CN113230451A - Injectable dermal filler and preparation method thereof - Google Patents
Injectable dermal filler and preparation method thereof Download PDFInfo
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- CN113230451A CN113230451A CN202110360171.5A CN202110360171A CN113230451A CN 113230451 A CN113230451 A CN 113230451A CN 202110360171 A CN202110360171 A CN 202110360171A CN 113230451 A CN113230451 A CN 113230451A
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Abstract
The invention discloses an injectable dermal filler and a preparation method thereof, wherein the dermal filler comprises the following raw materials in percentage by mass: polyester material, sodium hyaluronate and dispersant. The embodiment of the invention takes sodium hyaluronate as an emulsifier to prepare the skin filler; sodium hyaluronate in the dermal filler not only can fill dermal tissues and retain skin moisture, but also can be used as a suspension agent for microparticles. Compared with the existing technology for preparing particles by adopting an emulsification method, the preparation method provided by the embodiment of the invention can realize synchronous particle preparation and dermal filler preparation, and simplifies the preparation process.
Description
Technical Field
The invention relates to the technical field of medical cosmetology, in particular to an injectable dermal filler and a preparation method thereof.
Background
The injection soft tissue filler is a minimally invasive therapy for filling wrinkles and depressions of the skin, and the soft tissue fillers appearing in the market mainly comprise cross-linked sodium hyaluronate gel, collagen, polylactic acid, calcium hydroxyapatite and the like. The action time of the cross-linked sodium hyaluronate gel and the collagen in the skin is 6-12 months, and the action time of the polylactic acid and the hydroxyapatite calcium in the skin is about more than 2 years.
Polyester materials such as polylactic acid, polycaprolactone and the like have the advantages of good biocompatibility, anticoagulation, no toxicity, low immunity and the like, so that the polyester materials are widely applied to the fields of biological medicine and tissue engineering. Research in recent 30 years shows that the polyester material and the monomer thereof have good tissue compatibility, the polyester material can be hydrolyzed and degraded into low molecular weight fragments in a physiological environment, and the low molecular weight fragments can be swallowed by macrophages and degraded in cells. The polylactic acid and the polycaprolactone are used as raw materials of skin fillers, a plurality of products containing polylactic acid and/or polycaprolactone are already applied to filling skin wrinkles and depressions, and the main forms of the products are polylactic acid particles, polylactic acid microspheres, polycaprolactone microspheres and the like.
The existing conventional emulsification method adopts a highly toxic emulsifier when preparing particles, so that the particles need to be removed by post-treatment, then the particles are obtained by drying and separating, and finally the particles are mixed and dispersed with other dispersing agents or suspending agents to obtain the dermal filler, and the preparation process is complicated.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides an injectable dermal filler and a preparation method thereof, which can simplify the preparation process of the dermal filler.
The invention provides an injectable dermal filler in a first aspect, which comprises the following raw materials in percentage by mass: polyester material, sodium hyaluronate and dispersant.
Further, 20% -80% of polyester material, 10% -40% of sodium hyaluronate and 10% -60% of dispersing agent; the dermal filler is particles formed by wrapping sodium hyaluronate and a dispersing agent on the surface of a polyester material.
Further, the dermal filler also includes water; 5-20% of polyester particles, 1-5% of sodium hyaluronate, 2-10% of dispersing agent and 65-90% of water; the dermal filler is a suspension formed by polyester microparticles in sodium hyaluronate and a dispersing agent.
The fine particles herein may be spherical, irregular, rod-like, or the like.
Further, the dispersant is amino acid or mannitol.
Further, the dispersing agent is mannitol and amino acid; furthermore, the mass percentage of the amino acid in the dermal filler is 2-50%. The mass percentage of the mannitol in the dermal filler is 2-50%.
Further, the polyester material is selected from one or more of polycaprolactone, poly-L-lactic acid, poly-D-lactic acid, polyglycolic acid and polyhydroxyalkanoate; further, the intrinsic viscosity of the polyester material is 0.2 to 5.0 dL/g; further, the particle size of the polyester material is 0.01 to 200 μm.
Further, the amino acid is selected from one or more of glycine, alanine, valine, leucine, isoleucine, proline, serine, phenylalanine, tryptophan and histidine.
Further, the sodium hyaluronate has an intrinsic viscosity of 0.5-4.0 m3/kg。
The present invention provides in a second aspect a process for the preparation of a dermal filler according to the first aspect, the process comprising the steps of: the method comprises the following steps: dissolving sodium hyaluronate and a dispersing agent in water to prepare a first mixed solution; step two: dissolving polyester materials in an organic solvent to prepare a second mixed solution; step three: quickly adding the second mixed solution into the first mixed solution, and fully emulsifying to obtain an oil-in-water emulsion; step four: desolventizing the oil-in-water emulsion to obtain a suspension; step five: and carrying out freeze-drying treatment on the suspension to obtain the polyester particles.
Further, the organic solvent is one of ethyl acetate, chloroform, toluene and dichloromethane; further, the organic solvent is dichloromethane or chloroform.
Further, in the third step, the volume ratio of the first mixed solution to the second mixed solution is 1-20: 1; further, in the fourth step, the temperature of the desolventizing agent is 20-50 ℃.
Compared with the prior art, the embodiment of the invention at least has the following beneficial effects:
1. according to the embodiment of the invention, sodium hyaluronate with better biocompatibility is used as the emulsifier of the polyester particles, the process of removing the emulsifier is not needed, and the sodium hyaluronate is continuously used as the suspending agent in the later preparation stage, so that the skin cells can be effectively repaired, and the impurity removing process caused by the fact that polyvinyl alcohol and the like are used as the emulsifier for preparing the particles in the prior art can be avoided.
2. In the embodiment of the invention, after a solution of a polyester material and an aqueous solution prepared from sodium hyaluronate and a dispersant are mixed, the mixed solution is emulsified by a common stirring or emulsifying machine to form an oil-in-water emulsion, and then the emulsion is dried in vacuum to remove an organic solvent and part of water in the emulsion to obtain a suspension; the suspension can be used as dermal filler. Compared with the prior art of preparing the particles by an emulsification method, the embodiment of the invention not only omits the processes of removing the emulsifier and drying the particles, but also omits the process of redispersing the particles. Therefore, the embodiment of the invention can realize synchronous particle preparation and dermal filler preparation, and simplifies the preparation process.
3. The dermal filler prepared by the embodiment of the invention is not only suitable for injecting the deep dermis and the subcutaneous tissue to fill deeper wrinkles and depressions, but also suitable for injecting the superficial dermis with water and light to fill shallower wrinkles.
4. The dermal filler of the embodiment of the invention can be used as a long-acting hydro-optic needle.
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FIG. 1 is a scanning electron micrograph of polylactic acid fine particles according to example 1 of the present invention;
FIG. 2 is a scanning electron micrograph of polylactic acid fine particles according to example 2 of the present invention;
FIG. 3 is a scanning electron micrograph of polycaprolactone particles of example 3 of this invention;
FIG. 4 is a scanning electron micrograph of fine particles of polylactic acid-polycaprolactone-polylactic acid according to example 4 of the present invention;
FIG. 5 is a scanning electron micrograph of poly (L-lactic-co-glycolic acid) microparticles according to example 5 of the present invention;
FIG. 6 is a scanning electron micrograph of polycaprolactone microparticles in example 6 of this invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
Embodiments of the present invention provide, in a first aspect, an injectable dermal filler, where the dermal filler includes the following raw materials by mass: polyester material, sodium hyaluronate and dispersant.
According to the embodiment of the invention, sodium hyaluronate is adopted as the emulsifier and the suspending agent of the polyester microparticles, and the sodium hyaluronate is degradable and biocompatible, so that the sodium hyaluronate is not required to be removed, and the suspending agent is not required to be additionally added, and harmful substance residues caused by using other emulsifiers are avoided, so that compared with the prior art, the processes of impurity removal, microparticle redispersion and the like are omitted, and the preparation process of the skin filler is simplified; because sodium hyaluronate can repair skin cells, sodium hyaluronate can also be used as a functional raw material of a skin filler, promote proliferation and differentiation of epidermal cells and remove oxygen radicals, thereby preventing skin aging.
In a further embodiment, 20% -80% of polyester material, 10% -40% of sodium hyaluronate and 10% -60% of dispersing agent; the dermal filler is particles formed by wrapping sodium hyaluronate and a dispersing agent on the surface of a polyester material.
In a further embodiment, the dermal filler comprises the following raw materials in percentage by mass: 5-20% of polyester particles, 1-5% of sodium hyaluronate, 2-10% of dispersing agent and 65-90% of water; the dermal filler is a suspension formed by polyester microparticles in sodium hyaluronate and a dispersing agent.
The dermal filler provided by the embodiment of the invention is used in a suspension state in clinical use, for example, when the dermal filler is in a freeze-dried powder state, the dermal filler of the freeze-dried powder is re-dissolved to form a suspension for use; or the suspension obtained by vacuum drying the O/W emulsion in the preparation process is directly used for clinical application.
According to the embodiment of the invention, sodium hyaluronate is adopted as the emulsifier and the suspending agent of the polyester microparticles, and the sodium hyaluronate is degradable and biocompatible, so that the sodium hyaluronate is not required to be removed, and the suspending agent is not required to be additionally added, and harmful substance residues caused by using other emulsifiers are avoided, so that compared with the prior art, the processes of impurity removal, microparticle redispersion and the like are omitted, and the preparation process of the skin filler is simplified; because sodium hyaluronate can repair skin cells, sodium hyaluronate can also be used as a functional raw material of a skin filler, promote proliferation and differentiation of epidermal cells and remove oxygen radicals, thereby preventing skin aging.
In further embodiments, the dispersant is mannitol or an amino acid; thus, by using mannitol or amino acid as the dispersant, not only the polyester material in the second mixed solution can be uniformly dispersed; but also can be degraded in vivo, reducing the post-dispersion process of dermal fillers.
In a further embodiment, the mannitol is present in the dermal filler in a mass percentage of 2% to 50%, and the amino acid is present in the dermal filler in a mass percentage of 2% to 50%. Thus, the mannitol and the amino acid are used as the dispersing agent at the same time, so that the polyester-based material in the second mixed solution can be rapidly dispersed. In addition, amino acids are added to the dermal filler, and the amino acids serve not only as a dispersant but also as a functional material, so that the cosmetic effect of the dermal filler can be improved.
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 invention adopts the polyester material as the main component, so that the degradation time of the skin filler can be prolonged, and wrinkles and depressions of the skin can be effectively filled.
In a further embodiment, the polyester material has an intrinsic viscosity of 0.2 to 5.0 dL/g. Therefore, by selecting the polyester material with proper intrinsic viscosity, the degradation speed of the dermal filler can be effectively controlled, and the cosmetic effect of the dermal filler is improved.
In a further embodiment, the polyester material has a particle size of 0.01 to 200 μm. Therefore, the polyester material with the proper particle size can be selected, so that the depression and wrinkles of subcutaneous tissues can be effectively filled, and the rapid extrusion can be realized during injection, and the extrusion difficulty is avoided.
In further embodiments, the amino acid is selected from one or more of glycine, alanine, valine, leucine, isoleucine, proline, serine, phenylalanine, tryptophan, and histidine. Thus, the addition of the amino acid not only effectively disperses the liquid mixture of the polyester material, but also improves the cosmetic effect of the dermal filler.
In a further embodiment, the sodium hyaluronate has an intrinsic viscosity of 0.5 to 4.0m3In terms of/kg. Thus, by selecting sodium hyaluronate of an appropriate intrinsic viscosity, the expected degradation time of the dermal filler can be controlled.
The dermal filler prepared by the embodiment of the invention can be used for filling and correcting wrinkles such as facial wrinkles, hand wrinkles, neck wrinkles, stretch marks and the like.
Embodiments of the present invention provide, in a second aspect, a method of making a dermal filler from embodiments of the present invention described in the first aspect. The method comprises the following steps: dissolving sodium hyaluronate and a dispersing agent in water to prepare a first mixed solution; step two: dissolving polyester materials in an organic solvent to prepare a second mixed solution; step three: quickly adding the second mixed solution into the first mixed solution, and fully emulsifying to obtain an oil-in-water emulsion; step four: desolventizing the oil-in-water emulsion to obtain a suspension; step five: and carrying out freeze-drying treatment on the suspension to obtain the particles.
According to the embodiment of the invention, sodium hyaluronate and a dispersing agent are dissolved in water to obtain a first mixed solution; dissolving the polyester material in an organic solvent to obtain a second mixed solution; and then quickly adding the second mixed solution into the first mixed solution for emulsification, and removing the solvent from the emulsified liquid after emulsification to obtain a suspension. Compared with the prior art for preparing the particles, the method omits the processes of removing the emulsifier and drying the particles, can realize the synchronous preparation of the particles and the dermal filler, and simplifies the preparation process.
In a further embodiment, the organic solvent is one of ethyl acetate, chloroform, toluene, and dichloromethane; this enables the polyester-based material to be effectively dissolved. In still further embodiments, the organic solvent is chloroform or dichloromethane. This can improve the safety of the dermal filler.
In a further embodiment, in the third step, the volume ratio of the first mixed solution to the second mixed solution is 1-20: 1; in a further embodiment, the volume ratio of the first mixed solution to the second mixed solution is 3-15: 1; thus, a water-in-oil emulsion can be effectively obtained.
In a further embodiment, in the fourth step, the temperature of the desolventizing agent is 20-50 ℃.
It is further noted that any range recited herein includes the endpoints and any values therebetween and any subranges subsumed therein or any values therebetween unless otherwise specified.
Example 1
An injectable dermal filler comprises the following raw materials in percentage by mass: 35.6 percent of poly-L-lactic acid, 23.7 percent of sodium hyaluronate and 40.7 percent of mannitol; the dermal filler is a microparticle formed by wrapping sodium hyaluronate and mannitol on the surface of poly-L-lactic acid.
The preparation method comprises the following steps:
the method comprises the following steps: the intrinsic viscosity was adjusted to 0.9m3The sodium hyaluronate aqueous solution is prepared by dissolving/kg of sodium hyaluronate in water, wherein the mass percentage of the sodium hyaluronate in the sodium hyaluronate aqueous solution to the water is 1%. Adding 10.3g of mannitol into the sodium hyaluronate aqueous solution, and stirring and dissolving to obtain a first mixed solution; wherein the first mixed liquor is an aqueous phase.
Step two: weighing 9g of poly-L-lactic acid with the intrinsic viscosity of 1.5dL/g, and dissolving the poly-L-lactic acid in 100mL of dichloromethane to prepare a second mixed solution; wherein the second mixed solution is an oil phase.
Step three: and quickly adding the second mixed solution into the first mixed solution, and emulsifying for 3min by using an emulsifying machine under the condition that the rotating speed is 2000r/min to obtain O/W emulsion.
Step four: removing the solvent and part of water from the emulsion at the temperature of 30-50 ℃ to obtain a suspension; dividing the suspension into multiple parts, respectively placing in penicillin bottles, and lyophilizing for 48h to obtain dermal filler.
Redissolution test: adding 4 ml of water for injection into the prepared dermal filler, and slightly shaking for 20 seconds to redissolve to obtain a suspension; standing the suspension for 10min to remove air bubbles in the solution. This revealed that the dermal filler of the present embodiment had a short reconstitution time.
And (3) extrusion force testing: and (3) extracting the suspension after standing by using a 1 ml syringe, adding a 30G needle, detecting the extrusion force of the dermal filler by using a microcomputer-controlled electronic universal tester, and obtaining the average value of the extrusion force between 5N and 10N according to the detection result. It is clear from this that smooth pushing can be achieved with the dermal filler of this example.
Particle size of poly (L-lactic acid) microparticles: and (3) washing and drying the suspension after standing, observing the morphology of the particles by adopting a scanning electron microscope, and testing the particle size of the particles, wherein the particle size of the poly-L-lactic acid particles is 2-34 mu m as shown in figure 1. Therefore, the poly-L-lactic acid microparticles are uniform in shape and particle size, and not only are suitable for injection of deep dermis and subcutaneous tissues to fill deep wrinkles and depressions, but also suitable for injection of light and water in superficial dermis to fill shallow wrinkles.
Example 2
An injectable dermal filler comprises the following raw materials in percentage by mass: 48.0 percent of poly-L-lactic acid, 20.0 percent of sodium hyaluronate and 32.0 percent of glycine; the dermal filler is a microparticle formed by wrapping sodium hyaluronate and glycine on the surface of poly-L-lactic acid.
The preparation method comprises the following steps:
the method comprises the following steps: the intrinsic viscosity is 2.1m3The sodium hyaluronate aqueous solution is prepared by dissolving/kg of sodium hyaluronate in water, wherein the mass percentage of the sodium hyaluronate in the sodium hyaluronate aqueous solution to the water is 0.5%. Adding 4.0g of glycine into the sodium hyaluronate aqueous solution, and stirring and dissolving to obtain a first mixed solution; wherein the first mixed liquor is an aqueous phase.
Step two: weighing 6g of poly-L-lactic acid with the intrinsic viscosity of 1.8dL/g, and dissolving the poly-L-lactic acid in 80mL of trichloromethane to prepare a second mixed solution; wherein the second mixed solution is an oil phase.
Step three: and quickly adding the second mixed solution into the first mixed solution, and emulsifying for 2min by using an emulsifying machine under the condition that the rotating speed is 2500r/min to obtain O/W emulsion.
Step four: removing the solvent and part of water from the emulsion at the temperature of 20-50 ℃ to obtain a suspension; dividing the suspension into multiple parts, respectively placing in penicillin bottles, and lyophilizing for 48h to obtain dermal filler.
Redissolution test: adding 4 ml of water for injection into the prepared dermal filler, and slightly shaking for 25 seconds to redissolve to obtain a suspension; standing the suspension for 10min to remove air bubbles in the solution. This revealed that the dermal filler of the present embodiment had a short reconstitution time.
And (3) extrusion force testing: and (3) extracting the suspension after standing by using a 1 ml syringe, adding a 30G needle, detecting the extrusion force of the dermal filler by using a microcomputer-controlled electronic universal tester, and obtaining the average value of the extrusion force between 5N and 10N according to the detection result. It is clear from this that smooth pushing can be achieved with the dermal filler of this example.
Particle size of poly (L-lactic acid) microparticles: and (3) washing and drying the suspension after standing, observing the morphology of the particles by adopting a scanning electron microscope, and testing the particle size of the particles, wherein the particle size of the poly-L-lactic acid particles is 2-32 mu m as shown in figure 2.
Example 3
An injectable dermal filler comprises the following raw materials in percentage by mass: 5.3 percent of polycaprolactone, 3.4 percent of sodium hyaluronate, 3.2 percent of alanine and 88.1 percent of water; dermal fillers are suspensions of polycaprolactone in sodium hyaluronate and alanine.
The preparation method comprises the following steps:
the method comprises the following steps: the intrinsic viscosity is 2.6m3The sodium hyaluronate aqueous solution is prepared by dissolving/kg of sodium hyaluronate in water, wherein the mass percentage of the sodium hyaluronate in the sodium hyaluronate aqueous solution to the water is 0.8%. Adding 5.4g of alanine into the sodium hyaluronate aqueous solution, and stirring and dissolving to obtain a first mixed solution; wherein the first mixed liquor is an aqueous phase.
Step two: weighing 9g of polycaprolactone with the intrinsic viscosity of 1.6dL/g, and dissolving the polycaprolactone in 90mL of dichloromethane to prepare a second mixed solution; wherein the second mixed solution is an oil phase.
Step three: and quickly adding the second mixed solution into the first mixed solution, and emulsifying for 3min by using an emulsifying machine under the condition that the rotating speed is 2500r/min to obtain O/W emulsion.
Step four: removing the solvent and part of water from the emulsion at the temperature of 20-40 ℃ to obtain a suspension; dividing the suspension into multiple parts, and respectively filling into prefilled syringes to obtain dermal filler.
And (3) extrusion force testing: and (3) adding a 30G needle head into a prefilled syringe containing the suspension, detecting the extrusion force of the dermal filler by adopting a microcomputer-controlled electronic universal tester, and knowing that the average value of the extrusion force is 5N-10N according to the detection result. It is clear from this that smooth pushing can be achieved with the dermal filler of this example.
Particle size of polycaprolactone microparticles: and (3) washing and drying the suspension after standing, observing the morphology of the particles by adopting a scanning electron microscope, and testing the particle size of the particles, wherein the particle size of the polycaprolactone particles is 2-29 mu m as shown in figure 3.
Example 4
An injectable dermal filler comprises the following raw materials in percentage by mass: 45.2 percent of polylactic acid-polycaprolactone-polylactic acid, 21.7 percent of sodium hyaluronate and 33.1 percent of serine; the skin filler is a microparticle formed by wrapping sodium hyaluronate and serine on the surface of polylactic acid-polycaprolactone-polylactic acid.
The preparation method comprises the following steps:
the method comprises the following steps: the intrinsic viscosity was adjusted to 3.0m3The sodium hyaluronate aqueous solution is prepared by dissolving/kg of sodium hyaluronate in water, wherein the mass percentage of the sodium hyaluronate in the sodium hyaluronate aqueous solution to the water is 0.4%. Adding 5.5g of serine into a sodium hyaluronate aqueous solution, and stirring and dissolving to obtain a first mixed solution; wherein the first mixed liquor is an aqueous phase.
Step two: weighing 7.5g of polylactic acid-polycaprolactone-polylactic acid with the intrinsic viscosity of 1.3dL/g, and dissolving in 80mL of dichloromethane to prepare a second mixed solution; wherein the second mixed solution is an oil phase.
Step three: and quickly adding the second mixed solution into the first mixed solution, and emulsifying for 2.5min by using an emulsifying machine under the condition that the rotating speed is 2400r/min to obtain O/W emulsion.
Step four: removing the solvent and part of water from the emulsion at the temperature of 20-40 ℃ to obtain a suspension; dividing the suspension into multiple parts, respectively placing in penicillin bottles, and lyophilizing for 48h to obtain dermal filler.
Redissolution test: adding water for injection into the obtained dermal filler, and slightly shaking for 35 s to obtain suspension; standing the suspension for 10min to remove air bubbles in the solution. This revealed that the dermal filler of the present embodiment had a short reconstitution time.
And (3) extrusion force testing: and (3) extracting the suspension after standing by using a 1 ml syringe, adding a 30G needle, detecting the extrusion force of the dermal filler by using a microcomputer-controlled electronic universal tester, and obtaining the average value of the extrusion force between 5N and 10N according to the detection result. It is clear from this that smooth pushing can be achieved with the dermal filler of this example.
Particle size of polylactic acid-polycaprolactone-polylactic acid fine particles: and (3) washing and drying the suspension after standing, observing the morphology of the particles by adopting a scanning electron microscope, and testing the particle size of the particles, wherein the particle size of the polylactic acid-polycaprolactone-polylactic acid particles is 2-34 mu m as shown in figure 4.
Example 5
An injectable dermal filler comprises the following raw materials in percentage by mass: 36.6 percent of poly-L-lactic-glycolic acid, 16.3 percent of sodium hyaluronate and 47.1 percent of mannitol; the dermal filler is a microparticle formed by coating sodium hyaluronate and mannitol on the surface of poly-L-lactic-glycolic acid.
The preparation method comprises the following steps:
the method comprises the following steps: the intrinsic viscosity is 3.4m3The sodium hyaluronate aqueous solution is prepared by dissolving/kg of sodium hyaluronate in water, wherein the mass percentage of the sodium hyaluronate in the sodium hyaluronate aqueous solution to the water is 0.4%. Adding 11.6g of mannitol into the sodium hyaluronate aqueous solution, and stirring and dissolving to obtain a first mixed solution; wherein the first mixed liquor is an aqueous phase.
Step two: weighing 9g of poly L-lactic acid-glycolic acid with the intrinsic viscosity of 1.9dL/g, and dissolving the poly L-lactic acid-glycolic acid in 80mL of trichloromethane to prepare a second mixed solution; wherein the second mixed solution is an oil phase.
Step three: and quickly adding the second mixed solution into the first mixed solution, and emulsifying for 2min by using an emulsifying machine under the condition that the rotating speed is 2800r/min to obtain O/W emulsion.
Step four: removing the solvent and part of water from the emulsion at the temperature of 20-40 ℃ to obtain a suspension; dividing the suspension into multiple parts, respectively placing in penicillin bottles, and lyophilizing for 48h to obtain dermal filler.
Redissolution test: adding water for injection into the obtained dermal filler, and slightly shaking for 40 s to obtain suspension; standing the suspension for 10min to remove air bubbles in the solution. This revealed that the dermal filler of the present embodiment had a short reconstitution time.
And (3) extrusion force testing: and (3) extracting the suspension after standing by using a 1 ml syringe, adding a 30G needle, detecting the extrusion force of the dermal filler by using a microcomputer-controlled electronic universal tester, and obtaining the average value of the extrusion force between 5N and 10N according to the detection result. It is clear from this that smooth pushing can be achieved with the dermal filler of this example.
Particle size of poly L-lactic acid-glycolic acid fine particles: and (3) washing and drying the suspension after standing, observing the morphology of the particles by adopting a scanning electron microscope, and testing the particle size of the particles, wherein the particle size of the poly-L-lactic-co-glycolic acid particles is 2-34 mu m as shown in figure 5.
Example 6
An injectable dermal filler comprises the following raw materials in percentage by mass: 37.0 percent of polycaprolactone, 11.5 percent of sodium hyaluronate and 51.5 percent of mannitol; the dermal filler is a microparticle formed by wrapping sodium hyaluronate and mannitol on the surface of polycaprolactone.
The preparation method comprises the following steps:
the method comprises the following steps: the intrinsic viscosity is 3.8m3The sodium hyaluronate aqueous solution is prepared by dissolving/kg of sodium hyaluronate in water, wherein the mass percentage of the sodium hyaluronate in the sodium hyaluronate aqueous solution to the water is 0.3%. Adding 12.1g of mannitol into a sodium hyaluronate aqueous solution, and stirring and dissolving to obtain a first mixed solution; wherein the first mixed liquor is an aqueous phase.
Step two: weighing 8.7g of polycaprolactone with the intrinsic viscosity of 1.2dL/g, and dissolving the polycaprolactone in 90mL of dichloromethane to prepare a second mixed solution; wherein the second mixed solution is an oil phase.
Step three: and quickly adding the second mixed solution into the first mixed solution, and emulsifying for 3min by using an emulsifying machine under the condition that the rotating speed is 2300r/min to obtain O/W emulsion.
Step four: removing the solvent and part of water from the emulsion at the temperature of 20-40 ℃ to obtain a suspension; dividing the suspension into multiple parts, respectively placing in penicillin bottles, and lyophilizing for 48h to obtain dermal filler.
Redissolution test: adding water for injection into the prepared dermal filler, and slightly shaking for 45 seconds to redissolve to obtain suspension; standing the suspension for 10min to remove air bubbles in the solution. This revealed that the dermal filler of the present embodiment had a short reconstitution time.
And (3) extrusion force testing: and (3) extracting the suspension after standing by using a 1 ml syringe, adding a 30G needle, detecting the extrusion force of the dermal filler by using a microcomputer-controlled electronic universal tester, and obtaining the average value of the extrusion force between 5N and 10N according to the detection result. It is clear from this that smooth pushing can be achieved with the dermal filler of this example.
Particle size of polycaprolactone microparticles: and (3) washing and drying the suspension after standing, observing the morphology of the particles by adopting a scanning electron microscope, and testing the particle size of the particles, wherein the particle size of the polycaprolactone particles is 2-36 mu m as shown in figure 6.
In the description herein, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Furthermore, the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one such feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.
Claims (10)
1. The injectable dermal filler is characterized by comprising the following raw materials in percentage by mass: polyester material, sodium hyaluronate and dispersant.
2. The dermal filler of claim 1, wherein the polyester material is 20 to 80%, the sodium hyaluronate is 10 to 40%, and the dispersant is 10 to 60%; the dermal filler is particles formed by wrapping sodium hyaluronate and a dispersing agent on the surface of a polyester material.
3. The dermal filler of claim 1, further comprising water; 5-20% of polyester particles, 1-5% of sodium hyaluronate, 2-10% of dispersing agent and 65-90% of water; the dermal filler is a suspension formed by polyester microparticles in sodium hyaluronate and a dispersing agent.
4. The dermal filler of claim 1, wherein the dispersant is mannitol and an amino acid; preferably, the mass percent of the amino acid in the dermal filler is 2-50%, and the mass percent of the mannitol in the dermal filler is 2-50%.
5. The dermal filler of claim 1, wherein the polyester-based material is selected from one or more of polycaprolactone, poly-L-lactic acid, poly-D-lactic acid, poly-glycolic acid, and polyhydroxyalkanoate; 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 to 200 μm.
6. The dermal filler of claim 4, wherein the amino acids are selected from one or more of glycine, alanine, valine, leucine, isoleucine, proline, serine, phenylalanine, tryptophan, and histidine.
7. The dermal filler of claim 1, wherein the sodium hyaluronate has an intrinsic viscosity of 0.5 to 4.0m3/kg。
8. A process for the preparation of the dermal filler of any of claims 1 to 7, characterized in that it comprises the following steps:
the method comprises the following steps: dissolving sodium hyaluronate and a dispersing agent in water to prepare a first mixed solution;
step two: dissolving polyester materials in an organic solvent to prepare a second mixed solution;
step three: quickly adding the second mixed solution into the first mixed solution, and fully emulsifying to obtain an oil-in-water emulsion;
step four: desolventizing the oil-in-water emulsion to obtain a suspension;
step five: and carrying out freeze-drying treatment on the suspension to obtain the dermal filler containing the microparticles.
9. The method of claim 8, wherein the organic solvent is one of ethyl acetate, chloroform, toluene, and dichloromethane; preferably, the organic solvent is dichloromethane or trichloromethane.
10. The method according to claim 8, wherein in the third step, the volume ratio of the first mixed solution to the second mixed solution is 1-20: 1; preferably, in the fourth step, the temperature of the desolventizing agent is 20-50 ℃.
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| CN202110360171.5A CN113230451A (en) | 2021-04-02 | 2021-04-02 | Injectable dermal filler and preparation method thereof |
| PCT/CN2021/103197 WO2022205645A1 (en) | 2021-04-02 | 2021-06-29 | Injectable dermal filler and preparation method therefor |
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| CN202110360171.5A CN113230451A (en) | 2021-04-02 | 2021-04-02 | Injectable dermal filler and preparation method thereof |
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