CN116370707A - Injection filler and preparation method thereof - Google Patents
Injection filler and preparation method thereof Download PDFInfo
- Publication number
- CN116370707A CN116370707A CN202211701256.6A CN202211701256A CN116370707A CN 116370707 A CN116370707 A CN 116370707A CN 202211701256 A CN202211701256 A CN 202211701256A CN 116370707 A CN116370707 A CN 116370707A
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- microsphere
- stirring
- injection
- physiologically active
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- 238000002347 injection Methods 0.000 title claims abstract description 48
- 239000007924 injection Substances 0.000 title claims abstract description 48
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- 229940010747 sodium hyaluronate Drugs 0.000 claims description 31
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 31
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- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 claims description 8
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- ZKMNUMMKYBVTFN-HNNXBMFYSA-N (S)-ropivacaine Chemical compound CCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C ZKMNUMMKYBVTFN-HNNXBMFYSA-N 0.000 description 1
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 description 1
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- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
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Images
Classifications
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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
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/24—Collagen
-
- 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
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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
- A61L27/20—Polysaccharides
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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
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
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- 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
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- 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
- A61L27/58—Materials at least partially resorbable by the body
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- A—HUMAN NECESSITIES
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- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Transplantation (AREA)
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- Animal Behavior & Ethology (AREA)
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- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
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Abstract
The invention discloses an injection filler and a preparation method thereof. The injection filler provided by the invention has the advantages of cell compatibility, degradability, natural non-toxicity, cell proliferation induction and migration induction, and has a great application prospect in the biomedical field.
Description
Technical Field
The invention relates to the technical field of biomedicine, in particular to an injection filling agent and a preparation method thereof.
Background
The polymer microsphere is a small particle formed by dispersing polymer in a solvent, the particle size is generally different from a few microns to hundreds of microns, and the degradable polymer microsphere is prepared by a degradable polymer material, has the advantages of biodegradability, biocompatibility and the like, and has wide application in the biomedical field.
Because the degradable polymer microsphere has special performance, the degradable polymer microsphere has wide attention in the biomedical field, particularly in the aspects of tissue engineering, arterial embolism treatment and the like, a plurality of diseases in medicine need to be implanted with foreign materials in vivo, but the human body structure is very complex and fragile, the sensitivity and the compatibility of the foreign materials are very worthy of research, the biocompatibility and the degradability of the degradable polymer microsphere are different from those of other traditional implantable materials, the material itself has natural non-toxic and harmful effects, the material has cell compatibility, and the degradability of the degradable polymer microsphere also ensures the safety of the material. Development of suitable scaffold systems is critical for tissue engineering regeneration and repair. In medicine, defects and wounds of irregular shape often require filling and repair. In this case, the use of injectable stents is very attractive because they can easily fill irregularly shaped defects in situ in a minimally invasive manner, thereby improving patient comfort and satisfaction. With the increasing medical demands for minimally invasive surgery, the development of injectable stents is more urgent. Biodegradable microspheres have also been investigated as injectable cell carriers for bone tissue regeneration. The microsphere has the advantage of acting as a microcarrier for cell culture prior to injection into the body. Therefore, the microsphere has a place in the biomedical field and has great potential.
The majority of natural collagen is derived from animal tissue, skin extracts. Collagen extracted from animals is a water insoluble protein and is not likely to be redissolved without changing molecular weight, and thus, is poorly processable, directly limiting the development of many potential uses. In addition, animal-derived products have the disadvantages of potential safety hazards such as viral infectivity and the like, foreign immunity rejection and the like.
The prior art fillers for cosmetic use have the following problems: serious foreign body reaction, injection pain, poor filling effect and the like.
Disclosure of Invention
The invention mainly aims to provide an injection filling agent and a preparation method thereof, and aims to provide an injection filling agent which has cell compatibility, degradability, natural non-toxicity, cell proliferation and migration inducing performance, no foreign matter reaction and good filling effect.
To achieve the above object, the present invention provides an injection filler comprising: degradable polymer microsphere, physiologically active substance, thickener and surfactant.
Optionally, the content of the degradable polymer microsphere ranges from 10mg/ml to 200mg/ml; and/or the number of the groups of groups,
the content of the physiologically active substance is 10-200mg/ml; and/or the number of the groups of groups,
the content range of the thickener is 10-180mg/ml; and/or the number of the groups of groups,
the content of the surfactant is in the range of 1-100mg/ml.
Optionally, the content of the degradable polymer microsphere ranges from 10mg/ml to 80mg/ml; and/or the number of the groups of groups,
the content of the physiologically active substance is 10-50mg/ml; and/or the number of the groups of groups,
the content range of the thickener is 10-100mg/ml; and/or the number of the groups of groups,
the content of the surfactant is in the range of 1-50mg/ml.
Optionally, the particle size of the degradable polymer microsphere is 10-80 um.
Optionally, the physiologically active substance comprises at least one of recombinant collagen, animal-derived collagen, silk fibroin, tobacco protein, decellularized tissue matrix, or sodium hyaluronate; and/or the number of the groups of groups,
the degradable polymer microsphere comprises any one of polylactic acid microsphere, polycaprolactone microsphere or polylactic acid-glycolic acid copolymer microsphere, polylactic acid-ethylene glycol copolymer microsphere and polycaprolactone-ethylene glycol copolymer microsphere; and/or the number of the groups of groups,
the surfactant comprises any one of glycerol and mannitol; and/or the number of the groups of groups,
the thickener comprises any one of carboxymethyl cellulose, hydroxypropyl methyl cellulose, small molecule crosslinked sodium hyaluronate gel and macromolecular sodium hyaluronate gel.
The invention also provides a preparation method of the micromolecular crosslinked sodium hyaluronate gel, which comprises the following steps:
dissolving sodium hyaluronate in sodium hydroxide solution, adding a cross-linking agent, and uniformly stirring at 35-80 ℃ for 2-30 hours to obtain the micromolecular cross-linked sodium hyaluronate gel.
Optionally, the physiologically active substance comprises recombinant collagen, and the molecular weight of the recombinant collagen is 1-100 ten thousand; and/or the number of the groups of groups,
the degradable polymer microsphere comprises polylactic acid microsphere, wherein the weight average molecular weight of polylactic acid in the polylactic acid microsphere is 0.5-10 ten thousand; and/or the number of the groups of groups,
the degradable high molecular microsphere comprises a polycaprolactone microsphere, wherein the weight average molecular weight of polycaprolactone in the polycaprolactone microsphere is 0.2-5 ten thousand.
The invention also provides a preparation method of the injection filler, which comprises the following steps:
adding the degradable high polymer into dichloromethane, stirring and dissolving to obtain an oil phase mixed solution;
dissolving polyvinyl alcohol in water to obtain a water phase mixed solution; mixing the oil phase mixed solution with the water phase mixed solution, and emulsifying to obtain a degradable polymer microsphere freeze-drying agent;
dissolving a thickening agent and a surfactant in water for injection, and heating and stirring to obtain gel;
adding physiologically active substances and lidocaine into water for injection, and stirring to obtain an aqueous solution of the physiologically active substances;
adding the degradable polymer microsphere freeze-dried agent into the water solution of the physiological active substance, adding gel, mixing and stirring, adding a pH regulator to regulate the pH to 6.0-8.0, regulating the osmotic pressure to 120-320 mOsm/L, and stirring to obtain mixed gel;
and (3) aseptically filling the suspension gel to obtain the injection filler.
Adding the degradable polymer microsphere freeze-dried agent into an aqueous solution of a physiologically active substance, adding gel, mixing and stirring, adding a pH regulator to regulate the pH to 6.0-8.0, regulating the osmotic pressure to 120-320 mOsm/L, and stirring to obtain mixed gel, wherein the stirring speed is 100-1000 rpm; and/or the number of the groups of groups,
the stirring time is 1-72 hours.
Optionally, the degradable high molecular polymer, the dichloromethane, the polyvinyl alcohol, the thickener, the surfactant, the physiologically active substance and the lidocaine are subjected to front-end sterilization and the whole preparation process is subjected to aseptic control.
In the technical scheme provided by the invention, the injection filler comprises degradable polymer microspheres, physiological active substances, thickening agents and surfactants, the degradable polymer microspheres have special properties, natural and nontoxic effects, have cytocompatibility, and the biodegradability of the degradable polymer microspheres also ensures the safety of materials, the biocompatibility and the degradability of the degradable polymer microspheres are different from those of other traditional implantable materials, the physiological active substances have good biocompatibility and no virus hidden trouble, and the injection filler mainly prepared from the degradable polymer microspheres and the physiological active substances has good biocompatibility, is not a heat source, does not exist by microorganisms, viruses or other pathogens, is not abnormal or cancerogenic, does not cause immune and tissue-related diseases, and has great potential as an excellent biomedical material.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and other related drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
Fig. 1 is a process flow diagram of an embodiment of a method for preparing an injectable filler according to the present invention.
The achievement of the objects, functional features and advantages of the present invention will be further described with reference to the accompanying drawings, in conjunction with the embodiments.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention. In addition, the meaning of "and/or" as it appears throughout includes three parallel schemes, for example "A and/or B", including the A scheme, or the B scheme, or the scheme where A and B are satisfied simultaneously. In addition, the technical solutions of the embodiments may be combined with each other, but it is necessary to base that the technical solutions can be realized by those skilled in the art, and when the technical solutions are contradictory or cannot be realized, the combination of the technical solutions should be regarded as not exist and not within the protection scope of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Because the degradable polymer microsphere has special performance, the degradable polymer microsphere has wide attention in the biomedical field, particularly in the aspects of tissue engineering, arterial embolism treatment and the like, a plurality of diseases in medicine need to be implanted with foreign materials in vivo, but the human body structure is very complex and fragile, the sensitivity and the compatibility of the foreign materials are very worthy of research, the biocompatibility and the degradability of the degradable polymer microsphere are different from those of other traditional implantable materials, the material itself has natural non-toxic and harmful effects, the material has cell compatibility, and the degradability of the degradable polymer microsphere also ensures the safety of the material. Development of suitable scaffold systems is critical for tissue engineering regeneration and repair. The majority of natural collagen is derived from animal tissue, skin extracts. Collagen extracted from animals is a water insoluble protein and is not likely to be redissolved without changing molecular weight, and thus, is poorly processable, directly limiting the development of many potential uses. In addition, animal-derived products have the disadvantages of potential safety hazards such as viral infectivity and the like, foreign immunity rejection and the like.
In view of the above, the present invention provides an injection filler for solving the problems of serious foreign body reaction, injection pain, and poor filling effect, the injection filler comprising: degradable polymer microsphere, physiologically active substance, thickener and surfactant.
The main components of the injection filling agent in the scheme comprise degradable polymer microspheres, physiologically active substances, thickening agents and surfactants, and the auxiliary materials comprise pH regulator, analgesic components and water for injection. The degradable polymer microsphere is prepared from a degradable polymer material, and the polymer microsphere is small particles formed by dispersing polymers in a solvent, and the particle size is generally different from a few micrometers to hundreds of micrometers, so that the degradable polymer microsphere has the advantages of biodegradability, biocompatibility and the like. The injection filler also comprises a physiologically active substance, wherein the physiologically active substance has the excellent characteristics of no virus hidden trouble, high biocompatibility, excellent water solubility and the like, and also has the excellent characteristics of good hemostatic performance, low immunogenicity, cell proliferation and migration induction performance, high biocompatibility and the like, and the main components of the injection filler are degradable polymer microspheres, the physiologically active substance, a thickening agent and a surfactant, so that the injection filler also has the excellent characteristics of biodegradability, high biocompatibility, excellent water solubility and the like. The pH regulator is phosphate buffer solution, wherein the phosphate buffer solution comprises at least one of disodium hydrogen phosphate, sodium dihydrogen phosphate and sodium chloride, and the pH regulator can regulate pH and has an osmotic pressure regulating function; the analgesic component comprises at least one of lidocaine, procaine, bupivacaine, and ropivacaine.
Further, the content of the degradable polymer microsphere in the embodiment is in the range of 10-200mg/ml; the content of the physiologically active substance is 10-200mg/ml; the content range of the thickener is 10-180mg/ml; the content of the surfactant is in the range of 1-100mg/ml. The components in this concentration range can function more effectively.
In order to make the components in the injection filler fully function, in the embodiment, further, the content of the degradable polymer microsphere ranges from 10mg/ml to 80mg/ml; the content of the physiologically active substance is 10-50mg/ml; the content range of the thickener is 10-100mg/ml; the content of the surfactant is in the range of 1-50mg/ml.
Further, in this embodiment, the degradable polymeric microspheres have a particle size of 10-80 um, and further, the degradable polymeric microspheres have a particle size of 25-40 um with a duty ratio of more than 95%, so that they are not phagocytosed by macrophages in the human body due to the size and surface characteristics (completely smooth spherical shape) of the degradable polymeric microspheres.
In this embodiment, further, the physiologically active substance includes at least one of recombinant collagen, animal-derived collagen, silk fibroin, tobacco protein, decellularized tissue matrix, or sodium hyaluronate; the degradable polymer microsphere comprises any one of polylactic acid microsphere, polycaprolactone microsphere or polylactic acid-glycolic acid copolymer microsphere, polylactic acid-ethylene glycol copolymer microsphere and polycaprolactone-ethylene glycol copolymer microsphere; the surfactant comprises any one of glycerol and mannitol; the thickener comprises any one of carboxymethyl cellulose, hydroxypropyl methyl cellulose, small molecule crosslinked sodium hyaluronate gel and macromolecular sodium hyaluronate gel. Specifically, the recombinant collagen is preferably recombinant humanized collagen. Most of natural collagen is derived from animal tissues and skin extracts, and the collagen extracted from animals is water-insoluble protein and cannot be redissolved without changing molecular weight, so that the processability is very weak, and the development of many potential applications is directly limited. In addition, animal-derived products have the disadvantages of potential safety hazards such as viral infectivity and the like, foreign immunity rejection and the like. The recombinant humanized collagen is one of biological materials which are approved by FDA and NMPA earlier, not only has the excellent characteristics of no virus hidden trouble, high biocompatibility, excellent water solubility and the like, but also maintains the characteristics of the collagen, and the unique repeated structure of the recombinant humanized collagen enables the chemically active amino acid to be combined to the chemical bond position of the recombinant humanized collagen, so that the flexibility of the structure and the variability of the derivative of the recombinant humanized collagen are greatly improved, and the recombinant humanized collagen has the advantages of good hemostatic performance, low immunogenicity, induced cell proliferation and migration performance, high biocompatibility and the like; the method has wide application prospect in the aspects of constructing tissue engineering scaffolds such as skin, blood vessels, bones, hearts and the like, repairing wounds, oral cavity and vagina and other mucous membrane injuries caused by burns and scalds and external forces, treating leg ulcers, bedsores and the like, and injecting and filling, eliminating wrinkles, medical shaping, repairing after laser surgery, acne, dermatitis, eczema and the like; the degradable polymer microsphere comprises any one of polylactic acid microsphere, polycaprolactone microsphere or polylactic acid-glycolic acid copolymer microsphere, polylactic acid-ethylene glycol copolymer microsphere and polycaprolactone-ethylene glycol copolymer microsphere, is prepared from a degradable polymer material, has the advantages of biodegradability, biocompatibility and the like, and has wide application in the biomedical field.
Sodium hyaluronate is an inherent component in the human body, is a glucuronic acid, has no species specificity, and is widely present in tissues and organs such as placenta, amniotic fluid, lens, articular cartilage, dermis of skin and the like. It is distributed in cytoplasm and cell interstitium, and has lubricating and nourishing effects on cells and organelles contained in the cytoplasm and the cell interstitium. At the same time, it provides a microenvironment for cell metabolism, it is to make a kind of natural hyaluronic acid of human body into a kind of gel by means of injection method together with other medicines for promoting cell regeneration and removing wrinkles. Moisturizing is the most important role of sodium hyaluronate in cosmetics, and the relative humidity of the surrounding environment has less effect on its moisturizing properties than other moisturizers. In this embodiment, the sodium hyaluronate mainly has the functions of moisturizing, moisturizing and tightening.
The invention also provides a preparation method of the small molecule crosslinked sodium hyaluronate gel, which comprises the following steps:
dissolving sodium hyaluronate in sodium hydroxide solution, adding a cross-linking agent, and uniformly stirring at 35-80 ℃ for 2-30 hours to obtain the micromolecular cross-linked sodium hyaluronate gel.
In this embodiment, the thickener is replaced by the crosslinked sodium hyaluronate gel prepared according to the present embodiment, and no other thickener is added, and since sodium hyaluronate is a physiologically active substance as a main component of the injection filler, when the crosslinked sodium hyaluronate gel is added as a thickener, no other thickener is added, and only a part of the original sodium hyaluronate is subjected to the crosslinking operation according to the present embodiment, and the crosslinked sodium hyaluronate can play a supporting role.
Further, in this embodiment, the physiologically active substance includes recombinant collagen having a molecular weight of 1 to 100 ten thousand; the degradable polymer microsphere comprises polylactic acid microsphere, wherein the weight average molecular weight of polylactic acid in the polylactic acid microsphere is 0.5-10 ten thousand; the degradable high molecular microsphere comprises polycaprolactone microsphere, wherein the weight average molecular weight of polycaprolactone in the polycaprolactone microsphere is 0.2-5 ten thousand, and the recombinant collagen, the polylactic acid and the polycaprolactone are all macromolecular substances and have good biocompatibility.
The invention also provides a preparation method of the injection filler, and fig. 1 is a process flow chart of an embodiment of the preparation method of the injection filler.
Referring to fig. 1, the preparation method of the injection filler provided by the invention comprises the following steps:
adding the degradable high polymer into dichloromethane, stirring and dissolving to obtain an oil phase mixed solution;
dissolving polyvinyl alcohol in water to obtain a water phase mixed solution;
mixing the oil phase mixed solution with the water phase mixed solution, and emulsifying to obtain a degradable polymer microsphere freeze-drying agent;
adding the degradable polymer microsphere freeze-dried agent into the water solution of the physiological active substance, adding the thickening agent, the surfactant and the lidocaine, mixing and stirring, adding the pH regulator to adjust the pH to 6.0-8.0, adjusting the osmotic pressure to 120-320 mOsm/L, and stirring to obtain mixed gel;
and (3) aseptically filling the mixed gel to obtain the injection filling agent.
In this embodiment, the degradable polymer microsphere prepared by the method has good biocompatibility and degradability, and the current method for preparing the microsphere mainly comprises the following steps: spray drying, electrospray, and emulsion solvent evaporation. Different preparation methods can be selected according to different purposes, such as the preparation of inhalable drug-loaded microspheres by an electrospray method reported by Tianshi Feng et al for treating lung cancer, which is due to the special treatment of lung cancer, and the inhalation of microspheres with small particle size is required. The emulsion solvent volatilization method is convenient in implementation method, common in experimental conditions and easy in experimental facilities, so that the emulsion solvent volatilization method is widely used by researchers. General procedure for emulsion solvent volatilization: the polymer is dissolved in an organic solvent, poured into colostrum, and is emulsified, the organic solvent is volatilized and removed, and the obtained polymer droplets break through the constraint and are slowly deposited at the bottom to form microspheres. In the preparation process, for polymers, the emulsifying mode is O/W, W/O, W/O/W, O/W/O and the like, for organic solvents, common dichloromethane and ethyl acetate are available, and for the shape after balling, the polymer can be roughly divided into different microsphere morphologies such as solid microspheres, porous microspheres, hollow microspheres and hollow porous microspheres, wherein in the preparation of the solid microspheres and the porous microspheres, dichloromethane is commonly used as the organic solvent, hollow microspheres are commonly used as the organic solvent, and ethyl acetate is commonly used as the organic solvent, besides the morphology, the concentration, stirring speed, stirring mode, adding speed, water-oil ratio and the like of the polymers can influence the size of the microspheres, so that the microspheres with particle sizes required by experiments can be prepared by controlling different experimental conditions.
In this embodiment, further, in order to stir sufficiently, so that the degradable polymer microspheres are distributed uniformly, adding the freeze-drying agent of the degradable polymer microspheres into the aqueous solution of the physiologically active substance, adding the thickener, the surfactant and the lidocaine, mixing and stirring, adding the pH regulator to adjust the pH to 5.5-8.5, adjusting the osmotic pressure to 120-320 mOsm/L, and stirring to obtain a mixed gel, wherein the stirring speed is 100-1000 rpm; the stirring time is 1-72 hours, and under the stirring speed and stirring time of the embodiment, the degradable polymer microsphere freeze-drying agent can be fully mixed, and the degradable polymer microspheres in the mixed gel can be uniformly distributed.
Further, in this embodiment, the degradable high molecular polymer, the dichloromethane, the polyvinyl alcohol, the thickener, the surfactant, the physiologically active substance, and the lidocaine are subjected to front-end sterilization and the whole preparation process is subjected to aseptic control, and the fully sterilized injection filler does not exist in microorganisms, viruses, or other pathogens.
The following technical solutions of the present invention will be described in further detail with reference to specific examples and drawings, and it should be understood that the following examples are only for explaining the present invention and are not intended to limit the present invention.
Example 1
An injection filler comprising the following: polylactic acid microsphere with weight average molecular weight of 0.5 ten thousand and particle diameter of 10um content of 10mg/ml, recombinant collagen with molecular weight of 1 ten thousand and content of 10mg/ml, thickener with content of 10mg/ml, and surfactant with content of 1 mg/ml.
Example 2
An injection filler comprising the following: polylactic acid microsphere with weight average molecular weight of 9 ten thousand and particle diameter of 40um content of 100mg/ml, recombinant collagen with molecular weight of 5 ten thousand, thickener with content of 90mg/ml, and surfactant with content of 50mg/ml.
Example 3
An injection filler comprising the following: polylactic acid microsphere with weight average molecular weight of 10 ten thousand and particle diameter of 80um content of 200mg/ml, recombinant collagen with molecular weight of 10 ten thousand and content of 200mg/ml, thickener with content of 180mg/ml, and surfactant with content of 100mg/ml.
Example 4
An injection filler comprising the following: polycaprolactone microsphere with weight average molecular weight of 9 ten thousand and particle diameter of 40um content of 90mg/ml, recombinant collagen with molecular weight of 5 ten thousand, thickener with content of 90mg/ml, and surfactant with content of 50mg/ml.
Example 5
All the substances in the example 1 are added in proportion, namely 10mg of polylactic acid is added into methylene dichloride, and stirred and dissolved at room temperature to obtain an oil phase mixed solution; 1mg of polyvinyl alcohol is dissolved in water to obtain a water phase mixed solution; mixing the oil phase mixed solution with the water phase mixed solution, and emulsifying to obtain a degradable polymer microsphere freeze-drying agent; adding the degradable polymer microsphere freeze-dried agent into a recombinant protein water solution containing 10mg of recombinant protein, adding 10mg of carboxymethyl cellulose and 1mg of glycerol, mixing and stirring, adding a pH regulator to adjust the pH to 6.0, adjusting the osmotic pressure to 120mOsm/L, and stirring at 100 revolutions per minute for 1 hour to uniformly mix to obtain a suspension; sterilizing the suspension with high pressure steam at 115 deg.C for 20min, and packaging in prefilled syringe to obtain injection filler for injection, wherein the concentration of polylactic acid is 20mg/ml.
Example 6
All the substances in the example 2 are added in proportion, namely 100mg of polylactic acid is added into methylene dichloride, and stirred and dissolved at room temperature to obtain an oil phase mixed solution; 25mg of polyvinyl alcohol is dissolved in water to obtain a water phase mixed solution; mixing the oil phase mixed solution with the water phase mixed solution, and emulsifying to obtain a degradable polymer microsphere freeze-drying agent; adding the degradable polymer microsphere freeze-dried agent into a recombinant protein water solution containing 100mg of recombinant protein, adding 50mg of hydroxypropyl methylcellulose and 25mg of mannitol, mixing and stirring, adding a pH regulator to adjust the pH to 7.0, adjusting the osmotic pressure to 200mOsm/L, and stirring at 500 rpm for 48 hours to uniformly mix to obtain a suspension; sterilizing the suspension with high pressure steam at 120deg.C for 25min, and packaging in prefilled syringe to obtain injection filler with concentration of polylactic acid of 100mg/ml.
Example 7
Adding all the substances in the example 3 in proportion, namely adding 200mg of polylactic acid into dichloromethane, stirring and dissolving at room temperature to obtain an oil phase mixed solution; dissolving 50mg of polyvinyl alcohol in water to obtain a water phase mixed solution; mixing the oil phase mixed solution with the water phase mixed solution, and emulsifying to obtain a degradable polymer microsphere freeze-drying agent; adding the degradable polymer microsphere freeze-dried agent into a recombinant protein water solution containing 200mg of recombinant protein, adding 100mg of hydroxypropyl methylcellulose and 50mg of mannitol, mixing and stirring, adding a pH regulator to adjust the pH to 8.0, adjusting the osmotic pressure to 320mOsm/L, and stirring at 1000 rpm for 72 hours to uniformly mix to obtain a suspension; sterilizing the suspension with high pressure steam at 125deg.C for 30min, and packaging in prefilled syringe to obtain injection filler for injection, wherein the concentration of polylactic acid is 200mg/ml.
Example 8
All the substances in the example 4 are added in proportion, namely 100mg of polycaprolactone is added into dichloromethane, and stirred and dissolved at room temperature to obtain an oil phase mixed solution; 25mg of polyvinyl alcohol is dissolved in water to obtain a water phase mixed solution; mixing the oil phase mixed solution with the water phase mixed solution, and emulsifying to obtain a degradable polymer microsphere freeze-drying agent; adding the degradable polymer microsphere freeze-dried agent into a sodium hyaluronate aqueous solution containing 100mg of sodium hyaluronate, adding 50mg of crosslinked sodium hyaluronate gel and 50mg of mannitol, mixing and stirring, adding a pH regulator to adjust the pH to 7.0, adjusting the osmotic pressure to 200mOsm/L, and stirring for 48 hours at 500 rpm to uniformly mix to obtain a suspension; sterilizing the suspension with steam at 120deg.C for 25min, and packaging in prefilled syringe to obtain injection filler with concentration of polylactic acid of 100mg/ml.
Comparative example 1
The other components and conditions were the same as in example 5 except that polylactic acid was not added.
Comparative example 2
The other components and conditions were the same as in example 6 except for the recombinant protein aqueous solution.
Comparative example 3
The other components and conditions were the same as in example 7 except that polylactic acid was not added and that an aqueous solution of recombinant protein was not added.
Comparative example 4
The other components and conditions were the same as in example 8 except that the crosslinked sodium hyaluronate gel was not added.
Test method and results
The injection fillers prepared in examples 5 to 8 and comparative examples 1 to 4 were subjected to the following test:
90 male Wistar rats were randomly divided into 9 groups according to body weight, wherein one group was a blank group, the remaining 8 groups were injected with the fillers prepared in examples 5 to 8 and comparative examples 1 to 4, respectively, the hairs of the same area on the backs of all rats were removed, and the rest of the experimental animals except the blank group were observed after 10mg of the fillers injected in each example and comparative example, respectively, for 72 hours, to obtain tables 1 and 2.
Table 1 results of symptom observations in animals of experimental and control groups
Table 2 results of symptom observations in animals of test and control groups
From table 1, it can be seen that no abnormal reaction is found, all the test mice have no toxic symptoms, and the experimental results in table 2 show that the experimental group has an effective rate of 90% and the comparative group has an effective rate of not more than 60% after the experimental group is given to the test rats, which means that the polylactic acid microsphere or polycaprolactone microsphere and the recombinant collagen or sodium hyaluronate act together to achieve better effect, and the injection filler of the invention has better tightening and lifting effects on facial skin.
The foregoing is merely a preferred embodiment of the present invention and is not intended to limit the scope of the present invention, but various modifications and variations will be apparent to those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. An injection filler, characterized in that the injection filler comprises: degradable polymer microsphere, physiologically active substance, thickener and surfactant.
2. The injectable filler of claim 1, wherein the degradable polymeric microspheres are present in an amount ranging from 10 to 200mg/ml; and/or the number of the groups of groups,
the content of the physiologically active substance is 10-200mg/ml; and/or the number of the groups of groups,
the content range of the thickener is 10-180mg/ml; and/or the number of the groups of groups,
the content of the surfactant is in the range of 1-100mg/ml.
3. The injectable filler of claim 2, wherein the degradable polymeric microspheres are present in an amount ranging from 10 to 80mg/ml; and/or the number of the groups of groups,
the content of the physiologically active substance is 10-50mg/ml; and/or the number of the groups of groups,
the content range of the thickener is 10-100mg/ml; and/or the number of the groups of groups,
the content of the surfactant is in the range of 1-50mg/ml.
4. The injection filler according to claim 1, wherein the degradable polymeric microspheres have a particle size of 10 to 80 μm.
5. The injectable bulking agent of claim 1, wherein the physiologically active substance comprises at least one of recombinant collagen, animal derived collagen, silk fibroin, tobacco protein, decellularized tissue matrix, or sodium hyaluronate; and/or the number of the groups of groups,
the degradable polymer microsphere comprises any one of polylactic acid microsphere, polycaprolactone microsphere or polylactic acid-glycolic acid copolymer microsphere, polylactic acid-ethylene glycol copolymer microsphere and polycaprolactone-ethylene glycol copolymer microsphere; and/or the number of the groups of groups,
the surfactant comprises any one of glycerol and mannitol; and/or the number of the groups of groups,
the thickener comprises any one of carboxymethyl cellulose, hydroxypropyl methyl cellulose, small molecule crosslinked sodium hyaluronate gel and macromolecular sodium hyaluronate gel.
6. A method for preparing the small molecule crosslinked sodium hyaluronate gel according to claim 5, comprising the steps of:
dissolving sodium hyaluronate in sodium hydroxide solution, adding a cross-linking agent, and uniformly stirring at 35-80 ℃ for 2-30 hours to obtain the micromolecular cross-linked sodium hyaluronate gel.
7. The injectable filler of claim 5, wherein the physiologically active substance comprises recombinant collagen having a molecular weight of 1 to 100 tens of thousands; and/or the number of the groups of groups,
the degradable polymer microsphere comprises polylactic acid microsphere, wherein the weight average molecular weight of polylactic acid in the polylactic acid microsphere is 0.5-10 ten thousand; and/or the number of the groups of groups,
the degradable high molecular microsphere comprises a polycaprolactone microsphere, wherein the weight average molecular weight of polycaprolactone in the polycaprolactone microsphere is 0.2-5 ten thousand.
8. A method for preparing the injection filler according to any one of claims 1 to 4, comprising the steps of:
adding the degradable high polymer into dichloromethane, stirring and dissolving to obtain an oil phase mixed solution;
dissolving polyvinyl alcohol in water to obtain a water phase mixed solution;
mixing the oil phase mixed solution with the water phase mixed solution, and emulsifying to obtain a degradable polymer microsphere freeze-drying agent;
dissolving a thickening agent and a surfactant in water for injection, and heating and stirring to obtain gel;
adding physiologically active substances and lidocaine into water for injection, and stirring to obtain an aqueous solution of the physiologically active substances;
adding the degradable polymer microsphere freeze-dried agent into the water solution of the physiological active substance, adding gel, mixing and stirring, adding a pH regulator to regulate the pH to 6.0-8.0, regulating the osmotic pressure to 120-320 mOsm/L, and stirring to obtain mixed gel;
and (3) aseptically filling the mixed gel to obtain the injection filling agent.
9. The method for preparing an injection filler according to claim 8, wherein in the step of adding a freeze-dried agent of degradable polymer microspheres into an aqueous solution of a physiologically active substance, adding a gel, mixing and stirring, adding a pH regulator to adjust pH to 6.0-8.0, adjusting osmotic pressure to 120-320 mOsm/L, and stirring to obtain a suspension, the stirring speed is 100-1000 rpm; and/or the number of the groups of groups,
the stirring time is 1-72 hours.
10. The method for preparing an injection filler according to claim 8, wherein the degradable high molecular polymer, the methylene chloride, the polyvinyl alcohol, the thickener, the surfactant, the physiologically active substance, and the lidocaine are subjected to front-end sterilization and the whole preparation process is subjected to aseptic control.
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|---|---|---|---|
| CN202211701256.6A CN116370707A (en) | 2022-12-28 | 2022-12-28 | Injection filler and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116617466A (en) * | 2023-07-21 | 2023-08-22 | 北京万洁天元医疗器械股份有限公司 | Injectable gel and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116617466A (en) * | 2023-07-21 | 2023-08-22 | 北京万洁天元医疗器械股份有限公司 | Injectable gel and preparation method thereof |
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