Oral gargle as well as preparation method and application thereof

Abstract

The invention discloses an oral gargle as well as a preparation method and application thereof, relates to the technical field of oral care, and solves the problem that an existing product is difficult to safely and effectively relieve a dry mouth symptom for a long time. Comprising a moisturizing film-forming agent, an antibacterial disinfectant, an anti-allergy soothing agent and a flavoring agent, the moisturizing film-forming agent is polyethylene glycol active ester. The antibacterial disinfectant is selected from chlorhexidine, chlorhexidine acetate, benzalkonium chloride and polyhexamethylene biguanidine; the anti-allergy soothing agent is selected from allantoin, tocopherol acetate, tranexamic acid, dipotassium glycyrrhizinate, a calendula extract, a chamomile extract, matricaria recutita / eucalyptus globulus leaf oil, a tea leaf extract, a propolis extract and the like; the flavoring agent is selected from peppermint essence, xylitol, sucralose, saccharin sodium salt and sodium citrate. The mouthwash can be used as a product for preventing or treating xerostomia or oral mucositis, and the mouthwash is packaged in a powder form and forms a product unit together with an auxiliary bottle for dissolving the powder.

Description

Technical Field

[0001] This invention relates to the field of oral care technology, specifically to an oral rinser, its preparation method, and its application. Background Technology

[0002] Head and neck tumors are among the most common malignant tumors in my country, with oral and nasopharyngeal carcinomas being the most prevalent clinically, with an overall incidence rate of approximately 48.1 per 100,000. Radiotherapy is a core component of the comprehensive treatment system for these tumors, playing an irreplaceable clinical role in improving local tumor control rates and prolonging patient survival by precisely killing tumor cells. However, the killing effect of radiation is non-specific; while targeting tumor tissue, it inevitably damages adjacent normal tissues. Salivary gland tissue is highly sensitive to radiation; after irradiation, the acinar cells and ductal epithelium of the salivary glands are prone to rapid degeneration, atrophy, and fibrosis, leading to severe impairment of glandular secretory function. This radiation damage directly causes two key problems: a sharp decrease in saliva secretion and significantly thickened saliva. These two factors combined further lead to a series of radiation-induced oral complications, including but not limited to radiation-induced sialiditis, severe xerostomia, painful oral mucositis, rampant caries, and radiation-induced osteomyelitis of the jaw, which is extremely difficult to treat.

[0003] Among the aforementioned complications, persistent, severe xerostomia and accompanying dysphagia are the most common and have the most profound negative impact on patients' quality of life. It directly leads to decreased speech clarity, reduced chewing efficiency, abnormal taste perception, and dysphagia, often accompanied by chronic sore throat and sleep disturbances, severely interfering with daily physiological activities. Dysphagia and oral discomfort result in reduced dietary intake, leading to progressive deterioration of nutritional status; malnutrition, in turn, weakens patients' physical strength and immune function, creating a vicious cycle. This not only reduces patients' tolerance during treatment but also affects the precise implementation of radiotherapy, ultimately adversely impacting the effectiveness of tumor treatment, long-term prognosis, and patients' long-term quality of life. It is noteworthy that even with the clinical widespread adoption of precision radiotherapy techniques such as intensity-modulated radiotherapy (IMRT), approximately 20% of patients undergoing radiotherapy for head and neck tumors still cannot avoid developing long-term, severe xerostomia, indicating that this problem has not yet been fundamentally resolved.

[0004] Dry mouth is not a problem exclusive to patients undergoing radiotherapy for head and neck tumors; it affects a wider range of patients in clinical practice. These include patients with systemic diseases such as Sjögren's syndrome and diabetes, who often experience dry mouth due to autoimmune abnormalities or metabolic disorders; patients experiencing drug side effects, as dry mouth is a common side effect of hundreds of clinically used medications (such as antidepressants, antihypertensives, and antihistamines), affecting multiple treatment areas including cardiovascular and neuropsychiatric fields; patients undergoing surgical and dental treatments, including those who may experience permanent dry mouth after head and neck surgery (such as salivary gland removal); and those experiencing temporary dry mouth discomfort during dental treatments due to prolonged mouth opening or the use of saliva suction devices. While the causes of dry mouth differ among these groups, all lead to decreased oral comfort, and some severe cases may also experience physiological dysfunction and reduced quality of life.

[0005] Currently, clinical management of xerostomia remains significantly limited. There is a lack of specific drugs targeting the underlying cause, relying primarily on symptomatic relief. Existing commonly used methods include topical care products such as artificial saliva sprays and mouthwashes. The core problem with these is their short duration of action; they are easily washed away by subsequent drinking and eating, requiring frequent use to maintain effectiveness. Some products also have unpleasant tastes, reducing patient adherence to long-term use. Furthermore, while systemic cholinergic drugs can relieve symptoms by promoting saliva secretion, they often bring systemic side effects such as excessive sweating, gastrointestinal discomfort, and increased heart rate. Strict dosage control is required in clinical application, and they are not suitable for patients with underlying cardiovascular or gastrointestinal diseases. These limitations lead to generally low patient satisfaction, failing to meet the need for long-term, safe, and effective relief of xerostomia. Therefore, there is an urgent need to develop a novel oral care product that can mimic the physicochemical properties of natural saliva, possess strong and long-lasting moisturizing effects, effectively adhere to the oral mucosa, and significantly improve oral comfort and quality of life for radiotherapy patients. Summary of the Invention

[0006] To address the technical problem that existing oral care products cannot provide long-term, safe, and effective relief of dry mouth symptoms, this invention proposes an oral rinse, its preparation method, and its application.

[0007] The specific technical solution of the present invention is as follows: This invention first provides an oral rinse, comprising the following components in parts by weight: 95-99 parts of moisturizing film-forming agent, 0.1-0.5 parts of antibacterial disinfectant, 0.5-2 parts of anti-allergic soothing agent, and 0.01-0.5 parts of flavoring agent; The moisturizing film-forming agent is a polyethylene glycol active ester with an activation degree of not less than 95%; The antibacterial disinfectant is selected from one or a combination of at least two of chlorhexidine, chlorhexidine acetate, benzalkonium chloride, and polyhexamethylene biguanide; The anti-allergy soothing agent is selected from one or a combination of at least two of the following: allantoin, tocopherol acetate, tranexamic acid, dipotassium glycyrrhizate, calendula extract, chamomile extract, chamomile / eucalyptus leaf oil, tea extract, propolis extract, aloe vera extract, ginger root extract, zinc chloride, zinc citrate, zinc chloride, zinc citrate, and sodium bicarbonate buffer. The flavoring agent is one or a combination of at least two of the following: peppermint flavoring, xylitol, sucralose, sodium saccharin, spearmint flavoring, and sodium citrate.

[0008] Preferably, the polyethylene glycol active ester is prepared by the following method: Under inert gas protection, linear or multi-arm polyethylene glycol or its derivatives with a molecular weight of 1000~1000000 Da are reacted with an activating ester reagent in the presence of a catalyst. The product is washed, precipitated, and dried to obtain polyethylene glycol active ester.

[0009] Preferably, the activating ester reagent is one or more of N,N'-succinimide carbonate, N-hydroxysuccinimide, N-hydroxythiosuccinimide, p-nitrophenol carbonate, and pentafluorophenol carbonate.

[0010] Preferably, the catalyst is one or more of triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, pyridine, N,N-dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide, and diisopropylcarbodiimide.

[0011] Preferably, the reaction temperature is 40~60℃ and the reaction time is 4~8h.

[0012] The present invention also provides a method for preparing the above-mentioned oral rinse, comprising the following steps: At room temperature, a moisturizing film-forming agent, an antibacterial disinfectant, an anti-allergic soothing agent, and a flavoring agent are placed in a three-dimensional mixer and mixed evenly to obtain an oral rinse.

[0013] The present invention also provides the use of the above-mentioned oral rinse in the preparation of products for the prevention or treatment of dry mouth or oral mucositis.

[0014] Preferably, the dry mouth or oral mucositis is caused by diseases of the nasopharynx, oral cavity, lungs, etc., or by postoperative care, radiotherapy, systemic diseases, or drug side effects.

[0015] The present invention also provides an oral care product comprising the oral rinse; The mouthwash is packaged in powder form and together with an auxiliary bottle for dissolving the powder, forms a product unit.

[0016] Preferably, the mouthwash concentration is 0.05 g / mL, the dissolution time is less than 10 s, the pH after dissolution is 6.5~7.5, and it is prepared at 25°C with a shear rate of 10 s. -1 The viscosity under the given conditions is 1~10 mPa·s.

[0017] Compared with the prior art, the specific beneficial effects of the present invention are as follows: This invention discloses a polyethylene glycol active ester prepared by a specific method. Its solubility, viscosity, and rheological behavior highly mimic natural human saliva, and it achieves functional upgrades through specific molecular binding. Specifically, the active ester structure of the polyethylene glycol active ester can specifically bind to amino groups and other groups on the surface of oral mucosal cells, forming a robust molecular moisturizing film. This characteristic not only gives it excellent water-locking properties but also protects it from the effects of daily activities such as rinsing and eating, achieving a long-lasting moisturizing effect. This fundamentally solves the problem of short-lived effects in traditional products, greatly improving patient compliance and treatment satisfaction.

[0018] This invention, through precise formulation control, achieves a mouthwash whose viscosity and pseudoplasticity closely match the rheological behavior of healthy human saliva. It provides a natural and comfortable taste without any stickiness or thinness, effectively replacing the lubricating and moisturizing functions of saliva while adapting to the physiological environment of the oral cavity, thus improving patient acceptance. The product uses safe raw materials and has a simple composition, verified through in vitro experiments and animal models to have no irritating effect on the oral mucosa. It not only effectively improves dry mouth caused by radiotherapy, nasopharyngeal and oral lung diseases, or postoperative conditions, but also relieves irritating dry mouth caused by dental treatments. Simultaneously, it repairs damaged oral mucosa, reduces mucosal discomfort, and provides a favorable environment for oral wound healing.

[0019] The product of this invention exists in solid powder form, exhibiting significantly better stability than liquid formulations. It has a shelf life of up to 36 months under freezing conditions of -20±5℃ and can be stably stored for 24 months at room temperature. Furthermore, it is packaged in unit doses and comes with a dedicated dissolving bottle, ensuring accurate dosage and convenient operation, making it suitable for various usage scenarios such as homes and hospitals.

[0020] This invention is tailored to the unique pathophysiological characteristics of radiation-induced xerostomia, precisely addressing the core issues of existing symptomatic treatments, such as short duration of effect and poor patient compliance due to frequent use. Through in vitro viscosity, rheology, moisturizing, and adhesion experiments, as well as animal model validation, its high efficiency, long-lasting effect, and safety have been fully demonstrated, providing an ideal symptomatic treatment solution for various types of xerostomia patients and those with oral trauma. Attached Figure Description

[0021] Figure 1 For example, polyethylene glycol active ester A in Example 1 1 H NMR spectrum; Figure 2For example, polyethylene glycol active ester B in Example 2 1 H NMR spectrum; Figure 3 For example, the polyethylene glycol active ester C in Example 3 1 H NMR spectrum; Figure 4 This is a comparison graph of the viscosity-shear rate curves of the mouthwash of the present invention and the saliva of healthy individuals; Figure 5 This is a comparison graph showing the change in in vitro moisturizing rate of the mouthwash of the present invention and physiological saline over time; Figure 6 This is a diagram showing the results of an experiment on the adhesion of mouthwash to a simulated oral mucosa surface. Figure 7 HE staining image of oral mucosal tissue from an animal model experiment. Detailed Implementation

[0022] To make the technical solutions of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. It should be noted that the following embodiments are only used to better understand the technical solutions of the present invention and should not be construed as limiting the present invention.

[0023] Example 1. 500 g of four-arm polyethylene glycol (4-arm PEG-OH) with a molecular weight of 10000 Da was added to a reaction vessel and dissolved in 2 L of anhydrous dichloromethane. 40 g of N,N'-succinimide carbonate (DSC) and 30 g of triethylamine (TEA) were added as catalysts. The reaction was carried out under nitrogen protection at 30 °C with stirring for 6 h. After the reaction, 1 L of water was used to wash away byproducts, and the organic phase was precipitated with 2 L of ice-cold diethyl ether. The resulting white solid was washed three times with diethyl ether and dried to constant weight in a vacuum drying oven at 40 °C to obtain polyethylene glycol active ester A (4-arm PEG-SC-10k). NMR analysis showed its activation degree to be 99.38%. 1 The H NMR spectrum is shown in [reference]. Figure 1 .

[0024] Example 2. 500 g of four-arm polyethylene glycol acetic acid (4-arm PEG-AA) with a molecular weight of 20000 Da was added to a reaction vessel and dissolved in 2 L of anhydrous dichloromethane. 12 g of N-hydroxysuccinimide (NHS) and 23 g of N,N-dicyclohexylcarbodiimide (DCC) were added as catalysts. The reaction was carried out under nitrogen protection at 30 °C with stirring for 4 h. After the reaction, byproducts were removed by washing with 1 L of water, and the organic phase was precipitated with 2 L of ice-cold diethyl ether. The resulting white solid was washed three times with diethyl ether and dried to constant weight in a vacuum drying oven at 40 °C to obtain polyethylene glycol active ester B (4-arm PEG-SCM-20k). NMR analysis showed its activation degree to be 92.63%. 1 The H NMR spectrum is shown in [reference]. Figure 2 .

[0025] Example 3. 500 g of 8-arm polyethylene glycol valerate (8-arm PEG-GA) with a molecular weight of 40000 Da was added to a reaction vessel, and 1 L of anhydrous N,N-dimethylformamide was added to dissolve it. 44 g of N-hydroxythiosuccinimide (sNHS) and 31 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) were added as catalysts. The reaction was carried out under nitrogen protection at 40 °C with stirring for 5 h. After the reaction, the solvent was evaporated and dissolved in 2 L of dichloromethane. The byproducts were removed by washing with 1 L of water, and the organic phase was precipitated with 2 L of ice-cold diethyl ether. The resulting white solid was washed three times with diethyl ether and dried to constant weight in a vacuum drying oven at 40 °C to obtain polyethylene glycol active ester C (8-arm PEG-SG-40k). NMR analysis showed its activation degree to be 98%. 1 The H NMR spectrum is shown in [reference]. Figure 3 .

[0026] Example 4. This embodiment uses the following formula to prepare the mouthwash: Polyethylene glycol active ester A (prepared in Example 1) 98.7g, chlorhexidine 0.1g, allantoin 0.01g, calendula extract 0.01g, sodium bicarbonate buffer 0.8g, peppermint flavor 0.2g.

[0027] The preparation is carried out according to the following process: In an environment of 25℃ and humidity <30%, the powders of the above components are mixed evenly for 30 minutes using a three-dimensional mixer. The mixed powder is then packaged into aluminum foil bags, 1.0g per bag.

[0028] Example 5. This embodiment uses the following formula to prepare the mouthwash: 98.5 g of polyethylene glycol active ester B (prepared in Example 2), 0.1 g of chlorhexidine acetate, 0.01 g of allantoin, 0.3 g of zinc citrate, 0.8 g of sodium bicarbonate buffer, 0.2 g of peppermint flavor, and 0.09 g of silica.

[0029] The preparation is carried out according to the following process: In an environment of 25℃ and humidity <30%, the powders of the above components are mixed evenly for 30 minutes using a three-dimensional mixer. The mixed powder is then packaged into aluminum foil bags, 1.0g per bag.

[0030] Example 6. This embodiment uses the following formula to prepare the mouthwash: Polyethylene glycol active ester A (prepared in Example 1) 98.8g, chlorhexidine 0.1g, allantoin 0.02g, chamomile extract 0.03g, xylitol 0.15g, sodium bicarbonate buffer 0.8g, spearmint flavor 0.1g.

[0031] The preparation is carried out according to the following process: In an environment of 25℃ and humidity <30%, the powders of the above components are mixed evenly for 30 minutes using a three-dimensional mixer. The mixed powder is then packaged into aluminum foil bags, 1.0g per bag.

[0032] Example of an effect 1. Viscosity and rheological behavior testing: Using a rotational rheometer, at 25°C, the viscosity of the mouthwashes prepared in Examples 4-6 of this invention and the viscosity of natural saliva collected from healthy volunteers as a function of shear rate (1-1000 s⁻¹) were tested with respect to shear rate. -1 (Changes).

[0033] The results are as follows Figure 4 As shown, the mouthwashes of the present invention (Examples 4-6), like natural saliva, exhibit shear-thinning pseudoplastic fluid behavior, and within the physiologically relevant shear rate range (10-100 s⁻¹), they exhibit this behavior. -1 Within the range of saliva, the viscosity values ​​of the two are very close, proving that they have good biomimetic properties.

[0034] Example of effect 2. Moisturizing effect control experiment: Take equal volumes of the mouthwash of the present invention (Examples 4-6) and physiological saline, apply them evenly to a moisturizing board of a specific material, and place them in a constant temperature and humidity chamber at 25°C and 40% humidity. Weigh them periodically and calculate the moisturizing rate (remaining moisture / initial moisture × 100%).

[0035] The results are as follows Figure 5As shown, the mouthwash of the present invention maintains a moisturizing rate of over 80% within 4 hours, while the moisturizing rate of physiological saline drops to below 50% after 1 hour, indicating that the product of the present invention has a significantly superior long-lasting water-locking ability.

[0036] Example of an effect 3. Adhesion test: Using an in vitro mucosal simulation device, the fluorescently labeled mouthwash of the present invention (Example 6) and a control (ordinary PEG solution) were applied to the simulated oral mucosa surface, respectively, and then rinsed with simulated saliva at a constant flow rate. Adhesion was evaluated by detecting the fluorescence intensity of the surface after rinsing. The results are as follows: Figure 6 As shown, the mouthwash of the present invention retains more than 70% of its fluorescence intensity after rinsing (bottom three groups), which is significantly higher than that of ordinary PEG solutions (top three groups), proving that polyethylene glycol active esters endow the product with extremely strong mucosal adhesion ability.

[0037] Example of an effect: 4. Animal model experiments on oral mucosal improvement: A rat model of radiation-induced xerostomia was established, and rats were randomly divided into a model control group, a saline group, and a mouthwash group. After 14 days of continuous administration, the animals were sacrificed, and oral mucosal tissue was collected for pathological examination (HE staining). The results are as follows: Figure 7 As shown, compared with the model control group (A) and the saline group (B), the oral mucosal epithelial integrity of rats in the mouthwash group (C) of this invention was better, the infiltration of inflammatory cells was significantly reduced, and the degree of submucosal gland atrophy was improved, indicating that this mouthwash has a repairing and protective effect on radiation-damaged oral mucosa.

[0038] The above embodiments fully demonstrate that the polyethylene glycol mouthwash provided by the present invention has excellent effects in simulating saliva properties, long-lasting moisturizing, strong adhesion and mucosal repair, and can effectively meet the clinical needs of patients for relieving dry mouth symptoms. Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. An oral rinse, characterized in that, The components include the following parts by mass: 95-99 parts of moisturizing film-forming agent, 0.1-0.5 parts of antibacterial disinfectant, 0.5-2 parts of anti-allergic soothing agent, and 0.01-0.5 parts of flavoring agent; The moisturizing film-forming agent is a polyethylene glycol active ester with an activation degree of not less than 95%; The antibacterial disinfectant is selected from one or a combination of at least two of chlorhexidine, chlorhexidine acetate, benzalkonium chloride, and polyhexamethylene biguanide; The anti-allergy soothing agent is selected from one or a combination of at least two of the following: allantoin, tocopherol acetate, tranexamic acid, dipotassium glycyrrhizate, calendula extract, chamomile extract, chamomile / eucalyptus leaf oil, tea extract, propolis extract, aloe vera extract, ginger root extract, zinc chloride, zinc citrate, zinc chloride, zinc citrate, and sodium bicarbonate buffer. The flavoring agent is one or a combination of at least two of the following: peppermint flavoring, xylitol, sucralose, sodium saccharin, spearmint flavoring, and sodium citrate.

2. The oral rinse according to claim 1, characterized in that, The polyethylene glycol active ester was prepared by the following method: Under inert gas protection, linear or multi-arm polyethylene glycol or its derivatives with a molecular weight of 1000~1000000 Da are reacted with an activating ester reagent in the presence of a catalyst. The product is washed, precipitated, and dried to obtain polyethylene glycol active ester.

3. The oral rinse according to claim 2, characterized in that, The activating ester reagent is one or more of N,N'-succinimide carbonate, N-hydroxysuccinimide, N-hydroxythiosuccinimide, p-nitrophenol carbonate, and pentafluorophenol carbonate.

4. The oral rinse according to claim 2, characterized in that, The catalyst is one or more of triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, pyridine, N,N-dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide, and diisopropylcarbodiimide.

5. The oral rinse according to claim 2, characterized in that, The reaction temperature is 40~60℃, and the reaction time is 4~8h.

6. A method for preparing an oral rinse as described in claim 1, characterized in that, Includes the following steps: At room temperature, a moisturizing film-forming agent, an antibacterial disinfectant, an anti-allergic soothing agent, and a flavoring agent are placed in a three-dimensional mixer and mixed evenly to obtain an oral rinse.

7. The use of any one of the oral rinses according to claims 1 to 5 in the preparation of a product for the prevention or treatment of dry mouth or oral mucositis.

8. The application according to claim 7, characterized in that, Dry mouth or oral mucositis is caused by nasopharyngeal, oral, or lung diseases or postoperative, radiation therapy, systemic diseases or drug side effects.

9. An oral care product, characterized in that, The oral rinse containing any one of claims 1 to 5; The mouthwash is packaged in powder form and together with an auxiliary bottle for dissolving the powder, forms a product unit.

10. The oral care product according to claim 9, characterized in that, The mouthwash has a concentration of 0.05 g / mL, a dissolution time of less than 10 seconds, and a post-dissolution pH of 6.5–7.

5. It was prepared at 25°C with a shear rate of 10 s. -1 The viscosity under the given conditions is 1~10 mPa·s.

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