A gel and preparation method thereof

Abstract

The present application discloses a gel and a preparation method thereof, which are used in the technical field of anti-inflammatory drugs. The preparation method comprises the following steps: dissolving gallic acid (GA) in water, stirring for the first time, adding a first alkaline solution, and stirring for the second time to obtain a first solution; providing anhydrous copper chloride of a predetermined mass ratio and adding it to the first solution, and adding the first alkaline solution to adjust the pH value of the solution, and stirring to obtain a first mixture; centrifuging the first mixture, collecting the precipitate and washing it with a second alkaline solution, and storing it in the second alkaline solution at 4°C to obtain a second dispersion; stirring and adding a gel matrix, a predetermined concentration of adapalene, a second dispersion, hydroxypropyl chitosan, a water-soluble carbodiimide coupling agent, a chelating agent, an osmotic pressure regulator, a nonionic surfactant and a pH regulator in water to prepare a gel product. The gel of the present invention has good biocompatibility, antibacterial and anti-inflammatory properties, and has good application value.

Description

Technical Field

[0001] The present application relates to the technical field of anti-inflammatory drugs, and in particular to a gel and a preparation method thereof. Background Art

[0002] The inflammatory response is the result of the destruction of the balance between the pro-inflammatory and anti-inflammatory mechanisms in the body. This is manifested in that when the body is out of balance under external or internal stimulation, it will lead to a mild chronic inflammatory state and trigger a series of closely related diseases. The causes and clinical manifestations of such diseases are complex and diverse, and they often recur, which brings great difficulties to clinical treatment. Skin inflammation is caused by various internal and external infections or non-infectious factors that stimulate the skin, thereby stimulating the body's defense response, releasing chemokines to move inflammatory cells and immune cells to the local part of the body, and causing physiological or pathological reactions of varying degrees. Skin inflammation is a basic, non-specific innate immune response involving tissue decomposition and the removal of pathogen fragments. Common manifestations include redness, swelling, dryness, itching, etc. of the skin, mainly including contact dermatitis, atopic dermatitis, seborrheic dermatitis, etc. However, in the presence of external harmful stimuli that cause tissue damage, severe cases can cause septic shock, leading to uncontrolled differentiation and activation of keratinocytes, difficulty in wound healing, and prolonged and aggravated inflammation. Therefore, preventing and controlling the occurrence of inflammation is key.

[0003] At present, the methods for treating skin inflammation usually include daily care, topical medications and oral medications. Depending on the severity of skin inflammation, the selected treatment method will also be different. The dosage forms of topical medications include creams, gels, ointments, liniments and lotions. Among them, ointments and creams are prone to uneven application, contaminating clothes, and may cause inconvenience when used; while liniments and lotions are easy to evaporate, have high fluidity, and are also inconvenient to use. In contrast, gel is a thick liquid or semisolid preparation that overcomes the above shortcomings. It has a uniform and delicate texture and is easy to apply on the skin. Due to its good adhesion, it does not produce large fluidity and is more convenient to use. In addition, gel also has the characteristics of easy cleaning, fast drug release, long retention time and no irritation to the skin, so it has been favored by patients in recent years. Summary of the invention

[0004] One object of the present application is to provide a gel and a preparation method thereof, which are beneficial to enhancing the antibacterial, antioxidant, anti-inflammatory activity and biocompatibility of the gel product.

[0005] Another object of the present application is to provide a gel and a preparation method thereof, which are beneficial to enhancing the moisture absorption and moisture retention and UV resistance of the gel product, and have good absorption effect while being easy to store.

[0006] Another object of the present application is to provide a gel and a preparation method thereof, which has a simple preparation process, is easy to operate, and has the potential to be put into large-scale production.

[0007] In order to achieve the above purpose, the technical solution adopted in this application is: a method for preparing a gel, comprising the following steps:

[0008] S1, dissolving gallic acid (GA) in water, stirring for the first time, adding the first alkaline solution, and stirring for the second time to obtain the first solution;

[0009] S2, providing anhydrous copper chloride in a predetermined mass ratio and adding it to the first solution, and adding the first alkaline solution to adjust the pH value of the solution, and stirring to obtain a first mixture;

[0010] S3, centrifuging the first mixture, collecting the precipitate, washing it with a second alkaline solution, and storing it in the second alkaline solution at a low temperature to obtain a second dispersion;

[0011] S4, adding the gel matrix, adapalene of a predetermined concentration, the second dispersion, hydroxypropyl chitosan, a water-soluble carbodiimide coupling agent, a chelating agent, an osmotic pressure regulator, a nonionic surfactant and a pH regulator into water with stirring to prepare a gel product.

[0012] In one embodiment, in step S1, the gallic acid is added in an amount of 0.2wt.% to 2.0wt.%, the first stirring treatment temperature is 30°C to 50°C, the first stirring treatment time is 5min to 20min, and the second stirring treatment time is 15min to 25min.

[0013] In one embodiment, in step S2, the mass ratio of the first solution to anhydrous cupric chloride is 1:(2-5), and the stirring treatment time is 20h~30h.

[0014] In one embodiment, in step S4, the mass fraction of adapalene is 0.05%~0.5%, the mass fraction of the second dispersion is 0.1%~0.5%, the mass fraction of hydroxypropyl chitosan is 0.1%~0.2%, the mass fraction of the water-soluble carbodiimide coupling agent is 0.02%~0.15%, the mass fraction of the chelating agent is 0.05%~0.2%, the mass fraction of the osmotic pressure regulator is 3.0%~5.0%, the mass fraction of the non-ionic surfactant is 0.1%~0.6%, and the mass fraction of the pH regulator is 0.1%~0.3%.

[0015] In one embodiment, in step S4, the gel matrix is ​​selected from one or more of carbomer, gelatin, cellulose, xanthan gum and sodium alginate, the water-soluble carbodiimide coupling agent is selected from one or more of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and bis[4-(2,2-dimethyl-1-3-dioxyalkyl)]methylcarbodiimide, the non-ionic surfactant is selected from one or more of lauryl alcohol, oleyl alcohol, palmityl alcohol, polyoxyethylene hydrogenated castor oil, fatty acid polyoxyethylene ester, poloxamer, octylphenol and polysorbate 80, and the osmotic pressure regulator is selected from one or more of glycerol, propylene glycol, mannitol and sorbitol.

[0016] In one embodiment, the step S4 specifically includes the steps of:

[0017] S41, after adding the gel matrix into the water with stirring, purified water, adapalene of a predetermined concentration, the second dispersion, hydroxypropyl chitosan, a water-soluble carbodiimide coupling agent, a chelating agent and an osmotic pressure regulator are added and stirred for the third time, and after being immersed until the mixture is completely swollen, stirring is performed for the fourth time to obtain a second mixture;

[0018] S42, adding a nonionic surfactant into water and mixing to obtain a third mixture, vacuum stirring the blend of the second mixture and the third mixture, adding a pH adjuster to adjust the pH value to 4.5-5.5, and stirring to obtain a gel product.

[0019] In one embodiment, in step S3, the centrifugal treatment time is 15 min to 30 min, the first alkaline solution and the second alkaline solution used in steps S1, S2 and S3 are sodium hydroxide solutions, the concentration of the first alkaline solution is 0.8 g / mL to 1.2 g / mL, and the concentration of the second alkaline solution is 2×10 -8 g / mL~6×10 -8 g / mL.

[0020] In one embodiment, in step S41, the third stirring treatment time is 45 min to 90 min, the fourth stirring treatment time is 30 min to 60 min, the vacuum degree of the vacuum stirring treatment is not less than -0.06 MPa, and the stirring time is 10 min to 30 min.

[0021] In one embodiment, in step S4, the mass fraction of the second dispersion is 0.2%~0.4%, the mass fraction of the second mixture is 1.0%~1.5%, the mass fraction of the hydroxypropyl chitosan is 0.12%~0.2%, the mass fraction of the water-soluble carbodiimide coupling agent is 0.06%~0.12%, the mass fraction of the chelating agent is 0.05%~0.15%, the mass fraction of the osmotic pressure regulator is 3.5%~4.5%, and the mass fraction of the non-ionic surfactant is 0.1%~0.4%.

[0022] According to another aspect of the present application, a gel prepared by the above preparation method is also provided. DETAILED DESCRIPTION

[0023] Below, the present application is further described in conjunction with specific implementation methods. It should be noted that, under the premise of no conflict, the various embodiments or technical features described below can be arbitrarily combined to form new embodiments.

[0024] As used herein, the term "prepared from" is synonymous with "comprising". As used herein, the terms "comprising", "including", "having", "containing" or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that includes the listed elements is not necessarily limited to only those elements, but may include other elements not expressly listed or inherent to such composition, step, method, article, or apparatus.

[0025] When an amount, concentration or parameter is expressed as a range, a preferred range, or a range limited by a series of upper preferred values ​​and lower preferred values, this should be understood as specifically disclosing the range used formed by any pairing of any range upper limit or preferred value with any range lower limit or preferred value, regardless of whether the range is disclosed separately. For example, when it is disclosed that the range is "1 to 5", the described range should be interpreted as including the range "1 to 4", "1 to 3", "1 to 2 and 4 to 5", "1 to 3 and 5", etc. When a numerical range is described in this article, unless otherwise stated, the range includes its end values ​​and all integers and fractions within the range.

[0026] Approximate terms in the specification and claims are used to modify quantities, indicating that the present invention is not limited to the specific quantity, but also includes acceptable and modified parts close to the quantity without causing changes in the relevant basic functions. Accordingly, the use of "about", "approximately", etc. to modify a numerical value means that the present invention is not limited to the exact numerical value. In some examples, the approximate terms may correspond to the accuracy of the instrument for measuring the numerical value. In the specification and claims of this application, range limitations can be combined and / or interchanged, and if not otherwise stated, these ranges include all subranges contained therein.

[0027] According to one aspect of the present invention, a method for preparing a gel comprises the steps of:

[0028] S1, dissolving gallic acid (GA) in water, stirring for the first time, adding the first alkaline solution, and stirring for the second time to obtain the first solution;

[0029] S2, providing anhydrous copper chloride in a predetermined mass ratio and adding it to the first solution, and adding a first alkaline solution to adjust the pH value of the solution, and stirring to obtain a first mixture;

[0030] S3, centrifuging the first mixture, collecting the precipitate, washing it with a second alkaline solution, and storing it in the second alkaline solution at a low temperature to obtain a second dispersion;

[0031] S4, adding the gel matrix, adapalene of a predetermined concentration, the second dispersion, hydroxypropyl chitosan, a water-soluble carbodiimide coupling agent, a chelating agent, an osmotic pressure regulator, a nonionic surfactant and a pH regulator into water with stirring to prepare a gel product.

[0032] The present application introduces natural polyphenols, antibacterial nanoparticles and adapalene during the preparation of the gel, thereby further enhancing the anti-inflammatory and antibacterial properties of the gel, while having hygroscopic and moisturizing functions, human friendliness and good absorption effects. The preparation process is relatively simple, easy to operate, and has the potential to be put into large-scale production.

[0033] In one embodiment, in step S1, the gallic acid is added in an amount of 0.2wt.% to 2.0wt.%. Specifically, the gallic acid is added in an amount of 0.2wt.%, 0.5wt.%, 0.8wt.%, 1.1wt.%, 1.4wt.%, 1.7wt.%, 2.0wt.%. Further preferably, the gallic acid is added in an amount of 0.8wt.% to 1.5wt.%.

[0034] It is understandable that natural polyphenols are an organic compound that is generally distributed in plants in the form of glycosides, such as vegetables, fruits, nuts, soybeans, tea, and alcoholic beverages. They have good biological activity and have many benefits for human health, including antioxidant, anti-inflammatory, anti-cancer, and cardiovascular protection. In practical applications, natural polyphenols exert their biological activity through a variety of mechanisms, such as by blocking the cell cycle or inducing apoptosis by regulating signal transduction pathways, thereby inhibiting the proliferation and migration of cancer cells. Furthermore, polyphenol compounds also have beneficial effects such as anti-atherosclerosis, anti-infection, and anti-osteoporosis, and can be used not only to treat various diseases, such as inflammation or cancer, but also in cosmetic formulations and nutritional supplements for anti-aging purposes.

[0035] Furthermore, in the present application, gallic acid is first prepolymerized into gallic acid oligomer (PGA), so that a large number of phenolic hydroxyl groups and quinone groups are generated on the gallic acid molecular chain, and then complexed with Cu nanoparticles to form a stable metal-polyphenol network structure, thereby enhancing the tensile properties and adhesion to the skin of the gel product, while maintaining the shape stability of the gel during use, which is conducive to improving the absorption effect of the beneficial ingredients in the gel product by the human body. In addition, the multiple biological functions of gallic acid itself further enhance the antioxidant, anti-ultraviolet and anti-inflammatory properties of the gel product.

[0036] In one embodiment, in step S1, the first stirring treatment temperature is 30° C. to 50° C., specifically, the first stirring treatment temperature may be 30° C., 35° C., 40° C., 45° C., 50° C., and more preferably, the first stirring treatment temperature is 32° C. to 42° C. As one of the important factors affecting the polymerization reaction rate, stirring temperature, too high or too low temperature will affect the reaction rate and product quality.

[0037] In one embodiment, the first stirring treatment time is 5min~20min, specifically, the first stirring treatment time is 5min, 8min, 11min, 14min, 17min, 20min, and further preferably, the first stirring treatment time is 10min~18min. The second stirring treatment time is 15min~25min, specifically, the second stirring treatment time is 15min, 17min, 19min, 21min, 23min, 25min, and further preferably, the second stirring treatment time is 18min~23min. It is understood that suitable stirring time and stirring temperature can improve reaction efficiency and ensure product quality and stability.

[0038] In one embodiment, in step S2, the mass ratio of the first solution to the anhydrous copper chloride is 1: (2-5), specifically, the mass ratio of the first solution to the anhydrous copper chloride is 1: 2, 1: 2.5, 1: 3, 1: 3.5, 1: 4, 1: 4.5, 1: 5, and further preferably, the mass ratio of the first solution to the anhydrous copper chloride is 1: (2.5-4.5). When an excessive amount of anhydrous copper chloride is used, the excessive copper (Cu) will oxidize biological molecules, thereby causing damage to cells, enzymes and protein structures during use, and when the Cu content is too high, liver toxicity, nephrotoxicity, cytotoxicity and genotoxicity will increase, which is not conducive to the subsequent use of the gel product. On the other hand, when the Cu content is too low, the low Cu content affects the subsequent formation of Cu metal nanoparticles, further affecting the integrity of the metal-polyphenol network structure formed by complexation with PGA, thereby reducing the mechanical properties of the gel product. On the other hand, when the Cu content is too low, the antibacterial and anti-inflammatory properties are reduced, thereby reducing the application in the medical and antibacterial fields. Furthermore, insufficient Cu content may cause the nanoparticles to aggregate more easily, which is not conducive to the subsequent synthesis reaction.

[0039] In one embodiment, in step S2, the stirring treatment time is 20h to 30h, specifically, the stirring treatment time can be 20h, 22h, 24h, 26h, 28h, 30h, and more preferably, the stirring treatment time is 22h to 28h. Appropriate stirring time can improve reaction efficiency and reaction completeness, and ensure the quality and stability of the product.

[0040] In one embodiment, in step S4, the mass fraction of adapalene is 0.05% to 0.5%, and specifically, the mass fraction of adapalene is 0.05%, 0.14%, 0.23%, 0.32%, 0.41%, and 0.5%. It can be understood that adapalene, also known as 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, belongs to the retinoic acid class of drugs and has anti-inflammatory and retinoic acid properties. Adapalene can target and bind to retinoic acid receptors (RAR-β and RAR-γ), thereby inhibiting the production of inflammatory mediators (such as arachidonic acid lipid oxidation), achieving effective anti-inflammatory and improving skin damage caused by inflammation. As a dermatological drug, adapalene is mainly used to treat common acne, especially acne with acne, papules and pustules as the main manifestations, and can also be used to treat acne on the face, chest and back. Clinical studies have shown that Adapalene is effective in treating acne and its adverse reactions are much lower than other similar drugs.

[0041] In one embodiment, the mass fraction of the second dispersion is 0.1%~0.5%, specifically, the mass fraction of the second dispersion is 0.1%, 0.2%, 0.3%, 0.4%, and 0.5%. Further preferably, the concentration of the second dispersion is 0.2%~0.4%. It can be understood that the pre-polygallic acid-copper nanoparticles (Cu@PGA NPs) contained in the second dispersion have a high specific surface area and high reactivity, which are helpful to inhibit or kill pathogens, and are effective against a wide range of pathogenic microorganisms. Metal nanoparticles exert antibacterial effects through various mechanisms, including destroying the stability of bacterial cell membranes and cell walls; releasing metal ions to react with proteins and enzymes in bacteria, thereby causing bacterial death; inducing bacteria to produce a large amount of reactive oxygen, as well as inhibiting the activity of bacterial enzymes and interfering with DNA synthesis. The present invention uses copper nanoparticles to inhibit bacterial growth by destroying bacterial cell membranes, thereby enhancing the antibacterial and anti-inflammatory properties of the gel product.

[0042] In one embodiment, the hydroxypropyl chitosan mass fraction is 0.1% to 0.2%, specifically, the hydroxypropyl chitosan mass fraction is 0.1%, 0.12%, 0.14%, 0.16%, 0.18%, 0.2%, and further preferably, the hydroxypropyl chitosan mass fraction is 0.12% to 0.2%. It is understandable that the hydroxypropyl chitosan after hydroxypropyl modified chitosan is a polymer material with good water solubility, moisturizing, surface activity and biocompatibility. Further, due to adapalene having certain irritation, it is easy to cause dry skin, peeling and other phenomena. Further, the hydroxypropyl group of hydroxypropyl chitosan can improve its own water solubility, enhance antibacterial properties, and is conducive to the combination of hydroxypropyl chitosan and adapalene when used as a drug carrier, which helps to improve the release and absorption efficiency of adapalene, reduce the irritation to the skin when using adapalene, thereby optimizing the therapeutic effect, and further improving the anti-inflammatory properties of the gel product. In other words, the properties of hydroxypropyl chitosan are used to produce a synergistic effect with adapalene, thereby reducing the irritation of the gel product to the skin while further improving the moisturizing and tolerability of the gel product.

[0043] Furthermore, since the -NH2 group in hydroxypropyl chitosan can react with free radicals H + Combine to form -NH3 + Cation, -NH3 + Ions can combine with negatively charged anions on the bacterial cell wall, making the negative charge on the cell wall and cell membrane unevenly distributed, thereby hindering and breaking the synthesis and dissolution balance of the bacterial cell wall in the natural state, thereby destroying the normal physiological metabolism of bacteria and inhibiting their reproduction ability. In other words, hydroxypropyl chitosan has certain antibacterial properties, which further enhances the antibacterial properties of the gel product.

[0044] In one embodiment, the mass fraction of the water-soluble carbodiimide coupling agent is 0.02%~0.15%. Specifically, the mass fraction of the water-soluble carbodiimide coupling agent can be 0.02%, 0.04%, 0.06%, 0.08%, 0.10%, 0.12%, and 0.15%. Further preferably, the mass fraction of the water-soluble carbodiimide coupling agent is 0.06%~0.12%. The water-soluble carbodiimide coupling agent couples hydroxypropyl chitosan to the surface of Cu@PGANPs by coupling reaction with amine-containing compounds to form amide bonds, thereby coupling hydroxypropyl chitosan to the surface of Cu@PGANPs, further enhancing the stability of the coupled hydroxypropyl chitosan. In addition, since hydroxypropyl chitosan has a high metal binding efficiency, while reducing the toxic effects of metal ions, it increases the antioxidant properties of the gel product and further enhances the antibacterial effect of the gel. On the other hand, the coupling effect between copper ions and hydroxypropyl chitosan further enhances the tensile properties of the gel product, thereby maintaining stability during use or under external forces, further ensuring the release of active ingredients in the gel product and the wound coverage rate. Furthermore, not only does the interaction between the amino and hydroxyl groups in hydroxypropyl chitosan and copper ions enhance the mechanical properties of the gel product, but the combination of copper ions and hydroxypropyl chitosan can improve the stability and biocompatibility of the gel, thereby enhancing the stability of the gel product and human safety.

[0045] In one embodiment, the mass fraction of the chelating agent is 0.05% to 0.2%, specifically, the mass fraction of the chelating agent is 0.05%, 0.08%, 0.11%, 0.14%, 0.17%, 0.2%, and more preferably, the mass fraction of the chelating agent is 0.05% to 0.15%. It is understood that the chelating agent can form a stable complex with the metal ions, thereby reducing the irritation of the metal ions to the skin while regulating the reaction rate and reaction selectivity, thus helping to maintain the stability and uniformity of the gel system.

[0046] In one embodiment, the mass fraction of the osmotic pressure regulator is 3.0%-5.0%, specifically, the mass fraction of the osmotic pressure regulator is 3.0%, 3.5%, 4.0%, 4.5%, 5.0%. More preferably, the mass fraction of the osmotic pressure regulator is 3.5%-4.5%. Since the osmotic pressure regulator can help maintain the bioadhesion and tolerance of the gel product, thereby improving the comfort of use of the gel product, on the other hand, by adding the osmotic pressure regulator, the irritation of the gel to the skin and mucous membranes is reduced, which is conducive to the gel to exert better therapeutic and antibacterial effects, thereby further enhancing market competitiveness.

[0047] In one embodiment, the mass fraction of the nonionic surfactant is 0.1% to 0.6%, specifically, the mass fraction of the nonionic surfactant is 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, and more preferably, the mass fraction of the nonionic surfactant is 0.1% to 0.4%. It is understood that the nonionic surfactant can reduce the surface tension of the gel system, which is beneficial to improve the wettability and dispersibility of the gel. On the other hand, the nonionic surfactant can also be used as an emulsifier and dispersant to help evenly disperse the various components in the gel, further improving the stability and uniformity of the gel.

[0048] In one embodiment, the pH adjuster may be a sodium hydroxide solution, and the mass fraction of the pH adjuster is 0.1% to 0.3%. Specifically, the mass fraction of the pH adjuster may be 0.1%, 0.14%, 0.18%, 0.22%, 0.26%, or 0.3%. By regulating the pH value of the solution with the pH adjuster, the formation speed and final structure of the gel may be regulated, thereby improving the stability of the gel product.

[0049] In one embodiment, in step S4, the water is purified water, and the gel matrix is ​​one or more of carbomer, gelatin, cellulose, xanthan gum and sodium alginate. It is further preferred that the gel matrix is ​​carbomer homopolymer type C. It is understandable that the purified water is subjected to multi-stage filtration, deionization and sterilization treatment to ensure the quality and safety of the gel product during production. Carbomer homopolymer type C is a high molecular copolymer with good thickening and suspension ability, which can significantly improve the consistency and stability of the gel. On the other hand, the good biocompatibility and adhesion of carbomer homopolymer type C further prolong the retention time of the anti-inflammatory and antibacterial components in the gel on the skin and mucous membranes, so that the drug is more effectively released and acts on the target site, which is conducive to the gel product to produce better anti-inflammatory and antibacterial effects.

[0050] In one embodiment, the water-soluble carbodiimide coupling agent is selected from one or more of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride and bis[4-(2,2-dimethyl-1-3-dioxyalkyl)]methyl carbodiimide. Further preferably, the water-soluble carbodiimide coupling agent is selected from 1-ethyl-3-(3'-dimethylaminopropyl) carbodiimide. Since 1-ethyl-3-(3'-dimethylaminopropyl) carbodiimide has good water solubility, it is easy to remove in the subsequent purification step. Further, the mechanical properties of the gel product are enhanced by the action of the coupling agent, and the mechanical properties of the gel are improved.

[0051] In one embodiment, the nonionic surfactant is selected from one or more of lauryl alcohol, oleyl alcohol, palmityl alcohol, polyoxyethylene hydrogenated castor oil, polyoxyethylene fatty acid ester, poloxamer, octylphenol and polysorbate 80. Further preferably, the nonionic surfactant is selected from poloxamer 182. Poloxamer 182 has strong emulsifying ability and solubilizing ability, thereby improving the stability of the effective component in the gel. On the one hand, because poloxamer 182 has good chemical stability, it is not easy to cause degradation or deterioration, and has low toxicity, non-irritation, non-antigenicity and good biocompatibility, making it a commonly used auxiliary material component in the medical field. On the other hand, poloxamer 182 further exerts a solubilizing effect by forming nano micelles during the preparation of the gel, thereby improving the problem of reduced solubility and poor stability of adapalene. On the other hand, poloxamer has an adhesive effect, and the gel itself has a certain viscosity. Through the synergistic effect of the two, the storage stability of the gel product is improved, which is conducive to the subsequent use and preservation of the gel product.

[0052] In one embodiment, the osmotic pressure regulator is selected from one or more of glycerol, propylene glycol, mannitol and sorbitol. Further preferably, the osmotic pressure regulator is selected from glycerol and propylene glycol. It is understandable that not only glycerol and propylene glycol have an osmotic pressure regulating effect, but also the antiseptic effect of glycerol and the moisturizing function of propylene glycol are beneficial to enhancing the absorption effect of the effective components of the gel product. Furthermore, both glycerol and propylene glycol have good biocompatibility, which is beneficial to improving the safety of the gel product.

[0053] In one embodiment, the step S4 further comprises the steps of:

[0054] S41, after adding the gel matrix to the purified water with stirring, purified water, adapalene of a predetermined concentration, the second dispersion, hydroxypropyl chitosan, a water-soluble carbodiimide coupling agent, a chelating agent and an osmotic pressure regulator are added and stirred for the third time, and after being immersed until the mixture is completely swollen, stirred for the fourth time to obtain a second mixture;

[0055] S42, adding a nonionic surfactant into purified water to obtain a third mixture, vacuum stirring the blend of the second mixture and the third mixture, adding a pH adjuster to adjust the pH value to 4.5-5.5, and stirring to obtain a gel product.

[0056] The segmented mixing method is helpful to control the pH value during different reactions, thereby enhancing the reaction sufficiency of each reaction during the gel preparation process and further improving the metal-polyphenol network structure formed by Cu nanoparticles and PGA. Specifically, while improving the tensile properties and structural integrity of the gel product, the anti-inflammatory and antibacterial properties of the gel are further enhanced.

[0057] In one embodiment, a pH regulator is added in step S42 to adjust the pH value to 4.8-5.2. By regulating the pH value of the reaction environment, it is beneficial to improve the formation and performance of the gel network structure. On the other hand, the pH value of the inflammation area is usually reduced, so the gel product prepared under acidic conditions can better adapt to the inflammation environment and achieve accurate release of the active ingredients at the inflammation site.

[0058] In one embodiment, in step S41, the third stirring treatment time is 45min to 90min, the fourth stirring treatment time is 30min to 60min, the vacuum degree of the vacuum stirring treatment is not less than -0.06MPa, and the stirring time is 10min to 30min. Appropriate stirring time can improve reaction efficiency and reaction completeness, and ensure the quality and stability of the product.

[0059] In one embodiment, the step S42 further includes the steps of:

[0060] S421, adding a nonionic surfactant to purified water and mixing to obtain a third mixture, performing a first vacuum stirring on the blend of the second mixture and the third mixture, homogenizing the mixture, performing a second vacuum stirring, adding a pH adjuster to adjust the pH value to 4.5-5.5, and performing a third vacuum stirring to obtain a gel product.

[0061] Through vacuum stirring, the synthetic raw materials can react and mix in an environment without air interference, thereby improving the reaction efficiency and product quality. On the other hand, vacuum stirring helps to eliminate bubbles in the gel product, further enhancing the density and uniformity of the product.

[0062] In one embodiment, the vacuum stirring includes a first vacuum stirring treatment, a second vacuum stirring treatment and a third vacuum stirring treatment, wherein the time of the first vacuum stirring treatment is 10min~20min, specifically, the time of the first vacuum stirring treatment is 10min, 12min, 14min, 16min, 18min, 20min, the time of the second vacuum stirring treatment is 15min~25min, specifically, the time of the second vacuum stirring treatment is 15min, 17min, 19min, 21min, 23min, 25min, and the time of the third vacuum stirring treatment is 20min~30min, specifically, the time of the third vacuum stirring treatment is 20min, 22min, 24min, 26min, 28min, 30min. Through the vacuum stirring treatment, not only the reaction efficiency and the quality of the gel product are improved, but also the purity and stability of the gel product are enhanced, further improving the market competitiveness of the product.

[0063] In one embodiment, in step S3, the centrifugal treatment time is 15 min to 30 min, specifically, the centrifugal treatment time is 15 min, 20 min, 25 min, 30 min, and more preferably, the centrifugal treatment time is 18 min to 25 min. Centrifugal treatment of the precipitate helps to remove unreacted substances and attached soluble impurities in the precipitate, reduce aggregation between nanoparticles, further improve the stability and dispersibility of nanoparticles, and improve the purity and performance of the final prepared gel product.

[0064] In one embodiment, the first alkaline solution and the second alkaline solution used in steps S1, S2 and S3 are sodium hydroxide solutions, and the concentration of the first alkaline solution is 0.8 g / mL to 1.2 g / mL. Specifically, the concentration of the first alkaline solution is 0.8 g / mL, 0.9 g / mL, 1.0 g / mL, 1.1 g / mL, and 1.2 g / mL, and the concentration of the second alkaline solution is 2×10 -8 g / mL~6×10 -8 g / mL, specifically, the concentration of the second alkaline solution is 2×10 -8 g / mL, 3×10 - 8 g / mL, 4×10 -8 g / mL, 5×10 -8 g / mL, 6×10 -8 g / mL. Since the alkaline environment is conducive to the synthesis and size control of nanoparticles, the mechanical properties and stability of the gel product are improved. On the other hand, the use of low-concentration alkaline solutions can wash out the incompletely reacted raw materials and impurities in the intermediate products, thereby enhancing the purity of the products and reducing damage to the equipment and intermediate products. Furthermore, the use of alkaline solutions for washing is not only environmentally friendly, but also has low consumption costs. Compared with organic solvents, alkaline solutions are easier to recycle and handle, further reducing pollution to the environment. It is understandable that alkaline solutions are less corrosive to equipment and are suitable for large-scale industrial production applications.

[0065] In one embodiment, in step S4, the concentration of the second dispersion is 0.2% to 0.4%, the concentration of the second mixture is 1.0% to 1.5%, the concentration of hydroxypropyl chitosan is 0.12% to 0.2%, the concentration of the water-soluble carbodiimide coupling agent is 0.06% to 0.12%, the concentration of the chelating agent is 0.05% to 0.15%, the concentration of the osmotic pressure regulator is 3.5% to 4.5%, and the concentration of the nonionic surfactant is 0.1% to 0.4%. By introducing components of appropriate concentrations during the preparation process, the performance of the gel, antibacterial and anti-inflammatory properties are further enhanced.

[0066] According to another aspect of the present application, a gel material prepared by the above preparation method is also provided. The translucent Cu@PGA NPs adapalene hydroxypropyl chitosan gel prepared by the preparation method of the present application has high moisture absorption and moisture retention, good UV resistance, high solubility, strong antibacterial and anti-inflammatory properties, and has great potential for wide application in biomedicine and antibacterial fields due to its low toxicity and good biocompatibility.

[0067] Example 1

[0068] (1) First, dissolve 1.0% gallic acid (GA) in purified water and stir in a 35°C water bath for 15 min. Then, add a certain amount of 1.0 g / mL NaOH solution and continue stirring for 20 min to obtain a gallic acid solution (PGA solution).

[0069] (2) Provide anhydrous copper chloride in a mass ratio of 1:3 to PGA solution and add it to the PGA solution. Add a certain amount of NaOH solution with a concentration of 1.0 g / mL until the pH value of the solution is adjusted to about 8.0, and stir the reaction at room temperature for 25 hours.

[0070] (3) The mixture was centrifuged at 12,000 rpm for 20 min, and the precipitate was collected and repeatedly washed with an alkaline aqueous solution with a pH value of 8.0 until the supernatant of the solution was approximately in the state of deionized water. After the Cu@PGA NPs were obtained, they were dispersed in an alkaline solution with a pH value of 8.0 to obtain a second dispersion, which was then stored at 4°C for later use.

[0071] (4) First, add about 50% purified water to the colloid tank and stir at a rate of 30 Hz to 50 Hz. Slowly add carbomer homopolymer type C during stirring, then add about 25% purified water and keep stirring. Weigh 0.2% adapalene, 0.35% second dispersion, 0.12% hydroxypropyl chitosan, 0.08% 1-ethyl-3-(3'-dimethylaminopropyl) carbodiimide, 0.1% edetate disodium, 2.0% glycerol and 2.0% propylene glycol in the concentrations, add to the above carbomer homopolymer type C dispersion, continue stirring for 1.2 hours, stop, soak until it is completely swollen, and continue stirring for 45 minutes. The second mixture is prepared when no unswollen lumps are visually observed.

[0072] (5) Add 0.2% poloxamer 182 to 2% of the total amount of purified water, homogenize with a dispersing emulsifier, set the homogenization speed to 1000 rpm ~ 3000 rpm, and stop after 5 minutes of homogenization to obtain an aqueous solution of poloxamer 182. Add 0.2% adapalene to the aqueous solution of poloxamer 182, set the homogenization speed to 1000 rpm ~ 3000 rpm, and keep homogenizing for 15 minutes to obtain a drug dispersion in which adapalene is evenly dispersed.

[0073] (6) Use vacuum suction to transfer the second mixture through a 120-mesh screen to a vacuum emulsifier. Rinse the colloid tank several times with purified water of about 4% of the total preparation amount and transfer it to the vacuum emulsifier. Evacuate to below -0.06MPa and stir for 15 minutes until there are no obvious bubbles.

[0074] (7) Then, a homogenization treatment is performed, i.e., the drug dispersion is slowly added to mix with the second mixture, and the drug solution tank is rinsed with the remaining amount of purified water for several times and then added into a vacuum emulsifying mixer. The mixture is evacuated to below -0.06 MPa and homogenized for 20 min. Then, sodium hydroxide solution is slowly added to adjust the pH value to between 4.8 and 5.2, and the stirring is continued for 25 min to obtain Cu@PGA NPs adapalene hydroxypropyl chitosan gel.

[0075] Example 2

[0076] The difference between Example 2 and Example 1 is that in step (1), the concentration of gallic acid (GA) used is 1.5%.

[0077] Example 3

[0078] The difference between Example 3 and Example 1 is that in step (1), the concentration of gallic acid (GA) used is 0.8%.

[0079] Example 4

[0080] The difference between Example 4 and Example 1 is that in step (2), anhydrous copper chloride is provided in a mass ratio of 1:4 to the PGA solution and added to the PGA solution.

[0081] Example 5

[0082] The difference between Example 5 and Example 1 is that in step (2), anhydrous copper chloride is provided in a mass ratio of 1:2 to the PGA solution and added to the PGA solution.

[0083] Example 6

[0084] The difference between Example 6 and Example 1 is that in step (4), a second dispersion liquid with a Cu@PGA NPs concentration of 0.45% is weighed.

[0085] Example 7

[0086] The difference between Example 7 and Example 1 is that in step (4), a second dispersion liquid with a Cu@PGA NPs concentration of 0.25% is weighed.

[0087] Example 8

[0088] The difference between Example 8 and Example 1 is that in step (4), the concentration of hydroxypropyl chitosan weighed is 0.20%.

[0089] Example 9

[0090] The difference between Example 9 and Example 1 is that in step (4), the concentration of hydroxypropyl chitosan weighed is 0.08%.

[0091] Comparative Example 1

[0092] (1) First, dissolve 1.0% gallic acid (GA) in purified water and stir in a 35°C water bath for 15 min. Then, add a certain amount of 1.0 g / mL NaOH solution and continue stirring for 20 min to obtain PGA solution.

[0093] (2) First, add about 50% purified water to the colloid tank and stir it at a rate of 30 Hz to 50 Hz. Slowly add carbomer homopolymer type C during stirring, then add about 25% purified water and keep stirring. Weigh 0.2% adapalene, 0.35% PGA solution, 0.12% hydroxypropyl chitosan, 0.08% 1-ethyl-3-(3'-dimethylaminopropyl) carbodiimide, 0.1% edetate disodium, 2.0% glycerol and 2.0% propylene glycol in the concentrations respectively and add them to the above carbomer homopolymer type C dispersed phase. Continue stirring for 1.2 hours and then stop. Soak until it is completely swollen and continue stirring for 45 minutes. The second mixture is prepared when no unswollen lumps are visually observed.

[0094] (3) Add 0.2% poloxamer 182 to 2% of the total amount of purified water, and homogenize with a dispersing emulsifier. Set the homogenization speed to 1000 rpm~3000 rpm. After 5 minutes of homogenization, stop mixing to obtain an aqueous solution of poloxamer 182; add 0.2% adapalene to the aqueous solution of poloxamer 182, set the homogenization speed to 1000 rpm~3000 rpm, and keep homogenizing for 15 minutes to obtain a drug dispersion in which adapalene is evenly dispersed.

[0095] (4) Use vacuum suction to transfer the second mixture through a 120-mesh screen to a vacuum emulsifier. Rinse the colloid tank several times with purified water (about 4% of the total amount) and transfer it to the vacuum emulsifier. Evacuate to below -0.06MPa and stir for 15 minutes until there are no obvious bubbles.

[0096] (5) Then, a homogenization treatment is performed, i.e., the drug dispersion is slowly added to mix with the second mixture, the drug liquid tank is rinsed with the remaining amount of purified water for several times, and then added into a vacuum emulsifying mixer, and the mixture is evacuated to below -0.06 MPa, and homogenized and stirred for 20 minutes. Then, sodium hydroxide solution is slowly added to adjust the pH value to between 4.8 and 5.2, and the stirring and homogenization is continued for 25 minutes to obtain adapalene hydroxypropyl chitosan gel.

[0097] Comparative Example 2

[0098] (1) Weigh 1.0% anhydrous cupric chloride, add 1.0 g / mL NaOH solution until the pH value of the solution is adjusted to about 8.0, and stir the reaction at room temperature for 25 h.

[0099] (2) The mixture was centrifuged at 12,000 rpm for 20 min, and the precipitate was collected and repeatedly washed with an alkaline aqueous solution having a pH value of 8.0 until the supernatant of the solution was approximately in the state of deionized water. After the Cu NPs were obtained, they were dispersed in an alkaline aqueous solution having a pH value of 8.0 to prepare a second dispersion, which was stored at 4°C for future use.

[0100] (3) First, add about 50% purified water to the colloid tank and stir it at a rate of 30 Hz to 50 Hz. Slowly add carbomer homopolymer type C during stirring, then add about 25% purified water and keep stirring. Weigh 0.2% adapalene, 0.35% of the second dispersion containing Cu@PGA NPs, 0.12% hydroxypropyl chitosan, 0.08% 1-ethyl-3-(3'-dimethylaminopropyl) carbodiimide, 0.1% disodium edetate, 2.0% glycerol and 2.0% propylene glycol and add them to the above carbomer homopolymer type C dispersion phase. Continue stirring for 1.2 hours and then stop. Soak until it is completely swollen and continue stirring for 45 minutes. The second mixture is prepared when no unswollen lumps are visually observed.

[0101] (4) Add 0.2% poloxamer 182 to 2% of the total amount of purified water, homogenize with a dispersing emulsifier, set the homogenization speed to 1000 rpm~3000 rpm, and stop the homogenization after 5 minutes to obtain an aqueous solution of poloxamer 182. Add 0.2% adapalene to the aqueous solution of poloxamer 182, set the homogenization speed to 1000 rpm~3000 rpm, and keep homogenizing for 15 minutes to obtain a drug dispersion in which adapalene is evenly dispersed.

[0102] (5) Use vacuum suction to transfer the second mixture through a 120-mesh screen to a vacuum emulsifier. Rinse the colloid tank several times with purified water of about 4% of the total preparation amount and transfer it to the vacuum emulsifier. Evacuate to below -0.06MPa and stir for 15 minutes until there are no obvious bubbles.

[0103] (6) Then, a homogenization treatment is performed, i.e., the drug dispersion is slowly added to mix with the second mixture, and the drug liquid tank is rinsed with the remaining amount of purified water for several times and then added to a vacuum emulsifying mixer, and the mixture is evacuated to below -0.06 MPa, and homogenized and stirred for 20 minutes. Then, sodium hydroxide solution is slowly added to adjust the pH value to between 4.8 and 5.2, and the stirring and homogenization are continued for 25 minutes to obtain adapalene hydroxypropyl chitosan gel.

[0104] Comparative Example 3

[0105] (1) First, add about 50% purified water to the colloid tank and stir it at a rate of 30 Hz to 50 Hz. Slowly add carbomer homopolymer type C during stirring, then add about 25% purified water and keep stirring. Weigh 0.1% edetate disodium, 2.0% glycerol and 2.0% propylene glycol in concentrations respectively and add them to the above carbomer homopolymer type C dispersed phase. Continue stirring for 1.2 hours and then stop. Soak until it is completely swollen and continue stirring for 45 minutes. The second mixture is prepared when no unswollen lumps are visually observed.

[0106] (2) Add 0.2% poloxamer 182 to 2% of the total amount of purified water, homogenize with a dispersing emulsifier, set the homogenization speed to 1000 rpm ~ 3000 rpm, and stop after 5 minutes of homogenization to obtain an aqueous solution of poloxamer 182. Add 0.2% adapalene to the aqueous solution of poloxamer 182, set the homogenization speed to 1000 rpm ~ 3000 rpm, and keep homogenizing for 15 minutes to obtain a drug dispersion in which adapalene is evenly dispersed.

[0107] (3) Use vacuum suction to transfer the second mixture through a 120-mesh screen to a vacuum emulsifier. Rinse the colloid tank several times with purified water of about 4% of the total preparation amount and transfer it to the vacuum emulsifier. Evacuate to below -0.06MPa and stir for 15 minutes until there are no obvious bubbles.

[0108] (4) Then, a homogenization treatment is performed, i.e., the drug dispersion is slowly added to mix with the second mixture, and the drug liquid tank is rinsed with the remaining amount of purified water for several times and then added to a vacuum emulsifying mixer. The mixture is evacuated to below -0.06 MPa and homogenized for 20 minutes. Then, sodium hydroxide solution is slowly added to adjust the pH value to between 4.8 and 5.2, and the stirring is continued for 25 minutes to obtain adapalene gel.

[0109] Performance Evaluation

[0110] This application uses healthy mice for performance test. The specific experimental process is to apply the same amount of gel products prepared by Examples 1 to 9 and Comparative Examples 1 to 3 on the back of mice after depilation, wipe them clean after 4 hours, and then observe whether the application site has skin irritation symptoms such as peeling, redness, rash, erythema, etc. after 1 hour, 12 hours, 24 hours, 48 ​​hours and 72 hours. Anti-inflammatory and antioxidant performance tests are randomly divided into groups of mice, 4 in each group, respectively, experimental group, histamine group, diphenhydramine group, blank control group, and raised separately. After 7 days of adaptive feeding of mice, continuous administration was performed for 7 days, and subcutaneous injection of histamine was performed on the 15th day for modeling. Then, the mice were killed by cervical dislocation, and the skin tissues collected by dissection from each group of mice were used to prepare tissue homogenates by enzyme-linked immunosorbent assay (ELISA) kit detection method. The TNF-α (tumor necrosis factor α), IL-4 (interleukin-4), IL-6 (interleukin-6) and SOD (superoxide dismutase) contents of the samples of Examples 1 to 9, Comparative Examples 1 to 3 and the control group (without using gel) were detected according to the method on the ELISA kit instructions.

[0111] The adapalene gels prepared in Examples 1 to 9 and Comparative Examples 1 to 3 were subjected to in vitro anti-inflammatory tests. Oxidative stress and inflammation were measured by immunofluorescence staining, and the adapalene gels prepared in Examples 1 to 9 and Comparative Examples 1 to 3 were tested for antioxidant properties. The test results are shown in Table 1.

[0112] Table 1: Performance test of gel

[0113]

[0114] Understandably, TNF-α is a pro-inflammatory cytokine that is rapidly activated after trauma and participates in the early inflammatory response. It plays a key role in the initial stages of wound healing, promoting angiogenesis, clearing microorganisms, and regenerating tissue. IL-4 is an anti-inflammatory cytokine that helps reduce inflammation and promote wound healing, and its increased intensity generally represents its role in promoting anti-inflammatory and promoting healing. IL-6 has both pro-inflammatory and anti-inflammatory effects and plays an important role in the early stages of wound healing, and its increased levels are generally associated with an increased inflammatory response.

[0115] The inflammatory factor content of SOD usually represents the oxidative stress state during the wound healing process. SOD is an important antioxidant enzyme that can remove reactive oxygen species (ROS) in the body, thereby reducing the damage of oxidative stress to surrounding tissues. During the wound healing process, the generation and accumulation of ROS are important characteristics of the inflammatory stage. SOD helps to reduce the inflammatory response and promote wound healing by removing these harmful free radicals.

[0116] TNF-α is an inflammatory factor. Its elevated level will inhibit the activity of SOD, leading to a decrease in the body's antioxidant capacity, thereby exacerbating the inflammatory response. Therefore, TNF-α and SOD show a mutually inhibitory relationship in the inflammatory response, that is, the enhancement of TNF-α will lead to the weakening of SOD activity. The gel of the present application plays an anti-inflammatory and skin repair role by inhibiting the expression of inflammatory factors such as TNF-α, IL-4, and IL-6 in cells;

[0117] As shown in Table 1, it can be seen from Examples 1, 2 and 3 that as the content of GA added increases, the strength and moisture retention of the gel product decrease, making the gel structure rough, loose and uneven, thereby affecting the structure and antioxidant, antibacterial and anti-inflammatory properties of the gel product. On the other hand, as the content of GA added decreases, the antibacterial and anti-inflammatory effects of GA itself on the gel are reduced, so the antibacterial and anti-inflammatory properties of the gel product in Example 3 decrease to a certain extent. In other words, at an appropriate GA concentration, the prepared Cu@PGA NPs adapalene hydroxypropyl chitosan gel has a good structure while having good antioxidant, antibacterial and anti-inflammatory properties.

[0118] With reference to Example 1, Example 4 and Example 5, it can be known that with the increase of the content of anhydrous copper chloride added, excessive Cu will produce oxidation on biomolecules, thereby damaging cells, enzymes and protein structures when in use, and when the Cu content is too high, problems such as hepatotoxicity, nephrotoxicity, cytotoxicity and genetic toxicity will be increased, which is not conducive to the subsequent use of the gel product. On the other hand, when the anhydrous copper chloride content added is too low, the formation of subsequent Cu metal nanoparticles is affected due to the low Cu content, which further affects the integrity of the metal-polyphenol network structure formed by complexing with PGA, thereby reducing the tensile properties of the gel product, making it impossible for the gel to maintain a relatively stable shape when in use, affecting the release of the effective ingredient. Further, when the Cu content is too low, the antibacterial and anti-inflammatory properties are reduced, thereby reducing the application in medicine and antibacterial fields. In other words, insufficient Cu content may cause nanoparticles to be more easily aggregated, which is not conducive to the subsequent synthesis reaction. That is to say, by adding an appropriate amount of anhydrous cupric chloride, the obtained Cu@PGA NPs adapalene hydroxypropyl chitosan gel has a good structure and good antioxidant, antibacterial and anti-inflammatory properties.

[0119] As can be seen from Examples 1, 6 and 7, Cu metal nanoparticles can be complexed with PGA to form a metal-polyphenol network structure. Therefore, adding an appropriate amount of Cu@PGA NPs is beneficial to enhancing the integrity and mechanical properties of the gel structure, and thus is beneficial to improving the adhesion properties of the gel. It is understandable that after increasing the content of the second dispersion containing Cu@PGA NPs, the human safety of the gel product is reduced due to the irritation of the metal nanoparticles to the human body, so that after using the gel product prepared in Example 6, a slight erythema phenomenon appears in the test results. On the other hand, reducing the content of the second dispersion containing Cu@PGANPs further weakens the anti-inflammatory and antibacterial properties of the gel due to reducing the content of Cu@PGA NPs with anti-inflammatory and antibacterial properties.

[0120] By comparing Example 1, Example 8 and Example 9, it can be seen that adding a suitable amount of hydroxypropyl chitosan can alleviate the irritation of adapalene. It is understandable that in Example 8, increasing the amount of hydroxypropyl chitosan during the preparation process may increase toxicity to the human body and reduce safety during use. On the other hand, since hydroxypropyl chitosan also has a certain moisturizing effect, the amount of hydroxypropyl chitosan is reduced to further improve human safety, so no sensitivity is shown in the skin test results.

[0121] It can be seen from Example 1 and Comparative Example 1 that in Example 1, Cu metal nanoparticles are introduced to participate in the reaction during the preparation of the gel product. The high specific surface area and high reactivity of the metal nanoparticles help inhibit or kill the bacteria. Further, the metal nanoparticles exert antibacterial effects through various mechanisms, including destroying the stability of bacterial cell membranes and cell walls. Further, by releasing metal ions, they react with proteins and enzymes in bacteria, thereby causing bacterial death. On the other hand, the bacteria are induced to produce a large amount of reactive oxygen, and the activity of bacterial enzymes is inhibited and DNA synthesis is interfered. In other words, by introducing the PGA solution to react during the preparation process, the bacterial cell membrane is destroyed to inhibit bacterial growth, thereby enhancing the antibacterial and anti-inflammatory properties of the gel product. In contrast, the gel product in Comparative Example 1 has poor antioxidant and anti-inflammatory properties. Further, since no metal-polyphenol network structure is formed in the product, a large amount of metal nanoparticles irritate the skin and mucous membranes, further reducing the human safety of the gel product.

[0122] With reference to Example 1 and Comparative Example 2, it can be seen that in Example 1, the PGA solution is introduced to participate in the reaction during the preparation of the gel product, and the antioxidant and anti-inflammatory properties of the PGA solution itself further improve the antioxidant and anti-inflammatory properties of the gel product in Example 1. On the one hand, since the PGA solution can form a metal-polyphenol network structure with Cu metal nanoparticles, while enhancing the adhesion of the gel product, the antibacterial and anti-inflammatory activity of adapalene is further improved, and the toxic and side effects caused by the additional addition of chemical antibacterial agents are reduced, thereby avoiding adverse reactions to users and improving the safety of the gel product. On the other hand, since the gel product with a metal-polyphenol network structure formed has good tensile properties, it can stably maintain its shape during use, which is conducive to the absorption of the effective ingredients. Therefore, the gel product in Comparative Example 2 has poor antioxidant and anti-inflammatory properties, as well as certain irritation, that is, by introducing a PGA solution to react during the preparation process, the obtained Cu@PGA NPs adapalene hydroxypropyl chitosan gel has good antioxidant properties, anti-inflammatory properties and human safety.

[0123] By comparing Example 1 with Comparative Example 3, it can be seen that the adapalene gel product prepared in Comparative Example 3 has poor antioxidant and anti-inflammatory properties, and produces irritation symptoms such as erythema and peeling on the skin. In contrast, the Cu@PGA NPs adapalene hydroxypropyl chitosan gel in Example 1 has the antibacterial and anti-inflammatory properties provided by Cu@PGA NPs, adapalene and hydroxypropyl chitosan. While hydroxypropyl chitosan alleviates the irritation of adapalene to the skin, its own moisturizing property further promotes the absorption of the effective components in the gel, further improves the use effect of the gel, and thus improves the market competitiveness of the gel product.

[0124] The above describes the basic principles, main features and advantages of the present application. Those skilled in the art should understand that the present application is not limited by the above embodiments, and the above embodiments and the specification only describe the principles of the present application. The present application may have various changes and improvements without departing from the spirit and scope of the present application, and these changes and improvements fall within the scope of the present application for which protection is sought. The scope of protection claimed by the present application is defined by the attached claims and their equivalents.

Claims

1. A method for preparing a gel, characterized in that: The following steps are involved: S1, dissolving gallic acid in water, stirring for the first time, adding sodium hydroxide solution, stirring for the second time to obtain a first solution, wherein the gallic acid content is 0.2wt.%~2.0wt.%; S2, providing anhydrous cupric chloride in a predetermined mass ratio and adding it to the first solution, and adding sodium hydroxide solution to adjust the pH value of the solution, and preparing a first mixture after stirring, wherein the mass ratio of the first solution to the anhydrous cupric chloride is 1:(2-5); S3, centrifuging the first mixture, collecting the precipitate, washing it with a sodium hydroxide solution, and storing it in a sodium hydroxide solution at 4° C. to obtain a second dispersion; S4, adding the gel matrix, adapalene of a predetermined concentration, the second dispersion, hydroxypropyl chitosan, a water-soluble carbodiimide coupling agent, a chelating agent, an osmotic pressure regulator, a nonionic surfactant and a pH regulator into water with stirring to prepare a gel product.

2. The preparation method according to claim 1, characterized in that In the step S1, the first stirring treatment temperature is 30°C to 50°C, the first stirring treatment time is 5min to 20min, and the second stirring treatment time is 15min to 25min.

3. The preparation method according to claim 1, characterized in that: In step S2, the stirring treatment time is 20h~30h.

4. The preparation method according to claim 1, characterized in that: In the step S4, the mass fraction of adapalene is 0.05%-0.5%, the mass fraction of the second dispersion is 0.1%-0.5%, the mass fraction of hydroxypropyl chitosan is 0.1%-0.2%, the mass fraction of the water-soluble carbodiimide coupling agent is 0.02%-0.15%, the mass fraction of the chelating agent is 0.05%-0.2%, the mass fraction of the osmotic pressure regulator is 3.0%-5.0%, the mass fraction of the nonionic surfactant is 0.1%-0.6%, and the mass fraction of the pH regulator is 0.1%-0.3%.

5. The preparation method according to claim 4, characterized in that: In step S4, the gel matrix is ​​selected from one or more of carbomer, gelatin, cellulose, xanthan gum and sodium alginate, the water-soluble carbodiimide coupling agent is selected from one or more of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and bis[4-(2,2-dimethyl-1-3-dioxyalkyl)]methylcarbodiimide, the non-ionic surfactant is selected from one or more of lauryl alcohol, oleyl alcohol, palmityl alcohol, polyoxyethylene hydrogenated castor oil, fatty acid polyoxyethylene ester, poloxamer and polysorbate 80, and the osmotic pressure regulator is selected from one or more of glycerol, propylene glycol, mannitol and sorbitol.

6. The preparation method according to claim 1, characterized in that: It further comprises the steps of: S41, after adding the gel matrix into the water with stirring, purified water, adapalene with a predetermined mass fraction, the second dispersion, hydroxypropyl chitosan, a water-soluble carbodiimide coupling agent, a chelating agent and an osmotic pressure regulator are added and stirred for the third time, and after being immersed until the mixture is completely swollen, stirred for the fourth time to obtain a second mixture; S42, adding a nonionic surfactant into water and mixing to obtain a third mixture, vacuum stirring the blend of the second mixture and the third mixture, adding a pH adjuster to adjust the pH value to 4.5-5.5, and stirring to obtain a gel product.

7. The preparation method according to claim 1, characterized in that: In step S3, the centrifugal treatment time is 15 min to 30 min, the concentration of the sodium hydroxide solution used in steps S1 and S2 is 0.8 g / mL to 1.2 g / mL, and the concentration of the sodium hydroxide solution used in step S3 is 2×10 -8 g / mL~6×10 -8 g / mL.

8. The preparation method according to claim 6, characterized in that: In the step S41, the third stirring treatment time is 45min~90min, the fourth stirring treatment time is 30min~60min, and in the step S42, the vacuum degree of the vacuum stirring treatment is not less than -0.06MPa, and the stirring time is 10min~30min.

9. The preparation method according to claim 6, characterized in that: In the step S4, the mass fraction of the second dispersion is 0.2% to 0.4%, the mass fraction of the second mixture is 1.0% to 1.5%, the mass fraction of the hydroxypropyl chitosan is 0.12% to 0.2%, the mass fraction of the water-soluble carbodiimide coupling agent is 0.06% to 0.12%, the mass fraction of the chelating agent is 0.05% to 0.15%, the mass fraction of the osmotic pressure regulator is 3.5% to 4.5%, and the mass fraction of the non-ionic surfactant is 0.1% to 0.4%.

10. A gel, characterized in that: The method is prepared by any one of claims 1 to 9.

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