Micellar dispersion liquid and preparation method thereof

Abstract

The invention relates to a micelle dispersion liquid and a preparation method thereof, the dispersion liquid comprises a polymer micelle composed of an amphiphilic high-molecular polymer, an ionic salt, and one or more of sodium hyaluronate, sodium carboxymethyl cellulose and collagen, and the dispersion liquid can be used in the field of medical beauty, such as a filler or a hydro-optical needle.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medical aesthetics, and more particularly to a micellar dispersion for use in the field of medical aesthetics and a preparation method thereof. BACKGROUND

[0002] The micelles of amphiphilic high molecular weight polymers currently used in the field of medical aesthetics have poor stability in aqueous systems, especially under high-temperature sterilization or long-term storage conditions. Alternative embodiments include: A) using a sterile filling process instead of a high-temperature sterilization step, but the implementation cost is higher and the process risk control requirements are higher; B) using irradiation sterilization technology instead of high-temperature sterilization, but the accelerated degradation of the molecular chain of the polymer material needs to be considered, and the radiation resistance of the packaging material needs to be verified; C) developing a lyophilized powder formulation, which converts the liquid formulation into a solid form for long-term storage through a low-temperature freeze-drying process, but the cycle cost control of the freeze-drying process needs to be balanced during industrialization, and the reconstitution operation specification needs to be designed to ensure the uniformity of the reconstitution.

[0003] Therefore, there is a need for a micellar dispersion of amphiphilic high molecular weight polymers with enhanced stability, which can be high-temperature sterilized and stored for a long time. SUMMARY

[0004] The present application provides a micellar dispersion for use in the field of medical aesthetics, which has enhanced stability and can withstand high-temperature sterilization and long-term storage.

[0005] In one aspect of the present application, the present application provides a micellar dispersion comprising a polymer micelle composed of an amphiphilic high molecular weight polymer, an ionic salt, and one or more of sodium hyaluronate, sodium carboxymethyl cellulose, and collagen.

[0006] According to the micellar dispersion, the hydrophilic segment of the amphiphilic high molecular weight polymer has a molecular weight ranging from 500 Da to 20 kDa, and the hydrophobic segment has a molecular weight ranging from 1 kDa to 50 kDa.

[0007] According to the micellar dispersion, the mass concentration of the amphiphilic high molecular weight polymer is 0.1% to 50%.

[0008] According to the micellar dispersion, the amphiphilic high molecular weight polymer comprises a polyethylene glycol-caprolactone diblock copolymer and / or a polyethylene glycol-lactide diblock copolymer.

[0009] According to the micellar dispersion liquid, the sodium hyaluronate (HA), the sodium carboxymethyl cellulose (NaCMC) and the collagen protein have a molecular weight range of 10 kDa to 3000 kDa.

[0010] According to the micellar dispersion liquid, the sodium hyaluronate (HA), the sodium carboxymethyl cellulose (NaCMC) and the collagen protein have a mass concentration of 0.1% to 5%.

[0011] According to the micellar dispersion liquid, the ionic salt comprises one or more of acetate, phosphate, hydrogen phosphate, citrate, carbonate, bicarbonate, Tris-HCl buffer salt, boric acid-borax buffer salt, boric acid-sodium hydroxide buffer salt, sodium chloride and potassium chloride.

[0012] According to the micellar dispersion liquid, the micellar dispersion liquid further comprises one or more of glycerol, mannitol, deoxyribonucleic acid, polydeoxyribonucleotides, polynucleotides, vitamins and amino acids.

[0013] According to the micellar dispersion liquid, the micellar dispersion liquid further comprises a stabilizer comprising one or more of sodium hyaluronate (HA), sodium carboxymethyl cellulose (NaCMC) and collagen protein.

[0014] In another aspect of the present application, the present application provides a micellar dispersion liquid mainly composed of polymer micelles of amphiphilic high molecular polymers, ionic salt, and one or more of sodium hyaluronate (HA), sodium carboxymethyl cellulose (NaCMC) and collagen protein.

[0015] According to the micellar dispersion liquid, the micellar dispersion liquid further comprises water.

[0016] According to the micellar dispersion liquid, the amphiphilic high molecular polymers are mainly composed of polyethylene glycol-caprolactone diblock copolymer and / or polyethylene glycol-lactide diblock copolymer.

[0017] In another aspect of the present application, the present application further provides a method for preparing the micellar dispersion liquid of the present application, comprising the following steps:

[0018] The amphiphilic high molecular polymers, ionic salt, and one or more of sodium hyaluronate (HA), sodium carboxymethyl cellulose (NaCMC) and collagen protein are mixed, dissolved and stirred uniformly to obtain the micellar dispersion liquid.

[0019] According to the method, the method further comprises high-temperature sterilization after obtaining the mixed dispersion liquid.

[0020] According to the method, the high-temperature sterilization is moist heat sterilization, the temperature is 105°C to 134°C, and the sterilization time is 1 minute to 30 minutes.

[0021] In another aspect of the present application, the present application also provides a complex for injection into dermis, such as a medical aesthetic water-light needle, comprising the micellar dispersion solution described in the present application, wherein the concentration of ionic salt is 0.01% to 1%.

[0022] In another aspect of the present application, the present application also provides a dermal filler, such as a medical aesthetic filler, comprising the micellar dispersion solution described in the present application, wherein the concentration of ionic salt is 1% to 2%.

[0023] These and other aspects of the present application will become apparent from and be elucidated with reference to the embodiments described hereinafter. BRIEF DESCRIPTION OF DRAWINGS

[0024] Embodiments of the present application will now be described, by way of example only, with reference to the accompanying drawings in which:

[0025] Figure 1 is a schematic diagram of the stability evaluation of the sample prepared in the present application after the end of high-temperature sterilization.

[0026] Figure 2 is a schematic diagram of the stability evaluation of the sample prepared in the present application after the end of high-temperature sterilization, when stored for a long time.

[0027] Figure 3 is a schematic diagram of the stability evaluation of the sample prepared in the present application without high-temperature sterilization, when stored for a long time.

[0028] Figure 4 is a schematic diagram of the flowability of the sample prepared in the present application.

[0029] Figure 5 is a dissection diagram of part of the sample prepared in the present application after 1 week and 4 weeks of intradermal implantation of 0.2 mL on the back of New Zealand rabbits. No obvious adverse reactions occurred after implantation, and slow degradation of the sample was observed after 4 weeks.

[0030] Figure 6 is a dissection diagram of part of the sample prepared in the present application after 1 week and 4 weeks of intradermal implantation of 0.2 mL on the back of New Zealand rabbits. Foreign body reaction occurred after implantation, and slow degradation of the sample was observed after 4 weeks.

[0031] Figure 7 is a HE staining diagram of part of the sample prepared in the present application after 1 week of intradermal implantation of 0.2 mL on the back of New Zealand rabbits. The black arrows in the figure indicate macrophages, and the white arrows indicate lymphocytes. Inflammation cell infiltration was observed around the sample after 1 week of implantation.

[0032] Figure 8Figure 1 is a HE staining chart of a part of the sample prepared by the present application after 4 weeks of intradermal implantation of 0.2 mL on the back of New Zealand rabbits. The black arrow in the chart indicates macrophages. Four weeks after implantation, a small amount of inflammatory cell infiltration and slight capillary proliferation can be seen, and the implant is degraded.

[0033] Figure 9 Figure 2 is a HE staining chart of a part of the sample prepared by the present application after 1 week of intradermal implantation of 0.2 mL on the back of New Zealand rabbits. The black arrow in the chart indicates macrophages, and the white arrow indicates lymphocytes. One week after implantation, a large amount of inflammatory cell infiltration can be seen around the sample.

[0034] Figure 10 Figure 3 is a HE staining chart of a part of the sample prepared by the present application after 4 weeks of intradermal implantation of 0.2 mL on the back of New Zealand rabbits. The black arrow in the chart indicates macrophages, and the white arrow indicates lymphocytes. Four weeks after implantation, inflammatory cell infiltration and slight capillary proliferation can be seen, and the implant is degraded. DETAILED DESCRIPTION

[0035] The present application is the result of many attempts to find an amphiphilic high molecular polymer micelle dispersion liquid with significantly improved stability and a method for preparing the dispersion liquid. The micelle dispersion liquid includes amphiphilic high molecular polymer micelles, ionic salt, and stabilizer.

[0036] The amphiphilic high molecular polymer can be a polymer with hydrophilic segments and hydrophobic segments, such as polyethylene glycol-caprolactone (PEG-PCL) or polyethylene glycol-lactide (PEG-PLA). The polyethylene glycol-caprolactone can generally be a copolymer of ethylene glycol-caprolactone, for example, a polyethylene glycol-caprolactone two-block copolymer, with a molecular formula of CH3O-(CH2CH2O) n -(CH2CH2CH2CH2O) x wherein n is the polymerization degree of ethylene glycol, and x is the polymerization degree of caprolactone. The polyethylene glycol-lactide can generally be a copolymer of ethylene glycol-lactide, for example, a polyethylene glycol-lactide two-block copolymer, with a molecular formula of CH3O-(CH2CH2O) n -(CH(CH3)CO) xOH, wherein n is the degree of polymerization of ethylene glycol, and x is the degree of polymerization of lactide. Polyethylene glycol-caprolactone and polyethylene glycol-lactide are polymers with good biocompatibility, and have many application scenarios in the field of biological medicine, for example, they can be used as drug carriers to enhance the dispersibility and absorbability of hydrophobic drugs; as a surfactant in liquid dressings, they can reduce surface tension, help liquid dressings quickly cover wounds and quickly form films; as a cosmetic filler, they can be used to correct fine wrinkles and stimulate the production of new collagen. The molecular weight of polyethylene glycol in polyethylene glycol-caprolactone or polyethylene glycol-lactide ranges from 500 Da to 10 kDa, for example, 1 kDa, 3 kDa, 4 kDa, 5 kDa, 6 kDa, 7 kDa, 8 kDa, 9 kDa; the molecular weight of polycaprolactone or poly-lactide in polyethylene glycol-caprolactone or polyethylene glycol-lactide ranges from 1 kDa to 50 kDa, for example, 2 kDa, 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 47 kDa. When amphiphilic polymers are dispersed in a solution, they can exist in the form of micelles of the polymer, with a size generally between 1 and 1000 nm, more often between 10 and 100 nm, and a shape that can be spherical, rod-shaped or irregular. The mass concentration of amphiphilic high molecular weight polymers in the micellar dispersion can be 0.1% to 50%, for example, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 12%, 14%, 15%, 17%, 19%, 20%, 22%, 25%, 27%, 30%, 32%, 35%, 37%, 40%, 42%, 44%, 45%, 47%.

[0037] Ion salts as common excipient additives can be used to adjust pH or osmotic pressure. However, ion salts can weaken the electrostatic repulsion between micelles, causing micelles to precipitate, aggregate and separate in the aqueous phase. The present application can select a variety of ion salts or ion salt buffers formed in coordination, for example, including one or several of acetate, phosphate, hydrogen phosphate, citrate, carbonate, bicarbonate, Tris-HCl buffer salt, boric acid-borax buffer salt, boric acid-sodium hydroxide buffer salt, sodium chloride, potassium chloride. The mass concentration of ion salts in the micellar dispersion is 0.01% to 5%, for example, it can be 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.12%, 0.14%, 0.15%, 0.16%, 0.18%, 0.2%, 0.22%, 0.25%, 0.27%, 0.3%, 0.32%, 0.35%, 0.37%, 0.4%, 0.42%, 0.45%, 0.47%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.7%, 1.9%, 2%, 2.2%, 2.4%, 2.5%, 2.7%, 2.9%, 3%, 3.2%, 3.5%, 3.7%, 4%, 4.2%, 4.4%, 4.5%, 4.7%, 4.8%.

[0038] The present application discloses that the stability of the micelles in ionic solution can be enhanced by adding a hydrophilic molecule as a stabilizer, which has a specific molecular weight and concentration range, even to withstand some extreme conditions, such as after mixing into the ionic solution, even if high temperature sterilization is performed, and long-term storage, the micelle dispersion will remain stable. The stabilizer of the present application can be one or more of sodium hyaluronate (HA), sodium carboxymethyl cellulose (NaCMC), and collagen. In one embodiment of the present application, the molecular weight of sodium hyaluronate (HA), sodium carboxymethyl cellulose (NaCMC), and collagen ranges from 300 kDa to 3000 kDa; in another embodiment of the present application, the molecular weight of sodium hyaluronate (HA), sodium carboxymethyl cellulose (NaCMC), and collagen is 10 kDa, 30 kDa, 50 kDa, 100 kDa, 150 kDa, 200 kDa, 300 kDa, 500 kDa, 700 kDa, 1000 kDa, 1200 kDa, 1500 kDa, 1800 kDa, 2000 kDa, 2200 kDa, 2500 kDa, 2700 kDa, 2800 kDa. The total mass concentration of sodium hyaluronate (HA), sodium carboxymethyl cellulose (NaCMC), and collagen in the entire micelle dispersion is 0.1% to 5%, for example, it can be 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.2%, 1.5%, 1.7%, 2%, 2.2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 4.7%.

[0039] The method for preparing the micelle dispersion of the present application comprises mixing and dissolving the amphiphilic high molecular weight polymer micelles, ionic salt, and one or more of sodium hyaluronate (HA), sodium carboxymethyl cellulose (CMC), and collagen, and stirring uniformly to obtain a micelle dispersion; then high temperature sterilization is performed. Although high temperature sterilization can be performed first and then the micelle dispersion is divided, it is more beneficial to sterilize the micelle dispersion by first dividing and then high temperature sterilization. High temperature sterilization can be moist heat sterilization, for example, in a steam sterilization pot / box, heated to 105°C and above, for a certain period of time to achieve the purpose of sterilization. Common sterilization can be 121°C for 1 minute to 40 minutes, for example, 1 minute, 2 minutes, 3 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes. In one embodiment of the present application, when the micelle dispersion is configured, the micelles can be mixed with water first, and then the ionic salt and the stabilizer are added.

[0040] When the micellar dispersion of the present application is used in the mesoderm of the skin, it is generally desirable that the sample has low viscosity and high flowability, and is easy to diffuse in a certain range after injection into the body tissue, so as to achieve the effect of supplementing water. When the micellar dispersion of the present application is used in the medical and cosmetic skin filler, the viscosity of the sample can be generally increased by adjusting the concentration of ionic salt to reduce the flowability, and the sample is concentrated at the injection site after injection and slowly diffuses, so as to achieve the effects of physical filling and slowly stimulating collagen neogenesis.

[0041] Example 1

[0042] Sample preparation process

[0043] Taking sample #1 as an example, 10 g of polyethylene glycol-caprolactone copolymer, 0.1 g of sodium carbonate, 0.01 g of sodium bicarbonate, 0.9 g of sodium chloride, 1 g of sodium carboxymethyl cellulose, and 87.99 g of water are mixed and stirred for 24 h to form a uniform dispersion system, wherein the mass concentration of polyethylene glycol-caprolactone copolymer is 10%, the ionic salt concentration is 1.01%, and the mass concentration of sodium carboxymethyl cellulose is 1%. Then, the above dispersion system is loaded into a pre-filled syringe, and a piston is added. The above liquid-containing pre-filled syringe is placed in a high-pressure steam kettle for high-temperature and wet heat sterilization, and the condition is 121°C, and the temperature is kept for 15 min. After sterilization, wait for cooling, and sample is prepared.

[0044] The sample is observed with the naked eye, and the stability of the micelles can be evaluated, and the physicochemical properties of the sample are evaluated by corresponding instruments (see Example 2). There is also an evaluation of the ability of ionic salt to adjust the viscosity (see Example 3).

[0045] The preparation of samples #1-#19 is carried out according to the proportions in the following Table 1. Samples #1-#19 are all sterilized by wet heat sterilization after sub-packaging, and the condition is 121°C, and the temperature is kept for 15 min.

[0046] Table 1

[0047]

[0048] Example 2

[0049] Evaluation of the stability and physicochemical properties of the sample

[0050] Stability evaluation: the sample is placed in a light sufficient condition, and the micelles are observed for any aggregation, sedimentation and separation. For example, Figure 1 Figure a in the above figure is sample #9 prepared by the present application, which shows that the sample has "strong stability" and no any abnormality visible to the naked eye; Figure 1 Figure b in the above figure is sample #18 prepared by the present application, which shows that the sample has "weak stability" and has micelles visible to the naked eye; Figure 1Figure 19C in the figure is sample #19 prepared by the present application, which shows that the sample has "poor stability" and has very serious delamination.

[0051] pH evaluation: According to the method of pH value determination in Chinese Pharmacopoeia 2020 edition volume IV 0631, record the readings of pH meter (Shanghai Raymag, PHSJ-3F).

[0052] Viscosity evaluation: According to the method of viscosity determination in Chinese Pharmacopoeia 2020 edition volume IV 0633, the third method of rotational viscometer determination is used for evaluation. Take 0.5 mL sample, test on rotational viscometer (Anton Paar, ViscoQC300-L), and record the readings.

[0053] The evaluation results are as follows Table 2:

[0054] Table 2

[0055]

[0056]

[0057] Among samples #1-#18 using the technical scheme of the present application, most have good stability, and after 121℃ heat preservation for 15 min, no aggregation, sedimentation and separation of micelles occur, except that sample #7 has the problem of difficult dissolution of HA 4000kDa as stabilizer, which indicates that there may be an upper limit of molecular weight or concentration, and exceeding the upper limit will cause difficult dissolution, while sample #18 uses low molecular weight sodium hyaluronate, and the stability is further reduced, which indicates that when the molecular weight of the stabilizer is low, it may play the role of flocculating agent. Sample #19 without using the component scheme of the present application has aggregation, which indicates that the stability is weak.

[0058] At the same time, the long-term storage stability of part of the samples is evaluated. According to the shelf life acceleration aging formula, the acceleration factor is calculated as follows:

[0059]

[0060] In the formula:

[0061] Q 10 : aging factor of temperature increase or decrease of 10℃, in this example, the value is 2;

[0062] T AA : acceleration aging temperature, unit: ℃, in this example, the value is 40℃;

[0063] T RT : environmental temperature, unit: ℃, in this example, the value is 5℃.

[0064] According to the calculation result, the accelerated aging factor AAF = 11.31. Therefore, the time point of accelerated aging = the time point of real-time aging ÷ 11.31. Figure 2 a, b, c in the figure are respectively the results of sample #9 prepared by the application after wet heat sterilization treatment, stored at 40℃ for 32, 64, 129 days, corresponding to the results of storage at 5℃ for half a year, one year, two years respectively. It can be seen that the sample of the application has strong stability, and although it has been subjected to high temperature sterilization, there is no visible micellar aggregation and separation. Figure 3 a, b, c in the figure are respectively the results of sample #19 prepared by the application without wet heat sterilization, stored at 40℃ for 32, 64, 129 days, corresponding to the results of storage at 5℃ for half a year, one year, two years respectively. It can be seen that the sample contains an ionic solution, and visible micellar aggregation (the part marked by the circle in the figure) has occurred when it is stored for 64 days and 129 days. It can be seen that the technical solution of the application not only enhances the stability of the micelles under high temperature sterilization conditions, but also enhances the stability of the micelles in long-term storage.

[0065] Example 3

[0066] Evaluation of the ability of ionic salt to adjust viscosity

[0067] Viscosity evaluation: According to the viscosity determination method of Chinese Pharmacopoeia 2020 edition fourth part general rules 0633, the third method of rotating viscometer determination method is used for evaluation. Take 0.5 mL sample, test on rotating viscometer (Anton Paar, ViscoQC300-L), record the reading.

[0068] Flowability: extrude 0.5 mL sample, observe the diffusion and plasticity of the sample. For example Figure 4 a in the figure is sample #16 prepared by the application, which shows that the sample has large diffusion area and poor plasticity, indicating that it has "strong flowability" and is easy to diffuse in solution or body tissue; for example Figure 4 b in the figure is sample #15 prepared by the application, which shows that the sample has "moderate flowability", the sample diffuses slowly, but the plasticity is weak; for example Figure 4 c in the figure is sample #11 prepared by the application, which shows that the sample has "weak flowability", and the sample has strong plasticity and is not easy to diffuse.

[0069] The evaluation results are as follows Table 3:

[0070] Table 3

[0071] Sample Viscosity mPa-s Flowability 9 27610 Weak 10 55190 Weak 11 131030 Weak 14 31730 Weak 15 15910 Weak 16 8216 Strong

[0072] It can be seen that the sample prepared by the technical scheme of the present application can realize significant changes in viscosity and flowability by adjusting the concentration of ionic salt only when the molecular weight and concentration of micelles and stabilizers are fixed. This is a very important characteristic in certain application fields, for example, in the research and development of medical and cosmetic injections. If the product has strong flowability, it can usually be used as a water light needle to play a role in supplementing water; if the product has weak flowability and strong plasticity, it can usually be used as a filler to play a role in filling wrinkles.

[0073] Example 4

[0074] Animal implant safety evaluation of the sample

[0075] Adult New Zealand rabbits (purchased from Shaanxi Yifengda Biological Technology Co., Ltd.) were used, weighing 2.0-2.5 kg, half male and half female. After preparing the back skin, intradermal injection was performed, 8 injection points per rabbit, 0.2 mL of sample #2 or sample #9 was injected at each injection point with a 27G needle, and each injection area was directly spaced more than 2 cm apart. At 1 week and 4 weeks after implantation, dissection and pathological HE staining sections were prepared. Figure 5 Figures a and b of the present application are dissection diagrams of sample #9 prepared by the present application after intradermal implantation of 0.2 mL in the back of New Zealand rabbits for 1 week and 4 weeks, respectively. It can be seen that the sample has no visible adverse reactions 1 week and 4 weeks after implantation, and the material can be gradually degraded at 4 weeks. Figure 6 Figures a and b of the present application are dissection diagrams of sample #2 prepared by the present application after intradermal implantation of 0.2 mL in the back of New Zealand rabbits for 1 week and 4 weeks, respectively. Foreign body reaction was observed at 1 week and 4 weeks, which was dark and prominent in the intradermal injection, and the sample could be slowly degraded and absorbed at 4 weeks. Figure 7 and Figure 8 are HE staining diagrams of sample #9 prepared by the present application after intradermal implantation of 0.2 mL in the back of New Zealand rabbits for 1 week and 4 weeks, respectively. The black arrows in the figures indicate macrophages, and the white arrows indicate lymphocytes. It can be seen from Figure 7 that a large number of inflammatory cells infiltrate around the sample 1 week after implantation, and Figure 8 that a small amount of inflammatory cell infiltration and slight capillary proliferation can be seen 4 weeks after implantation, and the implant degrades. Figure 9 and Figure 10 are HE staining diagrams of sample #2 prepared by the present application after intradermal implantation of 0.2 mL in the back of New Zealand rabbits for 1 week and 4 weeks, respectively. It can be seen from Figure 9 that a large number of inflammatory cells infiltrate around the sample 1 week after implantation, and Figure 10 that inflammatory cell infiltration and slight capillary proliferation can be seen 4 weeks after implantation.

[0076] from Figure 5 , Figure 6 , Figure 7 , Figure 8 ,Figure 9 and Figure 10 It can be seen that the technical scheme of the present application has different stimulations on animal tissues, and the foreign body reaction caused by sodium carboxymethyl cellulose on the tissues is relatively more obvious than that of sodium hyaluronate. Therefore, for different application scenarios in the field of biological medicine, the stabilizer and the ion concentration can be selected according to the present application.

[0077] Those skilled in the art will appreciate that modifications (additions and / or removals) of various components / parts of the products, formulations, devices, methods, systems and embodiments described herein can be made without departing from the full scope and spirit of the present application, which encompass such modifications.

Claims

1. A micellar dispersion comprising polymer micelles of amphiphilic high molecular weight polymers, ionic salts, and further comprising one or more of sodium hyaluronate, sodium carboxymethylcellulose, and collagen.

2. The micellar dispersion of claim 1, wherein the amphiphilic high molecular weight polymers have hydrophilic segments with molecular weights ranging from 500 Da to 20 kDa and hydrophobic segments with molecular weights ranging from 1 kDa to 50 kDa.

3. The micellar dispersion of claim 1, wherein the amphiphilic high molecular weight polymers have a mass concentration ranging from 0.1% to 50%.

4. The micellar dispersion of claim 1, wherein the amphiphilic high molecular weight polymers comprise polyethylene glycol-caprolactone diblock copolymers and / or polyethylene glycol-lactide diblock copolymers.

5. The micellar dispersion of claim 1, wherein the sodium hyaluronate, sodium carboxymethylcellulose, and collagen have molecular weights ranging from 10 kDa to 3000 kDa.

6. The micellar dispersion of claim 1, wherein the sodium hyaluronate, sodium carboxymethylcellulose, and collagen have a mass concentration ranging from 0.1% to 5%.

7. The micellar dispersion of claim 1, wherein the ionic salts comprise one or more of acetate, phosphate, hydrogen phosphate, citrate, carbonate, bicarbonate, Tris-HCl buffer salts, boric acid-borax buffer salts, boric acid-sodium hydroxide buffer salts, sodium chloride, and potassium chloride.

8. The micellar dispersion of claim 1, further comprising one or more of glycerol, mannitol, deoxyribonucleic acid, polydeoxyribonucleotides, polynucleotides, vitamins, and amino acids.

9. A method of preparing the micellar dispersion of any one of claims 1-8, comprising the steps of: mixing and dissolving the amphiphilic high molecular weight polymers, ionic salts, and one or more of sodium hyaluronate, sodium carboxymethylcellulose, and collagen, and stirring until uniform to obtain the micellar dispersion.

10. The method of claim 9, further comprising autoclaving after obtaining the mixed dispersion.

11. The method of claim 10, wherein the autoclaving is wet heat sterilization at a temperature ranging from 105°C to 134°C for a time ranging from 1 minute to 30 minutes.

12. A complex for injection into the dermis comprising the micellar dispersion of any one of claims 1-8, wherein the ionic salts have a concentration ranging from 0.01% to 1%.

13. A dermal filler comprising the micellar dispersion of any one of claims 1-8, wherein the ionic salts have a concentration ranging from 1% to 2%. ​

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