CN114225105A - Preparation method of microporous structure polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microspheres and injectable soft tissue filler - Google Patents
Preparation method of microporous structure polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microspheres and injectable soft tissue filler Download PDFInfo
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- CN114225105A CN114225105A CN202111560028.7A CN202111560028A CN114225105A CN 114225105 A CN114225105 A CN 114225105A CN 202111560028 A CN202111560028 A CN 202111560028A CN 114225105 A CN114225105 A CN 114225105A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/56—Porous materials, e.g. foams or sponges
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Transplantation (AREA)
- Dermatology (AREA)
- Medicinal Chemistry (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a preparation method of a microporous structure polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere and an injectable soft tissue filler. The polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microspheres with porous structures are prepared by adopting an oil-in-water single-phase emulsification method, wherein an oil phase solution in the oil-in-water single-phase emulsification method is a dichloromethane solution of polycaprolactone and polyethylene glycol-poly-racemic lactic acid or a trichloromethane solution of polycaprolactone and polyethylene glycol-poly-racemic lactic acid, and an emulsifier is polyvinyl alcohol. According to the scheme of the embodiment of the invention, the microsphere is prepared by a simple oil-in-water single-phase emulsification method, the preparation process is simple to operate, the production cost is low, the production efficiency is high, and the method is suitable for industrial scale-up production.
Description
Technical Field
The invention relates to the technical field of medical cosmetic soft tissue filling, in particular to a preparation method of a polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere with a microporous structure and an injectable soft tissue filler.
Background
With the development of the medical beauty industry, injectable soft tissue fillers are more and more widely concerned, and the injection of the soft tissue fillers can realize the beauty effects of repairing nasolabial folds, filling temples, enlarging cheeks, improving statutory lines, filling mandibles, tightening contour lines of the chin and the like. At present, sodium hyaluronate (hyaluronic acid HA), which is the most commonly used injection filling material in the beauty industry, HAs a good filling effect, but because the degradation speed of hyaluronic acid is high, patients generally need to repeatedly inject the hyaluronic acid every 6 months or so.
In recent years, soft tissue filling products prepared from polycarbonate biodegradable polymers poly-L-lactic acid (PLLA) and Polycaprolactone (PCL) make up for the defects of short curative effect, high treatment frequency and unnatural effect of HA products. The curative effect of the polycarbonate product is generally about 1 to 2 years, and especially the curative effect of the PCL product can reach more than 5 years. When the PCL is used as a medical cosmetic filling material, the PCL is usually required to be prepared into micron-sized microspheres, and then the microspheres are injected into deep tissues of the skin through an injector, then the M2 type polarization of macrophages in the skin immune system is excited by the PCL microspheres through self foreign body reaction and 6-hydroxyhexanoic acid released in the degradation process of the PCL microspheres, the M2 type polarized macrophages can highly express related cytokines such as TGF-beta (transforming growth factor) and further induce fibroblasts to accelerate collagen secretion, and finally the tissue filling effect on the injection part is achieved. However, since PCL is degraded slowly at the initial stage of implantation into skin tissue, the skin improvement effect of patients at the initial stage of treatment is not obvious, and the skin improvement condition of most of the treated patients is gradually developed after 6 to 8 weeks after the treatment.
At present, the PCL microspheres are mainly prepared by an oil-in-water single-phase emulsification method, the polycaprolactone microsphere filler containing vitamin C and the preparation method thereof are provided in the prior art, and the vitamin C is loaded in the PCL to prepare the PCL microspheres by the oil-in-water single-phase emulsification method. Since vitamin C is a skin whitening ingredient and loaded in PCL microspheres does not affect the tissue filling effect of the microspheres, the effect of the PCL microspheres at the initial stage of tissue filling is not improved. The prior art also provides a polycaprolactone microsphere filler containing collagen peptide and a preparation method thereof, the microsphere prepared by compounding collagen and PCL can improve the treatment effect of the PCL microsphere at the initial stage of tissue filling, but because most of the collagen used in the current medical market is animal-derived, the polycaprolactone microsphere filler has higher sensitization and immunogenicity risks. Meanwhile, because collagen is only dissolved in a water phase solvent and is completely insoluble in an oil phase solvent, the microsphere needs to be prepared by a method for constructing double emulsion, the preparation process is too complex, the cost is high, the amplification production is not facilitated, at least more than two emulsifiers are usually required to be introduced in the preparation process, the product purification difficulty is high, the biological safety is poor, and the application of the microsphere in the field of beauty treatment is limited.
In addition, the PCL microspheres prepared by the emulsification method reported at present generally have a smooth and compact structure on the surface. According to literature reports, macrophage polarization induced by foreign body reaction is mainly dependent on the size and surface microstructure of foreign bodies, and M2 type polarization of macrophages is more easily caused by implants with rough surfaces and porous structures. On the other hand, on the mechanism of stimulating collagen regeneration by releasing 6-hydroxyhexanoic acid, the PCL material with a rough surface and a porous structure has a higher specific surface area, and after the PCL material is implanted into skin tissue, the contact area of the PCL material with the high specific surface area and tissue fluid is larger, so that the degradation of the PCL material and the release speed of the 6-hydroxyhexanoic acid are faster at the initial stage of implantation, and the effects of stimulating collagen regeneration and tissue filling are better.
Disclosure of Invention
One purpose of the invention is to solve the problem of poor immediate effect of PCL microsphere soft tissue filler in the early treatment period in the prior art.
A further object of the present invention is to provide an injectable soft tissue filler having excellent dispersibility of the aqueous phase, and the resulting suspension after dispersion is uniform and fine, and has good stability and good penetration.
Particularly, the invention provides a preparation method of the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microspheres with the microporous structure, which is characterized in that the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microspheres with the microporous structure are prepared by adopting an oil-in-water single-phase emulsification method, wherein an oil phase solution in the oil-in-water single-phase emulsification method is a dichloromethane solution of polycaprolactone and polyethylene glycol-poly-racemic lactic acid or a trichloromethane solution of polycaprolactone and polyethylene glycol-poly-racemic lactic acid, and an emulsifier is polyvinyl alcohol.
Optionally, in the oil phase solution, the polyethylene glycol-poly-racemic lactic acid is a polyethylene glycol monomethyl ether-poly-racemic lactic acid diblock copolymer or a poly-racemic lactic acid-polyethylene glycol-poly-racemic lactic acid triblock copolymer.
Optionally, in the oil phase solution, the molecular weight of the polyethylene glycol ranges from any value of 2-10KDa, the molecular weight of the poly-racemic lactic acid ranges from any value of 1-5KDa, and the mass concentration of the poly-racemic lactic acid ranges from any value of 0.01-5%.
Optionally, in the oil phase solution, the inherent viscosity of the polycaprolactone is any value of 0.5-1.0dl/g, and the mass concentration of the polycaprolactone is any value of 5-20%.
Optionally, the aqueous phase solution in the oil-in-water single-phase emulsification method is a solution obtained by dissolving the emulsifier in ultrapure water;
the volume ratio of the oil phase solution to the water phase solution is any ratio of 1:4-1: 20.
Optionally, in the aqueous solution, the molecular weight of the polyvinyl alcohol is 10-100KDa, and the mass concentration is any value of 0.5-3%.
Optionally, the oil-in-water single phase emulsification process comprises the steps of:
adding the aqueous phase solution into a reaction kettle;
adding the oil phase solution into the water phase solution under mechanical stirring, and continuing stirring until the dichloromethane solvent or the trichloromethane solvent in the oil phase solution is completely volatilized to obtain a reaction solution;
carrying out suction filtration on the reaction solution to obtain a polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere solution;
and cleaning, filtering and drying the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere solution to obtain polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere powder.
Optionally, in the step of adding the oil phase solution into the aqueous phase solution under mechanical stirring, and continuing stirring until the dichloromethane solvent or the chloroform solvent in the oil phase solution is completely volatilized to obtain a reaction solution, the stirring speed of mechanical stirring is any value of 200-2000rpm, and the stirring time is any value of 6-48 h;
optionally, in the step of performing suction filtration on the reaction solution to obtain the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere solution, the aperture of a filter membrane used in the suction filtration is any value of 0.45-3 μm;
optionally, in the step of cleaning, filtering and drying the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere solution to obtain polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere powder, drying is performed in a freeze drying or vacuum drying mode, and the vacuum drying temperature is any value of 30-50 ℃.
Optionally, the oil-in-water single phase emulsification method further comprises the steps of:
packaging the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere powder and then sterilizing to obtain sterile polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microspheres;
optionally, in the step of sterilizing after packaging the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere powder, cobalt 60 is used for irradiation sterilization, and the irradiation dose is any value of 7-15 kGy.
In particular, the present invention also provides a method for preparing an injectable soft tissue filler, comprising the steps of:
mixing the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microspheres prepared by the preparation method with a sterilized auxiliary material solution to obtain a mixed solution, wherein the mass percentage content of the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microspheres in the mixed solution is any one value of 10-50%;
subpackaging the mixed solution to obtain the injectable soft tissue filler.
According to the scheme of the embodiment of the invention, the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere with the microporous structure is prepared by an oil-in-water single-phase emulsification method, an oil phase solution in the oil-in-water single-phase emulsification method is a dichloromethane solution of polycaprolactone and polyethylene glycol-poly-racemic lactic acid or a trichloromethane solution of polycaprolactone and polyethylene glycol-poly-racemic lactic acid, and an emulsifier is polyvinyl alcohol, so that the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere with the microporous structure can be obtained. Because the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microspheres are in a porous structure, compared with solid microspheres in the prior art, the microspheres with the porous structure have lighter mass and loose packing density, and the stability of the microspheres in a further prepared liquid preparation can be greatly improved. Prior to the present application, the skilled person was not aware of the possibility to improve the stability of microspheres in further prepared liquid formulations by preparing microspheres of porous structure and that there is no technical solution how to prepare microspheres of porous structure. Moreover, the inventors have not realized that such excellent stability in application to liquid formulations would be so excellent, that the stability would be well beyond the expected effect, after preparation of microspheres to obtain such porous structures, thus obtaining unexpected technical effects. Meanwhile, the polyethylene glycol-poly-dl-lactic acid block copolymer is a medical grade auxiliary material approved by FDA, has the characteristics of good biological safety and no immunogenicity, the degradation rate of poly-dl-lactic acid in the copolymer in vivo is high, the degradation product lactic acid also has excellent effect of stimulating the regeneration of fibroblasts and collagen in the skin, and the treatment effect of the single-component polycaprolactone microsphere filler is effectively improved. Meanwhile, the polyethylene glycol-poly-dl-lactic acid has excellent solubility in an oil phase solvent dichloromethane or trichloromethane, so that the preparation of the microspheres can be carried out by a simple oil-in-water single-phase emulsification method, the preparation process is simple to operate, the production cost is low, the production efficiency is high, and the method is suitable for industrial large-scale production.
Furthermore, by controlling the reaction conditions, raw material selection and the like in the method, the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere with a microporous structure, which has small particle size (the particle size is 10-100 mu m), narrow distribution and good stability, can be finally prepared.
In addition, the microporous PCL/PEG-PDLLA composite microsphere soft tissue filler prepared by the method has excellent water phase dispersibility, and the dispersed suspension is uniform, fine and good in needle penetration, has quick response, outstanding filling effect and good plasticity when being used as a cosmetic filling material, is more suitable for stimulating the proliferation of fibroblasts in skin tissues and accelerating the secretion of collagen, and is an excellent medical cosmetic soft tissue filling product.
The above and other objects, advantages and features of the present invention will become more apparent to those skilled in the art from the following detailed description of specific embodiments thereof, taken in conjunction with the accompanying drawings.
Drawings
Some specific embodiments of the invention will be described in detail hereinafter, by way of illustration and not limitation, with reference to the accompanying drawings. The same reference numbers in the drawings identify the same or similar elements or components. Those skilled in the art will appreciate that the drawings are not necessarily drawn to scale. In the drawings:
fig. 1 shows a schematic flow diagram of a method of preparing an injectable soft tissue filler according to one embodiment of the invention;
FIG. 2 shows a schematic flow diagram of an oil-in-water single phase emulsification process according to one embodiment of the present invention;
FIG. 3 (a) shows a scanning electron microscope image of a PCL/PEG-PDLLA composite microsphere obtained by the preparation method according to the embodiment of the present invention;
FIG. 3 (b) is a graph showing the average aerodynamic particle size of PCL/PEG-PDLLA composite microspheres obtained by the preparation method according to the embodiment of the present invention;
FIG. 4 (a) shows a scanning electron microscope image of a PCL/PEG-PDLLA composite microsphere obtained by the preparation method according to the embodiment of the present invention;
FIG. 4 (b) is a graph showing the average aerodynamic particle size of PCL/PEG-PDLLA composite microspheres obtained by the preparation method according to the embodiment of the present invention;
FIG. 5 (a) shows a scanning electron microscope image of a PCL/PEG-PDLLA composite microsphere obtained by the preparation method according to the embodiment of the present invention;
FIG. 5 (b) is a graph showing the average aerodynamic particle size of PCL/PEG-PDLLA composite microspheres obtained by the preparation method according to the embodiment of the present invention;
FIG. 6 (a) shows a scanning electron microscope image of a PCL/PEG-PDLLA composite microsphere obtained by the preparation method according to the embodiment of the present invention;
FIG. 6 (b) is a graph showing the average aerodynamic particle size of PCL/PEG-PDLLA composite microspheres obtained by the preparation method according to the embodiment of the present invention;
FIG. 7 (a) shows a scanning electron microscope image of a PCL/PEG-PDLLA composite microsphere obtained by the preparation method according to the embodiment of the present invention;
FIG. 7 (b) is a graph showing the average aerodynamic particle size of PCL/PEG-PDLLA composite microspheres obtained by the preparation method according to the embodiment of the present invention;
fig. 8 (a) shows a scanning electron microscope image of PCL microspheres obtained by the preparation method according to the embodiment of the invention;
fig. 8 (b) shows a graph of the average aerodynamic particle size of PCL microspheres obtained by the preparation method according to the embodiment of the present invention;
FIG. 9 shows nuclear magnetic hydrogen spectra of PCL/PEG-PDLLA composite microspheres and PCL microspheres obtained by the preparation methods of examples 4 and 6 of the present invention;
FIG. 10 (a) shows loose packing density comparison data of PCL/PEG-PDLLA composite microspheres and PCL microspheres obtained by the preparation methods of examples 4 and 6 according to the present invention;
FIG. 10(b) is a scanning electron micrograph of a PCL/PEG-PDLLA composite microsphere obtained according to the preparation method of example four of the present invention;
FIG. 10(c) is another SEM photo of PCL/PEG-PDLLA composite microsphere obtained according to the fourth preparation method of the present invention;
fig. 11 (a) shows a photograph of an injectable soft tissue filler obtained according to a method of preparing an injectable soft tissue filler according to an embodiment of the present invention;
fig. 11 (b) shows a photograph of an injectable soft tissue filler solution injected through a 26g needle syringe;
FIG. 12 is a graph showing the evaluation of biosafety of injectable soft tissue fillers and the effect of stimulating tissue collagen proliferation by hematoxylin-eosin staining and collagen fiber staining of tissue sections according to an embodiment of the present invention;
fig. 13 is a graph showing the evaluation of biosafety of injectable soft tissue fillers and the effect of stimulating tissue collagen proliferation by collagen fiber staining of tissue sections according to an embodiment of the present invention.
Detailed Description
The following description of the embodiments of the present application is provided by way of specific examples, and other advantages and effects of the present application will be readily apparent to those skilled in the art from the disclosure herein. It is to be understood that the embodiments described are only a few embodiments of the present application and not all embodiments. The present application is capable of other and different embodiments and its several details are capable of modifications and/or changes in various respects, all without departing from the spirit of the present application. It is to be noted that the features in the following embodiments and examples may be combined with each other without conflict. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
It should be noted that the drawings provided in the following embodiments are only schematic representations of the basic idea of the present application, and the drawings only show the structures related to the present application rather than the numbers, shapes and sizes of the structures in practical implementation, the quantities and proportions of the components in practical implementation can be changed freely, and the layout of the material components can be more complicated.
In addition, in the following description, specific details are provided to facilitate a thorough understanding of the examples. However, it will be understood by those skilled in the art that the aspects may be practiced without these specific details.
Particularly, the invention provides a preparation method of a polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere with a microporous structure, which is characterized in that the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere with a porous structure is prepared by adopting an oil-in-water single-phase emulsification method, wherein an oil phase solution in the oil-in-water single-phase emulsification method is a dichloromethane solution of polycaprolactone and polyethylene glycol-poly-racemic lactic acid or a trichloromethane solution of polycaprolactone and polyethylene glycol-poly-racemic lactic acid, and an emulsifier is polyvinyl alcohol. The Polycaprolactone is known in english as Polycaprolactone, abbreviated PCL. The Polyethylene glycol is Polyethylene glycol in English, and is abbreviated as PEG. The Poly-dl-lactic acid is abbreviated as Poly (D, L-lactate), D, L-polylactate, and is abbreviated as PDLLA. The polyethylene glycol-poly-racemic lactic acid is hereinafter referred to as PEG-PDLLA. The polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere is hereinafter referred to as PCL/PEG-PDLLA composite microsphere. The polyvinyl alcohol is abbreviated as PVA and is known in English as polyvinyl alcohol.
Fig. 1 shows a schematic flow diagram of a method of preparing an injectable soft tissue filler according to one embodiment of the present invention. As shown in fig. 1, the preparation method comprises:
step S110, mixing the microporous polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microspheres prepared by the preparation method with a sterilized auxiliary material solution to obtain a mixed solution, wherein the mass percentage of the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microspheres in the mixed solution is any one of 10-50%;
and step S120, subpackaging the mixed solution to obtain the injectable soft tissue filler.
According to the scheme of the embodiment of the invention, the microporous polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microspheres are prepared by an oil-in-water single-phase emulsification method, an oil phase solution in the oil-in-water single-phase emulsification method is a dichloromethane solution of polycaprolactone and polyethylene glycol-poly-racemic lactic acid or a chloroform solution of polycaprolactone and polyethylene glycol-poly-racemic lactic acid, and an emulsifier is polyvinyl alcohol, so that the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microspheres with a porous structure can be obtained. Because the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microspheres are in a porous structure, compared with the solid microspheres in the prior art, the microspheres with the porous structure have lighter mass and apparent density, so that the stability of the microspheres in a further prepared liquid preparation can be greatly improved. Prior to the present application, the skilled person was not aware of the possibility to improve the stability of microspheres in further prepared liquid formulations by preparing microspheres of porous structure and that there is no technical solution how to prepare microspheres of porous structure. Moreover, the inventors have not realized that such excellent stability in application to liquid formulations would be so excellent, that the stability would be well beyond the expected effect, after preparation of microspheres to obtain such porous structures, thus obtaining unexpected technical effects. Meanwhile, the polyethylene glycol-poly-dl-lactic acid block copolymer is a medical grade auxiliary material approved by FDA, has the characteristics of good biological safety and no immunogenicity, the degradation rate of poly-dl-lactic acid in the copolymer in vivo is high, and the degradation product lactic acid has excellent effect of stimulating the regeneration of fibroblasts and collagen in the skin, thereby effectively making up the defect of poor immediate treatment effect of the single-component polycaprolactone microsphere filler. Meanwhile, the polyethylene glycol-poly-dl-lactic acid has excellent solubility in an oil phase solvent dichloromethane or trichloromethane, so that the preparation of the microspheres can be carried out by a simple oil-in-water single-phase emulsification method, the preparation process is simple to operate, the production cost is low, the production efficiency is high, and the method is suitable for industrial large-scale production.
In one embodiment, in the preparation method of the microporous polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere, the intrinsic viscosity of polycaprolactone in the oil phase solution is any value of 0.5-1.0dl/g, for example, 0.5dl/g, 0.6dl/g, 0.7dl/g, 0.8dl/g, 0.9dl/g or 1.0 dl/g. The polycaprolactone can be directly purchased in the market and also can be prepared by the existing preparation method, so that the polycaprolactone with the intrinsic viscosity is selected as a raw material, and the raw material source is wide and convenient. The mass concentration of the polycaprolactone may be 5 to 20%, for example, 5%, 8%, 10%, 12%, 15%, 18%, or 20%. The concentration of the polycaprolactone can be 0.01g/mL, 0.02g/mL, 0.05g/mL, 0.1g/mL, or 0.3g/mL, or any other concentration value from 0.01 to 0.3 g/mL. For a polycaprolactone raw material with a molecular weight, the low PCL acid concentration can effectively reduce the agglomeration phenomenon among PCL/PEG-PDLL composite microspheres in the emulsification process, so that the average particle size of the prepared composite microspheres is smaller.
The polyethylene glycol-poly-racemic lactic acid in the oil phase solution is a polyethylene glycol monomethyl ether-poly-racemic lactic acid diblock copolymer or a poly-racemic lactic acid-polyethylene glycol-poly-racemic lactic acid triblock copolymer. The molecular weight of polyethylene glycol in the oil phase solution is in any value of 2-10KDa, and can be 2KDa, 3KDa, 5KDa, 6KDa, 8KDa, 9KDa or 10 KDa. The molecular weight of the poly-racemic lactic acid in the oil phase solution is any value of 1-5KDa, and can be 1KDa, 2KDa, 3KDa, 4KDa or 5KDa, for example. The mass concentration of the poly-racemic lactic acid is 0.01 to 5%, and may be, for example, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, or 5%. The concentration of PEG-PDLLA in the oil phase solution may be 0.0025g/mL, 0.005 g/mL, 0.01g/mL, 0.02g/mL, or 0.05g/mL, or any other concentration value from 0.0025 to 0.05 g/mL. The high PEG-PDLLA concentration can ensure that the composite microspheres have better lactic acid generated by initial degradation and better collagen regeneration stimulation effect after being implanted into organisms.
The aqueous phase solution in this oil-in-water single-phase emulsification method is a solution obtained by dissolving the aforementioned emulsifier in ultrapure water. The volume ratio of the oil phase solution to the water phase solution is any ratio of 1:4-1:20, for example, 1:4, 1:8, 1:10 or 1:20, or any ratio of 1:4-1: 20. The lower the volume ratio of the oil phase is, the smaller the number of emulsion droplets dispersed in the water phase is, the less the emulsion droplets are easy to agglomerate, and further the stability of the emulsion is better, so that the average particle size of the prepared composite microspheres is smaller.
In the aqueous solution, the molecular weight of the polyvinyl alcohol is 10-100KDa, for example, 10KDa, 20KDa, 50KDa or 100KDa, or any one of 10-100 KDa. The mass concentration of the polyvinyl alcohol is 0.5 to 3%, and may be, for example, 0.5%, 1%, 1.5%, 2%, 2.5%, or 3%. The high PVA concentration can effectively reduce the agglomeration phenomenon among the PCL/PEG-PDLL composite microspheres in the emulsification process and improve the stability of the microsphere emulsion, so that the average particle size of the prepared composite microspheres is smaller.
FIG. 2 shows a schematic flow diagram of an oil-in-water single phase emulsification process according to one embodiment of the present invention.
As shown in fig. 2, the oil-in-water single-phase emulsification method includes:
step S100, adding the aqueous phase solution into a reaction kettle;
step S200, adding the oil phase solution into the water phase solution under mechanical stirring, and continuing stirring until the dichloromethane solvent or the trichloromethane in the oil phase solution is completely volatilized to obtain a reaction solution;
step S300, carrying out suction filtration on the reaction solution to obtain a microporous polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere solution;
step S400, cleaning, filtering and drying the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere solution to obtain polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere powder;
and S500, packaging the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere powder and then sterilizing to obtain the sterile polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere.
In step S200, the stirring speed of the mechanical stirring is any value of 200-2000rpm, such as 200rpm, 500rpm, 800rpm, 1000rpm, 1500rpm, 1800rpm or 2000 rpm. The stirring time of the mechanical stirring is any value of 6 to 48 hours, and may be, for example, 6 hours, 10 hours, 15 hours, 20 hours, 25 hours, 30 hours, 35 hours, 40 hours, 45 hours, or 48 hours. Under high-speed stirring, the better the dispersibility of emulsion drops in a water phase, the less possibility of agglomeration and the better stability of the emulsion, so that the prepared composite microspheres have smaller average particle size and more uniform particle size.
In step S300, the pore diameter of the filtration membrane used for the suction filtration is any of 0.45 to 3 μm, and may be, for example, 0.45 μm, 1 μm, 1.5 μm, 2 μm, 2.5 μm or 3 μm. The larger the pore size of the filter membrane, the higher the filtration efficiency and the faster the filtration speed, but the use of a large pore size filter membrane tends to lose some of the small size particles during the filtration process.
In step S400, the PCL/PEG-PDLLA composite microsphere solution is re-dispersed into ultrapure water, stirred and cleaned, and the PVA emulsifier on the surface of the composite microsphere is removed. In the drying step, the purified microspheres are freeze-dried or vacuum-dried at 30-50 ℃. The average particle diameter of the finally obtained microporous poly-L-lactic acid particles is 10-100 mu m. The polylactic acid particles finally obtained are in the form of powder.
In step S500, the irradiation dose is any one of 7 to 15kGy, and may be, for example, 7kGy, 8kGy, 9kGy, 10kGy, 12kGy, 14kGy, or 15kGy, by irradiation sterilization with cobalt 60.
By controlling the reaction conditions, raw material selection and the like in the method, the microporous PCL/PEG-PDLLA composite microsphere with small particle size (the particle size is 10-100 mu m), narrow distribution and good stability can be finally prepared.
In the first step of the preparation method of the injectable soft tissue filler, the auxiliary material can be one or more of sodium hyaluronate, sodium carboxymethylcellulose, dextran, glycerol, PEG-400, mannitol and tranexamic acid. By optimizing the formula of the auxiliary materials, the dispersibility and stability of the PCL/PEG-PDLLA composite microspheres in the filler are improved, and the PCL/PEG-PDLLA composite microsphere suspension which is uniform, fine and good in needle permeability is obtained. Meanwhile, after the auxiliary material is injected into organism soft tissues, the auxiliary material has certain effects of nourishing soft tissue cells and repairing tissues, and can achieve a better soft tissue filling effect by matching the auxiliary material with the poly-L-lactic acid.
When the auxiliary material is selected to be sodium hyaluronate, the mass percentage content of the sodium hyaluronate in the injectable soft tissue filler can be 1%, 2%, 3% or 5%, and any other proportion of 1-5% can also be adopted. The molecular weight of the sodium hyaluronate is 200KDa, 500KDa, 600KDa or 1000KDa, or any other molecular weight of 200KDa and 1000 KDa. The molecular weight of the sodium hyaluronate is selected within the range, and the sodium hyaluronate can be directly purchased and obtained on the market, so that the sodium hyaluronate with the molecular weight within the range is selected as an auxiliary material, and the auxiliary material is wide and convenient in source.
When the auxiliary material is selected to be sodium carboxymethyl cellulose, the mass percentage content of the sodium carboxymethyl cellulose in the injectable soft tissue filler can be 1%, 2%, 5% or 10% or any other proportion of 1-10%. The molecular weight of the sodium carboxymethylcellulose can be 50KDa, 100KDa, 200KDa or 500KDa, and can also be any other molecular weight of 50-500 KDa. The molecular weight of the sodium carboxymethylcellulose is selected within the range, and the sodium carboxymethylcellulose can be directly purchased and obtained on the market, so that the sodium carboxymethylcellulose with the molecular weight within the range is selected as an auxiliary material, and the auxiliary material is wide and convenient in source.
When the auxiliary material is selected to be glucan, the mass percentage of the glucan in the injectable soft tissue filler can be 1%, 2%, 5% or 20%, and any other proportion of the glucan in the range of 1-20%. The molecular weight of glucan is 20KDa, 40KDa, 70KDa or 500KDa, or any other molecular weight of 20-500 KDa. The molecular weight of the glucan is selected to be within the range, and the glucan can be directly purchased and obtained on the market, so that the glucan with the molecular weight within the range is selected as the auxiliary material, and the auxiliary material is wide and convenient in source.
When the adjuvant is selected to be glycerol, the content of glycerol in the injectable soft tissue filler can be 2%, 10% or 20% by mass, or any other proportion of 2-20% by mass. The glycerol is added into the soft tissue filler, so that the water delivery property of the surface of the PCL/PEG-PDLLA composite microsphere can be improved, and the suspension property and the stability of the microsphere in the filler are improved.
When the auxiliary material is PEG-400, the weight percentage content of the PEG-400 in the injectable soft tissue filler can be 5%, 10%, 20% or 30%, or any other proportion of 5-30%. The glycerol is added into the soft tissue filler, so that the water delivery property of the surface of the PCL/PEG-PDLLA composite microsphere can be improved, and the suspension property and the stability of the microsphere in the filler are improved.
When the auxiliary material is mannitol, the mass percentage content of the mannitol in the filler for injecting soft tissues can be 0.1%, 1% or 5%, or any other proportion of 0.1-5%. The mannitol is added into the soft tissue filler, so that the water delivery performance of the surface of the PCL/PEG-PDLLA composite microsphere can be improved, and the suspension property and stability of the microsphere in the filler are improved.
When the auxiliary material is selected to be tranexamic acid, the mass percentage content of the tranexamic acid in the soft tissue filler for injection can be 0.1%, 0.4%, 1% or 3%, and any other proportion of 0.1-3% can also be selected. The tranexamic acid is added into the soft tissue filler, so that the tissue swelling degree after the injection of the soft tissue filler can be reduced, and the skin whitening effect is achieved.
In the first step of the preparation method of the injectable soft tissue filler, the sterilization method is damp-heat sterilization, the damp-heat temperature is 121 ℃, and the damp-heat time can be 15min, 30min or 60min, or any time of 15-60 min. The moist heat time is within 15-60min, the soft tissue filler can be effectively sterilized, and the safety of the filler in clinical use is improved. The mass percentage content of the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microspheres in the mixed solution is any value of 10-50%, for example, 10%, 20%, 30% or 50%. According to the clinical soft tissue filling level requirement, the soft tissue filling agent with different batches can be prepared by changing the percentage content of the PCL/PEG-PDLLA composite microspheres in the filling agent, and the action time and the lasting effect of the filling agent in vivo are prolonged.
According to the scheme of the embodiment of the invention, the microporous PCL/PEG-PDLLA composite microsphere soft tissue filler prepared by the method has excellent water phase dispersibility, the suspension obtained after dispersion is uniform and fine, the needle penetration is good, the effect is quick, the filling effect is outstanding when the filler is used as a cosmetic filling material, the plasticity is good, the filler is more suitable for stimulating the proliferation of fibroblasts in skin tissues and accelerating the secretion of collagen, and the filler is an excellent medical cosmetic soft tissue filling product.
The following is illustrated in detail by specific examples:
examples 1,
The embodiment of the invention provides a preparation method of a microporous PCL/PEG-PDLLA composite microsphere, which comprises the following steps:
1) weighing 40g of PCL with intrinsic viscosity of 0.9dl/g and 20g of PDLLA-PEG-PDLLA (wherein the molecular weight of PEG is 10KDa, and the molecular weight of PDLLA is 3300KDa), and dissolving in 400mL of dichloromethane solvent to obtain oil phase solution;
2) dissolving 20g of PVA emulsifier in 2L of ultrapure water to prepare a water phase;
3) adding the oil phase into the water phase under the condition of mechanical stirring at 400rpm, and keeping for 6 hours;
4) filtering the reaction solution through a filter membrane of 3 mu m to obtain a reaction product PCL/PEG-PDLLA composite microsphere;
5) re-dispersing the PCL/PEG-PDLLA composite microspheres into 600mL of ultrapure water, mechanically stirring and cleaning the PVA emulsifier on the surfaces of the microspheres, then carrying out suction filtration to remove the cleaning aqueous solution, and repeating the cleaning-suction filtration process for 3 times to obtain purified PCL/PEG-PDLLA composite microspheres;
6) putting the proposed PCL/PEG-PDLLA composite microspheres into a freeze dryer, and freeze-drying to obtain PCL/PEG-PDLLA composite microsphere powder materials;
7) packaging the PCL/PEG-PDLLA composite microsphere powder, and performing irradiation sterilization with the irradiation dose of 15 kGy;
fig. 3 (a) shows a scanning electron microscope image of the PCL/PEG-PDLLA composite microspheres obtained by the preparation method according to the embodiment of the present invention. Fig. 3 (b) shows a graph of the average aerodynamic particle size of the PCL/PEG-PDLLA composite microspheres obtained by the preparation method according to the embodiment of the present invention. As shown in FIG. 3 (b), the average aerodynamic particle diameter Dv (50) of the PCL/PEG-PDLLA composite microsphere powder was 48 μm. The organic solvent residue of the dried poly (L-lactic acid) was determined by headspace gas chromatography, with less than 0.02% methylene chloride.
Examples 2,
The embodiment of the invention provides a preparation method of a microporous PCL/PEG-PDLLA composite microsphere, which comprises the following steps:
1) weighing 40g of PCL with intrinsic viscosity of 0.9dl/g and 2g of PDLLA-PEG-PDLLA (wherein the molecular weight of PEG is 10KDa, and the molecular weight of PDLLA is 3300KDa), and dissolving in 400mL of dichloromethane solvent to obtain oil phase solution;
2) dissolving 20g of PVA emulsifier in 2L of ultrapure water to prepare a water phase;
3) adding the oil phase into the water phase under the condition of mechanical stirring at 400rpm, and keeping for 6 hours;
4) filtering the reaction solution through a filter membrane of 3 mu m to obtain a reaction product PCL/PEG-PDLLA composite microsphere;
5) re-dispersing the PCL/PEG-PDLLA composite microspheres into 600mL of ultrapure water, mechanically stirring and cleaning the PVA emulsifier on the surfaces of the microspheres, then carrying out suction filtration to remove the cleaning aqueous solution, and repeating the cleaning-suction filtration process for 3 times to obtain the purified PCL/PEG-PDLLA composite microspheres.
6) Putting the proposed PCL/PEG-PDLLA composite microspheres into a freeze dryer, and freeze-drying to obtain the PCL/PEG-PDLLA composite microsphere powder material.
7) Packaging the PCL/PEG-PDLLA composite microsphere powder, and performing irradiation sterilization with the irradiation dose of 15 kGy;
fig. 4 (a) shows a scanning electron microscope image of the PCL/PEG-PDLLA composite microspheres obtained by the preparation method according to the embodiment of the present invention. Fig. 4 (b) shows a graph of the average aerodynamic particle size of the PCL/PEG-PDLLA composite microspheres obtained by the preparation method according to the embodiment of the present invention. As shown in FIG. 4 (b), the average aerodynamic particle diameter Dv (50) of the PCL/PEG-PDLLA composite microsphere powder was 48.8. mu.m. The organic solvent residue of the dried poly (L-lactic acid) was determined by headspace gas chromatography, with less than 0.02% methylene chloride.
Examples 3,
The embodiment of the invention provides a preparation method of a microporous PCL/PEG-PDLLA composite microsphere, which comprises the following steps:
1) weighing 40g of PCL with intrinsic viscosity of 0.9dl/g and 2g of PDLLA-PEG-PDLLA (wherein the molecular weight of PEG is 10KDa, and the molecular weight of PDLLA is 3300KDa), and dissolving in 400mL of dichloromethane solvent to obtain oil phase solution;
2) dissolving 10g of PVA emulsifier in 2L of ultrapure water to prepare a water phase;
3) adding the oil phase into the water phase under the condition of mechanical stirring at 400rpm, and keeping for 6 hours;
4) filtering the reaction solution through a filter membrane of 3 mu m to obtain a reaction product PCL/PEG-PDLLA composite microsphere;
5) re-dispersing the PCL/PEG-PDLLA composite microspheres into 600mL of ultrapure water, mechanically stirring and cleaning the PVA emulsifier on the surfaces of the microspheres, then carrying out suction filtration to remove the cleaning aqueous solution, and repeating the cleaning-suction filtration process for 3 times to obtain the purified PCL/PEG-PDLLA composite microspheres.
6) Putting the proposed PCL/PEG-PDLLA composite microspheres into a freeze dryer, and freeze-drying to obtain the PCL/PEG-PDLLA composite microsphere powder material.
7) Packaging the PCL/PEG-PDLLA composite microsphere powder, and performing irradiation sterilization with the irradiation dose of 15 kGy;
fig. 5 (a) shows a scanning electron microscope image of the PCL/PEG-PDLLA composite microspheres obtained by the preparation method according to the embodiment of the present invention. Fig. 5 (b) shows a graph of the average aerodynamic particle size of PCL/PEG-PDLLA composite microspheres obtained according to the preparation method of the embodiment of the present invention. As shown in FIG. 5 (b), the average aerodynamic particle diameter Dv (50) of the PCL/PEG-PDLLA composite microsphere powder was 68.1. mu.m. The organic solvent residue of the dried poly (L-lactic acid) was determined by headspace gas chromatography, with less than 0.02% methylene chloride.
Examples 4,
The embodiment of the invention provides a preparation method of a microporous PCL/PEG-PDLLA composite microsphere, which comprises the following steps:
1) weighing 20g of PCL with intrinsic viscosity of 0.9dl/g and 1g of PDLLA-PEG-PDLLA (wherein the molecular weight of PEG is 10KDa, and the molecular weight of PDLLA is 3300KDa), and dissolving in 400mL of dichloromethane solvent to obtain oil phase solution;
2) dissolving 20g of PVA emulsifier in 2L of ultrapure water to prepare a water phase;
3) adding the oil phase into the water phase under the condition of mechanical stirring at 600rpm, and keeping for 6 hours;
4) filtering the reaction solution through a filter membrane of 3 mu m to obtain a reaction product PCL/PEG-PDLLA composite microsphere;
5) re-dispersing the PCL/PEG-PDLLA composite microspheres into 600mL of ultrapure water, mechanically stirring and cleaning the PVA emulsifier on the surfaces of the microspheres, then carrying out suction filtration to remove the cleaning aqueous solution, and repeating the cleaning-suction filtration process for 3 times to obtain the purified PCL/PEG-PDLLA composite microspheres.
6) Putting the proposed PCL/PEG-PDLLA composite microspheres into a freeze dryer, and freeze-drying to obtain the PCL/PEG-PDLLA composite microsphere powder material.
7) Packaging the PCL/PEG-PDLLA composite microsphere powder, and performing irradiation sterilization with the irradiation dose of 15 kGy;
fig. 6 (a) shows a scanning electron microscope image of the PCL/PEG-PDLLA composite microspheres obtained by the preparation method according to the embodiment of the present invention. Fig. 6 (b) shows a graph of the average aerodynamic particle size of PCL/PEG-PDLLA composite microspheres obtained by the preparation method according to the embodiment of the present invention. As shown in FIG. 6 (b), the average aerodynamic particle diameter Dv (50) of the PCL/PEG-PDLLA composite microsphere powder was 41.5. mu.m. The organic solvent residue of the dried poly (L-lactic acid) was determined by headspace gas chromatography, with less than 0.02% methylene chloride.
Examples 5,
The embodiment of the invention provides a preparation method of a microporous PCL/PEG-PDLLA composite microsphere, which comprises the following steps:
1) weighing 20g of PCL with intrinsic viscosity of 0.9dl/g and 1g of PDLLA-PEG-PDLLA (wherein the molecular weight of PEG is 10KDa, and the molecular weight of PDLLA is 3300KDa), and dissolving in 200mL of dichloromethane solvent to obtain oil phase solution;
2) dissolving 20g of PVA emulsifier in 2L of ultrapure water to prepare a water phase;
3) adding the oil phase into the water phase under the condition of mechanical stirring at 600rpm, and keeping for 6 hours;
4) filtering the reaction solution through a filter membrane of 3 mu m to obtain a reaction product PCL/PEG-PDLLA composite microsphere;
5) re-dispersing the PCL/PEG-PDLLA composite microspheres into 600mL of ultrapure water, mechanically stirring and cleaning the PVA emulsifier on the surfaces of the microspheres, then carrying out suction filtration to remove the cleaning aqueous solution, and repeating the cleaning-suction filtration process for 3 times to obtain the purified PCL/PEG-PDLLA composite microspheres.
6) Putting the proposed PCL/PEG-PDLLA composite microspheres into a freeze dryer, and freeze-drying to obtain the PCL/PEG-PDLLA composite microsphere powder material.
7) Packaging the PCL/PEG-PDLLA composite microsphere powder, and performing irradiation sterilization with the irradiation dose of 15 kGy;
fig. 7 (a) shows a scanning electron microscope image of PCL/PEG-PDLLA composite microspheres obtained by the preparation method according to the embodiment of the present invention. Fig. 7 (b) shows a graph of the average aerodynamic particle size of PCL/PEG-PDLLA composite microspheres obtained according to the preparation method of the embodiment of the present invention. As shown in FIG. 7 (b), the average aerodynamic particle diameter Dv (50) of the PCL/PEG-PDLLA composite microsphere powder was 161. mu.m. The organic solvent residue of the dried poly (L-lactic acid) was determined by headspace gas chromatography, with less than 0.02% methylene chloride.
Examples 6,
The embodiment of the invention provides a preparation method of PCL microspheres, which comprises the following steps:
1) weighing 20g of PCL with the intrinsic viscosity of 0.9dl/g, and dissolving the PCL in 400mL of dichloromethane solvent to prepare an oil phase solution;
2) dissolving 20g of PVA emulsifier in 2L of ultrapure water to prepare a water phase;
3) adding the oil phase into the water phase under the condition of mechanical stirring at 600rpm, and keeping for 6 hours;
4) filtering the reaction solution through a filter membrane of 3 mu m to obtain a reaction product PCL microsphere;
5) dispersing the PCL microspheres into 600mL of ultrapure water again, mechanically stirring and cleaning the PVA emulsifier on the surfaces of the microspheres, then carrying out suction filtration to remove the cleaning aqueous solution, and repeating the cleaning-suction filtration process for 3 times to obtain the purified PCL microspheres.
6) Putting the proposed PCL microspheres into a freeze dryer, and freeze-drying to obtain the PCL microsphere powder material.
7) Packaging the PCL microsphere powder, and then performing irradiation sterilization, wherein the irradiation dose is 15 kGy;
fig. 8 (a) shows a scanning electron microscope image of PCL microspheres obtained by the preparation method according to the embodiment of the invention. Fig. 8 (b) shows a graph of the average aerodynamic particle size of PCL microspheres obtained by the preparation method according to the embodiment of the present invention. As shown in FIG. 8 (b), the average aerodynamic particle diameter Dv (50) of the PCL microsphere powder was 72.4. mu.m. The organic solvent residue of the dried poly (L-lactic acid) was determined by headspace gas chromatography, with less than 0.02% methylene chloride.
FIG. 9 shows nuclear magnetic hydrogen spectra of PCL/PEG-PDLLA composite microspheres and PCL microspheres obtained by the preparation methods of examples 4 and 6 of the present invention. As can be seen from FIG. 9, compared with the single-component PCL microspheres, the PCL/PEG-PDLLA composite microspheres exhibit an obvious proton oscillation peak of a PEG molecular chain at a position of 3.3-3.9ppm, which indicates that the microspheres are formed by compounding PCL and PEG-PDLLA.
Fig. 10 (a) shows loose packing density comparison data of PCL/PEG-PDLLA composite microspheres and PCL microspheres obtained according to the preparation methods of examples 4 and 6 of the present invention. As shown in FIG. 10 (a), the apparent density of the PCL/PEG-PDLLA composite microspheres is lower than that of the PCL microspheres, namely 0.36g/mL, compared with the apparent density of the single-component PCL microspheres, namely 0.49 g/mL. The lower apparent density can effectively improve the dispersibility and stability of the microspheres in the adjuvant solution, so that the suspension obtained after the microspheres are dispersed is uniform, fine and good in needle permeability. FIGS. 10(b) and (c) are SEM pictures of the PCL/PEG-PDLLA composite microsphere obtained according to the preparation method of example 4. As can be seen from (b) and (c) in fig. 10, the PCL/PEG-PDLLA composite microspheres are porous structures, and compared with non-porous microspheres, the microspheres with porous structures have lighter mass, which is beneficial to improving the stability of the microspheres in a liquid preparation, and meanwhile, the PCL microspheres with porous structures have higher specific surface area, and after the PCL microspheres are implanted into skin tissues, the contact area of the material with high specific surface area and interstitial fluid is larger, so that the degradation of the material itself and the release rate of 6-hydroxyhexanoic acid are faster at the initial stage of implantation, and the effects of stimulating collagen regeneration and tissue filling are better. .
Example 7,
The embodiment of the invention provides a preparation method of an injectable soft tissue filler, which comprises the following steps:
1) 2g of sodium hyaluronate (molecular weight 500kDa), 0.4g of tranexamic acid and 10mL of glycerol were added to 100mL of physiological saline for injection, and stirred at 400rpm for 6 hours until the sample was completely dissolved. Sterilizing the solution at 121 deg.C under wet heat for 15 min;
2) weighing 20g of the microporous PCL/PEG-PDLLA composite microspheres prepared in the embodiment 4, adding the microporous PCL/PEG-PDLLA composite microspheres into the sterilized auxiliary material solution, further stirring at 400rpm for 4h, and uniformly dispersing the composite microspheres in the auxiliary material solution;
3) accurately measuring 1mL of the mixed solution by using an injector, and sealing the injector to obtain the injectable soft tissue filler.
Fig. 11 (a) shows a photograph of an injectable soft tissue filler obtained according to a method for preparing an injectable soft tissue filler according to an embodiment of the present invention.
In order to verify that the injectable soft tissue filler has excellent water phase dispersibility, the suspension obtained after dispersion is uniform, fine and smooth, and good in needle penetration, and has the advantages of quick response, outstanding filling effect, good plasticity, capability of promoting the proliferation of collagen and fiber cells of surrounding tissues, less toxic and side effects and the like when being used as a cosmetic filling material, the inventor performs the following verification tests:
the injectable soft tissue filler solution was injected through a 26g needle syringe and found to have excellent needle penetration as shown in fig. 11 (b).
mu.L of the injectable soft tissue filler solution described above was injected subcutaneously into different experimental rats and the rats were sacrificed at weeks 2, 4, 8, 12 and 24 for dissection. Further, the biosafety of injectable soft tissue fillers and the effect of stimulating collagen proliferation of tissues were evaluated by hematoxylin-eosin staining (HE staining) and collagen fiber staining (Masson staining) of tissue sections. The HE staining method proves that the state of the subcutaneous injection tissue and the peripheral cells of the rat is good, and no obvious cell atrophy phenomenon exists at the tissue part after 24 weeks of injection, as shown in figure 12. Masson staining demonstrated significant collagen proliferation effects in the injected tissue and its periphery over time, and staining of tissue sections appeared dark blue (if the figures were gray-scale images, the dark blue color could not be seen, but in the actual effect images, the dark blue color was spread over other areas than the round cells in the figures), as shown in FIG. 13.
Example 8,
The embodiment of the invention provides a preparation method of an injectable soft tissue filler, which comprises the following steps:
1) 1.5g of sodium carboxymethylcellulose (molecular weight 200kDa), 0.12g of tranexamic acid, 0.3g of mannitol and 6mL of glycerol were added to 30mL of physiological saline for injection, and stirred at 600rpm for 6 hours until the sample was completely dissolved. Sterilizing the solution at 121 deg.C for 60 min;
2) weighing 9g of the PCL/PEG-PDLLA composite microspheres prepared in the embodiment 1, adding the composite microspheres into the sterilized auxiliary material solution, further stirring at 400rpm for 4h, and uniformly dispersing the composite microspheres in the auxiliary material solution;
3) accurately measuring 1mL of the mixed solution by using an injector, and sealing the injector to obtain the injectable soft tissue filler.
Examples 9,
The embodiment of the invention provides a preparation method of an injectable soft tissue filler, which comprises the following steps:
1) 1.5g of dextran (molecular weight 100KDa), 0.2g of tranexamic acid and 0.2g of mannitol and 3mL of glycerol were added to 30mL of physiological saline for injection, and stirred at 600rpm for 6h until the sample was completely dissolved. Sterilizing the solution at 121 deg.C for 30 min;
2) weighing 9g of the PCL/PEG-PDLLA composite microspheres prepared in the embodiment 4, adding the composite microspheres into the sterilized auxiliary material solution, further stirring at 400rpm for 4h, and uniformly dispersing the composite microspheres in the auxiliary material solution;
3) accurately measuring 1mL of the mixed solution by using an injector, and sealing the injector to obtain the injectable soft tissue filler.
Examples 10,
The embodiment of the invention provides a preparation method of an injectable soft tissue filler, which comprises the following steps:
1) 1.5g of sodium hyaluronate (molecular weight 500kDa), 0.4g of tranexamic acid, 0.5g of mannitol and 10mL of glycerol were added to 100mL of physiological saline for injection, and stirred at 400rpm for 6h until the sample was completely dissolved. Sterilizing the solution at 121 deg.C for 30 min;
2) weighing 15g of the PCL/PEG-PDLLA composite microspheres prepared in the embodiment 4, adding the composite microspheres into the sterilized auxiliary material solution, further stirring at 400rpm for 4h, and uniformly dispersing the composite microspheres in the auxiliary material solution;
3) accurately measuring 1mL of the mixed solution by using an injector, and sealing the injector to obtain the injectable soft tissue filler.
Thus, it should be understood by those skilled in the art that while various exemplary embodiments of the present invention have been illustrated and described in detail herein, many other variations or modifications which conform to the general principles of the invention may be directly determined or derived from the disclosure herein without departing from the spirit and scope of the invention. Accordingly, the scope of the invention should be understood and interpreted to cover all such other variations or modifications.
Claims (10)
1. The preparation method of the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere with the microporous structure is characterized in that the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere with the porous structure is prepared by adopting an oil-in-water single-phase emulsification method, wherein an oil phase solution in the oil-in-water single-phase emulsification method is a dichloromethane solution of polycaprolactone and polyethylene glycol-poly-racemic lactic acid or a trichloromethane solution of polycaprolactone and polyethylene glycol-poly-racemic lactic acid, and an emulsifier is polyvinyl alcohol.
2. The method according to claim 1, wherein the polyethylene glycol-poly-racemic lactic acid in the oil phase solution is a polyethylene glycol monomethyl ether-poly-racemic lactic acid diblock copolymer or a poly-racemic lactic acid-polyethylene glycol-poly-racemic lactic acid triblock copolymer.
3. The preparation method according to claim 2, wherein the molecular weight of the polyethylene glycol in the oil phase solution is in a range of any value from 2 to 10kDa, the molecular weight of the poly-racemic lactic acid is in a range of any value from 1 to 5kDa, and the mass concentration of the poly-racemic lactic acid is in a range of any value from 0.01 to 5%.
4. The preparation method according to claim 3, wherein the intrinsic viscosity of the polycaprolactone in the oil phase solution is any one of 0.5 to 1.0dl/g, and the mass concentration thereof is any one of 5 to 20%.
5. The production method according to any one of claims 1 to 4, wherein the aqueous phase solution in the oil-in-water single-phase emulsification method is a solution obtained by dissolving the emulsifier in ultrapure water;
the volume ratio of the oil phase solution to the water phase solution is any ratio of 1:4-1: 20.
6. The method according to claim 5, wherein the polyvinyl alcohol in the aqueous solution has a molecular weight of 10 to 100kDa and a mass concentration of 0.5 to 3%.
7. The method for preparing according to any one of claims 1 to 4, wherein the oil-in-water single-phase emulsification method comprises the steps of:
adding the aqueous phase solution into a reaction kettle;
adding the oil phase solution into the water phase solution under mechanical stirring, and continuing stirring until the dichloromethane solvent or the trichloromethane in the oil phase solution is completely volatilized to obtain a reaction solution;
carrying out suction filtration on the reaction solution to obtain a polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere solution;
and cleaning, filtering and drying the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere solution to obtain polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere powder.
8. The method according to claim 7, wherein in the step of adding the oil phase solution into the aqueous phase solution under mechanical stirring, and continuing stirring until the dichloromethane solvent or the chloroform in the oil phase solution is completely volatilized to obtain the reaction solution, the stirring speed of mechanical stirring is any value of 200-2000rpm, and the stirring time is any value of 6-48 h;
optionally, in the step of performing suction filtration on the reaction solution to obtain the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere solution, the aperture of a filter membrane used in the suction filtration is any value of 0.45-3 μm;
optionally, in the step of cleaning, filtering and drying the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere solution to obtain polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere powder, drying is performed in a freeze drying or vacuum drying mode, and the vacuum drying temperature is any value of 30-50 ℃.
9. The method of claim 7, wherein the oil-in-water single phase emulsification process further comprises the steps of:
packaging the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere powder and then sterilizing to obtain sterile polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microspheres;
optionally, in the step of sterilizing after packaging the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microsphere powder, cobalt 60 is used for irradiation sterilization, and the irradiation dose is any value of 7-15 kGy.
10. The preparation method of the injectable soft tissue filler is characterized by comprising the following steps:
mixing the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microspheres with a microporous structure prepared by the preparation method of any one of claims 1 to 9 with a sterilized adjuvant solution to obtain a mixed solution, wherein the mass percentage content of the polycaprolactone/polyethylene glycol-poly-racemic lactic acid composite microspheres in the mixed solution is any one of 10 to 50 percent;
subpackaging the mixed solution to obtain the injectable soft tissue filler.
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