A pharmaceutical composition for oral mucositis and a method of preparing the same

Abstract

The application belongs to the technical field of biological medicine, and discloses a kind of pharmaceutical composition for oral mucositis and preparation method thereof.The pharmaceutical composition is composed of traditional Chinese medicine extract component 55~70wt% and chemical component 30~45wt%, traditional Chinese medicine extract component is composed of white and extract 30~44wt%, Huangqin extract 20~28wt%, Huangqi extract 15~22wt%, Huanglian extract 8~15wt%, borneol 3~5wt%, and chemical component is composed of sodium hyaluronate 25~38wt%, D-panthenol 22~30wt%, allantoin 18~25wt%, dipotassium glycyrrhizinate 15~22wt%.The traditional Chinese medicine extract component in the application follows the compatibility principle of monarch, minister, assistant and messenger, and has integrated treatment effect of anti-inflammatory, repair, pain relief and infection prevention after being matched with chemical component, can significantly reduce the level of inflammation factor of oral mucositis, and significantly shorten the healing time of oral mucositis.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology and relates to a pharmaceutical composition for oral mucositis and its preparation method. Background Technology

[0002] Oral mucositis is a type of lesion characterized by inflammation, erosion, ulceration, and damage to the epithelial cells of the oral mucosa. It can be induced by various factors such as trauma, infection, immune disorders, drugs, radiotherapy, and chemotherapy. Clinical manifestations include redness, swelling, burning pain, ulceration, bleeding, dry mouth, and abnormal taste. In severe cases, secondary infections, eating disorders, and malnutrition may occur. It is a relatively common oral mucosal disease in clinical practice.

[0003] Oral mucositis (OM) induced by radiotherapy and chemotherapy is the most common and dose-limiting complication of radiotherapy and chemotherapy for malignant tumors, especially prevalent in the treatment of breast cancer, gynecological tumors (cervical cancer, ovarian cancer), and head and neck tumors. Chemotherapy drugs, as systemic cytotoxic agents, can directly kill rapidly proliferating epithelial cells in the oral mucosa, causing mucosal barrier damage, inflammatory infiltration, oxidative stress damage, and cell apoptosis, thereby inducing oral mucositis. Radiotherapy, especially head and neck radiotherapy, can directly damage mucosal tissue through ionizing radiation, leading to oral mucositis. This type of oral mucositis has a high complication rate, is prone to fungal, bacterial, or viral infections, and is accompanied by severe pain and malnutrition, affecting the progress of tumor treatment and patient prognosis.

[0004] Currently, clinically used drugs for treating oral mucositis caused by radiotherapy and chemotherapy are mainly single-function symptomatic treatments, and can be divided into the following categories: mucosal protectants, such as hyaluronic acid preparations, sucralfate, and pectin, which only achieve physical coverage of the mucosa and have a short duration of action; local analgesics, such as lidocaine mouthwash, which only relieve pain and cannot repair the mucosa or block the damage process; mucosal repair promoters, such as recombinant human epidermal growth factor (rhEGF) and vitamin preparations, which have poor stability and are easily inactivated in the oral environment; and anti-infective drugs, such as antifungal drugs like nystatin and fluconazole, antiviral drugs, and antibiotics, which only treat secondary infections and cannot prevent mucosal damage, and long-term use can easily lead to drug resistance. Therefore, developing a drug composition with integrated therapeutic effects has important clinical value for improving patient symptoms and ensuring the smooth implementation of tumor treatment. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention provides a pharmaceutical composition for oral mucositis and its preparation method. The pharmaceutical composition comprises 55-70 wt% of a traditional Chinese medicine extract and 30-45 wt% of a chemical component. The traditional Chinese medicine extract consists of 30-44 wt% of Bletilla striata extract, 20-28 wt% of Scutellaria baicalensis extract, 15-22 wt% of Astragalus membranaceus extract, 8-15 wt% of Coptis chinensis extract, and 3-5 wt% of borneol. The chemical component consists of 25-38 wt% of sodium hyaluronate, 22-30 wt% of D-panthenol, 18-25 wt% of allantoin, and 15-22 wt% of dipotassium glycyrrhizate. The traditional Chinese medicine extract components of this invention are formulated according to the principles of traditional Chinese medicine principles (principal, assistant, adjuvant, and guide), and when combined with the chemical component, they exhibit an integrated therapeutic effect of anti-inflammatory, repairing, analgesic, and anti-infective properties. This significantly reduces the level of inflammatory factors at the site of oral mucositis and significantly shortens the healing time of oral mucositis.

[0006] On one hand, the present invention provides a pharmaceutical composition for oral mucositis, the pharmaceutical composition comprising 55-70 wt% of a traditional Chinese medicine extract component and 30-45 wt% of a chemical component;

[0007] Furthermore, the herbal extract components consist of 30-44 wt% Bletilla striata extract, 20-28 wt% Scutellaria baicalensis extract, 15-22 wt% Astragalus membranaceus extract, 8-15 wt% Coptis chinensis extract, and 3-5 wt% Borneol; the chemical components consist of 25-38 wt% Sodium hyaluronate, 22-30 wt% D-panthenol, 18-25 wt% Allantoin, and 15-22 wt% Dipotassium glycyrrhizate.

[0008] Preferably, the herbal extract components consist of 44wt% Bletilla striata extract, 25wt% Scutellaria baicalensis extract, 19wt% Astragalus membranaceus extract, 8wt% Coptis chinensis extract, and 4wt% Borneol; the chemical components consist of 25wt% Sodium hyaluronate, 30wt% D-panthenol, 25wt% Allantoin, and 20wt% Dipotassium glycyrrhizate.

[0009] Furthermore, the content of 1,4-bis[4-(glucosyloxy)benzyl]-2-isobutylmalate in the Bletilla striata extract is not less than 1.5%; The content of baicalin in the Scutellaria baicalensis extract is not less than 85%; The Astragalus extract contains not less than 0.08% astragaloside A, not less than 0.02% isoflavone glucoside, and not less than 40% astragalus polysaccharide. The content of berberine hydrochloride in the Coptis chinensis extract is not less than 5.0%.

[0010] On the other hand, the present invention claims protection for a gel formulation in which the active ingredient is the above-mentioned pharmaceutical composition; The gel formulation consists of 5-10 wt% pharmaceutical composition, 1.3-2.6 wt% gel matrix, 6-15 wt% humectant, and distilled water to make up the balance; The gel matrix is ​​composed of 1-2 wt% carbomer-940 and 0.3-0.6 wt% triethanolamine; The moisturizer consists of 5-10 wt% glycerin and 1-5 wt% propylene glycol.

[0011] On the other hand, the present invention claims protection for a method for preparing the above-mentioned gel formulation, comprising: preparing a carbomer gel matrix, adding a humectant to the carbomer gel matrix, then adding a borneol solution, adding other traditional Chinese medicine extract components other than borneol after a first stirring, stirring a second time, then adding chemical components, and stirring a third time and allowing it to stand for defoaming for 2 hours to obtain the gel formulation.

[0012] Furthermore, the preparation method of the carbomer gel matrix is ​​as follows: Carbomer-940 is sprinkled on the surface of distilled water and allowed to swell for 24 hours. Then, triethanolamine is added, and the mixture is stirred at 200-300 rpm for 10-20 minutes. The pH of the system is adjusted to 6.5-7.0 to obtain the carbomer gel matrix.

[0013] Furthermore, the solvent used to dissolve the borneol solution is 95 vol% ethanol, and the solid-liquid ratio of borneol to solvent is 1:8; The first stirring speed is 200~250 rpm, and the time is 10~15 min; The second stirring speed is 200~300 rpm, and the time is 10~20 min; The third stirring speed is 200~300 rpm, and the time is 10~15 min.

[0014] Furthermore, the present invention seeks protection for the use of the above-described pharmaceutical composition or gel preparation in the preparation of a medicament for treating oral mucositis caused by radiotherapy and / or chemotherapy.

[0015] Furthermore, the pharmaceutical composition or the gel preparation shortens the healing time for oral mucositis.

[0016] Specifically, this invention, by applying a gel formulation containing the aforementioned pharmaceutical composition as the active ingredient, to patients with oral mucositis caused by radiotherapy and chemotherapy, significantly shortened the healing period for moderate to severe oral mucositis. The healing time for grade II oral mucositis was only 2.2–2.6 days, and for grade III, it was 6.5–7.4 days, compared to 9.5–10 days for grade II and 18.3–18.7 days for grade III in the control group. Compared to the conventional natural course of 14–21 days for moderate to severe oral mucositis, this invention can shorten the healing time by more than 60%, demonstrating significant clinical therapeutic advantages and broad application prospects in the treatment of oral mucositis caused by radiotherapy and chemotherapy.

[0017] Furthermore, the pharmaceutical composition or the gel formulation reduces the level of inflammatory factors at the site of oral mucosal inflammation; The inflammatory factors include IL-1 1β, IL 6. TNF α.

[0018] Specifically, the present invention conducted in vitro pharmacodynamic experiments on a gel formulation containing the above-mentioned pharmaceutical composition as the active ingredient and found that, compared with the blank control group, the IL-1 concentration in the tongue mucosa tissue of the model group mice was significantly higher. 1β, IL 6. TNF The levels of α-inflammatory factors were significantly increased, and the difference was statistically significant. P <0.01), compared with the model group, the levels of inflammatory factors in mice in the drug groups of Examples 1-4 were significantly reduced, and the differences were statistically significant ( P <0.01), compared with the control group, the expression levels of inflammatory factors in mice in the drug groups of Examples 1-4 were significantly reduced, and the differences were statistically significant. P <0.05). This indicates that the gel formulation of the present invention has a significant effect in reducing IL-1 in the treatment of oral mucositis by radiotherapy and chemotherapy. 1β, IL 6. TNF The effect of α expression level is better than that of anti-inflammatory effect.

[0019] Compared with the prior art, the technical solution provided by the present invention has at least the following beneficial effects or advantages: (1) The pharmaceutical composition of the present invention is composed of traditional Chinese medicine extracts and chemical components, wherein the traditional Chinese medicine extracts account for 55-70 wt% and the chemical components account for 30-45 wt%. The traditional Chinese medicine extracts consist of 30-44 wt% Bletilla striata extract, 20-28 wt% Scutellaria baicalensis extract, 15-22 wt% Astragalus membranaceus extract, 8-15 wt% Coptis chinensis extract, and 3-5 wt% Borneol. The combination of the traditional Chinese medicine extracts in the present invention follows the principle of monarch, minister, assistant, and guide in drug formulation. Bletilla striata extract is the monarch drug, which has the functions of film formation, tissue regeneration, and wound protection. Scutellaria baicalensis extract is the minister drug, which has the functions of anti-inflammatory and antioxidant. Astragalus membranaceus extract and Coptis chinensis extract are the assistant drugs, which have the functions of promoting repair, strengthening the body, antibacterial, and anti-infective. Borneol is the guide drug, which can synergistically relieve pain and enhance penetration and efficacy. The pharmaceutical composition of the present invention, when combined with the chemical components, has an integrated therapeutic effect of anti-inflammatory, repair, analgesia, and anti-infection, and has a better effect on oral mucositis caused by radiotherapy and chemotherapy. In the above-mentioned drug composition, Bletilla striata polysaccharide, sodium hyaluronate, and gel matrix can form a long-lasting protective film on the oral mucosa, resisting saliva erosion and providing a long-lasting effect; Scutellaria baicalensis extract, Astragalus membranaceus extract, dipotassium glycyrrhizate, and allantoin address the inflammation, oxidative stress, and apoptosis caused by radiotherapy and chemotherapy at the source; Bletilla striata extract, Astragalus membranaceus extract, D-panthenol, and sodium hyaluronate can accelerate epithelial regeneration and repair ulcer wounds; borneol provides cooling and analgesic relief without damaging the mucosa, and borneol can promote the mucosal penetration of the active ingredients and improve bioavailability.

[0020] (2) The pharmaceutical composition of the present invention can reduce the level of inflammatory factors in oral mucositis caused by radiotherapy and chemotherapy. In vitro pharmacodynamic experiments were conducted on a gel formulation containing the above-mentioned pharmaceutical composition as the active ingredient. The results showed that, compared with the blank control group, the level of IL-1 in the tongue mucosa tissue of the model group mice was significantly lower. 1β, IL 6. TNF The levels of α-inflammatory factors were significantly increased, and the difference was statistically significant. P <0.01), compared with the model group, the levels of inflammatory factors in mice in the drug groups of Examples 1-4 were significantly reduced, and the differences were statistically significant ( P <0.01), compared with the control group, the expression levels of inflammatory factors in mice in the drug groups of Examples 1-4 were significantly reduced, and the differences were statistically significant. P <0.05). This indicates that the gel formulation of the present invention has a significant effect in reducing IL-1 in the treatment of oral mucositis by radiotherapy and chemotherapy. 1β, IL 6. TNF The effect of α expression level is better than that of anti-inflammatory effect.

[0021] (3) The pharmaceutical composition of the present invention can significantly shorten the healing time of oral mucositis caused by radiotherapy and chemotherapy. When the gel preparation containing the above-mentioned pharmaceutical composition as the active ingredient was used in patients with oral mucositis caused by radiotherapy and chemotherapy, the healing cycle of moderate to severe oral mucositis was significantly shortened. The healing time for grade II oral mucositis was only 2.2–2.6 days, and for grade III it was 6.5–7.4 days, while in the control group it was 9.5–10 days for grade II and 18.3–18.7 days for grade III. Compared with the conventional natural course of moderate to severe oral mucositis (14–21 days), the present invention can shorten the healing time by more than 60%, demonstrating significant clinical therapeutic advantages and broad application prospects in the treatment of oral mucositis caused by radiotherapy and chemotherapy. Attached Figure Description

[0022] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0023] Figure 1 Images of a patient with oral mucositis before treatment with the gel formulation of this invention.

[0024] Figure 2 This image shows the recovery of oral mucositis after treatment with the gel formulation of this invention. Detailed Implementation

[0025] The technical solution of the present invention will be described below with reference to embodiments. However, the present invention is not limited to the following embodiments. Unless otherwise specified, the experimental methods and detection methods described in each embodiment are conventional methods; unless otherwise specified, the reagents and materials can be purchased commercially. Unless otherwise specified, the percentages in the following embodiments refer to mass percentages.

[0026] The Chinese medicinal herbs Bletilla striata, Scutellaria baicalensis, Phellodendron chinense, Astragalus membranaceus, and Coptis chinensis were all purchased from the Chencang District Medicinal Herbs Company in Baoji City.

[0027] The borneol was purchased from Jiangxi Yuanshangcao Spices Co., Ltd., CAS No. 507-70-0, with a purity of 96%.

[0028] Sodium hyaluronate was purchased from Guangdong (Huarong) Pharmaceutical Co., Ltd., CAS No. 9004-61-9, with a purity of 98%.

[0029] D-Panthenol (provitamin B5) was purchased from Nanjing Bermuda Biotechnology Co., Ltd., CAS No. 81-13-0, with a purity of 99%.

[0030] Allantoin was purchased from Wuhan Huajiu Pharmaceutical Technology Co., Ltd., CAS No. 97-59-6, with a purity of 99%.

[0031] Dipotassium glycyrrhizate was purchased from Jiangsu Orlistat Pharmaceutical Co., Ltd., CAS No. 68797-35-3, with a purity of 99%.

[0032] The pectin was purchased from Sichuan Huanxu Biotechnology Co., Ltd., CAS No. 9000-69-5, with a purity of 99%.

[0033] Bletilla striata extract was prepared by water extraction and alcohol precipitation. Bletilla striata tubers were washed, sliced, dried at 60℃, and pulverized through a 60-mesh sieve. The solid-liquid ratio of Bletilla striata powder to water was 1:8. The extraction temperature was 95℃, and the extraction time was 2 hours. The mixture was filtered through a 200-mesh filter cloth, and the extraction was repeated three times. The filtrates were combined and concentrated under reduced pressure to a relative density of 1.10~1.15 (60℃). 95 vol% ethanol was added to bring the alcohol content to 70 vol%. The mixture was allowed to stand at 4℃ for 24 hours, centrifuged at 5000 rpm for 20 minutes, and the precipitate was freeze-dried at -40℃ and a vacuum of less than 10 Pa for 48 hours to obtain the Bletilla striata extract. The content of 1,4-bis[4-(glucoseoxy)benzyl]-2-isobutyl malate was determined to be no less than 1.5%.

[0034] Scutellaria baicalensis extract was prepared by water extraction and alcohol precipitation. Scutellaria baicalensis root was washed, dried, and pulverized through a 40-mesh sieve. The ratio of Scutellaria baicalensis root to water was 1:20. The extraction temperature was 95℃ and the extraction time was 3h. The extract was filtered through a 200-mesh filter cloth and the process was repeated three times. The filtrates were combined and concentrated under reduced pressure to a relative density of 1.10~1.20 (60℃). 95 vol% ethanol was added to bring the alcohol content to 70 vol%. The extract was allowed to stand at 4℃ for 24h and centrifuged at 5000 rpm for 10min. The precipitate was dried at 60℃ and a vacuum of 0.08 MPa for 4h to obtain Scutellaria baicalensis extract. The content of baicalin was determined to be no less than 85%.

[0035] Astragalus extract was prepared by water extraction and alcohol precipitation. Astragalus roots were washed, sliced, dried at 60℃, and pulverized through a 20-mesh sieve. The ratio of astragalus root to water was 1:10. The extraction temperature was 100℃, and the extraction time was 1.5 h. The extract was filtered through a 200-mesh filter cloth, and the process was repeated three times. The filtrates were combined and concentrated under reduced pressure to a relative density of 1.10~1.20 (room temperature). 95 vol% ethanol was added to bring the alcohol content to 70 vol%, and the extract was allowed to stand at room temperature for 2 h, then allowed to stand at 4℃ for 22 h. The extract was then centrifuged at 5000 rpm for 10 min at 4℃. The precipitate was dried at 60℃ under a vacuum of 0.08 MPa for 4 h to obtain the astragalus extract. The astragaloside A content was determined to be no less than 0.08%, the verbascoside isoflavone glucoside content no less than 0.02%, and the astragalus polysaccharide content no less than 40%.

[0036] Coptis chinensis extract was prepared by water extraction and alcohol precipitation. Coptis chinensis root was washed, the fibrous roots were removed, dried at 60℃, and pulverized through a 20-mesh sieve. The ratio of Coptis chinensis root to water was 1:10, the extraction temperature was 90℃, and the extraction was performed three times for 1.5h, 1.5h, and 1h respectively. After each extraction, the extract was filtered through a 200-mesh filter cloth. The filtrates were combined and concentrated under reduced pressure to a relative density of 1.10~1.20 (60℃). 95 vol% ethanol was added to bring the alcohol content to 70 vol%, and the extract was allowed to stand at 4℃ for 24h. After centrifugation at 5000 rpm for 15min, the precipitate was dried at 60℃ and a vacuum of 0.08 MPa for 4h to obtain Coptis chinensis extract with a berberine hydrochloride content of not less than 5.0%.

[0037] Example 1 This embodiment provides the preparation of a gel formulation of a pharmaceutical composition for oral mucositis.

[0038] S1: Preparation of the pharmaceutical composition: Bletilla striata extract, Scutellaria baicalensis extract, Astragalus membranaceus extract, Coptis chinensis extract, and borneol were weighed according to a mass ratio of 30:28:22:15:5 to obtain the traditional Chinese medicine extract components. Sodium hyaluronate, D-panthenol, allantoin, and dipotassium glycyrrhizate were weighed according to a mass ratio of 35:25:20:20 and mixed evenly to obtain the chemical components.

[0039] S2: Gel preparation. Carbomer-940, triethanolamine, glycerol, propylene glycol, traditional Chinese medicine extract components, chemical components, and distilled water were weighed out in a mass ratio of 1.5:0.5:8:3:4.4:3.6:79. Borneol from the traditional Chinese medicine extract components was dissolved in 95 vol% ethanol at a solid-liquid ratio of 1:8. The solution was stirred at room temperature for 15 min until clear, yielding a borneol solution. Carbomer-940 was sprinkled onto the surface of distilled water and allowed to swell for 24 h. Triethanolamine was then added, and the mixture was stirred at 200 rpm for 20 min. The pH of the system was adjusted to 6.5–7.0 to obtain the carbomer gel matrix. Glycerol and propylene glycol were added sequentially to the carbomer gel matrix, followed by the slow addition of the borneol solution. The mixture was stirred at 200 rpm for 15 min, then the other traditional Chinese medicine extract components (excluding borneol) were added, and the mixture was stirred at 200 rpm for 10 min. The chemical components were then added, and the mixture was stirred at 200 rpm for 15 min. The mixture was then allowed to stand for 2 h to remove bubbles, yielding the gel formulation.

[0040] Example 2 This embodiment provides the preparation of a gel formulation of a pharmaceutical composition for oral mucositis.

[0041] S1: Preparation of the pharmaceutical composition: Bletilla striata extract, Scutellaria baicalensis extract, Astragalus membranaceus extract, Coptis chinensis extract, and borneol were weighed according to a mass ratio of 38:20:22:15:5 to obtain the traditional Chinese medicine extract components. Sodium hyaluronate, D-panthenol, allantoin, and dipotassium glycyrrhizate were weighed according to a mass ratio of 30:30:25:15 and mixed evenly to obtain the chemical components.

[0042] S2: Gel preparation. Carbomer-940, triethanolamine, glycerol, propylene glycol, traditional Chinese medicine extract components, chemical components, and distilled water were weighed out in a mass ratio of 1:0.3:5:1:2.5:2.5:87.7. Borneol from the traditional Chinese medicine extract components was dissolved in 95 vol% ethanol at a solid-liquid ratio of 1:8. The solution was stirred at room temperature for 15 min until clear, yielding a borneol solution. Carbomer-940 was sprinkled onto the surface of distilled water and allowed to swell for 24 h. Triethanolamine was then added, and the mixture was stirred at 250 rpm for 15 min. The pH of the system was adjusted to 6.5–7.0 to obtain the carbomer gel matrix. Glycerol and propylene glycol were added sequentially to the carbomer gel matrix, followed by the slow addition of the borneol solution. The mixture was stirred at 250 rpm for 10 min, then the other traditional Chinese medicine extract components (excluding borneol) were added, and the mixture was stirred at 250 rpm for 10 min. The chemical components were then added, and the mixture was stirred at 250 rpm for 15 min. The mixture was then allowed to stand for 2 h to remove bubbles, yielding the gel formulation.

[0043] Example 3 This embodiment provides the preparation of a gel formulation of a pharmaceutical composition for oral mucositis.

[0044] S1: Preparation of the pharmaceutical composition: Bletilla striata extract, Scutellaria baicalensis extract, Astragalus membranaceus extract, Coptis chinensis extract, and borneol were weighed according to a mass ratio of 44:25:19:8:4 to obtain the traditional Chinese medicine extract components. Sodium hyaluronate, D-panthenol, allantoin, and dipotassium glycyrrhizate were weighed according to a mass ratio of 25:30:25:20 and mixed evenly to obtain the chemical components.

[0045] S2: Gel preparation. Carbomer-940, triethanolamine, glycerol, propylene glycol, traditional Chinese medicine extract components, chemical components, and distilled water were weighed out in a mass ratio of 2:0.6:10:5:7:3:72.4. Borneol from the traditional Chinese medicine extract components was dissolved in 95 vol% ethanol at a solid-liquid ratio of 1:8. The solution was stirred at room temperature for 15 min until clear, yielding a borneol solution. Carbomer-940 was sprinkled onto the surface of distilled water and allowed to swell for 24 h. Triethanolamine was then added, and the mixture was stirred at 300 rpm for 10 min. The pH of the system was adjusted to 6.5–7.0 to obtain the carbomer gel matrix. Glycerol and propylene glycol were added sequentially to the carbomer gel matrix, followed by the slow addition of the borneol solution. The mixture was stirred at 200 rpm for 10 min, then the other traditional Chinese medicine extract components (excluding borneol) were added, and the mixture was stirred at 300 rpm for 20 min. The chemical components were then added, and the mixture was stirred at 300 rpm for 10 min. The mixture was then allowed to stand for 2 h to remove bubbles, yielding the gel formulation.

[0046] Example 4 This embodiment provides the preparation of a gel formulation of a pharmaceutical composition for oral mucositis.

[0047] S1: Preparation of the pharmaceutical composition: Bletilla striata extract, Scutellaria baicalensis extract, Astragalus membranaceus extract, Coptis chinensis extract, and borneol were weighed according to a mass ratio of 44:28:15:10:3 to obtain the traditional Chinese medicine extract components. Sodium hyaluronate, D-panthenol, allantoin, and dipotassium glycyrrhizate were weighed according to a mass ratio of 38:22:18:22 and mixed evenly to obtain the chemical components.

[0048] S2: Gel preparation. Carbomer-940, triethanolamine, glycerol, propylene glycol, traditional Chinese medicine extract components, chemical components, and distilled water were weighed out in a mass ratio of 1.5:0.5:8:3:4.4:3.6:79. Borneol from the traditional Chinese medicine extract components was dissolved in 95 vol% ethanol at a solid-liquid ratio of 1:8. The solution was stirred at room temperature for 15 min until clear, yielding a borneol solution. Carbomer-940 was sprinkled onto the surface of distilled water and allowed to swell for 24 h. Triethanolamine was then added, and the mixture was stirred at 200 rpm for 20 min. The pH of the system was adjusted to 6.5–7.0 to obtain the carbomer gel matrix. Glycerol and propylene glycol were added sequentially to the carbomer gel matrix, followed by the slow addition of the borneol solution. The mixture was stirred at 200 rpm for 15 min, then the other traditional Chinese medicine extract components (excluding borneol) were added, and the mixture was stirred at 200 rpm for 10 min. The chemical components were then added, and the mixture was stirred at 200 rpm for 15 min. The mixture was then allowed to stand for 2 h to remove bubbles, yielding the gel formulation.

[0049] Comparative Example 1 The preparation method of the gel formulation of the comparative pharmaceutical composition is the same as that in Example 2, except that: in S1, Scutellaria baicalensis extract is replaced with Phellodendron chinense extract (the preparation method is the same as that of Scutellaria baicalensis extract, and the content of berberine hydrochloride is not less than 30%), and the mass ratio of Bletilla striata extract, Phellodendron chinense extract, Astragalus membranaceus extract, Coptis chinensis extract and borneol is 20:38:22:15:5.

[0050] Comparative Example 2 The preparation method of the gel formulation of the comparative pharmaceutical composition is the same as that in Example 2, except that: Astragalus membranaceus is not added to the traditional Chinese medicine composition in S1, and the missing amount of Astragalus membranaceus is replaced by Scutellaria baicalensis.

[0051] Comparative Example 3 The preparation method of the gel formulation of the comparative pharmaceutical composition is the same as that in Example 2, except that in S1, sodium hyaluronate is replaced with pectin in an equal amount.

[0052] Example 5 This embodiment provides an in vitro pharmacodynamic experiment of a pharmaceutical composition gel formulation.

[0053] The experimental material consisted of BALB / c mice (SPF grade, 6-8 weeks old, weighing 18-22g), which were randomly divided into 8 groups (blank control group, model group, drug groups of Examples 1-4, and drug groups of Comparative Examples 1-3), with 9 BALB / c mice in each group. After one week of acclimatization, mice were intraperitoneally injected with 50mg / kg and 40mg / kg on days 1 and 3, respectively. FU (solvent is physiological saline, injection volume ≤0.5mL / mouse) was injected, followed by intraperitoneal anesthesia with 1% sodium pentobarbital solution (45mg / kg) 30min later. Then, the mice were irradiated with a 6MV X-ray linear accelerator (2000cGy, divided into four irradiations of 500cGy each), with an irradiation field area of ​​30cm×10cm. The muzzle of the mice was placed in the irradiation field, with a source-to-skin distance of 100cm. On the 2nd and 4th days, a 0.5cm×0.5cm area was superficially scraped with a sterile 18-gauge syringe needle (diameter 1.27mm). The needle scraped 10 times to complete mechanical stimulation (3% isoflurane inhalation anesthesia was used before mechanical stimulation, and the isoflurane concentration was maintained at 1%). The scraping continued until the mucosa was congested but not bleeding. The blank control group did not receive injection, mechanical stimulation, or irradiation, but only underwent the same anesthesia procedure. The model group mice developed ulcers on the 4th day (OMI score ≥3 points).

[0054] Dosage regimen: from injection 5 FU was administered starting on day 1 and continued until day 7, twice daily at 10:00 AM and 4:00 PM. Before administration, 3% isoflurane was used for inhalation anesthesia, with the isoflurane concentration maintained at 1%. Subsequently, 0.2 mL of the gel preparation was placed on a sterile cotton swab and thoroughly applied to the entire oral mucosa for 30 seconds. After administration, patients were kept from eating or drinking for 30 minutes. The model group used a blank gel without the drug composition to apply to the oral cavity, while the blank control group used sterile water. On day 7 of the experiment, the oral mucositis index (OMI) score (Table 1) was calculated, and samples were collected (whole tongue tissue, flash-frozen in liquid nitrogen, and stored at -80°C). The OMI score was calculated using a double-blind method.

[0055] The oral mucositis index scoring method is as follows: 0 points: The mucous membrane is completely healthy, with no vasodilation or erosion; 1 point: Mild erythema and local vasodilation of the mucosa, no mucosal erosion observed; 2 points: Severe erythema and vasodilation of the mucosa, accompanied by superficial erosion; 3 points: The total area of ​​mucosal ulcers accounts for less than 25% of the buccal mucosa area; 4 points: The total area of ​​mucosal ulcers accounts for about 25-50% of the buccal mucosa area, and the mucosal extensibility is reduced; 5 points: Mucosal ulcers almost cover the buccal mucosa, and the mucosal extensibility is reduced.

[0056] Inflammatory factor detection: Tongue mucosal tissue samples were placed in a glass homogenizer, and an appropriate amount of lysis buffer (w / v 1:9) was added. The mixture was then subjected to ice-based operation until fully lysed. The lysate was then analyzed for inflammatory factors (ELISA method), including IL-12. 1β, IL 6. TNF α level was analyzed using SPSS 26.0 software. Quantitative data were expressed as mean ± standard deviation (σ). Mean ± standard deviation (S) indicates the mean. One-way ANOVA was used for comparisons among multiple groups, and LSD-t tests were used for pairwise comparisons between groups. P <0.05 indicates a statistically significant difference. The test results are shown in Table 2.

[0057] Table 1. OMI scores of mice in each treatment group

[0058] Table 2. Results of inflammatory factor content detection in mice of each treatment group

[0059] Table 1 shows that the tongue mucosa of mice in the blank control group was healthy, with an OMI score of 0. In the model group, mice developed erythematous lesions of the tongue mucosa on day 4 after modeling, and by day 7, the lesions had progressed to large-area ulcers, almost completely covering the tongue mucosa, with an OMI score of 4.44. The tongue mucosa lesions in the drug groups of Examples 1-4 were milder, mainly manifesting as mild erythema, local vasodilation, and mild superficial erosion. The OMI scores of the drug groups of Examples 1-4 were statistically significantly different from those of the model group. P <0.01), there was no statistically significant difference between the drug groups in each example ( P >0.05). In comparative groups 1-3, the ulceration of the tongue mucosa in mice was reduced compared to the model group, but obvious ulceration was still visible. The OMI score was statistically significantly different from that in the model group. P <0.05), the OMI score of mice in the drug group of Example 3 was significantly different from that in the drug group of Comparative Example 1 (the difference was not specified in the original text). P <0.05).

[0060] Table 2 shows that, compared with the blank control group, the IL-1 levels in the tongue mucosa tissue of the model group mice were significantly higher. 1β, IL 6. TNF The levels of α-inflammatory factors were significantly increased, and the difference was statistically significant. P <0.01), compared with the model group, the levels of inflammatory factors in mice in the drug groups of Examples 1-4 were significantly reduced, and the differences were statistically significant ( P <0.01), compared with the control group, the expression levels of inflammatory factors in mice in the drug groups of Examples 1-4 were significantly reduced, and the differences were statistically significant. P <0.05). This indicates that the gel formulation of the present invention has a significant effect in reducing IL-1 in the treatment of oral mucositis by radiotherapy and chemotherapy. 1β, IL 6. TNF The effect of α expression level is better than that of anti-inflammatory effect.

[0061] Comparative Example 1 replaced the assistant herb Scutellaria baicalensis with Phellodendron amurense and increased its dosage to exceed that of the principal herb Bletilla striata. This violated the principles of herbal compatibility and resulted in a significant decrease in overall efficacy. Furthermore, Phellodendron amurense is bitter, cold, and has a stronger drying effect than Scutellaria baicalensis. Its properties are also more pronounced in the lower part of the body, making it unsuitable for damaged oral mucosa. This leads to increased irritation and pain, as well as excessive dryness and cracking of the mucosal wounds, resulting in a significant decrease in patient compliance. Additionally, the synergistic effect of Phellodendron amurense with Coptis chinensis and borneol is much weaker than that with Scutellaria baicalensis, resulting in a reduced local anti-inflammatory effect, decreased utilization of active ingredients, significantly reduced treatment efficacy for oral mucositis, and delayed mucosal healing.

[0062] Astragalus extract and Coptis extract, as adjuvant drugs, have the effects of promoting repair, strengthening the body, antibacterial and anti-infective. In Comparative Example 2, the Chinese medicine composition lacks Astragalus extract and replaces it with Scutellaria baicalensis. This not only loses the key adjuvant drug effects of replenishing qi and promoting tissue regeneration, strengthening the body and fighting infection, and harmonizing the properties of the medicine, but also results in an excessive amount of bitter and cold medicinal properties, increased irritation, and an imbalance in compatibility. It becomes an unbalanced formula that only focuses on clearing heat and does not repair, ultimately leading to slow mucosal healing, increased pain, easy infection and recurrence, and a significant decrease in overall efficacy.

[0063] Sodium hyaluronate is the core functional component in the chemical composition of this invention, possessing mucosal protection, long-lasting moisturizing, healing and repair promotion, and sustained-release effects of active ingredients. Comparative Example 3 replaced it with a similar component, pectin. However, pectin has poor film-forming properties, the film layer is brittle and easily broken, unable to form a stable protective barrier, and its moisturizing ability is extremely weak, failing to maintain wound moisture. Furthermore, pectin is easily dissolved and washed away in the saliva environment, significantly shortening the residence time of the gel and active ingredients on the mucosal surface, resulting in insufficient local effective concentration, a sharp drop in bioavailability, and continuous exposure of erosions and ulcers, directly leading to a significant increase in burning, stinging, and pulling pain, and a significant decrease in patient medication compliance. Pectin also lacks a three-dimensional network drug-carrying structure, failing to sustain the release of components, resulting in rapid drug release, large concentration fluctuations, and an inability to sustain anti-inflammatory and repair effects, significantly reducing overall efficacy.

[0064] Example 6 This embodiment provides the application of a gel formulation of a pharmaceutical composition in OM.

[0065] 1. Clinical Data 1.1 Diagnostic criteria All cases observed were from Taian Cancer Hospital. The patients (40 in total) were diagnosed with malignant tumors (such as head and neck tumors, breast cancer, and cervical cancer) and were receiving or about to receive radiotherapy and chemotherapy (radiotherapy dose ≥30Gy, and chemotherapy regimens containing fluorouracil, paclitaxel, cisplatin, etc., which are prone to inducing oral mucositis).

[0066] The oral mucositis was diagnosed as being caused by radiotherapy and chemotherapy, meeting the diagnostic criteria for radiotherapy-related oral mucositis in the "Guidelines for the Diagnosis and Treatment of Tumor Treatment-Related Oral Mucositis." The symptoms included oral mucosal hyperemia, erythema, erosion, and ulceration, with or without pain. The oral mucositis was graded according to WHO classifications I to III (excluding grade IV, i.e., ulcer confluent, bleeding, necrosis, and inability to eat; these patients are too severely ill and require priority symptomatic and supportive treatment, and are not included in the efficacy evaluation scope of this gel).

[0067] WHO scoring criteria for oral mucositis: Level 0: No abnormalities; Grade I: Oral mucosal erythema, painless; Grade II: Erythema, ulceration, solid food can be consumed; Grade III: Ulcers worsen, only able to consume liquid food; Grade IV: Ulcers fused, bleeding, necrosis, unable to eat.

[0068] 1.2 Age Standards Age 18-75 years old, gender not limited; conscious, able to accurately express their own pain sensations, cooperate in completing ulcer area measurement and related tests, and have good compliance.

[0069] 1.3 Physical Condition Standards The patient's Karnofsky Performance Status (KPS) score is ≥60, and they are able to eat independently (those with grade I-II mucositis can eat solid food, and those with grade III can eat liquid food). They have no serious underlying diseases such as severe liver or kidney dysfunction, cardiovascular or cerebrovascular diseases, or coagulation disorders.

[0070] The routine blood test results were basically normal (white blood cell count ≥3.0×10⁻⁶). 9 / L, platelets ≥100×10 9 / L, hemoglobin ≥90g / L), liver and kidney function (ALT, AST, Cr, BUN) indicators within the normal reference range or slightly abnormal (abnormal value ≤1.5 times the upper limit of normal), and no obvious systemic infection symptoms.

[0071] No oral deformities, severe periodontal disease, oral fungal infections (such as thrush), or other oral diseases, and no history of oral surgery (within the past 3 months).

[0072] 1.4 Medication Standards Students should not have used other medications for treating oral mucositis (such as mouthwash, oral ulcer powder, glucocorticoids, growth factor drugs, etc.) within 7 days prior to enrollment to avoid drug interactions that could affect efficacy evaluation. Those who had not received local oral radiotherapy before enrollment (except those who had only received systemic chemotherapy or radiotherapy for head and neck tumors but whose oral mucosa was not involved); No history of allergy to any of the ingredients in this gel formulation (Bletilla striata extract, Scutellaria baicalensis extract, Astragalus membranaceus extract, Coptis chinensis extract, borneol, sodium hyaluronate, D-panthenol, allantoin, dipotassium glycyrrhizate, and gel matrix excipients).

[0073] 2. Research Methods 2.1 Grouping Method The patients were divided into a treatment group and a control group based on whether they received treatment with the gel formulation of the present invention. The control group was given a blank gel matrix without the drug composition.

[0074] 2.2 Administration Method Treatment administration: The treatment group applied the gel preparation prepared in Example 3 of this invention. Before applying the gel, rinse the mouth gently with warm water to remove food debris and secretions. Gently dry the affected area with sterile gauze or cotton swabs to keep the area dry before applying the gel to enhance adhesion. Apply the gel to areas of oral mucositis (congestion, erosion, ulceration) in a focused manner. Apply the gel 4 times a day, after meals (after breakfast, lunch, and dinner) and before bedtime. Use 1 cm (about 0.5 mL of gel) each time. Usage instructions: Do not eat, drink, or rinse your mouth within 30 minutes after applying the medication, and keep your head elevated at 30° to ensure that the medication fully adheres to the mucous membrane surface; Treatment course: From the onset of oral mucositis until the ulcer is completely healed and the pain disappears (grade 0), continue medication for 3 days and then stop. The maximum treatment time should not exceed 4 weeks. If the ulcer has not healed by the maximum treatment time, it will be recorded as unhealed and another treatment plan will be adopted. Before and after oral images of some patients are shown. Figure 1 and Figure 2 Before treatment, the patient had glossitis.

[0075] Table 3. Patient grouping and WHO classification before application.

[0076] Table 4. Patient WHO classification at the end of the 1-week treatment course

[0077] Table 5 Healing time of oral mucositis in patients

[0078] As shown in Tables 3 and 4, the oral mucositis of patients treated with the gel formulation of this invention showed good recovery and significantly reduced the WHO classification of patients. At the end of the one-week treatment course, among 16 breast cancer patients with WHO classification II (6 cases) and III (10 cases), 14 patients (87.5%) recovered after treatment, and their WHO classifications all decreased to level 0. Two patients showed only erythema and no pain at the site of oral mucositis (level I). Among 17 cervical cancer patients with WHO classification II (5 cases) and III (12 cases), 13 patients (76.5%) recovered after treatment, and their WHO classifications all decreased to level 0. Four patients showed only erythema and no pain at the site of oral mucositis (level I). In contrast, at the end of the one-week treatment course, in the control group, one of the five breast cancer patients and one of the five cervical cancer patients showed a decrease in oral mucositis to level 0, with slow recovery and only a small number of patients recovering. The overall efficacy of the control group was significantly inferior to that of the treatment group.

[0079] As shown in Table 5, the gel formulation of this invention can significantly shorten the healing period of moderate to severe oral mucositis caused by radiotherapy and chemotherapy. The healing time for grade II oral mucositis is only 2.2-2.6 days, and for grade III it is 6.5-7.4 days, while in the control group it is 9.5-10 days for grade II and 18.3-18.7 days for grade III. Compared with the conventional natural course of moderate to severe oral mucositis of 14-21 days, this invention can shorten the healing time by more than 60%, demonstrating significant clinical therapeutic advantages.

[0080] As described above, the basic principles, main features, and advantages of the present invention have been well described. The above embodiments and specifications are merely descriptions of preferred embodiments of the present invention, and the present invention is not limited to the above embodiments. Various changes and improvements made to the technical solutions of the present invention by those skilled in the art without departing from the spirit and scope of the present invention should fall within the protection scope defined by the present invention.

Claims

1. A pharmaceutical composition for oral mucositis, characterized in that, The pharmaceutical composition comprises 55-70 wt% of traditional Chinese medicine extract and 30-45 wt% of chemical components; The herbal extract is composed of 30-44 wt% Bletilla striata extract, 20-28 wt% Scutellaria baicalensis extract, 15-22 wt% Astragalus membranaceus extract, 8-15 wt% Coptis chinensis extract, and 3-5 wt% Borneol. The chemical composition consists of 25-38 wt% sodium hyaluronate, 22-30 wt% D-panthenol, 18-25 wt% allantoin, and 15-22 wt% dipotassium glycyrrhizate.

2. The pharmaceutical composition according to claim 1, characterized in that, The herbal extract is composed of 44wt% Bletilla striata extract, 25wt% Scutellaria baicalensis extract, 19wt% Astragalus membranaceus extract, 8wt% Coptis chinensis extract, and 4wt% Borneol. The chemical composition consists of 25wt% sodium hyaluronate, 30wt% D-panthenol, 25wt% allantoin, and 20wt% dipotassium glycyrrhizate.

3. The pharmaceutical composition according to claim 1, characterized in that, The content of 1,4-bis[4-(glucoseoxy)benzyl]-2-isobutyl malate in the Bletilla striata extract is not less than 1.5%; The content of baicalin in the Scutellaria baicalensis extract is not less than 85%; The Astragalus extract contains not less than 0.08% astragaloside A, not less than 0.02% isoflavone glucoside, and not less than 40% astragalus polysaccharide. The content of berberine hydrochloride in the Coptis chinensis extract is not less than 5.0%.

4. A gel formulation, characterized in that, The active ingredient is the pharmaceutical composition according to any one of claims 1 to 3; The gel formulation consists of 5-10 wt% pharmaceutical composition, 1.3-2.6 wt% gel matrix, 6-15 wt% humectant, and distilled water to make up the balance; The gel matrix is ​​composed of 1-2 wt% carbomer-940 and 0.3-0.6 wt% triethanolamine; The moisturizer consists of 5-10 wt% glycerin and 1-5 wt% propylene glycol.

5. The method for preparing the gel formulation according to claim 4, characterized in that, include: To prepare a carbomer gel matrix, a humectant was added to the carbomer gel matrix, followed by the addition of a borneol solution. After a first stirring, other traditional Chinese medicine extracts (excluding borneol) were added, followed by a second stirring, and then the chemical components were added. After a third stirring, the mixture was allowed to stand for 2 hours to remove bubbles, thus obtaining the gel formulation.

6. The preparation method according to claim 5, characterized in that, The method for preparing the carbomer gel matrix is ​​as follows: Carbomer-940 is sprinkled on the surface of distilled water and allowed to swell for 24 hours. Then, triethanolamine is added, and the mixture is stirred at 200-300 rpm for 10-20 minutes. The pH of the system is adjusted to 6.5-7.0 to obtain the carbomer gel matrix.

7. The preparation method according to claim 5, characterized in that, The solvent used to dissolve the borneol solution is 95 vol% ethanol, and the solid-liquid ratio of borneol to solvent is 1:

8. The first stirring speed is 200~250 rpm, and the time is 10~15 min; The second stirring speed is 200~300 rpm, and the time is 10~20 min; The third stirring speed is 200~300 rpm, and the time is 10~15 min.

8. The use of the pharmaceutical composition according to any one of claims 1 to 3 or the gel formulation according to claim 4 in the preparation of a medicament for treating oral mucositis, characterized in that, The oral mucositis was caused by radiotherapy and / or chemotherapy.

9. The application according to claim 8, characterized in that, The pharmaceutical composition or the gel preparation shortens the healing time for oral mucositis.

10. The application according to claim 8, characterized in that, The pharmaceutical composition or the gel formulation reduces the level of inflammatory factors at the site of oral mucosal inflammation. The inflammatory factors include IL-1 1β, IL 6. TNF α.

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