - Gradient degradable skin filler and preparation method thereof

Info

Publication number: CN114177352B
Application number: CN202111579416.XA
Authority: CN
Inventors: 张立娟
Original assignee: Xi'an Denos Medical Technology Co ltd
Current assignee: Xi'an Zhenyan Biotechnology Co ltd
Priority date: 2021-12-22
Filing date: 2021-12-22
Publication date: 2023-01-10
Anticipated expiration: 2041-12-22
Also published as: CN114177352A

Abstract

The invention discloses a gradient degradable skin filler and a preparation method thereof, relating to the field of tissue filling and medical biomaterials; in the filler, a gel matrix phase serving as a carrier is subjected to secondary crosslinking, so that primary crosslinked gel particles with higher crosslinking degree can be uniformly dispersed in a matrix material with lower crosslinking degree, the gel particle matrix formed by the filler has high central crosslinking degree and low peripheral crosslinking degree; in addition, the stimulation of the collagen regeneration is realized by compounding degradable or non-degradable microspheres. The filler prepared by the secondary crosslinking process has excellent rheological mechanical property, has the deformation resistance and durability which are endowed by gel with high crosslinking degree, and has the softness and natural aesthetic property which are brought by gel with low crosslinking degree.

Description

Gradient degradable skin filler and preparation method thereof

Technical Field

The invention relates to the field of tissue filling and medical biomaterials, in particular to a gradient degradation dermal filler and a preparation method thereof.

Background

The face gradually presents aging changes under the influence of a variety of factors. Sunlight exposure over the years is the largest factor affecting aging changes in the skin, and it also plays a central role in many other facial cosmetic problems. Generally, with age, the fat, collagen and hyaluronic acid in the skin gradually decrease, and the face gradually loses its plump, youthful appearance, resulting in the appearance of wrinkles to varying degrees. The skin is repeatedly folded along with the facial expression actions for many years, and dynamic wrinkles are gradually formed, such as forehead, glabellar, nasolabial sulcus, perioral and periorbital areas; the facial tissue gradually loses its own elasticity and ability to resist tension, and inevitably begins to have a sagging appearance under the influence of gravity.

The simplest and effective method for combating wrinkles and rejuvenating to youth is to inject bulking agents. Neuber in 1893 attempted to fill facial defects with autologous fat; from 1910s to 1980s, researchers try to use paraffin oil and silica gel as shaping fillers, but since both of the fillers are non-degradable materials, the fillers are easy to cause various complications such as foreign body reaction, foreign body granuloma, nodule formation and the like, and the FDA in the United states prohibits all the applications of the silica gel in shaping and face-lifting in 1992; 1980, the first animal-derived degradable collagen products, fibrel and Zplast, used as bulking agents for injections were approved by the US FDA, but animal-derived collagens may cause allergic reactions, require skin tests before injection, and are at risk of contracting infectious diseases in animals. In 1996, rayl blue 2 (Restylane) produced by Q-Med AB in sweden entered the european market, in 2003, the FDA in the united states approved the first non-permanent filler (cross-linked sodium hyaluronate gel) -rayl blue 2 (Restylane) of non-animal origin for cosmetic filling, month 12 in 2008, rayl blue 2 (Restylane) was approved by SFDA in china to enter the chinese market, and up to now, a number of sodium hyaluronate filled products were approved for marketing.

Although the injection filler can prolong the in vivo retention time to 6-24 months after being treated by a crosslinking process, the long-term filling effect can not be realized. The microsphere component is added into the filling agent, so that the function of stimulating autologous collagen regeneration can be realized, and the long-term filling effect can be achieved. However, the existing products on the market mostly adopt the non-crosslinked gel matrix as the microsphere carrier, and after the gel matrix is implanted into the body, the matrix is degraded too fast, so that the maintenance of the short-term filling effect is not facilitated. Patents 201510593332.X, 201810505639.3, 201810505295.6 and 201911362126.2 disclose a product compounded by microspheres and crosslinked sodium hyaluronate gel and a preparation method thereof. However, the rheological property of the filler can be changed due to the addition of the microspheres, and if the crosslinking degree of the gel component is too high, the whole product has higher hardness and is difficult to inject; and the gel component with too low crosslinking degree still degrades rapidly, and can not realize more natural filling effect, so the current crosslinking process can not achieve the perfect combination of slow degradation of the filler and the requirement of easy operability.

In addition, both collagen and sodium hyaluronate are derived from animal tissue extraction or microbial fermentation, and the risk of immunogenicity and endotoxin pollution exists.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a gradient degradation dermal filler and a preparation method thereof.

In order to solve the technical problems, the invention provides the following technical scheme:

in a first aspect, a method for preparing a gradient degradation dermal filler is provided, which comprises the following steps:

(1) Preparing a matrix material into a matrix solution, adding a cross-linking agent into the matrix solution, placing the matrix solution at 25-60 ℃ for cross-linking, removing the cross-linking agent after cross-linking is finished, and granulating to obtain primary cross-linked gel particles; the matrix material is sodium carboxymethyl cellulose, sodium alginate or sodium polyglutamate;

(2) Preparing a matrix solution, adding a cross-linking agent at 2-8 ℃, dispersing the primary cross-linked gel particles in the matrix solution, filtering, placing at 40-60 ℃, and performing secondary cross-linking under stirring to obtain secondary cross-linked gel particles; compounding the secondary crosslinked gel particles with a non-crosslinked matrix solution, and sterilizing to obtain a gel phase;

(3) Preparing microspheres, and sterilizing the microspheres; the microsphere material is PCL, PLLA, PLGA, PVA, PMMA or calcium hydroxyapatite;

(4) Mixing the microspheres and the gel phase uniformly, or resuspending the microspheres with sterile water, sterile normal saline or sterile glycerol, and mixing with the gel phase to obtain a skin filler; the mass fraction of the microspheres in the dermal filler is 6-50%.

Further, in the step (1), the mass fraction of the matrix solution is 5-30%; the particle size of the primary crosslinking gel particles is 25-200 mu m.

Further, the crosslinking agent is at least one of glycidyl ethers, epoxides or carbodiimides.

Preferably, in the step (1), the concentration of the cross-linking agent is 0.5-10%, and the cross-linking time is 1.5-24h; after the crosslinking is finished, removing the crosslinking agent by dialysis, repeated cooking or solvent cleaning, and sieving to obtain the primary crosslinked gel particles.

Preferably, in the step (2), the mass fraction of the matrix solution is 1-10%; the concentration of the cross-linking agent is 0.2-3%, and the cross-linking time is 1.5-6h; after crosslinking, compounding a non-crosslinking matrix solution, and adjusting the final concentration of the gel to 10-35mg/mL to obtain a gel phase.

Preferably, in step (2), the gel phase has particles in the range of 200 to 600 μm.

Preferably, in the step (2), the stirring rotation speed is set as follows: stirring at 30-70rpm for 30-60min, stirring at 120-180rpm for 60min, and stirring at 300-500rpm.

Furthermore, in the step (3), the preparation method of the microspheres adopts the existing preparation method; the specific preparation method is properly adjusted according to the selected microsphere material.

Preferably, when the polymer material is PCL, PLLA, PLGA or PVA, the specific preparation method of the microsphere is: dissolving a high polymer material in a solvent to obtain a high polymer phase, adding the high polymer phase into a water phase or an oil phase containing an emulsifier, uniformly mixing to obtain an emulsion, and then processing the emulsion to obtain microspheres;

the solvent is dichloromethane, ethyl acetate or water, and the emulsifier is PVA, HPMC or Span.

Preferably, in the preparation process, a cross-linking agent can be added for cross-linking and emulsification as appropriate.

Further, the mass ratio of the polymer phase to the aqueous phase or the oil phase is 1.

Further, the mass fraction of the emulsifier in the water phase or the oil phase is 0.1-10%.

Preferably, in the step (3), after the emulsion is obtained, the emulsion is processed by an emulsion evaporation method, a spray drying method, a supercritical fluid method or a membrane emulsification method to obtain the microspheres.

Further, when the high molecular material is PMMA, calcium hydroxyapatite, the concrete preparation method of the microsphere is as follows:

PMMA microsphere preparation reference: zhao Bin, micron-sized monodisperse PMMA microspheres are prepared by a dispersion polymerization method, and are prepared by the method of Beijing chemical university, 2001[ D ];

hydroxyapatite calcium microsphere preparation reference: wangping, liguo Chang, hydroxyapatite microsphere preparation and ion adsorption/exchange performance research, artificial crystal bulletin, 2012, 03.

Further, in the step (3), the particle size of the microspheres is 10-100 μm; preferably 20-70 μm.

In a second aspect, a gradient degradable dermal filler is provided, which is prepared by the preparation method of the first aspect.

Compared with the prior art, the invention has the following beneficial effects:

1. in the filling agent, the gel matrix phase used as a carrier is subjected to secondary crosslinking, so that primary crosslinked gel particles with higher crosslinking degree can be uniformly dispersed in a matrix material with lower crosslinking degree, the gel matrix particles formed by the filling agent have high central crosslinking degree and low peripheral crosslinking degree; in addition, the stimulation of the collagen regeneration of the collagen is realized by compounding degradable or non-degradable microspheres. The filler prepared by the secondary crosslinking process has excellent rheological mechanical property, has the deformation resistance and durability which are endowed by high crosslinking degree gel, and has the softness and natural aesthetic property which are brought by low crosslinking degree gel.

2. The invention adopts raw materials of non-animal sources and non-fermentation sources, thereby avoiding immunogenicity risk and endotoxin risk without allergy risk;

3. after the filling agent is implanted into a body, the slow gradient degradation of a gel matrix phase and the stimulation of the collagen regeneration can be realized, and the short-term, medium-term and long-term filling effects of the filling agent material are ensured.

Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.

Drawings

The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this application, illustrate embodiment(s) of the invention and together with the description serve to explain the principles of the invention:

FIG. 1 is a graph showing the results of the modulus of elasticity of the fillers prepared in examples 1 to 3 and the fillers prepared in comparative examples 1 and 2;

FIG. 2 shows the results of the extrusion force measurements of the fillers prepared in examples 1 to 3 and the fillers prepared in comparative examples 1 and 2.

Detailed Description

For a fuller understanding of the technical content of the present invention, reference should be made to the following detailed description taken together with the accompanying drawings; it is to be understood that the embodiments described below are only a few embodiments of the present invention, and not all 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 features, benefits and advantages of the present invention will become apparent to those skilled in the art from a reading of the present disclosure.

All percentages, parts and ratios are by weight of the total composition of the invention, unless otherwise specified. The term "mass content" herein may be represented by the symbol "%".

The use of "including," "comprising," "containing," "having," or other variations thereof herein, is meant to encompass the non-exclusive inclusion, as such terms are not to be construed. The term "comprising" means that other steps and ingredients can be added that do not affect the end result. The term "comprising" also includes the terms "consisting of and" consisting essentially of. The compositions and methods/processes of the present invention can comprise, consist of, and consist essentially of the essential elements and limitations described herein, as well as any of the additional or optional ingredients, components, steps, or limitations described herein.

In the present invention, the gel particles and the non-crosslinked matrix solution can be formulated into a gel in a conventional manner.

In the present invention, the sterilization treatment may be at least one of moist heat, ethylene oxide, or radiation sterilization.

Example 1

The embodiment provides a preparation method of a gradient degradation dermal filler, which comprises the following steps:

1. preparation of gel phase:

1.1 preparing sodium polyglutamate into a sodium polyglutamate solution with the concentration of 25%, adding carbodiimide with the concentration of 1% into the sodium polyglutamate solution, then placing the solution at room temperature for crosslinking for 24 hours, dialyzing a gel block for 24 hours to remove a crosslinking agent, changing water once every 8 hours after crosslinking, and sieving to obtain crosslinked sodium polyglutamate gel particles, so that the particle size range of the crosslinked sodium polyglutamate gel particles is 25-200 mu m;

1.2 preparing 8% sodium polyglutamate solution, adding 0.2% carbodiimide at 2-8 ℃, adding the primary crosslinked sodium polyglutamate gel particles into the 8% sodium polyglutamate solution, stirring to enable the carbodiimide and the sodium polyglutamate solution to be uniformly adhered to the primary crosslinked sodium polyglutamate gel particles, then separating, placing the primary crosslinked sodium polyglutamate gel particles at 40 ℃ to start secondary crosslinking, setting 35rpm for stirring for 30min, then setting 125rpm for stirring for 30min, setting 375rpm for stirring for 5 hours to obtain secondary crosslinked gel particles, then compounding non-crosslinked sodium polyglutamate solution, adjusting the final concentration of gel to 30mg/mL, uniformly mixing, and performing wet heat sterilization to obtain a gel phase; the gel phase has particles in the range of 200-600 μm.

2. Preparing microspheres:

dissolving polycaprolactone material in dichloromethane at 2% concentration to obtain a polymer phase, simultaneously preparing an aqueous phase containing 0.5% of PVA, slowly adding the polymer phase into the aqueous phase at a mass ratio of 1:4, emulsifying at 2000rpm for 20min, and slowly stirring to volatilize dichloromethane to prepare polycaprolactone microspheres, wherein the microspheres are sterilized by ethylene oxide.

3. Preparation of the filler:

mixing the microspheres and the gel phase by adopting an aseptic processing technology, or carrying out resuspension on the microspheres by adopting sterile water, sterile normal saline or sterile glycerol, and then mixing the microspheres and the gel phase to prepare the skin filler, wherein the final mass fraction of the microspheres in the filler accounts for 30 percent, and the preparation of the skin filler is finished.

Example 2

1. preparation of gel phase:

1.1 preparing sodium alginate into a 10% sodium alginate solution, adding 8% polyethylene glycol diglycidyl ether into the sodium alginate solution, placing the solution at 60 ℃ for crosslinking for 2.5 hours, after the crosslinking is finished, crushing gel blocks into 0.3-0.5mm particles, placing the particles in water for boiling for 10min, repeating for 3 times after water is changed, and sieving the obtained gel to obtain once crosslinked sodium alginate gel particles, wherein the particle size of the once crosslinked sodium alginate gel particles is 25-200 mu m;

1.2 preparing a sodium alginate solution with the concentration of 2%, adding 0.6% polyethylene glycol diglycidyl ether at the temperature of 2-8 ℃, adding the primary crosslinked sodium alginate gel particles into the 2% sodium alginate solution, stirring to enable the polyethylene glycol diglycidyl ether and the sodium alginate solution to be uniformly adhered to the primary crosslinked sodium alginate gel particles, then separating, placing the primary crosslinked sodium alginate gel particles at the temperature of 60 ℃ to start secondary crosslinking, stirring at 70rpm for 30min, then setting 175rpm to stir for 30min, then setting 480rpm to stir for 1 hour to obtain secondary crosslinked gel particles, then compounding a non-crosslinked sodium alginate solution, adjusting the final concentration of gel to 16mg/mL, uniformly mixing, and performing moist heat sterilization to obtain a gel phase; the gel phase has particles in the range of 200-600 μm.

2. Preparing microspheres:

dissolving a poly-L-lactic acid material in ethyl acetate at a concentration of 10%, preparing an aqueous phase containing 5% HPMC, slowly adding a polymer phase into the aqueous phase at a mass ratio of 1.

3. Preparation of the filler:

mixing the microspheres with the gel phase by adopting an aseptic processing technology, or resuspending the microspheres with sterile water, sterile normal saline or sterile glycerol, and mixing the microspheres with the gel phase to prepare the filler, wherein the final mass fraction of the microspheres in the filler is 25%. The dermal filler is prepared.

Example 3

1. preparation of gel phase:

1.1, preparing sodium carboxymethylcellulose into a sodium carboxymethylcellulose solution with the concentration of 5%, adding epichlorohydrin with the final concentration of 2% into the sodium carboxymethylcellulose solution, then placing the solution at 50 ℃ for crosslinking for 6 hours, after the crosslinking is finished, alternately cleaning gel blocks by absolute ethyl alcohol/water, cleaning for 30min for a single time, cleaning for 4 cycles after 1 hour, placing the obtained gel in a vacuum drying box to volatilize the absolute ethyl alcohol in the gel blocks, and screening to obtain a crosslinked sodium carboxymethylcellulose gel particle, wherein the particle size of the crosslinked sodium carboxymethylcellulose gel particle is 25-200 mu m;

1.2, preparing a 1% sodium carboxymethylcellulose solution, adding 0.8% epichlorohydrin at 2-8 ℃, adding the primary crosslinked sodium carboxymethylcellulose gel particles into the 1% sodium carboxymethylcellulose solution, stirring to uniformly adhere the epichlorohydrin and the sodium carboxymethylcellulose solution to the primary crosslinked sodium carboxymethylcellulose gel particles, then separating, placing the primary crosslinked sodium carboxymethylcellulose gel particles at 50 ℃ to start secondary crosslinking, stirring at 50rpm for 30min, then stirring at 150rpm for 30min, then stirring at 425rpm for 2 hours to obtain secondary crosslinked gel particles, then compounding a non-crosslinked sodium carboxymethylcellulose solution, adjusting the final concentration of gel to 20mg/mL, uniformly mixing, performing wet heat sterilization to obtain a gel phase, wherein the particle range of the gel phase is 200-600 microns;

2. preparing microspheres:

dissolving a polyvinyl alcohol material in water at a concentration of 18%, preparing vegetable oil containing 8% span-80, slowly adding a polymer phase into an oil phase, wherein the mass ratio of the polymer phase to the oil phase is 1.

3. Preparation of the filler:

mixing the microspheres with a gel phase by adopting an aseptic processing technology, or resuspending the microspheres with sterile water, sterile normal saline or sterile glycerol, and mixing the microspheres with the gel phase to prepare the microsphere, wherein the final mass fraction of the microspheres is 10%; the dermal filler preparation is completed.

Preparation of control sample of injectable bulking agent

Comparative example 1

Compared with example 1, the difference is that: comparative example 1 a primary cross-linking process was used;

the method comprises the following specific steps:

1. preparation of gel phase:

preparing 10% sodium polyglutamate solution from sodium polyglutamate, adding 0.2% carbodiimide, placing the mixed solution at 40 ℃ for 6 hours to complete crosslinking, placing the crosslinked gel in a constant volume dialysis bag for dialysis for 12 hours to remove a crosslinking agent, sieving to obtain gel particles with the particle size range of 200-600 mu m, compounding non-crosslinked sodium polyglutamate solution, enabling the final concentration of the gel to be 30mg/mL, uniformly mixing, and performing moist heat sterilization to obtain a gel phase.

2. Preparing microspheres:

dissolving a polycaprolactone material in dichloromethane at a concentration of 2% to obtain a polymer phase, preparing an aqueous phase containing PVA with a content of 0.5%, slowly adding the polymer phase into the aqueous phase, wherein the mass ratio of the polymer phase to the aqueous phase is 1/4, emulsifying at 2000rpm for 20min, slowly stirring to volatilize the dichloromethane, and preparing polycaprolactone microspheres, wherein the microspheres are sterilized by ethylene oxide.

3. Preparation of the filler:

mixing the microspheres with a gel phase by adopting an aseptic processing technology, or resuspending the microspheres with sterile water, sterile normal saline or sterile glycerol, and mixing the microspheres with the gel phase to prepare the skin filler, wherein the final mass fraction of the microspheres is 30%.

Comparative example 2

Compared with example 3, the difference is that: only one-time crosslinking process is adopted;

the method comprises the following specific steps:

1. preparation of gel phase:

preparing sodium carboxymethylcellulose into a sodium carboxymethylcellulose solution with the concentration of 5%, adding epichlorohydrin with the final concentration of 2% into the sodium carboxymethylcellulose solution, then placing the solution at the temperature of 50 ℃ for 6 hours for crosslinking, after crosslinking, alternately cleaning gel blocks by absolute ethyl alcohol/water, cleaning for 30min once, taking 1 hour as a cleaning cycle, cleaning for 4 cycles, placing the obtained gel in a vacuum drying oven to volatilize the absolute ethyl alcohol in the gel blocks, sieving the gel blocks to obtain gel particles with the particle size range of 200-600 mu m, compounding a non-crosslinked sodium carboxymethylcellulose solution, adjusting the final concentration of the gel to 20mg/ml, uniformly mixing, and carrying out moist heat sterilization to obtain a gel phase;

2. preparing microspheres:

3. Preparation of the filler:

mixing the microspheres with a gel phase by adopting an aseptic processing technology, or resuspending the microspheres with sterile water, sterile normal saline or sterile glycerol, and mixing the microspheres with the gel phase to prepare the microsphere, wherein the final mass fraction of the microspheres is 10%; the dermal filler is prepared.

Performance testing

The elastic modulus and the extrusion force of the filler prepared by the invention are tested, and compared with the filler subjected to a cross-linking process only once, and the test results are shown in fig. 1 and 2. The results show that the fillers prepared in examples 1 to 3 of the present invention have higher elastic modulus and more suitable extrusion force.

Further comparison can be made, compared with examples 1-3, comparative example 1 has similar extrusion force, but the elastic modulus is also lower, which indicates that the gel crosslinking degree is low; the comparative example 2 has higher elastic modulus and higher extrusion force, and brings great difficulty to the clinical operation of the product.

The filler prepared in the embodiment 3 of the invention and the comparative examples 1 and 2 are injected into rats about 150 mu L in an intradermal way, and the fillers, 1w, 4w, 12w, 26w and 52w after injection are respectively measured in vitro dimensions by a digital caliper, and the volume of the implant is measured to evaluate the degradation condition and the effectiveness of the implant. The test results are shown in table 1.

Table 1:

according to the test results in table 1, the filler prepared by the invention can realize slow gradient degradation of gel components, so that the filling effect is more natural, and a window period exists between the filling effect and the tissue filling effect realized by stimulating the organism to generate collagen through microspheres, which is reflected in that the filling volume is firstly reduced and then increased, while the filler of comparative example 1 is relatively fast degraded (about 6 months).

The technical solutions provided by the embodiments of the present invention are described in detail above, and the principles and embodiments of the present invention are explained herein by using specific examples, and the descriptions of the embodiments are only used to help understanding the principles of the embodiments of the present invention; meanwhile, for a person skilled in the art, according to the embodiments of the present invention, there may be variations in the specific implementation manners and application ranges, and in summary, the content of the present description should not be construed as a limitation to the present invention.

Claims

1. A preparation method of a gradient degradation dermal filler is characterized by comprising the following steps:

(1) Preparing a matrix material into a matrix solution, adding a cross-linking agent into the matrix solution, placing the matrix solution at 25-60 ℃ for cross-linking, removing the cross-linking agent after cross-linking is finished, and granulating to obtain primary cross-linked gel particles; the matrix material is sodium carboxymethylcellulose, sodium alginate or sodium polyglutamate;

(3) Preparing microspheres and sterilizing the microspheres; the microsphere material is PCL, PLLA, PLGA, PVA, PMMA or calcium hydroxyapatite;

(4) Mixing the microspheres and the gel phase uniformly, or resuspending the microspheres with sterile water, sterile normal saline or sterile glycerol, and mixing with the gel phase to obtain a skin filler; the mass fraction of the microspheres in the dermal filler is 6-50%;

the cross-linking agent is at least one of glycidyl ether, epoxide or carbodiimide;

in the step (1), the concentration of the cross-linking agent is 0.5-10%, and the cross-linking time is 1.5-24h; after the crosslinking is finished, removing the crosslinking agent by dialysis, repeated cooking or solvent cleaning, and sieving to obtain primary crosslinked gel particles; in the step (1), the mass fraction of the matrix solution is 5-30%; the particle size of the primary crosslinked gel particles is 25-200 mu m;

in the step (2), the mass fraction of the matrix solution is 1-10%; the concentration of the cross-linking agent is 0.2-3%, and the cross-linking time is 1.5-6h; after crosslinking, compounding a non-crosslinking matrix solution, and adjusting the final concentration of the gel to 10-35mg/mL to obtain a gel phase; in the step (2), the particle range of the gel phase is 200-600 μm;

in the step (3), when the microsphere material is PCL, PLLA, PLGA or PVA, the specific preparation method of the microsphere is: dissolving a microsphere material in a solvent to obtain a high-molecular phase, adding the high-molecular phase into a water phase or an oil phase containing an emulsifier, uniformly mixing to obtain an emulsion, and treating the emulsion to obtain microspheres;

2. The method for preparing gradient degradation dermal filler according to claim 1, characterized in that the mass ratio of the polymer phase to the water phase or the oil phase is 1.

3. The method for preparing gradient degradation dermal filler according to claim 1, characterized in that the mass fraction of the emulsifier in the water phase or the oil phase is 0.1-10%.

4. The method for preparing gradient degradation dermal filler according to claim 1, wherein in the step (3), after the emulsion is obtained, the emulsion is processed by an emulsion evaporation method, a spray drying method, a supercritical fluid method or a membrane emulsification method to obtain the microsphere.

5. A gradient degradable dermal filler, characterized in that it is prepared by the preparation method of any one of claims 1 to 4.