Hydrogels for use in diabetic foot wound dressings and use thereof

Abstract

This application provides a hydrogel for diabetic foot wound dressing and its application. The hydrogel comprises: a hydrogel carrier for loading a traditional Chinese medicine extract; and the traditional Chinese medicine extract loaded on the hydrogel carrier. The traditional Chinese medicine extract is obtained by oil extraction and wall material embedding of a traditional Chinese medicine composition. The wall material is selected from one or more of β-cyclodextrin, hydroxypropyl-β-cyclodextrin, chitosan-modified β-cyclodextrin, and chitosan-phenylboronic acid-modified β-cyclodextrin. This application obtains the traditional Chinese medicine extract by embedding the oil extract of the traditional Chinese medicine composition raw material into the wall material, and loads the traditional Chinese medicine extract onto the hydrogel carrier to obtain a hydrogel for diabetic foot wound dressing. This hydrogel can provide a favorable microenvironment for wound healing, and in conjunction with the effective components in the traditional Chinese medicine extract, can effectively inhibit inflammation and promote wound healing.

Description

Technical Field

[0001] This application relates to the pharmaceutical field, specifically to a hydrogel for diabetic foot wound dressing and its application. Background Technology

[0002] Diabetes is a leading cause of death, affecting over 382 million people worldwide. Diabetic foot ulcers are one of the most common and serious complications of diabetes. Statistics show that 15% to 25% of people with diabetes will develop diabetic foot ulcers in their lifetime, usually caused by diabetic peripheral neuropathy or vascular disease. Diabetic peripheral neuropathy weakens foot structures and reduces sensation, increasing the risk of ulcers caused by repetitive mechanical stress, accompanied by perfusion disorders. Furthermore, diabetic foot ulcers often fail to heal due to poor blood sugar control, poor tissue oxygenation, and impaired immune responses. A weakened immune system also increases the risk of wound infection in diabetic patients. Patients with diabetic foot ulcers have a higher risk of recurrent ulcers, amputation, and death; therefore, greater attention needs to be paid to wound healing and limb repair in diabetic patients.

[0003] Traditional Chinese medicine extracts contain various active ingredients, such as polysaccharides, flavonoids, and terpenes, which have free radical scavenging, anti-inflammatory, and antibacterial effects. These ingredients are mild, do not induce drug resistance, and play an important role in wound healing. In the prior art, patent CN111467432A discloses a pharmaceutical composition for treating diabetic foot ulcers, prepared from the following raw materials in the indicated weight ratios: 5-15 parts of Coptis chinensis, 0.5-1.5 parts of Angelica sinensis, and 1-3 parts of Bletilla striata. A method for preparing a wet dressing based on this composition is also provided. This pharmaceutical composition for treating diabetic foot ulcers is inexpensive, easy to use, promotes wound healing through multiple targets, and reduces patient pain.

[0004] Therefore, a hydrogel for diabetic foot wound dressing can be provided to promote the healing of diabetic foot wounds. Summary of the Invention

[0005] This application provides a hydrogel for diabetic foot wound dressing and its application, which has good anti-inflammatory effects and can effectively promote the healing of diabetic foot wounds.

[0006] In a first aspect, this application provides a hydrogel for diabetic foot wound dressing, comprising: Hydrogel carriers for loading traditional Chinese medicine extracts; and A traditional Chinese medicine extract loaded on the hydrogel carrier; the traditional Chinese medicine extract is obtained from a traditional Chinese medicine composition through oil extraction and wall material embedding, wherein... The wall material is selected from one or more of β-cyclodextrin, hydroxypropyl-β-cyclodextrin, chitosan-modified β-cyclodextrin, and chitosan-phenylboronic acid-modified β-cyclodextrin.

[0007] In the technical solution of this application, a traditional Chinese medicine extract is obtained by embedding the oil extract of the raw material of the traditional Chinese medicine composition with a wall material. The traditional Chinese medicine extract is then loaded onto a hydrogel carrier to obtain a hydrogel for diabetic foot wound dressing. The hydrogel can provide a good microenvironment for wound healing. In combination with the effective components in the traditional Chinese medicine extract, it can effectively inhibit inflammation and promote wound healing.

[0008] In some embodiments of this application, the solute of the hydrogel carrier is a hydrophilic polymer material; In some embodiments of this application, the hydrophilic polymer material is selected from one or more of starch, cellulose, sodium alginate, hyaluronic acid, chitosan, collagen, polylysine, polyglutamic acid, polyacrylic acid, polymethacrylic acid, polyacrylamide, and polyethylene glycol.

[0009] In some embodiments of this application, the traditional Chinese medicine composition, by weight, includes the following raw materials: 5 parts ginseng, 1-5 parts angelica, 1-5 parts honeysuckle, 1-3 parts blister beetle, 1-5 parts camphor, and 2-10 parts red peony root.

[0010] In some embodiments of this application, the traditional Chinese medicine composition, by weight, includes the following raw materials: 5 parts ginseng, 2-3 parts angelica, 2-3 parts honeysuckle, 1.5-2.5 parts blister beetle, 3-5 parts camphor, and 5-7 parts red peony root.

[0011] In some embodiments of this application, the method for preparing chitosan-modified β-cyclodextrin includes the following steps: S10 reacts β-cyclodextrin with p-toluenesulfonyl chloride to obtain sulfonated β-cyclodextrin; S20 reacts sulfonated β-cyclodextrin with chitosan to obtain chitosan-modified β-cyclodextrin.

[0012] In some embodiments of this application, the preparation method of chitosan-phenylboronic acid modified β-cyclodextrin includes the following steps: S100 uses 1-ethyl-(3-dimethylaminopropyl)carbodiimide and N-hydroxysuccinimide to activate 3-carboxyphenylboronic acid to obtain activated 3-carboxyphenylboronic acid; S200 reacts the activated 3-carboxyphenylboronic acid with chitosan to obtain chitosanphenylboronic acid; S300 reacts the chitosan phenylboronic acid with β-cyclodextrin to obtain chitosan phenylboronic acid modified β-cyclodextrin.

[0013] In some embodiments of this application, the wall material is a mixture of chitosan-modified β-cyclodextrin and chitosan-phenylboronic acid-modified β-cyclodextrin in a mass ratio of 1:2~5.

[0014] In some embodiments of this application, the preparation method of the traditional Chinese medicine extract specifically includes the following steps: S1000 uses oil to extract the raw material to obtain a traditional Chinese medicine oil extract, wherein the mass ratio of oil to raw material is 1:1~3; S2000 uses the wall material to encapsulate the traditional Chinese medicine oil extract to obtain the traditional Chinese medicine extract, wherein the mass ratio of the wall material to the traditional Chinese medicine oil extract is 1:0.05~0.5.

[0015] In some embodiments of this application, the mass ratio of the hydrogel carrier to the traditional Chinese medicine extract is 100:0.1~20.

[0016] Secondly, this application provides the use of the hydrogel according to any embodiment of the first aspect in the preparation of a drug for treating diabetic foot wounds. Detailed Implementation

[0017] The various embodiments or implementation schemes in this specification are described in a progressive manner, with each embodiment focusing on the differences from other embodiments.

[0018] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "illustrative embodiment," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with an embodiment or example is included in at least one embodiment or example of this application. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0019] Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one of that feature. In the description of this application, "multiple" means at least two, such as two, three, etc., unless otherwise explicitly specified.

[0020] In existing technologies, many traditional Chinese medicine (TCM) compositions have been proven to be effective in treating diabetic foot wounds. These TCM compositions can be prepared from raw material powders, or water or oil extracts, by adding acceptable excipients or auxiliary ingredients to form commonly used formulations. The formulation can be a paste-like dressing, which is obtained by pulverizing the raw material, extracting it with oil, and then adding petrolatum to the extract.

[0021] This ointment-like dressing contains the active ingredients of a traditional Chinese medicine composition. When applied externally, it can increase local blood supply to the wound, inhibit inflammation, and promote wound healing. However, during use, it was found that although the ointment-like dressing has certain effects, it is quite irritating to the wound, and the wound is not easy to clean when changing the dressing, which can easily aggravate the patient's discomfort.

[0022] In Traditional Chinese Medicine (TCM), the treatment of diabetic foot wounds with external herbal poultices typically involves preparing herbs into a paste or ointment through methods such as cutting, pounding, or grinding, with or without excipients. This paste is then applied to specific areas. The efficacy varies depending on the herbs used, the processing method, and the application site. Compared to oral medication, external application allows for more direct contact with the affected area, resulting in a more direct and effective treatment. However, a drawback is that while the direct contact of the paste or ointment with the wound facilitates the release of active ingredients, it fails to provide a suitable microenvironment for wound healing. This makes it unsuitable for prolonged use, and the dressing can irritate the affected area, increasing patient discomfort, making it particularly unsuitable for healing chronic wounds.

[0023] Hydrogels are insoluble materials made from natural (or synthetic) polymers, with water (70-90% water content) as the dispersion medium. Thanks to their excellent physicochemical structure and functional properties, hydrogels are considered ideal dressings for treating chronic wounds. The high water content of hydrogel dressings keeps granulation tissue and epithelial tissue in a moist environment. Their soft texture and low interfacial tension give them good biocompatibility and non-irritation, and help reduce inflammation in the surrounding area. Hydrogel dressings are soft and elastic, easy to remove after wound healing without causing any discomfort to the patient. Hydrogel dressings can also lower the temperature of the skin wound, thereby reducing pain.

[0024] Hydrogel dressings, with their porous and resilient structure, can act as an extracellular matrix at the wound site, providing a favorable microenvironment for wound healing and ensuring a moist growth environment. Furthermore, hydrogel dressings have a closer contact with the wound, which is beneficial for the efficacy of the loaded active ingredients. At the same time, hydrogels are highly designable and can be loaded with a variety of active pharmaceutical ingredients, making them particularly suitable for dressings used to repair and heal chronic wounds such as diabetic foot wounds.

[0025] In response, the inventors further sought to combine the advantages of hydrogel dressings by loading the active ingredients of the traditional Chinese medicine formula onto the hydrogel. However, since the main effective active ingredients in the formula are the lipid-soluble active ingredients, and hydrogels only have a good loading effect on water-soluble ingredients, lipid-soluble ingredients are not easy to be directly loaded onto the hydrogel. Therefore, the efficacy of the traditional Chinese medicine composition cannot be fully realized.

[0026] The inventors thus encapsulated the oil extracts of the raw materials of the traditional Chinese medicine composition to obtain the traditional Chinese medicine extract with a hydrophilic outer microcapsule structure, which can be loaded onto a hydrogel.

[0027] This application provides a hydrogel for diabetic foot wound dressing and its application. The technical solution of this application is described in detail below.

[0028] In a first aspect, this application provides a hydrogel for diabetic foot wound dressing, comprising: Hydrogel carriers for loading traditional Chinese medicine extracts; and Traditional Chinese medicine extracts loaded on a hydrogel carrier; the traditional Chinese medicine extracts are obtained from the raw materials of a traditional Chinese medicine composition through oil extraction and wall material embedding, wherein, The wall material is selected from one or more of β-cyclodextrin, hydroxypropyl-β-cyclodextrin, chitosan-modified β-cyclodextrin, and chitosan-phenylboronic acid-modified β-cyclodextrin.

[0029] In the technical solution of this application, the oil extract of the traditional Chinese medicine formula is embedded in a wall material to obtain a traditional Chinese medicine extract. The traditional Chinese medicine extract is loaded onto a hydrogel carrier to obtain a hydrogel for diabetic foot wound dressing. The hydrogel can provide a good microenvironment for wound healing. Combined with the effective components in the traditional Chinese medicine extract, it can effectively inhibit inflammation and promote wound healing.

[0030] According to the technical solution of this application, a hydrogel loaded with traditional Chinese medicine extracts is used as a dressing. This combination offers the advantages of hydrogel dressings, namely, providing a favorable microenvironment for wound healing, and possessing soft elasticity, making it easy to remove after wound healing without causing any discomfort to the patient. The hydrogel dressing can also lower the temperature of the skin wound, thereby reducing pain. Furthermore, the loaded traditional Chinese medicine extracts can exert a long-lasting effect on the affected area, inhibiting inflammation, promoting wound healing, and reducing irritation to the affected area, thus alleviating patient discomfort.

[0031] In addition, the wall material in this application is selected from one or more of β-cyclodextrin, hydroxypropyl-β-cyclodextrin, chitosan-modified β-cyclodextrin, and chitosan-phenylboronic acid-modified β-cyclodextrin. β-Cyclodextrin is a type of cyclic oligosaccharide obtained by special treatment of starch. It is non-toxic and harmless, and has a hydrophilic outer and hydrophobic inner structure, thus exhibiting good inclusion properties. Therefore, it can be used as a wall material to encapsulate the oil extracts of traditional Chinese medicine. However, β-cyclodextrin has poor water solubility, and the traditional Chinese medicine extracts with microcapsule structures obtained by using it as a wall material alone cannot be stably loaded onto hydrogels. Therefore, hydroxypropyl-β-cyclodextrin can be selected as a wall material. It is a hydrophilic derivative obtained by the condensation of β-cyclodextrin and propylene oxide. Since the hydroxypropylation of β-cyclodextrin breaks the intramolecular hydrogen bonds, its water solubility is significantly improved. The traditional Chinese medicine extracts obtained by using it as a wall material can be better loaded onto hydrogels.

[0032] Furthermore, chitosan-modified β-cyclodextrin can be used as a wall material. Chitosan-modified β-cyclodextrin is obtained by branching chitosan onto β-cyclodextrin molecules. Using it as a wall material can not only further improve the water solubility of traditional Chinese medicine extracts, but also allow the chitosan chains on the surface of the microcapsule structure to crosslink with the hydrophilic polymer material of the hydrogel carrier through a large number of hydrogen bonds and intermolecular forces. This can give the hydrogel better mechanical strength while improving the stability of the traditional Chinese medicine extract loading. At the same time, chitosan has good antibacterial effects, which can inhibit the growth and reproduction of bacteria and prevent wound infection.

[0033] Furthermore, chitosan-modified β-cyclodextrin can be used as a wall material. The inventors found that when using chitosan-modified β-cyclodextrin as a wall material, its wound healing effect was not as expected. After analysis, it was found that although chitosan-modified β-cyclodextrin as a wall material can significantly improve the drug loading capacity and load stability of the hydrogel, during use, due to the high degree of cross-linking of the hydrogel, the release of the loaded traditional Chinese medicine active ingredients is slow, and they cannot exert their effects well. To address this, the inventors further modified β-cyclodextrin to obtain chitosan-phenylboronic acid-modified β-cyclodextrin with borate ester bonds exhibiting glucose-effect properties. Using this as a wall material, the borate ester bonds in the hydrogel exhibit good stability before use, ensuring that the active ingredients of the traditional Chinese medicine loaded on the hydrogel are not easily lost, thus improving its preservation stability. After use, due to the relatively high glucose concentration at the diabetic foot wound site, glucose can react with the borate ester bonds, causing them to break. This weakens the interaction between the hydrogel and the traditional Chinese medicine extract, promoting the release of the extract and enhancing its efficacy. Combined with the wound-healing microenvironment provided by the hydrogel, this promotes the healing of diabetic foot wounds.

[0034] In some embodiments of this application, the preparation method of chitosan-modified β-cyclodextrin includes the following steps: S10 reacts β-cyclodextrin with p-toluenesulfonyl chloride to obtain sulfonated β-cyclodextrin; S20 reacts sulfonated β-cyclodextrin with chitosan to obtain chitosan-modified β-cyclodextrin.

[0035] The above embodiments further illustrate the preparation method of chitosan-modified β-cyclodextrin. The main process is to first react p-toluenesulfonyl chloride with the hydroxyl groups on β-cyclodextrin to obtain sulfonated β-cyclodextrin, and then hydrolyze the sulfonated β-cyclodextrin in a chitosan solution to obtain chitosan-modified β-cyclodextrin.

[0036] In some embodiments of this application, the preparation method of chitosan-modified β-cyclodextrin specifically includes the following steps: S10: 40-60g of β-cyclodextrin is dispersed in 180-300mL of water to obtain a suspension. 10-20g of p-toluenesulfonyl chloride is added, and the mixture is reacted at 20-40℃ for 5-10h. After the reaction is completed, 20-60mL of 10-20wt% sodium hydroxide aqueous solution is added. The filtrate is collected by filtration, and the pH of the filtrate is adjusted to 6-7 to precipitate. The precipitate is collected by filtration and freeze-dried to obtain sulfonated β-cyclodextrin. S20 dissolves 5-10g of chitosan in 500-1000mL of 1-3wt% acetic acid aqueous solution to obtain a chitosan solution, dissolves 5-15g of sulfonated β-cyclodextrin in 100-300mL of N,N-dimethylformamide to obtain a sulfonated β-cyclodextrin solution, adds the sulfonated β-cyclodextrin solution to the chitosan solution, and reacts at 90-110℃ for 12-36h. After the reaction is completed, the resulting reaction solution is placed in a dialysis bag and dialyzed in water for 2-5 days. The dialyzed reaction solution is freeze-dried to obtain chitosan-modified β-cyclodextrin.

[0037] In some embodiments of this application, the solute of the hydrogel carrier is a hydrophilic polymer material.

[0038] In some embodiments of this application, the hydrophilic polymer material is selected from one or more of starch, cellulose, sodium alginate, hyaluronic acid, chitosan, collagen, polylysine, polyglutamic acid, polyacrylic acid, polymethacrylic acid, polyacrylamide, and polyethylene glycol.

[0039] In some of the above embodiments, hydrophilic polymer materials can form hydrogel carriers with good mechanical properties in water under appropriate conditions, which can be used to load traditional Chinese medicine extracts. Those skilled in the art can select according to actual needs.

[0040] Furthermore, commonly used hydrophilic polymers as solutes for hydrogel carriers include starch, cellulose, sodium alginate, hyaluronic acid, chitosan, collagen, polylysine, polyglutamic acid, polyacrylic acid, polymethacrylic acid, polyacrylamide, and polyethylene glycol. Those skilled in the art can select one or more of these as needed. As an example, in some embodiments of this application, sodium alginate is used as the solute for the hydrogel carrier.

[0041] In some embodiments of this application, the traditional Chinese medicine composition comprises, by weight, the following raw materials: 5 parts ginseng, 1-5 parts angelica, 1-5 parts honeysuckle, 1-3 parts blister beetle, 1-5 parts camphor, and 2-10 parts red peony root.

[0042] In some of the above embodiments, ginseng refers to the dried root and rhizome of *Panax ginseng*, a plant belonging to the Araliaceae family. It has a sweet taste and slightly warm nature, and enters the spleen, lung, heart, and kidney meridians. It greatly replenishes vital energy, restores the pulse and consolidates the body, tonifies the spleen and lungs, generates fluids, and calms the mind. It is used for weakness and collapse, cold limbs, and weak pulse. It is rich in various ginsenosides, lipids, sesquiterpenes, flavonoids, and other active ingredients.

[0043] Angelica sinensis, the dried root of the plant Angelica sinensis (family Apiaceae), has a sweet and pungent taste, is warm in nature, and enters the liver, heart, and spleen meridians. It is good at nourishing blood and promoting blood circulation, regulating menstruation and relieving pain, and can also dispel cold. It is also used in surgery and traumatology to reduce swelling and heal wounds. It is rich in fat-soluble active ingredients such as ligustilide, angelicone, caryopsisol, and n-butenylfuranolol.

[0044] Honeysuckle is a heat-clearing and detoxifying herb, made from the dried flower buds or newly opened flowers of the honeysuckle plant (Lonicera japonica), a member of the Caprifoliaceae family. It has a sweet and cold nature, and enters the lung, stomach, and large intestine meridians. It clears heat and detoxifies, reduces inflammation and swelling, and is used to treat exogenous wind-heat or febrile diseases, heatstroke, dysentery due to heat toxicity, carbuncles and boils, sore throat, and various infectious diseases. It is rich in flavonoids such as oxalic acid and honeysuckle glycosides, as well as active ingredients such as saponins.

[0045] Cantharides, the dried body of the southern large cantharides or the yellow-black small cantharides, are insects belonging to the family Cladosporidae. They are poisonous, pungent in taste, and hot in nature, entering the liver, stomach, and kidney meridians. They possess the effects of breaking up blood stasis, dispersing nodules and eliminating swelling, and attacking toxins and eroding sores. They are mainly used for abdominal masses, amenorrhea, stubborn tinea, scrofula, warts, carbuncles that do not ulcerate, and malignant sores with necrotic tissue. They primarily contain monoterpenoid active ingredients such as cantharidin.

[0046] Camphor is a granular substance refined by distillation from the roots, trunks, branches, and leaves of the camphor tree (Cinnamomum camphora), a plant belonging to the Lauraceae family. It has a pungent taste and warm properties, and enters the heart and spleen meridians. It is used to clear the orifices, relieve stagnation of qi, dispel foul odors, kill parasites, relieve itching, reduce swelling, and relieve pain. It is primarily used to treat fever with delirium, sudden collapse due to sudden illness, abdominal pain due to heatstroke, vomiting and diarrhea, beriberi due to cold and dampness, scabies, stubborn tinea, tinea capitis, frostbite, leg ulcers, burns, bruises, toothache, and conjunctivitis. It can also be synthesized artificially through chemical processes; its IUPAC name is 1,7,7-trimethylbicyclo[2.2.1]heptane-2-one, a terpenoid organic compound.

[0047] Red peony root is the dried root of Paeonia lactiflora or Paeonia veitchii, both belonging to the Ranunculaceae family. It is bitter and slightly cold in nature and enters the liver meridian. It can clear liver fire and cool the blood, as well as promote blood circulation and remove blood stasis. It combines the functions of cooling blood and heat, clearing liver fire, and dispersing blood stasis. It mainly contains monoterpenoid glycosides such as paeoniflorin, hydroxypaeoniflorin, benzoylpaeoniflorin, and benzoylhydroxypaeoniflorin.

[0048] In some of the above embodiments, ginseng, angelica, honeysuckle, blister beetle, camphor, and red peony root are used as raw materials for the traditional Chinese medicine composition. The resulting dressing, when applied externally, has the effects of increasing local blood supply to diabetic foot wounds, inhibiting inflammation, and promoting wound healing.

[0049] In some embodiments of this application, the traditional Chinese medicine composition, by weight, includes the following raw materials: 5 parts ginseng, 2-3 parts angelica, 2-3 parts honeysuckle, 1.5-2.5 parts blister beetle, 3-5 parts camphor, and 5-7 parts red peony root.

[0050] In some of the above embodiments, the mass fraction of the raw materials in the Chinese herbal extract is further defined. Under this mass fraction formulation, the resulting Chinese herbal composition has a better effect on promoting wound healing and inhibiting inflammation.

[0051] In some embodiments of this application, the preparation method of chitosan-phenylboronic acid modified β-cyclodextrin includes the following steps: S100 uses 1-ethyl-(3-dimethylaminopropyl)carbodiimide and N-hydroxysuccinimide to activate 3-carboxyphenylboronic acid to obtain activated 3-carboxyphenylboronic acid; S200 reacts the activated 3-carboxyphenylboronic acid with chitosan to obtain chitosanphenylboronic acid; S300 reacts the chitosan phenylboronic acid with β-cyclodextrin to obtain chitosan phenylboronic acid modified β-cyclodextrin.

[0052] In some embodiments of this application, the preparation method of chitosan-phenylboronic acid modified β-cyclodextrin specifically includes the following steps: S100 dissolves 1-3g of 3-carboxyphenylboronic acid in 100-200mL of methanol, then adds 0.1-0.5g of N-hydroxysuccinimide and 0.3-1g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide, and activates at 20-30℃ for 20-60min to obtain an activated 3-carboxyphenylboronic acid solution; S200 dissolves 5-10g of chitosan in 200-500mL of 1-3wt% acetic acid aqueous solution to obtain chitosan solution. The chitosan solution is then added to the activated 3-carboxyphenylboronic acid solution and reacted at 20-30℃ for 12-36h. After the reaction is completed, the resulting reaction solution is placed in a dialysis bag and dialyzed in water for 2-5 days. The dialyzed reaction solution is then freeze-dried to obtain chitosanphenylboronic acid. S300 disperses 10-30g of β-cyclodextrin in 200-300mL of water to obtain a suspension, then adds 5-10g of chitosan-phenylboronic acid, stirs and disperses, adjusts the pH to 7-8.5, and reacts at 20-30℃ for 12-36h. After the reaction is completed, the resulting reaction solution is placed in a dialysis bag and dialyzed in water for 2-5 days. The dialyzed reaction solution is then freeze-dried to obtain chitosan-phenylboronic acid modified β-cyclodextrin.

[0053] In some embodiments of this application, the wall material is a mixture of chitosan-modified β-cyclodextrin and chitosan-phenylboronic acid-modified β-cyclodextrin in a mass ratio of 1:2 to 5.

[0054] In some of the above embodiments, the inventors discovered that by using a mixture of chitosan-modified β-cyclodextrin and chitosan-phenylboronic acid-modified β-cyclodextrin as the wall material, the release rate of the traditional Chinese medicine extract in the hydrogel can be controlled by controlling the mass ratio of the two, thereby adjusting the duration of the hydrogel's efficacy and achieving better results.

[0055] In some embodiments of this application, the preparation method of the traditional Chinese medicine extract specifically includes the following steps: S1000 uses oil to extract raw materials to obtain Chinese herbal oil extracts, wherein the mass ratio of oil to raw materials is 1:1~3; S2000 uses a wall material to encapsulate the oil extract of traditional Chinese medicine to obtain the extract, wherein the mass ratio of the wall material to the oil extract of traditional Chinese medicine is 1:0.05~0.5.

[0056] In some embodiments of this application, the oil is one or more of sesame oil, peanut oil, and soybean oil. As an example, in some embodiments of this application, sesame oil is used to extract the raw material.

[0057] In some embodiments of this application, in step S1000, the raw material can be crushed and then extracted.

[0058] In some embodiments of this application, ultrasonic treatment may be performed during the extraction process in step S1000.

[0059] In some embodiments of this application, step S2000 specifically includes: Add 10-20g of wall material to 40-100mL of anhydrous ethanol to obtain an ethanol solution of wall material. Add 1-3g of Chinese herbal oil extract dropwise to the ethanol solution of wall material, mix evenly, let stand for 2-5 hours, and then vacuum dry at 60-80℃ to obtain the Chinese herbal extract.

[0060] In some embodiments of this application, the mass ratio of the hydrogel carrier to the traditional Chinese medicine extract is 100:0.1~20.

[0061] This application provides a method for preparing a hydrogel for diabetic foot wound dressing, comprising the following steps: A hydrophilic polymer material and a traditional Chinese medicine extract according to any embodiment of the first aspect are dispersed in water, and after full swelling, a crosslinking agent is added to obtain a hydrogel for diabetic foot wound dressing.

[0062] It should be noted that the type of crosslinking agent can be selected according to the type of hydrophilic polymer material. As an example, if sodium alginate is used as the hydrophilic polymer material, calcium ions can be used as the crosslinking agent.

[0063] As an example, a method for preparing a hydrogel for diabetic foot wound dressing includes the following steps: Dissolve 1-10g sodium alginate and 0.5-5g traditional Chinese medicine extract in 80-120mL of water and allow to swell for 20-30h to obtain a hydrosol; Place the hydrosol in a mold and immerse it in a 1-10 wt% calcium chloride aqueous solution for 5-20 minutes. Demold to obtain the hydrogel for diabetic foot wound dressing.

[0064] Secondly, this application provides the use of the hydrogel according to any embodiment of the first aspect in the preparation of a drug for treating diabetic foot wounds.

[0065] The following examples describe the disclosure of this invention in more detail. These examples are merely illustrative, as various modifications and variations will be apparent to those skilled in the art within the scope of this disclosure. Unless otherwise stated, all parts, percentages, and ratios reported in the following examples are based on mass, and all reagents used in the examples are commercially available or synthesized by conventional methods and can be used directly without further processing. The instruments used in the examples are also commercially available.

[0066] Example 1 Preparation of hydrogels for diabetic foot wound dressings: Dissolve 5g sodium alginate and 3g Chinese herbal extract in 100mL of water and allow to swell for 24 hours to obtain a hydrosol. The hydrosol was placed in a 0.5cm×2cm×2cm mold and immersed in a 10wt% calcium chloride aqueous solution for 10 minutes. After demolding, the hydrogel for diabetic foot wound dressing was obtained.

[0067] Preparation of Chinese herbal extracts: The raw materials of Chinese herbal medicine were pulverized and passed through a 300-mesh sieve for later use. 5g of ginseng powder, 2.5g of angelica powder, 3g of honeysuckle powder, 1.5g of cantharides powder, 4g of camphor powder, and 6g of red peony powder were added to 30mL of sesame oil, stirred evenly, and then ultrasonically extracted for 6h. The extract was centrifuged and the supernatant was collected to obtain the Chinese herbal oil extract. 10g of wall material was added to 60mL of anhydrous ethanol to obtain an ethanol solution of wall material. 2g of traditional Chinese medicine oil extract was added dropwise to the ethanol solution of wall material, mixed evenly, and allowed to stand for 5h. After the ethanol was recovered under reduced pressure, the extract was dried under vacuum at 70℃ to obtain the traditional Chinese medicine extract.

[0068] The wall material is a mixture of chitosan-modified β-cyclodextrin and chitosan-phenylboronic acid-modified β-cyclodextrin in a mass ratio of 1:3.

[0069] Preparation of chitosan-modified β-cyclodextrin: 50g of β-cyclodextrin was dispersed in 210mL of water to obtain a suspension. 15g of p-toluenesulfonyl chloride was added, and the mixture was reacted at 30℃ for 6h. After the reaction was completed, 50mL of 10wt% sodium hydroxide aqueous solution was added. The filtrate was collected by filtration, and the pH of the filtrate was adjusted to 7 to precipitate. The precipitate was collected by filtration and freeze-dried to obtain sulfonated β-cyclodextrin. 5g of chitosan was dissolved in 400mL of 1wt% acetic acid aqueous solution to obtain a chitosan solution. 20g of sulfonated β-cyclodextrin was dissolved in 200mL of N,N-dimethylformamide to obtain a sulfonated β-cyclodextrin solution. The sulfonated β-cyclodextrin solution was added to the chitosan solution, and the mixture was refluxed at 100℃ for 24h. After the reaction was completed, the resulting reaction solution was placed in a dialysis bag and dialyzed in water for 3 days. The dialyzed reaction solution was freeze-dried to obtain chitosan-modified β-cyclodextrin.

[0070] Preparation of chitosan-phenylboronic acid modified β-cyclodextrin: 2g of 3-carboxyphenylboronic acid was dissolved in 80mL of methanol, and then 0.4g of N-hydroxysuccinimide and 0.7g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide were added. The solution was activated at 25℃ for 40min to obtain an activated 3-carboxyphenylboronic acid solution. 5g of chitosan was dissolved in 300mL of 1wt% acetic acid aqueous solution to obtain a chitosan solution. The chitosan solution was added to the activated 3-carboxyphenylboronic acid solution and reacted at 25℃ for 24h. After the reaction was completed, the resulting reaction solution was placed in a dialysis bag and dialyzed in water for 3d. The dialyzed reaction solution was freeze-dried to obtain chitosanphenylboronic acid. S300 dispersed 20g of β-cyclodextrin in 200mL of water to obtain a suspension, then added 5g of chitosan phenylboronic acid, stirred and dispersed, adjusted pH=8, and reacted at 25℃ for 24h. After the reaction was completed, the resulting reaction solution was put into a dialysis bag and dialyzed in water for 3d. The dialyzed reaction solution was freeze-dried to obtain chitosan phenylboronic acid modified β-cyclodextrin.

[0071] Example 2 Preparation of hydrogel for diabetic foot wound dressing: The preparation method is similar to that in Example 1, except that the wall material used is hydroxypropyl-β-cyclodextrin.

[0072] Example 3 Preparation of hydrogel for diabetic foot wound dressing: The preparation method is similar to that in Example 1, except that the wall material used is chitosan-modified β-cyclodextrin.

[0073] Example 4 Preparation of hydrogel for diabetic foot wound dressing: The preparation method is similar to that in Example 1, except that the wall material used is chitosan-phenylboronic acid-modified β-cyclodextrin.

[0074] Comparative Example 1 Preparation of ointment dressing for diabetic foot wounds: The raw materials of traditional Chinese medicine are pulverized and passed through a 300-mesh sieve for later use. 5g of ginseng powder, 2.5g of angelica powder, 3g of honeysuckle powder, 1.5g of cantharides powder, 4g of camphor powder, and 6g of red peony powder are added to 30mL of sesame oil, stirred evenly, and then ultrasonically extracted for 6 hours. The extract is centrifuged and the supernatant is collected to obtain the Chinese medicine oil extract. Vaseline is added to make up the mass to 100g to obtain the final product.

[0075] Animal experiments: Healthy 8-10 week old adult male SD rats (weight: 200-250g) were selected for this study. All rats were housed in standard plastic cages under controlled conditions (20-25℃, 50%-70% humidity, 12-hour light / dark cycle, free access to food). Type 1 diabetes was induced in rats under aseptic conditions by a single intraperitoneal injection of 65 mg / kg streptozotocin (STZ, Sigma-Aldrich). Rats with a blood glucose level exceeding 16.7 mmol / L one week after administration were considered diabetic. Throughout the study, blood glucose levels were recorded via the tail vein of the rats using a glucometer (Johnson, China).

[0076] Sixty rats were selected to establish a diabetic wound model after three weeks of STZ-induced hyperglycemia. Under intraperitoneal anesthesia with sodium pentobarbital (35 mg / kg), full-thickness skin lesions with a diameter of 10 mm were created on the dorsal skin of the rats using a pore-forming device. After rinsing the wounds with physiological saline, the rats were divided into 6 groups of 10 each, receiving different treatments: Examples 1-5 and a control group (untreated). The Example groups and Control groups were treated with the corresponding hydrogel (one sheet at a time, 0.5 cm × 2 cm × 2 cm) or ointment dressing (0.5 g, spread evenly), respectively. The control group received no treatment. The wounds were wiped with physiological saline daily, and each wound was covered with sterile gauze and secured with elastic adhesive tape. All groups underwent daily wound cleaning and dressing changes with physiological saline for 15 days.

[0077] The wound healing status was recorded using a digital camera at 0, 5, 10, and 15 days post-surgery. ImageJ software was used to calculate the wound healing status, and the results are shown in Table 1. The formula for calculating the remaining wound area (Sr) is as follows: Sr(%) = S n / S0×100% Where S0 represents the initial wound area, S n This represents the wound area at different healing time points.

[0078] Ten days post-surgery, 0.1g of wound and surrounding tissue was placed in a centrifuge tube, 1.2mL of PBS (pH=7.4) was added, the mixture was shaken and centrifuged to collect the supernatant. The levels of IL-2 (interleukin-2) and TNF-α (tumor necrosis factor-α) in the wound and surrounding tissue were detected by ELISA using a kit. The results are shown in Table 2.

[0079] Table 1 Table 2 The results in Tables 1 and 2 show that, compared with the blank group, the wounds of the various examples and comparative examples healed faster and had lower levels of inflammatory factors, indicating that the extract of the traditional Chinese medicine formula provided in this application has a better anti-inflammatory effect and the ability to promote the healing of diabetic foot wounds. Comparing Examples 1-4 with Comparative Example 1, the examples showed better results, indicating that the hydrogel can provide a better environment for wound healing and effectively inhibit inflammation. It also showed better synergistic effects with the loaded traditional Chinese medicine extract. Furthermore, the experiment revealed that changing the dressing with the ointment-like dressing of Comparative Example 1 was inconvenient, requiring multiple wound cleanings. The mice were very noisy during dressing changes, and some wounds reopened, resulting in slower healing. By comparing Examples 1 to 4, Example 1 showed the best results. This may be because the hydrogel obtained in Example 2 had insufficient cross-linking, resulting in insufficient loading of the herbal extract during the preparation process. Although the hydrogels obtained in Examples 3 and 4 had good loading effects on the herbal extract, their release was too slow or too fast, which also affected the effectiveness of the herbal extract. Example 1, by adjusting the proportion of components in the wall material, obtained a hydrogel with a suitable release rate, which can exert a long-lasting anti-inflammatory effect and promote wound healing without wasting the efficacy during the dressing change cycle, thus achieving better anti-inflammatory and wound healing effects.

[0080] In summary, the traditional Chinese medicine composition and hydrogel for diabetic foot wound dressing provided by this invention have good anti-inflammatory and wound healing effects, and can be used in the treatment of diabetic foot, showing great clinical application prospects.

[0081] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.

Claims

1. A hydrogel for use in a diabetic foot wound dressing, characterized in that, include: Hydrogel carriers for loading extracts of traditional Chinese medicine; and A traditional Chinese medicine extract loaded on the hydrogel carrier; the traditional Chinese medicine extract is obtained from a traditional Chinese medicine composition through oil extraction and wall material embedding, wherein... The wall material is selected from one or more of β-cyclodextrin, hydroxypropyl-β-cyclodextrin, chitosan-modified β-cyclodextrin, and chitosan-phenylboronic acid-modified β-cyclodextrin.

2. The hydrogel of claim 1, wherein, The solute of the hydrogel carrier is a hydrophilic polymer material.

3. The hydrogel according to claim 2, wherein the hydrophilic polymer material is selected from one or more of starch, cellulose, sodium alginate, hyaluronic acid, chitosan, collagen, polylysine, polyglutamic acid, polyacrylic acid, polymethacrylic acid, polyacrylamide, and polyethylene glycol.

4. The hydrogel of claim 1, wherein, The traditional Chinese medicine composition comprises, by weight, the following raw materials: 5 parts ginseng, 1-5 parts angelica, 1-5 parts honeysuckle, 1-3 parts blister beetle, 1-5 parts camphor, and 2-10 parts red peony root.

5. The hydrogel of claim 1, wherein, The traditional Chinese medicine composition comprises, by weight, the following raw materials: 5 parts ginseng, 2-3 parts angelica, 2-3 parts honeysuckle, 1.5-2.5 parts blister beetle, 3-5 parts camphor, and 5-7 parts red peony root.

6. The hydrogel of claim 1, wherein, The preparation method of the chitosan-modified β-cyclodextrin includes the following steps: S10 reacts β-cyclodextrin with p-toluenesulfonyl chloride to obtain sulfonated β-cyclodextrin; S20 reacts sulfonated β-cyclodextrin with chitosan to obtain chitosan-modified β-cyclodextrin.

7. The hydrogel of claim 1, wherein The method for preparing chitosan-phenylboronic acid-modified β-cyclodextrin. Includes the following steps: S100 uses 1-ethyl-(3-dimethylaminopropyl)carbodiimide and N-hydroxysuccinimide to activate 3-carboxyphenylboronic acid to obtain activated 3-carboxyphenylboronic acid; S200 reacts the activated 3-carboxyphenylboronic acid with chitosan to obtain chitosanphenylboronic acid; S300 reacts the chitosan phenylboronic acid with β-cyclodextrin to obtain chitosan phenylboronic acid modified β-cyclodextrin.

8. The hydrogel of claim 1, wherein, The wall material is a mixture of chitosan-modified β-cyclodextrin and chitosan-phenylboronic acid-modified β-cyclodextrin in a mass ratio of 1:2~5.

9. The hydrogel of claim 1, wherein, The preparation method of the traditional Chinese medicine extract specifically includes the following steps: S1000 uses oil to extract the raw material to obtain a traditional Chinese medicine oil extract, wherein the mass ratio of oil to raw material is 1:1~3; S2000 uses the wall material to encapsulate the traditional Chinese medicine oil extract to obtain the traditional Chinese medicine extract, wherein the mass ratio of the wall material to the traditional Chinese medicine oil extract is 1:0.05~0.

5.

10. The use of a hydrogel according to any one of claims 1 to 9 in the preparation of a drug for treating diabetic foot wounds.

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