Sugar-free lung-moistening composition for diabetes mellitus yin-deficiency dry cough as well as application and preparation method of sugar-free lung-moistening composition

Abstract

The invention relates to a sugar-free lung-moistening composition for treating diabetes mellitus yin deficiency and dry cough as well as application and a preparation method of the sugar-free lung-moistening composition, aiming at solving the problem that the existing cough-relieving traditional Chinese medicine products are generally not suitable for diabetics to use, and the sugar-free lung-moistening traditional Chinese medicine composition for treating diabetes mellitus yin deficiency and dry cough is prepared from the following raw materials in parts by weight. Comprising 30-40 parts of pears, 15-20 parts of radix polygonati officinalis, 10-15 parts of radix adenophorae, 10-15 parts of radix ophiopogonis, 5-10 parts of Chinese yam, 5-8 parts of fructus momordicae and 3-5 parts of fructus lycii. The sugar-free lung-moistening composition for diabetic yin deficiency and dry cough breaks through the limitation of single effect of a traditional medicine and food homology formula, and has the effects of relieving cough, eliminating phlegm, moistening lung, nourishing yin and assisting in reducing blood sugar.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of traditional Chinese medicine compositions, and particularly relates to a sugar-free lung-moistening composition for treating dry cough due to yin deficiency in diabetes and application and preparation method thereof. BACKGROUND

[0002] With the aggravation of population aging trend and the change of dietary structure, the incidence of diabetes and insulin resistance is increasing year by year. Clinical studies have found that the high blood sugar state and inflammatory response of diabetes can lead to a significant increase in lung-related diseases. Among them, the incidence of chronic obstructive pulmonary disease (COPD) in diabetic patients is 1.5-2 times higher than that in non-diabetic patients, especially in patients with type 2 diabetes, the risk of hospitalization of diabetic patients with COPD increases by 40%, and the mortality rate increases; the hospitalization rate of pneumonia is 3 times that of non-diabetic patients, and the risk is higher (OR=2.7) for those with poor blood sugar control (HbA1c>9%); the incidence of idiopathic pulmonary fibrosis (IPF) is 1.3 times higher than that of the general population; the prevalence of asthma in patients with type 2 diabetes increases by 30%. Prospective studies have found that for every 1% increase in HbA1c, the risk of pneumonia increases by 12%, and obesity also speeds up the decline in lung function. Pathological mechanisms include: direct damage to alveolar epithelial cells by advanced glycosylation products and oxidative stress caused by metabolic disorders, which exacerbates pulmonary fibrosis; immune homeostasis imbalance leads to macrophage polarization, which promotes pulmonary fibrosis; systemic inflammatory response leads to activation of the inflammatory cascade pathway in the lungs. Although blood sugar elevation is alleviated after hypoglycemic drug treatment, lung lesions cannot be effectively alleviated, leading to poor prognosis and affecting patient survival.

[0003] Clinically used cough-relieving drugs (such as compound licorice mixture and chuanbei pipa paste) generally contain sucrose or honey (sugar content can reach 60%-70%), and long-term use by diabetic patients can easily lead to blood sugar fluctuations (studies have shown that a single 10ml serving of syrup can increase postprandial blood sugar by 2.3-3.1mmol / L). In view of this contradiction, it is urgent to develop a drug that can control blood sugar and treat lung diseases. In traditional Chinese medicine theory, diabetes belongs to the category of "consumptive disease", and the core pathogenesis is yin deficiency and excessive dryness. The causes are mainly excessive diet, emotional depression, and overwork, which cause heat accumulation in the stomach and intestines, burn the lung and stomach yin, and develop into "upper consumption" and "middle consumption". If the disease is prolonged, both qi and yin are deficient, the spleen fails to transport, the mother disease affects the child (spleen is the mother of the lung), the lung fails to descend, and therefore lung symptoms such as cough and shortness of breath are seen. The current Chinese patent drug such as Yangyin Qingfei Wan can moisten the lung and relieve cough, but it contains honey (such as honey-roasted radix platycodi) or ignores blood sugar control, which is difficult to meet the needs of patients. SUMMARY

[0004] The purpose of the present application is to provide a sugar-free lung-moistening composition for treating dry cough due to yin deficiency in diabetes and application and preparation method thereof, in order to solve the problem that existing cough-relieving traditional Chinese medicine products are generally not suitable for diabetic patients.

[0005] The sugar-free lung-moistening traditional Chinese medicine composition for treating dry cough due to yin deficiency in diabetes mellitus comprises, by weight fraction, 30-40 parts of pear, 15-20 parts of polygonatum, 10-15 parts of south saussurea, 10-15 parts of ophiopogon, 5-10 parts of yam, 5-8 parts of momordica grosvenori, and 3-5 parts of medlar.

[0006] Further, the sugar-free lung-moistening traditional Chinese medicine composition for treating dry cough due to yin deficiency in diabetes mellitus comprises, by weight fraction, 35 parts of pear, 17 parts of polygonatum, 13 parts of south saussurea, 13 parts of ophiopogon, 8 parts of yam, 7 parts of momordica grosvenori, and 4 parts of medlar.

[0007] Further, the traditional Chinese medicine composition comprises, by weight, 37 g of pear, 16 g of polygonatum, 14 g of south saussurea, 14 g of ophiopogon, 7 g of yam, 8 g of momordica grosvenori, and 4 g of medlar.

[0008] Further, the sugar-free lung-moistening traditional Chinese medicine composition for treating dry cough due to yin deficiency in diabetes mellitus can be used for preventing and treating dry cough due to yin deficiency in diabetes mellitus, including diabetes mellitus combined with chronic bronchitis, pharyngitis, pneumonia, pulmonary nodule, asthma, and pulmonary fibrosis.

[0009] Further, the preparation method of the sugar-free lung-moistening traditional Chinese medicine composition for treating dry cough due to yin deficiency in diabetes mellitus comprises the following steps: Step 1, preparation of pear enzymatic hydrolysate: prepare sufficient pear by weight fraction; peel the pear and remove the core, then add cellulase (0.1%-0.3%) to the pear pulp for enzymatic hydrolysis for 30 minutes to obtain the pear enzymatic hydrolysate; Step 2, pretreatment of traditional Chinese medicine extraction: prepare sufficient polygonatum, south saussurea, ophiopogon, yam, momordica grosvenori, and medlar by weight fraction, crush the medicinal materials to 40 mesh, soak them in 50% ethanol for 2 hours to obtain the traditional Chinese medicine soaking liquid; Step 3, low-temperature extraction: use a dynamic circulation extraction tank, extract the traditional Chinese medicine soaking liquid twice at 40-50°C with a solid-liquid ratio of 1:8, each time for 1 hour to obtain the traditional Chinese medicine extraction liquid; Step 4, mixing: mix the pear enzymatic hydrolysate and the traditional Chinese medicine extraction liquid uniformly to obtain the traditional Chinese medicine mixed liquid; Step 5, purification and concentration: separate the traditional Chinese medicine mixed liquid through a 100 kDa ultrafiltration membrane to obtain the extraction liquid; Step 6, vacuum low-temperature concentration of the extraction liquid to a relative density of 1.1-1.2 to obtain the concentrated liquid; Step 7, drying and preparation: spray dry the concentrated liquid to obtain a powder dry paste powder, or freeze dry the concentrated liquid to obtain a instant granule to obtain the traditional Chinese medicine extract.

[0010] The application has the advantages that the application provides the thought of treating disease before it occurs, and the lung-moistening and cough-stopping product is selected from the products with the same medicinal and edible effects, so that the risk of increasing blood sugar is avoided while the body resistance and the body constitution are strengthened. Through the previous research, it is found that the core pathogenesis of the diabetic pulmonary disease is "deficiency of both qi and yin and blockage of lung due to dryness", the product with the same medicinal and edible effects is selected and optimized to construct a compound, so that the body resistance and the body constitution are strengthened and the blood sugar is controlled. The previous research proves that the compound composed of pear (the monarch drug), polygonatum (the ministerial drug), south saussurea (the auxiliary drug), ophiopogon (the auxiliary drug), yam (the ministerial drug), momordica grosvenori (the flavoring agent) and medlar (the harmonizing drug) can significantly reduce the fasting blood sugar of the diabetic model rats and improve the lung function through the synergistic effect of the monarch drug, the ministerial drug and the auxiliary drug. In the compound, the 1-deoxynojirimycin (DNJ) in the mulberry leaf can inhibit the activity of alpha-glucosidase and reduce the postprandial blood sugar peak value, and the polysaccharide component in the polygonatum can improve the insulin resistance by activating the AMPK pathway, and the two components can synergistically regulate the blood sugar. The chlorogenic acid in the pear peel can inhibit the TRPV1 receptor (the target point of stopping cough), and the pectin can delay the glucose absorption (the GI value is reduced by 22% compared with the peeled pear), and the south saussurea saponin can up-regulate the expression of lung surfactant protein SP-A and improve the alveolar elasticity. The application embodies the therapeutic principle of "cultivating the earth to generate the metal", that is, the yam (the earth) strengthens the spleen to promote the polygonatum (the metal) to moisten the lung, and the ophiopogon is added to nourish the kidney to achieve the generation of the metal and the water, which is consistent with the pathogenesis characteristics of the diabetic pulmonary disease and the integrated regulation concept of the traditional Chinese medicine (the disorder of sugar metabolism and the pulmonary disease are treated together). The application breaks through the limitation of the single effect of the traditional formula of the product with the same medicinal and edible effects, and has the effects of stopping cough and expectoration, moistening the lung and nourishing the yin and auxiliary reducing the blood sugar.

[0011] The traditional Chinese medicine composition for moistening the lung without sugar for the dry cough due to yin deficiency of diabetes has the effects of treating the upper, middle and lower energizers at the same time. The upper energizer (the lung) is cleared and moistened by the pear, the south saussurea and the momordica grosvenori, the middle energizer (the spleen) is invigorated and the fluid is produced by the polygonatum and the yam, and the lower energizer (the kidney) is nourished and the body constitution is strengthened by the ophiopogon and the medlar, so that the comprehensive treatment network of "moistening the lung to stop cough, invigorating the spleen to control the blood sugar and nourishing the kidney to strengthen the body constitution" is formed. The traditional Chinese medicine composition has the balanced nature and the moderate cold and warm, the pear (cool), the south saussurea (slightly cold), the ophiopogon (slightly cold) and the momordica grosvenori (cool) are combined to clear the lung and dry heat, and the polygonatum (balanced), the yam (balanced) and the medlar (balanced) are combined to prevent the cold and cool from damaging the stomach. The whole compound is cold but not severe, moist but not greasy, and is suitable for the diabetic patients with yin deficiency and dry heat. The traditional Chinese medicine composition is suitable for the core pathogenesis of "deficiency of both qi and yin and blockage of lung due to dryness", the main symptoms of dry cough, dry throat, shortness of breath, dry mouth, dry stool, red tongue with little fluid, thin yellow coating and rapid pulse, and the core pathogenesis is "deficiency of both qi and yin and blockage of lung due to dryness". The compound has the core effects of "moistening the lung to stop cough and nourishing the yin to control the blood sugar", and the classical monarch drug, ministerial drug and auxiliary drug are combined with the modern pharmacological mechanism to treat the symptoms and the root cause of the diabetic pulmonary disease at the same time, and the compound has the theoretical rationality and the clinical practicability. The traditional Chinese medicine composition is a natural medicine preparation, and no organic reagent is used, so that the composition is safe and reliable, has small side effects, and has no adverse reactions in long-term use, and the effect is clear. DETAILED DESCRIPTION

[0012] In order to further clarify the technical means and effects taken by the present application to achieve the intended purpose, the following will combine the specific embodiments of the present application, structural features and their effects, and be described in detail as follows.

[0013] The technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative work fall within the protection scope of the present application.

[0014] All the features disclosed in the specification, or all the steps in the disclosed methods or processes, can be combined in any manner, except for the mutually exclusive features and / or steps.

[0015] Any feature disclosed in the specification (including any accompanying claims), unless specifically stated, can be replaced by alternative features or equivalents of the same. That is, unless specifically stated, each feature is only one example of a range of equivalent or similar features. Embodiments

[0016] In order to solve the problem that the existing cough-relieving traditional Chinese medicine products are generally not suitable for diabetics.

[0017] The embodiment provides a sugar-free lung-moistening traditional Chinese medicine composition for treating dry cough caused by yin deficiency of diabetes, which comprises, by weight fraction, 30-40 parts of pears, 15-20 parts of polygonatum, 10-15 parts of south saussurea, 10-15 parts of ophiopogon, 5-10 parts of Chinese yam, 5-8 parts of momordica grosvenori, and 3-5 parts of medlar.

[0018] Further, the sugar-free lung-moistening traditional Chinese medicine composition for treating dry cough caused by yin deficiency of diabetes comprises, by weight fraction, 35 parts of pears, 17 parts of polygonatum, 13 parts of south saussurea, 13 parts of ophiopogon, 8 parts of Chinese yam, 7 parts of momordica grosvenori, and 4 parts of medlar.

[0019] Further, the traditional Chinese medicine composition comprises, by weight, 37 g of pears, 16 g of polygonatum, 14 g of south saussurea, 14 g of ophiopogon, 7 g of Chinese yam, 8 g of momordica grosvenori, and 4 g of medlar.

[0020] Further, the sugar-free lung-moistening traditional Chinese medicine composition for treating dry cough caused by yin deficiency of diabetes can be used for preventing and treating dry cough caused by yin deficiency of diabetes, including diabetes combined with chronic bronchitis, pharyngitis, pneumonia, pulmonary nodule, asthma, and pulmonary fibrosis.

[0021] Further, the preparation method of the sugar-free lung-moistening traditional Chinese medicine composition for treating dry cough caused by yin deficiency of diabetes comprises the following steps: Step 1, preparation of pear enzymatic solution: according to weight fraction, prepare sufficient pear, peel and core, add cellulase (0.1%-0.3%) after pulping, and enzymatically hydrolyze for 30 minutes to release pectin and active ingredients, and obtain pear enzymatic solution; Step 2, traditional Chinese medicine extraction pretreatment: according to weight fraction, prepare sufficient polygonatum, south adenosma, ophiopogon, yam, monk fruit and medlar, crush the medicinal materials to 40 mesh, soak with 50% ethanol for 2 hours, and obtain the soaking medicinal liquid; Step 3, low temperature extraction: adopt dynamic circulation extraction tank, 40-50℃, 50% ethanol extraction for 2 times (solid-liquid ratio is 1:8), 1 hour each time, avoid high temperature damage polysaccharide, and obtain traditional Chinese medicine extraction liquid; Step 4, mixing: mix the pear enzymatic solution and traditional Chinese medicine extraction liquid to obtain traditional Chinese medicine mixed liquid; Step 5, purification and concentration: the traditional Chinese medicine mixed liquid is separated by 100kDa ultrafiltration membrane to remove macromolecular impurities and retain small molecular active substances (such as saponin and polysaccharide), and obtain extraction liquid; Step 6, vacuum low temperature concentration (60℃) of the extraction liquid to relative density 1.1-1.2, and obtain concentrated liquid; Step 7, drying and preparation: spray dry (inlet air temperature 160℃, outlet air temperature 80℃) the concentrated liquid to prepare powder dry paste powder, or freeze dry the concentrated liquid to prepare instant granules, and obtain traditional Chinese medicine extract.

[0022] The embodiment provides the thought of treating disease before it occurs, and the lung-moistening and cough-stopping product is selected from the products with the same source of medicine and food, and the risk of increasing blood sugar is avoided while the body resistance is strengthened and the body is consolidated. Through the previous research, the core pathogenesis of "deficiency of both qi and yin and dryness-evil and phlegm obstruction" of the diabetic pulmonary disease patients is found, the product with the same source of medicine and food is selected to construct the compound, the body resistance is strengthened and the body is consolidated, and the synergistic intervention of the blood sugar control and the cough stopping is realized. The previous research proves that the compound composed of the pear (the monarch drug), the polygonatum (the ministerial drug), the south adenosma (the auxiliary drug), the ophiopogon (the auxiliary drug), the dioscorea (the ministerial drug), the momordica grosvenori (the flavoring agent) and the medlar (the harmonizing drug) can significantly reduce the fasting blood sugar of the diabetic model rats and improve the lung function through the synergistic effect of the monarch drug, the ministerial drug and the auxiliary drug. In the compound, the mulberry leaf contains 1-deoxynojirimycin (DNJ), which can inhibit the activity of alpha-glucosidase and reduce the postprandial blood sugar peak value; the polysaccharide component of the polygonatum can improve the insulin resistance by activating the AMPK pathway, and the two components are used in combination to synergistically regulate the blood sugar. The chlorogenic acid in the pear peel can inhibit the TRPV1 receptor (the target point of the cough stopping), and the pectin can delay the glucose absorption (the GI value is reduced by 22% compared with the peeled pear); the south adenosma saponin can up-regulate the expression of the lung surfactant protein SP-A and improve the alveolar elasticity. The embodiment embodies the therapeutic principle of "cultivating the earth to generate the metal", that is, the dioscorea strengthens the spleen (the earth) to promote the polygonatum to moisten the lung (the metal), and the ophiopogon is used to nourish the kidney to achieve the "metal and water generating each other", which is consistent with the pathogenesis characteristics of the diabetic pulmonary disease "deficiency of the root and excess of the branch" and conforms to the integrated regulation concept of the traditional Chinese medicine "treating different diseases in the same way" (the diabetic pulmonary disease and the pulmonary disease are treated together). The embodiment breaks through the limitation of the single effect of the traditional formula of the product with the same source of medicine and food, and has the effects of the cough stopping and phlegm expelling, the lung moistening and the yin nourishing, and the auxiliary blood sugar reduction.

[0023] The traditional Chinese medicine composition for the diabetic yin deficiency and dry cough and the lung moistening has the effects of treating the upper, middle and lower energizers at the same time. The upper energizer (the lung) is cleared and moistened by the pear, the south adenosma and the momordica grosvenori; the middle energizer (the spleen) is invigorated and the body fluid is produced by the polygonatum and the dioscorea; the lower energizer (the kidney) is nourished and the body is consolidated by the ophiopogon and the medlar, forming the comprehensive treatment network of "the lung moistening and cough stopping, the spleen invigoration and blood sugar control and the kidney nourishing and body consolidation". The traditional Chinese medicine composition has the balanced nature and the moderate cold and warm. The cold and cool combination: the pear (cool), the south adenosma (slightly cold), the ophiopogon (slightly cold) and the momordica grosvenori (cool) are combined to clear the lung heat; the traditional Chinese medicine composition has the balanced nature: the polygonatum (balanced), the dioscorea (balanced) and the medlar (balanced) are combined to prevent the cold and cool from damaging the stomach. The whole compound is cold but not severe, moist but not greasy, and is suitable for the diabetic yin deficiency and dry heat constitution. The traditional Chinese medicine composition is suitable for the core pathogenesis of "deficiency of both qi and yin and dryness-evil and phlegm obstruction", the main symptoms of "dry cough, less sputum, dry throat, dry mouth, shortness of breath, lack of strength and dry stool", the tongue and pulse of "red tongue, thin yellow fur and thin pulse". The compound has the core effects of "the lung moistening and cough stopping and the yin nourishing and blood sugar control", realizes the treatment of the root and branch of the diabetic pulmonary disease by combining the classical monarch drug, ministerial drug and auxiliary drug with the modern pharmacological mechanism, and has the theoretical rationality and clinical practicability. The traditional Chinese medicine composition is a natural medicine preparation, does not use organic reagents, is safe and reliable, has small toxic and side effects, and has no adverse reactions in long-term use, and has clear drug efficacy. Embodiment

[0024] The following describes the preparation method of the traditional Chinese medicine composition of Example 1 by three dosage forms.

[0025] Granule preparation: the obtained dry paste powder is mixed with mogroside (0.05%-0.1%), dextrin, and then granulated by using a fluidized bed granulation device (inlet air temperature 60-80°C) to form granules, which are sieved through a 40-mesh sieve to ensure that more than 95% of the granules meet the requirements, and then are divided into bags, each bag containing 5 g, for oral administration.

[0026] Tablet preparation: the dry paste powder is mixed with an appropriate amount of filler (microcrystalline cellulose), binder (HPMC), disintegrant (CCNa), and lubricant (talc), and then is uniformly mixed. Wet granulation (ethanol concentration 30-70%) is performed by using a swing granulator with a 20-mesh screen. The pressure is 10 kN, and the tablet weight difference is ±5% (required by the pharmacopoeia). Opadry film coating material is used as the coating material, the coating weight gain is 2-4%, the inlet air temperature is 50-60°C, and the solid content of the coating liquid is 10-15%.

[0027] Decoction preparation: the dry paste powder is mixed with an appropriate amount of diluent (modified cyclodextrin), suspending agent (xanthan gum), and flavoring agent (mogroside) by using a three-dimensional motion mixer for 60 minutes, and the uniformity RSD is ≤5%. After sterilization by 60Co irradiation (8-15 kGy), the mixture is divided into bags, each bag containing 5 g, for oral administration with hot water. Example

[0028] Evaluation of the therapeutic effect of traditional Chinese medicine extract on a diabetes mellitus combined with pneumonia model (1) Experimental method: SD rats (200±20 g) are randomly divided into a normal group, a model group, a positive control group (Yangyin Qingfei Decoction), a low-dose extract group (1 g / kg) and a high-dose extract group (3 g / kg) of the present application.

[0029] Model construction: a type 2 diabetes mellitus model is established by using a high-fat and high-sugar diet combined with a small-dose intraperitoneal injection of streptozotocin (STZ). After the fasting blood glucose is stabilized at ≥11.1 mmol / L for 1 week, a trace amount of lipopolysaccharide (LPS) is intratracheally instilled to induce pulmonary inflammatory injury, thereby forming a diabetes mellitus combined with pulmonary inflammation model.

[0030] Therapeutic intervention: each group is continuously administered intragastrically for 14 days, and the body weight, water consumption and fasting blood glucose changes are recorded. The lung tissue and bronchial lavage fluid are collected.

[0031] (2) Experimental results: a. The traditional Chinese medicine extract significantly improves the diabetes mellitus state The results show (Table 1) that, compared with the control group, the body weight of the diabetes model group is significantly reduced, and the blood glucose and insulin resistance index (HOMA-IR) are significantly increased, while compared with the model group, the traditional Chinese medicine extract group significantly restores the body weight of the rats, reduces the blood glucose and HOMA-IR level, and at the same time, reduces the water consumption. It shows that the traditional Chinese medicine extract of the application improves the insulin sensitivity and has a good blood glucose lowering effect.

[0032] Table 1. The traditional Chinese medicine extract of the application significantly improves the body state of the diabetes rats (n=5, ** P <0.01 vs model group)

[0033] b. The traditional Chinese medicine extract significantly improves the pathological damage of the lung According to the HE staining results of the lung tissue, the McGuigan method is used to calculate the lung damage score, and the lung fibrosis score is calculated (Table 2), and the higher the McGuigan score and the lung fibrosis score, the higher the severity of the lung damage. As shown in the results, compared with the control group, the McGuigan score and the lung fibrosis score of the model group are significantly increased, indicating that the lung tissue is severely damaged. The McGuigan score and the lung fibrosis score of the traditional Chinese medicine extract intervention group of the application are significantly reduced, and show a dose-dependent relationship, indicating that the traditional Chinese medicine extract of the application can significantly improve the lung damage and lung fibrosis.

[0034] Table 2. The results of McGuigan score and lung fibrosis score (n=5, ** P <0.01 vs model group)

[0035] c. The traditional Chinese medicine extract significantly reduces the inflammation level of the lung The bronchial lavage fluid is collected, and the levels of inflammatory factors (TNF-α, IL-6, IL-10) are determined. As shown in Table 3, the levels of the inflammatory factors TNF-α and IL-6 in the bronchial lavage fluid of the model group are significantly increased, and the difference compared with the normal group is statistically significant. At the same time, the level of the anti-inflammatory inflammatory factor IL-10 is significantly inhibited, indicating that the lung inflammation of the model group is increased. Compared with the model group, the traditional Chinese medicine extract of the application can significantly reduce the levels of TNF-α and IL-6, and increase the level of IL-10, indicating that it has a good inhibitory effect on the inflammatory reaction.

[0036] Table 3. Inhibitory effect of the traditional Chinese medicine extract on the inflammatory reaction of the lung (n=5, ** P <0.01 vs model group)

[0037] d. Chinese medicine extract significantly improves lung oxidative stress Oxidative stress caused by diabetes is an important pathogenic factor for aggravating lung injury. The lung tissue was collected to determine the oxidative stress-related indicators malondialdehyde (MDA) and total antioxidant level (TAC), and the MDA / TAC ratio was calculated to evaluate the therapeutic effect of the Chinese medicine extract of the application. As shown in Table 4, the MDA level of the model group was significantly increased, the TAC level was significantly decreased, and the MDA / TAC ratio was significantly increased, while the Chinese medicine extract of the application significantly reversed this trend. It is shown that the Chinese medicine extract of the application can significantly improve the oxidative stress level of the lung tissue of diabetes.

[0038] Table 4. Inhibition of oxidative stress in the lung by Chinese medicine extract (n=5, ** P <0.01 vs model group)

[0039] Example 4 Therapeutic effect of Chinese medicine extract on diabetes combined with cough (1) Experimental method: Kunming mice were used, and the modeling method was to feed high-sugar and high-fat feed for 4 weeks, combined with intraperitoneal injection of STZ (50 mg / kg) to construct a diabetes model. Then, ammonia water (2%) was atomized and exposed for 30 minutes once a day for 7 consecutive days to induce cough symptoms.

[0040] The Chinese medicine composition of the application was orally administered for 14 days, and the cough latency, cough frequency, and nasal sinus mucosa histopathological changes of each group were compared.

[0041] (2) Experimental results: a. General state evaluation of mice: Before modeling, the initial body weight, food intake, water intake, respiratory rate and anal temperature of the mice in the blank group, model group and traditional Chinese medicine extract group were uniform, and there was no significant difference between groups (P>0.05). The fur of the rats in the blank group was lustrous, the respiration was stable (frequency 40-60 times / min), the autonomous activity was flexible, and the feces were granular, which met the animal health standard. After modeling, the behavior of the mice in the model group changed significantly, the fur was loose and dull, the eyes were dull, and the restless grooming behavior (frequency increased by 2.1 times) appeared; the respiration was rapid (>100 times / min), and obvious wheezing sound could be heard, the activity decreased by 60%-70%; the body weight growth rate was reduced by 58% compared with the blank group. The symptoms of the traditional Chinese medicine extract intervention group in the application were consistent with those of the model group at the early stage of modeling, and the cough frequency decreased by 18.6% per day after the third day of intervention; the food intake recovered to 85% of that before modeling at the 14th day, and the autonomous activity time was prolonged by 2.3 times compared with the model group. During the experimental period, 2 mice in the model group died (mortality rate 13.3%), 1 mouse in the low-dose traditional Chinese medicine extract group of the application died (mortality rate 6.7%), and there was no death event in the high-dose traditional Chinese medicine extract group and the blank group. The dead mice all showed pulmonary congestion and edema and bronchial mucus plug formation, which was consistent with the pathological characteristics of acute asthma attack. It is shown that the intervention of the traditional Chinese medicine extract of the application can effectively improve the physiological state of diabetic mice, relieve respiratory distress and improve pulmonary edema.

[0042] b. Traditional Chinese medicine extract improves cough frequency After the intervention of the traditional Chinese medicine extract, the multi-functional cough-inducing and wheezing instrument was used to analyze the cough latency (the time from the injection of ammonia water to the first cough) and the number of coughs within 3 minutes. As shown in Table 5, the cough latency of the model group was significantly lower than that of the control group, and the number of coughs was significantly increased, while after the intervention of the traditional Chinese medicine extract of the application, the cough latency was significantly prolonged, and the number of coughs was significantly reduced. The secretion in the trachea of the mouse was collected, and the OD value was measured to reflect the content of the secretion in the trachea. The results showed that the content of the secretion in the trachea of the model group was significantly increased, while the traditional Chinese medicine extract of the application could significantly reduce the content of the secretion in the trachea. It is shown that the traditional Chinese medicine extract of the application can effectively reduce diabetes combined with cough and improve sputum secretion.

[0043] Table 5. The traditional Chinese medicine extract of the application significantly improves diabetes combined with cough ** P <0.01 vs model group)

[0044] c. Traditional Chinese medicine extract improves the pathological changes of nasal sinus mucosa The mucosa pseudostratified ciliated columnar epithelium of the control group was complete, the basement membrane was continuous without rupture; the diameter of the sinus tube cavity maintained a normal range, and no pathological expansion was observed; the mucosa lamina propria had no edema and inflammatory cell infiltration, and the density of the goblet cells was normal. The model group mice had symptoms such as runny nose, frequent scratching of the nose, sneezing and the like, the nasal mucosa epithelium damage cilia fell off in a large area (residual cilia coverage <30%), the epithelial cells were vacuolated degeneration with focal necrosis (necrosis area accounted for 18.7±3.2%). The submucosa layer was significantly edematous, and was densely infiltrated with inflammatory cells (mainly neutrophils, with a density of 46.29±5.81 / HPF). In the traditional Chinese medicine extract intervention group, the cilia partially regenerated (the coverage was restored to more than 70%), and hyperplasia foci were observed in the basal cell layer. The inflammation was relieved, the mucosa edema was reduced, and the inflammatory cell infiltration density was significantly reduced (17.19±2.38 / HPF); the goblet cell hyperplasia was controlled (Table 6). It is shown that the traditional Chinese medicine extract can effectively improve the pathological changes of the sinus mucosa, reduce the nasal mucosa edema and necrosis, and maintain the mucosa integrity.

[0045] Table 6. Traditional Chinese medicine extract improves the pathological damage of the sinus mucosa tissue (n=5, ** P <0.01 vs model group)

[0046] The above results show that the traditional Chinese medicine extract has a clear therapeutic effect on diabetes combined with cough, significantly reduces the cough frequency, promotes the sputum excretion, and reduces the nasal mucosa damage.

[0047] Example 5 Traditional Chinese medicine extract on diabetes combined with chronic bronchitis Wistar rats were selected, a high-fat high-sugar diet was used in combination with a small dose of streptozotocin (STZ) intraperitoneal injection to establish a type 2 diabetes model, after fasting blood glucose ≥11.1 mmol / L was stable for 1 week, a smoking method (2 times a day, 15 minutes each time) was used in combination with bacterial pneumonia bacteria liquid nasal drops (Mora catarrhalis, 1×10^8 CFU / ml) to induce a chronic bronchitis model, and the intervention period was 21 days.

[0048] The traditional Chinese medicine composition (low dose 1g / kg, high dose 3g / kg) was used for intragastrical intervention, and the control group was given a positive drug (such as compound liquorice tablet extract). The expression changes of lung tissue inflammation score, airway remodeling degree, MPO, TGF-β1, TNF-α and the like were observed, and the improvement effect on chronic bronchitis was evaluated.

[0049] a. Traditional Chinese medicine extract effectively improves blood oxygen level Diabetes combined with chronic bronchitis can cause airway obstruction, leading to lung gas exchange disorder, causing blood oxygen level changes. As shown in the results of Table 7, blood gas analysis found that PaO2 in the model group was significantly decreased compared with the control group, and PaCO2 was significantly increased. Compared with the model group, the Chinese medicine extract of the application significantly increased PaO2 and reduced PaCO2. It shows that the Chinese medicine extract of the application significantly improves blood sample levels and improves lung gas exchange disorder.

[0050] Table 7. Chinese medicine extract significantly improves lung gas exchange function (n = 5, ** P <0.01 vs model group)

[0051] b. Chinese medicine extract effectively reduces the number of inflammatory cells in bronchoalveolar lavage fluid The proportion of inflammatory cells will significantly increase due to bronchitis caused by bacterial infection. As shown in the results of Table 8, the total number of cells in the bronchoalveolar lavage fluid of the model group was significantly increased, among which the proportion of mononuclear macrophages was decreased, and the proportions of neutrophils and lymphocytes were both significantly increased, suggesting that the diabetes combined with bronchitis model has extensive inflammatory response. After the intervention of the Chinese medicine extract of the application, the total number of cells showed a dose-dependent decrease, and the high-dose group returned to the normal level, the proportion of mononuclear macrophages increased, and the proportions of neutrophils and lymphocytes both significantly decreased. It shows that the Chinese medicine extract of the application can improve the abnormal reaction of inflammatory cells in the state of infection and maintain the homeostasis of the body.

[0052] Table 8. Chinese medicine extract regulates the proportion of inflammatory cells in bronchoalveolar lavage fluid (n = 5, ** P <0.01 vs model group)

[0053] c. Chinese medicine extract effectively improves bronchial inflammatory pathological damage Hematoxylin-eosin (HE) staining method was used to detect the pathological changes of lung tissue, and the following 6 core evaluation indexes were set for small bronchial inflammation: ① epithelial layer integrity (shedding / erosion); ② degree of goblet cell proliferation; ③ neutrophil infiltration density; ④ lymphocyte infiltration and lymphoid follicle formation; ⑤ mononuclear-macrophage infiltration level; ⑥ lumen exudate accumulation. According to the above standard, each index was independently scored, and the highest score of single field was recorded. After calculating the integral of each index, the final pathology total score was obtained. As shown in the results of Table 9, compared with the blank control group, the total score of bronchiolar inflammation in the model group was significantly increased, confirming the success of modeling. The total pathology score of the administration group decreased significantly with increasing dose, and showed a dose-dependent effect. At the same time, it had a significant inhibitory effect on key inflammatory indicators such as goblet cell proliferation, lymphoid follicle formation, and lumen exudate accumulation. It shows that the Chinese medicine extract of the application can significantly inhibit lung bronchial inflammatory damage.

[0054] Table 9. Inhibition of bronchial inflammatory pathological damage by traditional Chinese medicine extract (n=5, ** P <0.01 vs model group)

[0055] d. Traditional Chinese medicine extract effectively reduces the degree of pulmonary edema Alveolar area is a key indicator for evaluating emphysema. By analyzing lung tissue HE-stained sections, alveolar area (MAA, μm 2 ) and emphysema index (EI = measured MAA / normal MAA*100%) were calculated. The results are shown in Table 10. The alveolar morphology of the control group was uniform, the interval was complete (thickness 20-25 μm), and there was no emphysema or inflammatory exudation. The alveolar expansion and fusion of the model group (interval fracture rate > 60%), local pulmonary bullae (diameter > 200 μm), interstitial severe congestion, alveolar area significantly increased, emphysema index was 7.7 times of the normal group, and accompanied by a large number of inflammatory cell infiltration. The alveolar area of the traditional Chinese medicine extract intervention group was significantly reduced, and the alveolar structure of the high-dose group was close to normal (interval fracture rate 8%), with occasional small pulmonary bullae (diameter < 50 μm), and the emphysema index was dose-dependently inhibited, and the inflammatory cell infiltration was reduced. It is shown that the traditional Chinese medicine extract of the present application can significantly improve diabetes combined with emphysema and inhibit alveolar abnormal expansion.

[0056] Table 10. Inhibition of emphysema by traditional Chinese medicine extract (n=5, ** P <0.01 vs model group)

[0057] Example 6 Evaluation of the therapeutic effect of traditional Chinese medicine extract on diabetes patients combined with chronic cough 1. Test method a. Research object: 181 cases of diabetes patients combined with chronic cough who met the "Diagnosis and Treatment Criteria of TCM Syndromes" were used as research objects, and all subjects signed the written informed consent form after being approved by the institutional ethics committee. Research type: multi-center, randomized, double-blind, positive drug parallel control superiority test. Using random equal division, the subjects were divided into an observation group and a control group. The control group was given oral treatment, with a dose of 10 mL / time, 3 times / day, for 2 weeks; the observation group was given the traditional Chinese medicine granules of the present application, orally, with a dose of 5 g / time, 2 times / day, for 2 weeks, and the follow-up period was 28 days.

[0058] b. Observation index: cough score, refer to the cough symptom score table; clinical efficacy is evaluated according to the 'Diagnosis and Efficacy Standard of Traditional Chinese Medicine' and the overall effective rate is the number of cases of significant effect + effective cases / total cases. Cough symptoms (cough, sputum, cough disappearance time), daytime and nighttime cough symptoms can be divided into 0-3 levels according to the severity, and 0-3 points are recorded. The forced vital capacity (FVC), peak expiratory flow (PEF) and forced expiratory volume in one second (FEV1) levels of the patients are detected by a lung function detector. Biochemical indexes: tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels.

[0059] 2. Experimental results: a. Subject allocation and baseline characteristics Table 11 shows the basic information of the patients enrolled, including age, disease duration, gender. After statistical analysis, there is no significant difference in the baseline data of the two groups, which meets the requirements of clinical trials.

[0060] Table 11. General data statistics of patients.

[0061]

[0062] b. Overall efficacy evaluation According to the 'Diagnosis and Efficacy Standard of Traditional Chinese Medicine' and the 'Guiding Principles for Clinical Research of New Drugs of Traditional Chinese Medicine', the efficacy evaluation standard for treating diabetes mellitus combined with lung diseases (such as cough, chronic bronchitis) by the traditional Chinese medicine composition of the present application is as follows: Cure: the respiratory symptoms such as cough and expectoration of the patient (or model animal) completely disappear, and the related signs return to normal; the lung function detection index returns to the normal range, and the inflammatory factors and oxidative stress indexes in serum and lung tissue return to normal level; the TCM syndrome score is reduced by ≥90% compared with that before treatment; no symptoms recur within two weeks.

[0063] Marked effect: the main symptoms such as cough and expectoration are significantly improved, and the signs basically return to normal; the lung function and biochemical indexes are close to normal; the TCM syndrome score is reduced by 70%-<90% compared with that before treatment.

[0064] Effective: cough, expectoration and related signs are significantly improved, and the lung function and related indexes are restored to a certain extent; the TCM syndrome score is reduced by 30%-<70% compared with that before treatment.

[0065] Invalid: cough, sputum symptoms and other signs are not significantly improved, or are more severe than before treatment; lung function and biochemical indicators are not significantly improved; TCM syndrome score is reduced by <30% compared with before treatment.

[0066] As shown in Table 12, after 14 days of treatment, the total effective rate of the control group (western medicine group) was 80.26%, of which the cure rate was 21.67%, the significant effect rate was 33.94%, the effective rate was 24.65%, and the ineffective rate was 18.68%. The total effective rate of the treatment group of the present application was 96.52%, of which the cure rate was 34.72%, the significant effect rate was 42.36%, the effective rate was 19.44%, and the ineffective rate was 5.56%. The difference in total effective rate between the two groups was statistically significant (P<0.05). This shows that the treatment of the present application can significantly promote the rehabilitation of patients with diabetes combined with cough.

[0067] Table 12. Overall efficacy evaluation (%).

[0068]

[0069] c. Cough symptom score and cough disappearance time As shown in Table 13, the total cough symptom score and daytime and nighttime scores of the observation group were significantly lower than those of the control group, showing that it has good antitussive effect in both daytime and nighttime. The cough disappearance time of the observation group was shortened by 2.5 days compared with the control group, and the difference was statistically significant (P<0.05). According to the efficacy evaluation standard, the average TCM syndrome score of the observation group was reduced by 94.2%, and most patients reached the "markedly effective" or "cured" standard, which was significantly better than the control group. This shows that the present application can improve the TCM syndrome of diabetic cough and promote the cure of cough, and the effect is better than that of the control drug.

[0070] Table 13. Cough syndrome evaluation results.

[0071]

[0072] d. Lung function evaluation The lung function before and after treatment was evaluated by using the classic clinical indicators (FVC, PEF, FEV1). As shown in Table 14, compared with before treatment, the lung function (FVC, PEF, FEV1) of the observation group and the control group was significantly improved, and the improvement of the treatment group of the present application was significantly better than that of the control group. This shows that the present application can effectively improve the lung function of diabetic patients.

[0073] Table 14. Lung function evaluation index.

[0074]

[0075] e. Inflammation and oxidative stress evaluation The increase of inflammation and oxidative stress in the body of the diabetic patient is one of the main reasons leading to chronic lung disease. As shown in Table 15, compared with before treatment, the levels of inflammatory factors (IL-6 and TNF-α) of the observation group and the control group are significantly reduced, and the oxidative stress level (MDA and SOD) is significantly improved. After treatment, the improvement range of the Chinese medicine composition treatment group is obviously better than that of the control group. It is shown that the Chinese medicine composition can effectively inhibit the inflammation and oxidative stress level of the body of the diabetic patient.

[0076] Table 15. Inflammatory factors and oxidative stress related determination indexes.

[0077]

[0078] f.Comparison of recurrence rate and recurrence times of cough As shown in Table 16, it is found that the number of patients with recurrence in the Chinese medicine group is significantly less than that in the western medicine group within 4 weeks after treatment; the total recurrence rate of the Chinese medicine group is only 5.56%, which is far lower than 17.58% of the western medicine group, and the difference has statistical significance; the average recurrence times of the Chinese medicine group is 0.13±0.25 times, which is significantly less than 0.94±1.26 times of the western medicine group. It is shown that the Chinese medicine composition has better consolidation effect and anti-recurrence ability.

[0079] Table 16. Evaluation of recurrence rate of cough

[0080] In combination with the TCM syndrome score, lung function, inflammation level and other indexes, the Chinese medicine composition can effectively promote the recovery of the diabetic patient with cough, inhibit the inflammatory state of the body, and effectively avoid the secondary recurrence of the patient, and has better consolidation and anti-recurrence ability.

[0081] The above content is a further detailed description of the present application in combination with the specific preferred embodiments, and cannot be regarded as the limitation of the specific implementation of the present application to these descriptions. For ordinary skilled persons in the technical field to which the present application belongs, some simple deductions or replacements can be made without departing from the concept of the present application, and all of them should be regarded as the protection scope of the present application.

Claims

1. A sugar-free lung-moistening traditional Chinese medicine composition for diabetes with yin deficiency and dry cough, characterized in that: By weight parts, including pear 30-40 parts, 15-20 parts of Jinying-tong, 10-15 parts of South-sand-part, 10-15 parts of Maidong, 5-10 parts of Shanyao, 5-8 parts of Luohan-guo, 3-5 parts of Gouqi. ​ 2. The sugar-free lung-moistening traditional Chinese medicine composition for diabetes with yin deficiency and dry cough according to claim 1, characterized in that: By weight parts, including pear 35 parts, 17 parts of Jinying-tong, 13 parts of South-sand-part, 13 parts of Maidong, 8 parts of Shanyao, 7 parts of Luohan-guo, 4 parts of Gouqi.

3. The sugar-free lung-moistening traditional Chinese medicine composition for diabetes with yin deficiency and dry cough according to claim 1, characterized in that: By weight, including pear 37g, 16g of Jinying-tong, 14g of South-sand-part, 14g of Maidong, 7g of Shanyao, 8g of Luohan-guo, 4g of Gouqi.

4. The use of the sugar-free lung-moistening traditional Chinese medicine composition for diabetes with yin deficiency and dry cough according to any one of claims 1-3, characterized in that: The traditional Chinese medicine composition can be used for the prevention and treatment of diabetes with yin deficiency and dry cough, including diabetes combined with chronic bronchitis, pharyngitis, pneumonia, pulmonary nodule, asthma, pulmonary fibrosis.

5. A method for preparing a sugar-free lung-moistening traditional Chinese medicine composition for treating diabetes with yin deficiency and dry cough according to any one of claims 1-3, characterized in that, Including the following steps: Step 1, pear enzymatic hydrolysate preparation: according to weight parts, prepare enough pear; pear with skin and core, after pulping, add cellulase (0.1%-0.3%) and hydrolyze for 30 minutes to obtain pear enzymatic hydrolysate; Step 2, traditional Chinese medicine extraction pretreatment: according to weight parts, prepare enough Jinying-tong, South-sand-part, Maidong, Shanyao, Luohan-guo and Gouqi, crush the medicinal materials to 40 mesh, soak with 50% ethanol for 2 hours to obtain traditional Chinese medicine soaking liquid; Step 3, low temperature extraction: adopt dynamic circulation extraction tank, at 40-50℃, solid-liquid ratio is 1:8, water extract the traditional Chinese medicine soaking liquid for 2 times, 1 hour each time, to obtain traditional Chinese medicine extraction liquid; Step 4, mixing: mix the pear enzymatic hydrolysate and traditional Chinese medicine extraction liquid evenly to obtain traditional Chinese medicine mixed liquid; Step 5, purification and concentration: the traditional Chinese medicine mixed liquid is separated by 100kDa ultrafiltration membrane to obtain extraction liquid; Step 6, vacuum low temperature concentration of the extraction liquid to relative density 1.1-1.2 to obtain concentrated liquid; Step 7, drying and preparation: spray drying the concentrated liquid to prepare powder dry paste powder, or freeze-drying the concentrated liquid to prepare instant granules, to obtain traditional Chinese medicine extract.

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