An oral spray for treating oral candidiasis and a method of preparing the same

Abstract

The application discloses an oral spray for treating oral candida and a preparation method thereof, and relates to the technical field of treating oral candida. The oral spray for treating oral candida is composed of drug-loaded nanoparticles with magnetic and active oxygen dual responsiveness, a modified carbon nanotube hydrogel carrier, xylitol, sodium citrate, PEG-60 hydrogenated castor oil and deionized water. The drug-loaded nanoparticles with magnetic and active oxygen dual responsiveness are attached to the modified carbon nanotube hydrogel carrier, forming a double-drug material based on the modified carbon nanotube gel composite nanoparticles, improving the drug loading capacity, and being able to recognize the mucosa site parasitized by candida with high targetability in a magnetic and active oxygen dual responsive manner, and effectively combining with the mucosa site parasitized by candida. Meanwhile, the loaded drug components are slowly released at the infected mucosa site, so that the antibacterial property is synergistically exerted through chemical action and physical action, and the effectiveness of treating oral candida is improved.

Description

Technical Field

[0001] This invention belongs to the field of oral candidiasis treatment technology, specifically referring to an oral spray for treating oral candidiasis and its preparation method. Background Technology

[0002] Oral candidiasis, also known as fungal stomatitis, oral thrush, or thrush, is an infectious fungal disease of the oral mucosa. It is characterized by extensive damage to the papillae on the dorsum of the tongue, the appearance of a white pseudomembrane on the surface of the tongue mucosa, dry mouth, pain, and decreased taste. Candida albicans is the most common pathogen of oral candidiasis, mainly parasitizing the surface of the oral mucosa. The excessive proliferation of Candida albicans leads to oral mucosal infection, which not only significantly reduces people's quality of life and health index, but also increases the risk of oral mucosal cancer.

[0003] Antifungal drugs suitable for treating oral candidiasis include azoles (such as itraconazole, voriconazole, and fluconazole), polyenes (such as nystatin and amphotericin B), and pyrimidines (such as flucytosine). However, in clinical practice, long-term use of azoles and polyenes has led to increased resistance of strains to these drugs, rendering treatment ineffective. Given the limited availability of drugs for treating oral candidiasis and the increased virulence of drug-resistant strains, the immune systems of patients with oral candidiasis face severe challenges. Therefore, there is an urgent need to develop new antifungal drugs. Traditional Chinese medicine contains abundant bioactive substances. Whether in herbal formulas, as monomers, or as active ingredients, traditional Chinese medicine has shown good therapeutic effects in treating fungal diseases. Due to its advantages such as low cost, diversity, good efficacy, and internal regulation of the body, traditional Chinese medicine is widely favored and has become an urgent need in the treatment of oral candidiasis.

[0004] The existing technology currently has the following main problems:

[0005] Due to the unique physiological characteristics of the oral cavity, drugs are easily diluted and quickly cleared, making it difficult for them to bind to the mucosal sites where Candida resides. As a result, the bioavailability of the drugs is low, thus failing to exert an effective antibacterial therapeutic effect. Summary of the Invention

[0006] In view of the above situation and to overcome the defects of the prior art, the present invention proposes an oral spray for treating oral candidiasis, comprising the following components in parts by weight: 50-60 parts of drug-loaded nanoparticles with dual magnetic and reactive oxygen species responsiveness, 20-30 parts of modified carbon nanotube hydrogel carrier, 3-5 parts of xylitol, 3-5 parts of sodium citrate, 5-8 parts of PEG-60 hydrogenated castor oil, and 8-10 parts of deionized water.

[0007] The drug-loaded nanoparticles, which are both magnetic and reactive oxygen species responsive, comprise the following components in parts by weight: 40-60 parts reactive oxygen species responsive hyaluronic acid, 5-10 parts iron oxide, and 5-10 parts traditional Chinese medicine composition.

[0008] The modified carbon nanotube hydrogel carrier comprises the following components in parts by weight: 3-5 parts berberine, 8-10 parts amino multi-walled carbon nanotubes, 10-20 parts sodium alginate, and 20-30 parts calcium chloride.

[0009] The traditional Chinese medicine composition comprises the following components in parts by weight: Astragalus membranaceus 3-5 parts, Gardenia jasminoides 3-5 parts, Cimicifuga foetida 3-5 parts, Mentha haplocalyx 3-5 parts, Zingiber officinale 3-5 parts, and Glycyrrhiza uralensis 3-5 parts.

[0010] The method for preparing the drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness specifically includes the following steps:

[0011] (1) 4 mmol of 4-hydroxyphenylboronic acid pinacol and 8 mmol of N,N′-carbonyldiimidazole were dissolved in 5 mL of dichloromethane. The two solutions were then mixed in a 50 mL round-bottom flask and stirred in an oil bath at 30-40 °C for 0.5-1 h. The reaction product was washed three times with ultrapure water and then extracted with physiological saline. The intermediate substance was obtained by rotary evaporation. 6 mmol of the intermediate substance and 1 mmol of hyaluronic acid were added to 20 mL of dimethyl sulfoxide. Then 7 mmol of 4-dimethylaminopyridine was added. The mixture was first sonicated for 30-50 min and then stirred in an oil bath at 30-40 °C for 12 h. The mixture was then dialyzed and lyophilized. By grafting 4-hydroxyphenylboronic acid pinacol onto the main framework of hyaluronic acid, a material with reactive oxygen species responsiveness was prepared. It can be attracted by the high concentration of reactive oxygen species at the site of Candida infection and retained nearby without reacting with normal cells. This improved the specificity and effectiveness of oral Candida treatment and yielded reactive oxygen species responsive hyaluronic acid.

[0012] (2) After drying and pre-treatment, Astragalus membranaceus, Gardenia jasminoides, Cimicifuga foetida, Mentha haplocalyx, Zingiber officinale and Glycyrrhiza uralensis are pulverized and mixed evenly. 500g of Chinese medicine powder is placed in 6-8 times the amount of 80% ethanol solution and soaked overnight. Then, it is heated and extracted 1-3 times in a reflux condenser and rotary evaporator. The extracts are combined, filtered, and the total extract is concentrated under reduced pressure. The concentrate is centrifuged at high speed and spray-dried. Astragalus membranaceus is the chief ingredient to clear heat and dry dampness, purge fire and detoxify. Gardenia jasminoides is the assistant ingredient to clear and drain the fire of the three jiaos. Cimicifuga foetida and Mentha haplocalyx are added to help the clear qi of spleen yang rise and disperse the fire of the upper jiao. Finally, Zingiber officinale and Glycyrrhiza uralensis are added to warm the middle and harmonize. The combination of these medicines effectively improves the therapeutic effect of oral candidiasis and has fewer adverse reactions, thus obtaining a Chinese medicine composition.

[0013] (3) Weigh 5-10 mg of the traditional Chinese medicine composition described in step (2) and dissolve it in 5-10 mL of dimethyl sulfoxide. Then add iron(III) oxide and the reactive oxygen species-responsive hyaluronic acid described in step (1), sonicate for 1-2 hours, and then put the solution into a dialysis bag with a molecular weight of 3000 Da for dialysis. Change the aqueous solution every 2 hours and dialyze for 5-6 hours. Then freeze-dry. Through this process, a substance with a structure similar to "liposomes" is formed, which has a magnetic and reactive oxygen species dual-responsive release system and also has a certain degree of adhesion. Reactive oxygen species-responsive hyaluronic acid The outer shell is hydrophilic, and the inner core is ferric oxide. Loaded with a traditional Chinese medicine composition, it can release drug components in response to the mucosal sites of Candida parasitism, reduce the ineffective loss of drug components, effectively increase the drug concentration at the site of mucosal infection, thereby improving drug utilization and enhancing the effectiveness of treatment. Hyaluronic acid is coated on the surface of ferric oxide particles, which improves the stability of ferric oxide, reduces the risk of aggregation and easy oxidation, and further enhances the drug release targeting and drug loading capacity of ferric oxide, resulting in drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness.

[0014] Preferably, in step (3), the amount of ferric oxide added is 5-10 mg. Ferric oxide has good magnetic responsiveness and biocompatibility. When used as a drug carrier material, it can be directed to accumulate at the site of Candida infection to enhance the drug delivery effect. Furthermore, ferric oxide can also inhibit and kill Candida through its peroxidase activity.

[0015] This invention also provides a method for preparing an oral spray for treating oral candidiasis, specifically including the following steps:

[0016] S1. Disperse 0.8-1.0 g of amino-multi-walled carbon nanotubes in 100 mL of 1% poloxamer aqueous solution, sonicate for 10-30 min, add berberine, and continue sonication for 1-2 h. The sonication allows more berberine to be adsorbed and loaded onto the amino-multi-walled carbon nanotubes. Based on the carbon nanotube delivery system, it not only has good biocompatibility, but also significantly increases the drug loading, which is more conducive to exerting the antibacterial effect of berberine. At the same time, the hollow tubular structure of the amino-multi-walled carbon nanotubes can also destroy the bacterial cell wall through mechanical physical action, and play a synergistic antibacterial role with berberine, thus obtaining an amino-multi-walled carbon nanotube dispersion loaded with berberine.

[0017] S2. Dissolve 1.0-2.0g of sodium alginate in 100mL of distilled water and stir magnetically for 1-2 hours. Then add the berberine-loaded amino multi-walled carbon nanotube dispersion described in step S1 and continue stirring magnetically for 4-6 hours. Use a portable electrospray device to spray the composite solution into 100mL of 2-3% calcium chloride solution and let it stand for 6-8 hours to ensure complete gelation. Rinse the gel composite product with distilled water 3-5 times to remove excess calcium ions. The cross-linking effect of sodium alginate and calcium chloride forms a three-dimensional network structure on the surface of the berberine-loaded amino multi-walled carbon nanotubes, providing more adsorption sites, exhibiting good sustained-release properties, and increasing adhesion to mucous membranes. This effectively reduces drug clearance and migration, enhances binding to Candida infection sites, and thus helps improve the efficiency and sustainability of treatment, resulting in a modified carbon nanotube hydrogel carrier.

[0018] S3. Add drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness to the modified carbon nanotube hydrogel carrier described in step S2, stir magnetically for 30-40 min, and then sonicate for 3-4 h. Wash the obtained product with distilled water 3-5 times, and then freeze-dry. Freeze-drying technology can better preserve the original structure and properties of the product. By attaching drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness to the network structure of the modified carbon nanotube hydrogel carrier, a composite delivery system is formed, which significantly increases the drug loading and drug loading stability. It has high targeting of magnetic and reactive oxygen species responsive release, can enhance adhesion and binding to mucous membranes, and can slowly release the drug substances in it at the site of infection, exerting a long-lasting and efficient antibacterial effect, significantly improving the treatment efficacy of Candida, and obtaining a dual-drug-loaded material based on modified carbon nanotube gel composite nanoparticles.

[0019] S4. Stir the dual-drug-loaded material based on modified carbon nanotube gel composite nanoparticles, PEG-60 hydrogenated castor oil, and deionized water as described in step S3 until homogeneous. PEG-60 hydrogenated castor oil, as an efficient solubilizer, helps to uniformly disperse the dual-drug-loaded material based on modified carbon nanotube gel composite nanoparticles in deionized water. Then add xylitol and sodium citrate. Xylitol acts as a sweetener, and sodium citrate can adjust the pH, improve the stability of the drug system, and also play a role in cleaning the mouth, anti-inflammatory, and analgesic. After mixing evenly and fully dissolving, fill the container to obtain an oral spray for treating oral candidiasis.

[0020] Preferably, in step S1, the amount of berberine added is 0.3-0.5g. Berberine can destroy the cell wall structure of Candida and weaken the virulence of Candida.

[0021] The beneficial effects achieved by this invention are as follows:

[0022] This invention forms a dual-drug-loaded material based on modified carbon nanotube gel composite nanoparticles by attaching drug-loaded nanoparticles with both magnetic and reactive oxygen species (ROS) responsiveness to the modified carbon nanotube hydrogel carrier. This significantly improves drug loading and enables highly targeted recognition and effective binding of Candida albicans to mucosal sites with both magnetic and ROS responsiveness, reducing drug loss. Simultaneously, the dual-drug-loaded material slowly releases the loaded drug at the infected mucosal site, exerting antibacterial activity through synergistic chemical and physical effects, prolonging the antibacterial duration, and improving the effectiveness of treating oral Candida albicans. It exhibits specific, efficient, and long-lasting therapeutic effects; the drug-loaded nanoparticles, which possess both magnetic and reactive oxygen species responsiveness, use reactive oxygen species-responsive hyaluronic acid as a hydrophilic shell and magnetic iron oxide as a hydrophobic core to encapsulate the traditional Chinese medicine composition, forming nanoparticles with a "liposome"-like structure. This improves the drug loading capacity and stability, enabling dual-response release of drug components at the mucosal sites of Candida parasitism. They also possess a certain degree of adhesion, increasing the drug concentration at the mucosal infection site, thereby improving drug utilization and enhancing the effectiveness of treatment; in the modified carbon nanotube hydrogel carrier, berberine is first... Adsorption and encapsulation on amino-walled carbon nanotubes endow them with both chemical and physical bactericidal effects, while also addressing the issues of poor absorption and short duration of action of berberine. Furthermore, crosslinking sodium alginate and calcium chloride onto the surface of the berberine-loaded amino-walled carbon nanotubes forms an adhesive three-dimensional network structure with excellent adsorption and sustained-release properties. This facilitates the better adhesion of drug-loaded nanoparticles with both magnetic and reactive oxygen species responses to the modified carbon nanotube hydrogel carrier network structure. The modified carbon nanotube hydrogel carrier reduces the aggregation of drug-loaded nanoparticles, thus enhancing their adsorption capacity. The modified carbon nanotube hydrogel carrier has high targeting ability, and the two work synergistically to give full play to the chemical and physical antibacterial effects, effectively reducing the growth and reproduction of oral Candida, exerting a long-lasting and efficient therapeutic effect, and significantly improving the treatment effectiveness of oral Candida. The present invention uses drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness, modified carbon nanotube hydrogel carrier, xylitol, sodium citrate, PEG-60 hydrogenated castor oil and deionized water to make an oral spray for treating oral Candida, which can target and release the loaded drug components, and has a highly efficient and long-lasting therapeutic effect. Attached Figure Description

[0023] Figure 1 The figures show the drug loading results of Examples 1-4 and Comparative Examples 1-3 of the present invention;

[0024] Figure 2 The graph shows the sterilization rate results under different conditions in Examples 1-4 and Comparative Examples 1-3 of the present invention;

[0025] Figure 3 The graph shows the sterilization rate results of different contact times in Examples 1-4 and Comparative Examples 1-3 of the present invention.

[0026] Figure 4 The graph shows the treatment efficacy results of Examples 1-4 and Comparative Examples 1-3 of the present invention. Detailed Implementation

[0027] 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. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to this invention. The preferred embodiments and materials described herein are for illustrative purposes only and do not limit the scope of this application.

[0029] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods; unless otherwise specified, the experimental materials used in the following embodiments are all purchased from commercial channels.

[0030] Example 1

[0031] This embodiment proposes an oral spray for treating oral candidiasis, comprising the following components in parts by weight: 60 parts of drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness, 30 parts of modified carbon nanotube hydrogel carrier, 5 parts of xylitol, 5 parts of sodium citrate, 8 parts of PEG-60 hydrogenated castor oil, and 10 parts of deionized water.

[0032] The drug-loaded nanoparticles, which possess both magnetic and reactive oxygen species responsiveness, comprise the following components in parts by weight: 60 parts reactive oxygen species responsive hyaluronic acid, 10 parts iron oxide, and 10 parts traditional Chinese medicine composition.

[0033] The modified carbon nanotube hydrogel carrier comprises the following components in parts by weight: 5 parts berberine, 10 parts amino multi-walled carbon nanotubes, 20 parts sodium alginate, and 30 parts calcium chloride.

[0034] The traditional Chinese medicine composition comprises the following components in parts by weight: Astragalus membranaceus 5 parts, Gardenia jasminoides 5 parts, Cimicifuga foetida 5 parts, Mentha haplocalyx 5 parts, Zingiber officinale 5 parts, and Glycyrrhiza uralensis 5 parts.

[0035] The preparation method of drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness specifically includes the following steps:

[0036] (1) 4 mmol of 4-hydroxyphenylboronic acid pinacol and 8 mmol of N,N′-carbonyldiimidazole were dissolved in 5 mL of dichloromethane. The two solutions were then mixed in a 50 mL round-bottom flask and stirred in an oil bath at 40 °C for 1 h. The reaction product was washed three times with ultrapure water and then extracted with physiological saline. The intermediate substance was obtained by rotary evaporation. 6 mmol of the intermediate substance and 1 mmol of hyaluronic acid were added to 20 mL of dimethyl sulfoxide. Then 7 mmol of 4-dimethylaminopyridine was added. The mixture was first sonicated for 50 min and then stirred in an oil bath at 40 °C for 12 h. The mixture was then dialyzed and lyophilized. By grafting 4-hydroxyphenylboronic acid pinacol onto the main framework of hyaluronic acid, a material with reactive oxygen species responsiveness was prepared. It can be attracted by the high concentration of reactive oxygen species at the site of Candida infection and retained nearby without reacting with normal cells. This improved the specificity and effectiveness of oral Candida treatment and yielded reactive oxygen species responsive hyaluronic acid.

[0037] (2) After drying and pre-treatment, Astragalus membranaceus, Gardenia jasminoides, Cimicifuga foetida, Mentha haplocalyx, Zingiber officinale and Glycyrrhiza uralensis were pulverized and mixed evenly. 500g of Chinese medicine powder was placed in 8 times the amount of 80% ethanol solution and soaked overnight. Then, it was heated and extracted 3 times in a reflux condenser and a rotary evaporator. The extracts were combined, filtered, and the total extract was concentrated under reduced pressure. The concentrate was centrifuged at high speed and spray-dried. Astragalus membranaceus was used as the chief ingredient to clear heat and dry dampness, purge fire and detoxify. Gardenia jasminoides was used as the assistant ingredient to clear and drain the fire in the three jiaos. Cimicifuga foetida and Mentha haplocalyx were added to help the clear qi of spleen yang rise and disperse the fire in the upper jiao. Finally, Zingiber officinale and Glycyrrhiza uralensis were added to warm and harmonize the middle jiao. The combination of these drugs effectively improved the therapeutic effect of oral candidiasis and had fewer adverse reactions. The Chinese medicine composition was obtained.

[0038] (3) Weigh 10 mg of the traditional Chinese medicine composition described in step (2) and dissolve it in 10 mL of dimethyl sulfoxide. Then add iron oxide and the reactive oxygen species-responsive hyaluronic acid described in step (1). Sonicate for 2 h. The amount of iron oxide added is 10 mg. Iron oxide has good magnetic responsiveness and biocompatibility. It can be used as a drug carrier material. It can be directed to accumulate at the site of Candida infection to enhance the drug delivery effect. In addition, iron oxide can also inhibit and kill Candida with its peroxidase activity. Then put the solution into a dialysis bag with a molecular weight of 3000 Da for dialysis. Change the aqueous solution every 2 h. Dialyze for 6 h and then freeze dry. Through this process, a kind of "lipid" is formed. This material has a "plastic" structure and possesses a dual-responsive release system of magnetism and reactive oxygen species (ROS). It also exhibits a certain degree of adhesion. The ROS-responsive hyaluronic acid forms the hydrophilic outer shell, while the iron oxide (Fe3O4) forms the hydrophobic core. Loaded with a traditional Chinese medicine composition, it can responsively release drug components at the mucosal sites of Candida parasitism, reducing ineffective loss of drug components and effectively increasing the drug concentration at the site of mucosal infection, thereby improving drug utilization and enhancing the effectiveness of treatment. The hyaluronic acid coating on the surface of the iron oxide particles improves the stability of the iron oxide, reduces the risk of aggregation and easy oxidation, and further enhances the drug release targeting and drug loading capacity of the iron oxide, resulting in drug-loaded nanoparticles with both magnetic and ROS dual-responsive properties.

[0039] This embodiment provides a method for preparing an oral spray for treating oral candidiasis, specifically including the following steps:

[0040] S1. 1.0 g of amino-multi-walled carbon nanotubes were dispersed in 100 mL of 1% poloxamer aqueous solution and sonicated for 30 min. Berberine was added and sonicated for another 2 h. The amount of berberine added was 0.5 g. Berberine can destroy the cell wall structure of Candida albicans and weaken its virulence. The sonication treatment allows more berberine to be adsorbed and loaded onto the amino-multi-walled carbon nanotubes. Based on the carbon nanotube delivery system, it not only has good biocompatibility, but also significantly increases the drug loading, which is more conducive to the antibacterial effect of berberine. At the same time, the hollow tubular structure of amino-multi-walled carbon nanotubes can also destroy the bacterial cell wall through mechanical physical action, and play a synergistic antibacterial role with berberine, thus obtaining an amino-multi-walled carbon nanotube dispersion loaded with berberine.

[0041] S2. Dissolve 2.0g of sodium alginate in 100mL of distilled water and stir magnetically for 2h. Then add the berberine-loaded amino multi-walled carbon nanotube dispersion described in step S1 and continue stirring magnetically for 6h. Use a portable electrospray device to spray the composite solution into 100mL of 3% calcium chloride solution and let it stand for 8h to ensure complete gelation. Rinse the gel composite product 5 times with distilled water to remove excess calcium ions. The cross-linking effect of sodium alginate and calcium chloride forms a three-dimensional network structure on the surface of the berberine-loaded amino multi-walled carbon nanotubes, providing more adsorption sites, exhibiting good sustained-release properties, and increasing adhesion to mucous membranes. This effectively reduces drug clearance and migration, enhances binding to Candida infection sites, and thus helps improve the efficiency and sustainability of treatment, resulting in a modified carbon nanotube hydrogel carrier.

[0042] S3. Add drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness to the modified carbon nanotube hydrogel carrier described in step S2, stir magnetically for 40 min, and then sonicate for 4 h. Wash the obtained product five times with distilled water and then freeze-dry. Freeze-drying technology can better preserve the original structure and properties of the product. By attaching drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness to the network structure of the modified carbon nanotube hydrogel carrier, a composite delivery system is formed, which significantly increases the drug loading and drug loading stability. It has high targeting of magnetic and reactive oxygen species responsive release, can enhance adhesion and binding to mucous membranes, and can slowly release the drug substances in it at the site of infection, exerting a long-lasting and efficient antibacterial effect, significantly improving the treatment efficacy of Candida, and obtaining a dual-drug-loaded material based on modified carbon nanotube gel composite nanoparticles.

[0043] S4. Stir the dual-drug-loaded material based on modified carbon nanotube gel composite nanoparticles, PEG-60 hydrogenated castor oil, and deionized water as described in step S3 until homogeneous. PEG-60 hydrogenated castor oil, as a highly efficient solubilizer, helps to uniformly disperse the dual-drug-loaded material based on modified carbon nanotube gel composite nanoparticles in deionized water. Then add xylitol and sodium citrate. Xylitol acts as a sweetener, and sodium citrate can adjust the pH, improve the stability of the drug system, and also play a role in cleaning the mouth, anti-inflammation, and analgesia. After mixing evenly and fully dissolving, fill the container to obtain an oral spray for treating oral candidiasis.

[0044] Example 2

[0045] This embodiment proposes an oral spray for treating oral candidiasis, comprising the following components in parts by weight: 50 parts of drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness, 20 parts of modified carbon nanotube hydrogel carrier, 3 parts of xylitol, 3 parts of sodium citrate, 5 parts of PEG-60 hydrogenated castor oil, and 8 parts of deionized water.

[0046] The drug-loaded nanoparticles, which possess both magnetic and reactive oxygen species responsiveness, comprise the following components in parts by weight: 40 parts reactive oxygen species responsive hyaluronic acid, 5 parts iron oxide, and 5 parts traditional Chinese medicine composition.

[0047] The modified carbon nanotube hydrogel carrier comprises the following components in parts by weight: 3 parts berberine, 8 parts amino multi-walled carbon nanotubes, 10 parts sodium alginate, and 20 parts calcium chloride.

[0048] The traditional Chinese medicine composition comprises the following components in parts by weight: Astragalus membranaceus 3 parts, Gardenia jasminoides 3 parts, Cimicifuga foetida 3 parts, Mentha haplocalyx 3 parts, Zingiber officinale 3 parts, and Glycyrrhiza uralensis 3 parts.

[0049] The preparation method of drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness specifically includes the following steps:

[0050] (1) 4 mmol of 4-hydroxyphenylboronic acid pinacol and 8 mmol of N,N′-carbonyldiimidazole were dissolved in 5 mL of dichloromethane. The two solutions were then mixed in a 50 mL round-bottom flask and stirred in an oil bath at 30 °C for 0.5 h. The reaction product was washed three times with ultrapure water and then extracted with physiological saline. The intermediate substance was obtained by rotary evaporation. 6 mmol of the intermediate substance and 1 mmol of hyaluronic acid were added to 20 mL of dimethyl sulfoxide. Then 7 mmol of 4-dimethylaminopyridine was added. The mixture was first sonicated for 30 min and then stirred in an oil bath at 30 °C for 12 h. The mixture was then dialyzed and lyophilized. By grafting 4-hydroxyphenylboronic acid pinacol onto the main framework of hyaluronic acid, a material with reactive oxygen species responsiveness was prepared. It can be attracted by the high concentration of reactive oxygen species at the site of Candida infection and retained nearby without reacting with normal cells. This improved the specificity and effectiveness of oral Candida treatment and yielded reactive oxygen species responsive hyaluronic acid.

[0051] (2) After drying and pre-treatment, Astragalus membranaceus, Gardenia jasminoides, Cimicifuga foetida, Mentha haplocalyx, Zingiber officinale and Glycyrrhiza uralensis were pulverized and mixed evenly. 500g of Chinese medicine powder was placed in 6 times the amount of 80% ethanol solution and soaked overnight. Then, it was heated and extracted once in a reflux condenser and rotary evaporator. The extracts were combined, filtered, and the total extract was concentrated under reduced pressure. The concentrate was centrifuged at high speed and spray-dried. Astragalus membranaceus was used as the chief ingredient to clear heat and dry dampness, purge fire and detoxify. Gardenia jasminoides was used as the assistant ingredient to clear and drain the fire in the three jiaos. Cimicifuga foetida and Mentha haplocalyx were added to help the clear qi of spleen yang rise and disperse the fire in the upper jiao. Finally, Zingiber officinale and Glycyrrhiza uralensis were added to warm and harmonize the middle jiao. The combination of these medicines effectively improved the therapeutic effect of oral candidiasis and had fewer adverse reactions. The Chinese medicine composition was obtained.

[0052] (3) Weigh 5 mg of the traditional Chinese medicine composition described in step (2) and dissolve it in 5 mL of dimethyl sulfoxide. Then add iron(III) oxide and the reactive oxygen species-responsive hyaluronic acid described in step (1). Sonicate for 1 h. The amount of iron(III) oxide added is 5 mg. Iron(III) oxide has good magnetic responsiveness and biocompatibility. It can be used as a drug carrier material. It can be directed to accumulate at the site of Candida infection to enhance the drug delivery effect. In addition, iron(III) oxide can also inhibit and kill Candida through its peroxidase activity. Then put the solution into a dialysis bag with a molecular weight of 3000 Da for dialysis. Change the aqueous solution every 2 h. Dialyze for 5 h and then freeze dry. Through this process, a liposome-like substance is formed. This material, with its magnetic and reactive oxygen species (ROS) dual-responsive release system, also possesses a certain degree of adhesion. The ROS-responsive hyaluronic acid forms the hydrophilic outer shell, while the iron oxide (Fe3O4) forms the hydrophobic core. Loaded with a traditional Chinese medicine composition, it can responsively release drug components at the mucosal sites of Candida parasitism, reducing ineffective drug loss and effectively increasing drug concentration at the mucosal infection site, thereby improving drug utilization and enhancing treatment effectiveness. The hyaluronic acid coating on the surface of the iron oxide particles improves the stability of the iron oxide, reducing the risk of aggregation and easy oxidation, and further enhances the drug release targeting and drug loading capacity of the iron oxide, resulting in drug-loaded nanoparticles with both magnetic and ROS dual-responsive properties.

[0053] This embodiment provides a method for preparing an oral spray for treating oral candidiasis, specifically including the following steps:

[0054] S1. 0.8 g of amino-multi-walled carbon nanotubes were dispersed in 100 mL of 1% poloxamer aqueous solution and sonicated for 10 min. Berberine was added and sonicated for another 1 h. The amount of berberine added was 0.3 g. Berberine can destroy the cell wall structure of Candida albicans and weaken its virulence. The sonication treatment allows more berberine to be adsorbed and loaded onto the amino-multi-walled carbon nanotubes. Based on the carbon nanotube delivery system, it not only has good biocompatibility, but also significantly increases the drug loading, which is more conducive to the antibacterial effect of berberine. At the same time, the hollow tubular structure of amino-multi-walled carbon nanotubes can also destroy the bacterial cell wall through mechanical physical action, and play a synergistic antibacterial role with berberine, thus obtaining an amino-multi-walled carbon nanotube dispersion loaded with berberine.

[0055] S2. Dissolve 1.0g sodium alginate in 100mL distilled water and stir magnetically for 1h. Then add the berberine-loaded amino multi-walled carbon nanotube dispersion described in step S1 and continue stirring magnetically for 4h. Use a portable electrospray device to spray the composite solution into 100mL of 2% calcium chloride solution and let it stand for 6h to ensure complete gelation. Rinse the gel composite product three times with distilled water to remove excess calcium ions. The cross-linking effect of sodium alginate and calcium chloride forms a three-dimensional network structure on the surface of the berberine-loaded amino multi-walled carbon nanotubes, providing more adsorption sites, exhibiting good sustained-release properties, and increasing adhesion to mucous membranes. This effectively reduces drug clearance and migration, enhances binding to Candida infection sites, and thus helps improve the efficiency and sustainability of treatment, resulting in a modified carbon nanotube hydrogel carrier.

[0056] S3. Add drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness to the modified carbon nanotube hydrogel carrier described in step S2, stir magnetically for 30 min, and then sonicate for 3 h. Wash the obtained product three times with distilled water and then freeze-dry. Freeze-drying technology can better preserve the original structure and properties of the product. By attaching drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness to the network structure of the modified carbon nanotube hydrogel carrier, a composite delivery system is formed, which significantly increases the drug loading and drug loading stability. It has high targeting of magnetic and reactive oxygen species responsive release, can enhance adhesion and binding to the mucosa, and can slowly release the drug substances in it at the site of infection, exerting a long-lasting and efficient antibacterial effect, significantly improving the treatment efficacy of Candida, and obtaining a dual-drug-loaded material based on modified carbon nanotube gel composite nanoparticles.

[0057] S4. Stir the dual-drug-loaded material based on modified carbon nanotube gel composite nanoparticles, PEG-60 hydrogenated castor oil, and deionized water as described in step S3 until homogeneous. PEG-60 hydrogenated castor oil, as a highly efficient solubilizer, helps to uniformly disperse the dual-drug-loaded material based on modified carbon nanotube gel composite nanoparticles in deionized water. Then add xylitol and sodium citrate. Xylitol acts as a sweetener, and sodium citrate can adjust the pH, improve the stability of the drug system, and also play a role in cleaning the mouth, anti-inflammation, and analgesia. After mixing evenly and fully dissolving, fill the container to obtain an oral spray for treating oral candidiasis.

[0058] Example 3

[0059] This embodiment proposes an oral spray for treating oral candidiasis, comprising the following components in parts by weight: 55 parts of drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness, 25 parts of modified carbon nanotube hydrogel carrier, 4 parts of xylitol, 4 parts of sodium citrate, 6.5 parts of PEG-60 hydrogenated castor oil, and 9 parts of deionized water.

[0060] The drug-loaded nanoparticles, which possess both magnetic and reactive oxygen species responsiveness, comprise the following components in parts by weight: 50 parts reactive oxygen species responsive hyaluronic acid, 7.5 parts iron oxide, and 7.5 parts traditional Chinese medicine composition.

[0061] The modified carbon nanotube hydrogel carrier comprises the following components in parts by weight: 4 parts berberine, 9 parts amino multi-walled carbon nanotubes, 15 parts sodium alginate, and 25 parts calcium chloride.

[0062] The traditional Chinese medicine composition comprises the following components in parts by weight: Astragalus membranaceus 4 parts, Gardenia jasminoides 4 parts, Cimicifuga foetida 4 parts, Mentha haplocalyx 4 parts, Zingiber officinale 4 parts, and Glycyrrhiza uralensis 4 parts.

[0063] The preparation method of drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness specifically includes the following steps:

[0064] (1) 4 mmol of 4-hydroxyphenylboronic acid pinacol and 8 mmol of N,N′-carbonyldiimidazole were dissolved in 5 mL of dichloromethane. The two solutions were then mixed in a 50 mL round-bottom flask and stirred in an oil bath at 35 °C for 0.75 h. The reaction product was washed three times with ultrapure water and then extracted with physiological saline. The intermediate substance was obtained by rotary evaporation. 6 mmol of the intermediate substance and 1 mmol of hyaluronic acid were added to 20 mL of dimethyl sulfoxide. Then 7 mmol of 4-dimethylaminopyridine was added. The mixture was first sonicated for 40 min and then stirred in an oil bath at 35 °C for 12 h. The mixture was then dialyzed and lyophilized. By grafting 4-hydroxyphenylboronic acid pinacol onto the main framework of hyaluronic acid, a material with reactive oxygen species responsiveness was prepared. It can be attracted by the high concentration of reactive oxygen species at the site of Candida infection and retained nearby without reacting with normal cells. This improved the specificity and effectiveness of oral Candida treatment and yielded reactive oxygen species responsive hyaluronic acid.

[0065] (2) After drying and pre-treatment, Astragalus membranaceus, Gardenia jasminoides, Cimicifuga foetida, Mentha haplocalyx, Zingiber officinale and Glycyrrhiza uralensis were pulverized and mixed evenly. 500g of Chinese medicine powder was placed in 7 times the amount of 80% ethanol solution and soaked overnight. Then, it was heated and extracted twice in a reflux condenser and a rotary evaporator. The extracts were combined and filtered. The total extract was concentrated under reduced pressure. The concentrate was centrifuged at high speed and spray-dried. Astragalus membranaceus was used as the chief ingredient to clear heat and dry dampness, purge fire and detoxify. Gardenia jasminoides was used as the assistant ingredient to clear and drain the fire in the three jiaos. Cimicifuga foetida and Mentha haplocalyx were added to help the clear qi of spleen yang rise and disperse the fire in the upper jiao. Finally, Zingiber officinale and Glycyrrhiza uralensis were added to warm the middle and harmonize. The combination of these drugs effectively improved the therapeutic effect of oral candidiasis and had fewer adverse reactions. The Chinese medicine composition was obtained.

[0066] (3) Weigh 7.5 mg of the traditional Chinese medicine composition described in step (2) and dissolve it in 7.5 mL of dimethyl sulfoxide. Then add ferric oxide and the reactive oxygen species-responsive hyaluronic acid described in step (1). Sonicate for 1.5 h. The amount of ferric oxide added is 7.5 mg. Ferric oxide has good magnetic responsiveness and biocompatibility. It can be used as a drug carrier material and can be directed to accumulate at the site of Candida infection to enhance the drug delivery effect. Ferric oxide can also inhibit and kill Candida through its peroxidase activity. Then put the solution into a dialysis bag with a molecular weight of 3000 Da for dialysis. Change the aqueous solution every 2 h and dialyze for 5.5 h. Then freeze dry. Through this process, a kind of This substance, resembling a liposome structure, possesses a dual-responsive release system of magnetism and reactive oxygen species (ROS), along with certain adhesive properties. ROS-responsive hyaluronic acid forms the hydrophilic outer shell, while iron oxide (Fe3O4) forms the hydrophobic core. Loaded with a traditional Chinese medicine composition, it can responsively release drug components at the mucosal sites of Candida parasitism, reducing ineffective drug loss and effectively increasing drug concentration at the mucosal infection site, thereby improving drug utilization and enhancing treatment effectiveness. The hyaluronic acid coating on the surface of the iron oxide particles improves the stability of the iron oxide, reducing the risk of aggregation and easy oxidation, and further enhances the drug release targeting and loading capacity of the iron oxide, resulting in drug-loaded nanoparticles with both magnetic and ROS-responsive properties.

[0067] This embodiment provides a method for preparing an oral spray for treating oral candidiasis, specifically including the following steps:

[0068] S1. 0.9 g of amino-multi-walled carbon nanotubes were dispersed in 100 mL of 1% poloxamer aqueous solution and sonicated for 20 min. Berberine was added and sonicated for another 1.5 h. The amount of berberine added was 0.4 g. Berberine can destroy the cell wall structure of Candida albicans and weaken its virulence. The sonication treatment allows more berberine to be adsorbed and loaded onto the amino-multi-walled carbon nanotubes. Based on the carbon nanotube delivery system, it not only has good biocompatibility, but also significantly increases the drug loading, which is more conducive to exerting the antibacterial effect of berberine. At the same time, the hollow tubular structure of amino-multi-walled carbon nanotubes can also destroy the bacterial cell wall through mechanical physical action, and play a synergistic antibacterial role with berberine, thus obtaining an amino-multi-walled carbon nanotube dispersion loaded with berberine.

[0069] S2. Dissolve 1.5g of sodium alginate in 100mL of distilled water and stir magnetically for 1.5h. Then add the berberine-loaded amino multi-walled carbon nanotube dispersion described in step S1 and continue stirring magnetically for 5h. Spray the composite solution into 100mL of 2.5% calcium chloride solution using a portable electrospray device. Let it stand for 7h to ensure complete gelation. Rinse the gel composite product 4 times with distilled water to remove excess calcium ions. The cross-linking effect of sodium alginate and calcium chloride forms a three-dimensional network structure on the surface of the berberine-loaded amino multi-walled carbon nanotubes, providing more adsorption sites, exhibiting good sustained-release properties, and increasing adhesion to mucous membranes. This effectively reduces drug clearance and migration, enhances binding to Candida infection sites, and thus helps improve the efficiency and sustainability of treatment, resulting in a modified carbon nanotube hydrogel carrier.

[0070] S3. Add drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness to the modified carbon nanotube hydrogel carrier described in step S2, stir magnetically for 35 min, and then sonicate for 3.5 h. Wash the obtained product four times with distilled water and then freeze-dry. Freeze-drying technology can better preserve the original structure and properties of the product. By attaching drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness to the network structure of the modified carbon nanotube hydrogel carrier, a composite delivery system is formed, which significantly increases the drug loading and drug loading stability. It has high targeting of magnetic and reactive oxygen species responsive release, can enhance adhesion and binding to mucous membranes, and can slowly release the drug substances in it at the site of infection, exerting a long-lasting and efficient antibacterial effect, significantly improving the treatment efficacy of Candida, and obtaining a dual-drug-loaded material based on modified carbon nanotube gel composite nanoparticles.

[0071] S4. Stir the dual-drug-loaded material based on modified carbon nanotube gel composite nanoparticles, PEG-60 hydrogenated castor oil, and deionized water as described in step S3 until homogeneous. PEG-60 hydrogenated castor oil, as a highly efficient solubilizer, helps to uniformly disperse the dual-drug-loaded material based on modified carbon nanotube gel composite nanoparticles in deionized water. Then add xylitol and sodium citrate. Xylitol acts as a sweetener, and sodium citrate can adjust the pH, improve the stability of the drug system, and also play a role in cleaning the mouth, anti-inflammation, and analgesia. After mixing evenly and fully dissolving, fill the container to obtain an oral spray for treating oral candidiasis.

[0072] Example 4

[0073] This embodiment proposes an oral spray for treating oral candidiasis, comprising the following components in parts by weight: 60 parts of drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness, 20 parts of modified carbon nanotube hydrogel carrier, 5 parts of xylitol, 5 parts of sodium citrate, 8 parts of PEG-60 hydrogenated castor oil, and 10 parts of deionized water.

[0074] The drug-loaded nanoparticles, which possess both magnetic and reactive oxygen species responsiveness, comprise the following components in parts by weight: 40 parts reactive oxygen species responsive hyaluronic acid, 5 parts iron oxide, and 10 parts traditional Chinese medicine composition.

[0075] The modified carbon nanotube hydrogel carrier comprises the following components in parts by weight: 3 parts berberine, 10 parts amino multi-walled carbon nanotubes, 20 parts sodium alginate, and 20 parts calcium chloride.

[0076] The traditional Chinese medicine composition comprises the following components in parts by weight: Astragalus membranaceus 5 parts, Gardenia jasminoides 5 parts, Cimicifuga foetida 5 parts, Mentha haplocalyx 5 parts, Zingiber officinale 5 parts, and Glycyrrhiza uralensis 5 parts.

[0077] The preparation method of drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness specifically includes the following steps:

[0078] (1) 4 mmol of 4-hydroxyphenylboronic acid pinacol and 8 mmol of N,N′-carbonyldiimidazole were dissolved in 5 mL of dichloromethane. The two solutions were then mixed in a 50 mL round-bottom flask and stirred in an oil bath at 40 °C for 0.5 h. The reaction product was washed three times with ultrapure water and then extracted with physiological saline. The intermediate substance was obtained by rotary evaporation. 6 mmol of the intermediate substance and 1 mmol of hyaluronic acid were added to 20 mL of dimethyl sulfoxide. Then 7 mmol of 4-dimethylaminopyridine was added. The mixture was first sonicated for 30 min and then stirred in an oil bath at 40 °C for 12 h. The mixture was then dialyzed and lyophilized. By grafting 4-hydroxyphenylboronic acid pinacol onto the main framework of hyaluronic acid, a material with reactive oxygen species responsiveness was prepared. It can be attracted by the high concentration of reactive oxygen species at the site of Candida infection and retained nearby without reacting with normal cells. This improved the specificity and effectiveness of oral Candida treatment and yielded reactive oxygen species responsive hyaluronic acid.

[0079] (2) After drying and pre-treatment, Astragalus membranaceus, Gardenia jasminoides, Cimicifuga foetida, Mentha haplocalyx, Zingiber officinale and Glycyrrhiza uralensis were pulverized and mixed evenly. 500g of Chinese medicine powder was placed in 8 times the amount of 80% ethanol solution and soaked overnight. Then, it was heated and extracted 3 times in a reflux condenser and a rotary evaporator. The extracts were combined, filtered, and the total extract was concentrated under reduced pressure. The concentrate was centrifuged at high speed and spray-dried. Astragalus membranaceus was used as the chief ingredient to clear heat and dry dampness, purge fire and detoxify. Gardenia jasminoides was used as the assistant ingredient to clear and drain the fire in the three jiaos. Cimicifuga foetida and Mentha haplocalyx were added to help the clear qi of spleen yang rise and disperse the fire in the upper jiao. Finally, Zingiber officinale and Glycyrrhiza uralensis were added to warm and harmonize the middle jiao. The combination of these drugs effectively improved the therapeutic effect of oral candidiasis and had fewer adverse reactions. The Chinese medicine composition was obtained.

[0080] (3) Weigh 10 mg of the traditional Chinese medicine composition described in step (2) and dissolve it in 10 mL of dimethyl sulfoxide. Then add iron oxide and the reactive oxygen species-responsive hyaluronic acid described in step (1). Sonicate for 1-2 hours. The amount of iron oxide added is 5 mg. Iron oxide has good magnetic responsiveness and biocompatibility. It can be used as a drug carrier material. It can be directed to accumulate at the site of Candida infection to enhance the drug delivery effect. In addition, iron oxide can also inhibit and kill Candida with its peroxidase activity. Then put the solution into a dialysis bag with a molecular weight of 3000 Da for dialysis. Change the aqueous solution every 2 hours and dialyze for 5 hours. Then freeze dry. Through this process, a kind of "lipid" is formed. This material has a "plastic" structure and possesses a dual-responsive release system of magnetism and reactive oxygen species (ROS). It also exhibits a certain degree of adhesion. The ROS-responsive hyaluronic acid forms the hydrophilic outer shell, while the iron oxide (Fe3O4) forms the hydrophobic core. Loaded with a traditional Chinese medicine composition, it can responsively release drug components at the mucosal sites of Candida parasitism, reducing ineffective loss of drug components and effectively increasing the drug concentration at the site of mucosal infection, thereby improving drug utilization and enhancing the effectiveness of treatment. The hyaluronic acid coating on the surface of the iron oxide particles improves the stability of the iron oxide, reduces the risk of aggregation and easy oxidation, and further enhances the drug release targeting and drug loading capacity of the iron oxide, resulting in drug-loaded nanoparticles with both magnetic and ROS dual-responsive properties.

[0081] This embodiment provides a method for preparing an oral spray for treating oral candidiasis, specifically including the following steps:

[0082] S1. 1.0 g of amino-multiwalled carbon nanotubes were dispersed in 100 mL of 1% poloxamer aqueous solution and sonicated for 10 min. Berberine was added and sonicated for another 1 h. The amount of berberine added was 0.3 g. Berberine can destroy the cell wall structure of Candida albicans and weaken its virulence. The sonication treatment allows more berberine to be adsorbed and loaded onto the amino-multiwalled carbon nanotubes. Based on the carbon nanotube delivery system, it not only has good biocompatibility, but also significantly increases the drug loading, which is more conducive to the antibacterial effect of berberine. At the same time, the hollow tubular structure of amino-multiwalled carbon nanotubes can also destroy the bacterial cell wall through mechanical physical action, and play a synergistic antibacterial role with berberine, thus obtaining an amino-multiwalled carbon nanotube dispersion loaded with berberine.

[0083] S2. Dissolve 2.0g of sodium alginate in 100mL of distilled water and stir magnetically for 1h. Then add the berberine-loaded amino multi-walled carbon nanotube dispersion described in step S1 and continue stirring magnetically for 4h. Use a portable electrospray device to spray the composite solution into 100mL of 2% calcium chloride solution and let it stand for 6h to ensure complete gelation. Rinse the gel composite product 5 times with distilled water to remove excess calcium ions. The cross-linking effect of sodium alginate and calcium chloride forms a three-dimensional network structure on the surface of the berberine-loaded amino multi-walled carbon nanotubes, providing more adsorption sites, exhibiting good sustained-release properties, and increasing adhesion to mucous membranes. This effectively reduces drug clearance and migration, enhances binding to Candida infection sites, and thus helps improve the efficiency and sustainability of treatment, resulting in a modified carbon nanotube hydrogel carrier.

[0084] S3. Add drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness to the modified carbon nanotube hydrogel carrier described in step S2, stir magnetically for 30 min, and then sonicate for 3 h. Wash the obtained product 5 times with distilled water and then freeze-dry. Freeze-drying technology can better preserve the original structure and properties of the product. By attaching drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness to the network structure of the modified carbon nanotube hydrogel carrier, a composite delivery system is formed, which significantly increases the drug loading and drug loading stability. It has high targeting of magnetic and reactive oxygen species responsive release, can enhance adhesion and binding to mucous membranes, and can slowly release the drug substances in it at the site of infection, exerting a long-lasting and efficient antibacterial effect, significantly improving the treatment efficacy of Candida, and obtaining a dual-drug-loaded material based on modified carbon nanotube gel composite nanoparticles.

[0085] S4. Stir the dual-drug-loaded material based on modified carbon nanotube gel composite nanoparticles, PEG-60 hydrogenated castor oil, and deionized water as described in step S3 until homogeneous. PEG-60 hydrogenated castor oil, as a highly efficient solubilizer, helps to uniformly disperse the dual-drug-loaded material based on modified carbon nanotube gel composite nanoparticles in deionized water. Then add xylitol and sodium citrate. Xylitol acts as a sweetener, and sodium citrate can adjust the pH, improve the stability of the drug system, and also play a role in cleaning the mouth, anti-inflammation, and analgesia. After mixing evenly and fully dissolving, fill the container to obtain an oral spray for treating oral candidiasis.

[0086] Comparative Example 1

[0087] This comparative example provides an oral spray for treating oral candidiasis, which differs from Example 1 in that the drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness do not contain reactive oxygen species responsive hyaluronic acid; the preparation method of the drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness does not include step (1); the preparation method of the oral spray for treating oral candidiasis is the same as that of Example 1.

[0088] Comparative Example 2

[0089] This comparative example provides an oral spray for treating oral candidiasis, which differs from Example 1 in that the modified carbon nanotube hydrogel carrier does not contain amino multi-walled carbon nanotubes; the preparation method of the drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness is the same as in Example 1; and amino multi-walled carbon nanotubes are not added in the preparation method S1 of the oral spray for treating oral candidiasis.

[0090] Comparative Example 3

[0091] This comparative example provides an oral spray for treating oral candidiasis, which differs from Example 1 in that the oral spray for treating oral candidiasis does not contain iron oxide, sodium alginate and calcium chloride; the preparation method (3) of drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness does not include iron oxide; and the preparation method of the oral spray for treating oral candidiasis does not include step S2.

[0092] Experimental Example 1

[0093] Drug loading experiment

[0094] Test samples: oral sprays for treating oral candidiasis prepared in Examples 1-4 and Comparative Examples 1-3.

[0095] Test method: Accurately weigh 1 g / mL of the traditional Chinese medicine composition and dilute it to 20 mg / mL. Using distilled water as a blank, scan the wavelength range of 330-500 nm using a UV spectrophotometer. Maximum absorption is observed at 350 nm. Then, dilute the traditional Chinese medicine component to a drug solution of 0-20 mg / mL and measure the absorbance A at 350 nm. The standard curve equation is obtained by regression: A = 0.1082C + 0.0235, r 2 =0.9945, the optimal linear range is 2-8 mg / mL; weigh 1 mL of test sample and dissolve it in 1 mL of methanol solution, vortex for 20 min with stirring to ensure full drug extraction, let stand for 1 h, centrifuge at 10000 rpm for 5 min, take 1 mL of supernatant and dilute to 50 mL volumetric flask, measure absorbance with distilled water as blank, and calculate the drug loading (%).

[0096] Figure 1The figures show the drug loading results for Examples 1-4 and Comparative Examples 1-3. As shown, the drug loading of Examples 1-4 was 36.8-38.6%, indicating a relatively high drug loading. The drug loading of Comparative Examples 1-3 was 21.7-25.3%, indicating a relatively low drug loading. The drug-loaded nanoparticles of Comparative Example 1, which exhibit both magnetic and reactive oxygen species responsiveness, do not contain reactive oxygen species-responsive hyaluronic acid, thus failing to form an externally hydrophilic and internally hydrophobic structure with iron oxide, which is detrimental to the encapsulation of the traditional Chinese medicine composition, resulting in a low drug loading. The modified carbon nanotube hydrogel carrier of Comparative Example 2 does not contain amino-multi-walled carbon nanotubes, failing to form a dual-drug-loaded material based on modified carbon nanotube gel composite nanoparticles, resulting in a low drug loading. The oral spray for treating oral candidiasis of Comparative Example 3 does not contain iron oxide, sodium alginate, and calcium chloride, failing to form a three-dimensional network structure and reducing adsorption sites, which is detrimental to the adsorption performance of the modified carbon nanotube hydrogel carrier surface on the drug-loaded nanoparticles, resulting in a low drug loading.

[0097] Experimental Example 2

[0098] bactericidal test

[0099] Test samples: oral sprays for treating oral candidiasis prepared in Examples 1-4 and Comparative Examples 1-3.

[0100] Test method: (1) The test sample was subjected to two different conditions, pH7.0 and pH7.0+H2O2+magnetism, respectively, and the disinfection simulation field test was carried out according to the "Disinfection Technical Specifications 2002 Edition". The sample was exposed to Candida for 5 minutes. The sterilization rate (%) under different conditions was calculated based on the number of microorganisms before and after disinfection.

[0101] (2) The test samples were subjected to a simulated field test for disinfection according to the "Disinfection Technical Specifications 2002 Edition". They were exposed to Candida for 0h, 2h, 4h and 6h respectively. The sterilization rate (%) was calculated based on the number of microorganisms before and after disinfection.

[0102] Sterilization rate (%) = [1-10] -lg（X 0 / X t ） ]×100%

[0103] Where X0 represents the number of microorganisms before disinfection, X t The number of microorganisms after disinfection is lg(X0 / X). t () represents the average number of logs killed.

[0104] Figure 2 The graph shows the sterilization rate results under different conditions for Examples 1-4 and Comparative Examples 1-3; Figure 3 The graph shows the sterilization rate results of different contact times for Examples 1-4 and Comparative Examples 1-3; as shown. Figure 2 Examples 1-4 showed bactericidal rates of 79.58-79.83% and 99.98-100.00% under pH 7.0 and pH 7.0 + H2O2 + magnetic conditions, respectively, exhibiting significant reactive oxygen species and magnetic response release characteristics, indicating strong bactericidal targeting. Comparative Examples 1-3 showed bactericidal rates of 79.42-79.46% and 92.43-96.67% under pH 7.0 and pH 7.0 + H2O2 + magnetic conditions, respectively, with lower bactericidal rates, indicating moderate bactericidal targeting. Figure 3 In Examples 1-4, the sterilization rates at 0h, 2h, 4h, and 6h were 99.96-100.00%, 99.96-100.00%, 99.95-100.00%, and 99.94-100.00%, respectively, indicating a relatively long sterilization time. In Comparative Examples 1-3, the sterilization rates at 0h, 2h, 4h, and 6h were 99.71-99.80%, 99.55-99.75%, 99.47-99.69%, and 99.32-99.60%, respectively, indicating a relatively short sterilization time. The drug-loaded nanoparticles in Comparative Example 1, which exhibit both magnetic and reactive oxygen species responsiveness, do not contain reactive oxygen species-responsive hyaluronic acid, thus failing to form a sustained-release structure similar to liposomes. This also hinders the reduction of the risk of magnetite aggregation and oxidation, limiting the magnetic response release of magnetite. The modified carbon nanotube hydrogel carrier in Comparative Example 2 does not contain amino multi-walled carbon nanotubes, thus failing to form a carbon nanotube-based gel carrier. This hinders the better control of the carrier's release rate and also negatively impacts the stability of the modified carbon nanotube hydrogel carrier, thereby adversely affecting the stability of the drug-loaded nanoparticles and resulting in generally poor bactericidal targeting and duration of action. Similarly, the oral spray for treating oral candidiasis in Comparative Example 3 does not contain iron(III) oxide, sodium alginate, or calcium chloride, preventing the effective use of the magnetic response release properties of iron(III) oxide and the formation of an adhesive three-dimensional network structure on the surface of the modified carbon nanotube hydrogel carrier to effectively adsorb and sustain the release of the drug-loaded nanoparticles. This also negatively affects the reactive oxygen species responsiveness of the nanoparticles, leading to poor bactericidal targeting and duration of action.

[0105] Experimental Example 3

[0106] Treatment efficacy experiment

[0107] Test samples: oral sprays for treating oral candidiasis prepared in Examples 1-4 and Comparative Examples 1-3.

[0108] Test Method: 140 patients with varying degrees of oral candidiasis were selected, characterized by extensive lesions of the lingual papillae, white pseudomembrane on the lingual mucosa, dry mouth, pain, and decreased taste. Their ages ranged from 25 to 65 years. Patients were randomly assigned to 7 groups of 20 each, using a random number table. Each group received a corresponding test sample, administered via oral spray three times daily. The effects were observed after 7 days. Treatment efficacy was assessed according to the following criteria, and the effective rate (%) was calculated:

[0109] Effective: Oral candidiasis symptoms completely disappear; oral candidiasis symptoms change from severe to moderate, from moderate to mild, and from mild to normal.

[0110] Ineffective: No significant improvement was observed in the symptoms of oral candidiasis.

[0111] The formula for calculating the treatment effectiveness rate is as follows:

[0112] Treatment effectiveness rate (%) = (Number of effective cases / 20) × 100%

[0113] Figure 4 The figures show the treatment efficacy results of Examples 1-4 and Comparative Examples 1-3. As shown, the treatment efficacy rate of Examples 1-4 was 80-95%, indicating good treatment effect; the treatment efficacy rate of Comparative Examples 1-3 was 55-65%, indicating poor treatment effect. The drug-loaded nanoparticles of Comparative Example 1, which possess both magnetic and reactive oxygen species responsiveness, do not contain reactive oxygen species-responsive hyaluronic acid, which is detrimental to increasing drug loading and prevents targeted recognition of Candida albicans mucosal sites through reactive oxygen species response, resulting in poor treatment effect. The modified carbon nanotube hydrogel of Comparative Example 2... The carrier does not contain amino-walled carbon nanotubes, which prevents the physical antibacterial effect of carbon nanotubes from being exerted. It also hinders the improvement of the stability and adsorption sites of the modified carbon nanotube hydrogel carrier, limiting the antibacterial targeting and persistence of the drug-loaded nanoparticles, resulting in poor treatment efficacy. The oral spray for treating oral candidiasis in Comparative Example 3 does not contain iron tetroxide, sodium alginate, and calcium chloride, so it cannot target and identify the mucosal sites where Candida parasitizes through magnetic response, nor can it effectively adhere to the mucosal infection sites, which is not conducive to improving drug utilization and results in poor treatment efficacy.

[0114] The above experimental results show that the drug loading, bactericidal activity, and therapeutic effect of Examples 1-4 of the present invention are significantly better than those of Comparative Examples 1-3. Among them, Example 1, which uses drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness and a modified carbon nanotube hydrogel carrier, has a higher drug loading, better bactericidal targeting and action time, and better therapeutic effect. By attaching drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness to the modified carbon nanotube hydrogel carrier, a dual-drug-loaded material based on modified carbon nanotube gel composite nanoparticles is formed, which significantly improves the drug loading. It can highly target and identify the mucosal sites of Candida parasitic by the dual magnetic and reactive oxygen species responsiveness and effectively bind to them, thereby increasing the drug concentration at the mucosal infection site. At the same time, the dual-drug-loaded material slowly releases the loaded drug components at the infected mucosal site, exerting antibacterial activity through chemical and physical actions, prolonging the antibacterial action time, and improving the effectiveness of treating oral Candida.

[0115] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention.

[0116] The present invention and its embodiments have been described above. This description is not restrictive, and the accompanying drawings are only one embodiment of the present invention. The actual application is not limited to this. In conclusion, if those skilled in the art are inspired by this description and design similar methods and embodiments without departing from the spirit of the present invention, they should all fall within the protection scope of the present invention.

Claims

1. An oral spray for treating oral candidiasis, characterized in that: The oral spray for treating oral candidiasis is composed of the following components in parts by weight: 50-60 parts of drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness, 20-30 parts of modified carbon nanotube hydrogel carrier, 3-5 parts of xylitol, 3-5 parts of sodium citrate, 5-8 parts of PEG-60 hydrogenated castor oil, and 8-10 parts of deionized water; the drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness are composed of the following components in parts by weight: 4 parts of reactive oxygen species responsive hyaluronic acid. 0-60 parts, 5-10 parts of ferric oxide, 5-10 parts of traditional Chinese medicine composition; the modified carbon nanotube hydrogel carrier is made from the following components in parts by weight: 3-5 parts of berberine, 8-10 parts of amino multi-walled carbon nanotubes, 10-20 parts of sodium alginate, 20-30 parts of calcium chloride; the traditional Chinese medicine composition is made from the following raw materials in parts by weight: 3-5 parts of astragalus, 3-5 parts of gardenia, 3-5 parts of cimicifuga, 3-5 parts of peppermint, 3-5 parts of dried ginger, 3-5 parts of licorice. The method for preparing the drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness specifically includes the following steps: (1) Dissolve 4 mmol of 4-hydroxyphenylboronic acid pinacol and 8 mmol of N,N′-carbonyldiimidazole in 5 mL of dichloromethane respectively. Mix the two solutions in a 50 mL round-bottom flask and stir in an oil bath at 30-40 °C for 0.5-1 h. Wash the reaction product three times with ultrapure water, then extract with physiological saline, and rotary evaporate to obtain the intermediate substance. Add 6 mmol of the intermediate substance and 1 mmol of hyaluronic acid to 20 mL of dimethyl sulfoxide, then add 7 mmol of 4-dimethylaminopyridine. First, sonicate for 30-50 min, then stir in an oil bath at 30-40 °C for 12 h. Dialyze and freeze dry to obtain reactive oxygen species responsive hyaluronic acid. (2) After drying and pre-treatment, Astragalus membranaceus, Gardenia jasminoides, Cimicifuga foetida, Mentha haplocalyx, Zingiber officinale and Glycyrrhiza uralensis are pulverized and mixed evenly. 500g of Chinese herbal powder is placed in 6-8 times the amount of 80% ethanol solution and soaked overnight. Then, it is heated and extracted 1-3 times in a reflux condenser and rotary evaporator. The extracts are combined, filtered, and the total extract is concentrated under reduced pressure. The concentrate is centrifuged at high speed and spray-dried to obtain the Chinese herbal composition. (3) Weigh 5-10 mg of the traditional Chinese medicine composition described in step (2) and dissolve it in 5-10 mL of dimethyl sulfoxide. Then add iron oxide and the reactive oxygen species responsive hyaluronic acid described in step (1), sonicate for 1-2 h, and then put the solution into a dialysis bag with a molecular weight of 3000 Da for dialysis. Change the aqueous solution every 2 h and dialyze for 5-6 h. Then freeze dry to obtain drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness.

2. A method for preparing an oral spray for treating oral candidiasis according to claim 1, characterized in that: Specifically, the following steps are included: S1. Disperse 0.8-1.0 g of amino multi-walled carbon nanotubes in 100 mL of 1% poloxamer aqueous solution, sonicate for 10-30 min, add berberine, and continue sonication for 1-2 h to obtain an amino multi-walled carbon nanotube dispersion loaded with berberine. S2. Dissolve 1.0-2.0g of sodium alginate in 100mL of distilled water and stir magnetically for 1-2 hours. Then add the amino multi-walled carbon nanotube dispersion loaded with berberine described in step S1 and continue stirring magnetically for 4-6 hours. Use a portable electrospray device to spray the composite solution into 100mL of calcium chloride solution with a mass fraction of 2-3%. Let it stand for 6-8 hours to ensure complete gelation. Rinse the gel composite product with distilled water 3-5 times to remove excess calcium ions and obtain the modified carbon nanotube hydrogel carrier. S3. Add the drug-loaded nanoparticles with both magnetic and reactive oxygen species responsiveness to the modified carbon nanotube hydrogel carrier described in step S2, stir magnetically for 30-40 min, then sonicate for 3-4 h, wash the obtained product with distilled water 3-5 times, and then freeze dry to obtain a dual drug-loaded material based on modified carbon nanotube gel composite nanoparticles. S4. Stir the dual-drug-carrying material based on modified carbon nanotube gel composite nanoparticles, PEG-60 hydrogenated castor oil and deionized water as described in step S3 until uniform, then add xylitol and sodium citrate, mix evenly, dissolve completely and fill into the container to obtain an oral spray for treating oral candidiasis. In step S1, the amount of berberine added is 0.3-0.5g.

3. The oral spray for treating oral candidiasis according to claim 1, characterized in that: In step (3), the amount of iron(III) oxide added is 5-10 mg.

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