WO2022205645A1 - Injectable dermal filler and preparation method therefor - Google Patents
Injectable dermal filler and preparation method therefor Download PDFInfo
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- WO2022205645A1 WO2022205645A1 PCT/CN2021/103197 CN2021103197W WO2022205645A1 WO 2022205645 A1 WO2022205645 A1 WO 2022205645A1 CN 2021103197 W CN2021103197 W CN 2021103197W WO 2022205645 A1 WO2022205645 A1 WO 2022205645A1
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- dermal filler
- sodium hyaluronate
- mixed solution
- suspension
- dispersant
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- 229920002385 Sodium hyaluronate Polymers 0.000 claims abstract description 81
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Abstract
An injectable dermal filler, comprising the following raw materials: a polyester material, sodium hyaluronate, and a dispersant. The polyester material is selected from one or more of polycaprolactone, poly-L-lactic acid, poly-D-lactic acid, polyglycolic acid, and polyhydroxyalkanoate; the dispersant is mannitol and amino acid; and the amino acid is selected from one or more of glycine, alanine, valine, leucine, isoleucine, proline, serine, phenylalanine, tryptophan, and histidine. A preparation method for the dermal filler.
Description
相关申请的交叉引用CROSS-REFERENCE TO RELATED APPLICATIONS
本申请基于申请号为202110360171.5、申请日为2021年04月07日、名称为“一种可注射的皮肤填充剂及其制备方法”的中国专利申请提出,并要求中国专利申请的优先权,该中国专利申请的全部内容在此引入本申请作为参考。This application is based on the Chinese patent application with the application number of 202110360171.5 and the application date of April 7, 2021, entitled "An injectable dermal filler and its preparation method", and claims the priority of the Chinese patent application. The entire contents of the Chinese patent application are incorporated herein by reference.
本申请涉及医学美容技术领域,具体地涉及一种可注射的皮肤填充剂及其制备方法。The present application relates to the technical field of medical cosmetology, in particular to an injectable dermal filler and a preparation method thereof.
注射软组织填充剂是皮肤皱纹与凹陷填充的微创疗法,市场上出现的软组织填充剂主要有交联透明质酸钠凝胶、胶原蛋白、聚乳酸以及羟基磷灰石钙等。其中交联透明质酸钠凝胶和胶原蛋白在皮肤内的作用时间为6~12个月,聚乳酸和羟基磷灰石钙在皮肤内的作用时间大约有2年以上。Injection of soft tissue fillers is a minimally invasive treatment for skin wrinkles and sag filling. Soft tissue fillers on the market mainly include cross-linked sodium hyaluronate gel, collagen, polylactic acid and calcium hydroxyapatite. Among them, the action time of cross-linked sodium hyaluronate gel and collagen in the skin is 6 to 12 months, and the action time of polylactic acid and calcium hydroxyapatite in the skin is about more than 2 years.
聚酯类材料如聚乳酸、聚己内酯等,具有良好的生物相容性、抗凝血性、无毒和低免疫性等优点,因此被广泛应用于生物医药和组织工程领域。近30年的研究表明,聚酯类材料及其单体都具有良好的组织相容性,聚酯类材料在生理环境中可水解降解成低分子量碎片,而低分子量碎片可被巨噬细胞内吞并在细胞内降解。其中聚乳酸和聚己内酯作为皮肤填充剂的原料,已经有含有聚乳酸和/或聚己内酯的多个产品应用于皮肤皱纹和凹陷的填充,其主要的形态为聚乳酸微粒、聚乳酸微球和聚己内酯微球等。Polyester materials such as polylactic acid, polycaprolactone, etc., have the advantages of good biocompatibility, anticoagulation, non-toxicity and low immunity, so they are widely used in the fields of biomedicine and tissue engineering. Research in the past 30 years has shown that polyester materials and their monomers have good histocompatibility. Polyester materials can be hydrolyzed and degraded into low molecular weight fragments in a physiological environment, and low molecular weight fragments can be absorbed by macrophages. phagocytosis is degraded intracellularly. Among them, polylactic acid and polycaprolactone are used as the raw materials of dermal fillers, and many products containing polylactic acid and/or polycaprolactone have been used to fill skin wrinkles and depressions. Lactic acid microspheres and polycaprolactone microspheres, etc.
现有的常规乳化方法在制备微粒时,采用了较大毒性的乳化剂,因此需要后处理除去,然后通过干燥分离的方式得到微粒,最后将微粒和其它分散剂或悬浮剂进行混合分散,得到皮肤填充剂,制备过程比较繁琐。The existing conventional emulsification method adopts a relatively toxic emulsifier when preparing the microparticles, so it needs to be removed after post-treatment, and then the microparticles are obtained by drying and separation, and finally the microparticles and other dispersants or suspending agents are mixed and dispersed to obtain Dermal fillers, the preparation process is complicated.
发明内容SUMMARY OF THE INVENTION
针对现有技术存在的问题,本申请提供一种可注射的皮肤填充剂及其制备方法,能够简化皮肤填充剂的制备过程。In view of the problems existing in the prior art, the present application provides an injectable dermal filler and a preparation method thereof, which can simplify the preparation process of the dermal filler.
本申请在第一方面提供了一种可注射的皮肤填充剂,所述皮肤填充剂包括如下质量百分数的原料:聚酯类材料,透明质酸钠,分散剂。In a first aspect, the present application provides an injectable dermal filler, the dermal filler includes the following raw materials by mass percentage: polyester material, sodium hyaluronate, and dispersant.
进一步,所述聚酯类材料20%~80%,透明质酸钠10%~40%,分散剂10%~60%;所述皮肤填充剂是由透明质酸钠和分散剂包裹在聚酯类材料表面而形成的微粒。Further, the polyester material is 20% to 80%, the sodium hyaluronate is 10% to 40%, and the dispersant is 10% to 60%; the skin filler is made of sodium hyaluronate and dispersant wrapped in polyester particles formed on the surface of similar materials.
进一步,所述的皮肤填充剂还包括水;聚酯类微粒5%~20%,透明质酸钠1%~5%,分散剂2%~10%和水65%~90%;所述皮肤填充剂是由聚酯类微粒在透明质酸钠和分散剂中形成的混悬液。Further, the dermal filler also includes water; 5% to 20% of polyester microparticles, 1% to 5% of sodium hyaluronate, 2% to 10% of dispersant and 65% to 90% of water; the skin The filler is a suspension of polyester microparticles in sodium hyaluronate and a dispersant.
这里的微粒可以是球状、不规则形状或棒状等。The microparticles here may be spherical, irregular, rod-like, or the like.
进一步,所述分散剂为氨基酸或甘露醇。Further, the dispersing agent is amino acid or mannitol.
进一步,所述分散剂为甘露醇和氨基酸;更进一步,所述氨基酸在所述皮肤填充剂中的质量百分数为2%~50%。所述甘露醇在所述皮肤填充剂中的质量百分数为2%~50%。Further, the dispersing agent is mannitol and amino acid; further, the mass percentage of the amino acid in the dermal filler is 2% to 50%. The mass percentage of the mannitol in the dermal filler is 2% to 50%.
进一步,所述聚酯类材料选自聚己内酯、聚左旋乳酸、聚右旋乳酸、聚羟基乙酸和聚羟基烷酸酯中的一种或多种;更进一步,所述聚酯类材料的特性粘度为0.2~5.0dL/g;再进一步,所述聚酯类材料的粒径为0.01~200μm。Further, the polyester-based material is selected from one or more of polycaprolactone, poly-L-lactic acid, poly-D-lactic acid, polyglycolic acid and polyhydroxyalkanoate; further, the polyester-based material The intrinsic viscosity of the polyester material is 0.2-5.0 dL/g; further, the particle size of the polyester-based material is 0.01-200 μm.
进一步,所述氨基酸选自甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、丝氨酸、苯丙氨酸、色氨酸和组氨酸中的一种或多种。Further, the amino acid is selected from one or more of glycine, alanine, valine, leucine, isoleucine, proline, serine, phenylalanine, tryptophan and histidine kind.
进一步,所述透明质酸钠的特性粘度为0.5~4.0m
3/kg。
Further, the intrinsic viscosity of the sodium hyaluronate is 0.5 to 4.0 m 3 /kg.
本申请在第二方面提供了一种如第一方面所述皮肤填充剂的制备方法,该制备方法包括如下步骤:步骤一:将透明质酸钠和分散剂溶于水中,配制成第一混合液;步骤二:将聚酯类材料溶于有机溶剂中,配制成第二混合液;步骤三:将所述第二混合液快速加入所述第一混合液中,并充分乳化,得到水包油 的乳化液;步骤四:将所述水包油的乳化液进行脱溶剂得到混悬液;步骤五:将所述悬浮液进行冻干处理,得到聚酯类微粒。The present application provides, in a second aspect, a method for preparing a dermal filler as described in the first aspect, the preparation method comprising the following steps: Step 1: dissolving sodium hyaluronate and a dispersant in water, and preparing a first mixture Step 2: Dissolve the polyester material in an organic solvent to prepare a second mixed solution; Step 3: Quickly add the second mixed solution to the first mixed solution, and fully emulsify to obtain a water-in-water solution oil emulsion; step 4: desolventizing the oil-in-water emulsion to obtain a suspension; step 5: lyophilizing the suspension to obtain polyester microparticles.
进一步,所述有机溶剂为乙酸乙酯、三氯甲烷、甲苯和二氯甲烷中的一种;更进一步,所述有机溶剂为二氯甲烷或三氯甲烷。Further, the organic solvent is one of ethyl acetate, chloroform, toluene and dichloromethane; further, the organic solvent is dichloromethane or chloroform.
进一步,在所述步骤三中,所述第一混合液和所述第二混合液的体积比为1~20:1;更进一步,在所述步骤四中,所述脱溶剂的温度为20~50℃。Further, in the step 3, the volume ratio of the first mixed solution and the second mixed solution is 1-20:1; further, in the step 4, the temperature of the desolvation is 20 ~50°C.
本申请实施例与现有技术相比至少具有如下有益效果:Compared with the prior art, the embodiments of the present application have at least the following beneficial effects:
1、本申请实施例通过采用生物相容性更好的透明质酸钠作为聚酯类微粒的乳化剂,不需要除去乳化剂的过程,在制备后期将透明质酸钠继续作为悬浮剂,由此不仅能够对皮肤细胞进行有效修复,而且还能够避免现有技术中采用聚乙烯醇等作为制备微粒的乳化剂所产生的除杂质过程。1. In the examples of this application, by using sodium hyaluronate with better biocompatibility as the emulsifier of polyester microparticles, the process of removing the emulsifier is not required, and sodium hyaluronate will continue to be used as a suspending agent in the later stage of preparation, and the This can not only effectively repair skin cells, but also avoid the process of removing impurities caused by using polyvinyl alcohol and the like as emulsifiers for preparing microparticles in the prior art.
2、本申请实施例将聚酯类材料的溶液,以及透明质酸钠和分散剂配制的水溶液混合后,通过普通搅拌或乳化机对混合液进行乳化处理,形成水包油的乳化液,之后对乳化液进行真空干燥,以去除乳化液中的有机溶剂和部分水,得到混悬液;该混悬液可以用作皮肤填充剂。相对于现有采用乳化法制备微粒技术,本申请实施例不仅省去了脱除乳化剂与微粒干燥的过程,而且还省去了微粒再分散的过程。由此,本申请实施例能够实现微粒制备和皮肤填充剂制备同步进行,简化了制备过程。2. In the examples of this application, after mixing the solution of polyester material and the aqueous solution prepared by sodium hyaluronate and dispersant, the mixed solution is emulsified by ordinary stirring or emulsifier to form an oil-in-water emulsion, and then The emulsion is vacuum dried to remove the organic solvent and part of the water in the emulsion to obtain a suspension; the suspension can be used as a dermal filler. Compared with the existing technology for preparing microparticles by emulsification, the embodiments of the present application not only save the process of removing the emulsifier and drying the microparticles, but also save the process of redispersing the microparticles. Therefore, in the embodiments of the present application, the preparation of microparticles and the preparation of the dermal filler can be performed simultaneously, which simplifies the preparation process.
3、本申请实施例制备的皮肤填充剂不仅适合真皮深层和皮下组织注射以填充较深的皱纹和凹陷,还适合真皮浅层水光注射以填充较浅的皱纹。3. The dermal fillers prepared in the examples of the present application are not only suitable for deep dermis and subcutaneous tissue injection to fill deep wrinkles and depressions, but also suitable for superficial dermal water light injection to fill shallow wrinkles.
4、本申请实施例的皮肤填充剂能够作为长效水光针使用。4. The dermal fillers of the embodiments of the present application can be used as long-acting water light needles.
附图是用来提供对本申请实施例的进一步理解,并且构成说明书的一部分,与下面的具体实施方式一起用于解释本申请实施例,但并不构成对本申请实施例的限制。在附图中:The accompanying drawings are used to provide further understanding of the embodiments of the present application, and constitute a part of the specification, and are used to explain the embodiments of the present application together with the following specific embodiments, but do not constitute limitations to the embodiments of the present application. In the attached image:
图1是本申请实施例1中聚左旋乳酸微粒的扫描电镜图;Fig. 1 is the scanning electron microscope picture of poly-L-lactic acid microparticles in the embodiment 1 of the present application;
图2是本申请实施例2中聚左旋乳酸微粒的扫描电镜图;Fig. 2 is the scanning electron microscope image of poly-L-lactic acid microparticles in the embodiment 2 of the application;
图3是本申请实施例3中聚已内酯微粒的扫描电镜图;Fig. 3 is the scanning electron microscope picture of polycaprolactone microparticles in the embodiment 3 of the present application;
图4是本申请实施例4中聚乳酸-聚已内酯-聚乳酸微粒的扫描电镜图;4 is a scanning electron microscope image of polylactic acid-polycaprolactone-polylactic acid particles in Example 4 of the present application;
图5是本申请实施例5中聚L-乳酸-羟基乙酸微粒的扫描电镜图;5 is a scanning electron microscope image of poly-L-lactic acid-glycolic acid particles in Example 5 of the present application;
图6是本申请实施例6中聚已内酯微粒的扫描电镜图。6 is a scanning electron microscope image of polycaprolactone microparticles in Example 6 of the present application.
为使本申请的目的、技术方案和优点更加清楚,下面将结合本申请实施例,对本申请的技术方案进行清楚、完整地描述。显然,所描述的实施例是本申请的一部分实施例,而不是全部的实施例。基于本申请中的实施例,本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例,都属于本申请保护的范围。In order to make the objectives, technical solutions and advantages of the present application clearer, the technical solutions of the present application will be clearly and completely described below with reference to the embodiments of the present application. Obviously, the described embodiments are some, but not all, embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative work shall fall within the protection scope of the present application.
本申请实施例在第一方面提供一种可注射的皮肤填充剂,所述皮肤填充剂包括如下质量百分数的原料:聚酯类材料,透明质酸钠,分散剂。The embodiments of the present application provide, in a first aspect, an injectable dermal filler, the dermal filler comprising the following raw materials by mass percentage: polyester material, sodium hyaluronate, and a dispersant.
本申请实施例采用透明质酸钠作为聚酯类微粒的乳化剂和悬浮剂,由于透明质酸钠是可降解和生物相容的,因此不需要除去透明质酸钠,也不需要额外加入悬浮剂,避免了使用其它乳化剂所造成的有害物质残留,从而相对现有技术省略了除杂质、微粒再分散等过程,简化了皮肤填充剂的制备过程;由于透明质酸钠能够修复皮肤细胞,因此透明质酸钠还可以作为皮肤填充剂的功能性原料,促进表皮细胞增殖和分化以及清除氧自由基,从而防止皮肤老化。In the examples of this application, sodium hyaluronate is used as the emulsifier and suspending agent for polyester microparticles. Since sodium hyaluronate is degradable and biocompatible, there is no need to remove sodium hyaluronate or add additional suspension. It avoids the residue of harmful substances caused by the use of other emulsifiers, thus omitting the process of removing impurities and particle redispersion compared with the prior art, and simplifying the preparation process of dermal fillers; because sodium hyaluronate can repair skin cells, Therefore, sodium hyaluronate can also be used as a functional raw material for dermal fillers, promoting the proliferation and differentiation of epidermal cells and scavenging oxygen free radicals, thereby preventing skin aging.
在进一步的实施例中,聚酯类材料20%~80%,透明质酸钠10%~40%,分散剂10%~60%;所述皮肤填充剂是由透明质酸钠和分散剂包裹在聚酯类材料表面而形成的微粒。In a further embodiment, 20% to 80% of polyester material, 10% to 40% of sodium hyaluronate, and 10% to 60% of dispersant; the dermal filler is wrapped by sodium hyaluronate and dispersant Microparticles formed on the surface of polyester materials.
在进一步的实施例中,所述皮肤填充剂,包括如下质量百分数的原料:聚酯类微粒5%~20%,透明质酸钠1%~5%,分散剂2%~10%和水65%~90%;所 述皮肤填充剂是由聚酯类微粒在透明质酸钠和分散剂中形成的混悬液。In a further embodiment, the dermal filler includes the following raw materials by mass percentage: 5% to 20% of polyester microparticles, 1% to 5% of sodium hyaluronate, 2% to 10% of dispersant and 65% of water. % to 90%; the skin filler is a suspension formed by polyester microparticles in sodium hyaluronate and a dispersant.
本申请实施例的皮肤填充剂在临床使用时是以混悬液状态去使用,例如当皮肤填充剂是冻干粉状态时,则将冻干粉的皮肤填充剂复溶形成混悬液来使用;或者将制备过程中O/W的乳化液进行真空干燥后得到的混悬液直接用于临床使用。The dermal fillers of the embodiments of the present application are used in the state of suspension during clinical use. For example, when the dermal fillers are in the state of freeze-dried powder, the dermal filler of the freeze-dried powder is reconstituted to form a suspension for use. Or the suspension obtained after vacuum drying of the O/W emulsion in the preparation process is directly used for clinical use.
本申请实施例采用透明质酸钠作为聚酯类微粒的乳化剂和悬浮剂,由于透明质酸钠是可降解和生物相容的,因此不需要除去透明质酸钠,也不需要额外加入悬浮剂,避免了使用其它乳化剂所造成的有害物质残留,从而相对现有技术省略了除杂质、微粒再分散等过程,简化了皮肤填充剂的制备过程;由于透明质酸钠能够修复皮肤细胞,因此透明质酸钠还可以作为皮肤填充剂的功能性原料,促进表皮细胞增殖和分化以及清除氧自由基,从而防止皮肤老化。In the examples of this application, sodium hyaluronate is used as the emulsifier and suspending agent for polyester microparticles. Since sodium hyaluronate is degradable and biocompatible, there is no need to remove sodium hyaluronate or add additional suspension. It avoids the residue of harmful substances caused by the use of other emulsifiers, thus omitting the process of removing impurities and particle redispersion compared with the prior art, and simplifying the preparation process of dermal fillers; because sodium hyaluronate can repair skin cells, Therefore, sodium hyaluronate can also be used as a functional raw material for dermal fillers, promoting the proliferation and differentiation of epidermal cells and scavenging oxygen free radicals, thereby preventing skin aging.
在进一步的实施例中,所述分散剂为甘露醇或氨基酸;由此,通过采用甘露醇或氨基酸作为分散剂,不仅能够将第二混合液中的聚酯类材料进行均匀分散;而且还能够在体内被降解掉,减少了皮肤填充剂后分散的过程。In a further embodiment, the dispersing agent is mannitol or amino acid; thus, by using mannitol or amino acid as the dispersing agent, not only can the polyester material in the second mixed solution be uniformly dispersed; but also It is degraded in the body, reducing the process of dispersing after dermal fillers.
在进一步的实施例中,所述甘露醇在所述皮肤填充剂中的质量百分数为2%~50%,所述氨基酸在所述皮肤填充剂中的质量百分数为2%~50%。由此,通过将甘露醇和氨基酸同时作为分散剂,能够对第二混合液中聚酯类材料实现快速分散。另外,在皮肤填充剂中添加氨基酸,氨基酸不仅作为分散剂,而且还作为功能性原料,能够提高皮肤填充剂的美容效果。In a further embodiment, the mass percentage of the mannitol in the dermal filler is 2% to 50%, and the mass percentage of the amino acid in the dermal filler is 2% to 50%. Thus, by using mannitol and amino acid as dispersants at the same time, rapid dispersion of the polyester-based material in the second mixed solution can be achieved. In addition, adding amino acids to dermal fillers can improve the cosmetic effect of dermal fillers as not only dispersants but also functional raw materials.
在进一步的实施例中,所述聚酯类材料选自聚左旋乳酸、聚右旋乳酸、聚羟基乙酸、聚羟基烷酸酯和聚己内酯中的一种或多种。本申请实施例采用聚酯类材料作为主要成分,不仅能够延长皮肤填充剂的降解时间,还能够对皮肤皱纹和凹陷进行有效填充。In a further embodiment, the polyester-based material is selected from one or more of poly-L-lactic acid, poly-D-lactic acid, polyglycolic acid, polyhydroxyalkanoate and polycaprolactone. The embodiment of the present application uses polyester material as the main component, which can not only prolong the degradation time of the dermal filler, but also effectively fill skin wrinkles and depressions.
在进一步的实施例中,所述聚酯类材料的特性粘度为0.2~5.0dL/g。由此,通过选择合适的特性粘度的聚酯类材料,能够有效控制皮肤填充剂的降解速度, 从而提高皮肤填充剂的美容效果。In a further embodiment, the intrinsic viscosity of the polyester-based material is 0.2-5.0 dL/g. Therefore, by selecting a polyester-based material with an appropriate intrinsic viscosity, the degradation rate of the dermal filler can be effectively controlled, thereby improving the cosmetic effect of the dermal filler.
在进一步的实施例中,所述聚酯类材料的粒径为0.01~200μm。由此,通过选择合适粒径的聚酯类材料,不仅能够对皮下组织的凹陷和皱纹进行有效填充,而且能够在注射时能够实现快速推挤,避免推挤困难。In a further embodiment, the particle size of the polyester material is 0.01-200 μm. Therefore, by selecting a polyester material with an appropriate particle size, not only can the depressions and wrinkles of the subcutaneous tissue be effectively filled, but also rapid pushing can be achieved during injection, avoiding difficulty in pushing.
在进一步的实施例中,所述氨基酸选自甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、丝氨酸、苯丙氨酸、色氨酸和组氨酸中的一种或多种。由此,通过添加氨基酸,不仅能够对聚酯类材料的混合液进行有效分散,而且能够提高皮肤填充剂的美容效果。In a further embodiment, the amino acid is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, proline, serine, phenylalanine, tryptophan and histidine one or more of. Thus, by adding the amino acid, not only can the mixed solution of the polyester-based material be effectively dispersed, but also the cosmetic effect of the dermal filler can be improved.
在进一步的实施例中,所述透明质酸钠的特性粘度为0.5~4.0m
3/kg。由此,通过选择合适特性粘度的透明质酸钠,能够控制皮肤填充剂的预期降解时间。
In a further embodiment, the intrinsic viscosity of the sodium hyaluronate is 0.5-4.0 m 3 /kg. Thus, by selecting the appropriate intrinsic viscosity of sodium hyaluronate, the expected degradation time of the dermal filler can be controlled.
本申请实施例制备的皮肤填充剂可用于面部皱纹、手部皱纹、颈部皱纹、妊娠纹等皱纹的填充纠正。The dermal fillers prepared in the examples of the present application can be used for filling and correcting wrinkles such as facial wrinkles, hand wrinkles, neck wrinkles, and stretch marks.
本申请实施例在第二方面提供了由本申请实施例在第一方面所述皮肤填充剂的制备方法。该方法包括步骤一:将透明质酸钠和分散剂溶于水中,配制成第一混合液;步骤二:将聚酯类材料溶于有机溶剂中,配制成第二混合液;步骤三:将所述第二混合液快速加入所述第一混合液中,并充分乳化,得到水包油的乳化液;步骤四:将所述水包油的乳化液进行脱溶剂得到混悬液;步骤五:将所述悬浮液进行冻干处理,得到微粒。In a second aspect, the embodiments of the present application provide the preparation method of the dermal filler described in the first aspect of the embodiments of the present application. The method includes step 1: dissolving sodium hyaluronate and dispersant in water to prepare a first mixed solution; step 2: dissolving polyester materials in an organic solvent to prepare a second mixed solution; step 3: mixing The second mixed solution is quickly added to the first mixed solution, and fully emulsified to obtain an oil-in-water emulsion; step 4: desolventize the oil-in-water emulsion to obtain a suspension; step 5 : The suspension is lyophilized to obtain microparticles.
本申请实施例通过将透明质酸钠和分散剂溶解在水中获得第一混合液;并将聚酯类材料溶解在有机溶剂中获得第二混合液;之后将第二混合液快速加入第一混合液中进行乳化处理,并将乳化处理后的乳化液进行脱溶剂得到混悬液。相对于现有制备微粒技术,省去了脱除乳化剂与微粒干燥的过程,能够实现微粒制备和皮肤填充剂制备同步进行,简化了制备过程。In the examples of the present application, a first mixed solution is obtained by dissolving sodium hyaluronate and a dispersant in water; a second mixed solution is obtained by dissolving the polyester material in an organic solvent; and then the second mixed solution is quickly added to the first mixed solution The emulsification treatment is carried out in the liquid, and the emulsified liquid after the emulsification treatment is desolvated to obtain a suspension. Compared with the existing technology for preparing microparticles, the process of removing the emulsifier and drying the microparticles is omitted, and the preparation of microparticles and the preparation of the dermal filler can be performed simultaneously, which simplifies the preparation process.
在进一步的实施例中,所述有机溶剂为乙酸乙酯、三氯甲烷、甲苯和二氯甲烷中的一种;由此,能够在对聚酯类材料进行有效的溶解。在更进一步的实施例中,所述有机溶剂为三氯甲烷或二氯甲烷。由此,能够提高皮肤填充剂 的安全性。In a further embodiment, the organic solvent is one of ethyl acetate, chloroform, toluene and dichloromethane; thus, the polyester material can be effectively dissolved. In a further embodiment, the organic solvent is chloroform or dichloromethane. Thereby, the safety of the dermal filler can be improved.
在进一步的实施例中,在所述步骤三中,所述第一混合液和所述第二混合液的体积比为1~20:1;在更进一步的实施例中,所述第一混合液和所述第二混合液的体积比为3~15:1;由此,能够有效获得油包水的乳化液。In a further embodiment, in the step 3, the volume ratio of the first mixed solution and the second mixed solution is 1-20:1; in a further embodiment, the first mixed solution The volume ratio of the liquid to the second mixed liquid is 3 to 15:1; thus, a water-in-oil emulsion can be effectively obtained.
在进一步的实施例中,在所述步骤四中,所述脱溶剂的温度为20~50℃。In a further embodiment, in the step 4, the temperature of the desolvation is 20-50°C.
另外注意的是,如果没有特别说明,本申请所记载的任何范围包括端值以及端值之间的任何数值以及以端值或者端值之间的任意数值所构成的任意子范围。It is also noted that, unless otherwise specified, any range recited in this application includes the endpoints and any values between the endpoints and any sub-ranges formed by the endpoints or any numbers between the endpoints.
实施例1Example 1
一种可注射的皮肤填充剂,包括如下质量百分数的原料:聚左旋乳酸35.6%,透明质酸钠23.7%,甘露醇40.7%;皮肤填充剂是由透明质酸钠和甘露醇包裹在聚左旋乳酸表面而形成的微粒。An injectable dermal filler, comprising the following raw materials by mass percentage: poly-L-lactic acid 35.6%, sodium hyaluronate 23.7%, mannitol 40.7%; the dermal filler is wrapped in poly-L-lactic acid by sodium hyaluronate and mannitol. particles formed on the surface of lactic acid.
具体制备方法如下:The specific preparation method is as follows:
步骤一:将特性粘度为0.9m
3/kg的透明质酸钠溶于水中,制取透明质酸钠水溶液,其中透明质酸钠水溶液中透明质酸钠与水的质量百分比为1%。向透明质酸钠水溶液中加入10.3g甘露醇,并搅拌溶解,得到第一混合液;其中第一混合液是水相。
Step 1: dissolving sodium hyaluronate with an intrinsic viscosity of 0.9 m 3 /kg in water to prepare a sodium hyaluronate aqueous solution, wherein the mass percentage of sodium hyaluronate and water in the sodium hyaluronate aqueous solution is 1%. 10.3 g of mannitol was added to the sodium hyaluronate aqueous solution, and the mixture was stirred and dissolved to obtain a first mixed solution; wherein the first mixed solution was an aqueous phase.
步骤二:称取特性粘度为1.5dL/g的聚左旋乳酸9g,溶于100mL的二氯甲烷中,配制成第二混合液;其中第二混合液是油相。Step 2: Weigh 9 g of poly-L-lactic acid with an intrinsic viscosity of 1.5 dL/g, dissolve it in 100 mL of dichloromethane, and prepare a second mixed solution; wherein the second mixed solution is an oil phase.
步骤三:将第二混合液快速加入第一混合液中,并利用乳化机在转速为2000r/min的条件下乳化3min,得到O/W的乳化液。Step 3: Quickly add the second mixed solution to the first mixed solution, and use an emulsifier to emulsify for 3 minutes at a rotational speed of 2000 r/min to obtain an O/W emulsion.
步骤四:将乳化液在30~50℃的条件下脱除溶剂和部分水分,得到混悬液;将混悬液分成多份,分别置于西林瓶中,冻干48h得到皮肤填充剂。Step 4: remove the solvent and part of the water from the emulsion at 30-50° C. to obtain a suspension; divide the suspension into multiple portions, place them in vials, and freeze-dry for 48 hours to obtain a dermal filler.
复溶试验:向制得的皮肤填充剂中加入4毫升注射用水,轻轻摇晃20秒即可复溶,得到混悬液;将混悬液静置10min即可除去溶液中的气泡。由此可知,本实施的皮肤填充剂复溶时间短。Reconstitution test: add 4 ml of water for injection to the prepared dermal filler, shake gently for 20 seconds to reconstitute to obtain a suspension; let the suspension stand for 10 minutes to remove air bubbles in the solution. From this, it can be seen that the reconstitution time of the dermal filler of the present embodiment is short.
推挤力测试:用1毫升注射器抽取静置后的混悬液,加30G针头,采用微机控制电子万能试验机检测该皮肤填充剂的推挤力,根据检测结果可知,推挤力平均值在5N~10N。由此可知,采用本实施例的皮肤填充剂可实现顺利推挤。Pushing force test: Use a 1 ml syringe to extract the suspension after standing, add a 30G needle, and use a microcomputer-controlled electronic universal testing machine to test the pushing force of the dermal filler. According to the test results, the average pushing force is 5N~10N. It can be seen from this that the dermal filler of this embodiment can achieve smooth pushing.
聚左旋乳酸微粒的粒径大小:将静置后的混悬液经水洗干燥后,采用扫描电子显微镜观察微粒的形貌,并测试微粒的粒径大小,如图1所示,聚左旋乳酸微粒的粒径为2~34μm。由此可知,本申请聚左旋乳酸微粒形貌和粒径大小均匀,不仅适合真皮深层和皮下组织注射以填充较深的皱纹和凹陷,还适合真皮浅层水光注射以填充较浅的皱纹。The particle size of the poly-L-lactic acid particles: After the suspension after standing is washed and dried, the morphology of the particles is observed with a scanning electron microscope, and the particle size of the particles is tested. As shown in Figure 1, the poly-L-lactic acid particles The particle size is 2 to 34 μm. It can be seen that the morphology and particle size of the poly-L-lactic acid particles of the present application are uniform, and it is not only suitable for deep dermis and subcutaneous tissue injection to fill deep wrinkles and depressions, but also suitable for superficial dermal water light injection to fill shallow wrinkles.
实施例2Example 2
一种可注射的皮肤填充剂,包括如下质量百分数的原料:聚左旋乳酸48.0%,透明质酸钠20.0%,甘氨酸32.0%;皮肤填充剂是由透明质酸钠和甘氨酸包裹在聚左旋乳酸表面而形成的微粒。An injectable dermal filler, comprising the following raw materials by mass percentage: poly-L-lactic acid 48.0%, sodium hyaluronate 20.0%, glycine 32.0%; the dermal filler is wrapped on the surface of poly-L-lactic acid by sodium hyaluronate and glycine particles formed.
具体制备方法如下:The specific preparation method is as follows:
步骤一:将特性粘度为2.1m
3/kg的透明质酸钠溶于水中,制取透明质酸钠水溶液,其中透明质酸钠水溶液中透明质酸钠与水的质量百分比为0.5%。向透明质酸钠水溶液中加入4.0g的甘氨酸,并搅拌溶解,得到第一混合液;其中第一混合液是水相。
Step 1: dissolving sodium hyaluronate with an intrinsic viscosity of 2.1 m 3 /kg in water to prepare a sodium hyaluronate aqueous solution, wherein the mass percentage of sodium hyaluronate and water in the sodium hyaluronate aqueous solution is 0.5%. 4.0 g of glycine was added to the sodium hyaluronate aqueous solution, and the mixture was stirred and dissolved to obtain a first mixed solution; wherein the first mixed solution was an aqueous phase.
步骤二:称取特性粘度为1.8dL/g的聚左旋乳酸6g,溶于80mL的三氯甲烷中,配制成第二混合液;其中第二混合液是油相。Step 2: Weigh 6 g of poly-L-lactic acid with an intrinsic viscosity of 1.8 dL/g, dissolve it in 80 mL of chloroform, and prepare a second mixed solution; wherein the second mixed solution is an oil phase.
步骤三:将第二混合液快速加入第一混合液中,并利用乳化机在转速为2500r/min的条件下乳化2min,得到O/W的乳化液。Step 3: Quickly add the second mixed solution to the first mixed solution, and use an emulsifier to emulsify for 2 minutes at a rotational speed of 2500 r/min to obtain an O/W emulsion.
步骤四:将乳化液在20~50℃的条件下脱除溶剂和部分水分,得到混悬液;将混悬液分成多份,分别置于西林瓶中,冻干48h得到皮肤填充剂。Step 4: remove the solvent and part of the water from the emulsion at 20-50° C. to obtain a suspension; divide the suspension into multiple portions, place them in vials, and freeze-dry for 48 hours to obtain a dermal filler.
复溶试验:向制得的皮肤填充剂中加入4毫升注射用水,轻轻摇晃25秒即可复溶,得到混悬液;将混悬液静置10min即可除去溶液中的气泡。由此可知,本实施的皮肤填充剂复溶时间短。Reconstitution test: add 4 ml of water for injection to the prepared dermal filler, shake gently for 25 seconds to reconstitute to obtain a suspension; let the suspension stand for 10 minutes to remove air bubbles in the solution. From this, it can be seen that the reconstitution time of the dermal filler of the present embodiment is short.
推挤力测试:用1毫升注射器抽取静置后的混悬液,加30G针头,采用微机控制电子万能试验机检测该皮肤填充剂的推挤力,根据检测结果可知,推挤力平均值在5N~10N。由此可知,采用本实施例的皮肤填充剂可实现顺利推挤。Pushing force test: Use a 1 ml syringe to extract the suspension after standing, add a 30G needle, and use a microcomputer-controlled electronic universal testing machine to test the pushing force of the dermal filler. According to the test results, the average pushing force is 5N~10N. It can be seen from this that the dermal filler of this embodiment can achieve smooth pushing.
聚左旋乳酸微粒的粒径大小:将静置后的混悬液经水洗干燥后,采用扫描电子显微镜观察微粒的形貌,并测试微粒的粒径大小,如图2所示,聚左旋乳酸微粒的粒径为2~32μm。The particle size of the poly-L-lactic acid particles: After the suspension after standing is washed and dried, the morphology of the particles is observed with a scanning electron microscope, and the particle size of the particles is tested. As shown in Figure 2, the poly-L-lactic acid particles The particle size is 2 to 32 μm.
实施例3Example 3
一种可注射的皮肤填充剂,包括如下质量百分数的原料:聚已内酯5.3%,透明质酸钠3.4%,丙氨酸3.2%和水88.1%;皮肤填充剂是由聚己内酯在透明质酸钠和丙氨酸中形成的混悬液。An injectable skin filler, comprising the following raw materials by mass percentage: polycaprolactone 5.3%, sodium hyaluronate 3.4%, alanine 3.2% and water 88.1%; the skin filler is made of polycaprolactone in Suspension formed in sodium hyaluronate and alanine.
具体制备方法如下:The specific preparation method is as follows:
步骤一:将特性粘度为2.6m
3/kg的透明质酸钠溶于水中,制取透明质酸钠水溶液,其中透明质酸钠水溶液中透明质酸钠与水的质量百分比为0.8%。向透明质酸钠水溶液中加入5.4g丙氨酸,并搅拌溶解,得到第一混合液;其中第一混合液是水相。
Step 1: dissolving sodium hyaluronate with an intrinsic viscosity of 2.6 m 3 /kg in water to prepare a sodium hyaluronate aqueous solution, wherein the mass percentage of sodium hyaluronate and water in the sodium hyaluronate aqueous solution is 0.8%. 5.4 g of alanine was added to the sodium hyaluronate aqueous solution, and the mixture was stirred and dissolved to obtain a first mixed solution; wherein the first mixed solution was an aqueous phase.
步骤二:称取特性粘度为1.6dL/g的聚已内酯9g,溶于90mL的二氯甲烷中,配制成第二混合液;其中第二混合液是油相。Step 2: Weigh 9 g of polycaprolactone with an intrinsic viscosity of 1.6 dL/g, dissolve it in 90 mL of dichloromethane, and prepare a second mixed solution; wherein the second mixed solution is an oil phase.
步骤三:将第二混合液快速加入第一混合液中,并利用乳化机在转速为2500r/min的条件下乳化3min,得到O/W的乳化液。Step 3: quickly add the second mixed solution to the first mixed solution, and emulsify for 3 min with an emulsifying machine at a rotational speed of 2500 r/min to obtain an O/W emulsion.
步骤四:将乳化液在20~40℃的条件下脱除溶剂和部分水分,得到混悬液;将混悬液分成多份,分别灌装于预灌装注射器中,得到皮肤填充剂。Step 4: remove the solvent and part of the water from the emulsion at 20-40°C to obtain a suspension; divide the suspension into multiple portions and fill them into prefilled syringes to obtain a dermal filler.
推挤力测试:将含混悬液的预灌装注射器,加30G针头,采用微机控制电子万能试验机检测该皮肤填充剂的推挤力,根据检测结果可知,推挤力平均值在5N~10N。由此可知,采用本实施例的皮肤填充剂可实现顺利推挤。Pushing force test: add a 30G needle to the pre-filled syringe containing the suspension, and use a microcomputer-controlled electronic universal testing machine to test the pushing force of the dermal filler. According to the test results, the average pushing force is between 5N and 10N. . It can be seen from this that the dermal filler of this embodiment can achieve smooth pushing.
聚已内酯微粒的粒径大小:将静置后的混悬液经水洗干燥后,采用扫描电子显微镜观察微粒的形貌,并测试微粒的粒径大小,如图3所示,聚已内酯微 粒的粒径为2~29μm。The particle size of the polycaprolactone particles: after the suspension after standing is washed and dried, the morphology of the particles is observed with a scanning electron microscope, and the particle size of the particles is tested, as shown in Figure 3. The particle diameter of the ester fine particles is 2 to 29 μm.
实施例4Example 4
一种可注射的皮肤填充剂,包括如下质量百分数的原料:聚乳酸-聚已内酯-聚乳酸45.2%,透明质酸钠21.7%,丝氨酸33.1%;皮肤填充剂是由透明质酸钠和丝氨酸包裹在聚乳酸-聚已内酯-聚乳酸表面而形成的微粒。An injectable skin filler, comprising the following raw materials by mass percentage: polylactic acid-polycaprolactone-polylactic acid 45.2%, sodium hyaluronate 21.7%, serine 33.1%; the skin filler is composed of sodium hyaluronate and Microparticles formed by wrapping serine on the surface of polylactic acid-polycaprolactone-polylactic acid.
具体制备方法如下:The specific preparation method is as follows:
步骤一:将特性粘度为3.0m
3/kg的透明质酸钠溶于水中,制取透明质酸钠水溶液,其中透明质酸钠水溶液中透明质酸钠与水的质量百分比为0.4%。向透明质酸钠水溶液中加入5.5g丝氨酸,并搅拌溶解,得到第一混合液;其中第一混合液是水相。
Step 1: dissolving sodium hyaluronate with an intrinsic viscosity of 3.0 m 3 /kg in water to prepare a sodium hyaluronate aqueous solution, wherein the mass percentage of sodium hyaluronate and water in the sodium hyaluronate aqueous solution is 0.4%. 5.5 g of serine was added to the sodium hyaluronate aqueous solution, and the mixture was stirred and dissolved to obtain a first mixed solution; wherein the first mixed solution was an aqueous phase.
步骤二:称取特性粘度为1.3dL/g的聚乳酸-聚已内酯-聚乳酸7.5g,溶于80mL的二氯甲烷中,配制成第二混合液;其中第二混合液是油相。Step 2: Weigh 7.5 g of polylactic acid-polycaprolactone-polylactic acid with an intrinsic viscosity of 1.3dL/g, dissolve it in 80 mL of dichloromethane, and prepare a second mixed solution; wherein the second mixed solution is an oil phase. .
步骤三:将第二混合液快速加入第一混合液中,并利用乳化机在转速为2400r/min的条件下乳化2.5min,得到O/W的乳化液。Step 3: Quickly add the second mixed solution to the first mixed solution, and use an emulsifying machine to emulsify for 2.5 minutes at a rotational speed of 2400 r/min to obtain an O/W emulsion.
步骤四:将乳化液在20~40℃的条件下脱除溶剂和部分水分,得到混悬液;将混悬液分成多份,分别置于西林瓶中,冻干48h得到皮肤填充剂。Step 4: remove the solvent and part of the water from the emulsion at 20-40° C. to obtain a suspension; divide the suspension into multiple portions, place them in vials, freeze-dry for 48 hours, and obtain a dermal filler.
复溶试验:向制得的皮肤填充剂中加入注射用水,轻轻摇晃35秒即可复溶,得到混悬液;将混悬液静置10min即可除去溶液中的气泡。由此可知,本实施的皮肤填充剂复溶时间短。Reconstitution test: add water for injection to the prepared dermal filler, shake gently for 35 seconds to reconstitute to obtain a suspension; let the suspension stand for 10 minutes to remove air bubbles in the solution. From this, it can be seen that the reconstitution time of the dermal filler of the present embodiment is short.
推挤力测试:用1毫升注射器抽取静置后的混悬液,加30G针头,采用微机控制电子万能试验机检测该皮肤填充剂的推挤力,根据检测结果可知,推挤力平均值在5N~10N。由此可知,采用本实施例的皮肤填充剂可实现顺利推挤。Pushing force test: Use a 1 ml syringe to extract the suspension after standing, add a 30G needle, and use a microcomputer-controlled electronic universal testing machine to test the pushing force of the dermal filler. According to the test results, the average pushing force is 5N~10N. It can be seen from this that the dermal filler of this embodiment can achieve smooth pushing.
聚乳酸-聚已内酯-聚乳酸微粒的粒径大小:将静置后的混悬液经水洗干燥后,采用扫描电子显微镜观察微粒的形貌,并测试微粒的粒径大小,如图4所示,聚乳酸-聚已内酯-聚乳酸微粒的粒径为2~34μm。Particle size of polylactic acid-polycaprolactone-polylactic acid particles: After the suspension after standing is washed and dried with water, the morphology of the particles is observed with a scanning electron microscope, and the particle size of the particles is tested, as shown in Figure 4 As shown, the particle size of the polylactic acid-polycaprolactone-polylactic acid microparticles is 2 to 34 μm.
实施例5Example 5
一种可注射的皮肤填充剂,包括如下质量百分数的原料:聚L-乳酸-羟基乙酸36.6%,透明质酸钠16.3%,甘露醇47.1%;皮肤填充剂是由透明质酸钠和甘露醇包裹在聚L-乳酸-羟基乙酸表面而形成的微粒。An injectable skin filler, comprising the following raw materials by mass percentage: poly-L-lactic acid-glycolic acid 36.6%, sodium hyaluronate 16.3%, mannitol 47.1%; the skin filler is composed of sodium hyaluronate and mannitol Microparticles formed on the surface of poly-L-lactic-glycolic acid.
具体制备方法如下:The specific preparation method is as follows:
步骤一:将特性粘度为3.4m
3/kg的透明质酸钠溶于水中,制取透明质酸钠水溶液,其中透明质酸钠水溶液中透明质酸钠与水的质量百分比为0.4%。向透明质酸钠水溶液中加入11.6g甘露醇,并搅拌溶解,得到第一混合液;其中第一混合液是水相。
Step 1: dissolving sodium hyaluronate with an intrinsic viscosity of 3.4 m 3 /kg in water to prepare a sodium hyaluronate aqueous solution, wherein the mass percentage of sodium hyaluronate and water in the sodium hyaluronate aqueous solution is 0.4%. 11.6 g of mannitol was added to the aqueous sodium hyaluronate solution, and stirred to dissolve to obtain a first mixed solution; wherein the first mixed solution was an aqueous phase.
步骤二:称取特性粘度为1.9dL/g的聚L-乳酸-羟基乙酸9g,溶于80mL的三氯甲烷中,配制成第二混合液;其中第二混合液是油相。Step 2: Weigh 9 g of poly-L-lactic acid-glycolic acid with an intrinsic viscosity of 1.9 dL/g, dissolve it in 80 mL of chloroform, and prepare a second mixed solution; wherein the second mixed solution is an oil phase.
步骤三:将第二混合液快速加入第一混合液中,并利用乳化机在转速为2800r/min的条件下乳化2min,得到O/W的乳化液。Step 3: Quickly add the second mixed solution to the first mixed solution, and use an emulsifier to emulsify for 2 minutes at a rotational speed of 2800 r/min to obtain an O/W emulsion.
步骤四:将乳化液在20~40℃的条件下脱除溶剂和部分水分,得到混悬液;将混悬液分成多份,分别置于西林瓶中,冻干48h得到皮肤填充剂。Step 4: remove the solvent and part of the water from the emulsion at 20-40° C. to obtain a suspension; divide the suspension into multiple portions, place them in vials, freeze-dry for 48 hours, and obtain a dermal filler.
复溶试验:向制得的皮肤填充剂中加入注射用水,轻轻摇晃40秒即可复溶,得到混悬液;将混悬液静置10min即可除去溶液中的气泡。由此可知,本实施的皮肤填充剂复溶时间短。Reconstitution test: add water for injection to the prepared dermal filler, shake gently for 40 seconds to reconstitute to obtain a suspension; let the suspension stand for 10 minutes to remove air bubbles in the solution. From this, it can be seen that the reconstitution time of the dermal filler of the present embodiment is short.
推挤力测试:用1毫升注射器抽取静置后的混悬液,加30G针头,采用微机控制电子万能试验机检测该皮肤填充剂的推挤力,根据检测结果可知,推挤力平均值在5N~10N。由此可知,采用本实施例的皮肤填充剂可实现顺利推挤。Pushing force test: Use a 1 ml syringe to extract the suspension after standing, add a 30G needle, and use a microcomputer-controlled electronic universal testing machine to test the pushing force of the dermal filler. According to the test results, the average pushing force is 5N~10N. It can be seen from this that the dermal filler of this embodiment can achieve smooth pushing.
聚L-乳酸-羟基乙酸微粒的粒径大小:将静置后的混悬液经水洗干燥后,采用扫描电子显微镜观察微粒的形貌,并测试微粒的粒径大小,如图5所示,聚L-乳酸-羟基乙酸微粒的粒径为2~34μm。Particle size of poly-L-lactic acid-glycolic acid particles: After the suspension after standing is washed and dried with water, the morphology of the particles is observed with a scanning electron microscope, and the particle size of the particles is tested, as shown in Figure 5, The particle size of the poly-L-lactic-glycolic acid fine particles is 2 to 34 μm.
实施例6Example 6
一种可注射的皮肤填充剂,包括如下质量百分数的原料:聚已内酯 37.0%,透明质酸钠11.5%,甘露醇51.5%;皮肤填充剂是由透明质酸钠和甘露醇包裹在聚已内酯表面而形成的微粒。An injectable skin filler, comprising the following raw materials by mass percentage: polycaprolactone 37.0%, sodium hyaluronate 11.5%, and mannitol 51.5%; the skin filler is wrapped in polycaprolactone by sodium hyaluronate and mannitol. Microparticles formed on the surface of lactones.
具体制备方法如下:The specific preparation method is as follows:
步骤一:将特性粘度为3.8m
3/kg的透明质酸钠溶于水中,制取透明质酸钠水溶液,其中透明质酸钠水溶液中透明质酸钠与水的质量百分比为0.3%。向透明质酸钠水溶液中加入12.1g甘露醇,并搅拌溶解,得到第一混合液;其中第一混合液是水相。
Step 1: dissolving sodium hyaluronate with an intrinsic viscosity of 3.8 m 3 /kg in water to prepare a sodium hyaluronate aqueous solution, wherein the mass percentage of sodium hyaluronate and water in the sodium hyaluronate aqueous solution is 0.3%. 12.1 g of mannitol was added to the sodium hyaluronate aqueous solution, and stirred and dissolved to obtain a first mixed solution; wherein the first mixed solution was an aqueous phase.
步骤二:称取特性粘度为1.2dL/g的聚已内酯8.7g,溶于90mL的二氯甲烷中,配制成第二混合液;其中第二混合液是油相。Step 2: Weigh 8.7 g of polycaprolactone with an intrinsic viscosity of 1.2 dL/g, dissolve it in 90 mL of dichloromethane, and prepare a second mixed solution; wherein the second mixed solution is an oil phase.
步骤三:将第二混合液快速加入第一混合液中,并利用乳化机在转速为2300r/min的条件下乳化3min,得到O/W的乳化液。Step 3: Quickly add the second mixed solution to the first mixed solution, and emulsify for 3 min with an emulsifying machine at a rotational speed of 2300 r/min to obtain an O/W emulsion.
步骤四:将乳化液在20~40℃的条件下脱除溶剂和部分水分,得到混悬液;将混悬液分成多份,分别置于西林瓶中,冻干48h得到皮肤填充剂。Step 4: remove the solvent and part of the water from the emulsion at 20-40° C. to obtain a suspension; divide the suspension into multiple portions, place them in vials, freeze-dry for 48 hours, and obtain a dermal filler.
复溶试验:向制得的皮肤填充剂中加入注射用水,轻轻摇晃45秒即可复溶,得到混悬液;将混悬液静置10min即可除去溶液中的气泡。由此可知,本实施的皮肤填充剂复溶时间短。Reconstitution test: add water for injection to the prepared dermal filler, shake gently for 45 seconds to reconstitute to obtain a suspension; let the suspension stand for 10 minutes to remove air bubbles in the solution. From this, it can be seen that the reconstitution time of the dermal filler of the present embodiment is short.
推挤力测试:用1毫升注射器抽取静置后的混悬液,加30G针头,采用微机控制电子万能试验机检测该皮肤填充剂的推挤力,根据检测结果可知,推挤力平均值在5N~10N。由此可知,采用本实施例的皮肤填充剂可实现顺利推挤。Pushing force test: Use a 1 ml syringe to extract the suspension after standing, add a 30G needle, and use a microcomputer-controlled electronic universal testing machine to test the pushing force of the dermal filler. According to the test results, the average pushing force is 5N~10N. It can be seen from this that the dermal filler of this embodiment can achieve smooth pushing.
聚已内酯微粒的粒径大小:将静置后的混悬液经水洗干燥后,采用扫描电子显微镜观察微粒的形貌,并测试微粒的粒径大小,如图6所示,聚已内酯微粒的粒径为2~36μm。The particle size of the polycaprolactone particles: After the suspension after standing is washed and dried with water, the morphology of the particles is observed with a scanning electron microscope, and the particle size of the particles is tested, as shown in Figure 6. The particle diameter of the ester fine particles is 2 to 36 μm.
在本说明书的描述中,描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外,在不相互矛盾的情况下,本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。In the description of this specification, the particular features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, those skilled in the art may combine and combine the different embodiments or examples described in this specification, as well as the features of the different embodiments or examples, without conflicting each other.
此外,术语“第一”、“第二”仅用于描述目的,而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此,限定有“第一”、“第二”的特征可以明示或隐含地包括至少一个该特征。在本申请的描述中,“多个”的含义是两个或两个以上,除非另有明确具体的限定。In addition, the terms "first" and "second" are only used for descriptive purposes, and should not be construed as indicating or implying relative importance or implying the number of indicated technical features. Thus, a feature delimited with "first", "second" may expressly or implicitly include at least one of that feature. In the description of the present application, "plurality" means two or more, unless otherwise expressly and specifically defined.
以上所述,仅为本申请的具体实施方式,但本申请的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本申请揭露的技术范围内,可轻易想到变化或替换,都应涵盖在本申请的保护范围之内。因此,本申请的保护范围应以所述权利要求的保护范围为准。The above are only specific embodiments of the present application, but the protection scope of the present application is not limited to this. should be covered within the scope of protection of this application. Therefore, the protection scope of the present application should be subject to the protection scope of the claims.
Claims (10)
- 一种可注射的皮肤填充剂,其特征在于,包括如下质量百分数的原料:聚酯类材料,透明质酸钠,分散剂。An injectable dermal filler is characterized in that it comprises the following raw materials by mass percentage: polyester material, sodium hyaluronate, and dispersant.
- 根据权利要求1所述的皮肤填充剂,其特征在于,所述聚酯类材料20%~80%,透明质酸钠10%~40%,分散剂10%~60%;所述皮肤填充剂是由透明质酸钠和分散剂包裹在聚酯类材料表面而形成的微粒。The dermal filler according to claim 1, wherein the dermal filler comprises 20%-80% of the polyester material, 10%-40% of sodium hyaluronate, and 10%-60% of the dispersant; It is a particle formed by coating the surface of polyester material with sodium hyaluronate and dispersant.
- 根据权利要求1所述的皮肤填充剂,其特征在于,还包括水;聚酯类微粒5%~20%,透明质酸钠1%~5%,分散剂2%~10%和水65%~90%;所述皮肤填充剂是由聚酯类微粒在透明质酸钠和分散剂中形成的混悬液。The dermal filler according to claim 1, further comprising water; 5% to 20% of polyester microparticles, 1% to 5% of sodium hyaluronate, 2% to 10% of dispersant and 65% of water ~90%; the dermal filler is a suspension formed by polyester microparticles in sodium hyaluronate and a dispersant.
- 根据权利要求1所述的皮肤填充剂,其特征在于,所述分散剂为甘露醇和氨基酸;优选地,所述氨基酸在所述皮肤填充剂中的质量百分数为2%~50%,所述甘露醇在所述皮肤填充剂中的质量百分数为2%~50%。The dermal filler according to claim 1, wherein the dispersing agent is mannitol and amino acid; preferably, the mass percentage of the amino acid in the dermal filler is 2% to 50%, and the mannitol The mass percentage of alcohol in the dermal filler is 2% to 50%.
- 根据权利要求1所述的皮肤填充剂,其特征在于,所述聚酯类材料选自聚己内酯、聚左旋乳酸、聚右旋乳酸、聚羟基乙酸和聚羟基烷酸酯中的一种或多种;优选地,所述聚酯类材料的特性粘度为0.2~5.0dL/g;更优选地,所述聚酯类材料的粒径为0.01~200μm。The dermal filler according to claim 1, wherein the polyester material is selected from the group consisting of polycaprolactone, poly-L-lactic acid, poly-D-lactic acid, polyglycolic acid and polyhydroxyalkanoate or more; preferably, the intrinsic viscosity of the polyester material is 0.2-5.0 dL/g; more preferably, the particle size of the polyester material is 0.01-200 μm.
- 根据权利要求4所述的皮肤填充剂,其特征在于,所述氨基酸选自甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、丝氨酸、苯丙氨酸、色氨酸和组氨酸中的一种或多种。The dermal filler according to claim 4, wherein the amino acid is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, proline, serine, phenylalanine, One or more of tryptophan and histidine.
- 根据权利要求1所述的皮肤填充剂,其特征在于,所述透明质酸钠的特性粘度为0.5~4.0m 3/kg。 The dermal filler according to claim 1, wherein the intrinsic viscosity of the sodium hyaluronate is 0.5-4.0 m 3 /kg.
- 一种如权利要求1至7任一所述皮肤填充剂的制备方法,其特征在于,包括如下步骤:A preparation method of the dermal filler as described in any one of claims 1 to 7, characterized in that, comprising the steps:步骤一:将透明质酸钠和分散剂溶于水中,配制成第一混合液;Step 1: Dissolve sodium hyaluronate and dispersant in water to prepare a first mixed solution;步骤二:将聚酯类材料溶于有机溶剂中,配制成第二混合液;Step 2: dissolving the polyester material in an organic solvent to prepare a second mixed solution;步骤三:将所述第二混合液快速加入所述第一混合液中,并充分乳化,得 到水包油的乳化液;Step 3: the second mixed solution is quickly added to the first mixed solution, and fully emulsified to obtain an oil-in-water emulsion;步骤四:将所述水包油的乳化液进行脱溶剂,得到混悬液;Step 4: desolventizing the oil-in-water emulsion to obtain a suspension;步骤五:将所述悬浮液进行冻干处理,得到含微粒的皮肤填充剂。Step 5: freeze-drying the suspension to obtain a microparticle-containing dermal filler.
- 根据权利要求8所述的方法,其特征在于,所述有机溶剂为乙酸乙酯、三氯甲烷、甲苯和二氯甲烷中的一种;优选地,所述有机溶剂为二氯甲烷或三氯甲烷。The method according to claim 8, wherein the organic solvent is one of ethyl acetate, chloroform, toluene and dichloromethane; preferably, the organic solvent is dichloromethane or trichloromethane Methane.
- 根据权利要求8所述的方法,其特征在于,在所述步骤三中,所述第一混合液和所述第二混合液的体积比为1~20:1;优选地,在所述步骤四中,所述脱溶剂的温度为20~50℃。The method according to claim 8, wherein in the step 3, the volume ratio of the first mixed solution and the second mixed solution is 1-20:1; preferably, in the step In the fourth step, the temperature of the desolvation is 20-50°C.
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