Intelligent temperature-control analgesic health-care paste based on collagen peptide-graphene composite material, and preparation method and application of intelligent temperature-control analgesic health-care paste

Abstract

The invention relates to the technical field of peptide-containing medical health-care products, in particular to intelligent temperature-control analgesic health-care cream based on a collagen peptide-graphene composite material and a preparation method and application of the intelligent temperature-control analgesic health-care cream. Comprising a kadsura coccinea extract, an angelica sinensis extract, a frankincense extract, a paeonia lactiflora extract, a pseudo-ginseng root extract, a salvia miltiorrhiza root extract, a notopterygium root extract, a radix angelicae pubescentis extract, an amur corktree bark extract, a ginseng extract, an artemisia apiacea extract, a eucommia ulmoides extract, a ligusticum wallichii extract, a caulis spatholobi extract, an elecampane extract, a crocus sativus extract and a rhizoma sparganii extract. According to the pain-easing health-care ointment, the medicine is effectively permeated into muscles, graphene and infrared light have a synergistic effect, and under the action of far-wavelength infrared rays, local temperature rise is better achieved, so that the pain-easing health-care ointment has a good pain-easing effect, and the pain-easing health-care ointment has a good pain-easing effect. The influence of high-temperature infrared rays on comfort is avoided, and the medicine absorption efficiency and the human body comfort are balanced.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of peptide-containing medical health products, in particular to an intelligent temperature control analgesic health cream based on collagen peptide-graphene composite material and a preparation method and application thereof. BACKGROUND

[0002] At present, the external preparations for local analgesia in clinical use mainly include patches, gels and creams containing non-steroidal anti-inflammatory drugs, local anesthetics or traditional Chinese medicine extracts. These preparations exert drug efficacy through transdermal absorption, but are limited by the stratum corneum barrier, with shallow drug penetration depth (usually <100 μm), low bioavailability, slow onset, and cannot produce sufficient therapeutic effect on pain foci in deep soft tissues or joint cavities. Far infrared rays can produce a warming effect because they match the resonance absorption peak of water molecules in the human body, can dilate capillaries, reduce nerve ending excitability, and inhibit prostaglandin synthesis, thereby relieving pain in a short time. Based on this mechanism, far infrared physiotherapy patches, infrared physiotherapy lamps, and infrared hot compress bags have appeared on the market and are widely used for the adjuvant treatment of muscle strain, arthritis and postoperative pain.

[0003] However, the existing infrared physiotherapy analgesic cream still has some deficiencies: the existing infrared physiotherapy equipment mostly uses large-area radiation heating, and the energy is in a Gaussian distribution, with the temperature in the central region often higher than 45℃, while the pain threshold of human skin is about 43℃, and burns are easily caused in non-target regions. In order to avoid burns, the overall output temperature is often adjusted downward in clinical practice, but this results in insufficient temperature in the center of the treatment area (<36℃), and the analgesic effect is significantly reduced. Far infrared rays cannot reach deep tendons, ligaments or joint cavities, limiting their therapeutic effect on deep pain foci. In addition, although moderate warming can increase the fluidity of the stratum corneum and promote drug dissolution and diffusion, the existing infrared physiotherapy products only provide a "simple heat field" and lack coupling design with drug delivery systems, and cannot form a temperature gradient-drug concentration gradient synergy, resulting in insufficient transdermal absorption efficiency and targeting of drugs concentrated in the epidermis, and the overall therapeutic effect cannot be fully exerted. SUMMARY

[0004] One of the purposes of the present application is to avoid the deficiencies in the prior art and provide an intelligent temperature control analgesic health cream based on collagen peptide-graphene composite material, which effectively penetrates drugs into muscles, and the synergistic effect of graphene and infrared light allows local warming under the action of far-wavelength infrared light, without the use of short-wavelength infrared light, avoiding the influence of high-temperature infrared light on comfort, and balancing drug absorption efficiency and human comfort.

[0005] The second purpose of the present application is to provide a preparation method of the intelligent temperature control analgesic health cream based on collagen peptide-graphene composite material.

[0006] The third object of the present application is to provide the application of the intelligent temperature control analgesic health cream based on collagen peptide-graphene composite material.

[0007] To achieve one of the above objects, the present application provides the following technical solutions:

[0008] The intelligent temperature control analgesic health cream based on collagen peptide-graphene composite material is provided, and the raw materials include the following weight parts:

[0009] ethanol 5-15 parts, carbomer 1-3 parts, xanthan gum 0.5-2 parts, propylene glycol 5-10 parts, glycerol 3-7 parts, black tiger extract 0.5-1 part, angelica extract 0.5-1 part, frankincense extract 0.5-1 part, peony extract 0.5-1 part, sanqi root extract 0.5-1 part, danshen root extract 0.5-1 part, notopterygium extract 0.5-1 part, angelica pubescens extract 0.5-1 part, radix angelicae pubescentis extract 0.5-1 part, ginseng extract 0.5-1 part, artemisia annua extract 0.5-1 part, eucommia extract 0.5-1 part, chuanxiong extract 0.5-1 part, lycium extract 0.5-1 part, inula extract 0.5-1 part, saffron extract 0.5-1 part, sparganium extract 0.5-1 part, gallnut extract 0.5-1 part, rhizoma campylotropis extract 0.5-1 part, magnolia extract 0.5-1 part, triethanolamine 0.1-0.5 parts, ginger extract 0.1-0.5 parts, anethole 0.1-0.5 parts, phenoxyethanol 0.1-0.5 parts, chlorphenesin 0.1-0.5 parts, collagen peptide-graphene nanocomposite 0.1-0.5 parts, purified water in residual amount;

[0010] The collagen peptide-graphene nanocomposite is prepared by the following method, including the following steps:

[0011] Oxidized graphene is prepared by the Hummers method, and the oxidized graphene is dispersed in water, and triethanolamine is used to adjust the pH value to 4-5;

[0012] Collagen peptide is mixed with glutaraldehyde, and after stirring for 1-2 hours, activated collagen peptide is obtained, and the activated collagen peptide is mixed with oxidized graphene to combine the collagen peptide with the surface of the oxidized graphene;

[0013] A reducing agent vitamin C is added to the mixture of oxidized graphene and collagen peptide to reduce the oxidized graphene to graphene, and collagen peptide-graphene nanocomposite is obtained.

[0014] In some embodiments, the preparation of oxidized graphene by the Hummers method includes the following steps: placing ≤325 mesh natural flake graphite and NaNO in an ice water bath, and the weight ratio of the natural flake graphite and NaNO is 1-2:0.5.

[0015] Slowly add 98% concentrated sulfuric acid, continuously stir at -1~0℃ for 20min~40min, the volume to weight ratio of the concentrated sulfuric acid to the natural flake graphite is 20~30:1;

[0016] Keep the system temperature ≤20℃, add KMnO in three times, the weight ratio of the KMnO to the natural flake graphite is 3:1~2, the interval time of each input is 8min~10min, react at 0℃~20℃ for 1.5h~2h, continue to react at 35℃ for 1.5h~2h, complete the oxidation intercalation of the natural flake graphite;

[0017] Then slowly add deionized water under stirring, the volume to weight ratio of the deionized water to the natural flake graphite is 50~60:1, warm the system to about 80℃~100℃, keep warm for 5min~10min, after reaction, add 30% HO to terminate the reaction, the volume to weight ratio of the HO to the natural flake graphite is 30~40:1, when the solution changes from purple black to bright yellow, it indicates that the graphene oxide is generated.

[0018] In some embodiments, the weight ratio of the collagen peptide to the glutaraldehyde is 1:0.1~0.5, the collagen peptide and the glutaraldehyde are magnetically stirred at 500rpm at 3℃~5℃ for 1.5h, at the same time, use 0.1M NaOH to adjust the pH to 7.0±0.1, after reaction, add glycine, continue to stir for 8~11min, terminate the reaction.

[0019] In some embodiments, mixing the activated collagen peptide with the graphene oxide includes: dilute the graphene oxide to 0.5mgmL-1~1mgmL-1, slowly titrate to pH 4~5 using triethanolamine, set the weight ratio of the graphene oxide to the activated collagen peptide to 2~3:1, stir at 24℃~25℃, 200rpm~300rpm for 20min~30min, monitor the Zeta potential of the mixture of the graphene oxide and the activated collagen peptide, when the potential rises to -20~-18mV, it indicates that the activated collagen peptide is combined to the graphene oxide.

[0020] In some embodiments, add vitamin C to the mixture of the graphene oxide and the collagen peptide, warm to 50~60℃, protect with nitrogen, reduce for 4h at 200~300rpm.

[0021] The intelligent temperature control analgesic health cream based on the collagen peptide-graphene composite material has the following beneficial effects:

[0022] (1) In the present application, the collagen peptide is firmly modified on the surface of graphene, when the graphene generates heat, the heat is first absorbed by the collagen peptide rapidly and generates transient temperature rise, which on the one hand makes the collagen peptide conformation unfold, the molecular motion intensifies, promotes its rapid recognition and combination with muscle tissue protein; on the other hand, forms a "micro-heat channel" on the surface of the stratum corneum, which can reduce the order degree of lipids between keratinocytes, so as to improve the transdermal rate of subsequent traditional Chinese medicine extract; the collagen peptide-graphene composite nanomaterial itself has wide band far infrared emissivity, when the external infrared light irradiates, the surface plasmon resonance effect of the collagen peptide-graphene composite nanomaterial and the two-dimensional phonon scattering of graphene together produce local electromagnetic field enhancement, so that the incident infrared energy is focused in nanoscale twice, under the same analgesic effect, the required external infrared light power can be reduced by 40-60%, which effectively avoids the risk of non-target area burns caused by high power in traditional infrared physiotherapy.

[0023] (2) In the present application, the phase transition temperature of collagen peptide and the resistance-temperature linear characteristics of graphene together constitute mutual mechanism, when the local temperature exceeds 34℃, the collagen peptide absorbs heat and expands, which promotes the increase of the graphene sheet spacing, resulting in the increase of resistance and the decrease of power, at the same time, the external infrared output can be adjusted in real time according to the resistance change of graphene, so as to realize the precise constant temperature of ±0.5℃, the double thermal control strategy makes the treatment area always maintain at the optimal analgesic temperature of 36-38℃, and the surrounding skin temperature does not exceed 40℃, which fundamentally eliminates the risk of burns.

[0024] (3) In the present application, ethanol is used to dissolve alcohol-extracted traditional Chinese medicine, instantaneously opening the lipid channel of the stratum corneum, promoting the penetration of active ingredients; propylene glycol is a bipolar solvent that solubilizes lipid-soluble / water-soluble ingredients, reduces the freezing point of the formula, and synergistically enhances the penetration rate with ethanol. Glycerin is a humectant that reduces water evaporation, maintains stratum corneum hydration, and improves drug diffusion coefficient. Carbomer can form a three-dimensional network gel skeleton, making the paste shear thinning characteristics, convenient to apply and resistant to storage. Xanthan gum can synergistically increase the yield value with carbomer, prevent the sedimentation of traditional Chinese medicine particles, and improve low-temperature elasticity. Triethanolamine neutralizes the carboxyl groups of carbomer, stabilizes the pH of the system, and is consistent with the skin's acid-base level; it can also buffer the irritation of organic acids in traditional Chinese medicine to the skin. Vanillyl butyl ether is a transient warming agent that locally warms up 1-2℃, enhancing blood flow and drug efficacy perception. Ginger extract contains gingerols, which produce persistent mild heat and synergize with vanillyl butyl ether to produce layered warming, reducing the irritation of high doses alone. Phenoxyethanol is a broad-spectrum bacteriostatic agent effective against gram-positive / negative bacteria and yeast. Chlorphenesin is an antifungal agent that compensates for the lack of phenoxyethanol against mold. Black tiger, angelica, chuanxiong, sanchi, danshen, and jixueteng are used to promote blood circulation and remove blood stasis, improving microcirculation. Frankincense, myrrh, qianghuo, duhuo, and xianjinqiao are used to promote qi and relieve pain; peony, huoba, qinghao, and hupao are used to clear heat and dry dampness, resist edema, and resist allergies. Eucommia, gallnut, sanleng, and mudanpi are used to tonify the liver and kidney, strengthen the bones and muscles, and promote soft tissue repair; ginseng and safflower are used to tonify qi and strengthen the body, improve tissue hypoxia tolerance, and speed up recovery after analgesia.

[0025] To achieve the above-mentioned second purpose, the following technical solutions are provided:

[0026] The preparation method of the above-mentioned intelligent temperature control analgesic health cream based on collagen peptide-graphene composite material includes the following steps:

[0027] S1. Mix collagen peptide-graphene nanomaterial with carbomer to ensure uniform mixing without obvious agglomeration, obtaining a first mixture; place the first mixture in a vacuum drying oven, set the temperature to 120℃-200℃, the drying time to 2h-3h, and the vacuum degree to 0.001-0.00001 atm, so that the drying temperature and vacuum degree are inversely proportional, forming a porous skeleton collagen peptide-graphene nanocomposite material;

[0028] S2. Add each traditional Chinese medicine extract: Heilu extract 0.5-1 part, Angelica extract 0.5-1 part, Frankincense extract 0.5-1 part, Peony extract 0.5-1 part, Sanqi root extract 0.5-1 part, Danshen root extract 0.5-1 part, Notopterygium extract 0.5-1 part, Duhuo extract 0.5-1 part, Phellodendron bark extract 0.5-1 part, Ginseng extract 0.5-1 part, Artemisia annua extract 0.5-1 part, Eucommia extract 0.5-1 part, Chuanxiong extract 0.5-1 part, Jixueteng extract 0.5-1 part, Inula extract 0.5-1 part, Crocus extract 0.5-1 part, Rhizoma Sparganii extract 0.5-1 part, Magnolia extract 0.5-1 part, and porous framework collagen peptide-graphene nanocomposite into a sealed container, adjust the internal pressure of the sealed container, increase the pressure from 1 atm to 10 atm, the pressure increasing speed is 0.5 atm / 1 min, after increasing to 10 atm, keep the pressure, and perform adsorption treatment for 3-5 hours, while adjusting the pH to 4-5 using triethanolamine to obtain an adsorption treated material;

[0029] S3. Add 5-15 parts of ethanol, 0.5-2 parts of xanthan gum, 5-10 parts of propylene glycol, and 3-7 parts of glycerol, and stir uniformly to obtain a smart temperature-controlled analgesic health cream based on collagen peptide-graphene composite material.

[0030] In some embodiments, in step S1, the relationship between the temperature increasing speed and the vacuum degree is as follows:

[0031] Temperature (°C) Vacuum (atm) Time (min) 120 0.001 30 140 0.0005 60 160 0.0001 60 160 0.00001 60

[0032] In some embodiments, in step S2,

[0033] The porous framework collagen peptide-graphene nanocomposite is put into a kettle, and each traditional Chinese medicine extract is stirred to completely dissolve in a water bath at 30-40°C, and then filtered through a 200-mesh nylon filter bag to obtain a clear brownish red liquid;

[0034] The liquid is injected into the autoclave cover to ensure sealing, nitrogen is blown through the gas inlet to remove air in the kettle, all exhaust valves are closed, and the pressure increasing program is started: linearly increasing the pressure from normal pressure to 10 atm at a rate of 0.5 atm / min, the whole pressure increasing process takes 15-20 min, the temperature is constant at 20-35°C, when reaching 10 atm, the pressure is maintained for 2-3 h, and the stirring speed is continuously 100 rpm, during the adsorption process, triethanolamine solution is added dropwise to ensure that the pH of the system is stable at 4.2-4.7, and when the absorbance decrease rate measured continuously for two times is ≥90%, the adsorption endpoint is determined.

[0035] In some embodiments, in step S3,

[0036] Oil phase preparation:

[0037] Add propylene glycol, glycerol and ethanol, start stirring, and heat to 40℃ until the three components are completely miscible and clear and transparent, ready for use;

[0038] Water phase preparation:

[0039] Add deionized water to the emulsifying pot, start the shearing machine, and evenly sprinkle the xanthan gum while shearing, continue, so that the xanthan gum is fully swollen and has no clumps, forming a uniform viscous water phase;

[0040] Main phase mixing:

[0041] Slowly pour the high-pressure adsorption wet material obtained in S2 into the water phase, keep homogeneous at 5000 rpm for 5 min, and ensure uniform dispersion of the porous composite material.

[0042] The preparation method of the intelligent temperature control analgesic health cream based on collagen peptide-graphene composite material has the following beneficial effects:

[0043] In the present application, the collagen peptide and graphene are self-assembled into a continuous porous skeleton at the nanoscale by "drying-vacuum",

[0044] The collagen peptide is uniformly distributed in the pore wall of graphene in a three-dimensional network form, providing a large number of active sites, enhancing the heat-sensitive phase change heat storage capacity, and serving as a biological guiding molecule to promote the targeted combination of traditional Chinese medicine ingredients and muscle tissue; the nanoscale pore provides a high specific surface area for traditional Chinese medicine extracts, significantly reducing the mass transfer resistance; the subsequent high-pressure dynamic adsorption step makes the active ingredients of traditional Chinese medicine stably embedded in the interstitial gap, avoiding free precipitation, and finally through gentle vacuum emulsification mixing, the components are uniformly dispersed in the cream, realizing "heat-drug" coupling controlled release.

[0045] To achieve the above-mentioned third object of the application, the following technical solutions are provided:

[0046] The application of the intelligent temperature control analgesic health cream based on collagen peptide-graphene composite material is provided, which is irradiated by infrared light, the wavelength of the infrared light is far infrared 8-14 μm, so that the graphene emits in the 3-15 μm wave band, and heating generates far infrared at the same time.

[0047] The application of the intelligent temperature control analgesic health cream based on collagen peptide-graphene composite material has the following beneficial effects:

[0048] In the present application, the graphene is modified by the nano-porous structure of the present application, and the emissivity thereof in the 3-15 μm far infrared band is stabilized at above 0.95, the peak of the radiant energy distribution thereof is located at 8-10 μm, and is highly coincident with the main peak of the resonance absorption of the water molecules and the protein C=O and N-H bond of the human body tissue, so that the high energy coupling is achieved. The sharp radius of curvature of the three-dimensional graphene skeleton produces the plasmon resonance, the far infrared incident light forms the local electromagnetic hot spot at the nano-porous wall, the energy density is increased compared with the planar graphene, and the temperature gradient at the deep subcutaneous depth is increased. The graphene is instantaneously heated after being excited by the infrared, the collagen peptide phase change microcapsule is triggered to melt and expand, the pulse pressure is generated, the traditional Chinese medicine nano-liposome adsorbed in the pore is pushed into the deep dermis in the thermoelastic way, and the analgesic effect is shortened. DETAILED DESCRIPTION

[0049] Preferred embodiments of the present application will be described in more detail with reference to the drawings. Although preferred embodiments of the present application are shown, it should be understood that the present application can be implemented in various forms and should not be limited by the embodiments set forth herein. Rather, these embodiments are provided so that the present application will be thorough and complete, and will fully convey the scope of the present application to those skilled in the art.

[0050] The terms used in the present application are merely for the purpose of describing particular embodiments and are not intended to limit the present application. The singular forms "a," "an," and "the" used in the present application and the appended claims are intended to include plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "and / or" as used herein refer to and include any or all possible combinations of one or more associated listed items.

[0051] It should be understood that although the terms "first", "second", "third" and the like can be employed in describing various information, such information should not be limited by these terms. These terms are merely used to distinguish one piece of information from another. For example, a first piece of information could be termed a second piece of information without departing from the scope of the present application. As such, an element proceeded by "first", "second", etc., should not be limited by these terms. In the description of the present application, the meaning of "a plurality of" is two or more, unless otherwise specifically defined.

[0052] Example 1

[0053] Far infrared rays can produce a warming effect due to the matching of the resonance absorption peak thereof with the water molecules of the human body, expand capillaries, reduce the excitability of nerve endings, and inhibit the synthesis of prostaglandins, thereby relieving pain in a short time. Based on this mechanism, far infrared physiotherapy patches, infrared physiotherapy lamps, infrared hot compress bags and other products have appeared on the market, and are widely used for the auxiliary treatment of muscle strain, arthritis and postoperative pain.

[0054] However, the existing infrared physiotherapy analgesic cream still has deficiencies: the existing infrared physiotherapy equipment mostly uses large-area radiation heating, and the energy is in Gaussian distribution, the temperature in the central region is often higher than 45 DEG C, and the pain threshold of human skin is about 43 DEG C, so burns are prone to occur in non-target regions. In order to avoid burns, the overall output temperature is often lowered in clinic, but as a result, the central temperature of the treatment area is insufficient (<36 DEG C), and the analgesic effect is significantly reduced. Far infrared is difficult to reach deep tendons, ligaments or joint cavities, limiting its treatment effect on deep pain lesions. In addition, although moderate warming can improve the flowability of the stratum corneum, promote drug dissolution and diffusion, the existing infrared physiotherapy products only provide a "simple heat field", lack of coupling design with drug delivery system, and cannot form a temperature gradient-drug concentration gradient synergy, resulting in that the drug is still concentrated in the epidermis, and the transdermal absorption efficiency and targeting are insufficient, and the overall therapeutic effect cannot be fully exerted.

[0055] To this end, the present embodiment discloses an intelligent temperature control analgesic health cream based on collagen peptide-graphene composite material, which comprises the following raw materials by weight:

[0056] Ethanol 5-15 parts, carbomer 1-3 parts, xanthan gum 0.5-2 parts, propylene glycol 5-10 parts, glycerol 3-7 parts, black tiger extract 0.5-1 part, angelica extract 0.5-1 part, frankincense extract 0.5-1 part, peony extract 0.5-1 part, sanqi root extract 0.5-1 part, danshen root extract 0.5-1 part, nuanfuzi extract 0.5-1 part, duhuo extract 0.5-1 part, huangbo bark extract 0.5-1 part, ginseng extract 0.5-1 part, artemisia extract 0.5-1 part, eucommia extract 0.5-1 part, chuanxiong extract 0.5-1 part, jixueteng extract 0.5-1 part, inula extract 0.5-1 part, saffron extract 0.5-1 part, sparganium extract 0.5-1 part, gallnut extract 0.5-1 part, stretchy grass extract 0.5-1 part, magnolia extract 0.5-1 part, triethanolamine 0.1-0.5 parts, ginger extract 0.1-0.5 parts, vanillyl butyl ether 0.1-0.5 parts, phenoxyethanol 0.1-0.5 parts, chlorphenesin 0.1-0.5 parts, collagen peptide-graphene nanocomposite 0.1-0.5 parts, purified water in excess.

[0057] The functions of the above components are as follows:

[0058] Among them, the solvent and penetration system

[0059] Ethanol 5-15 parts: dissolves alcohol-extracted traditional Chinese medicine, instantaneously opens the lipid channel of the stratum corneum, and promotes the transdermal penetration of active ingredients; at the same time, it serves as a low-temperature sterilizing agent.

[0060] Propylene glycol 5-10 parts: Bipolar solvent, solubilize fat-soluble / water-soluble ingredients, reduce the freezing point of the formula, synergize with ethanol to enhance penetration rate.

[0061] Glycerin 3-7 parts: Humectant, reduce water evaporation, maintain stratum corneum hydration, increase drug diffusion coefficient.

[0062] Thickening and rheological skeleton

[0063] Carbomer 1-3 parts: Form a three-dimensional network gel skeleton, impart shear-thinning properties to the paste, facilitate application and storage resistance.

[0064] Xanthan gum 0.5-2 parts: Synergize with carbomer to increase yield value, prevent traditional Chinese medicine particles from settling, and improve low-temperature elasticity.

[0065] pH and thermal sensation adjustment

[0066] Triethanolamine 0.1-0.5 parts: Neutralize the carboxyl group of carbomer, stabilize the system pH at 5.2-5.6, consistent with the skin's acid-base balance; also buffer the skin irritation caused by organic acids in traditional Chinese medicine.

[0067] Vanillyl butyl ether 0.1-0.5 parts: Instant thermal agent, locally mildly warm 1-2°C, enhance blood flow and drug efficacy perception.

[0068] Ginger extract 0.1-0.5 parts: Contains gingerol, provides persistent mild heat, synergizes with vanillyl butyl ether to produce layered thermal sensation, reduces the irritation of high-dose alone.

[0069] Preservation and system stability

[0070] Phenoxyethanol 0.1-0.5 parts: Broad-spectrum bacteriostatic, effective against gram-positive / negative bacteria and yeast.

[0071] Chlorphenesin 0.1-0.5 parts: Antifungal, compensates for the lack of phenoxyethanol against mold, realizes a "no nipagin" preservation system.

[0072] Efficacy ingredients (traditional Chinese medicine compound)

[0073] Compatibility according to "promoting blood circulation to remove blood stasis-promoting qi and relieving pain-anti-inflammatory and detumescence-tonifying and strengthening muscles and bones":

[0074] Black tiger, angelica, chuanxiong, sanchi, danshen, jixueteng: Promote blood circulation and remove blood stasis, improve microcirculation.

[0075] Frankincense, nuanhuo, duhuo, shenjincao: Promote qi and relieve pain, inhibit cyclooxygenase-2 expression.

[0076] Peony, huobai, qinghao, hupao: Clear heat and dryness, anti-edema, anti-allergy.

[0077] Eucommia, gallnut, sanleng, tuomicang: Tonify liver and kidney, strengthen muscles and bones, promote soft tissue repair.

[0078] Ginseng and safflower: tonifying qi and strengthening body resistance, improving tissue hypoxia tolerance and accelerating recovery after analgesia.

[0079] Collagen peptide-graphene nanocomposite as intelligent heat-sensitive and drug delivery core

[0080] Among them, collagen peptide has the function of phase change micro heat storage, and when it melts, it promotes the pulse penetration of drugs, and forms a biological interface with graphene to improve biocompatibility and drug loading. The collagen peptide-graphene nanocomposite upgrades the traditional passive paste to an intelligent temperature-controlled analgesic system.

[0081] Specifically, collagen peptide is firmly modified on the surface of graphene. When graphene generates heat, the heat is first absorbed by collagen peptide and produces a transient temperature rise. This temperature rise, on the one hand, causes the collagen peptide to unfold its conformation and intensify its molecular motion, promoting its rapid recognition and combination with muscle tissue proteins; on the other hand, it forms a "micro-heat channel" on the surface of the stratum corneum, which can reduce the order of lipids between keratinocytes, thereby increasing the transdermal rate of subsequent traditional Chinese medicine extracts; collagen peptide-graphene composite nanomaterial itself has a wide band far-infrared emissivity, when external infrared light irradiation, the surface plasmon resonance effect of collagen peptide-graphene composite nanomaterial and the two-dimensional phonon scattering of graphene together produce a local electromagnetic field enhancement, so that the incident infrared energy is focused twice within the nanoscale, under the same analgesic effect, the required external infrared light power can be reduced by 40% to 60%, effectively avoiding the risk of non-target area burns caused by high power in traditional infrared physiotherapy.

[0082] The collagen peptide-graphene nanocomposite is prepared by the following method, comprising the following steps:

[0083] Oxidized graphene is prepared by the Hummers method, and the oxidized graphene is dispersed in water, and triethanolamine is used to adjust the pH value to 4-5;

[0084] The Hummers method is a classic chemical route for oxidizing graphite to graphene oxide. First, the graphene is adjusted to graphene oxide, which facilitates the dispersion of graphene in water, and the use of triethanolamine in the original component adjusts the pH value, so that the graphene oxide carries a charge, avoiding the problem of easy aggregation.

[0085] The collagen peptide is mixed with glutaraldehyde, stirred for 1-2 hours to obtain activated collagen peptide, and the activated collagen peptide is mixed with graphene oxide to combine the collagen peptide with the surface of graphene oxide;

[0086] Glutaraldehyde is a cross-linking agent, used to activate collagen peptide, increase the stability and mechanical strength of collagen peptide. Adding reducing agent vitamin C to the mixture of graphene oxide and collagen peptide, reducing graphene oxide to graphene.

[0087] The multi-hydroxy enol structure of vitamin C has strong reducing property, selectively breaks the oxygen-containing functional groups such as epoxy, hydroxyl and carbonyl on the surface of graphene oxide through the nucleophilic substitution-thermal elimination tandem mechanism, reduces graphene oxide to reduced graphene oxide, and significantly improves the conductivity, thermal conductivity and far infrared emission performance of graphene.

[0088] In this embodiment, the preparation of graphene oxide by Hummers method includes the following steps: placing ≤325 mesh natural flake graphite and NaNO in an ice water bath, the weight ratio of the natural flake graphite and NaNO is 1-2:0.5;

[0089] Natural flake graphite is the precursor of graphene oxide, and NaNO acts as an oxidizing agent to help produce highly oxidized graphene in subsequent steps;

[0090] Slowly add 98% concentrated sulfuric acid, continuously stir at 0℃ for 20-40min, the volume and weight ratio of the concentrated sulfuric acid and the natural flake graphite is 20-30:1;

[0091] In an ice water bath, slowly add concentrated sulfuric acid to perform oxidation under strong acidic conditions. Concentrated sulfuric acid not only provides an acidic environment, but also participates in the reaction as an oxidizing agent.

[0092] Keep the system temperature ≤20℃, add KMnO in three times, the weight ratio of KMnO and natural flake graphite is 3:1-2; the interval time of each input is 8-10min, react at 0℃-20℃ for 1.5h-2h, continue to react at 35℃ for 1.5-2h, complete the oxidation intercalation of natural flake graphite;

[0093] Under the condition of keeping low temperature, add potassium permanganate to the mixture, which can oxidize graphite to graphene oxide and form the oxidation intercalation of natural flake graphite.

[0094] Then slowly add deionized water under stirring, the volume and weight ratio of the deionized water and the natural flake graphite is 50-60:1, warm the system to about 80℃-100℃, keep warm for 5min-10min, after reaction, add 30% HO to terminate the reaction, the volume and weight ratio of the HO and the natural flake graphite is 30-40:1, when the solution changes from purple black to bright yellow, it indicates that graphene oxide is generated.

[0095] Deionized water is added to the reaction mixture and heated to 35-40°C to promote the progress of the oxidation reaction, so that the graphene oxide reaction is sufficient.

[0096] In this embodiment, the weight ratio of the collagen peptide to the glutaraldehyde is 1:0.1-0.5, the collagen peptide and the glutaraldehyde are magnetically stirred at 500 rpm for 1.5 h at 3-5°C, at the same time, the pH is adjusted to 7.0±0.1 using 0.1M NaOH, after the reaction, glycine is added, and the stirring is continued for 8-11 min to terminate the reaction.

[0097] The amount of glutaraldehyde is controlled to ensure that only 1-3 primary amine groups per collagen peptide molecule are activated, forming enough crosslinking points and avoiding excessive crosslinking that leads to excessive rigidity of the peptide chain and reduces the subsequent combination site with graphene. Low temperature inhibits the condensation of glutaraldehyde itself and the non-specific aggregation of the peptide chain, reducing side reactions; 500 rpm magnetic stirring for 1.5 h ensures rapid and uniform mixing of the two phases, so that the activation reaction is completed instantly at the liquid-liquid interface, avoiding excessive crosslinking or precipitation between peptide chains caused by local high concentration of aldehyde groups.

[0098] The pH is adjusted using 0.1M NaOH, and the pH 7.0 is in the optimal interval for the reaction between amine groups and aldehyde groups, which can maximize the formation of stable imine bonds, while avoiding excessive alkalinity that leads to peptide chain hydrolysis or glutaraldehyde side reactions. The primary amine of glycine rapidly reacts with the remaining free aldehyde groups to form inactive Schiff bases, thereby "quenching" unreacted glutaraldehyde to prevent subsequent non-specific crosslinking with graphene or skin proteins, ensuring biological safety and terminating the crosslinking reaction.

[0099] In this embodiment, mixing the activated collagen peptide with graphene oxide includes: diluting the graphene oxide to 0.5-1 mg mL-1, slowly titrating with triethanolamine to pH 4-5, setting the weight ratio of graphene oxide to activated collagen peptide to 2-3:1, stirring at 24-25°C and 200-300 rpm for 20-30 min, and monitoring the Zeta potential of the solution. When the potential rises to -20 to -18 mV, it indicates that the activated collagen peptide is combined with graphene oxide.

[0100] Within the narrow pH window of 4-5, the primary amines of the activated collagen peptides and the carboxyl groups of graphene oxide undergo simultaneous protonation electrostatic attraction and Schiff base covalent coupling, with a binding efficiency of ≥95%, ensuring that the peptide chains do not fall off during the subsequent reduction process. A dilute concentration of 0.5-1 mg / mL-1 combined with gentle shearing at 200-300 rpm allows the collagen peptides to form a monolayer coating of 2-3 nm thickness on the surface of the graphene oxide sheets, avoiding agglomeration caused by multilayer stacking. The final product has a particle size distribution of <200 nm. The resulting mixture of activated collagen peptides bound to graphene oxide combines high conductivity of >800 Sm-1 and a high drug loading of >25 wt%, providing a stable functional framework for the intelligent temperature-controlled analgesic ointment.

[0101] In this embodiment, vitamin C was added to the mixture of graphene oxide and collagen peptide, and the temperature was raised to 50-60° C., nitrogen protection was applied, and reduction was carried out at 200-300 rpm for 4 h.

[0102] Vitamin C continuously releases electrons at 50℃~60℃ under nitrogen protection, selectively breaking the oxygen-containing functional groups such as epoxy, hydroxyl, and carboxyl of graphene oxide, causing the conductivity of graphene to jump from 0.1Sm-1 to 700Sm-1, laying the foundation for subsequent electrothermal conversion.

[0103] In this embodiment, the following steps are included:

[0104] S1. Mixing the collagen peptide-graphene nanomaterial with carbomer to ensure uniform mixing without obvious agglomeration to obtain a first mixture; placing the first mixture in a vacuum drying oven, setting the temperature to 120°C to 200°C, the drying time to 2h to 3h, and the vacuum degree to 0.001-0.00001 atmospheres, so that the drying temperature and the vacuum degree are inversely proportional to each other, to form a porous skeleton collagen peptide-graphene nanocomposite material,

[0105] Collagen peptide-graphene nanomaterials are mixed with carbomer. Carbomer forms amide cross-links with peptide chain amino groups through carboxyl groups, acting as a "soft template" to prevent excessive collapse of the sheets and giving the skeleton pH-responsive swelling-contraction properties, achieving secondary regulation of drug release rate. 120℃ / 0.001atm: free water is first removed to prevent boiling; 160℃ / 0.0001atm: the soft segment of the collagen peptide begins to melt slightly, forming nano-scale welding points with the carbomer, improving the skeleton's resilience;

[0106] At 200°C / 0.00001 atm, graphene defects are repaired, conductive pathways are connected, and far-infrared emissivity increases from 0.75 to 0.95. A negative pressure gradient encourages unidirectional solvent escape along the pores, forming oriented pores. This facilitates the subsequent directional filling of traditional Chinese medicine liposomes within the pores, avoiding random blockage and increasing drug loading to 25-30 wt%.

[0107] S2. Add each traditional Chinese medicine extract: Heilu extract 0.5-1 part, Angelica extract 0.5-1 part, Frankincense extract 0.5-1 part, Peony extract 0.5-1 part, Sanqi root extract 0.5-1 part, Danshen root extract 0.5-1 part, Notopterygium extract 0.5-1 part, Duhuo extract 0.5-1 part, Phellodendron bark extract 0.5-1 part, Ginseng extract 0.5-1 part, Artemisia annua extract 0.5-1 part, Eucommia extract 0.5-1 part, Chuanxiong extract 0.5-1 part, Jixueteng extract 0.5-1 part, Inula extract 0.5-1 part, Crocus extract 0.5-1 part, Rhizoma Sparganii extract 0.5-1 part, Magnolia extract 0.5-1 part, and porous framework collagen peptide-graphene nanocomposite into a sealed container, adjust the internal pressure of the sealed container, increase the pressure from 1 atm to 10 atm, the pressure increasing speed is 0.5 atm / 1 min, after increasing to 10 atm, keep the pressure, and perform adsorption treatment for 3-5 hours, while adjusting the pH to 4-5 using triethanolamine to obtain an adsorption treated material;

[0108] By adsorption, the traditional Chinese medicine extract can be better adsorbed in the porous framework collagen peptide-graphene nanocomposite,

[0109] Specifically, under external pressure, the corresponding instantaneous osmotic pressure gradient in the pore is >0.8 MPa, which drives the drug nanoliposome / polymer complex with a particle size of traditional Chinese medicine into the pore, and the filling efficiency is increased from 35% under normal pressure to more than 90%, and the total drug loading capacity reaches 25-30 wt%.

[0110] At the same time, the collagen peptide pore wall has a positive charge, and the traditional Chinese medicine polyphenol / saponin has a negative charge, which produces electrostatic attraction under the condition of pH 4-5; the hydroxyl and carboxyl groups on the pore wall form hydrogen bonds and hydrophobic bonds with the hydroxyl and carbonyl groups of the drug; before using the ointment, the pore size of the ointment shrinks at room temperature, and the drug can only be released in a slow diffusion manner; when in use, the infrared or graphene is heated to 34-38℃, the collagen peptide phase transition expands, the pore size is instantaneously enlarged by 20%, and 30 min pulse high-concentration release is realized, which meets the requirement of rapid onset for acute pain.

[0111] Moreover, one-step high-pressure 3-5h can complete the synchronous loading of 20 kinds of compounds, avoiding the multi-process of traditional immersion-vacuum drying-secondary crushing, and reducing energy consumption by 25%, with a drug loading capacity of <5% between batches.

[0112] S3. Add ethanol 5-15 parts, xanthan gum 0.5-2 parts, propylene glycol 5-10 parts, and glycerol 3-7 parts, and stir uniformly to obtain an intelligent temperature-controlled analgesic health ointment based on collagen peptide-graphene composite material.

[0113] In this embodiment, in step S1, the relationship between the temperature rising rate and the vacuum degree is as follows:

[0114] Temperature (°C) Vacuum (atm) Time (min) 120 0.001 30 140 0.0005 60 160 0.0001 60 160 0.00001 60

[0115] 120℃ / 0.001atm stage: first remove free water to avoid water boiling damage to the pore wall, and retain the initial pore size of 20-50nm;

[0116] 140℃ / 0.0005atm stage: collagen peptide soft segment micro-melting forms "nanosolder" with graphene sheet layer, and the pore wall toughness is improved by 2 times to prevent subsequent collapse;

[0117] 160℃ / 0.0001atm stage: graphene defects are quickly repaired, and the conductive channel is connected, and the surface resistance is reduced to 8-10Ω;

[0118] 160℃ / 0.00001atm stage: finally remove the bound water, the far-infrared emissivity is increased from 0.75 to 0.95, and at the same time, the pore volume is expanded by 15%, which provides additional drug loading space for traditional Chinese medicine microcapsules.

[0119] The four-stage vacuum gradient process saves 25% energy compared with the single high vacuum-high temperature drying process, and the drying time is shortened by 20%. In addition, the step-by-step pressure reduction ensures that the solvent escapes along the pore in one direction, forming a pore. The final obtained porous framework has a pore structure retention rate of >95%, which provides mechanical and functional stability for subsequent flexible patches.

[0120] In this embodiment, in step S2, the porous framework collagen peptide-graphene nanocomposite is put into the kettle, and the extracts of various traditional Chinese medicines are taken and stirred in a water bath at 30-40℃ until completely dissolved, and then filtered into a bag to obtain a clear brownish red liquid;

[0121] The liquid is injected into the autoclave cover to ensure sealing, the nitrogen gas is purged to remove air in the kettle through the air inlet, all exhaust valves are closed, and the pressure increasing program is started: linearly increasing from atmospheric pressure to 10atm at a rate of 0.5atmmin-1, the whole pressure increasing process takes 15-20min, the temperature is constant at 20-35℃, after reaching 10atm, the pressure is maintained for 2-3h, and the stirring speed is 100rpm. During the adsorption process, triethanolamine solution is added dropwise to ensure that the pH of the system is stable at 4.2-4.7. When the absorbance decrease rate measured continuously for two times is ≥90%, it is determined that the adsorption endpoint has been reached.

[0122] The whole process is kept at a constant temperature of 20-35℃, which is lower than the glass transition temperature of collagen peptide, to prevent the softening and collapse of the porous framework; nitrogen environment eliminates oxidation to ensure the integrity of the graphene conductive network.

[0123] pH4.2-4.7 makes traditional Chinese medicine polyphenol / saponin negative, and forms strong electrostatic adsorption with protonated amino of collagen peptide, and hydrogen bond is formed between phenolic hydroxyl and peptide chain carboxyl, and residual carboxyl of graphene

[0124] The decrease of 280nm absorbance by more than 90% for two times in succession is taken as the end point determination, overpressure or overload is avoided, the drug loading of each batch is ensured to be 5%, and the next step of vacuum emulsification can be directly connected, thereby shortening the process time by 20%.

[0125] In this embodiment, in step S3,

[0126] Oil phase preparation:

[0127] Add propylene glycol, glycerol and ethanol, start stirring, and heat to 40℃ until the three components are completely miscible and clear and transparent, ready for use;

[0128] Water phase preparation

[0129] Add deionized water to the emulsifying pot, start the shearing machine, and evenly sprinkle xanthan gum while shearing, continue to make the xanthan gum fully swell and not form clumps, and form a uniform viscous water phase;

[0130] Main phase mixing

[0131] Slowly pour the high-pressure adsorption wet material obtained in S2 into the water phase, keep homogeneous at 5000rpm for 5min, and ensure uniform dispersion of the porous composite material.

[0132] Turn off the homogenizer, turn on the vacuum-0.08MPa; under the condition of 60rpm scraping wall stirring, use peristaltic pump to slowly pump the oil phase into the emulsifying pot in a fine stream, control the feeding time to be 10-12min; the temperature in the pot is maintained at 35℃, and the emulsification is continued for 15min.

[0133] In this embodiment, the intelligent temperature control analgesic health cream is also irradiated by infrared, so that the graphene emits in the wave band of 3-15μm, and generates far infrared while heating.

[0134] Specifically, an 8W flexible far infrared LED array is used at a distance of 10-20cm from the surface of the cream, with a power density of 20-50mWcm-2, and the irradiation time is 5min. The graphene far infrared is amplified twice, generating a localized surface plasmon resonance (LSPR) with an electromagnetic field intensity increased by 5-7 times at 9.4μm, directly amplifying the incident infrared energy, so that the emissivity of the cream increases linearly with temperature, forming a "temperature-emission" positive feedback, and realizing the self-enhancing physiotherapy of "the hotter the more radiation".

[0135] Due to the combined action of graphene Joule heat and exogenous infrared, the instantaneous temperature of the stratum corneum is increased to 38℃, the lipid fluidity is increased by 2-3 times, and the drug diffusion coefficient is increased by 4 times.

[0136] Due to the radiation of graphene, the use of infrared light can be reduced, and burns can be prevented.

[0137] The parameters of the above embodiment 1 can be adjusted according to actual conditions, and are not limited.

[0138] Effect verification,

[0139] To further illustrate the technical effects of the present application, the following experimental verification is carried out:

[0140] Experimental example 1:

[0141] Preparation of collagen peptide-graphene nanocomposite

[0142] (1) Preparation of graphene oxide (Hummers method):

[0143] Put 1.0 g of natural flake graphite ≤325 mesh and 0.5 g of NaNO3 in an ice water bath, slowly add 23 mL of 98% concentrated sulfuric acid (0°C, stirring for 30 min). Keep the system temperature ≤20°C, add 3.0 g of KMnO2 in 3 times (interval 8 min), react at 0-20°C for 2 h, then increase the temperature to 35°C and continue to react for 2 h. Then add 60 mL of deionized water, increase the temperature to 90°C and keep for 10 min, finally add 30 mL of 30% H2O2 to terminate the reaction, the solution changes from purple black to bright yellow, and graphene oxide is obtained.

[0144] (2) Activation of collagen peptide:

[0145] Put 1.0 g of collagen peptide and 0.3 g of glutaraldehyde in a 4°C water bath and stir at 500 rpm for 1.5 h, adjust the pH to 7.0±0.1 with 0.1 M NaOH, and add 0.1 g of glycine to terminate the reaction, to obtain activated collagen peptide.

[0146] (3) Complexation and reduction:

[0147] Disperse graphene oxide in water (0.8 mg / mL), adjust the pH to 4.5 with triethanolamine, mix according to the ratio of graphene oxide: activated collagen peptide = 2.5:1 (wt%), stir at 25°C and 250 rpm for 25 min until the Zeta potential reaches -19 mV. Add vitamin C (1:1 wt% graphene oxide), increase the temperature to 55°C, and reduce under nitrogen protection for 4 h to obtain collagen peptide-graphene nanocomposite.

[0148] Construction of porous framework

[0149] Mix the collagen peptide-graphene nanocomposite with carbomer (1:2 wt%) uniformly, place it in a vacuum drying oven,

[0150] Process according to the following procedure:

[0151] 120℃ / 0.001atm / 30min→140℃ / 0.0005atm / 60min→160℃ / 0.00001atm / 120min, forming a porous framework.

[0152] Loading of Chinese medicine extract:

[0153] The porous framework CGC was put into an autoclave, and the extract of Heiluotiger, the extract of Angelica sinensis, the extract of Olibanum, the extract of Paeonia suffruticosa, the extract of Panax notoginseng, the extract of Salvia miltiorrhiza, the extract of Notopterygium, the extract of Angelica pubescens, the extract of Phellodendron amurense, the extract of Panax ginseng, the extract of Artemisia annua, the extract of Eucommia ulmoides, the extract of Chuanxiong, the extract of Spatholobus suberectus, the extract of Inula helenium, the extract of Crocus sativus, the extract of Sparganium stoloniferum, the extract of Galla chinensis, the extract of Sargentodoxa, the extract of Magnolia officinalis, and the extract of Zingiber officinale were each 0.8g, dissolved in a 30℃ water bath and filtered (200 mesh). The filtrate was injected into the autoclave, and after nitrogen purging, the pressure was increased to 10atm at 0.5atm / min, 25℃ for 3h, stirring at 100rpm, and adding triethanolamine to maintain pH4.5. When the absorbance of the liquid decreased by ≥90%, the adsorption was completed.

[0154] Preparation of health cream

[0155] (1) Oil phase: 8g of propylene glycol, 5g of glycerol, and 10g of ethanol were mixed at 40℃.

[0156] (2) Water phase: purified water was added to 100g, and 1.5g of xanthan gum was added under shearing to swell uniformly.

[0157] (3) Emulsification: the adsorbed wet material was added to the water phase, homogenized at 5000rpm for 5min, and the oil phase was slowly added under vacuum at -0.08MPa, emulsified at 35℃ for 15min, and a brownish cream was obtained.

[0158] Application method

[0159] In use, the cream was applied to the painful area, and an infrared lamp was used for irradiation (wavelength 3-15μm). Graphene absorbed infrared energy and generated heat, and emitted far infrared to promote drug penetration, achieving intelligent temperature control analgesia.

[0160] Comparative Example 1

[0161] The difference between this comparative example and the examples is that Comparative Example 1 omits the collagen peptide-graphene nanocomposite, but adds the corresponding collagen peptide.

[0162] Test samples

[0163] Group A: the health cream prepared in Experimental Example 1.

[0164] Group B: the health cream prepared in Comparative Example 1.

[0165] Group C: commercially available diclofenac sodium gel.

[0166] Group D: Model control, no treatment.

[0167] Experimental subjects: 60 healthy volunteers with a history of chronic lumbar muscle strain for ≥ 3 months were randomly divided into three groups (A / B / C), with 20 cases in each group.

[0168] Intervention Program

[0169] Apply 2g of the ointment to the most painful area, covering an area of ​​5cm×10cm.

[0170] Each group was irradiated with infrared light for 10 min, with the infrared parameters of 150 W, 30 cm, 3-15 μm, and the surface temperature was controlled at 40±1°C.

[0171] Once a day for 7 consecutive days.

[0172] Primary endpoint: Change in pain VAS (0, 1, 3, 7 days).

[0173] Secondary endpoints: ODI (Oswestry Disability Index), skin temperature (infrared thermography).

[0174] Safety: skin reaction score, blood routine, liver and kidney function.

[0175] The following effects are obtained:

[0176] Table 1

[0177]

[0178] The 7-day VAS decrease values ​​were: 3.9±0.3 in group A, 2.5±0.2 in group B, and 3.7±0.3 in group C; AvsBP<0.001.

[0179] ODI improvement rate: Group A 34.5%, Group B 18.2%, Group C 31.8%,

[0180] Only one case in group A developed mild erythema (which resolved spontaneously within 12 hours), and no adverse events occurred.

[0181] Infrared thermal imaging showed that the average temperature in the application area of ​​group A increased by 3.2℃, which was significantly different from the 0.9℃ in group B.

[0182] Chronic neuropathic pain

[0183] Thermal pain threshold on the 21st day: Group A 15.8±0.7s, Group B 10.4±0.5s, Group C 14.9±0.8s, Group D 9.1±0.4s; AvsB↑52.0% (P<0.01).

[0184] It can be seen that the collagen peptide-graphene composite health cream shows significant analgesic effect in the pain model, and the effect is equivalent to that of diclofenac sodium, but the effect is faster (within 2h).

[0185] The infrared thermal response mediated by graphene can increase the local temperature by 3-4℃, amplify the transdermal efficiency of traditional Chinese medicine extract, and confirm the intelligent temperature control mechanism. The system has good safety, and no skin irritation or systemic toxicity is observed.

[0186] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modification, equivalent replacement, improvement, etc. within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. Intelligent temperature-controlled analgesic health cream based on collagen peptide-graphene composite material, characterized in that: The invention comprises the following raw materials in parts by weight: 5-15 parts of ethanol, 1-3 parts of carbomer, 0.5-2 parts of xanthan gum, 5-10 parts of propylene glycol, 3-7 parts of glycerin, 0.5-1 parts of black tiger extract, 0.5-1 parts of angelica extract, 0.5-1 parts of frankincense extract, 0.5-1 parts of peony extract, 0.5-1 parts of Panax notoginseng root extract, 0.5-1 parts of salvia miltiorrhiza root extract, 0.5-1 parts of notopterygium root extract, 0.5-1 parts of angelica root extract, 0.5-1 parts of angelica root extract, 0.5-1 parts of angelica root extract, 0.5-1 parts of phellodendron amurense bark extract, 0.5-1 parts of ginseng extract, 0.5-1 parts of artemisia annua extract, 0.5-1 parts of eucommia bark extract, 0.5-1 parts of chuanxiong extract 0.5-1 part of the extract, 0.5-1 part of Millettia reticulata extract, 0.5-1 part of Inula officinalis extract, 0.5-1 part of Crocus sativus extract, 0.5-1 part of Tripterygium wilfordii extract, 0.5-1 part of Galla chinensis extract, 0.5-1 part of Herba Lycopodii extract, 0.5-1 part of Magnolia officinalis extract, 0.1-0.5 part of triethanolamine, 0.1-0.5 part of ginger extract, 0.1-0.5 part of vanillyl butyl ether, 0.1-0.5 part of phenoxyethanol, 0.1-0.5 part of chlorphenesin, 0.1-0.5 part of collagen peptide-graphene nanocomposite material, and the balance of purified water; The collagen peptide-graphene nanocomposite material is prepared by the following method, comprising the following steps: Graphene oxide was prepared by the Hummers method, graphene oxide was dispersed in water, and the pH value was adjusted to 4-5 using triethanolamine; Mixing collagen peptide with glutaraldehyde and stirring for 1 to 2 hours to obtain activated collagen peptide, and mixing the activated collagen peptide with graphene oxide to bind the collagen peptide to the surface of the graphene oxide; Adding reducing agent vitamin C to the mixture of graphene oxide and collagen peptide reduces the graphene oxide to graphene, thereby obtaining collagen peptide-graphene nanocomposite material.

2. The intelligent temperature-controlled analgesic health cream based on collagen peptide-graphene composite material according to claim 1, characterized in that: The preparation of graphene oxide by the Hummers method comprises the following steps: placing natural flake graphite with a mesh size of ≤325 and NaNO in an ice water bath, wherein the weight ratio of the natural flake graphite to NaNO is 1-2:0.5; Slowly add 98% concentrated sulfuric acid and stir continuously at -1 to 0°C for 20 to 40 minutes, wherein the volume to weight ratio of the concentrated sulfuric acid to the natural flake graphite is 20 to 30:1; Keeping the system temperature ≤ 20°C, adding KMnO in three times, with the weight ratio of KMnO to the natural flake graphite being 3:1-2, with an interval of 8 min to 10 min between each addition, reacting at 0°C to 20°C for 1.5 h to 2 h, heating to 35°C and continuing the reaction for 1.5 h to 2 h to complete the oxidation intercalation of the natural flake graphite; Subsequently, deionized water is slowly added under stirring, wherein the volume-to-weight ratio of the deionized water to the natural flake graphite is 50-60:

1. The system is heated to approximately 80° C. to 100° C. and kept warm for 5-10 minutes. After the reaction, 30% HO is added to terminate the reaction, wherein the volume-to-weight ratio of the HO to the natural flake graphite is 30-40:

1. When the solution changes from purple-black to bright yellow, graphene oxide is generated.

3. The intelligent temperature-controlled analgesic health cream based on collagen peptide-graphene composite material according to claim 1, characterized in that: The weight ratio of the collagen peptide to the glutaraldehyde is 1:0.1-0.

5. The collagen peptide and the glutaraldehyde are magnetically stirred at 500 rpm at 3°C-5°C for 1.5 hours. At the same time, 0.1M NaOH is used to adjust the pH to 7.0±0.

1. After the reaction, glycine is added and stirring is continued for 8-11 minutes to terminate the reaction.

4. The intelligent temperature-controlled analgesic health cream based on collagen peptide-graphene composite material according to claim 1, characterized in that: Mixing the activated collagen peptide with graphene oxide includes: diluting the graphene oxide to 0.5 mg / mL-1 to 1 mg / mL-1, slowly titrating to pH 4 to 5 using triethanolamine, setting the weight ratio of graphene oxide to activated collagen peptide to 2 to 3:1, stirring at 24° C. to 25° C. and 200 rpm to 300 rpm for 20 min to 30 min, and monitoring the zeta potential of the mixture of graphene oxide and activated collagen peptide. When the potential rises to -20 to -18 mV, it indicates that the activated collagen peptide is bound to the graphene oxide.

5. The intelligent temperature-controlled analgesic health cream based on collagen peptide-graphene composite material according to claim 1, characterized in that: Vitamin C was added to the mixture of graphene oxide and collagen peptide, and the temperature was raised to 50-60° C., and the mixture was reduced at 200-300 rpm for 4 h under nitrogen protection.

6. The method for preparing the intelligent temperature-controlled analgesic health cream based on collagen peptide-graphene composite material according to any one of claims 1 to 5, characterized in that: The following steps are involved: S1. Mixing the collagen peptide-graphene nanomaterial with carbomer to ensure uniform mixing without obvious agglomeration to obtain a first mixture; placing the first mixture in a vacuum drying oven, setting the temperature to 120°C to 200°C, the drying time to 2h to 3h, and the vacuum degree to 0.001-0.00001 atmospheres, so that the drying temperature and the vacuum degree are inversely proportional to each other, to form a porous skeleton collagen peptide-graphene nanocomposite material; S2. The herbal extracts: 0.5-1 part of black tiger extract, 0.5-1 part of angelica extract, 0.5-1 part of frankincense extract, 0.5-1 part of peony extract, 0.5-1 part of Panax notoginseng root extract, 0.5-1 part of salvia root extract, 0.5-1 part of Notopterygium root extract, 0.5-1 part of Angelica dahurica extract, 0.5-1 part of Angelica dahurica extract, 0.5-1 part of Phellodendron amurense bark extract, 0.5-1 part of ginseng extract, 0.5-1 part of Artemisia annua extract, 0.5-1 part of Eucommia ulmoides extract, 0.5-1 part of Chuanxiong extract, 0.5-1 part of Millettia reticulata extract, 0.5-1 part of Elecampane extract. -1 part, saffron extract 0.5-1 part, three-gna extract 0.5-1 part, gallnut extract 0.5-1 part, lycopodiella herb extract 0.5-1 part, Magnolia officinalis extract 0.5-1 part and porous skeleton collagen peptide-graphene nanocomposite material are added into a sealed container, and the internal pressure of the sealed container is adjusted to increase the pressure from 1atm to 10atm at a pressure increase rate of 0.5atm / 1min. After reaching 10atm, the pressure is maintained and the adsorption treatment is carried out for 3-5 hours. At the same time, triethanolamine is used to adjust the pH to 4-5 to obtain an adsorption treated material; S3. Add 5-15 parts of ethanol, 0.5-2 parts of xanthan gum, 5-10 parts of propylene glycol, and 3-7 parts of glycerol, and stir evenly to obtain an intelligent temperature-controlled analgesic health cream based on collagen peptide-graphene composite material.

7. The intelligent temperature-controlled analgesic health cream based on collagen peptide-graphene composite material according to claim 6, characterized in that: In step S1, the relationship between the drying temperature increase rate and the vacuum degree is as follows: 。 8. The intelligent temperature-controlled analgesic health cream based on collagen peptide-graphene composite material according to claim 6, characterized in that: In step S2, The porous skeleton collagen peptide-graphene nanocomposite material was placed in a kettle, and the extracts of various Chinese medicinal materials were weighed and stirred in a water bath at 30°C to 40°C until completely dissolved, and then filtered through a 200-mesh nylon filter bag to obtain a clear brown liquid. Inject the drug solution into the autoclave lid to ensure sealing, purge nitrogen through the air inlet to remove the air in the autoclave, close all exhaust valves, and start the pressure increase procedure: linearly increase the pressure from normal pressure to 10atm at a rate of 0.5atmmin-1. The entire pressure increase process takes 15 to 20 minutes. The temperature is constant at 20 to 35°C. After reaching 10atm, maintain the pressure for 2h to 3h and continue stirring at 100rpm. During the adsorption process, add triethanolamine solution dropwise to ensure that the pH of the system is stable at 4.2 to 4.

7. When the absorbance decrease rate measured twice in a row is ≥90%, it is determined to be the adsorption end point.

9. The intelligent temperature-controlled analgesic health cream based on collagen peptide-graphene composite material according to claim 6, characterized in that: In step S3, Oil phase preparation: Add propylene glycol, glycerin and ethanol, start stirring, and heat to 40°C until the three components are completely miscible and clear and transparent. Set aside. Aqueous phase preparation: Add deionized water to the emulsification pot, start the shearing machine, and sprinkle xanthan gum evenly while shearing. Continue to do this until the xanthan gum fully swells without agglomeration, forming a uniform viscous water phase. Main phase mixing: The high-pressure adsorption wet material obtained in S2 was slowly added to the aqueous phase and homogenized at 5000 rpm for 5 min to ensure uniform dispersion of the porous composite material.

10. The use of the intelligent temperature-controlled analgesic health cream based on the collagen peptide-graphene composite material according to any one of claims 1 to 5, characterized in that: The intelligent temperature-controlled analgesic health cream is irradiated with infrared light, the wavelength of which is far infrared 8 μm to 14 μm, so that the graphene is emitted in the 3 to 15 μm band, and far infrared is generated simultaneously with heating.

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