WO2023151669A1 - 一种注射美容产品及其制备方法和应用 - Google Patents

一种注射美容产品及其制备方法和应用 Download PDF

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WO2023151669A1
WO2023151669A1 PCT/CN2023/075506 CN2023075506W WO2023151669A1 WO 2023151669 A1 WO2023151669 A1 WO 2023151669A1 CN 2023075506 W CN2023075506 W CN 2023075506W WO 2023151669 A1 WO2023151669 A1 WO 2023151669A1
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cmc
gel
microspheres
injection
cosmetic product
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French (fr)
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张璇
王斌
张海茹
王卓
夏雯蓉
高健
董西健
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辛克莱制药股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/731—Cellulose; Quaternized cellulose derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0241—Containing particulates characterized by their shape and/or structure
    • A61K8/025—Explicitly spheroidal or spherical shape
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/042—Gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/85—Polyesters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/91—Injection

Definitions

  • the invention relates to the field of medical cosmetology or medical preparations, in particular to an injection cosmetic product and its preparation method and application.
  • Carboxymethyl Cellulose is a water-soluble cellulose ether obtained by chemically modifying natural cellulose. Due to the poor water solubility of the acidic structure of carboxymethyl cellulose, in order to be able to apply it better, its products are generally made into sodium salts, and the molecular formula is [C 6 H 7 O 2 (OH) 2 OCH 2 COONa] n, CMC-Na is white fibrous or granular powder, odorless, tasteless, hygroscopic, easy to disperse in water to form a transparent colloidal solution, CMC-Na is a polymer with a wide range of molecular weight, degree of substitution and degree of polymerization, The gel formed by it has different properties, can be preserved for a long time without corruption, has high viscosity, strong shape retention, good biocompatibility and film-forming performance, etc., and has broad application prospects in food, daily necessities, medicine, etc.
  • Sodium carboxymethyl cellulose has many hydroxyl and carboxyl groups, is hygroscopic and can absorb a large amount of water, and the hydrogel prepared with sodium carboxymethyl cellulose has high water content, good hydrophilicity, high swelling rate, and biocompatibility Good sex and biodegradable, are widely used in the field of biomedicine.
  • CMC-Na gel has the same rheology as many water-soluble high molecular polymers, and the CMC-Na gel of low molecular weight is the sol that can flow, and the viscosity is less and tends to be fluid, and the CMC-Na gel viscosity of medium and high molecular weight is relatively high. Large, semi-solid pseudoplastic fluid.
  • CMC-Na gel also has thixotropy, that is, the gel state tends to change to fluidity under the action of external force, and will return to the previous gel state when the mechanical force is removed.
  • Good thixotropy makes CMC-Na gel very suitable as an injection carrier material. Therefore, CMC-Na gel is often used as an injection beauty product in the field of medical beauty.
  • CMC-Na gel with lower shear viscosity which has lower viscosity and poor thixotropy. Although it has good fluidity and is easy to prepare, CMC-Na gel with low viscosity and low thixotropy
  • Na gel used as the carrier of microspheres, it will cause the aggregation of micron-sized particles in the product, which is more obvious when the product is stored during the shelf life.
  • Patent application CN112999990A also records that the improvement of microsphere suspension performance can reduce the adhesion and aggregation of microspheres in long-term storage.
  • the invention relates to an injectable cosmetic product, which includes degradable microspheres and CMC-Na gel.
  • the CMC-Na carrier gel can allow the microspheres to be uniformly suspended in the CMC-Na gel for a long time, and maintain the independent three-dimensional structure of the microspheres , so that the microspheres can be evenly distributed in the human body after injection, greatly reducing the chance of lumps and foreign body granulomas.
  • CMC-Na gels with specific properties or specifications can effectively disperse microspheres evenly in the gel, and simultaneously combine microspheres and CMC.
  • the present invention has obtained a gel containing degradable microspheres and CMC-Na, wherein the content of CMC-Na is 2-3wt.%, its viscosity-average molecular weight is 80-1.2 million Da, and the shear viscosity range is 40000 -65000mPa ⁇ s, the product is not easy to cause the deposition and aggregation of microspheres and the blockage of the syringe, and the quality is stable during the shelf life, the use effect is good, and the adverse reactions are greatly reduced.
  • a kind of injectable cosmetic product it is characterized in that: comprise degradable microsphere and CMC-Na gel, the content of CMC-Na is 2-3wt.% in the described cosmetic product, the shear viscosity range of CMC-Na gel is 10000-80000mPa s, the preferred range is 30000-70000mPa s, 40000-65000mPa s, 30000-50000mPa s; CMC-Na viscosity average molecular weight is 80-1.2 million Da, the range of substitution degree (DS) is: 0.7 -1.0, preferably 0.8-1.0, 0.8-0.95.
  • the viscosity-average molecular weight range can also be specifically selected from 900,000 Da, 950,000 Da, 1.100,000 Da, and 1.150,000 Da to obtain a better balance between the immediate filling effect and the sustained-release effect.
  • the degradable microspheres are PCL microspheres, PLLA microspheres or PLGA microspheres.
  • the average particle diameter of the degradable microspheres is in the range of 25-50 ⁇ m.
  • Injectable cosmetic products as described above which also include glycerin and PBS buffer.
  • the cosmetic injection product as mentioned above also includes a syringe and a needle, and the degradable microspheres and CMC-Na gel are pre-filled in the syringe.
  • a method for preparing the aforementioned CMC-Na gel step 1: Pour into a beaker a PBS buffer solution with a pH of 6.5-8 configured by dihydrogen phosphate and sodium hydroxide, and place the beaker on a stirring table to make the buffer Stir the solution; step 2, slowly pour in CMC-Na, make the CMC-Na fully contact with the buffer and stir for 2-5h, until you see that there is no agglomeration in the gel, that is, CMC-Na that has not been stirred; step 3. Add glycerin to the gel and stir thoroughly for about 5 minutes; Step 4. Use a vacuum stirring and defoaming machine to perform stirring and degassing treatment.
  • a method for preparing the aforementioned injectable beauty products step 1): pouring dihydrogen phosphate and hydroxide into a beaker Sodium-prepared PBS buffer with a pH of 6.5-8, put the beaker on the stirring table to stir the buffer; step 2), slowly pour in CMC-Na, which accounts for 2-3wt.% of the beauty product filling, Make CMC-Na fully contact with the buffer and stir for 2-5h until you see that there is no agglomeration in the gel, that is, it is not stirred; step 3), add 0.9-1.1wt.
  • step 4 use a vacuum stirring and defoaming machine to stir and remove air bubbles; step 5), add weighed microspheres of 28-38wt.% to the gel, after preliminary stirring , using a vacuum stirring and defoaming machine for stirring and defoaming treatment.
  • the CMC-Na gel with a viscosity average molecular weight of 80-1.2 million Da and a shear viscosity of 40000-65000mPa ⁇ s is the most suitable for injecting cosmetic products.
  • the gel can be uniformly dispersed (whether before or after injection), effectively reducing the generation of lumps and foreign body granulomas; and when pushed into a syringe, the pushing force and pushing speed are moderate, and the doctor is more concerned about the injection speed. It is easy to control, improves the injection accuracy, makes the injection smoother, and fills more evenly.
  • Fig. 2 is the scanning electron micrograph of PLGA microsphere
  • Fig. 3 is the scanning electron micrograph of PLLA microsphere
  • Figure 4a, Figure 4b, Figure 4c, Figure 4d, Figure 4e and Figure 4f are micrographs of 6 kinds of CMC-Na gels loaded with PCL microspheres; Figure 4e' and Figure 4f' are No. 5 loaded PCL microspheres , Micrograph of No. 6 CMC-Na gel extruded from the syringe.
  • Embodiment 1 the preparation of PCL microsphere
  • Preparation method Vortex dissolve 500mg PCL in 2.5ml DCM to form an oil phase; add the oil phase dropwise to 25ml 1% MC solution while stirring, then stir for 30s, and use a high-speed shear mixer at 14000r/min to shear Cut for 1min, stir at 1000r/min for 3h; wash and centrifuge 3 times, 10min each time, pre-freeze for 2h, and dry for 24h.
  • the proportion of microspheres smaller than 20 ⁇ m is ⁇ 1%, the proportion of microspheres of 20-25 ⁇ m is ⁇ 19%, the proportion of microspheres of 25-50 ⁇ m is ⁇ 65%, and the proportion of microspheres larger than 50 ⁇ m is ⁇ 15%; more Preferably, the proportion of microspheres smaller than 20 ⁇ m is ⁇ 1%, the proportion of microspheres of 20-25 ⁇ m is ⁇ 15%, the proportion of microspheres of 25-50 ⁇ m is ⁇ 70%, and the proportion of microspheres larger than 50 ⁇ m is ⁇ 14%.
  • Embodiment 2 the preparation of PLGA microsphere
  • Preparation method vortex dissolve 500mg PLGA in 2.5ml DCM, then add 500 ⁇ l inner water phase, vortex for 5min, dropwise add to 10ml 2% PVA solution while stirring, stir for 1min, then add to 150ml of 0.2% PVA solution, stirred for 2min, sheared with a high-speed shear mixer at 15000r/min for 30s, stirred at 1000r/min for 3h; washed and centrifuged for 3 times, each time for 10min, pre-frozen for 2h, and dried for 24h.
  • the PLGA microspheres are smooth, with good roundness and suitable particle size.
  • the particle size analysis of PLGA microspheres shows that the particle size distribution of PLGA microspheres is relatively uniform, and 20-50 ⁇ m microspheres account for about 40%.
  • Embodiment 3 Preparation of PLLA microspheres
  • Preparation method Vortex 500mg PLLA dissolved in 2.5ml DCM, add to 10ml 2% PVA solution, shear at 15000r/min for 3min with a high-speed shear mixer, then add to 150ml 0.2% PVA solution, stir 1000r/min for 3h ;Wash and centrifuge 3 times, 10min each time, pre-freeze for 2h, and dry for 24h.
  • the PLLA microspheres are smooth, with good roundness, good dispersion and suitable particle size.
  • the particle size distribution of PLLA microspheres was relatively uniform, and the microspheres of 20-50 ⁇ m accounted for about 32.18%.
  • Embodiment 4 the detection of the CMC-Na viscosity-average molecular weight of 6 kinds of specifications and the preparation of CMC-Na gel.
  • CMC-Na choose the CMC-Na raw material of 6 kinds of different specifications on the market, described CMC-Na is purchased from Ashland LLC. and Sigma company respectively, detects the viscosity average molecular weight of the CMC-Na of above-mentioned 6 kinds of specifications, detection method as follows:
  • Step 1 Accurately weigh 25mg of CMC-Na raw material, dissolve the raw material in about 40mL 0.2mol/L sodium chloride solution, and place the solution at 50°C for 16 hours. The solution was then transferred completely and made up to 50 mL. Using an Ubbelohde viscometer with an inner diameter of 0.53 mm and a 0.2 mol/L sodium chloride solution as a blank control solution, the viscosity was measured according to the fourth general rule 0633 of the "Chinese Pharmacopoeia" (2020 edition) Viscosity determination method (method 2).
  • Step 2 Calculate the intrinsic viscosity [ ⁇ ] according to formula (1) and formula (2).
  • [ ⁇ ] ln ⁇ r /c formula (1)
  • ⁇ r T/T0 formula (2)
  • T is the outflow time unit of the test solution in s
  • T0 is the blank outflow time unit in s
  • C is the concentration of the test solution
  • the degree of substitution and the range of degree of substitution of CMC-Na gel come from the product label, and the viscosity-average molecular weight and degree of substitution of 6 specifications of CMC-Na gel are described in the following table:
  • Step 1 Pour a certain amount of PBS buffer solution with a pH of 6.5-8 prepared by dihydrogen phosphate and sodium hydroxide into the beaker, and stir;
  • Step 2 Slowly pour a certain amount of CMC-Na powder (the proportion of the final product filling is 2-3wt.%), make the powder fully contact with the buffer and stir for 2-5h until the gel is seen Until there is no agglomeration, that is, powder that has not been stirred;
  • Step 3 adding a certain amount of glycerin (the proportion of the final product filling is 0.9-1.1wt.%) to the gel, and fully stirring for about 5 minutes;
  • Step 4 Use a vacuum stirring and degassing machine to perform stirring and degassing treatment, and prepare 6 kinds of CMC-Na gels respectively.
  • Embodiment 5 Detect the shear viscosity and the thixotropic index of the CMC-Na gel of 6 kinds of specifications:
  • Table 2 shows the shear viscosity and thixotropic index of No. 1-6 CMC-Na gels, and the shear viscosity and thixotropic index after adding PCL microspheres.
  • the shear viscosity of No. 1 CMC-Na gel is far less than 10000mPa s
  • the shear viscosity of No. 2 CMC-Na gel is around 10000mPa s
  • its shear viscosity is all low
  • the process of gel preparation also shows that No. 1 and No. 2 CMC-Na gels have low viscosity and are close to liquid fluids.
  • 3-5 CMC-Na gel is in the range of 40000-65000mPa ⁇ s, the thixotropic index is between 3-5, and its viscosity is moderate and has certain fluid and colloid properties.
  • the shear viscosity of No. 6 CMC-Na gel is above 65000mPa ⁇ s and as high as 78121mPa ⁇ s.
  • the shear viscosity and thixotropic index of No. 1-6 CMC-Na gels were changed.
  • the shear viscosity increased significantly, and the thixotropic index also changed.
  • the shear viscosities of No. 1 and No. 2 gels were about 5500 and 20000 mPa ⁇ s respectively, the viscosity value was low, and the thixotropic index was lower than 3. Compared with the gel of the ball, the whole is still close to the fluid state.
  • CMC-Na gel For an injectable beauty product containing PCL microspheres, the choice of CMC-Na gel has a great influence on the product, because the degree of dispersion of PCL microspheres in the gel will directly affect the quality of the product, and the uniformity of PCL microspheres Dispersion will greatly reduce the chances of lumps and foreign body granulomas.
  • CMC-Na gel has a certain thixotropy (characterized by thixotropic index), which makes CMC-Na gel suitable as a carrier material for injection.
  • the thixotropy also needs to meet certain requirements to support the tendency of the gel to be fluid when the force is applied to make the injection stable and controllable. After injection, it quickly returns to a viscous gel to maintain a uniform suspension of the microspheres and reduce precipitation aggregation. This property of CMC-Na gel plays an important role in the stable injection of injectable cosmetic products.
  • Example 6 The PCL microspheres obtained in Example 6 (taking the weight average molecular weight of 10,000 as an example) were stirred and mixed in 6 kinds of CMC-Na gels respectively, and observed under a microscope (XP-550C polarizing microscope) after standing still. Micrographs are shown in Figure 4a- Figure 4f, which correspond to No. 1-6 CMC-Na gels, respectively. As can be seen from Figure 4a and Figure 4b, No. 1 CMC-Na gel (viscosity average molecular weight is 359781, shear viscosity is 357.5) and No.
  • the measurement method is: after balancing the test sample at room temperature for 1 hour, set the test distance to full scale, start the test at a specific test speed (20mm/min, 30mm/min, 50mm/min), and record the pushing force data.
  • a specific test speed (20mm/min, 30mm/min, 50mm/min)
  • the pushing speed of 30mm/min is the ideal speed.
  • the pushing speed close to this speed can make it easier for doctors to operate easily, and on the other hand, it can ensure that the product is injected evenly when injected into the skin. . Both fast injection and slow injection will affect the injection quality and injection feeling.
  • PCL microspheres with weight average molecular weights of 10000Da and 40000Da and CMC-Na gels of 6 specifications were evenly mixed, and loaded into a syringe with a 27G needle to test their pushing force, in order to observe the microspheres after pushing.
  • Dispersion in CMC-Na gel, and some photomicrographs of injection cosmetic product fillers after extrusion are also taken, see Figure 4e'- Figure 4f'.
  • the test results show that the pushing force of No. 1-2 CMC-Na gel is relatively small at the pushing speed of 30mm/min, and the pushing force of No. 1 gel is even below 20N, which is easy for doctors to apply during actual injection >25N pushing force, so as to accelerate the injection speed and affect the injection quality.
  • No. 3-5 CMC-Na gels can reach a pushing force in the range of 25-40N at a pushing speed of 30mm/min. This pushing force is moderate and convenient for doctors to operate. Maintaining this constant pushing speed can ensure When the product is injected into the skin, the injection is uniform, so that the doctor can control the injection speed more accurately, thereby improving the doctor's injection accuracy, making the injection smoother and filling more uniform, so that the injection effect is more natural. In addition, it can significantly reduce the pain during injection, improve the comfort of injection, and reduce the swelling feeling after injection.
  • No. 6 CMC-Na gel has a pushing force of more than 40N at a pushing speed of 30mm/min. Not only will it cause fatigue to the doctor, but it will also significantly affect the doctor's control over the injection speed, making the injection fast and slow, increasing the pain during injection, and the quality of the injection drops sharply. For details, see Table 3-4.
  • the injection beauty product containing microspheres is prepared from CMC-Na with a viscosity average molecular weight of 80-1.2 million Da, a degree of substitution of 0.7-1.0, and a shear viscosity range of 40000-65000mPa.s.
  • the uniform distribution of the microspheres is not easy to cause lumps and foreign body granulomas; after being loaded into the syringe, it can be injected into the skin at a constant pushing force and pushing speed, so that the doctor can control the injection speed more accurately and fill more evenly.
  • the injection effect is more natural Of course, it also significantly reduces the pain during injection and improves the comfort of injection.

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Abstract

一种注射美容产品，所述的注射美容产品包括可降解微球和CMC-Na凝胶，所述美容产品中CMC-Na 的含量为2-3 wt.%，所述CMC-Na 凝胶中CMC-Na的粘均分子量80-120万Da，所述CMC-Na凝胶的剪切粘度范围为40000-65000mPa•s。还提供了制备所述的注射美容产品的方法以及所述的CMC-Na凝胶在制备注射美容产品中的应用。所述的CMC-Na 载体凝胶可以让微球在CMC-Na 凝胶中长期均匀悬浮，保持微球各自独立的三维结构，使得注射后微球得以在人体中均匀分布，大大减少肿块和异物肉芽肿的几率。

Description

一种注射美容产品及其制备方法和应用 技术领域
本发明涉及医疗美容或医用制剂领域，具体涉及一种注射美容产品及其制备方法和应用。
背景技术
羧甲基纤维素(Carboxymethyl Cellulose，CMC)，是由天然纤维素经过化学改性得到的一种水溶性纤维素醚。由于羧甲基纤维素酸式结构的水溶性不好，为了能够更好地对其进行应用，其产品普遍制成钠盐，分子式为[C6H7O2(OH)2OCH2COONa]n，CMC-Na为白色纤维状或颗粒状粉末，无臭、无味、有吸湿性，易于分散在水中形成透明的胶体溶液，CMC-Na具有宽泛的分子量、取代度和聚合度的聚合物，其形成的凝胶具有迥异的属性，能长期保存不腐败，粘度高，保型力强，生物相容性和成膜性能好等优点，在食品，日用品，医药等方面有广阔的应用前景。
羧甲基纤维素钠具有许多羟基和羧基，具有吸湿性并且能够吸收大量的水分，用羧甲基纤维素钠制备的水凝胶含水量高、亲水性好、溶胀率高、生物相容性好且生物可降解，被广泛应用于生物医药领域。CMC-Na凝胶具有许多水溶性高分子聚合物一样的流变性，低分子量的CMC-Na凝胶为可以流动的溶胶，粘度较小倾向于流体状，中高分子量的CMC-Na凝胶粘度较大，为半固体的假塑性流体。此外，CMC-Na凝胶还具有触变性，即凝胶在受到外力的作用下，其凝胶状态倾向转变为流动性，当机械力去除后又会回复到之前的凝胶状态。良好的触变性使得CMC-Na凝胶非常适宜作为注射用载体材料使用，因此，CMC-Na凝胶常常用作医美领域的注射美容产品。
现有市售的注射美容产品多采用较低剪切粘度的CMC-Na凝胶，其粘度较低，触变性不佳，虽然流动性能好易于配制，但是低粘度、低触变性能的CMC-Na凝胶作为微球的载体时，会使得产品中出现微米级的颗粒聚集，这一点在产品货架期储藏时更加明显。专利申请CN112999990A也记载了微球悬浮性能的提升可以减少长期贮存中微球的粘连聚集。针对可降解微球，微球数量在体内不断降解后，其浓度发生变化，容易沉降。因此，如何获得一种可降解微球在CMC-Na凝胶中分散均匀且具有较佳的触变性、 达到既能使填充微球在CMC-Na凝胶中保持均匀分布不会出现聚集，又能使注射器推挤时力量和速度均匀稳定同时避免针管堵塞的效果，是现有技术亟待解决的技术问题。
发明内容
本发明涉及一种注射美容产品，包括可降解微球和CMC-Na凝胶，CMC-Na载体凝胶可以让微球在CMC-Na凝胶中长期均匀悬浮，保持微球各自独立的三维结构，使得注射后微球得以在人体中均匀分布，大大减少肿块和异物肉芽肿的几率。我们通过研究发现，不同性质的CMC-Na凝胶中微球的分散程度显著不同，特定性质或规格的CMC-Na凝胶可以有效让微球在凝胶中均匀分散，同时将微球和CMC-Na凝胶置入注射器中注射时，推挤力适中、注射均匀且不易引起注射器堵塞。本发明通过研究，获得了一种包含可降解微球与CMC-Na凝胶，其中CMC-Na的含量为2-3wt.％，其粘均分子量80-120万Da，剪切粘度范围为40000-65000mPa·s，该产品不易导致微球的沉积、聚集以及注射器的堵塞、并且在货架期内质量稳定、使用效果好，大大降低了不良反应。
一种注射美容产品，其特征在于：包括可降解微球和CMC-Na凝胶，所述美容产品中CMC-Na的含量为2-3wt.％，CMC-Na凝胶的剪切粘度范围为10000-80000mPa·s，优选范围为30000-70000mPa·s、40000-65000mPa·s、30000-50000mPa·s；CMC-Na粘均分子量为80-120万Da，取代度(DS)的范围为：0.7-1.0、优选0.8-1.0、0.8-0.95。粘均分子量范围还可以具体优选自90万Da、95万Da、110万Da、115万Da以得到更好的即时填充效果与缓释效果的平衡。
如前所述的注射美容产品，所述可降解微球为PCL微球、PLLA微球或PLGA微球。
如前所述的注射美容产品，所述可降解微球的平均粒径范围为25-50μm。
如前所述的注射美容产品，其中还包括甘油和PBS缓冲液。
如前所述的注射美容产品，还包括注射器和针头，所述注射器中预灌装有所述的可降解微球和CMC-Na凝胶。
一种制备前述CMC-Na凝胶的方法，步骤1：向烧杯中倒入磷酸二氢盐与氢氧化钠配置好的pH为6.5-8的PBS缓冲液，把烧杯放在搅拌台上使缓冲液搅拌起来；步骤2、缓缓倒入CMC-Na，使CMC-Na与缓冲液充分接触并搅拌2-5h，直到看到凝胶中没有结块即未搅拌开的CMC-Na为止；步骤3、向凝胶中加入甘油，充分搅拌约5min；步骤4、使用真空搅拌脱泡机进行搅拌除气泡处理。
一种制备前述注射美容产品的方法，步骤1)：向烧杯中倒入磷酸二氢盐与氢氧化 钠配置好的pH为6.5-8的PBS缓冲液，把烧杯放在搅拌台上使缓冲液搅拌起来；步骤2)、缓缓倒入占美容产品填充物2-3wt.％的CMC-Na，使CMC-Na与缓冲液充分接触并搅拌2-5h，直到看到凝胶中没有结块即未搅拌开的为止；步骤3)、向凝胶中加入占美容产品填充物0.9-1.1wt.％的甘油，充分搅拌约5min；步骤4)、使用真空搅拌脱泡机进行搅拌除气泡处理；步骤5)、向凝胶中加入称量好的28-38wt.％的微球，初步搅拌后，使用真空搅拌脱泡机进行搅拌除气泡处理。
有益的技术效果：
通过检测可降解微球在各种CMC-Na凝胶中的性质(剪切粘度、触变性等)，并结合微球在CMC-Na凝胶中的分散情况以及注射美容产品的推挤力和推挤速度，最终确定粘均分子量为80-120万Da、剪切粘度为40000-65000mPa·s的CMC-Na凝胶是最适合用于注射美容产品的，微球在该性质的CMC-Na凝胶中能够均匀分散(无论是在注射前，还是在注射后)，有效减少肿块和异物肉芽肿的产生；且装入注射器推动时，推挤力和推挤速度适中，医生对注射速度更容易把控，提升了注射精准度，推注更平顺，填充更均匀。
附图说明
图1a和图1b分别为Mw＝1万Da、4万Da的PCL微球的扫描电镜照片；
图2为PLGA微球的扫描电镜照片；
图3为PLLA微球的扫描电镜照片；
图4a、图4b、图4c、图4d、图4e和图4f为负载PCL微球的6种CMC-Na凝胶的显微图片；图4e’和图4f’为负载PCL微球的5号、6号CMC-Na凝胶从注射器中挤出后的显微图片。
具体实施方式
以下通过实施例来进一步说明本发明，但并不限于此。
实施例1：PCL微球的制备
制备方法：将500mg PCL涡旋溶解于2.5ml DCM中形成油相；将所述油相一边搅拌一边逐滴加入到25ml 1％MC溶液中，再搅拌30s，利用高速剪切搅拌机14000r/min剪切1min，搅拌1000r/min3h；水洗离心3次，每次10min，预冻2h，干燥24h。
通过光学显微镜观察发现，制备的微球圆整度较好，粒径合适(参见附图1a、图 1b)。利用形态粒度分析仪(Topsizerplus)对PCL微球的粒径范围进行了分析，过程如下：
称取0.1g微球置于离心管中，加入10ml水，振荡，分散，超声处理30min，再分散到预装500mL去离子水的烧杯中，使用欧美克粒径仪Topsizerplus测定粒径，测定三次，取平均值。经检测分析，PCL微球粒径分布较为均匀，其中20～50μm微球占比约65％。优选的，小于20μm的微球占比≤1％，20-25μm的微球占比≤19％，25-50μm的微球占比≥65％，大于50μm的微球占比≤15％；更优选，小于20μm的微球占≤1％，20-25μm的微球占比≤15％，25-50μm的微球占比≥70％，大于50μm的微球占比≤14％。
实施例2：PLGA微球的制备
制备方法：将500mg PLGA涡旋溶解于2.5ml DCM中，再加入500μl内水相，涡旋5min，滴注法一边搅拌一边逐滴加入到10ml 2％PVA溶液中，再搅拌1min，再加入至150ml 0.2％PVA溶液中，搅拌2min，高速剪切搅拌机15000r/min速度剪切30s，采用1000r/min转速搅拌3h；水洗离心3次，每次10min，预冻2h，干燥24h。
由图2可见，PLGA微球光滑，圆整度好，粒径合适。经微球粒径分析，PLGA微球粒径分布较为均匀，其中20～50μm微球占比约40％。
实施例3：PLLA微球的制备
制备方法：将500mg PLLA涡旋溶解于2.5ml DCM中，加入到10ml 2％PVA溶液中，高速剪切搅拌机15000r/min转速剪切3min，再加入至150ml 0.2％PVA溶液中,搅拌1000r/min3h；水洗离心3次，每次10min，预冻2h，干燥24h。
由图3可见，PLLA微球光滑，圆整度好，分散性好，粒径合适。PLLA微球粒径分布较为均匀，其中20～50μm微球占比约32.18％。
实施例4:6种规格的CMC-Na粘均分子量的检测及CMC-Na凝胶的制备。
选取市场上6种不同规格的CMC-Na原料，所述CMC-Na分别购自亚仕兰公司(Ashland LLC.)和Sigma公司，检测上述6种规格的CMC-Na的粘均分子量，检测方法如下：
步骤一：精确称取25mg CMC-Na原料，将原料溶解在约40mL 0.2mol/L氯化钠溶液中，并将溶液在50℃下放置16小时。然后将溶液完全转移并定容至50mL。使用内径为0.53mm的乌氏粘度计和0.2mol/L氯化钠溶液作为空白对照溶液，按照《中国药典》(2020年版)第四部通则0633粘度测定法(方法2)测定粘度。
步骤二：根据式(1)和式(2)计算特性粘度[η]。
[η]＝lnηr/c      式(1)
ηr＝T/T0         式(2)
T为供试品溶液流出时间单位s，T0是空白流出时间单位为s，C是供试品溶液的浓度；
步骤三：根据公式(3)计算粘均分子量(M)，Mark Houwink公式：
[η]＝KMα          式(3)
羧甲基纤维素钠在0.2mol/L氯化钠溶液中溶解时，K＝0.043mL/g，α＝0.74，分别测得上述6种规格的CMC-Na的粘均分子量。
CMC-Na凝胶的取代度和取代度范围来自产品标签，6种规格CMC-Na凝胶的粘均分子量和取代度值如下表所述：
表1
选取6种规格的CMC-Na原料分别用于制备凝胶，制备方法如下：
步骤1、向烧杯中倒入一定量的磷酸二氢盐与氢氧化钠配置好的pH为6.5-8的PBS缓冲液，搅拌；
步骤2、缓缓倒入一定量的(终产品填充物中的占比为2-3wt.％)CMC-Na粉末，使粉末与缓冲液充分接触并搅拌2-5h，直到看到凝胶中没有结块即未搅拌开的粉末为止；
步骤3、向凝胶中加入一定量的(终产品填充物中的占比为0.9-1.1wt.％)的甘油，充分搅拌约5min；
步骤4、使用真空搅拌脱泡机进行搅拌除气泡处理，分别制备6种规格的CMC-Na凝胶。
实施例5：对6种规格的CMC-Na凝胶的剪切粘度和触变指数进行检测：
触变指数和剪切粘度的检测方法分别如下：
取凝胶样品10-20ml，采用博勒飞LV型旋转黏度计，选择合适的转子，调节温度为25±1℃，测量5.6r/min与56r/min两转速下的动力黏度，触变指数为5.6r/min与56r/min的动力黏度比值。
取4.0g羧甲基纤维素钠为原料，置于称重的250ml烧杯中，加入150ml热水，在热水浴中保持30分钟，快速搅拌，直至粉末完全湿润。冷却，加入足够的水，直到混合物总重量达到200g，静置，不时搅拌，直到完全溶解。利用旋转流变仪(BrookfieldDV2T流变仪)，加入适量样品置于测试平台上，在25℃和1s-1剪切速率的条件下，检测剪切粘度。
6种规格的CMC-Na凝胶的剪切粘度和触变指数如表2所示：
表2
实施例6PCL微球与CMC-Na凝胶混合
将称量好的28-38wt.％(在注射美容产品填充物中的占比)的PCL微球分别加入到制备好的6种CMC-Na凝胶中，加入甘油，(其中，CMC-Na在注射美容产品填充物中占比2-3wt.％，甘油占所述注射美容产品填充物的0.9-1.1wt.％)，初步搅拌后，使用真空搅拌脱泡机进行搅拌除气泡处理，以均匀混合；分别测量混合后的剪切粘度、触变指数等(见表2)。
表2显示的是1-6号CMC-Na凝胶的剪切粘度和触变指数，以及加入PCL微球后的剪切粘度和触变指数。通过表2可以看出，1号CMC-Na凝胶的剪切粘度远小于10000mPa·s，2号CMC-Na凝胶的剪切粘度在10000mPa·s左右，其剪切粘度都较低，且凝胶配制过程中也显示，1号和2号CMC-Na凝胶粘度较低，接近于液态状的流体。3-5号CMC-Na凝胶的剪切粘度在40000-65000mPa·s的范围内，触变指数在3-5之间，其粘度适中并兼具一定的流体和胶体性能。6号CMC-Na凝胶的剪切粘度在65000mPa·s以上，高达78121mPa·s。
加入PCL微球后，1-6号CMC-Na凝胶的剪切粘度和触变指数均有所改变，其中剪 切粘度明显增加，触变指数也发生变化。而1万Da和4万Da分子量的PCL微球之间差异不大。加入重均分子量为10000Da和40000Da的PCL微球后，1号和2号凝胶的剪切粘度分别在5500和20000mPa·s左右，粘度值较低，触变指数低于3，与未加入微球的凝胶相比，整体仍接近于流体状。加入PCL微球后的3、4和5号凝胶，剪切粘度有所升高，剪切粘度在60000-100000mPa·s，触变指数3-5，整体呈凝胶状，可对微球有较好的支撑(参见图4c-图4e)。6号凝胶加入微球后，剪切粘度达到了130000mPa·s左右，触变指数大于5，配制过程中可以明显感受到凝胶粘稠不易搅拌。
对于一款含有PCL微球的注射用美容产品来说，CMC-Na凝胶的选择对产品的影响很大，因为PCL微球在凝胶中的分散程度将直接影响产品质量，PCL微球均匀分散将大大减少肿块和异物肉芽肿的几率。本领域知晓，PCL微球在CMC-Na凝胶中的分散程度与CMC-Na凝胶的剪切粘度高度相关，低粘度的CMC-Na凝胶将会导致微球在流体状凝胶中沉降聚集(特别是在产品长时间储藏过程中)，过高粘度的CMC-Na凝胶会使得微球混匀困难分布不均。因此选取一定剪切粘度的CMC-Na凝胶对注射用美容产品来说是至关重要的。此外，CMC-Na凝胶还具有一定的触变性(可用触变指数来表征)，这使得CMC-Na凝胶适宜作为注射用载体材料。因为注射用美容产品需要将微球和CMC-Na凝胶装入注射器中，因此触变性也需要满足一定的要求，以支持受力时凝胶倾向为流体使得注射稳定和可控，也能在注射后迅速恢复为粘稠的凝胶状以保持对微球的均匀悬浮、减少沉淀聚集等。CMC-Na凝胶的这一性质对注射用美容产品的稳定注射具有重要作用。
实施例7显微镜观察
将实施例6得到的PCL微球(以重均分子量1万为例)分别在6种规格的CMC-Na凝胶中搅拌混匀，静置后在显微镜(XP-550C偏光显微镜)下观察。显微照片如图4a-图4f所示，其分别对应1-6号CMC-Na凝胶。通过图4a和图4b可以看出，1号CMC-Na凝胶(粘均分子量为359781，剪切粘度为357.5)和2号凝胶(粘均分子量为568455，剪切粘度为10080mPa·s)中的微球均沉降在底部并聚集成堆，这可能跟1号和2号CMC-Na凝胶更倾向于流体特性缺乏对微球的支撑有关。而根据现有资料记载，注射美容产品中微球的聚集容易导致肿块和异物肉芽肿的产生，增加炎症反应；通过图4c、图4d和图4e可以看出，3号(粘均分子量为821654，剪切粘度为40618)、4号(粘均分子量为1043366，剪切粘度为47606)、5号(粘均分子量为1143576，剪切粘度为64800)CMC-Na凝胶中的微球均能够均匀分散，且微球之间较少粘连，均一度较好， 由于能够提供足够的支撑微球在凝胶中也不会发生沉降。通过图4f可以看出，6号CMC-Na凝胶(粘均分子量为1426951，剪切粘度为78121)中的微球是不均匀分散的，这在搅拌混匀时也表现明显，微球容易散布在凝胶的各处，互相聚集，虽然进行了混匀搅拌，但是仍然很难将微球在凝胶中均匀分散，这可能跟6号凝胶的粘度较高，微球在高粘度凝胶中很难分散有关。综上，通过显微结果可以看出，3-5号规格的CMC-Na凝胶能够更好的分散微球，使其均匀分布，这对注射美容产品中减少肿块和异物肉芽肿是十分有利的。
实施例8注射器中推挤力的测定
将PCL微球和CMC-Na凝胶装入注射器中，使用HSV-1K电子式拉力试验机进行推动力的测定。测定方法为：室温下将测试样品平衡1h后，将测试距离设置为满量程，以特定测试速度(20mm/min、30mm/min、50mm/min)开始测试，记录推挤力数据。我们选取了前述三种测试速度，其中30mm/min的推挤速度是较为理想的速度，接近这一推挤速度一方面可以便于医生操作不容易失误，另一方面可以保证产品注入皮肤时注射均匀。而过快注射和过慢注射都会影响注射质量和注射体感。
分别将重均分子量为10000Da和40000Da的PCL微球以及6种规格的CMC-Na凝胶均匀混合，装入带有27G针头的注射器中测试它们的推挤力，为了观察推挤后微球在CMC-Na凝胶中的分散情况，还拍摄了部分注射美容产品填充物挤出后显微照片，参见图4e’-图4f’。测试结果显示，1-2号CMC-Na凝胶在30mm/min的推挤速度下，推挤力偏小，1号凝胶的推挤力甚至在20N以下，医生在实际注射时很容易施加＞25N的推挤力，从而加快注射速度影响注射质量。而3-5号CMC-Na凝胶在30mm/min的推挤速度下，均可以达到25-40N范围的推挤力，该推挤力适中便于医生操作，维持该恒定的推挤速度可以保证产品注入皮肤时注射均匀、使医生对注射速度把控的更加精准，从而提升医生注射精准度，推注更平顺，填充时更均匀，从而让注射效果更自然。此外还可以明显减少注射时的疼痛，提高注射的舒适度，减少注射后肿胀感。6号CMC-Na凝胶在30mm/min的推挤速度下，推挤力达到了40N以上，与1-5号凝胶相比明显需要更大的推挤力，而较大的推挤力不仅会让医生产生疲劳感，而且会明显影响医生对注射速度的把控，使得注射时快时慢，增加注射时的疼痛感，注射质量急剧下降。具体参见表3-4。

表3负载PCL微球(Mw＝1万Da)的凝胶
表4负载PCL微球(Mw＝4万Da)的凝胶
通过显微观察，3-5号凝胶在经过注射器推挤后，微球仍然能够均匀分散(因为3-5号凝胶的显微照片相似，只选了5号凝胶推挤后的显微图片，如图4e’)，可见，3-5号凝胶在去掉作用力(推挤力)后，能够很好的恢复其胶体性能，保持微球在其中的均匀分散，这可能跟它们特定的剪切粘度和触变指数有关。图4f’显示的是6号凝胶在经过注射器推挤后的图像，可以看出，PCL微球从注射器中挤出后，聚集明显，而且微球之间互相粘连，有挤压过的痕迹。
此外，为了检测PLGA和PLLA微球在CMC-Na凝胶中的效果，我们在实验中也配制了加入PLGA和PLLA微球的CMC-Na凝胶，并对它们进行相同的检测和分析，其实验结果与PCL微球类似，在此不再赘述。
综上，通过以上分析可以看出，粘均分子量为80-120万Da，取代度为0.7-1.0，剪切粘度范围为40000-65000mPa.s的CMC-Na制备的含有微球的注射美容产品，微球分布均匀不容易导致肿块和异物肉芽肿的产生；装入注射器后，能够以恒定的推挤力和推挤速度注射入皮肤，使医生对注射速度把控更精准，填充更均匀，注射效果更自 然，同时还明显减少了注射时的疼痛，提高注射的舒适度。
以上所述仅是本专利的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本专利技术原理的前提下，还可以做出若干改进和替换，这些改进和替换也应视为本专利的保护范围。

Claims (14)

  1. 一种注射美容产品，其特征在于：包括可降解微球和CMC-Na凝胶，所述美容产品中CMC-Na的含量为2-3wt.％，所述CMC-Na凝胶中CMC-Na的粘均分子量80-120万Da，所述CMC-Na凝胶的剪切粘度范围为40000-65000mPa·s。
  2. 根据权利要求1所述的注射美容产品，其特征在于：所述CMC-Na凝胶中CMC-Na的取代度的范围为：0.7-1.0。
  3. 根据权利要求1所述的注射美容产品，其特征在于：所述注射美容产品的触变指数为3-5。
  4. 根据权利要求1所述的注射美容产品，其特征在于：所述可降解微球为PCL微球、PLLA微球或PLGA微球。
  5. 根据权利要求1所述的注射美容产品，其特征在于：所述可降解微球的平均粒径范围为25-50μm。
  6. 根据权利要求1所述的注射美容产品，其特征在于：所述可降解微球的含量为28-38％。
  7. 根据权利要求1所述的注射美容产品，其特征在于：其中还包括甘油和PBS缓冲液。
  8. 根据权利要求1所述的注射美容产品，其特征在于：还包括注射器，所述注射器中预灌装有所述的可降解微球和CMC-Na凝胶。
  9. 根据权利要求1所述的注射美容产品，其特征在于：所述的CMC-Na凝胶的制备包括：
    步骤1)、向烧杯中倒入磷酸二氢盐与氢氧化钠配置好的pH为6.5-8的PBS缓冲液，均匀搅拌；
    步骤2)、将所述PBS缓冲液缓缓倒入CMC-Na，使所述CMC-Na与PBS缓冲液充分接触并搅拌2-5h；
    步骤3)、加入甘油，搅拌约5min；
    步骤4)、使用真空搅拌脱泡机进行搅拌除气泡处理。
  10. 一种制备权利要求1所述的注射美容产品的方法，其特征在于：
    步骤1)：向烧杯中倒入磷酸二氢盐与氢氧化钠配置好的pH为6.5-8的PBS缓冲液，均匀搅拌；
    步骤2)、将所述PBS缓冲液缓缓倒入CMC-Na，使所述CMC-Na与PBS缓冲液充分接触并搅拌2-5h，直到没有未搅拌开的CMC-Na为止；
    步骤3)、加入甘油，充分搅拌约5min；
    步骤4)、使用真空搅拌脱泡机进行搅拌除气泡处理；
    步骤5)、加入所述微球，初步搅拌后，使用真空搅拌脱泡机进行搅拌除气泡处理。
  11. 根据权利要求10所述的方法，其特征在于：步骤5)中，向凝胶中加入占美容产品28-38wt.％的微球。
  12. 根据权利要求10所述的方法，其特征在于：步骤2)中CMC-Na占美容产品的2-3wt.％。
  13. 根据权利要求10所述的方法，其特征在于：步骤3)甘油占美容产品的0.9-1.1wt.％。
  14. 根据权利要求1所述的CMC-Na凝胶在制备注射美容产品中的应用，其特征在于：所述的注射美容产品包括可降解微球和CMC-Na凝胶。
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