Dialdehyde group-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection

Abstract

The invention relates to the technical field of medical cosmetology, and particularly discloses a dialdehyde group-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection, which comprises the following raw materials: a water-soluble chitosan aqueous solution and a dialdehyde group-containing oxidized polysaccharide aqueous solution, the water-soluble chitosan comprises one of carboxyl alkyl chitosan, hydroxyalkyl chitosan, carboxyl alkyl chitosan sodium salt and hydroxyalkyl chitosan sodium salt. The used raw materials do not contain cross-linking agents, safety risks caused by the fact that the cross-linking agents remain in the body are avoided, and the hydrogel is used for filling wrinkles, improving facial contours and promoting regeneration and repair of skin, so that the skin looks young and smooth.

Description

Technical Field

[0001] The present application relates to the technical field of medical aesthetics. More specifically, it relates to an aldehyde group-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection. Background Art

[0002] A hydrogel is a polymer material with a three-dimensional network structure that can retain a large volume of water without dissolving. The formation of a hydrogel can be achieved by chemical, radiation, or physical cross-linking methods to form a three-dimensional network polymer structure that is insoluble in water but can swell in water, making it widely used in the fields of aesthetics and biomedicine.

[0003] Chitosan is a natural basic polysaccharide with good biocompatibility, environmental friendliness, biodegradability, and renewable properties, and has good application prospects in the fields of wound repair, plastic surgery, etc. Carboxymethyl cellulose has excellent water absorption properties, unique rheological properties, and controllable drug release properties. Chitosan, carboxymethyl cellulose, and a cross-linking agent are mixed and cross-linked to form a hydrogel, which has a stable three-dimensional network structure, good biocompatibility, mechanical strength, and stability, and can fill wrinkles, increase skin volume, and improve facial contours in cosmetic injection, making the skin look more plump and youthful.

[0004] However, existing cosmetic injection gels are usually composed of cross-linked hyaluronic acid components, and the cross-linking agents contained therein will remain in the body and cause safety risks. Summary of the Invention

[0005] In order to improve the problem that adding a cross-linking agent to a hydrogel can cause tissue irritation, thereby affecting the health of cells and tissues, the present application provides an aldehyde group-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection.

[0006] In a first aspect, the present application provides an aldehyde group-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection, adopting the following technical solution: A dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection, comprising the following raw materials: an aqueous solution of water-soluble chitosan and an aqueous solution of dialdehyde-containing oxidized polysaccharide, wherein the water-soluble chitosan includes one of carboxyalkyl chitosan, hydroxyalkyl chitosan, sodium carboxyalkyl chitosan, and sodium hydroxyalkyl chitosan; the dialdehyde-containing oxidized polysaccharide is one of oxidized hydroxyethyl cellulose containing dialdehyde groups, oxidized hydroxypropyl cellulose containing dialdehyde groups, sodium or potassium salt of oxidized carboxymethyl cellulose containing dialdehyde groups, oxidized chitosan containing dialdehyde groups, oxidized hydroxyethyl chitosan containing dialdehyde groups, oxidized hydroxypropyl chitosan containing dialdehyde groups, sodium or potassium salt of oxidized carboxymethyl chitosan containing dialdehyde groups, oxidized hydroxyethyl chitin containing dialdehyde groups, oxidized hydroxypropyl chitin containing dialdehyde groups, sodium or potassium salt of oxidized carboxymethyl chitin containing dialdehyde groups, sodium or potassium salt of oxidized sodium hyaluronate containing dialdehyde groups, or sodium or potassium salt of oxidized sodium alginate containing dialdehyde groups.

[0007] By adopting the above technical solution, the aqueous solution of dialdehyde-containing oxidized polysaccharide and water-soluble chitosan are chemically crosslinked to form a gel after being mixed at the use site through a dual syringe, which is an injectable in-situ forming hydrogel. Both the dialdehyde-containing oxidized polysaccharide and water-soluble chitosan have good biocompatibility, reducing possible adverse reactions after injection, such as inflammation or allergic reactions, and improving the safety of cosmetic injection; the material is liquid at the initial stage of injection, enabling it to diffuse in the tissue space. As the chemical crosslinking reaction forms a network crosslinking in the tissue, a stable filling effect is formed at the injection site. At the same time, it tightly binds and adheres to the molecules of tissue cells, avoiding displacement or causing cavity-type occupancy.

[0008] The aqueous solution of dialdehyde-containing oxidized polysaccharide and water-soluble chitosan can generate a dynamic covalent network, which not only enhances the stability of the hydrogel but also provides a good attachment matrix for cell growth. At the same time, the degradation products of the material provide nutrients for cell growth, promoting the growth of tissue cells and inducing tissue regeneration and repair during the gradual degradation of the material in the body, avoiding problems such as tissue sagging and cavities caused by simple filling; the hydrogel is used for cosmetic purposes such as filling wrinkles, improving facial contours, and increasing skin volume, providing an immediate cosmetic effect and promoting skin regeneration and repair, making the skin look younger and smoother. Moreover, the raw materials used in this application do not contain crosslinking agents, and there will be no safety risks caused by the residue of crosslinking agents in the body.

[0009] The water absorption rate of cross-linked sodium hyaluronate gel in the background technology is too high. After being injected into the body, it continuously absorbs water and swells, causing tissue maceration. Since cross-linked sodium hyaluronate is internally cross-linked and is already in a cross-linked state before injection, there is a lack of connection / adhesion with tissues after injection, which is a simple space-occupying filling. As a result, it is easy to shift after filling, and after degradation, it forms tissue cavities, exacerbating skin relaxation and sagging. The aldehyde group-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection prepared in this application controls the water absorption expansion rate by controlling the ratio, process, etc., avoids maceration, can penetrate into tissue gaps, form a cross-linked network, and tightly combine with tissues to avoid displacement and cavity-type space occupation.

[0010] Optionally, the mass ratio of the water-soluble chitosan to the aldehyde group-containing oxidized polysaccharide is 0.5 - 5:0.5 - 5, and the concentrations of both the water-soluble chitosan and the aldehyde group-containing oxidized polysaccharide are 0.5 - 5%.

[0011] By adopting the above technical solution, the water-soluble chitosan has a molecular structure similar to that of natural extracellular matrix polysaccharide components, has good water solubility, biocompatibility and biodegradability, has the function of activating cell repair potential, promoting the repair of damaged tissues, maintaining cell viability, inhibiting scarring, anti-inflammatory and analgesic, moisturizing and soothing effects, and can promote the repair and regeneration of tissues at the injection site, achieving a lifting and tightening effect.

[0012] The active aldehyde groups in the aldehyde group-containing oxidized polysaccharide molecules can react with the amino groups in the water-soluble chitosan to form a Schiff base reaction and self-assemble to generate a hydrogel. It has biodegradability, is applied to cosmetic wrinkle removal, moisturizing and tissue filling, can be completely degraded within a certain period of time without the need for removal, the reaction conditions are mild, no cross-linking agent needs to be added, and the biological safety is good.

[0013] At the same time, the dialdehyde group oxidized polysaccharide-water-soluble chitosan hydrogel has the functions of inducing tissue regeneration and repair and stimulating collagen neogenesis, achieving excellent cosmetic effects. Further limiting the mass ratio of the water-soluble chitosan and the dialdehyde group oxidized polysaccharide within a certain range makes the hydrogel formed by cross-linking the water-soluble chitosan and the dialdehyde group oxidized polysaccharide have excellent tissue repair and filling properties. There is no cross-linking agent in the hydrogel, and the tissue compatibility is good, avoiding tissue irritation caused by the inability to absorb cross-linking agent residues. The simple filling effect of cross-linked sodium hyaluronate cannot promote tissue repair, and tissue cavities may form at the filling site, leading to side effects such as tissue relaxation and collapse.

[0014] Optionally, the preparation method of the aldehyde group-containing oxidized polysaccharide includes the following steps: Dissolve carboxymethyl cellulose in water, add an oxidant, stir in the dark at room temperature for 20 - 22 h, then add ethylene glycol to terminate the reaction, add ethanol for precipitation to obtain a product, and place the product in an alcohol system for impurity removal, dehydration and drying to obtain the aldehyde group-containing oxidized polysaccharide.

[0015] By adopting the above technical solution, carboxymethyl cellulose is oxidized using an oxidizing agent, and carboxymethyl cellulose and the oxidizing agent undergo an oxidation reaction to obtain oxidized carboxymethyl cellulose. Ethylene glycol is added to terminate the reaction, and after precipitation, impurity removal, dehydration, and drying, oxidized carboxymethyl cellulose is obtained. The obtained oxidized carboxymethyl cellulose contains highly active aldehyde groups, making it easier to react with hydroxypropyl chitosan. Moreover, the oxidized carboxymethyl cellulose still retains hydroxyl groups, ensuring hydrophilicity and biocompatibility, and enabling the material to have better performance in promoting wound healing, preventing adhesion, etc.

[0016] Optionally, the mass-volume ratio of the carboxymethyl cellulose, the oxidizing agent, and ethylene glycol is 1:0.3:100, g:g:μL.

[0017] By adopting the above technical solution, the dosage ratio of the carboxymethyl cellulose, the oxidizing agent, and ethylene glycol is further defined, enabling the carboxymethyl cellulose and the oxidizing agent to react fully, effectively reducing the molecular weight of the carboxymethyl cellulose, making the material have good fluidity in the initial stage of injection into tissues, capable of penetrating into tissue gaps, and forming a gel network during the gradual crosslinking process, enabling the material to be tightly combined with tissues, and simultaneously better regulating the degradation performance of the material.

[0018] Optionally, it further includes one of hydroxyapatite microspheres, chitin microspheres, low-degree deacetylation chitosan microspheres, chitin / chitosan composite microspheres, polylactic acid microspheres, polycaprolactone microspheres, and polymethyl methacrylate microspheres.

[0019] By adopting the above technical solution, hydroxyapatite microspheres and chitin / chitosan composite microspheres have good biocompatibility and stability, can induce bone tissue regeneration, and are used for shaping parts such as the nose bridge, chin, and cheekbones. At the same time, the microspheres prepared by a special process have good tissue compatibility and can stimulate and induce collagen regeneration. They are used in the face to cooperate with the gel to provide an immediate volume filling effect. At the same time, the microspheres promote collagen regeneration, tighten the skin, achieve tissue lifting, and improve the facial contour.

[0020] After the material is injected, the microsphere component can stimulate the generation of collagen in the surrounding tissues. Over time, the increase in collagen helps to tighten and restore the elasticity of the skin, prolong the duration of the beauty effect, and make the beauty effect more lasting.

[0021] The selected microsphere component is a biodegradable material, which can be safely degraded in the body. Over time, it will be gradually absorbed by the body, while stimulating the generation of its own collagen, ensuring the natural transition and safety of the beauty effect.

[0022] When used subperiosteally, it can play a role in inducing bone tissue regeneration and bone remodeling. A good bone shape can better support facial tissues, improve the overall facial contour, and improve the appearance aging caused by bone loss due to bone tissue absorption caused by aging.

[0023] Poly(lactic acid) microspheres have good biocompatibility. After being injected into skin tissue, they can gradually decompose and be absorbed, stimulate the production of collagen, and promote skin firmness and elasticity. Polycaprolactone microspheres can continuously induce fibroblasts to secrete and synthesize collagen, gradually fill the facial depressions caused by collagen loss. After gradually degrading in vivo, the newly generated autologous collagen will replace the original position and repair the skin elastic network. Poly(methyl methacrylate) microspheres are used for filling and shaping parts. While filling wrinkles, they stimulate continuous proliferation of collagen, enabling the thinning bone tissue to extend osteoidally and restoring a youthful contour.

[0024] Optionally, the preparation method of the hydroxyapatite microspheres includes the following steps: calcine bovine bone at 500 - 1000 °C for 4 - 8 h, then disperse it in absolute ethanol, stir for 15 - 20 min, dry to obtain hydroxyapatite, and ball mill to obtain hydroxyapatite microspheres.

[0025] By adopting the above technical solution, calcining hydroxyapatite increases the pore size of hydroxyapatite. A larger pore size is better for cells to attach and grow, playing the role of a cell scaffold, improving biocompatibility, helping to improve the permeability and diffusivity of the system, making nutrients and cytokines more likely to diffuse at the injection site, and promoting tissue regeneration and repair.

[0026] The gel fills wrinkles and improves the facial contour in facial aesthetic injections. It can effectively fill fine lines and wrinkles on the face, increase facial volume, improve the facial contour and proportion. The microspheres promote the regeneration of collagen, improve skin elasticity and firmness, and obtain long-term aesthetic effects.

[0027] Optionally, the preparation method of the hydroxyapatite microspheres includes the following steps: grind shells into powder, then disperse it in dilute nitric acid solution, stir for 1 - 2 h until no bubbles are generated, filter to remove residues to obtain an aqueous calcium nitrate solution; Dissolve methyl phosphate in absolute ethanol to obtain a methyl phosphate ethanol solution. Mix the methyl phosphate ethanol solution and the aqueous calcium nitrate solution according to a calcium-phosphorus molar ratio of 1.67, adjust the pH to 8 - 10 with ammonia water, react at 80 - 90 °C for 45 - 48 h until the solution becomes a gel state. After the reaction, dry, calcine, then disperse it in an ethanol solution, add poly(lactic acid) fiber, stir evenly, and then add agarose gel and mix evenly, dry to obtain hydroxyapatite, and ball mill to obtain hydroxyapatite microspheres.

[0028] By adopting the above technical solution, calcium carbonate in the shell powder reacts with dilute nitric acid solution to form calcium nitrate, which becomes a solution state. The reaction product of calcium nitrate solution and methyl phosphate alcohol solution in the solution state is calcined to form hydroxyapatite.

[0029] When the hydroxyapatite is calcined, due to the growth of crystal grains and the perfection of crystal structure, its mechanical strength and hardness are improved, and it has better wear resistance and thermal stability, and has suitable biological activity, which is used in the fields of orthopedics, dental restoration and cosmetic filling.

[0030] The polylactic acid fiber has the functions of skin filling and facial contour reshaping. After being injected into the deep layer of the skin, it can stimulate the surrounding tissues to produce collagen, thereby improving the elasticity and firmness of the skin, reducing wrinkles and fine lines. The polylactic acid fiber can be loaded on the surface of hydroxyapatite, increasing the filling effect of hydroxyapatite and with a longer duration. The polylactic acid fiber also has good biocompatibility and can be naturally degraded.

[0031] The agarose gel has a certain viscosity and can coat the hydroxyapatite, making the connection between the hydroxyapatite and the polylactic acid fiber closer, enabling the polylactic acid fiber to be stably loaded on the surface of the hydroxyapatite, increasing the comprehensive performance of the hydroxyapatite, making the hydroxyapatite have better biological activity, capable of deep filling of the skin, stimulating the surrounding tissues to produce collagen, thereby improving the elasticity and firmness of the skin, reducing wrinkles and fine lines. In the weeks to months after injection, as collagen is gradually generated, the effect will gradually increase and the duration is relatively long, generally lasting for 1 - 2 years.

[0032] Optionally, the mass ratio of the shell, polylactic acid fiber and agarose gel is 1:0.2 - 0.4:0.07 - 0.09.

[0033] By adopting the above technical solution, further limiting the mass ratio of the shell, polylactic acid fiber and agarose gel within a certain range makes the prepared hydroxyapatite have a better filling effect. The polylactic acid fiber can be loaded on the surface of the hydroxyapatite, and the agarose gel makes the polylactic acid fiber stably loaded on the surface of the hydroxyapatite. The prepared hydroxyapatite has good biological activity, long - term effect, biocompatibility and degradability, can deeply fill the skin, and has a wide range of applications.

[0034] Optionally, the preparation method of the polylactic acid fiber includes the following steps: Mix polylactic acid, polycaprolactone and maleic anhydride, and melt - extrude to obtain a polylactic acid composite masterbatch, and then melt - spin to obtain a polylactic acid fiber primary product; Disperse β - cyclodextrin in water, add the polylactic acid fiber primary product, stir evenly, and dry to obtain the polylactic acid fiber.

[0035] By adopting the above technical solution, polylactic acid has good filling effect, biocompatibility and small side effects. Polylactic acid is dispersed in an ethanol solution. Polycaprolactone has the ability of skin filling and tissue regeneration and is biodegradable. When injected under the skin, it can stimulate the generation of collagen, thereby improving the elasticity and firmness of the skin. β-cyclodextrin has inclusion property, good biocompatibility and safety, can include carboxymethyl cellulose, improve its stability and bioavailability in vivo, and thus enhance the beauty effect; After mixing polycaprolactone, β-cyclodextrin and polylactic acid, polylactic acid fibers are made. They have good filling ability. There is a cavity in the β-cyclodextrin structure, which can envelope various compound molecules, can coat polycaprolactone and polylactic acid, making polycaprolactone, β-cyclodextrin and polylactic acid closely connected. Polycaprolactone, β-cyclodextrin and polylactic acid cooperate to jointly improve biocompatibility and biodegradability and promote tissue regeneration.

[0036] During the process of gradually being absorbed in vivo, the polylactic acid fibers can stimulate the surrounding tissues to produce new collagen, thereby enhancing the elasticity and firmness of the skin. Improve the internal structure of the skin, fill the gaps caused by aging or skin damage, restore the fullness and smoothness of the skin, and reduce the appearance of wrinkles and fine lines. The biocompatibility and biodegradability of the polylactic acid fibers make them ideal skin regeneration materials. It can promote the natural repair process of the skin, accelerate wound healing, and improve the skin quality and appearance. The effect of injecting polylactic acid fibers is more lasting and safe.

[0037] Optionally, the mass ratio of the polylactic acid, β-cyclodextrin and polycaprolactone is 1:0.3 - 0.5:0.1 - 0.2.

[0038] By adopting the above technical solution, further limiting the mass ratio of polylactic acid, β-cyclodextrin and polycaprolactone within a certain range makes the prepared polylactic acid fibers have good comprehensive performance. β-cyclodextrin can coat the polylactic acid fibers, and the prepared polylactic acid fibers have good filling ability, improve biocompatibility and biodegradability, and promote tissue regeneration.

[0039] In the second aspect, the present application provides a preparation method of an aldehyde group-containing oxidized polysaccharide - water-soluble chitosan hydrogel for cosmetic injection, including the following steps: Disperse water-soluble chitosan in water and stir at a speed of 300 - 400 r / min for 1 - 2 h to obtain a water-soluble chitosan solution; Dissolve the aldehyde group-containing oxidized polysaccharide in water to obtain an aldehyde group-containing oxidized polysaccharide aqueous solution. After mixing the aldehyde group-containing oxidized polysaccharide aqueous solution with the water-soluble chitosan solution, it is obtained.

[0040] By adopting the above technical solution, a hydrogel is prepared by uniformly mixing an aqueous solution of oxidized polysaccharide containing dialdehyde groups and an aqueous solution of water-soluble chitosan. The operation is simple, the preparation efficiency is high, and the obtained hydrogel has good filling ability.

[0041] In summary, the present application has the following beneficial effects: 1. The oxidized polysaccharide-water-soluble chitosan hydrogel containing dialdehyde groups in the present application is a single-component polysaccharide solution before injection, with good flow permeability. At the initial stage of contact between the two components during injection, it still has good flow permeability and can penetrate into the tissue space. After entering, the hydrogel gradually crosslinks to form a crosslinked network structure, which tightly binds to the tissue, avoiding the risks of displacement and cavity-type occupancy.

[0042] 2. In the oxidized polysaccharide-water-soluble chitosan hydrogel containing dialdehyde groups in the present application, mixed microspheres can be dispersed in the aqueous solution of oxidized polysaccharide containing dialdehyde groups or the aqueous solution of water-soluble chitosan, or the microspheres can be uniformly dispersed therein at the initial stage of mixing the aqueous solution of oxidized polysaccharide containing dialdehyde groups and the aqueous solution of water-soluble polysaccharide. No matter which dispersion method is used when using the oxidized polysaccharide-water-soluble chitosan hydrogel containing dialdehyde groups, the microspheres can be uniformly carried into the tissue space. While the hydrogel degrades, the microspheres play a role in stimulating tissue regeneration, thereby achieving tissue lifting, improving the facial contour, avoiding collapse after filling caused by degradation, promoting collagen regeneration, and tightening the skin.

[0043] 3. The raw materials used in the present application do not contain crosslinking agents, and there will be no safety risks caused by the residue of crosslinking agents in the body. Specific Embodiments

[0044] The following further elaborates on the present application in conjunction with embodiments.

[0045] The raw materials used in the examples and comparative examples can all be obtained commercially.

[0046] Example 1 An oxidized polysaccharide-water-soluble chitosan hydrogel containing dialdehyde groups for cosmetic injection, comprising the following raw materials: an aqueous solution of water-soluble chitosan and an aqueous solution of oxidized polysaccharide containing dialdehyde groups. The water-soluble chitosan is carboxyethyl chitosan from Qingdao Boyite Biomaterials Co., Ltd.; the mass ratio of carboxyethyl chitosan to oxidized polysaccharide containing dialdehyde groups is 1:1, and the concentrations of both carboxyethyl chitosan and oxidized polysaccharide containing dialdehyde groups are 2.5%. Among them, the dosage of carboxyethyl chitosan is 250 mg.

[0047] Preparation method of oxidized polysaccharide containing dialdehyde groups, comprising the following steps: Dissolve 2 g of carboxymethyl cellulose in 40 mL of water, add an oxidizing agent (the oxidizing agent is sodium periodate), stir in the dark at room temperature for 21 h, then add ethylene glycol to terminate the reaction, add ethanol for precipitation to obtain a product, place the product in an alcohol system (the alcohol system is ethanol), and obtain oxidized carboxymethyl cellulose through impurity removal, dehydration, and drying, and select the required amount for the preparation of oxidized polysaccharide-water-soluble chitosan hydrogel containing dialdehyde groups for cosmetic injection.

[0048] The mass-volume ratio of carboxymethyl cellulose, oxidizing agent, and ethylene glycol is 1:0.3:100, g:g:μL.

[0049] The above-mentioned preparation method of oxidized polysaccharide-water-soluble chitosan hydrogel containing dialdehyde groups for cosmetic injection, comprising the following steps: Disperse carboxyethyl chitosan in water, stir at a speed of 350 r / min for 1.5 h to obtain a carboxyethyl chitosan solution; Dissolve oxidized carboxymethyl cellulose in water to obtain an oxidized carboxymethyl cellulose aqueous solution, and after mixing the oxidized carboxymethyl cellulose aqueous solution and the carboxyethyl chitosan solution, it is obtained (when using, complete the injection before gel formation, that is, it is not in a gel state during injection and forms a gel after being injected into the body).

[0050] Example 2 An oxidized polysaccharide-water-soluble chitosan hydrogel containing dialdehyde groups for cosmetic injection, different from Example 1 in that the water-soluble chitosan is hydroxypropyl chitosan, from Qingdao Boyite Biomaterials Co., Ltd.; The mass ratio of hydroxypropyl chitosan and oxidized carboxymethyl cellulose is 0.1:1, and the concentrations of both hydroxypropyl chitosan and oxidized carboxymethyl cellulose are 5%.

[0051] Example 3 An oxidized polysaccharide-water-soluble chitosan hydrogel containing dialdehyde groups for cosmetic injection, different from Example 1 in that the water-soluble chitosan is sodium hydroxyethyl chitosan, from Qingdao Boyite Biomaterials Co., Ltd.; the mass ratio of sodium hydroxyethyl chitosan and oxidized carboxymethyl cellulose is 1:10, and the concentrations of both sodium hydroxyethyl chitosan and oxidized carboxymethyl cellulose are 0.5%.

[0052] Example 4 An oxidized polysaccharide-water-soluble chitosan hydrogel containing dialdehyde groups for cosmetic injection, different from Example 1 in that the water-soluble chitosan is carboxymethyl chitosan, and the oxidized polysaccharide containing dialdehyde groups is oxidized hyaluronic acid, and the carboxymethyl chitosan and oxidized hyaluronic acid are from Qingdao Boyite Biomaterials Co., Ltd.

[0053] The mass ratio of carboxymethyl chitosan to oxidized hyaluronic acid is 1:1, and the concentrations of both carboxymethyl chitosan and oxidized hyaluronic acid are 3%.

[0054] Example 5 A dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection, which is different from Example 1 in that it further includes 2 g of chitin microspheres from Qingdao Boyite Biomaterials Co., Ltd. Preparation method of the dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel: After mixing the oxidized carboxymethyl cellulose aqueous solution and the carboxyethyl chitosan solution, add chitin microspheres to obtain it.

[0055] Example 6 A dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection, which is different from Example 1 in that it further includes 2 g of low-degree deacetylation chitosan microspheres, the degree of deacetylation of the low-degree deacetylation chitosan is 55%, from Qingdao Boyite Biomaterials Co., Ltd. Preparation method of the dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel: After mixing the oxidized carboxymethyl cellulose aqueous solution and the carboxyethyl chitosan solution, add low-degree deacetylation chitosan microspheres to obtain it.

[0056] Example 7 A dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection, which is different from Example 1 in that it further includes 2.5 g of chitin / chitosan composite microspheres. The preparation method of the chitin / chitosan composite microspheres includes the following steps: Purify chitin (disperse 2 g of chitin in 100 mL of 0.2 mol / L NaOH solution, heat and stir in a water bath at 60 °C for 1 h, wash with water, and dry), then crush and sieve, and then perform spheronization treatment to obtain round and smooth chitin microspheres (particle size 20 - 50 μm). Coating 10 mL of 5% chitosan aqueous solution onto the chitin microspheres, after compounding, disperse the microspheres in 30 mL of 95% ethanol solution, and adjust the pH to 7.3 using 0.1 mol / L NaOH solution to obtain chitin / chitosan composite microspheres. Preparation method of the dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel: After mixing the oxidized carboxymethyl cellulose aqueous solution and the carboxyethyl chitosan solution, add chitin / chitosan composite microspheres to obtain it.

[0057] Example 8 A dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection, which is different from Example 1 in that it further includes 2 g of hydroxyapatite microspheres. The preparation method of the hydroxyapatite microspheres includes the following steps: calcine 100 g of bovine bone at 500 °C for 4 h, then disperse it in 300 mL of absolute ethanol, stir for 15 min, and dry to obtain hydroxyapatite. Use a ball mill to spheroidize the hydroxyapatite to obtain hydroxyapatite microspheres with a particle size of 20 - 40 μm.

[0058] The preparation method of the dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel is to mix the oxidized carboxymethyl cellulose aqueous solution and the carboxyethyl chitosan solution, and then add the hydroxyapatite microspheres to obtain it.

[0059] Example 9 A dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection, which is different from Example 1 in that it further includes 2 g of hydroxyapatite microspheres. The preparation method of the hydroxyapatite microspheres includes the following steps: calcine 120 g of bovine bone at 550 °C for 8 h, then disperse it in 350 mL of absolute ethanol, stir for 20 min, and dry to obtain hydroxyapatite. Use a ball mill to spheroidize the hydroxyapatite to obtain hydroxyapatite microspheres with a particle size of 20 - 40 μm.

[0060] The preparation method of the dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel is to mix the oxidized carboxymethyl cellulose aqueous solution and the carboxyethyl chitosan solution, and then add the hydroxyapatite microspheres to obtain it.

[0061] Example 10 A dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection, which is different from Example 1 in that the preparation method of the hydroxyapatite microspheres includes the following steps: grind 120 g of shells into powder, then disperse it in 300 mL of a 14% dilute nitric acid solution, stir for 1.5 h until no bubbles are generated, filter to remove the residue to obtain an aqueous calcium nitrate solution; Dissolve methyl phosphate in 400 mL of absolute ethanol to obtain a methyl phosphate ethanol solution. Mix the methyl phosphate ethanol solution and the aqueous calcium nitrate solution according to a calcium-phosphorus molar ratio of 1.67, adjust the pH to 9 with ammonia water, react at 85 °C for 46 h until the solution becomes a gel state. After the reaction, dry, calcine, then disperse it in an ethanol solution, add polylactic acid fibers, stir evenly, and then add agarose gel and mix evenly, dry to obtain hydroxyapatite. Use a ball mill to spheroidize the hydroxyapatite to obtain hydroxyapatite microspheres with a particle size of 20 - 40 μm.

[0062] The mass ratio of the shells, polylactic acid fibers, and agarose gel is 1:0.2:0.07.

[0063] Preparation method of polylactic acid fiber, comprising the following steps: Mix 100 g of polylactic acid, polycaprolactone, and 6 g of maleic anhydride, and melt-extrude at a temperature of 160 °C to obtain a polylactic acid composite masterbatch, and then melt-spin to obtain a polylactic acid fiber primary product; Disperse β-cyclodextrin in 500 g of water, add the polylactic acid fiber primary product, stir evenly, filter and dry to obtain polylactic acid fiber.

[0064] Melt-spinning parameters: Spinning is carried out in a melt-spinning machine, the spinning temperature is 150 °C, the winding speed is 700 m / min, the fiber is drawn, the draw ratio is 1.5 times, and the hot plate temperature is 60 °C.

[0065] The mass ratio of polylactic acid, β-cyclodextrin, and polycaprolactone is 1:0.3:0.2.

[0066] Preparation method of dialdehyde group-containing oxidized polysaccharide-water-soluble chitosan hydrogel: Mix an oxidized carboxymethyl cellulose aqueous solution and a carboxyethyl chitosan solution, and then add hydroxyapatite microspheres to obtain it.

[0067] Example 11 A dialdehyde group-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection, which is different from Example 10 in that no polylactic acid fiber is added.

[0068] Example 12 A dialdehyde group-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection, which is different from Example 10 in that no agarose gel is added.

[0069] Example 13 A dialdehyde group-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection, which is different from Example 10 in that the mass ratio of shell, polylactic acid fiber, and agarose gel is 1:0.4:0.09.

[0070] Example 14 A dialdehyde group-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection, which is different from Example 10 in that the mass ratio of shell, polylactic acid fiber, and agarose gel is 1:0.1:0.13.

[0071] Example 15 A dialdehyde group-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection, which is different from Example 10 in that in the preparation method of polylactic acid fiber, no β-cyclodextrin is added.

[0072] Example 16 An aldehyde group-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection, which is different from Example 10 in that in the preparation method of the polylactic acid fiber, polycaprolactone is not added.

[0073] Example 17 An aldehyde group-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection, which is different from Example 10 in that the mass ratio of polylactic acid, β-cyclodextrin and polycaprolactone is 1:0.5:0.1.

[0074] Example 18 An aldehyde group-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection, which is different from Example 10 in that the mass ratio of polylactic acid, β-cyclodextrin and polycaprolactone is 1:0.1:0.5.

[0075] Comparative Example 1 An aldehyde group-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection, which is different from Example 1 in that carboxyethyl chitosan is not added.

[0076] Comparative Example 2 An aldehyde group-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection, which is different from Example 1 in that oxidized carboxymethyl cellulose is not added.

[0077] Performance detection test The aldehyde group-containing oxidized polysaccharide-water-soluble chitosan hydrogels for cosmetic injection prepared in Examples 1-18 and the solutions obtained in Comparative Examples 1-2 were subjected to performance tests; 1. Degradation rate test: Take the samples prepared in the examples, weigh (W0), soak them in 10 mL of PBS (0.01 M, pH = 7.4) solution, place them in a shaker at 37 °C, with a shaking speed of 70 r / min, change the PBS solution weekly, measure for 6 months, take out the samples for each measurement, rinse them thoroughly with distilled water, and vacuum freeze-dry to constant weight (W t ), degradation rate = (W0 - W t ) / W0 × 100%.

[0078] 2. Viscoelasticity test: Take the samples prepared in the examples and comparative examples and test them with a rheometer. Test fixture: upper plate 20 mm flat plate, lower plate 60 mm flat plate; gap: 1 mm; test description: perform amplitude scanning at a constant temperature of 10 °C.

[0079] 3. Water absorption rate test: Take a certain weight of dried microspheres, W0 grams, put them into a stainless steel wire cage, place them in 500 mL of distilled water, let them stand for 8 hours, take them out until the stainless steel wire cage stops dripping, and weigh the weight of the microspheres, W1 grams. Water absorption rate = (W1 - W0) / W0 × 100%.

[0080] 4. Plasticity effect test: The beauty filler materials obtained by injecting and filling the backs of newly born white mice in the examples and comparative examples were tested. The injection volume for each white mouse was 1 mL. The changes in the backs were observed 1 month, 3 months, and 6 months after injection. The test results are shown in Table 1-2.

[0081] Table 1 Test data of examples and comparative examples

[0082] Table 2 Test data of examples and comparative examples

[0083] As can be seen from Table 1-2, the dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel for beauty injection prepared in Examples 1-4 of the present application has good mechanical properties. Among them, the degradation rate of Example 1 at 14 days was 25.34%, the degradation rate at 1 month was 33.26%, the degradation rate at 6 months was 66.78%, the viscosity was 110 Pa, the elasticity was 468 Pa, and there was no change after 6 months of injection. The skin of the white mouse remained smooth, flat, and translucent. In Comparative Examples 1-2, only one raw material component was added respectively. As can be seen from Table 1-2, 1 month after injection, the skin of the white mouse was smooth, flat, and dull. 3 and 6 months after injection, the skin of the white mouse was smooth, uneven, and dull. It shows that the prepared hydrogel forms a stable filling effect at the injection site, and at the same time binds and adheres tightly to the molecules of tissue cells, avoiding displacement or causing cavity-type occupation, and making the skin look younger and smoother, reflecting good elastic properties, maintaining a firm current structural strength, and contributing to the maintenance of the plasticity effect after injection.

[0084] The raw materials of Examples 5-9 also include chitin microspheres, low-degree deacetylation chitosan microspheres, chitin / chitosan composite microspheres, and hydroxyapatite microspheres respectively. Compared with Example 1, the performance test effects of the degradation rate, viscosity, and elasticity of the obtained hydrogel are significantly better than those of Example 1, indicating that chitin microspheres, low-degree deacetylation chitosan microspheres, chitin / chitosan composite microspheres, and hydroxyapatite microspheres all have good biocompatibility and stability, and are used in combination with the gel on the face to provide an immediate volume filling effect, better support the facial tissues, and improve the overall facial contour.

[0085] Example 10 The raw materials further include hydroxyapatite microspheres respectively. Compared with Examples 8-9, the preparation method of hydroxyapatite microspheres is further improved. It can be seen from Tables 1-2 that the performance test results of the degradation rate, viscosity, elasticity, and water absorption rate of the obtained hydrogel are significantly better than those of Examples 8-9, indicating that polylactic acid fibers can be loaded on the surface of hydroxyapatite, increasing the filling effect of hydroxyapatite and having a long-lasting effect. Agarose gel can coat hydroxyapatite, making the connection between hydroxyapatite and polylactic acid fibers closer, filling the deep layer of the skin, and improving the elasticity and firmness of the skin.

[0086] In the preparation methods of Examples 11-12, polylactic acid fibers and agarose gel are not added to hydroxyapatite microspheres respectively. In Examples 13-14, the mass ratios of shell, polylactic acid fibers, and agarose gel are changed. It can be seen from Tables 1-2 that the performance test results of the degradation rate, viscosity, elasticity, and water absorption rate of the hydrogel in Examples 11-12 are significantly worse than those in Example 10. The performance test results of the degradation rate, viscosity, elasticity, and water absorption rate of Example 14 are significantly better than those of Examples 11-12 but worse than those of Example 10 and Example 13, indicating that polylactic acid fibers can be loaded on the surface of hydroxyapatite, and agarose gel enables polylactic acid fibers to be stably loaded on the surface of hydroxyapatite. The prepared hydroxyapatite has good bioactivity, long-lasting effect, biocompatibility, and degradability, and can fill the deep layer of the skin.

[0087] In the preparation methods of Examples 15-16, β-cyclodextrin and polycaprolactone are not added to polylactic acid fibers respectively. In Examples 17-18, the mass ratios of polylactic acid, β-cyclodextrin, and polycaprolactone are changed. It can be seen from Tables 1-2 that the performance test results of the degradation rate, viscosity, elasticity, and water absorption rate of the hydrogel in Examples 15-16 are significantly worse than those in Example 10. The performance test results of the degradation rate, viscosity, elasticity, and water absorption rate of Example 18 are significantly better than those of Examples 15-16 but worse than those of Example 10 and Example 17, indicating that β-cyclodextrin can coat polycaprolactone and polylactic acid, making the connection between polycaprolactone, β-cyclodextrin, and polylactic acid close. The prepared polylactic acid fibers have good filling ability, improved biocompatibility and biodegradability, and can promote tissue regeneration.

[0088] This specific embodiment is only an interpretation of the present application and does not limit the present application. After reading this specification, those skilled in the art can make modifications to this embodiment without creative contributions as needed, but as long as they are within the scope of the claims of the present application, they are protected by the patent law.

Claims

1. A water-soluble chitosan hydrogel containing a dialdehyde group and an oxidized polysaccharide for cosmetic injection, characterized in that: The invention comprises the following raw materials: a water-soluble chitosan aqueous solution and an oxidized polysaccharide aqueous solution containing dialdehyde groups, wherein the water-soluble chitosan comprises one of carboxyalkyl chitosan, hydroxyalkyl chitosan, carboxyalkyl chitosan sodium salt and hydroxyalkyl chitosan sodium salt; the oxidized polysaccharide containing dialdehyde groups is one of oxidized hydroxyethyl cellulose containing dialdehyde groups, oxidized hydroxypropyl cellulose containing dialdehyde groups, oxidized carboxymethyl cellulose sodium salt or potassium salt containing dialdehyde groups, oxidized chitosan containing dialdehyde groups, oxidized hydroxyethyl chitosan containing dialdehyde groups, oxidized hydroxypropyl chitosan containing dialdehyde groups, oxidized carboxymethyl chitosan sodium salt or potassium salt containing dialdehyde groups, oxidized hydroxyethyl chitin containing dialdehyde groups, oxidized hydroxypropyl chitin containing dialdehyde groups, oxidized carboxymethyl chitin sodium salt or potassium salt containing dialdehyde groups, oxidized hyaluronic acid sodium salt or potassium salt containing dialdehyde groups, or oxidized alginate sodium salt or potassium salt containing dialdehyde groups.

2. The dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection according to claim 1, characterized in that: The mass ratio of the water-soluble chitosan to the oxidized polysaccharide containing dialdehyde groups is 0.5-5:0.5-5, and the concentrations of the water-soluble chitosan and the oxidized polysaccharide containing dialdehyde groups are both 0.5-5%.

3. The dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection according to claim 1, characterized in that: The preparation method of the oxidized polysaccharide containing dialdehyde groups comprises the following steps: dissolving carboxymethyl cellulose in water, adding an oxidant, stirring for 20-22 hours at room temperature in the dark, adding ethylene glycol to terminate the reaction, adding ethanol for precipitation to obtain a product, placing the product in an alcohol system, removing impurities, dehydrating and drying to obtain the oxidized polysaccharide containing dialdehyde groups.

4. The dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection according to claim 3, characterized in that: The mass volume ratio of the carboxymethyl cellulose, the oxidant and the ethylene glycol is 1:0.3:100, g:g:μL.

5. The dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection according to claim 1, characterized in that: It also includes one of hydroxyapatite microspheres, chitin microspheres, low-deacetylation chitosan microspheres, chitin / chitosan composite microspheres, polylactic acid microspheres, polycaprolactone microspheres, and polymethyl methacrylate microspheres.

6. The dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection according to claim 5, characterized in that: The preparation method of hydroxyapatite microspheres comprises the following steps: calcining bovine bones at 500-1000°C for 4-8h, dispersing the bones in anhydrous ethanol, stirring for 15-20min, drying to obtain hydroxyapatite, and ball milling to obtain hydroxyapatite microspheres.

7. The dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection according to claim 5, characterized in that: The preparation method of hydroxyapatite microspheres comprises the following steps: grinding shells into powder, dispersing the powder in a dilute nitric acid solution, stirring for 1-2 hours until no bubbles are generated, filtering to remove residues, and obtaining a calcium nitrate aqueous solution; Methyl phosphate is dissolved in anhydrous ethanol to obtain a methyl phosphate ethanol solution, and the methyl phosphate ethanol solution and the calcium nitrate aqueous solution are mixed in a calcium-phosphorus molar ratio of 1.67, and the pH is adjusted to 8-10 with ammonia water. The reaction is carried out at 80-90°C for 45-48 hours until the solution becomes a gel state. After the reaction is completed, it is dried and calcined, and then dispersed in an ethanol solution, polylactic acid fiber is added, stirred evenly, and then agarose gel is added and mixed evenly, and dried to obtain hydroxyapatite, and ball milling is performed to obtain hydroxyapatite microspheres.

8. The dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection according to claim 7, characterized in that: The mass ratio of the shell, polylactic acid fiber and agarose gel is 1:0.2-0.4:0.07-0.

09.

9. The dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection according to claim 7, characterized in that: The preparation method of the polylactic acid fiber comprises the following steps: The polylactic acid, polycaprolactone and maleic anhydride are mixed, melt-extruded to obtain a polylactic acid composite masterbatch, and then melt-spun to obtain a polylactic acid fiber primary product; The beta-cyclodextrin is dispersed in water, and the polylactic acid fiber primary product is added, stirred evenly, and dried to obtain the polylactic acid fiber.

10. The dialdehyde-containing oxidized polysaccharide-water-soluble chitosan hydrogel for cosmetic injection according to claim 9, characterized in that: The mass ratio of the polylactic acid, beta-cyclodextrin and polycaprolactone is 1:0.3-0.5:0.1-0.2.

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