Injectable filler, preparation method and application thereof

Abstract

This application discloses an injectable filler comprising polyester microspheres and sodium carboxymethylcellulose gel. The sterilized sodium carboxymethylcellulose gel exhibits an elastic modulus G' of 190 to 800 Pa at a frequency of 1 Hz, and a ratio of the elastic modulus G' to the viscous modulus G', G' / G'', of 1.1 to 2.5. The injectable filler exhibits ideal viscoelastic properties, with the polyester microspheres exhibiting good dispersion stability within the formulation and moderate extrusion force. This filler is less likely to cause needle blockage or complications during injection, resulting in high safety, a natural filling effect, and a high aesthetic appearance after injection. Furthermore, the filler exhibits good cohesion, making it less likely to shift after injection.

Description

Technical Field

[0001] The present invention relates to the field of medical aesthetics, and in particular to an injectable filler, a preparation method and applications thereof. Background Art

[0002] With aging and various external stimuli, the loss of collagen in the dermis accelerates, causing the skin to become loose and wrinkles to appear. Medical cosmetic fillers can be used to improve skin condition. Currently, polyester microsphere fillers have become a hot topic of research in the medical aesthetics field due to their multiple advantages. For example, polyester microspheres have high biocompatibility, provide tissue support, and can induce fibroblast proliferation and myofibroblast differentiation, promoting collagen synthesis, thereby compensating for skin aging caused by collagen loss. Polyester microspheres also remain in the body for a long time, reducing the number of injections and effectively alleviating the pain of patients seeking cosmetic surgery.

[0003] Increasing the polyester microsphere content in polyester microsphere-filled formulations is a common method used in the field to enhance their cosmetic efficacy. However, polyester microspheres are hydrophobic, and increasing their concentration places high demands on the gel in the formulation. Improper gel selection can lead to poor dispersion and storage stability of the polyester microspheres in the formulation, resulting in needle blockage during injection and increased injection pressure, making injection more difficult for the physician and more painful for the patient. Alternatively, uncontrolled injection pressure can lead to excessive local injection volume, resulting in complications such as local nodules or granulomas.

[0004] Therefore, there is an urgent need in this field to develop an injectable filling material with ideal cosmetic effects, good dispersion stability of polyester microspheres in preparations and good storage stability of preparations, high safety in use, natural filling effect, and little injection pain. Summary of the Invention

[0005] The technical problem to be solved by this application is to overcome the drawbacks of existing formulations, such as poor dispersion and storage stability of polyester microspheres, which can lead to complications such as needle blockage, increased injection force, increased injection pain, and the development of nodules or granulomas during injection. The present application provides an injectable filler, preparation method, and application thereof. The injectable filler of this application exhibits ideal viscoelastic properties, good dispersion stability of the polyester microspheres in the formulation, moderate injection force, and is less likely to cause needle blockage or complications during injection. It is highly safe to use, provides a natural filling effect, has a high aesthetic appearance after injection, and is less likely to shift after injection.

[0006] This application solves the above technical problems through the following technical solutions.

[0007] The present application provides an injectable filler, which comprises polyester microspheres and sodium carboxymethylcellulose gel; the injectable filler has been sterilized;

[0008] The elastic modulus G' of the sodium carboxymethyl cellulose gel after sterilization at a frequency of 1 Hz is 190-800 Pa, and the ratio G' / G'' of the elastic modulus G' to the viscous modulus G'' is 1.1-2.5.

[0009] In some embodiments, the elastic modulus G' of the sodium carboxymethyl cellulose gel at a frequency of 1 Hz after sterilization is preferably 200~600 Pa, more preferably 200~500 Pa, for example, 205Pa, 250Pa, 300Pa, 350Pa, 400Pa, 450Pa, 500Pa, 550Pa, 600Pa, 650Pa, 700Pa, 750Pa or 800Pa.

[0010] In some embodiments, the G` / G`` of the sodium carboxymethyl cellulose gel after sterilization at a frequency of 1 Hz is preferably 1.1-2, for example, 1.14, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4 or 2.5.

[0011] In some embodiments, the viscous modulus G`` of the sodium carboxymethyl cellulose gel after sterilization at a frequency of 1 Hz is 170~500 Pa, preferably 170~400 Pa, and more preferably 170~350 Pa, for example, 180 Pa, 200 Pa, 250 Pa, 300 Pa, 320 Pa, 350 Pa, 400 Pa, 450 Pa or 500 Pa.

[0012] In some embodiments, the sodium carboxymethyl cellulose gel is sterilized within 1 second. -1 The shear viscosity η at the shear rate is 160~650 Pa·s, preferably 170~550 Pa·s, for example, 170 Pa·s, 200 Pa·s, 250 Pa·s, 300 Pa·s, 350 Pa·s, 400 Pa·s, 450 Pa·s, 500 Pa·s, 550 Pa·s, 600 Pa·s or 650 Pa·s.

[0013] In some embodiments, the mass percentage of sodium carboxymethyl cellulose in the sodium carboxymethyl cellulose gel is 3.8% to 6%, preferably 4% to 5.5%, for example 4.5%.

[0014] In some embodiments, the viscosity of the sodium carboxymethyl cellulose used to prepare the sodium carboxymethyl cellulose gel is 5800-15000 mPa·s, preferably 5800-12500 mPa·s, for example 6000 mPa·s, 7000 mPa·s, 8000 mPa·s, 9000 mPa·s, 10000 mPa·s, 11000 mPa·s, 12000 mPa·s, 13000 mPa·s, 14000 mPa·s or 15000 mPa·s. The viscosity is the viscosity of a 2% by mass sodium carboxymethyl cellulose gel prepared by mixing sodium carboxymethyl cellulose and water using a rotational viscometer according to the European Pharmacopoeia method.

[0015] In some embodiments, the degree of substitution of the sodium carboxymethyl cellulose used to prepare the sodium carboxymethyl cellulose gel is 0.75-0.82, preferably 0.75-0.8, such as 0.78 or 0.79.

[0016] In some embodiments, the material of the polyester microspheres is selected from polycaprolactone.

[0017] In some embodiments, the weight average molecular weight of the polyester microsphere material is 10,000-40,000, preferably 10,000-25,000.

[0018] In some embodiments, the content of polyester microspheres in the injectable filler is 200-400 mg / g, preferably 300-350 mg / g, for example 330 mg / g.

[0019] In some embodiments, the polyester microspheres have a particle size of 20-50 μm accounting for more than 80%, preferably more than 90%.

[0020] In some embodiments, the particle size D50 of the polyester microspheres is 20-50 μm, preferably 25-45 μm.

[0021] In some embodiments, the sodium carboxymethylcellulose gel further comprises at least one of a lubricant, a buffer, and an anesthetic.

[0022] The lubricating moisturizer is selected from at least one of a polyol lubricating moisturizer, a carbohydrate lubricating moisturizer, and a polymer lubricating moisturizer. Preferably, the polyol lubricating moisturizer is selected from at least one of glycerol, propylene glycol, and sorbitol. Preferably, the carbohydrate lubricating moisturizer is selected from at least one of sodium hyaluronate, trehalose, and mannitol. The polymer lubricating moisturizer is polyethylene glycol.

[0023] The buffer is a buffer acceptable in the medical aesthetics field for regulating the pH and osmotic pressure of the system, preferably a phosphate buffer, more preferably a mixture of dihydrogen phosphate and dihydrogen phosphate. Preferably, the dihydrogen phosphate is selected from disodium hydrogen phosphate and / or dipotassium hydrogen phosphate. Preferably, the dihydrogen phosphate is selected from sodium dihydrogen phosphate and / or potassium dihydrogen phosphate.

[0024] Wherein, the anesthetic is selected from at least one of lidocaine hydrochloride, lidocaine carbonate, tetracaine, prilocaine, procaine, mepivacaine and bupivacaine.

[0025] The mass percentage of the lubricating moisturizer to the sodium carboxymethyl cellulose gel is 0.5% to 3%, preferably 0.5% to 1.5%, such as 0.8%, 1% or 1.2%.

[0026] Wherein, the mass percentage of the anesthetic to the sodium carboxymethyl cellulose gel is 0.1% to 0.6%.

[0027] The amount of the buffer used can be conventional in the art, and is generally used to adjust the pH value of the injectable filler to 6-8, and / or adjust the osmotic pressure of the injectable filler to isotonic.

[0028] In some embodiments, the elastic modulus G' of the injectable filler at a frequency of 1 Hz is 800-3500 Pa, preferably 900-3100 Pa, for example 800 Pa, 1000 Pa, 1500 Pa, 2000 Pa, 2500 Pa, 3000 Pa or 3500 Pa.

[0029] In some embodiments, the injectable filler has a viscous modulus G`` of 550~2500 Pa at a frequency of 1 Hz, preferably 600~2000 Pa, and more preferably 600~1800 Pa, for example, 550Pa, 600Pa, 800Pa, 1000Pa, 1200Pa, 1400Pa, 1600Pa, 1800Pa, 2000Pa, 2200Pa, 2400Pa or 2500Pa.

[0030] In some embodiments, the injectable filler has a G` / G`` ratio of 1.2 to 2.5 at a frequency of 1 Hz, preferably 1.2 to 2, such as 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4 or 2.5.

[0031] In some embodiments, the method for preparing the polyester microspheres comprises the following steps: assembling the polyester microsphere materials described above into microspheres by an emulsified solvent volatilization method, followed by sterilization.

[0032] In a preferred embodiment, the method for preparing the polyester microspheres comprises the following steps: an organic phase comprises the material of the polyester microspheres and an organic solvent; an aqueous phase comprises a surfactant and water; and the organic phase and the aqueous phase are mixed, emulsified, solidified, and sterilized to obtain the polyester microspheres.

[0033] The organic solvent is selected from a halogenated alkane solvent and / or an ester solvent. Preferably, the halogenated alkane solvent is a chlorinated alkane solvent, more preferably selected from dichloromethane and / or chloroform. Preferably, the ester solvent is a C2-C6 alkyl acetate, more preferably ethyl acetate.

[0034] The mass volume ratio of the polyester microsphere material to the organic solvent is 80-450 g / L, preferably 100-300 g / L.

[0035] The volume ratio of the organic phase to the aqueous phase is 1:(3-20), preferably 1:(5-15), for example 1:10.

[0036] Wherein, the surfactant is polyvinyl alcohol, preferably polyvinyl alcohol 1788.

[0037] The mass volume ratio of the surfactant to the water is 8-50 g / L, preferably 15-40 g / L.

[0038] The viscosity of the aqueous phase is 2-10 mPa·s, and is measured using a rotational viscometer at 25°C.

[0039] Wherein, the water is purified water.

[0040] The method for preparing the aqueous phase comprises the following steps: mixing the surfactant and the water at a mixing temperature of 60-120°C.

[0041] Wherein, the emulsification method includes mechanical stirring emulsification method, membrane emulsification method or homogeneous emulsification method.

[0042] The curing method includes a reduced pressure volatilization method and / or an air blowing method. According to conventional techniques in the art, the purpose of the curing is to remove the organic solvent in the system and promote the curing of the emulsion into microspheres.

[0043] The curing step may further include any one of collecting, drying, and screening. Preferably, the drying method is vacuum drying, which is commonly used in the art. More preferably, the drying temperature is 25-45°C. More preferably, the drying time is 12-48 hours.

[0044] The present application also provides a method for preparing an injectable filler, comprising the following steps:

[0045] Solution A: Mix unsterilized polyester microspheres and unsterilized sodium carboxymethyl cellulose gel and sterilize them;

[0046] Solution B: sterilize unsterilized polyester microspheres and unsterilized sodium carboxymethyl cellulose gel separately to prepare sterile polyester microspheres and sterile sodium carboxymethyl cellulose gel, and then mix the polyester microspheres and the sodium carboxymethyl cellulose gel under sterile conditions.

[0047] In scheme A of some embodiments, the sterilization method is moist heat sterilization.

[0048] In solution B of some embodiments, the sterilization method of the non-sterile polyester microspheres is irradiation sterilization or moist heat sterilization. Preferably, the irradiation sterilization is selected from beta irradiation sterilization or gamma irradiation sterilization.

[0049] In scheme B of some embodiments, the sterilization method of the non-sterile sodium carboxymethyl cellulose gel is moist heat sterilization.

[0050] In a preferred embodiment, the moist heat sterilization is carried out under anaerobic conditions, preferably under inert atmosphere conditions, and more preferably under nitrogen conditions.

[0051] In a preferred embodiment, the moist heat sterilization time is 10 to 40 minutes, more preferably 15 to 30 minutes.

[0052] In a preferred embodiment, the temperature of the moist heat sterilization is 100-130°C, for example 121°C.

[0053] The present application also provides an injectable filler, which is prepared by the above-mentioned method for preparing the injectable filler.

[0054] The present application also provides a use of the injectable filler as described above in the preparation of medical or cosmetic products.

[0055] Among them, the medical or cosmetic products include filling and shaping products.

[0056] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present application.

[0057] The reagents and raw materials used in this application are commercially available.

[0058] The positive progress of the present application is that the injectable filler of the present application has ideal viscoelastic properties, the polyester microspheres have good dispersion stability and storage stability in the preparation, the injection pushing force is uniform, and it is not easy to cause needle blockage during injection, or excessive local injection due to uneven pushing force, thereby inducing complications such as nodules or granulomas. It is highly safe to use, has a natural filling effect, is aesthetically pleasing, and is not prone to displacement after injection. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 This is a diagram of the injectable filler obtained in Example 1 after centrifugation;

[0060] Figure 2 This is a diagram of the injectable filler obtained in Example 2 after centrifugation;

[0061] Figure 3 This is a diagram of the injectable filler obtained in Example 3 after centrifugation;

[0062] Figure 4 This is a diagram of the injectable filler obtained in Comparative Example 1 after centrifugation;

[0063] Figure 5 This is a diagram of the injectable filler obtained in Comparative Example 2 after centrifugation;

[0064] Figure 6 The rheological diagram of the injectable filler prepared in Example 1;

[0065] Figure 7 The rheological diagram of the injectable filler prepared in Example 2;

[0066] Figure 8 The rheological diagram of the injectable filler prepared in Example 3;

[0067] Figure 9 The rheological diagram of the injectable filler prepared in Example 4;

[0068] Figure 10 The rheological diagram of the injectable filler prepared in Example 5;

[0069] Figure 11 The rheological diagram of the injectable filler prepared in Example 6;

[0070] Figure 12 The rheological diagram of the injectable filler prepared in Example 7;

[0071] Figure 13 The rheological diagram of the injectable filler prepared in Comparative Example 1;

[0072] Figure 14 Rheological diagram of the injectable filler prepared for Comparative Example 2. DETAILED DESCRIPTION

[0073] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. In the following examples, the experimental methods without specific conditions are selected according to conventional methods and conditions or according to the product specifications.

[0074] (1) Test method for elastic modulus G` and viscous modulus G` of the products in the following examples and comparative examples: Dynamic frequency scanning was performed using a rheometer. The test temperature was set to 25°C, the frequency range was 0.1-10 Hz, the shear strain was 0.5%, the number of sampling points for each order of magnitude was 10, and the elastic modulus G` and viscous modulus G` were recorded at a frequency of 1 Hz.

[0075] (2) Shear viscosity η test method of the products in the following examples and comparative examples: shear rate scanning was performed using a rheometer, with the detection temperature set at 25°C and the shear rate range of 0.1s -1 ~100s -1 , set the gap to 0.3mm, the scanning time to 3min, and the number of sampling points for each order of magnitude to 20. Record the shear rate for 1s -1 Shear viscosity value under certain conditions.

[0076] (3) Viscosity test method for the products in the following examples and comparative examples: Using the European Pharmacopoeia method, sodium carboxymethyl cellulose and water were mixed using a rotational viscometer to prepare a sodium carboxymethyl cellulose gel with a mass percentage of 2%.

[0077] (4) The reagents and raw materials used in the following examples are all commercially available, and the purity of the reagents used is injection grade.

[0078] (5) The preparation method of sterile polycaprolactone microspheres in the following examples and comparative examples includes the following steps:

[0079] (a) Preparation of the aqueous phase: Add an appropriate amount of purified water to a container, slowly add 20 g of polyvinyl alcohol 1788, stir until completely dissolved, and adjust the volume to 1 L to obtain an aqueous phase with a viscosity of 7.5 mPa·s.

[0080] (b) Preparation of organic phase: Add an appropriate amount of dichloromethane to a container, weigh 20 g of polycaprolactone with a weight average molecular weight of 15,000, add it to the container, stir until completely dissolved, and adjust the volume to 100 mL to obtain an organic phase;

[0081] (c) Membrane emulsification: The organic phase was slowly poured into the aqueous phase, and the mixed liquid was rapidly emulsified using a membrane emulsifier with a membrane tube pore size of 40 μm to obtain an emulsion;

[0082] (d) solidification: stirring the emulsified emulsion and blowing nitrogen gas to volatilize the dichloromethane until the dichloromethane is completely evaporated;

[0083] (e) Collection: After the dichloromethane is completely evaporated, the suspension is centrifuged to collect the solid component, which is then dried and sterilized by irradiation to produce spherical or elliptical polycaprolactone microspheres. The microspheres have a particle size of 20-50 μm, accounting for 86.4% and a D50 of 33.3 μm.

[0084] (6) The pH value of the phosphate solution in the following examples and comparative examples is 7.

[0085] (7) Preparation of sodium carboxymethylcellulose gel used in the following examples and comparative examples

[0086] Sodium carboxymethyl cellulose gel 1: 94.5 g of phosphate solution (pH 7), 4.5 g of sodium carboxymethyl cellulose (viscosity 6000 mPa·s, degree of substitution 0.78) and 1 g of glycerol were mixed to prepare non-sterile sodium carboxymethyl cellulose gel (shear viscosity 265.2 Pa·s). The non-sterile sodium carboxymethyl cellulose gel was placed in a suitable sealed container and sterilized by wet heat at 121°C for 15 min under nitrogen atmosphere to obtain sodium carboxymethyl cellulose gel 1, which was soluble in water at 1 s. -1 The shear viscosity under the conditions is 170.2 Pa·s; the elastic modulus G` at 1 Hz is 205.2 Pa, the viscous modulus G`` is 180.5 Pa, and G` / G`` is 1.14.

[0087] Sodium carboxymethyl cellulose gel 2: The preparation method is similar to that of sodium carboxymethyl cellulose gel 1, except that the raw materials are different, and sodium carboxymethyl cellulose with a viscosity of 8000 mPa·s and a degree of substitution of 0.78 is used instead. -1 The shear viscosity under normal conditions is 347.6 Pa·s (the shear viscosity before sterilization is 426.8 Pa·s); the elastic modulus G` at 1 Hz is 479.6 Pa, the viscous modulus G`` is 319.3 Pa, and G` / G`` is 1.50.

[0088] Sodium carboxymethyl cellulose gel 3: The preparation method is similar to that of sodium carboxymethyl cellulose gel 2, the only difference is that nitrogen is not added during sterilization. Sodium carboxymethyl cellulose gel 3 is sterilized in 1s -1 The shear viscosity under normal conditions is 275 Pa·s (the shear viscosity before sterilization is 426.8 Pa·s); the elastic modulus G` at 1 Hz is 355.6 Pa, the viscous modulus G`` is 245.2 Pa, and G` / G`` is 1.45.

[0089] Sodium carboxymethyl cellulose gel 4: The preparation method is similar to that of sodium carboxymethyl cellulose gel 2, the only difference is that the sterilization time is 30 minutes; sodium carboxymethyl cellulose gel 4 is sterilized in 1 second. -1The shear viscosity under normal conditions is 246 Pa·s (the shear viscosity before sterilization is 426.8 Pa·s); the elastic modulus G` at 1 Hz is 300.5 Pa, the viscous modulus G`` is 229.8 Pa, and G` / G`` is 1.31.

[0090] Sodium carboxymethyl cellulose gel 5: The preparation method is similar to that of sodium carboxymethyl cellulose gel 1, except that the raw materials are different. Sodium carboxymethyl cellulose with a viscosity of 12000 mPa·s and a degree of substitution of 0.79 is used instead. Sodium carboxymethyl cellulose gel 5 has a viscosity of 12000 mPa·s and a degree of substitution of 0.79. -1 The shear viscosity under normal conditions is 547 Pa·s (the shear viscosity before sterilization is 567.1 Pa·s); the elastic modulus G` at 1 Hz is 597.2 Pa, the viscous modulus G`` is 334.1 Pa, and G` / G`` is 1.79.

[0091] Sodium carboxymethyl cellulose gel 6: The preparation method is similar to that of sodium carboxymethyl cellulose gel 5, the only difference is that nitrogen is not added during sterilization; Sodium carboxymethyl cellulose gel 6 is sterilized in 1s -1 The shear viscosity under normal conditions is 320.7 Pa·s (the shear viscosity before sterilization is 567.1 Pa·s); the elastic modulus G` at 1 Hz is 446.6 Pa, the viscous modulus G`` is 304.7 Pa, and G` / G`` is 1.47.

[0092] Sodium carboxymethyl cellulose gel 7: The preparation method is similar to that of sodium carboxymethyl cellulose gel 5, the only difference is that the sterilization time is 30 minutes; sodium carboxymethyl cellulose gel 7 is sterilized in 1 second. -1 The shear viscosity under normal conditions is 326.6 Pa·s (the shear viscosity before sterilization is 567.1 Pa·s); the elastic modulus G` at 1 Hz is 491.7 Pa, the viscous modulus G`` is 309.7 Pa, and G` / G`` is 1.59.

[0093] Sodium carboxymethyl cellulose gel 8: The preparation method is similar to that of sodium carboxymethyl cellulose gel 1, the only difference is that the raw materials are different, and sodium carboxymethyl cellulose with a viscosity of 12000mPa·s and a degree of substitution of 0.85 is used instead. -1 The shear viscosity under normal conditions is 161.7 Pa·s (the shear viscosity before sterilization is 212.7 Pa·s); the elastic modulus G` at 1 Hz is 241.9 Pa, the viscous modulus G`` is 245.8 Pa, and G` / G`` is 0.98.

[0094] Sodium carboxymethyl cellulose gel 9: The preparation method is similar to that of sodium carboxymethyl cellulose gel 1, except that the raw material is replaced with sodium carboxymethyl cellulose with a viscosity of 12000 mPa·s and a degree of substitution of 0.85, and nitrogen is not added during sterilization. -1The shear viscosity under the conditions is 114.3 Pa·s (the shear viscosity before sterilization is 212.7 Pa·s); the elastic modulus G` at 1 Hz is 179.5 Pa, the viscous modulus G`` is 201.9 Pa, and G` / G`` is 0.89.

[0095] Preparation of Injectable Fillers in Examples 1-7 and Comparative Examples 1-2

[0096] The sodium carboxymethylcellulose gel prepared above and 49 g of sterile polycaprolactone microspheres prepared by the above method were mixed under sterile conditions to prepare an injectable filler.

[0097] The difference between the above examples and comparative examples is only the type of sodium carboxymethylcellulose gel, see Table 1 below for details.

[0098] Table 1

[0099]

[0100] Effect Example 1

[0101] The elastic modulus G', viscous modulus G'', elastic modulus to viscous modulus ratio G' / G'', shear viscosity η and stability of the injectable fillers prepared in the above examples and comparative examples were tested. The results are shown in Table 2.

[0102] (1) Stability study method: Weigh about 1g of the injectable filler prepared in the above examples or comparative examples and put it into a 1.5mL centrifuge tube. Centrifuge at 25℃ and 20000rpm for 5min. Observe the product status. The results are shown in the attached Figures 1-3 and Table 2.

[0103] (2) Test method for elastic modulus G' and viscous modulus G': Dynamic frequency sweep was performed using a rheometer, with the test temperature set at 25°C, the frequency range at 0.1-10 Hz, the shear strain at 0.5%, and 10 sampling points at each order of magnitude. The elastic modulus G' and viscous modulus G'' at a frequency of 1 Hz were obtained. The rheological diagrams of the injectable fillers prepared in Examples 1-7 and Comparative Examples 1-2 are shown in FIG. Figures 6 to 14 .

[0104] (3) Shear viscosity η test method: Use a rheometer to perform shear rate scanning, set the detection temperature to 25°C, and the shear rate range to 0.1s -1 ~100s -1 , set the gap to 0.3 mm, the scanning time to 3 min, the number of sampling points for each order of magnitude to 20, and the shear rate to 1 s -1 Shear viscosity value under certain conditions.

[0105] Table 2

[0106]

[0107] The product states of the injectable fillers obtained in Examples 1 to 3 after centrifugation are shown in Table 1. Figures 1-3 The product state of the injectable fillers prepared in Examples 4 to 7 after centrifugation is similar to Figure 2 The states are the same, no stratification, omitted in the drawings; the states of the injectable fillers prepared in Comparative Examples 1 and 2 after centrifugation are shown in FIG. Figures 4 and 5 .

[0108] The results show that the injectable fillers prepared using the methods of the present examples showed no significant stratification after centrifugation, indicating that the microspheres in the injectable fillers prepared using the methods of the present examples exhibited good dispersion stability, resisted sedimentation during transportation or long-term storage, and were highly safe for use. In contrast, the injectable fillers prepared in the comparative examples exhibited significant stratification, indicating that the microspheres exhibited poor dispersion stability in the sodium carboxymethylcellulose gel and were prone to sedimentation, increasing injection risks and potentially leading to needle blockage and complications.

[0109] according to Figures 6 to 14 As shown in the rheological diagram, the elastic modulus and viscous modulus curves of the injectable filler prepared in the Examples of the present application do not intersect, indicating gel properties. This demonstrates ideal filling and support, avoiding problems such as displacement after filling into tissue. Furthermore, the viscoelasticity meets the requirements of this field, resulting in a natural filling effect. In contrast, the elastic modulus and viscous modulus curves of the injectable filler prepared in the Comparative Example both intersect, indicating a matrix that is more viscous, lacking gel properties and prone to problems such as displacement after filling.

[0110] Effect Example 2

[0111] Pushing force test method: Take one filled sample, install a Terumo 27G (0.4*12mm) needle, remove all bubbles from the needle, place it in the detector of a universal tensile tester, and test at a speed of 30mm / min to measure the maximum pushing force. The results are shown in Table 3.

[0112] Table 3

[0113]

[0114] According to the maximum pushing force results, the injectable filler prepared in the embodiment of the present application has a moderate pushing force, which meets the injection requirements of doctors and can effectively avoid the risks of injection difficulty or complications caused by excessive or insufficient pushing force.

[0115] Finally, it should be noted that in this application, the terms "comprises", "includes" or any other variations thereof are intended to cover non-exclusive inclusion, so that a process, method, article or apparatus that includes a series of elements includes not only those elements, but also includes other elements not explicitly listed, or also includes elements that are inherent to such process, method, article or apparatus.

[0116] Although the present application has been disclosed above through the description of the specific embodiments of the present application, it should be understood that those skilled in the art may design various modifications, improvements or equivalents to the present application within the spirit and scope of the attached solutions. Such modifications, improvements or equivalents should also be considered to be included in the scope of protection claimed in the present application.

Claims

1. An injectable filler, characterized in that: The invention comprises polyester microspheres and sodium carboxymethyl cellulose gel; wherein the elastic modulus G' of the sodium carboxymethyl cellulose gel at a frequency of 1 Hz after sterilization is 190-800 Pa, and the ratio of the elastic modulus G' to the viscous modulus G'' is 1.1-2.5; the sodium carboxymethyl cellulose gel is sterilized in 1 s -1 The shear viscosity η at the shear rate is 160-650 Pa·s; the mass percentage of sodium carboxymethyl cellulose in the sodium carboxymethyl cellulose gel is 3.8%-6%; the viscosity of the sodium carboxymethyl cellulose used to prepare the sodium carboxymethyl cellulose gel is 5800-15000 mPa·s, and the degree of substitution is 0.75-0.

82.

2. The injectable filler according to claim 1, wherein The injectable filler satisfies at least one of the following conditions (1) to (12): (1) The elastic modulus G' of the sodium carboxymethyl cellulose gel after sterilization at a frequency of 1 Hz is 200 to 600 Pa; (2) After sterilization, the G` / G`` of the sodium carboxymethyl cellulose gel at a frequency of 1 Hz is 1.1 to 2; (3) The viscous modulus G`` of the sodium carboxymethyl cellulose gel after sterilization at a frequency of 1 Hz is 170 to 500 Pa; (4) The material of the polyester microspheres is polycaprolactone; (5) The weight average molecular weight of the polyester microsphere material is 10,000 to 40,000; (6) The content of polyester microspheres in the injectable filler is 200-400 mg / g; (7) The polyester microspheres have a particle size of 20 to 50 μm and account for more than 80%; (8) The particle size D50 of the polyester microspheres is 20-50 μm; (9) The sodium carboxymethylcellulose gel further comprises at least one of a lubricant, a buffer, and an anesthetic; (10) The elastic modulus G' of the injectable filler at a frequency of 1 Hz is 800 to 3500 Pa; (11) The injectable filler has a viscous modulus G'' of 550 to 2500 Pa at a frequency of 1 Hz; (12) The injectable filler has a G` / G`` ratio of 1.2 to 2.5 at a frequency of 1 Hz.

3. The injectable filler according to claim 2, wherein The injectable filler satisfies at least one of the following conditions (1) to (18): (1) The elastic modulus G' of the sodium carboxymethyl cellulose gel after sterilization at a frequency of 1 Hz is 200 to 500 Pa; (2) The viscous modulus G`` of the sodium carboxymethyl cellulose gel after sterilization at a frequency of 1 Hz is 170 to 400 Pa; (3) After the sodium carboxymethyl cellulose gel is sterilized, -1 The shear viscosity η at the shear rate is 170~550Pa·s; (4) The mass percentage of sodium carboxymethyl cellulose in the sodium carboxymethyl cellulose gel is 4% to 5.5%; (5) The viscosity of the sodium carboxymethyl cellulose used in preparing the sodium carboxymethyl cellulose gel is 5800~12500 mPa·s; (6) The degree of substitution of the sodium carboxymethyl cellulose used in preparing the sodium carboxymethyl cellulose gel is 0.75-0.8; (7) The weight average molecular weight of the polyester microsphere material is 10,000 to 25,000; (8) The content of the polyester microspheres in the injectable filler is 300-350 mg / g; (9) The polyester microspheres have a particle size of 20 to 50 μm and account for more than 90%; (10) The particle size D50 of the polyester microspheres is 25-45 μm; (11) The lubricating moisturizer is selected from at least one of a polyol lubricating moisturizer, a sugar lubricating moisturizer, and a polymer lubricating moisturizer; (12) The buffer is a phosphate buffer; (13) The anesthetic is at least one selected from the group consisting of lidocaine hydrochloride, lidocaine carbonate, tetracaine, prilocaine, procaine, mepivacaine, and bupivacaine; (14) The mass percentage of the lubricating moisturizer in the sodium carboxymethyl cellulose gel is 0.5% to 3%; (15) The mass percentage of the anesthetic in the sodium carboxymethyl cellulose gel is 0.1% to 0.6%; (16) The elastic modulus G' of the injectable filler at a frequency of 1 Hz is 900 to 3100 Pa; (17) The injectable filler has a viscous modulus G'' of 600 to 2000 Pa at a frequency of 1 Hz; (18) The injectable filler has a G` / G`` ratio of 1.2 to 2 at a frequency of 1 Hz.

4. The injectable filler according to claim 3, wherein The injectable filler satisfies at least one of the following conditions (1) to (7): (1) The viscous modulus G`` of the sodium carboxymethyl cellulose gel after sterilization at a frequency of 1 Hz is 170 to 350 Pa; (2) The polyol lubricating and moisturizing agent is selected from at least one of glycerol, propylene glycol and sorbitol; (3) The carbohydrate lubricating and moisturizing agent is selected from at least one of sodium hyaluronate, trehalose and mannitol; (4) The polymer lubricating and moisturizing agent is polyethylene glycol; (5) The buffer is a mixture of dihydrogen phosphate and dihydrogen phosphate; (6) The mass percentage of the lubricating moisturizer in the sodium carboxymethyl cellulose gel is 0.5% to 1.5%; (7) The viscous modulus G'' of the injectable filler at a frequency of 1 Hz is 600~1800 Pa.

5. A method for preparing the injectable filler according to any one of claims 1 to 4, characterized in that: The steps include: Option A: Mix unsterilized polyester microspheres and unsterilized sodium carboxymethylcellulose gel and then sterilize them; Solution B: sterilize unsterilized polyester microspheres and unsterilized sodium carboxymethyl cellulose gel separately to prepare sterile polyester microspheres and sterile sodium carboxymethyl cellulose gel, and then mix the sterile polyester microspheres and the sterile sodium carboxymethyl cellulose gel under sterile conditions.

6. The method for preparing the injectable filler according to claim 5, wherein: The preparation method satisfies at least one of the following conditions (1) to (3): (1) In Scheme A, the sterilization method is moist heat sterilization; (2) In scheme B, the sterilization method of the non-sterile polyester microspheres is irradiation sterilization or moist heat sterilization; (3) In Scheme B, the sterilization method of the non-sterile sodium carboxymethyl cellulose gel is moist heat sterilization.

7. The method for preparing the injectable filler according to claim 6, characterized in that: The preparation method satisfies at least one of the following conditions (1) to (4): (1) The irradiation sterilization is selected from beta irradiation sterilization or gamma irradiation sterilization; (2) The moist heat sterilization is carried out under anaerobic conditions; (3) The moist heat sterilization time is 10 to 40 minutes; (4) The temperature of the moist heat sterilization is 100~130℃.

8. The method for preparing the injectable filler according to claim 7, characterized in that: The preparation method satisfies the following conditions (1) and / or (2): (1) The moist heat sterilization is carried out under inert atmosphere conditions; (2) The moist heat sterilization time is 15 to 30 minutes.

9. An injectable filler, characterized in that The injectable filler is prepared by the method for preparing the injectable filler according to any one of claims 5 to 8.

10. Use of the injectable filler according to any one of claims 1 to 4 and 9 in the preparation of medical or cosmetic products.

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