Injectable filler as well as preparation method and application thereof

Abstract

The invention discloses an injectable filling agent. The injectable filling agent comprises polyester microspheres and sodium carboxymethyl cellulose gel, wherein after the sodium carboxymethyl cellulose gel is sterilized, the elastic modulus G of the sodium carboxymethyl cellulose gel at the frequency of 1Hz is 190-800Pa, and the ratio G / G of the elastic modulus G to the viscous modulus G is 1.1-2.5. The injectable filling agent has ideal viscoelasticity, the polyester microspheres are good in dispersion stability and moderate in pushing force in the preparation, the problems of needle blockage or complications induction and the like are not prone to occurring during injection, the use safety is high, the filling effect is natural, the attractiveness is high after injection, cohesiveness is good, and the problems of displacement and the like are not prone to occurring after injection.

Description

Technical Field

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

[0002] With the increase of age and various external stimuli, the loss rate of collagen in the dermis of human skin begins to accelerate, causing the skin to become loose and develop wrinkles. The skin condition can be improved by medical aesthetic filling. At present, polyester microsphere-based filling materials have become a research hotspot in the field of medical aesthetics due to their multiple advantages. For example, polyester microspheres have high biocompatibility, can support tissues, and can also induce the proliferation of fibroblasts and the differentiation of myofibroblasts, promoting collagen synthesis, thereby compensating for the problem of skin aging caused by collagen loss; polyester microspheres have a long residence time in the body, reducing the number of injections, and can effectively reduce the pain of patients.

[0003] For polyester microsphere-based filling preparations, the field often improves the cosmetic efficacy of the preparations by increasing the content of polyester microspheres in the preparations. However, polyester microspheres are hydrophobic materials. When increasing the concentration of polyester microspheres in the preparations, higher requirements are imposed on the gels in the preparations. If the gel is not properly selected, the dispersion stability and storage stability of polyester microspheres in the preparations will be poor, and needle clogging will occur during injection, resulting in an increase in injection pushing force, increasing the injection difficulty for doctors and the injection pain of patients, or causing an excessive local injection amount due to uncontrollable pushing force, and then complications such as local nodules or granulomas will occur.

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

[0005] The technical problem to be solved by the present application is to overcome the defects that the dispersion stability and storage stability of polyester microspheres in the existing preparations are poor, which in turn leads to problems such as easy needle clogging, increased pushing force, increased injection pain, and complications such as nodules or granulomas during injection, and to provide an injectable filler, a preparation method thereof, and an application thereof. The injectable filler of the present application has ideal viscoelastic properties, good dispersion stability of polyester microspheres in the preparation, moderate pushing force, is not prone to needle clogging or inducing complications during injection, has high safety in use, and has a natural filling effect, high aesthetic degree after injection, and is not prone to problems such as displacement after injection.

[0006] The present 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; Among them, the elastic modulus G` of the sodium carboxymethylcellulose 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.

[0008] In some embodiments, the elastic modulus G` of the sodium carboxymethylcellulose gel after sterilization at a frequency of 1 Hz is preferably 200 - 600 Pa, more preferably 200 - 500 Pa, such as 205 Pa, 250 Pa, 300 Pa, 350 Pa, 400 Pa, 450 Pa, 500 Pa, 550 Pa, 600 Pa, 650 Pa, 700 Pa, 750 Pa or 800 Pa.

[0009] In some embodiments, the G` / G`` of the sodium carboxymethylcellulose gel after sterilization at a frequency of 1 Hz is preferably 1.1 - 2, such as 1.14, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4 or 2.5.

[0010] In some embodiments, the viscous modulus G`` of the sodium carboxymethylcellulose gel after sterilization at a frequency of 1 Hz is 170 - 500 Pa, preferably 170 - 400 Pa, more preferably 170 - 350 Pa, such as 180 Pa, 200 Pa, 250 Pa, 300 Pa, 320 Pa, 350 Pa, 400 Pa, 450 Pa or 500 Pa.

[0011] In some embodiments, the sodium carboxymethylcellulose gel after sterilization at 1 s -1 The shear viscosity η at the shear rate is 160 - 650 Pa·s, preferably 170 - 550 Pa·s, such as 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.

[0012] In some embodiments, the mass percentage of sodium carboxymethylcellulose in the sodium carboxymethylcellulose gel is 3.8% - 6%, preferably 4% - 5.5%, such as 4.5%.

[0013] In some embodiments, the viscosity of the sodium carboxymethylcellulose used for preparing the sodium carboxymethylcellulose gel is 5,800 to 15,000 mPa·s, preferably 5,800 to 12,500 mPa·s, such as 6,000 mPa·s, 7,000 mPa·s, 8,000 mPa·s, 9,000 mPa·s, 10,000 mPa·s, 11,000 mPa·s, 12,000 mPa·s, 13,000 mPa·s, 14,000 mPa·s or 15,000 mPa·s. The viscosity is measured by the method of the European Pharmacopoeia using a rotational viscometer. Sodium carboxymethylcellulose and water are mixed to prepare a sodium carboxymethylcellulose gel with a mass percentage of 2%.

[0014] In some embodiments, the degree of substitution of the sodium carboxymethylcellulose used for preparing the sodium carboxymethylcellulose gel is 0.75 to 0.82, preferably 0.75 to 0.8, such as 0.78 or 0.79.

[0015] In some embodiments, the material of the polyester microspheres is selected from polycaprolactone.

[0016] In some embodiments, the weight-average molecular weight of the material of the polyester microspheres is 10,000 to 40,000, preferably 10,000 to 25,000.

[0017] In some embodiments, the content of polyester microspheres in the injectable filler is 200 to 400 mg / g, preferably 300 to 350 mg / g, such as 330 mg / g.

[0018] In some embodiments, the proportion of polyester microspheres with a particle size of 20 to 50 μm is more than 80%, preferably more than 90%.

[0019] In some embodiments, the D50 of the polyester microspheres is 20 to 50 μm, preferably 25 to 45 μm.

[0020] In some embodiments, the sodium carboxymethylcellulose gel further comprises at least one of a lubricating and moisturizing agent, a buffer and an anesthetic.

[0021] Among them, the lubricating and moisturizing agent is selected from at least one of polyol lubricating and moisturizing agents, saccharide lubricating and moisturizing agents and polymer lubricating and moisturizing agents. Preferably, the polyol lubricating and moisturizing agent is selected from at least one of glycerol, propylene glycol and sorbitol. Preferably, the saccharide lubricating and moisturizing agent is selected from at least one of sodium hyaluronate, trehalose and mannitol. The polymer lubricating and moisturizing agent is polyethylene glycol.

[0022] Among them, the buffer is a buffer acceptable in the field of medical aesthetics for adjusting the pH value and osmotic pressure of the system, preferably a phosphate buffer, more preferably a mixture of disodium hydrogen phosphate and sodium dihydrogen phosphate. Preferably, the disodium hydrogen phosphate is selected from sodium hydrogen phosphate and / or potassium hydrogen phosphate. Preferably, the sodium dihydrogen phosphate is selected from sodium dihydrogen phosphate and / or potassium dihydrogen phosphate.

[0023] Among them, the anesthetic is selected from at least one of lidocaine hydrochloride, lidocaine carbonate, tetracaine, prilocaine, procaine, mepivacaine, and bupivacaine.

[0024] Among them, the mass percentage of the lubricating and moisturizing agent in the sodium carboxymethylcellulose gel is 0.5% - 3%, preferably 0.5% - 1.5%, such as 0.8%, 1%, or 1.2%.

[0025] Among them, the mass percentage of the anesthetic in the sodium carboxymethylcellulose gel is 0.1% - 0.6%.

[0026] Among them, the dosage of the buffer can be conventional in the art, 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.

[0027] 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, such as 800 Pa, 1000 Pa, 1500 Pa, 2000 Pa, 2500 Pa, 3000 Pa, or 3500 Pa.

[0028] In some embodiments, the viscous modulus G'' of the injectable filler at a frequency of 1 Hz is 550 - 2500 Pa, preferably 600 - 2000 Pa, more preferably 600 - 1800 Pa, such as 550 Pa, 600 Pa, 800 Pa, 1000 Pa, 1200 Pa, 1400 Pa, 1600 Pa, 1800 Pa, 2000 Pa, 2200 Pa, 2400 Pa, or 2500 Pa.

[0029] In some embodiments, the G' / G'' of the injectable filler at a frequency of 1 Hz is 1.2 - 2.5, preferably 1.2 - 2, such as 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, or 2.5.

[0030] In some embodiments, the method for preparing the polyester microspheres comprises the following steps: assembling the materials of the polyester microspheres as described above into microspheres by the emulsification solvent evaporation method, and sterilizing them.

[0031] In a preferred embodiment, the method for preparing the polyester microspheres comprises the following steps: the organic phase comprises the material of the polyester microspheres and an organic solvent; the aqueous phase comprises a surfactant and water; the organic phase and the aqueous phase are mixed, emulsified, solidified, and sterilized to obtain the polyester microspheres.

[0032] Among them, the organic solvent is selected from halogenated alkane solvents and / or ester solvents. Preferably, the halogenated alkane solvent is a chloroalkane solvent, more preferably selected from dichloromethane and / or trichloromethane. Preferably, the ester solvent is a C2-C6 alkyl acetate, more preferably ethyl acetate.

[0033] Among them, the mass-volume ratio of the material of the polyester microspheres to the organic solvent is 80-450 g / L, preferably 100-300 g / L.

[0034] Among them, the volume ratio of the organic phase to the aqueous phase is 1:(3-20), preferably 1:(5-15), such as 1:10.

[0035] Among them, the surfactant is polyvinyl alcohol, preferably polyvinyl alcohol 1788.

[0036] Among them, the mass-volume ratio of the surfactant to the water is 8-50 g / L, preferably 15-40 g / L.

[0037] Among them, the viscosity of the aqueous phase is 2-10 mPa·s. The viscosity of the aqueous phase is measured by a rotational viscometer at 25°C.

[0038] Among them, the water is purified water.

[0039] Among them, the method for preparing the aqueous phase comprises the following steps: the surfactant and the water are mixed, and the mixing temperature is 60-120°C.

[0040] Among them, the emulsification method includes mechanical stirring emulsification method, membrane emulsification method or homogenization emulsification method.

[0041] Among them, the solidification method includes vacuum evaporation method and / or air flow blowing method. According to the conventional method in the art, the purpose of solidification is to remove the organic solvent in the system and promote the emulsion to solidify into microspheres.

[0042] Among them, after the solidification operation, it may further include any one of the operations of collection, drying and sieving. Preferably, the drying method can be vacuum drying commonly used in the art. More preferably, the drying temperature is 25-45°C. More preferably, the drying time is 12-48 h.

[0043] The present application also provides a method for preparing an injectable filler, comprising the following steps: Scheme A: Mix the non-sterilized polyester microspheres and the non-sterilized sodium carboxymethyl cellulose gel, and then perform sterilization, and that's it. Scheme B: Sterilize the non-sterilized polyester microspheres and the non-sterilized sodium carboxymethyl cellulose gel separately to obtain sterile polyester microspheres and sterile sodium carboxymethyl cellulose gel, and then mix the polyester microspheres and the sodium carboxymethyl cellulose gel under sterile conditions, and that's it.

[0044] In Scheme A of some embodiments, the sterilization method is moist heat sterilization.

[0045] In Scheme B of some embodiments, the sterilization method of the non-sterilized polyester microspheres is irradiation sterilization or moist heat sterilization. Preferably, the irradiation sterilization is selected from β-irradiation sterilization or γ-irradiation sterilization.

[0046] In Scheme B of some embodiments, the sterilization method of the non-sterilized sodium carboxymethyl cellulose gel is moist heat sterilization.

[0047] In a preferred embodiment, the moist heat sterilization is carried out under anaerobic conditions, preferably under an inert atmosphere condition, and more preferably under a nitrogen-filled condition.

[0048] In a preferred embodiment, the time of the moist heat sterilization is 10 - 40 min, and more preferably 15 - 30 min.

[0049] In a preferred embodiment, the temperature of the moist heat sterilization is 100 - 130 °C, such as 121 °C.

[0050] The present application also provides an injectable filler, which is prepared by the preparation method of the injectable filler as described above.

[0051] The present application also provides an application of the injectable filler as described above in the preparation of medical or cosmetic products.

[0052] Among them, the medical or cosmetic products include filling and shaping products.

[0053] On the basis of conforming to the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present application.

[0054] The reagents and raw materials used in the present application are all commercially available.

[0055] The positive and progressive effects of the present application are as follows: 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, it is not easy to clog the needle during injection, or there is no problem of excessive local injection caused by uneven pushing force, which may induce complications such as nodules or granulomas, it has high use safety, natural filling effect, high aesthetics, and is not easy to shift after injection. Description of the Drawings

[0056] Figure 1 It is the state diagram of the injectable filler obtained in Example 1 after centrifugation; Figure 2 It is the state diagram of the injectable filler obtained in Example 2 after centrifugation; Figure 3 It is the state diagram of the injectable filler obtained in Example 3 after centrifugation; Figure 4 It is the state diagram of the injectable filler obtained in Comparative Example 1 after centrifugation; Figure 5 It is the state diagram of the injectable filler obtained in Comparative Example 2 after centrifugation; Figure 6 It is the rheogram of the injectable filler obtained in Example 1; Figure 7 It is the rheogram of the injectable filler obtained in Example 2; Figure 8 It is the rheogram of the injectable filler obtained in Example 3; Figure 9 It is the rheogram of the injectable filler obtained in Example 4; Figure 10 It is the rheogram of the injectable filler obtained in Example 5; Figure 11 It is the rheogram of the injectable filler obtained in Example 6; Figure 12 It is the rheogram of the injectable filler obtained in Example 7; Figure 13 It is the rheogram of the injectable filler obtained in Comparative Example 1; Figure 14 It is the rheogram of the injectable filler obtained in Comparative Example 2. Detailed Embodiments

[0057] The present application will be further described below by way of examples, but the present application is not limited to the scope of the described examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0058] (1) Test method for the elastic modulus G` and viscous modulus G`` of the products in the following examples and comparative examples: A rheometer is used for dynamic frequency scanning. The test temperature is set at 25 °C, the frequency change range is 0.1~10 Hz, the shear strain is 0.5%, the number of sampling points per order of magnitude is 10, and the elastic modulus G` and viscous modulus G`` at a frequency of 1 Hz are recorded.

[0059] (2) Test method for the shear viscosity η of the products in the following examples and comparative examples: A rheometer was used to perform a shear rate scan. The detection temperature was set at 25 °C, and the shear rate range was 0.1 s -1 ~100 s -1 , the gap was set at 0.3 mm, the scan time was 3 min, and the number of sampling points for each order of magnitude was 20. Record the shear viscosity value at a shear rate of 1 s -1 condition.

[0060] (3) Viscosity test method for the products in the following examples and comparative examples: Using the method of the European Pharmacopoeia, a rotary viscometer was used to mix sodium carboxymethylcellulose and water to prepare the viscosity of a 2% sodium carboxymethylcellulose gel by mass percentage.

[0061] (4) All the reagents and raw materials used in the following examples are commercially available, and the purity of the reagents used is of injection grade.

[0062] (5) The preparation method of the sterile polycaprolactone microspheres in the following examples and comparative examples includes the following steps: (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 make up to 1 L to obtain an aqueous phase with a viscosity of 7.5 mPa·s; (b) Preparation of the organic phase: Add an appropriate amount of dichloromethane to a container, weigh 20 g of polycaprolactone with a weight average molecular weight of 15000 and add it to the container, stir until completely dissolved, and make up to 100 mL to obtain an organic phase; (c) Membrane emulsification: Slowly pour the above organic phase into the aqueous phase, and use a membrane emulsifier to quickly perform membrane emulsification on the mixed liquid. The pore size of the membrane tube is 40 μm to obtain an emulsion; (d) Curing: Stir the emulsified emulsion, blow nitrogen to volatilize dichloromethane until dichloromethane is completely volatilized; (e) Collection: After dichloromethane is completely volatilized, centrifuge the suspension to collect the solid component, and perform drying and irradiation sterilization to obtain spherical or oval polycaprolactone microspheres. The proportion of microspheres with a particle size of 20 - 50 μm is 86.4%, and D50 is 33.3 μm.

[0063] (6) The pH value of the phosphate solution in the following examples and comparative examples is 7.

[0064] (7) Preparation of the sodium carboxymethylcellulose gel used in the following examples and comparative examples Sodium carboxymethyl cellulose gel 1: 94.5 g of phosphate solution (pH value 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 obtain an unsterilized sodium carboxymethyl cellulose gel (shear viscosity 265.2 Pa·s); the unsterilized sodium carboxymethyl cellulose gel was placed in a suitable airtight container, and under nitrogen filling conditions, it was sterilized by moist heat at 121 °C for 15 min to obtain sodium carboxymethyl cellulose gel 1, whose shear viscosity at 1 s -1 is 170.2 Pa·s; the storage modulus G` at 1 Hz is 205.2 Pa, the loss modulus G`` is 180.5 Pa, and G` / G`` is 1.14.

[0065] 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, replaced with sodium carboxymethyl cellulose with a viscosity of 8000 mPa·s and a degree of substitution of 0.78. Sodium carboxymethyl cellulose gel 2 has a shear viscosity of 347.6 Pa·s at 1 s -1 (the shear viscosity before sterilization is 426.8 Pa·s); the storage modulus G` at 1 Hz is 479.6 Pa, the loss modulus G`` is 319.3 Pa, and G` / G`` is 1.50.

[0066] Sodium carboxymethyl cellulose gel 3: The preparation method is similar to that of sodium carboxymethyl cellulose gel 2, except that nitrogen is not filled during sterilization. Sodium carboxymethyl cellulose gel 3 has a shear viscosity of 275 Pa·s at 1 s -1 (the shear viscosity before sterilization is 426.8 Pa·s); the storage modulus G` at 1 Hz is 355.6 Pa, the loss modulus G`` is 245.2 Pa, and G` / G`` is 1.45.

[0067] Sodium carboxymethyl cellulose gel 4: The preparation method is similar to that of sodium carboxymethyl cellulose gel 2, except that the sterilization time is 30 min; sodium carboxymethyl cellulose gel 4 has a shear viscosity of 246 Pa·s at 1 s -1 (the shear viscosity before sterilization is 426.8 Pa·s); the storage modulus G` at 1 Hz is 300.5 Pa, the loss modulus G`` is 229.8 Pa, and G` / G`` is 1.31.

[0068] 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, replaced with sodium carboxymethyl cellulose with a viscosity of 12000 mPa·s and a degree of substitution of 0.79; sodium carboxymethyl cellulose gel 5 has a shear viscosity of 1 s -1The shear viscosity under the [condition] is 547 Pa·s (the shear viscosity before sterilization is 567.1 Pa·s); the storage modulus G` at 1 Hz is 597.2 Pa, the loss modulus G`` is 334.1 Pa, and G` / G`` is 1.79.

[0069] Sodium carboxymethylcellulose gel 6: The preparation method is similar to that of sodium carboxymethylcellulose gel 5, except that nitrogen is not filled during sterilization; sodium carboxymethylcellulose gel 6 at 1 s -1 The shear viscosity under the [condition] is 320.7 Pa·s (the shear viscosity before sterilization is 567.1 Pa·s); the storage modulus G` at 1 Hz is 446.6 Pa, the loss modulus G`` is 304.7 Pa, and G` / G`` is 1.47.

[0070] Sodium carboxymethylcellulose gel 7: The preparation method is similar to that of sodium carboxymethylcellulose gel 5, except that the sterilization time is 30 min; sodium carboxymethylcellulose gel 7 at 1 s -1 The shear viscosity under the [condition] is 326.6 Pa·s (the shear viscosity before sterilization is 567.1 Pa·s); the storage modulus G` at 1 Hz is 491.7 Pa, the loss modulus G`` is 309.7 Pa, and G` / G`` is 1.59.

[0071] Sodium carboxymethylcellulose gel 8: The preparation method is similar to that of sodium carboxymethylcellulose gel 1, except that the raw material is different, replaced with sodium carboxymethylcellulose with a viscosity of 12000 mPa·s and a degree of substitution of 0.85. Sodium carboxymethylcellulose gel 8 at 1 s -1 The shear viscosity under the [condition] is 161.7 Pa·s (the shear viscosity before sterilization is 212.7 Pa·s); the storage modulus G` at 1 Hz is 241.9 Pa, the loss modulus G`` is 245.8 Pa, and G` / G`` is 0.98.

[0072] Sodium carboxymethylcellulose gel 9: The preparation method is similar to that of sodium carboxymethylcellulose gel 1, except that the raw material is replaced with sodium carboxymethylcellulose with a viscosity of 12000 mPa·s and a degree of substitution of 0.85, and nitrogen is not filled during sterilization. Sodium carboxymethylcellulose gel 9 at 1 s -1 The shear viscosity under the [condition] is 114.3 Pa·s (the shear viscosity before sterilization is 212.7 Pa·s); the storage modulus G` at 1 Hz is 179.5 Pa, the loss modulus G`` is 201.9 Pa, and G` / G`` is 0.89.

[0073] Preparation of injectable fillers in Examples 1 - 7 and Comparative Examples 1 - 2 Mix the above - prepared sodium carboxymethylcellulose gel and 49 g of the sterile polycaprolactone microspheres prepared by the above method under sterile conditions to obtain an injectable filler.

[0074] The difference between the above-mentioned examples and comparative examples lies only in the type of sodium carboxymethylcellulose gel. For details, please refer to Table 1 below.

[0075] Table 1

[0076] Effect Example 1 The elastic modulus G`, viscous modulus G``, ratio of elastic modulus to viscous modulus G` / G``, shear viscosity η and stability of the injectable fillers prepared in the above-mentioned examples and comparative examples were studied. The results are shown in Table 2.

[0077] (1) Stability research method: Weigh about 1 g of the injectable filler prepared in the above-mentioned example or comparative example and put it into a 1.5 mL centrifuge tube. Centrifuge at 25 °C and 20,000 rpm for 5 min, and observe the product state. The results are shown in the appendix Figures 1 - 3 and Table 2.

[0078] (2) Test method for elastic modulus G` and viscous modulus G``: Dynamic frequency scanning was carried out using a rheometer. The test temperature was set at 25 °C, the frequency change range was 0.1~10 Hz, the shear strain was 0.5%, and the number of sampling points per decade was 10. 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 Figures 6 - 14 .

[0079] (3) Test method for shear viscosity η: Shear rate scanning was carried out using a rheometer. The detection temperature was set at 25 °C, the shear rate range was 0.1 s -1 ~100 s -1 , the gap was set at 0.3 mm, the scanning time was 3 min, and the number of sampling points per decade was 20. The shear viscosity value under the condition of a shear rate of 1 s -1 was taken.

[0080] Table 2

[0081] The product states of the injectable fillers prepared in Examples 1~3 after centrifugation are shown in Figures 1 - 3 , and the product states of the injectable fillers prepared in Examples 4~7 after centrifugation are the same as those of Figure 2 , without stratification, which are omitted in the drawings; the product states of the injectable fillers prepared in Comparative Examples 1~2 after centrifugation are shown in Figures 4 - 5 .

[0082] According to the results, there is no obvious layering phenomenon after centrifugation of the injectable filler prepared by the method of the embodiment of the present application, indicating that the microspheres in the injectable filler prepared by the method of the embodiment of the present application have good dispersion stability, can resist the problem of microsphere sedimentation caused by transportation or long-term storage, and have high use safety. The injectable filler prepared by the comparative example shows obvious layering, indicating that the microspheres have poor dispersion stability in the sodium carboxymethylcellulose gel, are easy to sediment, increase the injection risk, and are prone to problems such as needle clogging and induction of complications.

[0083] According to Figures 6 - 14 the rheogram, for the injectable filler prepared by the embodiment of the present application, the elastic modulus curve and the viscous modulus curve do not cross, showing the gel property, having an ideal filling and supporting effect, avoiding problems such as displacement after filling into tissues, and the viscoelasticity meets the requirements of products in this field, and the filling effect is natural. For the injectable filler prepared by the comparative example, the elastic modulus curve and the viscous modulus curve cross, and the matrix is more inclined to a viscous solution, losing the gel property, and is prone to problems such as displacement after filling.

[0084] Effect Example 2 Pushing force test method: Take 1 sample after filling, install a 27G (0.4*12mm) needle of Terumo, exhaust the air bubbles at the needle tip, place it in the detector of a universal tensile tester, and conduct the test at a speed of 30 mm / min to test the maximum pushing force. The results are shown in Table 3.

[0085] Table 3

[0086] According to the results of the maximum pushing force, the pushing force of the injectable filler prepared by the embodiment of the present application is moderate, meeting the injection requirements of doctors, and can effectively avoid risks such as difficult injection or complications caused by too large or too small pushing force.

[0087] Finally, it should also be noted that in the present application, the terms "comprising", "including" or any other variant thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device comprising a series of elements not only includes those elements, but also includes other elements not expressly listed, or further includes elements inherent to such process, method, article or device.

[0088] Although the present application has been disclosed above through the description of specific embodiments of the present application, it should be understood that those skilled in the art can design various modifications, improvements or equivalents to the present application within the spirit and scope of the appended claims. These modifications, improvements or equivalents should also be considered to be included within the scope claimed by the present application.

Claims

1. An injectable filler, characterized in that, It includes polyester microspheres and sodium carboxymethylcellulose gel; wherein, the elastic modulus G` of the sodium carboxymethylcellulose 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.

2. The injectable filler according to claim 1, wherein The injectable filler satisfies at least one of the following conditions (1) - (16): (1) The elastic modulus G` of the sodium carboxymethylcellulose gel after sterilization at a frequency of 1 Hz is 200 - 600 Pa; (2) The G` / G`` of the sodium carboxymethylcellulose gel after sterilization at a frequency of 1 Hz is 1.1 - 2; (3) The viscous modulus G`` of the sodium carboxymethylcellulose gel after sterilization at a frequency of 1 Hz is 170 - 500 Pa; (4)The shear viscosity η of the carboxymethylcellulose sodium gel after sterilization is 160 - 650 Pa·s at a shear rate of 1 s -1 -1; (5) The mass percentage of sodium carboxymethylcellulose in the sodium carboxymethylcellulose gel is 3.8% - 6%; (6) The viscosity of the sodium carboxymethylcellulose used to prepare the sodium carboxymethylcellulose gel is 5800 - 15000 mPa·s; (7) The degree of substitution of the sodium carboxymethylcellulose used to prepare the sodium carboxymethylcellulose gel is 0.75 - 0.82; (8) The material of the polyester microspheres is polycaprolactone; (9) The weight-average molecular weight of the material of the polyester microspheres is 10000 - 40000; (10) The content of polyester microspheres in the injectable filler is 200 - 400 mg / g; (11) The proportion of polyester microspheres with a particle size of 20 - 50 μm is more than 80%; (12) The D50 of the particle size of the polyester microspheres is 20 - 50 μm; (13) The sodium carboxymethylcellulose gel further includes at least one of a lubricating and moisturizing agent, a buffer, and an anesthetic; (14) The elastic modulus G` of the injectable filler at a frequency of 1 Hz is 800 - 3500 Pa; (15) The viscous modulus G`` of the injectable filler at a frequency of 1 Hz is 550 - 2500 Pa; (16) The G` / G`` of the injectable filler at a frequency of 1 Hz is 1.2 - 2.

5.

3. The injectable filler according to claim 2, wherein The injectable filler satisfies at least one of the following conditions (1) - (18): (1) The elastic modulus G` of the sodium carboxymethylcellulose gel after sterilization at a frequency of 1 Hz is 200 - 500 Pa; (2) The viscous modulus G`` of the sodium carboxymethylcellulose gel after sterilization at a frequency of 1 Hz is 170 - 400 Pa; (3)The shear viscosity η of the sodium carboxymethyl cellulose gel after sterilization at a shear rate of 1 s -1 is 170 to 550 Pa·s; (4) The mass percentage of sodium carboxymethylcellulose in the sodium carboxymethylcellulose gel is 4% - 5.5%; (5) The viscosity of the sodium carboxymethylcellulose used to prepare the sodium carboxymethylcellulose gel is 5800 - 12500 mPa·s; (6) The degree of substitution of the sodium carboxymethylcellulose used to prepare the sodium carboxymethylcellulose gel is 0.75 - 0.8; (7) The weight-average molecular weight of the material of the polyester microspheres is 10000 - 25000; (8) The content of the polyester microspheres in the injectable filler is 300 - 350 mg / g; (9) The proportion of polyester microspheres with a particle size of 20 - 50 μm is more than 90%; The D50 of the polyester microspheres described in (10) is 25 - 45 μm; The lubricating and moisturizing agent described in (11) is selected from at least one of polyol lubricating and moisturizing agents, saccharide lubricating and moisturizing agents, and polymer lubricating and moisturizing agents; The buffer described in (12) is a phosphate buffer; The anesthetic described in (13) is selected from at least one of lidocaine hydrochloride, lidocaine carbonate, tetracaine, prilocaine, procaine, mepivacaine, and bupivacaine; The mass percentage of the lubricating and moisturizing agent in the sodium carboxymethylcellulose gel described in (14) is 0.5% - 3%; The mass percentage of the anesthetic in the sodium carboxymethylcellulose gel described in (15) is 0.1% - 0.6%; The storage modulus G` of the injectable filler at a frequency of 1 Hz described in (16) is 900 - 3100 Pa; The loss modulus G`` of the injectable filler at a frequency of 1 Hz described in (17) is 600 - 2000 Pa; The G` / G`` of the injectable filler at a frequency of 1 Hz described in (18) is 1.2 - 2.

4. The injectable filler according to claim 3, wherein The injectable filler satisfies at least one of the following conditions (1) - (7): (1) The loss modulus G`` of the sodium carboxymethylcellulose gel after sterilization at a frequency of 1 Hz is 170 - 350 Pa; (2) The polyol lubricating and moisturizing agent is selected from at least one of glycerol, propylene glycol, and sorbitol; (3) The saccharide 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 disodium hydrogen phosphate and sodium dihydrogen phosphate; (6) The mass percentage of the lubricating and moisturizing agent in the sodium carboxymethylcellulose gel is 0.5% - 1.5%; (7) The loss modulus G`` of the injectable filler at a frequency of 1 Hz is 600 - 1800 Pa.

5. A method for preparing an injectable filler according to any one of claims 1 to 4, characterized in that, It includes the following steps: Scheme A: Mix the unsterilized polyester microspheres and the unsterilized sodium carboxymethylcellulose gel, and then sterilize them; Scheme B: Sterilize the unsterilized polyester microspheres and the unsterilized sodium carboxymethylcellulose gel separately to obtain sterile polyester microspheres and sterile sodium carboxymethylcellulose gel, and then mix the sterile polyester microspheres and the sterile sodium carboxymethylcellulose gel under sterile conditions; 6. The preparation method of the injectable filler according to claim 5, characterized in that, The preparation method satisfies at least one of the following conditions (1) - (3): (1) In Scheme A, the sterilization method is moist heat sterilization; (2) In Scheme B, the sterilization method of the unsterilized polyester microspheres is irradiation sterilization or moist heat sterilization; (3) In Scheme B, the sterilization method of the unsterilized sodium carboxymethylcellulose gel is moist heat sterilization.

7. The preparation method of the injectable filler according to claim 6, characterized in that, The preparation method satisfies at least one of the following conditions (1) - (4): (1) The irradiation sterilization is selected from β - irradiation sterilization or γ - irradiation sterilization; (2) The moist heat sterilization is carried out under an anaerobic condition; (3) The time of the moist heat sterilization is 10 - 40 min; (4) The temperature of the moist heat sterilization is 100 - 130 °C.

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

9. An injectable filler, characterized in that, Prepared by the preparation method of the injectable filler according to any one of claims 5 to 8.

10. Use of an injectable filler according to any one of claims 1 to 4, 9 in the preparation of a medical or cosmetic product.

Images