A traditional Chinese medicine ion eutectic introduction agent, a preparation method thereof and an application thereof to preventing diabetic foot

Abstract

This invention discloses a traditional Chinese medicine ionopolymer delivery agent, its preparation method, and its application in the prevention of diabetic foot ulcers, belonging to the field of pharmaceutical technology. The traditional Chinese medicine ionopolymer delivery agent comprises a vitamin B1 lipoic acid ionopolymer, safflower, kudzu root, and salvia miltiorrhiza, with a mass ratio of 4:(1-2):(2-4):(2-4). The delivery gel comprises the delivery agent, a gel matrix, and a preservative, with a mass ratio of 4:4:(0.45-0.7). This invention exhibits synergistic effects from multiple components, simultaneously improving local neuropathy, ischemia, hypoxia, and inflammatory responses in diabetic foot ulcers. It demonstrates good transdermal absorption, stable efficacy, and high safety. The preparation method is simple and easily industrialized, filling a gap in related effective topical preparations and possessing extremely high clinical application value.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a traditional Chinese medicine ion eutectic delivery agent, its preparation method, and its application in preventing diabetic foot. Background Technology

[0002] Diabetes mellitus is a disease characterized by an absolute or relative deficiency of insulin in the body. In recent years, the number of diabetic patients worldwide has been increasing, and a significant proportion of these patients also suffer from diabetic foot ulcers. This complication is characterized by a high recurrence rate, a high disability rate, and a high mortality rate. Furthermore, a long-term high-sugar environment can induce peripheral neuropathy, lower limb microvascular ischemia and hypoxia, and a decline in the body's immune function, leading to slow wound healing, recurrent infections, and in severe cases, amputation or even death.

[0003] Currently, clinical treatments for diabetic foot ulcers have significant limitations. Clinical practice primarily focuses on systemic blood glucose control, which only slows disease progression and cannot specifically repair the damaged microenvironment and vascular endothelial damage in the foot. Local treatment mainly involves routine dressing changes and anti-infection measures, lacking specific drugs that can simultaneously improve the triple pathological damage of nerves, blood vessels, and inflammation. Commercially available preparations are mostly wound care products, with no dedicated drugs for early prevention of diabetic foot ulcers. Furthermore, traditional topical preparations suffer from poor transdermal absorption, insufficient local drug concentration, and limited target sites, making it difficult to reverse the cellular function damage and tissue microenvironment imbalance caused by high glucose levels, and thus failing to fundamentally reduce the incidence of ulcers and the risk of amputation.

[0004] It is evident that there is a lack of drugs specifically for the prevention of diabetic foot in clinical practice, and existing treatments are extremely expensive, placing a heavy burden on society and patients. Summary of the Invention

[0005] In order to overcome the shortcomings of the prior art, the purpose of this invention is to provide a traditional Chinese medicine ion eutectic delivery agent, its preparation method and its application in the prevention of diabetic foot, so as to fill the current gap of no drugs specifically for the prevention of diabetic foot.

[0006] To achieve the above objectives, the present invention employs the following technical solution: In a first aspect, the present invention discloses a traditional Chinese medicine ionopolymer delivery agent, comprising vitamin B1. The alpha-lipoic acid ion eutectic, safflower, kudzu root, and salvia miltiorrhiza; wherein, the vitamin B1 The mass ratio of the thioctic acid ion eutectic, safflower, kudzu root and salvia miltiorrhiza is 4:(1-2):(2-4):(2-4).

[0007] Preferably, the vitamin B1 The molar ratio of vitamin B1 to lipoic acid in the lipoic acid ion eutectic is 1:1 to 3:1.

[0008] Among the above-mentioned traditional Chinese medicine ionopolymer delivery agents, vitamin B1 The core active ingredient is a thioctic acid ion eutectic, which forms a stable ion eutectic system through a specific molar ratio, significantly improving both lipid and water solubility and facilitating transdermal absorption. The synergistic effect of three traditional Chinese medicines—safflower, kudzu root, and salvia miltiorrhiza—works with vitamin B1. The combination of thioctic acid ion eutectic achieves synergistic effects of nourishing nerves, promoting blood circulation, reducing inflammation and swelling, and improving microcirculation. The precise mass ratio of each component ensures maximum efficacy while avoiding the toxic side effects caused by excessive dosage of a single component.

[0009] In a second aspect, this invention discloses a traditional Chinese medicine ion eutectic delivery gel, the specific technical solution of which is as follows: A traditional Chinese medicine ion eutectic delivery gel includes a gel matrix, a preservative, and the aforementioned traditional Chinese medicine ion eutectic delivery agent; wherein the mass ratio of the gel matrix, the preservative, and the traditional Chinese medicine ion eutectic delivery agent is 4:4:(0.45-0.7).

[0010] Preferably, the gel matrix is ​​made of carbomer, sodium carboxymethyl cellulose, chitosan, sodium alginate, xanthan gum, gelatin, etc., and the preservative is made of ethylparaben, propylparaben, methylparaben, potassium sorbate, etc.

[0011] In a preferred embodiment of the present invention, the gel matrix is ​​carbomer and the preservative is ethylparaben.

[0012] The aforementioned herbal iontophoresis gel uses herbal iontophoresis agents as its core active ingredient, combined with a gel matrix and preservatives. The three components are scientifically matched in mass ratio, ensuring both the stability and adhesion of the gel, while also enabling the slow and continuous release of the active ingredients, thus prolonging the drug's action time. Carbomer, as the gel matrix, has good biocompatibility and swelling properties, allowing it to adhere evenly to the wound surface, protecting it and reducing friction. Ethylparaben, as a preservative, effectively inhibits microbial growth, extends the shelf life of the preparation, and has minimal skin irritation, ensuring medication safety.

[0013] In a third aspect, the present invention discloses a method for preparing the above-mentioned traditional Chinese medicine ion eutectic delivery gel, the specific technical solution of which is as follows: A method for preparing a traditional Chinese medicine ion eutectic delivery gel includes: The gel matrix was dissolved in water to prepare the gel matrix system; The preservative system was prepared by dissolving the preservative in anhydrous ethanol. The preservative system was added to the gel matrix system and mixed thoroughly to obtain the preservative-gel system. The traditional Chinese medicine ion eutectic delivery agent was dissolved in water, then added to the preservative-gel system, and stirred until homogeneous to obtain the traditional Chinese medicine ion eutectic delivery gel.

[0014] Preferably, in the above method, the preparation of the traditional Chinese medicine ionopolymer delivery agent includes: Vitamin B1 and lipoic acid were dissolved in anhydrous ethanol to obtain vitamin B1 ethanol solution and lipoic acid ethanol solution, respectively. Dissolve potassium hydroxide in anhydrous ethanol at a molar ratio of 1:1 with lipoic acid to obtain a potassium hydroxide ethanol solution. Add potassium hydroxide ethanol solution dropwise to thioctic acid ethanol solution and react for 30-180 minutes to obtain the reaction solution; Add an ethanolic solution of vitamin B1 to the reaction solution, react for 2-24 hours, centrifuge, collect the supernatant, and dry to obtain vitamin B1. Thioctanoic acid ion eutectic; Vitamin B1 A traditional Chinese medicine ion eutectic agent was prepared by dissolving thioctic acid ion eutectic and traditional Chinese medicine ions (safflower, kudzu root, and salvia miltiorrhiza) in water.

[0015] Preferably, the centrifugation speed is 1500 r / min and the time is 5 min; the drying is carried out by vacuum drying for 24-72 h.

[0016] Preferably, the gel matrix is ​​dissolved in water using ultrasonic-assisted dissolution treatment and heated to 50-90°C to obtain the gel matrix system.

[0017] The above preparation method has clear steps, is simple to operate, and operates under mild conditions. It requires no complex equipment and can be industrialized for large-scale production. The stepwise preparation of the gel matrix system and the preservative system avoids gel denaturation caused by direct contact between the preservative and the gel matrix, ensuring a uniform gel texture. The combination of ultrasonic solubilization and heat treatment promotes rapid swelling of the gel matrix, shortens the preparation time, and avoids the destruction of the active ingredients by high temperatures. The centrifugation purification and vacuum drying steps can enhance the activity of vitamin B1. The purity and yield of the thioctic acid ion eutectic are ensured to guarantee consistent product quality and stable efficacy.

[0018] In a fourth aspect, the present invention also provides the application of the above-mentioned traditional Chinese medicine iontophoresis delivery agent and traditional Chinese medicine iontophoresis delivery gel, and related topical drugs, the specific technical solutions of which are as follows: This paper first proposes the application of the above-mentioned traditional Chinese medicine ion eutectic delivery agents and traditional Chinese medicine ion eutectic delivery gels in the preparation of drugs for the treatment and / or prevention of diabetic foot ulcers.

[0019] A topical medicine for treating and / or preventing diabetic foot ulcers is disclosed for the first time, which is made from the above-mentioned traditional Chinese medicine ion eutectic delivery agent and traditional Chinese medicine ion eutectic delivery gel with or without pharmaceutically acceptable excipients.

[0020] The above-mentioned applications and topical medications target the core pathological sites of diabetic foot ulcers, simultaneously improving local neuropathy, ischemia-hypoxia, and inflammatory responses. They can both prevent the occurrence of diabetic foot ulcers and promote the healing of existing ulcers, reducing the recurrence rate and amputation risk. Topical medications can be flexibly adjusted according to clinical needs, with or without pharmaceutically acceptable excipients, to suit patients with different conditions. They are highly safe, have no obvious toxic side effects, and are suitable for long-term use.

[0021] Compared with the prior art, the present invention has the following beneficial effects: The traditional Chinese medicine ion eutectic delivery agent disclosed in this invention uses vitamin B1-lipoic acid ion eutectic as the core, combined with three traditional Chinese medicines: safflower, kudzu root, and salvia miltiorrhiza. By scientifically limiting the mass ratio of each component, it achieves synergistic effects of multiple components, solving the technical problem of existing drugs for the prevention and treatment of diabetic foot ulcers having a single target and limited effect. Among them, the vitamin B1 and lipoic acid ion eutectic forms a stable ion eutectic system through a specific molar ratio (1:1-3:1). Compared with the use of vitamin B1 or lipoic acid alone, its fat solubility and water solubility are significantly improved, making it easier to penetrate the skin barrier and quickly exert the effects of nourishing nerves, anti-oxidation, and improving microcirculation. The three traditional Chinese medicines, safflower, kudzu root, and salvia miltiorrhiza, work synergistically. Safflower promotes blood circulation and removes blood stasis, kudzu root promotes body fluid and unblocks the meridians, and salvia miltiorrhiza nourishes blood and promotes blood circulation. Combined with the vitamin B1-lipoic acid ion eutectic, based on the complex pathological process of diabetic foot, the high permeability of ionic liquid and the antioxidant properties of vitamin B1-lipoic acid are used in combination with the traditional Chinese medicines salvia miltiorrhiza, safflower, and kudzu root to improve the pathological microenvironment of diabetic patients, such as foot microcirculation disorders, local hyperglycemia, inflammation, and oxidative stress, thereby alleviating the core inducing factors of ulcer formation from the root. The precise proportions of each component avoid poor efficacy due to excessive or insufficient amounts of a single component, balancing drug efficacy and safety. Furthermore, the readily available raw materials and scientifically formulated ratios provide a highly effective and safe traditional Chinese medicine iontophoresis preparation for the prevention and treatment of diabetic foot ulcers.

[0022] Furthermore, by combining a gel matrix with a preservative, this invention also prepares a gel product based on the aforementioned traditional Chinese medicine ion-co-melting delivery agent, solving the technical problems of poor transdermal absorption, insufficient local drug concentration, easy deterioration, and poor stability in existing topical preparations. Preferably, when carbomer is selected as the gel matrix and ethylparaben is selected as the preservative, carbomer has good swelling properties, adhesion, and biocompatibility, which allows the gel to adhere evenly to the diabetic foot ulcer wound, prolonging the drug's action time, preventing rapid drug loss, and promoting the slow and continuous release of active ingredients, increasing local drug concentration, and enhancing efficacy; ethylparaben, as a highly effective pharmaceutical preservative, can effectively inhibit the growth of microorganisms in the gel, prolong the shelf life of the preparation, and has low skin irritation, ensuring medication safety. Compared to traditional topical ointments and lotions, this gel has a uniform texture and is easy to use. It can be applied directly to the wound, exerting the synergistic therapeutic effect of the Chinese medicine ion-fusible delivery agent, while the protective effect of the gel matrix reduces wound friction, prevents infection, and further promotes ulcer healing. At the same time, the proportions of each component are well-matched, balancing gel stability and drug efficacy.

[0023] This invention also discloses a method for preparing a traditional Chinese medicine ion-co-melting delivery gel. This method involves simple reaction operations, mild conditions, and is suitable for large-scale industrial production. During the preparation process, the gel matrix and preservative are prepared separately and then mixed, avoiding gel denaturation caused by direct contact between the preservative and the gel matrix, ensuring a uniform gel texture and good stability. In the preparation of the traditional Chinese medicine ion-co-melting delivery agent, steps such as stepwise dissolution, precise temperature control, centrifugal purification, and vacuum drying yield a high-purity and stable vitamin B1-lipoic acid ion-co-melting compound, effectively avoiding impurity residues, improving the purity of the active ingredients, and thus enhancing the efficacy of the formulation. The entire preparation process requires no complex equipment, is easy to control, effectively reduces production costs, and ensures batch-to-batch stability, making it suitable for industrial-scale application. Furthermore, the combination of ultrasonic-assisted dissolution and 50-90℃ heating treatment can promote rapid and full swelling of the gel matrix, shorten the preparation time, and avoid high temperature damage to the activity of active ingredients. The precise limitation of centrifugation speed (1500r / min) and time (5min) and vacuum drying time (24-72h) can further improve the purity and yield of ion eutectic and ensure uniform product quality.

[0024] Based on the above innovations, the aforementioned traditional Chinese medicine iontophoresis delivery agents and gels can be used to prepare drugs for the treatment and / or prevention of diabetic foot ulcers, thereby solving the technical challenges of the current lack of specific drugs for diabetic foot ulcers, long treatment cycles, high recurrence rates, and high disability rates. This drug, with the traditional Chinese medicine iontophoresis delivery agent or gel as its core, can be flexibly adjusted according to clinical needs, with or without pharmaceutically acceptable excipients, to suit patients with different conditions. It specifically targets the core pathological points of diabetic foot ulcers, simultaneously improving three major problems: local neuropathy, ischemia-hypoxia, and inflammatory response. It can both prevent the occurrence of diabetic foot ulcers and promote the healing of existing ulcers, reducing ulcer recurrence rates and the risk of amputation. Compared to existing treatments that only control blood sugar or simply fight infection, its efficacy is more comprehensive and significant. Attached Figure Description

[0025] Figure 1 This document presents the reaction principle, ultraviolet (UV) spectrum, and infrared (IR) spectrum results of the ionic liquid delivery agent for traditional Chinese medicine. A shows a schematic diagram of the preparation of the ionic liquid delivery agent; B shows the UV characterization spectrum; and C shows the IR characterization spectrum. Figure 2 The effect of traditional Chinese medicine ion-co-melting infusion gel on cell migration caused by high glucose and the microenvironment of foot tissue in diabetic mice. Detailed Implementation

[0026] To enable those skilled in the art to better understand the present invention, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of the present invention.

[0027] It should be noted that the terms "first," "second," etc., in the specification, claims, and accompanying drawings of this invention are used to distinguish similar objects and are not necessarily used to describe a specific order or sequence. It should be understood that such data can be interchanged where appropriate so that the embodiments of the invention described herein can be implemented in orders other than those illustrated or described herein. Furthermore, the terms "comprising" and "having," and any variations thereof, are intended to cover a non-exclusive inclusion; for example, a process, method, system, product, or apparatus that comprises a series of steps or units is not necessarily limited to those steps or units explicitly listed, but may include other steps or units not explicitly listed or inherent to such processes, methods, products, or apparatus.

[0028] The present invention will now be described in further detail with reference to the accompanying drawings: Example 1 Weigh 67.4 mg of vitamin B1 and dissolve it in 10 mL of anhydrous ethanol to obtain an anhydrous ethanol solution of vitamin B1; weigh 420 mg of lipoic acid and dissolve it in 10 mL of anhydrous ethanol to obtain an anhydrous ethanol solution of lipoic acid; weigh 120 mg of potassium hydroxide and dissolve it in 4 mL of anhydrous ethanol to obtain an anhydrous ethanol solution of potassium hydroxide. Add the anhydrous ethanol solution of potassium hydroxide dropwise to the anhydrous ethanol solution of lipoic acid and stir for 30 min. Then add the anhydrous ethanol solution of vitamin B1 and react for 12 hours; centrifuge at 1500 rpm for 5 min, collect the supernatant, and dry it in a vacuum drying oven for 48 h.

[0029] Sprinkle 200 mg of carbomer into 10 mL of pure water (sonic dissolution can be used to aid dissolution), place in a 70 °C metal bath, and stir to allow the carbomer to fully swell; dissolve 200 mg of ethylparaben (preservative) in 3 mL of anhydrous ethanol, add to the above gel matrix, and stir evenly to obtain mixture B; 10mg of vitamin B1-lipoic acid ion eutectic delivery agent, 5mg of kudzu root, 5mg of salvia miltiorrhiza, and 2.5mg of safflower are dissolved in water and stirred evenly. Then, the mixture is added to mixture B and stirred evenly again to form a traditional Chinese medicine ion eutectic delivery gel.

[0030] Example 2 Weigh 67.4 mg of vitamin B1 and dissolve it in 10 mL of anhydrous ethanol to obtain an anhydrous ethanol solution of vitamin B1; weigh 630 mg of lipoic acid and dissolve it in 10 mL of anhydrous ethanol to obtain an anhydrous ethanol solution of lipoic acid; weigh 120 mg of potassium hydroxide and dissolve it in 4 mL of anhydrous ethanol to obtain an anhydrous ethanol solution of potassium hydroxide. Add the anhydrous ethanol solution of potassium hydroxide dropwise to the anhydrous ethanol solution of lipoic acid and stir for 30 min. Then add the anhydrous ethanol solution of vitamin B1 and react for 12 hours; centrifuge at 1500 rpm for 5 min, collect the supernatant, and dry it in a vacuum drying oven for 48 h.

[0031] 200 mg of carbomer was sprinkled into 10 mL of pure water (ultrasonic dissolution can be used to aid dissolution), placed in a 70°C metal bath, and stirred to allow the carbomer to fully swell. 200 mg of ethylparaben was fully dissolved in 3 mL of anhydrous ethanol and added to the above gel matrix. The mixture was stirred until homogeneous to obtain mixture B. 10 mg of vitamin B1-lipoic acid ion eutectic delivery agent, 5 mg of kudzu root, 5 mg of danshen, and 2.5 mg of safflower were dissolved in water, stirred until homogeneous, and then added to mixture B. The mixture was stirred until homogeneous to obtain the herbal ion eutectic delivery gel.

[0032] Example 3 Weigh 67.4 mg of vitamin B1 and dissolve it in 10 mL of anhydrous ethanol to obtain an anhydrous ethanol solution of vitamin B1; weigh 630 mg of lipoic acid and dissolve it in 10 mL of anhydrous ethanol to obtain an anhydrous ethanol solution of lipoic acid; weigh 120 mg of potassium hydroxide and dissolve it in 4 mL of anhydrous ethanol to obtain an anhydrous ethanol solution of potassium hydroxide. Add the anhydrous ethanol solution of potassium hydroxide dropwise to the anhydrous ethanol solution of lipoic acid and stir for 30 min. Then add the anhydrous ethanol solution of vitamin B1 and react for 12 hours; centrifuge at 1500 rpm for 5 min, collect the supernatant, and dry it in a vacuum drying oven for 48 h.

[0033] Dissolve 200 mg of carbomer in 10 mL of pure water (ultrasonic dissolution may be used), place in a 70°C metal bath, and stir to allow the carbomer to fully swell. Dissolve 200 mg of ethylparaben in 3 mL of anhydrous ethanol, add to the above gel matrix, and stir until homogeneous to obtain mixture B. Dissolve 10 mg of vitamin B1-lipoic acid ion eutectic delivery agent, 10 mg of kudzu root, 10 mg of salvia miltiorrhiza, and 5 mg of safflower in water, stir until homogeneous, add to mixture B, and continue stirring until homogeneous to obtain the traditional Chinese medicine ion eutectic delivery gel.

[0034] Example 4 Weigh 67.4 mg of vitamin B1 and dissolve it in 10 mL of anhydrous ethanol to obtain an anhydrous ethanol solution of vitamin B1; weigh 420 mg of lipoic acid and dissolve it in 10 mL of anhydrous ethanol to obtain an anhydrous ethanol solution of lipoic acid; weigh 120 mg of potassium hydroxide and dissolve it in 4 mL of anhydrous ethanol to obtain an anhydrous ethanol solution of potassium hydroxide. Add the anhydrous ethanol solution of potassium hydroxide dropwise to the anhydrous ethanol solution of lipoic acid and stir for 30 min. Then add the anhydrous ethanol solution of vitamin B1 and react for 12 hours; centrifuge at 1500 rpm for 5 min, collect the supernatant, and dry it in a vacuum drying oven for 48 h.

[0035] Dissolve 200 mg of carbomer in 10 mL of pure water (ultrasonic dissolution may be used), place in a 70°C metal bath, and stir to allow the carbomer to fully swell. Dissolve 200 mg of ethylparaben in 3 mL of anhydrous ethanol, add to the above gel matrix, and stir until homogeneous to obtain mixture B. Dissolve 10 mg of vitamin B1-lipoic acid ion eutectic delivery agent, 10 mg of kudzu root, 10 mg of salvia miltiorrhiza, and 5 mg of safflower in water, stir until homogeneous, add to mixture B, and continue stirring until homogeneous to obtain the traditional Chinese medicine ion eutectic delivery gel.

[0036] See Figure 1 , Figure 1 Image A illustrates the chemical reaction process for preparing an ionic eutectic from vitamin B1 (VB1) and lipoic acid (LA): In anhydrous ethanol, KOH is added as a base to deprotonate the carboxyl group of LA to form a carboxylate anion (LA). - Product: Ionic eutectic [VB1]+ [LA] - The VB1 cation and LA anion are combined by ionic bonds to form a stable ionic liquid structure, which provides a basis for subsequent transdermal absorption and drug efficacy.

[0037] Figure 1 Section B showcases VB1, LA, a physical mixture (VB1+LA), and an ionic eutectic [VB1]. + [LA] - UV absorption curve: VB1 (black): Characteristic absorption peak in the 200-260 nm range, absorption rapidly drops to 0 after 300 nm. LA (red): Characteristic absorption peak in the 200-280 nm range, absorption also drops to 0 after 300 nm. Physical mixture (blue): Absorption peak is the superposition of VB1 and LA, no significant absorption after 300 nm. Ionic eutectic (purple): Absorption significantly weakens in the 200-300 nm range, and a new broad absorption band appears in the 300-400 nm range, indicating that VB1 and LA underwent an ionization reaction, forming a new electronic transition structure, rather than a simple physical mixture.

[0038] Figure 1 Figure C shows the infrared transmission spectra of three groups of samples. The formation of ion eutectics was verified by the shift / disappearance of characteristic peaks. 3000~3500cm -1 VB1 and the physical mixture both have a temperature of 30-48 cm⁻¹ -1 A strong absorption is observed at this point (corresponding to the stretching vibrations of NH and OH). The position and intensity of this peak change in the ionic eutectic, indicating a change in the hydrogen bonding environment after ionization. (2800–3000 cm⁻¹) -1 Physical mixture at 2931cm -1 The presence of alkyl CH stretching vibrations at this point, with a weakened peak intensity in the ionic eutectic, indicates a change in the alkyl chain environment of LA due to ionization. (1600~1700 cm⁻¹) -1 The C=O stretching vibration of the carboxyl group in LA (~1700 cm⁻¹) -1 It disappears in ion eutectic and instead appears at 1669 cm⁻¹. -1 Carboxylate (-COO) appears at the site - The characteristic stretching vibrations of LA directly prove that LA deprotonates to form anion, which then forms an ionic bond with VB1 cation. (1500~1600 cm⁻¹) -1 : Aromatic ring / amide vibration of VB1 (1615 cm) -1 1565cm -1 The displacement in the ion eutectic reached 1615 cm⁻¹ -1 This indicates that the quaternary ammonium cation environment of VB1 is altered due to ion pairing. (500~1000 cm³)-1 : Ion eutectic at 791 cm -1 773cm -1 A new peak appears at this point, corresponding to the characteristic framework vibration of the ion eutectic system, further confirming the formation of the new structure.

[0039] To better illustrate the beneficial effects of this invention, the pharmacodynamics of the traditional Chinese medicine ion-co-melting delivery gel is verified below: 1. Cell scratch healing experiment Log-phase human umbilical vein endothelial cells (HUVECs) were collected and a cell injury model was constructed using 33 mmol / L high-glucose medium. Cells were randomly divided into groups 1-4 (Examples 1-4) and a high-glucose control group, with each group receiving corresponding interventions. Uniform scratches were created on the cell monolayer using a sterile pipette tip, and the scratch healing process was recorded at 0h, 4h, 8h, and 12h to assess cell migration ability.

[0040] See Figure 2 In the upper half of the results, it was found that the cell migration ability of the high glucose control group was significantly inhibited, and there were still obvious gaps in the scratches after 12 hours. The cell migration speed of groups 1-4 of the present invention was significantly faster than that of the high glucose control group, and the scratch area was significantly reduced after 12 hours. Among them, group 4 of the present invention had the best healing effect, and the scratches were basically filled with cells. This indicates that the herbal ion co-melting gel of the present invention can effectively improve cell migration function under high glucose injury and provide a cellular basis for the healing of diabetic foot wounds.

[0041] 2. Detection of the microenvironment in the paw tissue of diabetic mice SPF-grade Kunming mice were used to establish a diabetic model by intraperitoneal injection of streptozotocin (STZ). After successful modeling, mice were randomly divided into groups 1-4 (Examples 1-4) and a high-glucose control group. The corresponding preparation was applied topically to the paws of mice in each group once daily for 14 consecutive days. After the administration period, paw tissue was collected from the mice, and immunofluorescence staining and immunohistochemical staining were used to detect the expression of relevant indicators. PGP9.5 immunofluorescence staining: to label peripheral nerve fibers and assess nerve regeneration; VEGF immunofluorescence staining: labeling vascular endothelial growth factor to assess angiogenesis; Immunohistochemical staining of AGEs: labeling advanced glycation end products and assessing the improvement of damage to the high-glycemic microenvironment.

[0042] See results Figure 2 The detailed analysis of the lower half is as follows: 2.1 Neuroregeneration-related indicators (PGP 9.5) In the high-glucose control group, the PGP9.5 fluorescence signal in the foot tissue was weak and scattered, indicating significant peripheral nerve damage in diabetic mice. The PGP9.5 fluorescence signal in groups 1-4 was significantly enhanced and more continuous, with the signal expression in group 4 being the most prominent. This indicates that the preparation of the present invention can effectively promote foot nerve regeneration and repair peripheral neuropathy in diabetic mice.

[0043] 2.2 Angiogenesis-related markers (VEGF) In the high-glucose control group, the red fluorescence of VEGF in the foot tissue was sparse, indicating that the local angiogenesis capacity was low and the ischemic and hypoxic state was significant. In the groups of Examples 1-4, the VEGF fluorescence signal was significantly increased and more widely distributed, indicating that the preparation of the present invention can promote microvascular formation in the foot, improve local microcirculation, and alleviate the pathological state of ischemia and hypoxia.

[0044] 2.3 Advanced Glucose End-Stage Morphology (AGEs) In the high-sugar control group, the foot tissue showed the deepest brown staining from immunohistochemical staining, indicating that AGEs accumulate in large quantities under high-sugar conditions, which is the core cause of tissue damage in diabetes. The brown staining intensity was significantly reduced in groups 1-4, with group 4 showing the lightest staining, indicating that the formulation of the present invention can effectively reduce the generation of AGEs and improve tissue damage induced by the high-sugar microenvironment.

[0045] As can be seen, this experiment verified the efficacy of the herbal ion eutectic delivery gel of this invention from two aspects: cell migration function and tissue microenvironment repair. First, it can significantly enhance the migration ability of cells damaged by high glucose and promote wound healing. Second, it can effectively promote nerve regeneration and angiogenesis in the foot of diabetic mice and simultaneously improve neuropathy and ischemia-hypoxia. Third, it can reduce the accumulation of AGEs and alleviate high glucose-induced tissue damage, providing reliable experimental evidence for its application in the prevention and treatment of diabetic foot ulcers.

[0046] In summary, the herbal ionopolymer delivery agent prepared in this invention provides multi-dimensional intervention against the complex pathological microenvironment of diabetic foot, including microcirculatory disorders, local hyperglycemia, inflammation, and oxidative stress. Specifically, safflower (Carthamus tinctorius) invigorates blood circulation, relieves pain, and disperses blood stasis; kudzu root (Pueraria lobata) and salvia miltiorrhiza (Salvia miltiorrhiza) lower blood sugar and reduce inflammation. The ionopolymer delivery agent is an ionic liquid composed of vitamin B1 and lipoic acid, utilizing its high permeability and antioxidant properties to jointly prevent diabetic foot.

[0047] The above content is only for illustrating the technical concept of the present invention and should not be construed as limiting the scope of protection of the present invention. Any modifications made to the technical solution based on the technical concept proposed in this invention shall fall within the scope of protection of the claims of this invention.

Claims

1. A traditional Chinese medicine ionopolymer delivery agent, characterized in that, Including vitamin B1 The alpha-lipoic acid ion eutectic, safflower, kudzu root, and salvia miltiorrhiza; wherein, the vitamin B1 The mass ratio of the thioctic acid ion eutectic, safflower, kudzu root and salvia miltiorrhiza is 4:(1-2):(2-4):(2-4).

2. The traditional Chinese medicine ionopolymer delivery agent according to claim 1, characterized in that, The vitamin B1 The molar ratio of vitamin B1 to lipoic acid in the lipoic acid ion eutectic is 1:1 to 3:

1.

3. A traditional Chinese medicine ion-co-melting delivery gel, characterized in that, It includes a gel matrix, a preservative, and the traditional Chinese medicine ion eutectic delivery agent as described in claim 1; wherein the mass ratio of the gel matrix, the preservative, and the traditional Chinese medicine ion eutectic delivery agent is 4:4:(0.45-0.7).

4. The herbal ion-co-melting delivery gel according to claim 3, characterized in that, The gel matrix is ​​made of carbomer, sodium carboxymethyl cellulose, chitosan, sodium alginate, xanthan gum, or gelatin; the preservative is made of ethylparaben, propylparaben, methylparaben, or potassium sorbate.

5. The method for preparing the traditional Chinese medicine ion-co-melting delivery gel according to claim 3 or 4, characterized in that, include: The gel matrix was dissolved in water to prepare the gel matrix system; The preservative system was prepared by dissolving the preservative in anhydrous ethanol. The preservative system was added to the gel matrix system and mixed thoroughly to obtain the preservative-gel system. The traditional Chinese medicine ion eutectic delivery agent was dissolved in water, then added to the preservative-gel system, and stirred until homogeneous to obtain the traditional Chinese medicine ion eutectic delivery gel.

6. The method for preparing the traditional Chinese medicine ion-co-melting delivery gel according to claim 5, characterized in that, The preparation of the traditional Chinese medicine ionopolymer delivery agent includes: Vitamin B1 and lipoic acid were dissolved in anhydrous ethanol to obtain vitamin B1 ethanol solution and lipoic acid ethanol solution, respectively. Dissolve potassium hydroxide in anhydrous ethanol at a molar ratio of 1:1 with lipoic acid to obtain a potassium hydroxide ethanol solution. Add potassium hydroxide ethanol solution dropwise to thioctic acid ethanol solution and react for 30-180 minutes to obtain the reaction solution; Add an ethanolic solution of vitamin B1 to the reaction solution, react for 2-24 hours, centrifuge, collect the supernatant, and dry to obtain vitamin B1. Thioctanoic acid ion eutectic; Vitamin B1 A traditional Chinese medicine ion eutectic agent is prepared by dissolving thioctic acid ion eutectic and traditional Chinese medicine ions in water.

7. The method for preparing the traditional Chinese medicine ion eutectic delivery gel according to claim 6, characterized in that, The centrifugation speed is 1500 r / min and the time is 5 min; the drying is carried out by vacuum drying for 24-72 h.

8. The method for preparing the traditional Chinese medicine ion-co-melting delivery gel according to claim 5, characterized in that, The gel matrix is ​​dissolved in water using ultrasonic-assisted dissolution and heated to 50-90℃ to obtain the gel matrix system.

9. The use of the traditional Chinese medicine ion eutectic delivery agent according to claim 1 or 2, and the traditional Chinese medicine ion eutectic delivery gel according to claim 3 or 4, in the preparation of medicaments for the treatment and / or prevention of diabetic foot ulcers.

10. A topical medication for treating and / or preventing diabetic foot ulcers, characterized in that, It is made from the traditional Chinese medicine ion eutectic delivery agent as described in claim 1 or 2, or the traditional Chinese medicine ion eutectic delivery gel as described in claim 3 or 4, with or without pharmaceutically acceptable excipients.

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