CN115197341B - Hyaluronic acid-polydeoxyribonucleotide copolymer and preparation method and application thereof - Google Patents
Hyaluronic acid-polydeoxyribonucleotide copolymer and preparation method and application thereof Download PDFInfo
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- CN115197341B CN115197341B CN202110399899.9A CN202110399899A CN115197341B CN 115197341 B CN115197341 B CN 115197341B CN 202110399899 A CN202110399899 A CN 202110399899A CN 115197341 B CN115197341 B CN 115197341B
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- hyaluronic acid
- polydeoxyribonucleotide
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- mixed solution
- pdrn
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- 229920001577 copolymer Polymers 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (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-carboxylic acid Chemical compound 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 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 55
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 53
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- 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 description 6
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- 239000005547 deoxyribonucleotide Substances 0.000 description 4
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- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000032544 Cicatrix Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 108010003272 Hyaluronate lyase Proteins 0.000 description 1
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Chemical group CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical group CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Chemical group CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
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- 230000005262 alpha decay Effects 0.000 description 1
- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical group O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 description 1
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- VJVOFLWZDWLHNR-MRCUWXFGSA-N icosan-9-yl (z)-docos-13-enoate Chemical compound CCCCCCCCCCCC(CCCCCCCC)OC(=O)CCCCCCCCCCC\C=C/CCCCCCCC VJVOFLWZDWLHNR-MRCUWXFGSA-N 0.000 description 1
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- 239000002773 nucleotide Substances 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/60—Sugars; Derivatives thereof
- A61K8/606—Nucleosides; Nucleotides; Nucleic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/59—Mixtures
- A61K2800/592—Mixtures of compounds complementing their respective functions
Abstract
The invention provides a preparation method of a hyaluronic acid-polydeoxyribonucleotide copolymer, which comprises the following steps: dissolving hyaluronic acid or salt thereof and polydeoxyribonucleotide in water, and degassing to form a mixed solution; performing irradiation crosslinking on the mixed solution under high-energy rays to obtain hyaluronic acid-polydeoxyribonucleotide copolymer hydrogel; and crushing and drying the hydrogel to obtain the hyaluronic acid-polydeoxyribonucleotide copolymer. The hyaluronic acid-polydeoxyribonucleotide copolymer is prepared by a radiation irradiation mode, and impurities such as a chemical cross-linking agent, an initiator and the like are not required to be added in the preparation process; the hyaluronic acid and the polydeoxyribonucleotide polymer chain are combined through covalent bonds, so that compared with the common physical mixing, the degradation time can be slowed down, and polydeoxyribonucleotide can be slowly released, so that the effect maintenance time can be prolonged; the copolymer powder has stable property and is convenient to store and use.
Description
Technical Field
The invention belongs to the technical field of preparation of high polymer materials, and particularly relates to a hyaluronic acid-polydeoxyribonucleotide copolymer, a preparation method and application thereof.
Background
Hyaluronic Acid (HA) is a linear polysaccharide composed of (1→3) -2-acetamido-2-deoxy- β -D-glucose- (1→4) -O- β -D-glucuronic acid disaccharide repeating units, which is widely present in many connective tissues such as skin, vitreous humor, cartilage and joint synovial fluid, and plays a physiological role in moisturizing, nutrition and repair. HA HAs good physical and chemical properties and biocompatibility, and is often applied to the fields of cosmetology and plastic, wound dressing, ophthalmic surgery, joint cavity injection, surgical protection, drug carriers, cosmetic raw materials and the like.
Polydeoxyribonucleotide (PDRN) is a polymer of deoxyribonucleotides, and the PDRN molecule is polymerized from 13 or more deoxyribonucleotide monomers. The earliest research on the pharmacological activity of the PDRN is that PDRN is extracted from germ cells of sea trout by Mastelli company in 1952, and the research shows that the PDRN component contained in the male testis of the sea trout is a novel substance, and DNA fragments of the PDRN component are most similar to those of a human body, so that the PDRN can promote the regeneration of cells of the human body, quickly recover wounds, reduce scar formation, relieve pain and the like.
There are more and more products combining HA and PDRN, but most of the existing products are physical mixture of free HA and free PDRN or physical mixture of chemically crosslinked HA and free PDRN, so the products have the problems of easy degradation, poor stability, inconvenient preservation and use, etc.
Disclosure of Invention
The present invention provides a hyaluronic acid-polydeoxyribonucleotide copolymer, a preparation method and uses thereof, aiming at the problems existing in the prior art.
In particular, the invention relates to the following aspects:
1. a method for preparing a hyaluronic acid-polydeoxyribonucleotide copolymer, said method comprising the steps of:
dissolving hyaluronic acid or salt thereof and polydeoxyribonucleotide in water, and degassing to form a mixed solution;
performing irradiation crosslinking on the mixed solution under high-energy rays to obtain hyaluronic acid-polydeoxyribonucleotide copolymer hydrogel;
and crushing and drying the hydrogel to obtain the hyaluronic acid-polydeoxyribonucleotide copolymer.
2. The preparation method according to claim 1, wherein the mass ratio of the hyaluronic acid or a salt thereof and polydeoxyribonucleotide in the mixed solution is 1:1 to 10:1, preferably 1:1 to 5:1.
3. The method according to claim 1, wherein the mass ratio of the hyaluronic acid or a salt thereof in the mixed solution is 0.05% to 5%, preferably 1% to 5%, and the mass ratio of the polydeoxyribonucleotide is 0.05% to 2%, preferably 0.05% to 1%.
4. The method according to item 1, wherein the hyaluronic acid or salt thereof has a molecular weight of 50 to 300 Da, preferably 150 to 300 Da.
5. The method according to item 1, wherein the polydeoxyribonucleotide has a molecular weight of 5 to 100 Da.
6. The method according to item 1, wherein the high-energy ray is a gamma ray.
7. The method according to claim 6, wherein the dose of gamma radiation is 10 to 30kGy, preferably 20kGy.
8. A hyaluronic acid-polydeoxyribonucleotide copolymer, characterized in that said copolymer is obtained by the preparation method according to any of claims 1-7.
9. The use of the copolymer according to item 8 in medical treatment or cosmetology.
10. A medical and/or cosmetic article comprising the hyaluronic acid-polydeoxyribonucleotide copolymer produced by the method for producing a hyaluronic acid-polydeoxyribonucleotide copolymer according to any of claims 1-7.
By controlling proper irradiation conditions, the invention can achieve better crosslinking effect while reducing the degradation of hyaluronic acid, and has high yield of irradiated glue.
The hyaluronic acid-polydeoxyribonucleotide copolymer is prepared by a radiation irradiation mode, and impurities such as a chemical cross-linking agent, an initiator and the like are not required to be added in the preparation process; the hyaluronic acid and the polydeoxyribonucleotide polymer chain in the product are combined through covalent bonds, so that the degradation time can be slowed down compared with the common physical mixing, and polydeoxyribonucleotide is slowly released, so that the effect maintenance time is prolonged; the hyaluronic acid-polydeoxyribonucleotide copolymer powder has stable property and is convenient to store and use.
Detailed Description
The invention will be further illustrated with reference to the following examples, which are to be understood as merely further illustrating and explaining the invention and are not to be construed as limiting the invention.
Unless defined otherwise, technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the materials and methods are described herein below. In case of conflict, the present specification, including definitions therein, will control and materials, methods, and examples, will control and be in no way limiting. The invention is further illustrated below in connection with specific examples, which are not intended to limit the scope of the invention.
Hyaluronic Acid (HA) is composed of disaccharide units of D-glucuronic acid and N-acetylglucosamine, HAs negative charges, exists in soft connective tissues of most transfer objects, shows various important physiological functions of lubricating joints, regulating permeability of vascular walls, regulating diffusion and operation of proteins and water electrolytes, promoting wound healing and the like, and particularly HAs a special water-retaining effect, and is widely applied to the fields of medicines and cosmetics. Meanwhile, the hyaluronic acid molecule is in a rigid spiral column shape in space, the inner side of the column generates strong water absorption due to a large number of hydroxyl groups, and on the other hand, a hydrophobic region is formed on the hyaluronic acid molecule chain due to the continuous directional arrangement of the hydroxyl groups, so that the hyaluronic acid can form a three-dimensional reticular structure. Furthermore, hyaluronate also exhibits different physicochemical properties depending on its molecular weight. Natural hyaluronic acid is easy to be degraded by hyaluronidase in a human body, and the degradation of the hyaluronic acid is effectively reduced mainly through crosslinking at present, so that the in-vivo maintenance time is prolonged. In order to achieve the desired in vivo maintenance time, the crosslinking degree of the gel is generally increased by increasing the amount of the crosslinking agent or optimizing the crosslinking conditions and methods.
Deoxyribonucleic acid (DNA) products are excellent repair products in the fields of high-end medicine and medicine, and can quickly repair injured scars, creatively promote cell surface collagen synthesis and reverse aging signs. Powerful functions of resisting radiation and shrinking pores and can make skin regenerated. Polydeoxyribonucleotide (PDRN) is a polymer of deoxyribonucleotides, and the PDRN molecule is polymerized from 13 or more deoxyribonucleotide monomers. Is derived from salmon sperm DNA controlled purification and sterilization processes (95% similarity to human DNA). This procedure ensures that there are no active proteins and peptides that might elicit an immune response. In vitro and in vivo experiments showed that: the most relevant mechanism of action of PDRN is the involvement of the adenosine A2A receptor, while PDRN provides nucleosides and nucleotides for the so-called "rescue pathway", binding to the adenosine A2A receptor being a unique property of PDRN.
There have been increasing numbers of products using HA in combination with PDRN, but most of the existing products are physical mixtures of free HA with free PDRN or physical mixtures of chemically crosslinked HA with free PDRN. The physical mixed product of free HA and free PDRN HAs the defects of easy degradation in vivo, poor stability and short effective maintenance time. The traditional chemical crosslinking method has the defects that chemical crosslinking agents, initiators and other substances are required to be added in the crosslinking process, so that impurities are introduced, and the safety of products is not facilitated. Physical mixing of chemically crosslinked HA with free PDRN also does not achieve sustained release of PDRN in vivo.
The invention provides a preparation method of a hyaluronic acid-polydeoxyribonucleotide copolymer (HA-PDRN copolymer), which is characterized by comprising the following steps:
dissolving hyaluronic acid or salt thereof and polydeoxyribonucleotide in water, and degassing to form a mixed solution;
performing irradiation crosslinking on the mixed solution under high-energy rays to obtain hyaluronic acid-polydeoxyribonucleotide copolymer hydrogel;
and crushing and drying the hydrogel to obtain the hyaluronic acid-polydeoxyribonucleotide copolymer.
High energy radiation refers to several ionizing radiation rays commonly encountered in daily radioactive work, including gamma rays, X-rays, electron Beams (EB), and the like. The high-energy ray irradiation can effectively induce the polymer to generate free radicals to form a covalent cross-linked network structure. The radiation crosslinking method of high energy rays has unique advantages: no initiator is needed to be added, and the product is pure and safe, and is more suitable for preparing materials in the biomedical field; the monomer has a large selection range, or can be directly synthesized from the polymer; can be carried out at normal temperature or low temperature, and has lower operation cost; the synthesis and sterilization of the hydrogel can be completed in one step, and the cost is reduced. Radiation crosslinking can be divided into two methods depending on the preparation process: firstly, irradiating a solid polymer to crosslink the solid polymer, and then adding water to swell the solid polymer to form hydrogel; the aqueous polymer solution is directly irradiated to crosslink the aqueous polymer solution to form a hydrogel. The first method is generally used for radiation crosslinking in an aqueous state because of low crosslinking efficiency. In the state of an aqueous solution, the radical generated by the hydroradiolysis (OH, H, etc.) generates a macromolecular radical by abstracting hydrogen on a macromolecular chain, thereby initiating a crosslinking reaction.
Under the irradiation of high-energy rays, the activation of the high-molecular polymer can generate various chemical changes. For example, chemical bonds are formed between molecular chains, i.e. irradiation crosslinking, molecular main chain cleavage, i.e. irradiation degradation, copolymerization between different molecules, i.e. grafting or block copolymerization, etc. Therefore, it is difficult to infer the specific polymerization mode between hyaluronic acid molecules and PDRN molecules under irradiation of high-energy rays, and in the present invention we aim to examine specific conditions of irradiation reaction to obtain a preparation method of HA-PDRN copolymer with high yield and low PDRN residual rate.
According to the prior art, we speculate that the reaction of hyaluronic acid and polydeoxyribonucleotide to form hyaluronic acid-polydeoxyribonucleotide copolymer is carried out by the steps of, in aqueous solution, generating free radicals H and OH by electron beam radiolysis of water, and the generated free radicals attack carboxyl groups in the molecular chain of hyaluronic acid and amide in the molecular chain of PDRN to generate hyaluronic acid and PDRN macromolecular free radicals, and covalent bond polymerization is generated between the macromolecular free radicals. Of course, there are inter-HA chain crosslinking, HA backbone degradation, intra-HA chain crosslinking, etc. at the same time in this process, and thus screening of reaction conditions is of great importance. The ideal reaction conditions are to reach an equilibrium state of copolymerization and degradation. In a specific embodiment, the resulting copolymer has the structure shown below.
In a specific embodiment, the high energy rays are gamma rays. Gamma rays, also known as gamma particle streams, are rays released when the nuclear energy level transitions are de-excited, and are electromagnetic waves with wavelengths shorter than 0.01 angstroms. Gamma rays were first discovered by the french scientist p.v. verrad to be the third nuclear ray discovered subsequent to the alpha, beta rays. The new nuclei generated after alpha decay and beta decay of the radioactive nuclei are often at a high energy level, and gamma photons are radiated to a low energy level. Both nuclear decay and nuclear reactions produce gamma rays. Which is an electromagnetic wave having a wavelength shorter than 0.2 angstroms. The wavelength of gamma rays is shorter than that of X rays, so gamma rays have a stronger penetrating power than X rays.
In a specific embodiment, the dose of gamma radiation is 10 to 30kGy, for example, 10kGy, 15kGy, 20kGy, 25kGy, 30kGy, preferably 20kGy.
The hyaluronic acid or salts thereof described herein include hyaluronic acid and various forms of salts thereof, preferably hyaluronic acid soluble salts, including, but not limited to, sodium hyaluronate, calcium hyaluronate, magnesium hyaluronate, potassium hyaluronate, zinc hyaluronate, and the like.
The molecular weight of hyaluronic acid or a salt thereof is not limited. In a specific embodiment, the molecular weight of the hyaluronic acid or the salt thereof is 50-300 Da, for example, 50-60 Da, 70 Da, 80 Da, 90 Da, 100 Da, 110 Da, 120 Da, 130 Da, 140 Da, 150 Da, 160 Da, 170 Da, 180 Da, 190 Da, 200 Da, 210 Da, 220 Da, 230 Da, 240 Da, 250 Da, 300 Da, and preferably 150 Da-300 Da.
In a specific embodiment, the mass ratio of the hyaluronic acid or the salt thereof and the polydeoxyribonucleotide in the mixed solution is 1:1 to 10:1, for example, may be 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, preferably 1:1 to 5:1.
In a specific embodiment, the mass ratio of the hyaluronic acid or the salt thereof in the mixed solution is 0.05% to 5%, i.e., the mass of the hyaluronic acid or the salt thereof is 0.05% to 5% of the mass of the mixed solution. For example, 0.05%, 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, preferably 1% to 5%.
In a specific embodiment, the polydeoxyribonucleotide has a molecular weight of 5 to 100 Da, for example, 5 to 10 Da, 20 Da, 30 Da, 40 Da, 50 Da, 60 Da, 70 Da, 80 Da, 90 Da, 100 Da.
In a specific embodiment, the mass ratio of the polydeoxyribonucleotide in the mixed solution is 0.05% -2%, i.e. the mass of the polydeoxyribonucleotide is 0.05% -2% of the mass of the mixed solution. For example, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, preferably 0.05% to 1%.
The pulverization and drying in the above steps may be carried out by conventionally known pulverization or drying methods. Among them, the drying method is preferably freeze drying.
The invention also provides the hyaluronic acid-polydeoxyribonucleotide copolymer prepared by the preparation method.
The invention further provides the application of the hyaluronic acid-polydeoxyribonucleotide copolymer in medical treatment and cosmetology.
The hyaluronic acid-polydeoxyribonucleotide copolymer is prepared by a radiation irradiation mode, and impurities such as a chemical cross-linking agent, an initiator and the like are not required to be added in the preparation process; especially when hyaluronic acid with a molecular weight of 50-300 Da and gamma-ray radiation with a dosage of 10-30 kGy are used, the obtained copolymer has good stability, and particularly, the copolymer has good stability after being stored for 6 months through appearance observation, swelling degree test and ultraviolet absorption test, and is convenient to store and use.
Examples
The invention will be further illustrated with reference to the following examples, which are to be understood as merely further illustrating and explaining the invention and are not to be construed as limiting the invention.
The experimental methods used in the following examples are conventional methods, if no special requirements are imposed.
The sodium hyaluronate used in the following examples and comparative examples was produced by Hua Xi Biotech Co., ltd. Other materials, reagents, etc., unless otherwise specified, are commercially available.
Example 1
2g of sodium hyaluronate (molecular weight: 150. Mu. Da) and 1g of PDRN (molecular weight: 50. Mu. Da) were weighed out, 100g of deionized water was added thereto, and the mixture was stirred and dissolved. The dissolved solution was evacuated to remove air bubbles. Transferring the solution with bubbles removed into a sealed container, and placing in 60 And (3) irradiating under a Co irradiation source, wherein the dosage is 20kGy. And after the irradiation is finished, taking out the container, and observing the gel forming condition of the solution in the container. And (3) separating the glue solution after centrifugation, comparing the PDRN residual rate in the supernatant with that in the solution, crushing the gel, and freeze-drying to calculate the yield.
The method for calculating the yield comprises the following steps: after centrifuging the reaction system, sucking out the upper layer solution, freeze-drying the rest gel, weighing the total weight of the dried powder to be M1, and recording the feeding amount (namely the total amount of sodium hyaluronate and PDRN) to be M, wherein the yield=M1/M is 100%.
The method for measuring the PDRN residual rate comprises the following steps: the benzene ring structure of the base on the DNA chain has stronger absorption in the ultraviolet region, and the absorption peak is at 260 nm. The supernatant after centrifugation was diluted to 100ml, and the absorbance at 260nm was measured by an ultraviolet spectrophotometer and designated A1. The absorbance of the dosed amount of the aqueous PDRN solution at 260nm was designated A. PDRN residual = A1/a 100%. The greater the residual rate, i.e., the more PDRN is unreacted.
Examples 2 to 4
Examples 2-4 differ from example 1 in the molecular weight of sodium hyaluronate. Other reaction conditions were the same as in example 1. The molecular weight of example 2 is 50 Da, the molecular weight of example 3 is 250 Da, and the molecular weight of example 4 is 300 Da.
Examples 5 to 7, comparative example 1
Examples 5 to 7 and comparative example 1 differ from example 1 in the radiation dose. Other reaction conditions were the same as in example 1. The radiation dose of example 5 was 10kGy, the radiation dose of example 6 was 30kGy, the radiation dose of example 7 was 40kGy, and the radiation dose of comparative example 1 was 5kGy.
Comparative example 2
Comparative example 2 differs from example 1 in that the molecular weight of sodium hyaluronate is 10 ten thousand Da. Other reaction conditions were the same as in example 1.
The reaction conditions of the specific examples and comparative examples are shown in Table 1.
Table 1 reaction conditions for each of examples and comparative examples
The results of the reaction yield and PDRN residual rate measured by the method described in example 1 are shown in table 2.
TABLE 2 yield and PDRN residual Rate results
Stability test
Stability tests were performed on the hyaluronic acid-polydeoxyribonucleotide copolymers prepared in examples 1-7 above. The specific method is that the copolymer powder prepared in the above example is placed in a drug stability test box at 40+/-2 ℃ and is sampled and tested for appearance, swelling degree and ultraviolet absorption at 260nm in 0 day, 1 month, 2 months, 3 months and 6 months. The results are shown in Table 3.
Appearance: the property change of the copolymer powder in the long-term placing process can be intuitively reflected, and the stability of the copolymer powder is indicated by the fact that the color and the state are unchanged along with the time.
Swelling degree: because the copolymer obtained by the invention is a polymer network with a complex structure, the modification degree cannot be directly measured, and the modification degree can be indirectly reflected through the swelling degree. HA is a linear polymer capable of absorbing a large amount of moisture to swell, but after irradiation modification, the water absorbing capacity is weakened due to the formation of a network structure. The higher the swelling degree of the high molecular polymer, the lower the modification degree. The swelling increases as the polymer degrades during the rest.
A 260nm : this parameter was stable, indicating that PDRN did not degrade from the HA chain during placement.
The method for measuring the swelling degree comprises the following steps: 0.1g of copolymer powder is taken and placed in a plate, deionized water is dripped until the copolymer powder is completely expanded, redundant water is removed, and the weight of the gel after the copolymer powder is fully expanded is weighed. The gel weight was divided by the weighed powder weight of 0.1g to give the swelling degree.
The ultraviolet absorption measuring method at 260nm comprises the following steps: taking 0.05g of powder, adding 1ml of deionized water, fully swelling, centrifuging after vortex mixing to obtain supernatant, and measuring ultraviolet absorption at 260nm by an ultraviolet spectrophotometer.
TABLE 3 determination of copolymer stability
Wherein 0 represents 0 day, 1 represents 1 month, 2 represents 2 months, 3 represents 3 months, 4 represents 4 months, 5 represents 5 months, and 6 represents 6 months.
As can be seen from table 2, the molecular weight of hyaluronic acid has an effect on both the polymer yield and PDRN residual rate, and generally, the PDRN residual rate decreases as the molecular weight of hyaluronic acid increases at a certain irradiation dose. When the molecular weight of hyaluronic acid is more than 150 Da, the increase of the molecular weight of hyaluronic acid has little influence on the polymer yield and the PDRN residual rate. When the molecular weight of hyaluronic acid is less than 10 ten thousand Da, no gel is formed after irradiation. The irradiation dose has a great influence on the polymer yield and the PDRN residual rate, and as the irradiation dose increases from 5 to 40kGy, the yield increases first and then decreases, and unreacted PDRN decreases first and then increases. The irradiation dose is between 10 and 30kGy, the yield is more than 60 percent, wherein the irradiation dose is 20kGy, and the yield is the maximum and exceeds 90 percent. After the irradiation dose was increased to 40kGy, the yield was greatly reduced, below 50%, and there was a large amount of PDRN unreacted.
As is clear from Table 3, the polymer obtained in the present invention is white to yellowish powder, and the HA-PDRN copolymer powder obtained under the preparation conditions of the present invention HAs appearance, swelling degree, A during the standing 260nm No obvious change exists, which indicates that the product can be stably stored. The stability data of example 7 shows that the product obtained at an irradiation dose of 40kGy is darker in colour and has a tendency to degrade during the standing process.
Claims (11)
1. A method for preparing a hyaluronic acid-polydeoxyribonucleotide copolymer, said method comprising the steps of:
dissolving hyaluronic acid or salt thereof and polydeoxyribonucleotide in water, and degassing to form a mixed solution;
performing irradiation crosslinking on the mixed solution under high-energy rays to obtain hyaluronic acid-polydeoxyribonucleotide copolymer hydrogel;
crushing and drying the hydrogel to obtain a hyaluronic acid-polydeoxyribonucleotide copolymer;
the molecular weight of the hyaluronic acid or the salt thereof is 50-300 Da;
the high-energy rays are gamma rays;
the dosage of the gamma-ray radiation is 10-30 kGy.
2. The method according to claim 1, wherein the mass ratio of the hyaluronic acid or a salt thereof to the polydeoxyribonucleotide in the mixed solution is 1:1 to 10:1.
3. The method according to claim 2, wherein the mass ratio of the hyaluronic acid or a salt thereof to the polydeoxyribonucleotide in the mixed solution is 1:1 to 5:1.
4. The method according to claim 1, wherein the mass ratio of the hyaluronic acid or a salt thereof in the mixed solution is 0.05% to 5%, and the mass ratio of the polydeoxyribonucleotide is 0.05% to 2%.
5. The method according to claim 4, wherein the mass ratio of the hyaluronic acid or the salt thereof in the mixed solution is 1% to 5%, and the mass ratio of the polydeoxyribonucleotide is 0.05% to 1%.
6. The method according to claim 1, wherein the hyaluronic acid or a salt thereof has a molecular weight of 150 to 300 Da.
7. The method according to claim 1, wherein the polydeoxyribonucleotide has a molecular weight of 5 to 100 Da.
8. The method of claim 7, wherein the dose of gamma radiation is 20kGy.
9. A hyaluronic acid-polydeoxyribonucleotide copolymer, characterized in that it is obtained by the preparation method according to any of claims 1-8.
10. Use of the copolymer according to claim 9 for the preparation of medical and cosmetic articles.
11. A medical and/or cosmetic article comprising the hyaluronic acid-polydeoxyribonucleotide copolymer produced by the method for producing a hyaluronic acid-polydeoxyribonucleotide copolymer according to any of claims 1-8.
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| EP0696210B1 (en) * | 1993-04-30 | 1998-09-02 | Laboratoires Sebbin | Use of hyaluronic acid and/or polydeoxyribonucleotide based hydrogels as materials for filling prostheses and prostheses obtained |
| CN1944495A (en) * | 2006-09-29 | 2007-04-11 | 北京大学 | Water gel containing natural high molecule and its radiation preparing method |
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| KR20170060599A (en) * | 2015-11-24 | 2017-06-01 | (주)한국비엠아이 | Composition for injection of hyaluronic acid comprising cross-linked hyaluronic acid derivative and DNA fraction, and use thereof |
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| CN1944495A (en) * | 2006-09-29 | 2007-04-11 | 北京大学 | Water gel containing natural high molecule and its radiation preparing method |
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