Use of a traditional Chinese medicine composition in the preparation of a medicament for treating oral ulcers

Abstract

The present invention belongs to the technical field of traditional Chinese medicine, and specifically discloses an application of a traditional Chinese medicine composition in the preparation of a medicament for treating oral ulcers. The traditional Chinese medicine composition of the present invention comprises 11 medicinal materials such as total ginsenosides of ginseng stem and leaf, astragalus membranaceus, rehmannia glutinosa, Dioscorea opposita, Trichosanthes kirilowii Maxim., Rubus idaeus, Ophiopogon japonicus, Schisandra chinensis, Lycium barbarum, Alisma orientale, Poria cocos, etc. The traditional Chinese medicine composition of the present invention can significantly reduce the area of oral ulcers and effectively reduce the level of TNF-α in the oral ulcer tissues of rats; for recurrent oral ulcers caused by the decline of the immune function of rats, after intervention with the composition of the present invention, the level of CD3 + cells in the serum of rats increases, and at the same time, the ratio of CD4 + / CD8 + is up-regulated, indicating that the composition of the present invention can improve the immune function of rats and effectively treat oral ulcers caused by abnormal immune function, enriching the selectivity of clinical drug use.

Description

Technical Field

[0001] The present invention belongs to the technical field of traditional Chinese medicine, and particularly relates to the application of a traditional Chinese medicine composition in the preparation of a medicament for treating oral ulcers. Background Art

[0002] Oral ulcer (OU) is a common and frequently recurring oral disease with a high prevalence rate in the population, which can be as high as over 20%. It is generally called "oral inflammation" or "aphtha" among the people. It is a localized ulcerative injury of the oral mucosa characterized by periodic recurrence. It can heal on its own and can occur in any part of the oral mucosa. It is more common in the mucous membranes of the lips, cheeks, soft palate or gums of the oral cavity. One or more round or oval ulcers of varying sizes occur, with a grayish-white or yellowish false membrane covering the surface, a central depression, clear boundaries, and the surrounding mucous membrane is red and slightly swollen. The local pain of the ulcer is obvious, and it has the characteristics of periodicity, recurrence and self-limitation. In severe cases, it will also affect appetite and cause great inconvenience to daily diet.

[0003] Recurrent oral ulcer (ROU) is the most common type of oral ulcer disease, accounting for more than 90% of OU. Recurrent oral ulcer is also known as recurrent aphthous stomatitis, recurrent oral ulcer, and recurrent aphtha. ROU is self-limiting and occurs periodically. The course of the disease is generally 1-2 weeks, and it has obvious burning pain during the attack, which affects the patient's eating. In the "Qianjin Yaofang·Oral Diseases" by Sun Simiao in the Tang Dynasty, it has already pointed out the characteristics of this disease recurring frequently and being difficult to treat for those who relapse: "For those suffering from oral ulcers and tooth problems, they are prohibited from eating oil, noodles, wine, sauce, sour vinegar, saltiness, greasiness, dried dates, and still need to be cautious after recovery. If not cautious for a long time, it will recur soon, and once it recurs, it will be difficult to heal." It can be seen that ROU brings great pain to patients and seriously affects the quality of life of patients. Therefore, actively treating ROU has important clinical significance.

[0004] The etiology of ROU is relatively complex and there are large individual differences. It may be caused by the interaction of several factors, including abnormal immune function of the body, virus infection, metabolic disorders, vitamin deficiency, endocrine disorders, digestive function disorders, and psychological, mental and social factors. Although there is no unified conclusion on the etiology and pathogenesis so far, most scholars believe that ROU is a disease related to the immune function state, and the imbalance of immune cells and the disorder of immune function are important factors for its occurrence and recurrence. CD4 + , CD8 + , T cell subsets are important lymphocytes that play immune effector functions. CD4 + plays an inductive and auxiliary role in the process of cellular immunity, and CD8 +It plays an inhibitory and poisonous role, and the change directions of the two major cell subsets are antagonistic and coordinated with each other. Under normal circumstances, the effects between the subsets are antagonistic to each other and reach a balance. When the immune function is imbalanced, the number and ratio of each lymphocyte are disordered, thus causing the occurrence of diseases. Clinical research and animal experiments have shown that recurrent oral ulcers may be related to the disorder of the body's immune function.

[0005] According to the theoretical system of traditional Chinese medicine, there are the following causes of oral ulcers: First, being affected by the six exogenous pathogenic factors, mainly the two pathogenic factors of dryness and fire. Dryness pathogen is dry and astringent, and it is easy to damage body fluids. Fire is a yang pathogen, and its nature is upward. When body fluids are damaged and fire burns, oral ulcers occur. Therefore, oral ulcers are more likely to recur in autumn and when the climate suddenly changes. Second, improper diet. Eating too much spicy and fatty foods or being picky eaters can cause internal heat to generate, which attacks upward along the meridians, fumigates the mouth and tongue, and often consumes the yin fluids of the heart, lungs, and kidneys, resulting in oral ulcers. Third, extreme emotions. If the patient usually overthinks, is upset and sleepless, the five emotions are stagnated and transformed into fire, the heart fire is hyperactive, and it burns and fumigates the mouth and tongue upward. Or the heart fire descends to the small intestine and attacks the mouth along the meridian, both of which can cause oral ulcers in the mouth and tongue; or usually there is much anger, liver qi stagnation, the liver qi is not dredged, stagnates and transforms into fire, secretly consuming yin blood, resulting in disharmony of the thoroughfare and conception vessels. During menstruation, the menstrual qi is more stagnated, the liver fire is exuberant, and it burns the mouth and tongue upward, causing oral ulcers. Fourth, congenital yin deficiency. The patient's body is inherently deficient in yin fluids, or the yin is damaged due to long-term illness, and virtual fire is generated internally, burning the mouth and tongue, resulting in oral ulcers in the mouth and tongue. Fifth, overwork and internal injury, or long-term illness damaging the spleen, the spleen qi is damaged, water and dampness cannot be transported, and it cannot moisten the mouth and tongue, resulting in oral ulcers; or stagnation for a long time turns into heat, and damp-heat steams upward, which can also cause oral ulcers. Even more seriously, the spleen qi is extremely deficient, damaging the spleen yang, the spleen yang is insufficient, cold-dampness generates heat, which soaks the mouth upward, and oral ulcers can occur. Sixth, congenital endowment deficiency, or long-term use of cold-natured drugs, damaging the spleen and kidneys, spleen-kidney yang deficiency, internal exuberance of yin cold, cold-dampness soaks the mouth and tongue upward, cold congeals blood stasis, and over time causes oral ulcers in the mouth and tongue. In short, being affected by the six exogenous pathogenic factors of dryness and fire, and internal injury of the viscera with exuberant heat are the main pathogenic factors, and the main viscera involved are the heart and spleen (stomach).

[0006] At present, the clinical treatment methods for oral ulcers can be roughly divided into "external treatment methods" and "internal treatment methods". The "external treatment methods" mainly aim at the ulcer surface for anti-inflammatory, analgesic, antiseptic and promoting healing treatments; while the "internal treatment methods" often target immune system and metabolic disorders, and commonly use oral vitamins, antibacterial drugs, hormonal drugs or traditional Chinese medicine components for treatment. The pharmaceutical preparations for treating oral ulcers mainly include: (1) anti-inflammatory drugs: ① film agents, such as aureomycin film and compound tetracycline film; ② gargles, such as 2% tetracycline gargle, 0.12% chlorhexidine solution, etc.; ③ ointments and pastes, such as aureomycin betamethasone paste, aureomycin glycerol, etc.; ④ glucocorticoids, such as dexamethasone patches, dexamethasone paste, 0.1% or 0.5% triamcinolone ointment, 0.1% betamethasone ointment, etc.; ⑤ ultrasonic nebulizers; (2) analgesic drugs, such as 0.5% dyclonine hydrochloride solution, 3% diclofenac sodium, etc.; (3) corrosive drugs, such as 50% trichloroacetic acid, etc.; (4) biological products, such as Solcoseryl oral paste, etc.; (5) traditional Chinese medicines, such as Kouyanqing granules, oral ulcer powder, oral inflammation spray, Guilin watermelon frost, etc.

[0007] The above-mentioned treatment drugs are mainly Western medicine varieties, mostly using hormones, anesthetics, immunomodulators, and vitamins for treatment. These drugs have defects such as uncertain curative effects, many side effects, and are prone to drug resistance, with a high recurrence rate and adverse reactions. In severe cases, they can cause dysbacteriosis, oral mucosal exfoliation and superinfection, and the action target is single. Long-term use will affect the health status of patients. The treatment of oral ulcers with traditional Chinese medicine has a long history and, as an important aspect of modern oral disease treatment, has received increasing attention in recent years. Developing traditional Chinese medicine for treating oral ulcers will have extremely important clinical value. Summary of the Invention

[0008] In order to enrich the drug selection for clinical treatment of oral ulcers, the purpose of the present invention is to provide the application of a traditional Chinese medicine composition in the preparation of drugs for treating oral ulcers.

[0009] The invention purpose of the present invention is achieved by the following technical solutions.

[0010] The application of a traditional Chinese medicine composition in the preparation of drugs for treating oral ulcers, wherein the traditional Chinese medicine composition comprises the following components: ginsenoside of ginseng stem and leaf, schizandra chinensis, astragalus membranaceus, Chinese yam, rehmannia glutinosa, raspberry, ophiopogon japonicus, poria cocos, trichosanthes kirilowii maxim, alisma orientale, wolfberry fruit.

[0011] Preferably, the disease refers to recurrent oral ulcer or traumatic oral ulcer.

[0012] More preferably, the disease refers to recurrent oral ulcer.

[0013] Even further, the disease is recurrent oral ulcer caused by abnormal immune function.

[0014] Preferably, the Chinese medicine composition is Shenqi Jiangtang Granules.

[0015] "Shenqi Jiangtang Granule (National Medicine Standard Z10950075)" is a Chinese patent medicine for the treatment of diabetes developed and produced by Lunan Houpu Pharmaceutical Co., Ltd. The medicine is composed of 11 kinds of medicines, including ginseng stem and leaf saponins, Schisandra chinensis, Astragalus membranaceus, Chinese yam, Rehmannia glutinosa, Rubus idaeus, Ophiopogon japonicus, Poria cocos, Radix Trichosanthis, Rhizoma Alismatis, and Fructus Lycii. In Shenqi Jiangtang Granule, ginseng and Astragalus membranaceus are both monarch drugs, which complement each other and can greatly replenish vital energy, make qi vigorous and yin fluid be generated, and thirst can be quenched when fluid is generated. Rehmannia glutinosa, Ophiopogon japonicus, and Radix Trichosanthis are both ministerial drugs, which can clear away heat and nourish yin, produce fluid and moisten dryness, and are compatible with ginseng and Astragalus membranaceus, which are neither warm nor dry, and can nourish qi and yin, clear away heat and moisten dryness and quench thirst. Fructus Lycii, Schisandra chinensis, and Raspberry are both adjuvant drugs, which seal the kidney gate and prevent the essence from flowing down, and cooperate with the monarch and minister drugs to nourish the kidney and retain essence, and benefit both the liver and kidney. Chinese yam and poria cocos are both adjuvant drugs, which can strengthen the spleen and stomach, consolidate the kidney and eliminate dampness. The monarch, minister, assistant and adjuvant cooperate with each other, taking into account both the innate and acquired factors, and together form a prescription that nourishes both qi and yin and treats the lungs, spleen, liver and kidneys.

[0016] The present invention has conducted a lot of in-depth research on the basis of Shenqijiangtang Granules for treating diabetes, and found that Shenqijiangtang Granules has a significant therapeutic effect on oral ulcers, especially on recurrent oral ulcers.

[0017] Compared with the prior art, the present invention has achieved remarkable technical effects:

[0018] The Chinese medicine composition of the present invention can significantly reduce the area of ​​oral ulcers and effectively reduce the level of TNF-α in rat oral ulcer tissues; for recurrent oral ulcers caused by decreased immune function in rats, after intervention with the composition of the present invention, CD3 + Cell levels increased, while upregulating CD4 + / CD8 + The ratio of indicates that the composition of the present invention can improve the immune function of rats, effectively treat oral ulcers caused by abnormal immune function, and enrich the selectivity of clinical medication. DETAILED DESCRIPTION

[0019] In order to enable those skilled in the art to fully understand the present invention, the present invention is further described below through specific examples. However, those skilled in the art should be aware that the following examples are only for illustrative purposes and are not intended to limit the scope of protection of the present invention.

[0020] Example 1 Experimental study on the effect of Shenqijiangtang granules on oral ulcers in rats

[0021] An oral ulcer model was created using acetic acid, and Shenqi Jiangtang Granules were given to oral ulcer model rats a certain number of times a day to observe whether Shenqi Jiangtang Granules has the effect of reducing ulcers.

[0022] 1 Experimental animals and drugs

[0023] Animals: 60 SPF-grade rats, 30 males and 30 females, with body weights of 180 - 220 g, provided by Lunan Pharmaceutical Group Co., Ltd., license number: SYXK(Lu)20180008.

[0024] Shenqi Jiangtang Granules (Approval number: Z10950075, produced by Lunan Houpu Pharmaceutical Co., Ltd.); Guilin Watermelon Frost (Approval number: Z45021599, produced by Guilin Sanjin Pharmaceutical Co., Ltd.). Other reagents or materials can be obtained through commercial channels if not otherwise specified.

[0025] 2 Experimental methods

[0026] 2.1 Model establishment: Except for the blank group, the above rats were anesthetized with 10% chloral hydrate at a dose of 0.35 ml / 100 g. After anesthesia, 20% acetic acid was injected subcutaneously into the right buccal mucosa of the rats, 0.05 ml per rat. Rats in the blank group were injected with an equal volume of 0.9% sodium chloride solution. Oral ulcers could be formed after 24 h. The gross morphology of the oral ulcers in each group of rats was observed. The results showed that no ulcers appeared in the control group. Obvious oral ulcers could be presented after injecting acetic acid. Macroscopically, the mucosa of the ulcer surface showed a concave defect, approximately round, with a yellowish-white surface and surrounding congestion and edema, indicating that the preparation of the oral ulcer model was successful.

[0027] 2.2 Experimental grouping and drug administration

[0028] On the second day after model establishment, except for the normal control group, the successfully modeled rats were randomly divided into 5 groups, namely the model control group, the positive control group (Guilin Watermelon Frost at 200 mg / kg), and the high-, medium-, and low-dose groups of Shenqi Jiangtang Granules (3 g / kg, 1.5 g / kg, 0.75 g / kg). The high-, medium-, and low-dose groups of Shenqi Jiangtang Granules were administered by gavage, slowly injecting the liquid medicine into the rats' mouths to make the liquid medicine fully contact with the ulcers; for Guilin Watermelon Frost, the powder was directly taken. When administering the drug, the powder (1 / 4 of the rat dose) was evenly applied to the ulcer surface, and the remaining powder (3 / 4 of the rat dose) was prepared into a suspension with 0.5% sodium carboxymethylcellulose solution and then administered by gavage; the model control group and the normal control group were respectively administered an equal volume of 0.5% sodium carboxymethylcellulose solution; twice a day for 10 consecutive days. The maximum transverse diameter (d1) and the maximum longitudinal diameter (d2) of the oral ulcers in each group of rats before and on the 4th, 7th, and 10th days after drug administration were measured with a vernier caliper, and the ulcer area was calculated (ulcer area = 3.14 × d1 × d2 × 1 / 4). After the last measurement, each group of rats was sacrificed, and the tissue at the oral ulcer site was removed. Part of the ulcer tissue was homogenized with 9 times the amount of normal saline, centrifuged at 4°C and 3000 r / min for 10 min, and the supernatant was separated. The TNF-α level was measured according to the kit method.

[0029] 3 Experimental Results

[0030] 3.1 Effect on the Oral Ulcer Area of Rats

[0031] The measurement results of the oral ulcer area of rats in each group are shown in Table 1. Since the oral ulcers of rats have a certain degree of self-healing, with the passage of time, the ulcer area gradually decreases.

[0032] Table 1 Effect of Shenqi Jiangtang Granules on the Oral Ulcer Area of Rats (x±s, n = 10)

[0033]

[0034] Note: Compared with the model group, *p < 0.05 indicates significant difference.

[0035] As can be seen from Table 1, there was no significant difference in the oral ulcer area of rats in each group at the beginning of the experiment; on the 4th, 7th, and 10th days of drug administration, compared with the model group, the oral ulcer areas of the high-dose group of Shenqi Jiangtang Granules and the positive control group of rats were significantly reduced. The oral ulcer area of the high-dose group of Shenqi Jiangtang Granules was slightly higher than that of the positive control group, but significantly higher than that of the model group.

[0036] 3.2 Effect on the TNF-α Level in the Tissues of the Oral Ulcer Site of Rats

[0037] The measurement results of the TNF-α level in the tissues of the oral ulcer site of each rat are shown in Table 2.

[0038] Table 2 Effect of Shenqi Jiangtang Granules on the TNF-α Level in the Oral Ulcer Tissues of Rats

[0039]

[0040] Note: Compared with the blank group, △ p < 0.05 indicates significant difference; compared with the model group, *p < 0.05 indicates significant difference.

[0041] As can be seen from the data in Table 2, compared with the blank group, the TNF-α level in the oral ulcer tissues of the model group of rats was significantly increased (p < 0.05), indicating that the model group of rats showed significant inflammatory symptoms. Compared with the model group, the TNF-α levels in the oral ulcer tissues of the medium-dose, high-dose groups of Shenqi Jiangtang Granules and the positive control group of rats were significantly reduced (p < 0.05). The results show that the medium-dose and high-dose of Shenqi Jiangtang Granules have a therapeutic effect on acetic acid-induced oral ulcers.

[0042] Experimental Example 2 Experimental Study of Shenqi Jiangtang Granules on Oral Ulcers in Rats

[0043] The rats were modeled by immunological methods. After successful modeling, a certain dose of Shenqi Jiangtang Granules was given to the rats in the oral ulcer model group every day, and the contents of T cell subsets CD4 + and CD8 + as well as the CD4 + / CD8 + value in the rat serum were measured.

[0044] 1 Experimental materials

[0045] SPF-grade rats were used as experimental animals and provided by Lunan Pharmaceutical Group Co., Ltd. There were 70 rats in total, with an equal number of males and females, and the body weight was 180 - 220 g. Shenqi Jiangtang Granules (National Drug Approval Number: Z10950075, produced by Lunan Houpu Pharmaceutical Co., Ltd.); Vitamin B12 (produced by China Resources Zizhu Pharmaceutical Co., Ltd.). Freund's complete adjuvant was purchased from Sigma Company, and CD3 + , CD4 + , CD8 + immunohistochemistry kits were purchased from Boster Company; other reagents or materials could be obtained through commercial channels without special instructions.

[0046] 2 Experimental methods

[0047] 2.1 Model construction

[0048] Ten rats were taken. After observing that the oral mucosa of the rats was in normal morphology, the rats were sacrificed by cervical dislocation. Then, 5 ml of syringe was used to inject normal saline under the oral mucosa of the rats to separate the connective tissue from the oral mucosa. The oral mucosa was peeled off with a dissector, and the excess connective tissue was removed. The taken tissue was placed in a -80 °C low-temperature refrigerator and frozen for 6 h. After freezing, the mucosal tissue was ground with a glass grinder and added with PBS buffer solution with a concentration of 0.1 ml / L and pH 7.4 to make tissue homogenate. After completion, it was stored in a -80 °C low-temperature refrigerator and taken out in advance when needed. During the experiment, the tissue homogenate was mixed with Freund's adjuvant at a ratio of 1:1, and an antigen emulsion was prepared according to the operation process described in the instruction manual. Fifty rats in the pre-experiment model group had their rat hair on the spine removed before injection. After disinfecting the skin with 75% alcohol, 0.1 ml of antigen emulsifier was subcutaneously injected at one point on each side, once a week for 5 injection cycles; another ten normal group rats were injected with an equal amount of normal saline on both sides of the spine.

[0049] Before modeling, it was observed that the oral mucosa of the pre-experiment rats was intact and pink in color. After two injections, the activity of the rats decreased, and the water and food intake decreased. After all injection cycles were completed, mucosal ulcers appeared in the mouths of the modeled rats. The ulcers showed a specific mucosal manifestation of red around, yellow inside, and concave in shape, indicating successful modeling.

[0050] 2.2 Experimental grouping and dosing regimen

[0051] The successfully modeled animals were randomly divided into 5 groups, with 10 animals in each group, half male and half female, namely the model group, the positive control group, the low-dose group of Shenqi Jiangtang Granules, the medium-dose group of Shenqi Jiangtang Granules, and the high-dose group of Shenqi Jiangtang Granules. Each group was administered continuously for 7 days according to the following dosing regimens.

[0052] Normal group: gavaged with 2 ml / kg normal saline;

[0053] Model group: gavaged with 2 ml / kg normal saline;

[0054] Positive control group: gavaged with vitamin B12 at a dose of 54 mg / kg;

[0055] Low-dose group of Shenqi Jiangtang Granules: gavaged with Shenqi Jiangtang Granules at a dose of 0.75 g / kg;

[0056] Medium-dose group of Shenqi Jiangtang Granules: gavaged with Shenqi Jiangtang Granules at a dose of 1.5 g / kg;

[0057] High-dose group of Shenqi Jiangtang Granules: gavaged with Shenqi Jiangtang Granules at a dose of 3 g / kg.

[0058] After the experiment, the rats were fasted and water-deprived for 10 h. After anesthesia with chloral hydrate, the upper and lower jaws were separated with hemostatic forceps to observe the healing of oral ulcers in rats of each group. The abdominal artery blood was drawn to detect the levels of CD3 + , CD4 + , CD8 + in the serum of rats.

[0059] 2.3 Experimental results

[0060] The measured results of CD3 + , CD4 + , CD8 + in the serum of rats in each group were expressed as x±s, and the data were analyzed using SPSS 20.0 software. The measured results of CD3 + , CD4 + , CD8 + in the serum of rats in each group are shown in Table 3.

[0061] Table 3 Measurement of CD3 + , CD4 + , CD8 + in the serum of rats

[0062]

[0063] Note: Compared with the normal group, △ p < 0.05 indicates significant difference; compared with the model group, *p < 0.05 indicates significant difference.

[0064] From the data in Table 3, we can see that compared with the normal group, the CD3 + The content value decreased significantly, and the difference was statistically significant (p < 0.05). + Compared with the model group, the positive control group, the low-dose, medium-dose, and high-dose Shenqijiangtang granules groups showed a significant increase in CD3+ content (p<0.05), and the CD4 + The content was significantly increased (p < 0.05), among which the low, medium and high dose groups of Shenqijiangtang Granule were better than the positive control group, among which the medium and high dose groups of Shenqijiangtang Granule were significantly better than the positive control group and the normal group. + level, improves CD4 + / CD8 + The level of CD3 in serum of rats in the model group + The decrease in CD3 cells in rat serum indicated that the immune function of rats with recurrent oral ulcers decreased. + Cell levels increased, while upregulating CD4 + / CD8 + The ratio of indicates that Shenqi Jiangtang Granules can significantly improve the immune function of rats and effectively treat oral ulcers caused by abnormal immune function.

Claims

1. Application of Shenqi Jiangtang Granule in preparing medicine for treating oral ulcer diseases.

2. The application according to claim 1, characterized in that, The diseases mentioned refer to recurrent oral ulcer or traumatic oral ulcer.

3. The application according to claim 2, characterized in that, The diseases mentioned refer to recurrent oral ulcer.

4. The application according to claim 2, wherein The diseases mentioned are recurrent oral ulcers caused by abnormal immune function.

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