Injectable filling freeze-drying agent as well as preparation method and application thereof

Abstract

The invention discloses an injectable filling freeze-drying agent as well as a preparation method and application thereof. The injectable filling freeze-drying agent comprises polylactic acid microspheres, sodium carboxymethyl cellulose and a freeze-drying protective agent, the viscosity of the sodium carboxymethyl cellulose is 30 to 300 mPa.s; the mass ratio of the polylactic acid microspheres to the sodium carboxymethyl cellulose to the freeze-drying protective agent is 1: (0.4-0.9). The injectable filling freeze-drying agent is uniform in texture, highly fluffy, rapid and complete in redissolution and excellent in performance. The redissolved microspheres are good in dispersion stability in the preparation, moderate in injection pushing force, not prone to the problems of needle blocking and the like, capable of reducing the injection difficulty of doctors, high in use safety, natural in filling effect and small in injection pain feeling. The injectable filling freeze-drying agent can also be used in cooperation with various composite solutions with active ingredients, still has an ideal redissolving effect, expands the application scene and the function dimension of the injectable filling freeze-drying agent, and brings richer and more personalized treatment choices for beauty seekers.

Description

Technical Field

[0001] This invention relates to the field of medical aesthetics, and in particular to an injectable lyophilized filler, its preparation method, and its application. Background Technology

[0002] As we age and are exposed to various external stimuli, the rate of collagen loss in the dermis of human skin accelerates, leading to sagging skin and wrinkles. This can be improved through cosmetic fillers. Currently, polylactic acid (PLA) microspheres have become a research hotspot in the field of cosmetic medicine due to their multiple advantages. For example, PLA microspheres have high biocompatibility, providing tissue support and inducing fibroblast proliferation and myofibroblast differentiation, thus promoting collagen synthesis and compensating for skin aging caused by collagen loss. Furthermore, PLA microspheres have a long residence time in the body, reducing the number of injections and effectively minimizing patient discomfort.

[0003] Polylactic acid (PLA) microspheres are often lyophilized because they undergo slow degradation in the liquid phase, affecting their morphology and degradation time, which in turn impacts injection safety and efficacy. Commercially available PLA microsphere filler powders generally suffer from long reconstitution times, increasing patient waiting time, surgical difficulty, and the risk of contamination; poor reconstitution results in poor microsphere dispersion after reconstitution, leading to clumping or solid adhering to the vial wall, causing needle blockage during injection. This increases injection pressure, making injection more difficult for doctors and causing pain for patients. Uncontrollable pressure can also 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 filler material with ideal cosmetic effects, short resolution time and good resolution effect of polylactic acid microspheres, good dispersion stability in formulations, high safety in use, natural filling effect and low injection pain. Summary of the Invention

[0005] The technical problem this application aims to solve is to overcome the shortcomings of existing polylactic acid microsphere-containing injectable filler powders, such as long reconstitution time and poor dispersion stability of microspheres in the system, leading to complications such as needle blockage, increased injection force, increased injection pain, and the formation of nodules or granulomas during injection. This application provides an injectable filler lyophilized agent, its preparation method, and its application. The injectable filler lyophilized agent of this application has a uniform texture, is highly fluffy, reconstitutes rapidly and completely, and exhibits excellent performance. After reconstitution, the microspheres have good dispersion stability in the formulation, moderate injection force, and are less prone to problems such as needle blockage, reducing the difficulty of injection for doctors, ensuring high safety, providing a natural filling effect, and minimizing injection pain. The injectable filler lyophilized agent of this application can also be used synergistically with various complex solutions containing active ingredients, still maintaining ideal reconstitution effects, expanding its application scenarios and functional dimensions, and providing patients with richer and more personalized treatment options.

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

[0007] This application provides an injectable filler lyophilizing agent comprising polylactic acid microspheres, sodium carboxymethyl cellulose and a lyophilizing protectant; the viscosity of the sodium carboxymethyl cellulose is 30~300 mPa·s; the mass ratio of the polylactic acid microspheres to the sodium carboxymethyl cellulose is 1:(0.4~0.9).

[0008] In some embodiments, the mass ratio of the polylactic acid microspheres to the sodium carboxymethyl cellulose is preferably 1:(0.45~0.9), more preferably 1:(0.5~0.8), for example 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8 or 1:0.9.

[0009] In some embodiments, the mass ratio of the polylactic acid microspheres to the lyophilization protectant is 1:(0.5~1.2), preferably 1:(0.5~0.9), for example 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1 or 1:1.2.

[0010] In some embodiments, the viscosity of the sodium carboxymethyl cellulose is preferably 30-100 mPa·s, more preferably 30-70 mPa·s, for example 30 mPa·s, 40 mPa·s, 50 mPa·s, 60 mPa·s, 70 mPa·s, 80 mPa·s, 90 mPa·s, 100 mPa·s, 110 mPa·s, 130 mPa·s, 150 mPa·s, 180 mPa·s, 240 mPa·s, 280 mPa·s, or 300 mPa·s. The viscosity is the viscosity obtained by mixing sodium carboxymethyl cellulose and water to prepare a 2% (w / w) sodium carboxymethyl cellulose gel using a rotational viscometer according to the European Pharmacopoeia method.

[0011] In some embodiments, the sodium carboxymethyl cellulose has a weight-average molecular weight of 6WDa to 15WDa, preferably 6WDa to 12WDa, such as 6WDa, 7WDa, 8WDa, 9WDa, 10WDa, 11WDa, 12WDa, 13WDa or 15WDa.

[0012] In some embodiments, the degree of substitution of the sodium carboxymethyl cellulose is 0.65 to 0.85, preferably 0.68 to 0.79, for example 0.65, 0.66, 0.68, 0.7, 0.71, 0.72, 0.73, 0.75, 0.76, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84 or 0.85.

[0013] In some embodiments, the lyophilization protectant is selected from polyol lyophilization protectants and / or sugar lyophilization protectants.

[0014] The polyol freeze-drying protectant is selected from mannitol and / or sorbitol.

[0015] The sugar freeze-drying protectant is selected from trehalose and / or sucrose.

[0016] In some embodiments, the polylactic acid microspheres are made of at least one selected from poly-L-lactic acid, poly-D-lactic acid, and racemic polylactic acid.

[0017] In some embodiments, the polylactic acid microspheres have a weight-average molecular weight of 2WDa to 50WDa, preferably 2WDa to 20WDa.

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

[0019] In some embodiments, the particle size D50 of the polylactic acid microspheres is 20-60 μm, preferably 25-45 μm.

[0020] In some embodiments, the injectable filler lyophilized agent also includes an anesthetic.

[0021] The anesthetic agent is selected from at least one of lidocaine hydrochloride, lidocaine carbonate, tetracaine, prilocaine, procaine, mepivacaine, and bupivacaine.

[0022] The mass ratio of the polylactic acid microspheres to the anesthetic is 1:(0.04~0.2).

[0023] In some embodiments, the preparation method of the polylactic acid microspheres includes the following steps: assembling the polylactic acid microsphere material as described above into microspheres using an emulsification solvent evaporation method.

[0024] In a preferred embodiment, the method for preparing the polylactic acid microspheres includes the following steps: the organic phase includes the material of the polylactic acid microspheres and an organic solvent; the aqueous phase includes a surfactant and water; the organic phase and the aqueous phase are mixed, emulsified, and solidified to obtain the polylactic acid microspheres.

[0025] The emulsification method includes mechanical stirring emulsification, membrane emulsification, or homogenization emulsification.

[0026] The curing method includes reduced pressure evaporation and / or airflow blowing. As is customary in the art, the purpose of the curing is to remove the organic solvent from the system, thereby promoting the solidification of the emulsion into microspheres.

[0027] The curing process may further include collection, drying, and sieving. Preferably, the drying method is vacuum drying, which is conventionally used in the art. Preferably, the drying temperature is 25~45°C. Preferably, the drying time is 12~48 hours.

[0028] This application also provides a method for preparing the injectable lyophilized filler as described above, comprising the following steps: mixing the polylactic acid microspheres, the sodium carboxymethyl cellulose, the lyophilization protectant and the solvent, and then freeze-drying them to obtain the filler.

[0029] In some embodiments, the mass ratio of the polylactic acid microspheres to the solvent is 1:(15~45), preferably 1:(25~40).

[0030] In some embodiments, the freeze-drying includes pre-freezing and drying operations.

[0031] In a preferred embodiment, the pre-freezing is a gradient pre-freezing, including a first-stage pre-freezing and a second-stage pre-freezing; the temperature of the first-stage pre-freezing is -25 to -10°C, and the holding time is 45 to 90 minutes; the temperature of the second-stage pre-freezing is -55 to -30°C, and the holding time is 70 to 110 minutes.

[0032] Preferably, the temperature for the first stage of pre-freezing is -25 to -15°C, for example -25°C, -20°C, -15°C, or -10°C.

[0033] Preferably, the holding time for the first stage of pre-freezing is 50-70 minutes.

[0034] Preferably, the temperature for the second stage of pre-freezing is -45 to -35°C, for example -55°C, -50°C, -45°C, -40°C, -35°C, or -30°C.

[0035] Preferably, the second stage of pre-freezing time is 80-100 minutes.

[0036] Preferably, the cooling rate of the room temperature to the first stage of pre-freezing is 20~50℃ / h, for example 20℃ / h, 25℃ / h, 30℃ / h, 35℃ / h, 40℃ / h, 45℃ / h or 50℃ / h.

[0037] Preferably, the cooling rate from the first stage of prefreezing to the second stage of prefreezing is 10~30℃ / h, for example 10℃ / h, 15℃ / h, 20℃ / h, 25℃ / h or 30℃ / h.

[0038] In a preferred embodiment, the drying includes sublimation drying and desorption drying; the sublimation drying temperature is -20~4℃, the holding time is 1500~2500min, and the vacuum degree is 0.1~1mbar; the desorption drying temperature is 5~40℃, the desorption drying time is 900~2000min, and the vacuum degree is 0.1~1mbar.

[0039] Preferably, the sublimation drying temperature is -15 to 0°C, more preferably -15 to -3°C, for example -20°C, -18°C, -15°C, -12°C, -10°C, -9°C, -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, -1°C, 0°C, 2°C, or 4°C.

[0040] Preferably, the temperature for the analytical drying is 10~30°C, for example 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C or 40°C.

[0041] Preferably, the heating rate from pre-freezing to sublimation drying is 3~10℃ / h, for example 3℃ / h, 4℃ / h, 5℃ / h, 6℃ / h, 7℃ / h, 8℃ / h, 9℃ / h or 10℃ / h.

[0042] Preferably, the heating rate from sublimation drying to analytical drying is 20~70℃ / h, more preferably 30~60℃ / h, for example 20℃ / h, 25℃ / h, 30℃ / h, 35℃ / h, 40℃ / h, 42℃ / h, 45℃ / h, 50℃ / h, 55℃ / h, 60℃ / h, 65℃ / h or 70℃ / h.

[0043] In some embodiments, the freeze-drying process further includes a sterilization step. The sterilization method is irradiation sterilization.

[0044] The irradiation sterilization is selected from β irradiation sterilization or γ irradiation sterilization.

[0045] The irradiation sterilization dose is 15~45kGy, preferably 20~30kGy.

[0046] This application also provides an injectable filler lyophilizer, which is prepared by the injectable filler lyophilizer preparation method described above.

[0047] This application also provides an injectable filler comprising the injectable filler lyophilized agent and dispersion as described above.

[0048] In some embodiments, the dispersion includes water for injection.

[0049] In a preferred embodiment, the dispersion further includes a buffer and / or an active ingredient.

[0050] The buffer is a buffer acceptable in the medical aesthetics field for adjusting the pH and osmotic pressure of a system, preferably a phosphate buffer, and more preferably a mixture of dihydrogen phosphate and disodium hydrogen phosphate. Preferably, the dihydrogen phosphate is selected from disodium hydrogen phosphate and / or dipotassium hydrogen phosphate. More preferably, the disodium hydrogen phosphate is selected from sodium dihydrogen phosphate and / or potassium dihydrogen phosphate.

[0051] The amount of buffer used can be conventional in the art, generally used to adjust the pH value of the injectable lyophilized agent to 6-8, and / or adjust the osmotic pressure of the injectable lyophilized agent to isotonic.

[0052] The active ingredient is selected from at least one of a hydrating active ingredient, a whitening active ingredient, and an anti-inflammatory active ingredient. Preferably, the hydrating active ingredient is selected from sodium hyaluronate. Preferably, the whitening active ingredient is selected from at least one of tranexamic acid, glutathione, and L-ascorbic acid. Preferably, the anti-inflammatory active ingredient is selected from PDRN and / or L-carnosine.

[0053] In a preferred embodiment, the active ingredient is sodium hyaluronate, and the weight-average molecular weight of the sodium hyaluronate is 10WDa~100WDa, preferably 10WDa~80WDa, for example 10WDa, 20WDa, 30WDa, 40WDa, 50WDa, 60WDa, 70WDa, 80WDa, 90WDa or 100WDa.

[0054] In a preferred embodiment, the active ingredient is sodium hyaluronate, and the mass percentage of sodium hyaluronate in the dispersion is 0.3% to 1%, preferably 0.3% to 0.8%, for example 0.5%.

[0055] This application also provides the use of the injectable filler lyophilized agent as described above or the injectable filler as described above in the preparation of medical or cosmetic products.

[0056] The medical or cosmetic products mentioned include filler or shaping products.

[0057] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of this application.

[0058] All reagents and raw materials used in this application are commercially available.

[0059] The positive advancements of this application are as follows: The injectable lyophilized filler has a uniform texture, is highly fluffy, reconstitutes rapidly and completely, and exhibits excellent performance, avoiding risks such as bacterial contamination that can occur due to prolonged reconstitution time. After reconstitution, the microspheres exhibit good dispersion stability in the formulation, with moderate injection force, reducing the likelihood of needle blockage and other problems, thus lowering the difficulty for doctors to administer injections, ensuring high safety, producing natural-looking filling effects, and minimizing injection pain. Furthermore, this injectable lyophilized filler can be used synergistically with various complex solutions containing active ingredients, maintaining ideal reconstitution effects, expanding its application scenarios and functional dimensions, and providing patients with richer and more personalized treatment options. Attached Figure Description

[0060] Figure 1 This is a sample image of the injectable lyophilized agent 1 prepared in Example 1;

[0061] Figure 2 This is a state diagram of injectable filler 1 in Example 1 after reconstitution and mixing for 25 seconds;

[0062] Figure 3 This is a state diagram of injectable filler 8 in Comparative Example 2 after 10 minutes of reconstitution and mixing;

[0063] Figure 4 The extrusion force spectrum of the injectable filler 1 prepared in Example 1 in Example 2 is shown.

[0064] Figure 5 The extrusion force spectrum of the injectable filler 4 prepared in Example 2 is shown in Example 2.

[0065] Figure 6 The extrusion force spectrum of the injectable filler 7 prepared in Comparative Example 1 in Example 2 is shown.

[0066] Figure 7 The extrusion force spectrum of the injectable filler 9 prepared in Comparative Example 3 in Example 2 is shown. Detailed Implementation

[0067] The present application is further illustrated below by way of embodiments, but these embodiments are not intended to limit the scope of the present application. Experimental methods not specifically described in the following embodiments are performed according to conventional methods and conditions, or as selected in accordance with the product instructions.

[0068] (1) The viscosity test method of sodium carboxymethyl cellulose in the following examples and comparative examples: The viscosity of sodium carboxymethyl cellulose gel was prepared by mixing sodium carboxymethyl cellulose and water with a mass percentage of 2% using the method of the European Pharmacopoeia and a rotational viscometer.

[0069] (2) The microspheres used in the following examples and comparative examples are polylactic acid microspheres with a particle size of 20~50μm accounting for 86% and a D50 of 34μm.

[0070] Example 1

[0071] Preparation of injectable lyophilized filler 1: 150 mg of polylactic acid microspheres, 90 mg of sodium carboxymethyl cellulose, 120 mg of mannitol, and 3.75 g of water were mixed, freeze-dried, and sterilized by gamma irradiation at a dose of 25 kGy to obtain injectable lyophilized filler 1 (see [link to product description]). Figure 1 );

[0072] The sodium carboxymethyl cellulose has a viscosity (EP, 2wt%) of 36 mPa·s, a weight-average molecular weight of 9.05 WDa, and a degree of substitution of 0.79. The freeze-drying process includes pre-freezing and drying. Pre-freezing comprises the following steps: a first-stage pre-freezing is performed by cooling from room temperature to -20°C at a rate of 40°C / h, held for 60 min; a second-stage pre-freezing is performed by cooling to -40°C at a rate of 25°C / h, held for 100 min; drying follows pre-freezing, including sublimation drying and desorption drying. Sublimation drying is performed at -5°C, under a vacuum of 0.1 mbar, for a holding time of 2000 min, with a heating rate of 5°C / h from the second-stage pre-freezing to sublimation drying; desorption drying is performed at 30°C, under a vacuum of 0.1 mbar, for a holding time of 1000 min, with a heating rate of 42°C / h from sublimation drying to desorption drying.

[0073] Preparation of injectable filler 1: Mix the above-prepared injectable filler lyophilized agent 1 with 5 mL of water.

[0074] Preparation of injectable filler 2: Mix the above-prepared injectable filler lyophilized agent 1 with 6 mL of water.

[0075] Preparation of injectable filler 3: Mix the above-prepared injectable filler lyophilized agent 1 with 5 mL of sodium hyaluronate aqueous solution; wherein, the weight average molecular weight of sodium hyaluronate in the sodium hyaluronate aqueous solution is 10WDa~40WDa, and the mass percentage is 0.5%.

[0076] Example 2

[0077] Preparation of injectable filler lyophilized agent 2: Compared with Example 1, the only difference is that the amount of sodium carboxymethyl cellulose added is 75 mg, and other conditions and parameters are the same as those of injectable filler lyophilized agent 1;

[0078] Preparation of injectable filler 4: Mix the above-prepared injectable filler lyophilized agent 2 with 5 mL of water.

[0079] Example 3

[0080] Preparation of injectable filler lyophilized agent 3: Compared with Example 1, the only difference is that the amount of sodium carboxymethyl cellulose added is 120 mg, and the other conditions and parameters are the same as those of injectable filler lyophilized agent 1;

[0081] Preparation of injectable filler 5: Mix the above-prepared injectable filler lyophilized agent 3 with 5 mL of water.

[0082] Example 4

[0083] Preparation of injectable filler lyophilizer 4: Compared with Example 1, the only difference is the type of sodium carboxymethyl cellulose. The viscosity (EP, 2wt%) of sodium carboxymethyl cellulose is 51 mPa·s, the weight-average molecular weight is 9.8 WDa, and the degree of substitution is 0.74. Other conditions and parameters are the same as those of injectable filler lyophilizer 1.

[0084] Preparation of injectable filler 6: Mix the above-prepared injectable filler lyophilized agent 4 with 5 mL of water.

[0085] Comparative Example 1

[0086] Preparation of injectable filler 5: Compared with Example 1, the only difference is that the amount of sodium carboxymethyl cellulose added is 40 mg, and other conditions and parameters are the same as those of injectable filler 1;

[0087] Preparation of injectable filler 7: Mix the above-prepared injectable filler lyophilized agent 5 with 5 mL of water.

[0088] Comparative Example 2

[0089] Preparation of injectable filler 6: Compared with Example 1, the only difference is that the amount of sodium carboxymethyl cellulose added is 200 mg, and the other conditions and parameters are the same as those of injectable filler 1;

[0090] Preparation of injectable filler 8: Mix the above-prepared injectable filler lyophilized agent 6 with 5 mL of water.

[0091] Comparative Example 3

[0092] Preparation of injectable filler lyophilizer 7: Compared with Example 1, the only difference is that a lower viscosity sodium carboxymethyl cellulose is replaced. The viscosity (EP, 2wt%) of sodium carboxymethyl cellulose is 24 mPa·s, the weight average molecular weight is 4.9 WDa, and the degree of substitution is 0.81. Other conditions and parameters are the same as those of injectable filler lyophilizer 1.

[0093] Preparation of injectable filler 9: Mix the above-prepared injectable filler lyophilized agent 7 with 5 mL of water.

[0094] Comparative Example 4

[0095] Preparation of injectable filler lyophilizer 8: Compared with Example 1, the only difference is the type of sodium carboxymethyl cellulose. The viscosity (EP, 2wt%) of sodium carboxymethyl cellulose is 580 mPa·s, the weight-average molecular weight is 25WDa, and the degree of substitution is 0.8. Other conditions and parameters are the same as those of injectable filler lyophilizer 1.

[0096] Preparation of injectable filler 10: Mix the above-prepared injectable filler lyophilized agent 8 with 5 mL of water.

[0097] Example 1

[0098] The reconstitution time during the preparation process of the injectable filler in the above embodiments and comparative examples was tested, i.e. the time required for the components to completely dissolve and disperse evenly. The results are shown in Table 1.

[0099] Table 1

[0100]

[0101] The results show that the type and amount of sodium carboxymethyl cellulose added have a significant impact on the resolution effect. The injectable filler lyophilized agent prepared in the example has a uniform texture, is highly fluffy, and has no obvious crystallization. When resolvated with water, the powder disperses quickly in the water, and the resolution speed is fast. Figure 2 The diagram shows the state of injectable filler 1 after complete reconstitution. The diagrams for injectable fillers prepared in other embodiments after complete reconstitution according to the times specified in Table 1 are also shown. Figure 2 similar.

[0102] When the injectable lyophilized filler prepared in Example 1 is reconstituted with an aqueous solution of sodium hyaluronate containing active ingredients and having viscosity, the reconstitution time is still short, the reconstitution effect is ideal, there is no clumping, the use is highly safe, the doctor's operation time is shortened, the operation difficulty is reduced, and its application scenarios and functional dimensions are expanded to achieve personalized treatment.

[0103] When the amount or viscosity of sodium carboxymethyl cellulose added exceeds the limits specified in this application (see Comparative Examples 2 and 4), some powder clumps together during reconstitution with water, making it difficult to dissolve and resulting in a long reconstitution time. This increases the difficulty of the doctor's operation and the waiting time for the patient. Uneven reconstitution can also lead to excessively high local concentrations, which can easily cause strong foreign body reactions and pose risks such as blood vessel blockage. When sodium hyaluronate aqueous solution is used as the dispersion, the reconstitution effect is even worse, making it difficult to expand its application scenarios and functional dimensions. Figure 3 This is a state diagram of the injectable filler 8 in Comparative Example 2 after mixing for 10 minutes.

[0104] Example 2

[0105] Pushing force test method: Take one sample after reconstitution, mix the sample evenly and add it to a 2.5mL syringe. After installing the Terumo 27G (0.4*12mm) needle, remove the air bubbles at the needle and place it in the detector of the universal tensile tester. After standing for 5 minutes, conduct the test at a speed of 30mm / min to test the maximum pushing force and the average pushing force, and calculate the ratio between the two. The results are shown in Table 2.

[0106] Table 2

[0107]

[0108] According to the extrusion force results, the extrusion force spectrum of the injectable filler prepared in this application embodiment is relatively flat, with a small difference between the average extrusion force and the maximum extrusion force. This indicates that the injectable filler prepared in the embodiments exhibits good dispersion stability of the microspheres in the system after dispersion, and maintains ideal dispersion stability even after a period of time, reducing the likelihood of needle clogging during injection. The extrusion force spectrum of injectable filler 1 prepared in Example 1 is shown below. Figure 4 The extrusion force spectrum of the injectable filler 4 prepared in Example 2 is shown in [reference needed]. Figure 5 The extrusion force profiles of the injectable fillers obtained in other embodiments are similar to those obtained in other embodiments. Figure 4 resemblance.

[0109] When the amount of sodium carboxymethyl cellulose added is lower than the limit specified in this application (Comparative Example 1) or the viscosity of sodium carboxymethyl cellulose is lower than the limit specified in this application (Comparative Example 3), the extrusion force spectrum shows that the extrusion force is relatively high in the initial stage, which is presumably due to the microspheres settling and clogging the needle after a period of time. It is evident that the dispersion stability of the microspheres in the system is relatively poor after reconstitution. The extrusion force spectrum of the injectable filler 7 prepared in Comparative Example 1 is shown below. Figure 6 The extrusion force spectrum of the injectable filler 9 prepared in Comparative Example 3 is shown in [reference needed]. Figure 7 .

[0110] Example 3

[0111] The shear viscosity η of the injectable fillers prepared in the above examples and comparative examples before and after irradiation sterilization was tested, and the results are shown in Table 3.

[0112] Shear viscosity η test method: Shear rate scanning was performed using a rheometer, with the detection temperature set at 25℃ and the shear rate range at 0.1 s⁻¹. -1 ~100s -1 The gap was set to 0.3 mm, the scanning time to 3 min, the number of sampling points per order of magnitude to 20, and the shear rate to be 1 s. -1 The shear viscosity values ​​under the specified conditions are shown in Table 3.

[0113] Table 3

[0114]

[0115] The results show that the injectable filler prepared in this application has a moderate shear viscosity and is suitable for medical aesthetic injection.

[0116] Finally, it should be noted that the terms “comprising,” “including,” or any other variations thereof in this application are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus.

[0117] Although this application has been disclosed above through the description of specific embodiments, it should be understood that those skilled in the art can devise various modifications, improvements, or equivalents to this application within the spirit and scope of the appended solutions. Such modifications, improvements, or equivalents should also be considered to be included within the scope of protection claimed in this application.

Claims

1. An injectable lyophilized filler, characterized in that, It includes polylactic acid microspheres, sodium carboxymethyl cellulose and a freeze-drying protectant; the viscosity of the sodium carboxymethyl cellulose is 30~300 mPa·s; the mass ratio of the polylactic acid microspheres to the sodium carboxymethyl cellulose is 1:(0.4~0.9).

2. The injectable lyophilizable filler as described in claim 1, characterized in that, The injectable lyophilized filler satisfies at least one of the following conditions (1) to (10): (1) The mass ratio of the polylactic acid microspheres to the sodium carboxymethyl cellulose is 1:(0.45~0.9). (2) The mass ratio of the polylactic acid microspheres to the lyophilization protectant is 1:(0.5~1.2); (3) The viscosity of the sodium carboxymethyl cellulose is 30~100 mPa·s; (4) The weight-average molecular weight of the sodium carboxymethyl cellulose is 6WDa~15WDa; (5) The degree of substitution of the sodium carboxymethyl cellulose is 0.65~0.85; (6) The lyophilization protectant is selected from polyol lyophilization protectants and / or sugar lyophilization protectants; (7) The material of the polylactic acid microspheres is selected from at least one of polylactic acid, polydextral lactic acid and racemic polylactic acid; (8) The proportion of polylactic acid microspheres with a particle size of 20~50μm is more than 80%; (9) The particle size D50 of the polylactic acid microspheres is 20~60μm; (10) The injectable filler lyophilized agent also includes an anesthetic.

3. The injectable lyophilizable filler as described in claim 2, characterized in that, The injectable lyophilized filler satisfies at least one of the following conditions (1) to (11): (1) The mass ratio of the polylactic acid microspheres to the sodium carboxymethyl cellulose is 1:(0.5~0.8); (2) The mass ratio of the polylactic acid microspheres to the lyophilization protectant is 1:(0.5~0.9); (3) The viscosity of the sodium carboxymethyl cellulose is 30~70 mPa·s; (4) The weight-average molecular weight of the sodium carboxymethyl cellulose is 6WDa~12WDa; (5) The degree of substitution of the sodium carboxymethyl cellulose is 0.68~0.79; (6) The polyol freeze-drying protectant is selected from mannitol and / or sorbitol; (7) The sugar freeze-drying protectant is selected from trehalose and / or sucrose; (8) The proportion of polylactic acid microspheres with a particle size of 20~50μm is more than 90%; (9) The particle size D50 of the polylactic acid microspheres is 25~45μm; (10) The anesthetic agent is selected from at least one of lidocaine hydrochloride, lidocaine carbonate, tetracaine, prilocaine, procaine, mepivacaine and bupivacaine; (11) The mass ratio of the polylactic acid microspheres to the anesthetic is 1: (0.04~0.2).

4. A method for preparing an injectable lyophilizable filler as described in any one of claims 1 to 3, characterized in that, The process includes the following steps: mixing the polylactic acid microspheres, the sodium carboxymethyl cellulose, the freeze-drying protectant, and the solvent, and then freeze-drying them to obtain the final product.

5. The method for preparing the injectable lyophilizable filler as described in claim 4, characterized in that, The method for preparing the injectable lyophilized agent satisfies at least one of the following conditions (1) to (3): (1) The mass ratio of the polylactic acid microspheres to the solvent is 1:(15~45); (2) The freeze-drying includes pre-freezing and drying operations; (3) The freeze-drying process also includes sterilization.

6. The method for preparing the injectable lyophilizable filler as described in claim 5, characterized in that, The method for preparing the injectable lyophilized agent satisfies at least one of the following conditions (1) to (4): (1) The mass ratio of the polylactic acid microspheres to the solvent is 1:(25~40); (2) The pre-freezing is a gradient pre-freezing, including a first stage pre-freezing and a second stage pre-freezing; the temperature of the first stage pre-freezing is -25~-10℃, and the holding time is 45~90min; the temperature of the second stage pre-freezing is -55~-30℃, and the holding time is 70~110min; (3) The drying includes sublimation drying and desorption drying; the temperature of the sublimation drying is -20~4℃, the holding time is 1500~2500min, and the vacuum degree is 0.1~1mbar; the temperature of the desorption drying is 5~40℃, the time of the desorption drying is 900~2000min, and the vacuum degree is 0.1~1mbar; (4) The sterilization method is irradiation sterilization.

7. The method for preparing the injectable lyophilizable filler as described in claim 6, characterized in that, The method for preparing the injectable lyophilized agent satisfies at least one of the following conditions (1) to (12): (1) The temperature for the first stage of pre-freezing is -25~-15℃; (2) The holding time for the first stage of pre-freezing is 50~70 min; (3) The temperature for the second stage of pre-freezing is -45~-35℃; (4) The second stage of pre-freezing time is 80~100min; (5) The cooling rate of the room temperature to the first stage of pre-freezing is 20~50℃ / h; (6) The cooling rate from the first stage of pre-freezing to the second stage of pre-freezing is 10~30℃ / h; (7) The temperature for the sublimation drying is -15~0℃; (8) The temperature for the analytical drying is 10~30℃; (9) The heating rate from pre-freezing to sublimation drying is 3~10℃ / h; (10) The heating rate from sublimation drying to analytical drying is 20~70℃ / h, preferably 30~60℃ / h; (11) The irradiation sterilization is selected from β irradiation sterilization or γ irradiation sterilization; (12) The dose of the irradiation sterilization is 15~45kGy, preferably 20~30kGy.

8. An injectable lyophilized filler, characterized in that, It is prepared by the method for preparing injectable filler lyophilized agent as described in any one of claims 4 to 7.

9. An injectable filler, characterized in that, Includes the injectable filler lyophilizer and dispersion as described in any one of claims 1 to 3 and 8; Preferably, the dispersion comprises water for injection; More preferably, the dispersion further includes a buffer and / or an active ingredient; More preferably, the buffer is a phosphate buffer; More preferably, the active ingredient is selected from at least one of a hydrating active ingredient, a whitening active ingredient, and an anti-inflammatory active ingredient; the hydrating active ingredient is preferably selected from sodium hyaluronate; the whitening active ingredient is preferably selected from at least one of tranexamic acid, glutathione, and L-ascorbic acid; and the anti-inflammatory active ingredient is preferably selected from PDRN and / or L-carnosine. More preferably, the active ingredient is sodium hyaluronate, the weight-average molecular weight of the sodium hyaluronate is 10WDa~100WDa, and the mass percentage of sodium hyaluronate in the dispersion is 0.3%~1%.

10. The use of an injectable filler lyophilized as described in any one of claims 1 to 3 and 8, or an injectable filler as described in claim 9, in the preparation of medical or cosmetic products.

Images