Traditional Chinese medicine composition for treating diabetic lower limb blood vessel ischemia as well as preparation method and application of traditional Chinese medicine composition

Abstract

The invention discloses a traditional Chinese medicine composition for treating diabetic lower limb vascular ischemia as well as a preparation method and application of the traditional Chinese medicine composition. The traditional Chinese medicine composition is prepared from the following sixteen raw material medicines according to a specific weight ratio: radix aucklandiae, pericarpium citri reticulatae, rhizoma cyperi, fructus aurantii, folium perillae, herba schizonepetae, radix saposhnikoviae, rhizoma seu radix notopterygii, radix angelicae pubescentis, radix gentianae macrophyllae, ramulus mori, loofah sponge, radix angelicae sinensis, rhizoma chuanxiong, cassia The traditional Chinese medicine composition can be prepared into various oral preparations, and the preparation method comprises the steps of crushing, extracting, filtering, concentrating and the like. Pharmacodynamic experiments show that the traditional Chinese medicine composition can significantly improve expression of angiogenesis factors, improve blood perfusion of lower limbs, promote angiogenesis and effectively treat diabetic lower limb blood vessel ischemia and symptoms such as limb numbness, pain and ulcer caused by diabetic lower limb blood vessel ischemia, and has the advantages of being definite in curative effect, high in safety and low in cost.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of traditional Chinese medicine, in particular to a traditional Chinese medicine composition for treating diabetic hindlimb ischemia, a preparation method thereof, a traditional Chinese medicine preparation containing the composition and application. BACKGROUND

[0002] Diabetic hindlimb ischemia (HLI) is one of the serious complications of diabetes, which is caused by atherosclerotic occlusion of lower limb arteries and diabetic microangiopathy. Its clinical manifestations include intermittent claudication, rest pain, limb numbness, paresthesia, etc., and often further develop into diabetic foot ulcer, ischemic necrosis, and eventually lead to high amputation rate and even death. Due to the damage of hyperglycemic environment to endogenous angiogenic potential and the inhibition of collateral circulation formation, the condition of diabetic HLI patients is often more severe and the prognosis is worse.

[0003] At present, the treatment methods of modern medicine mainly include risk factor control (blood glucose, blood pressure, blood lipid), drug treatment (anti-platelet drugs, vasodilators) and blood revascularization surgery (vascular bypass grafting, endovascular treatment). However, drug treatment has side effects such as gastrointestinal reactions and bleeding risks; blood revascularization surgery is traumatic and expensive, and often cannot be implemented for patients with diffuse vascular lesions or poor "non-selective" outflow tract, resulting in a huge unmet clinical need.

[0004] From the pathological mechanism, angiogenesis is a physiological process that promotes the growth of new blood vessels in the existing vasculature, and plays an important role in tissue growth and survival. Therapeutic angiogenesis is therefore a promising treatment strategy, which provides the conditions for angiogenesis by applying cytokines or hemangioblasts into ischemic tissues to transform the local microenvironment, thereby promoting the generation of capillary networks and the establishment of collateral circulation in ischemic tissues. However, the high blood sugar environment of diabetes can lead to the dysregulation of the expression of various pro-angiogenic factors such as VEGF, PDGF-BB and bFGF, thereby systematically damaging the endogenous angiogenic potential. Therefore, effectively inducing angiogenesis has become a key approach to success in the treatment of diabetic HLI.

[0005] Diabetic HLI belongs to the category of "pulse stagnation" and "detached ulcer" in traditional Chinese medicine, and the advantage of traditional Chinese medicine in treating this disease is to establish collateral circulation and improve microangiogenesis. Therefore, it is of great clinical significance and application value to develop a traditional Chinese medicine compound preparation that can multi-target, synergistically regulate key factors of angiogenesis, and safely and effectively induce angiogenesis in ischemic lower limbs of diabetic patients. SUMMARY

[0006] In order to solve the above technical problems, the present application provides a traditional Chinese medicine composition for treating diabetic hindlimb ischemia, a preparation thereof, a preparation method and use.

[0007] To achieve the object of the present application, the present application adopts the following technical solutions:

[0008] The first aspect of the present application provides a traditional Chinese medicine composition for treating lower extremity ischemia of diabetes, which comprises the following raw medicinal materials by weight: 5-25 parts of costus root, 5-25 parts of dried tangerine or orange peel, 10-35 parts of cyperus, 5-25 parts of immature bitter orange fruit, 5-40 parts of perilla leaf, 5-25 parts of schizonepeta, 5-25 parts of sileris herb, 5-30 parts of notopterygium, 5-35 parts of angelica pubescens, 10-55 parts of gentiana, 10-60 parts of mulberry branchlet, 5-35 parts of luffa, 15-60 parts of angelica sinensis, 5-25 parts of chuanxiong rhizome, 5-35 parts of cassia twig, and 5-25 parts of licorice.

[0009] Preferably, the traditional Chinese medicine composition comprises the following raw medicinal materials by weight: 8-15 parts of costus root, 8-15 parts of dried tangerine or orange peel, 15-25 parts of cyperus, 7-20 parts of immature bitter orange fruit, 10-30 parts of perilla leaf, 7-15 parts of schizonepeta, 7-15 parts of sileris herb, 10-25 parts of notopterygium, 10-25 parts of angelica pubescens, 20-50 parts of gentiana, 20-50 parts of mulberry branchlet, 12-25 parts of luffa, 20-40 parts of angelica sinensis, 8-15 parts of chuanxiong rhizome, 10-25 parts of cassia twig, and 7-20 parts of licorice.

[0010] More preferably, the traditional Chinese medicine composition comprises the following raw medicinal materials by weight: 10 parts of costus root, 10 parts of dried tangerine or orange peel, 20 parts of cyperus, 10 parts of immature bitter orange fruit, 20 parts of perilla leaf, 10 parts of schizonepeta, 10 parts of sileris herb, 15 parts of notopterygium, 15 parts of angelica pubescens, 40 parts of gentiana, 40 parts of mulberry branchlet, 15 parts of luffa, 30 parts of angelica sinensis, 10 parts of chuanxiong rhizome, 15 parts of cassia twig, and 10 parts of licorice.

[0011] The “raw medicinal material” in the present application refers to a medicinal decoction piece meeting the standard of Chinese Pharmacopoeia.

[0012] In the present prescription, gentiana, mulberry branchlet, luffa, angelica sinensis, chuanxiong rhizome, and cassia twig tonify blood and activate blood, and dredge channels and collaterals; immature bitter orange fruit, sileris herb, angelica pubescens, and notopterygium dispel wind and dampness, and relieve arthralgia; cyperus, perilla leaf, and licorice regulate medicinal flavors and harmonize various drugs. The various medicinal flavors in the present prescription act as an indivisible whole, interact with each other, and take effect through multiple pharmacological actions, thereby jointly playing the role of promoting lower extremity angiogenesis, improving symptoms of lower extremity ischemia of diabetes, and treating diseases related to lower extremity ischemia of diabetes.

[0013] The second aspect of the present application provides a traditional Chinese medicine preparation, which comprises the traditional Chinese medicine composition of the first aspect of the present application. The "traditional Chinese medicine preparation" refers to a form suitable for clinical administration prepared by the conventional process of pharmacy. The traditional Chinese medicine preparation can further comprise one or more pharmaceutically acceptable carriers; the "pharmaceutically acceptable carriers" include, but are not limited to, fillers (such as starch, lactose), lubricants (such as magnesium stearate, talc), disintegrants (such as sodium carboxymethyl starch, low-substitution hydroxypropyl cellulose), binders (such as povidone, hydroxypropyl methyl cellulose), flavoring agents (such as aspartame, stevioside) and preservatives (such as potassium sorbate) and the like.

[0014] Preferably, the traditional Chinese medicine preparation is an oral preparation, which is one of a decoction, a granule, a capsule, a tablet, a plaster, a pill, a powder or any other pharmaceutically acceptable form thereof.

[0015] The third aspect of the present application provides a method for preparing the traditional Chinese medicine composition of the first aspect of the present application, comprising the following steps:

[0016] (a) weighing each raw material according to the ratio and mixing them, then crushing;

[0017] (b) adding a solvent to the powder obtained in step (a) for extraction;

[0018] (c) filtering after the extraction is completed, and collecting the filtrate;

[0019] (d) concentrating the filtrate obtained in step (c) to a predetermined concentration, and obtaining the product.

[0020] Preferably, the solvent in step (b) is one or a combination of water, alcohol and ethyl acetate;

[0021] More preferably, the solvent is water;

[0022] Preferably, the method of extraction in step (b) is decoction;

[0023] More preferably, the decoction is performed 2-4 times, and the amount of solvent added each time is 2-4 times the total weight of the raw materials.

[0024] The fourth aspect of the present application provides the use of the traditional Chinese medicine composition of the first aspect of the present application, the traditional Chinese medicine preparation of the second aspect of the present application and the composition prepared by the method of the third aspect of the present application in the preparation of a medicament for preventing or treating lower limb ischemia and / or the symptoms caused by diabetes.

[0025] Preferably, the symptoms include numbness of the limbs, pain of the limbs, diabetic foot ulcers or ischemic necrosis of the diabetic foot.

[0026] The "diabetic lower limb ischemia" in the present application refers to a pathological state of diabetic patients complicated with lower limb arteriosclerosis obliterans, resulting in insufficient blood perfusion, hypoxia and nutritional disorder of lower limb tissues, and the clinical features thereof include intermittent claudication, rest pain, limb numbness, reduced skin temperature, and the like, and the severe cases can develop into diabetic foot ulcer and even ischemic necrosis.

[0027] The present application has the following beneficial effects:

[0028] (1) The traditional Chinese medicine composition in the present application is scientifically matched according to the principles of traditional Chinese medicine, and the pharmacodynamic experiments prove that the traditional Chinese medicine composition in the present application can significantly improve the expression levels of vascular endothelial growth factor (VEGF-A), platelet-derived growth factor (PDGF-BB) and basic fibroblast growth factor (FGF-2), effectively promote angiogenesis, improve blood perfusion of lower limbs, increase temperature of affected limbs, improve limb function and necrosis, and has definite clinical efficacy.

[0029] (2) The preparation form of the present application is various, and various oral dosage forms such as decoction, granules, capsules, tablets and ointments can be prepared according to the clinical needs to meet the medication needs of different patients.

[0030] (3) The present application uses all medicinal and edible or clinically commonly used traditional Chinese medicinal materials, has high safety and small side effects, and is particularly suitable for chronic patients who need long-term medication.

[0031] (4) The medicinal materials selected in the present application are low in price, and the preparation process is simple, which can greatly reduce the medical expenses of patients and alleviate the economic burden. At the same time, the present application provides a new effective treatment option for diabetic lower limb ischemia patients, especially "non-selective" patients who cannot undergo blood revascularization, fills the gap of clinical intervention, and has important clinical significance and social value. BRIEF DESCRIPTION OF DRAWINGS

[0032] Figure 1 is a laser speckle blood flow imaging graph of lower limbs of mice in each group in the experiment;

[0033] Figure 2 is a curve graph of changes in limb necrosis scores of mice in each group, Sham is a sham operation group, Model is a model group, LQJTY-L is a low-dose LQJTY group, LQJTY-H is a high-dose LQJTY group, and XLTZ is a positive control silodexide group.

[0034] Figure 3 is a curve graph of changes in limb walking function scores of mice in each group, Sham is a sham operation group, Model is a model group, LQJTY-L is a low-dose LQJTY group, LQJTY-H is a high-dose LQJTY group, and XLTZ is a positive control silodexide group. DETAILED DESCRIPTION

[0035] The present application is further illustrated in detail by the following preparation examples and pharmacodynamic experiments, which are only used to explain the present application and are not intended to limit the scope of protection. The raw medicinal materials used in the present application are common decoction pieces available in the market, which meet the standards of the current edition of Chinese Pharmacopoeia.

[0036] Preparation Example

[0037] Example 1

[0038] The following raw medicinal materials were weighed: 10 g of Aucklandia, 10 g of dried tangerine or orange peel, 20 g of Cyperus, 10 g of immature Bitter Orange, 20 g of Perilla, 10 g of Schizonepeta, 10 g of Saposhnikovia, 15 g of Notopterygium, 15 g of Radix Angelicae Pubescentis, 40 g of Gentiana, 40 g of White Willow, 15 g of Luffa, 30 g of Angelica sinensis, 10 g of Chuanxiong, 15 g of Ramulus Cinnamomi, and 10 g of Radix Glycyrrhizae. The above medicinal materials were mixed and crushed into coarse powder. Water was added to the total weight of the raw medicinal materials, and the mixture was decocted twice for 1 hour each time. The filtrates were combined and filtered, and the filtrate was concentrated to a total volume of 100 mL to obtain the traditional Chinese medicine decoction of Example 1, which was stored at 4°C for later use.

[0039] The formulations of Examples 2-3 and Comparative Examples 1-3 were configured according to Table 1. The preparation methods of Examples 2-3 and Comparative Examples 1-3 were the same as that of Example 1. The filtrate was concentrated to a total volume of 100 mL to obtain the traditional Chinese medicine decoction of Examples 2-3 and Comparative Examples 1-3, which was stored at 4°C for later use.

[0040] Table 1: Raw medicinal material ratio table (unit: g)

[0041]

[0042]

[0043] Pharmacodynamic evaluation

[0044] 1. Construction of a mouse model of lower limb ischemia caused by diabetes

[0045] SPF male C57BL / 6J mice (6-8 weeks old) were selected as experimental animals and were adaptively fed for one week under standard laboratory conditions. The model was constructed in two stages.

[0046] 1.1 Diabetes model induction: Except for the blank control group fed with ordinary maintenance feed, the rest of the mice were fed with high-fat feed (20% kcal protein, 20% kcal carbohydrate and 60% kcal fat) for 8 weeks. Subsequently, the high-fat diet mice were fasted overnight, and a freshly prepared streptozotocin (STZ, dissolved in 0.1 mol / L, pH 4.5 citrate buffer) solution was injected intraperitoneally every day, with an injection dose of 40 mg / kg, for 5 consecutive days. One week after the end of STZ injection, fasting blood glucose was measured by tail tip blood sampling, and mice with fasting blood glucose values stable at ≥11.1 mmol / L were identified as successful diabetes modeling and used for subsequent experiments.

[0047] 1.2 Lower limb ischemia model construction: The left lower limb was selected for modeling, and the right lower limb served as the self-control. For the mice successfully modeled with diabetes, isoflurane inhalation anesthesia was used, and the mice were fixed in a supine position. The hair on the surgical area was removed with a depilatory agent and then disinfected with iodophor. About 1 cm of skin was incised at the left inguinal region along the femoral artery, and the femoral artery and vein were bluntly separated to avoid damaging the nerves. The right femoral artery was doubly ligated at the proximal and distal ends using 6-0 suture thread, and then the blood vessel segment between the two ligation points was excised to completely block the blood flow, simulating lower limb ischemia. After the operation, careful observation was made to see if there was bleeding, and if necessary, electrocoagulation was used for hemostasis, the skin incision was sutured, and the mice were monitored during the entire recovery process.

[0048] Modeling success criteria: The blood flow perfusion of the surgical side (left lower limb) and the contralateral healthy limb (right lower limb) was monitored using a laser speckle blood flow imaging system, and a decrease in the ratio of the surgical limb / healthy limb blood flow index of about 70% was used as the criterion for successful construction of the lower limb ischemia model. All animal experimental operations were in accordance with relevant ethical standards and were approved by the unit animal ethics committee.

[0049] 2. Detection of angiogenic factor expression levels

[0050] From the 85 mice successfully modeled, 35 mice were selected and randomly divided into 7 groups (n=5): a blank control group (given an equal volume of normal saline), Example 1, Example 2, Example 3, Comparative Example 1, Comparative Example 2, and Comparative Example 3. Each group was given the corresponding drug once a day by gavage (gavage volume 5 mL per mouse), and the administration was continued for 3 weeks. After the last administration, the mice were fasted for 12 hours without water deprivation, anesthetized by intraperitoneal injection of pentobarbital sodium, and blood was collected from the abdominal aorta into an anticoagulant tube. After the blood sample was placed at 4°C for 2 hours, it was centrifuged at 3000 rpm for 15 minutes, the upper plasma was separated, and it was stored at -20°C for testing.

[0051] The concentrations of vascular endothelial growth factor-A (VEGF-A), platelet-derived growth factor-BB (PDGF-BB) and basic fibroblast growth factor (FGF-2) in the plasma of mice in each group were detected by enzyme-linked immunosorbent assay (ELISA) method, and the operation was strictly in accordance with the instructions of the kit. The average determination value of each factor in the blank control group was taken as the reference (set as 1.00), and the relative expression level change of each administration group was calculated, and the results are shown in Table 2.

[0052] Table 2 Relative expression level of angiogenic factors in serum of mice in each group

[0053] Blank group Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 VEGF-A 1.00 3.72 2.75 3.95 1.42 1.53 1.71 PDGF-BB 1.00 3.47 2.78 3.77 1.55 1.87 1.98 FGF-2 1.00 3.55 2.87 3.83 1.47 1.61 1.87

[0054] The results show that the expression levels of VEGF-A, PDGF-BB and FGF-2 in the serum of diabetic lower limb ischemia model mice in the groups of examples 1-3 can be significantly improved, and the effect is significantly better than that of the blank control group, and there is a certain dose-effect trend (example 3>example 1>example 2). Although the effect of example 3 is better than that of example 1, there is a concentration effect decrease, and in the case of balancing the efficacy and price, the ratio of example 1 is the optimal choice. Although the groups of comparative examples 1-3 have a certain improvement compared with the blank group, the effect of promoting the expression of angiogenic factors is much lower than that of any example group, which shows that the traditional Chinese medicine composition of the application is an organic whole, and the scientific compatibility is crucial to the efficacy.

[0055] 3. Histological detection

[0056] 3.1 Preparation of experimental drugs

[0057] The drug (Liujidran) of the application: the traditional Chinese medicine decoction prepared in example 1 is placed in a 4℃ refrigerator for storage. The dose conversion is carried out by the body surface area method, and the equivalent dose conversion coefficient of mice and humans is calculated as 9.1. Assuming that the average body weight of humans is 60 kg, the total weight of the prescription in this study is the total weight of each medicine 295 g, and the daily dose for humans is 4.92 g crude drug / kg, which is converted to the equivalent dose of mice of about 44.74 g crude drug / (kg·d) (calculation: 4.92 g / kg x 9.1 ≈ 44.74 g / kg), which is used as the high dose, and half of it (22.37 g crude drug / (kg·d)) is used as the low dose. Before gavage, the concentrated decoction is diluted to the required concentration with normal saline according to the body weight of the mice, and the gavage volume is 10 mL / kg.

[0058] Positive control drug (sulodexide suspension): Take sulodexide tablets, grind into fine powder, add an appropriate amount of normal saline, and grind thoroughly to prepare a suspension. According to the human clinical daily dose of 200 mg / 60 kg, the equivalent dose for mice is 30.33 mg / (kg·d) (calculation: (200 mg / 60 kg) x 9.1 ≈ 30.33 mg / kg). The concentration is 3.033 mg / mL, and the intragastric volume is 10 mL / kg.

[0059] Preparation of streptozotocin (STZ) solution: 200 mg of STZ was dissolved in 20 mL of 0.1 mol / L pH 4.5 citric acid-sodium citrate buffer to prepare a solution with a concentration of 10 mg / mL. The whole process was operated on ice and stored in the dark. Each mouse was injected intraperitoneally at a dose of 40 mg / kg, corresponding to 4 ml / kg. The solution should be prepared within 30 minutes to ensure the stability and effectiveness of the drug.

[0060] 3.2 Experimental grouping and drug administration

[0061] The remaining 50 mice with successful modeling were randomly divided into 5 groups according to body weight. After 7 days of adaptive feeding, drug treatment was started, and the specific grouping was as follows:

[0062] Sham operation group (SHAM): only isolate the femoral artery without ligation and resection, and give an equal volume of normal saline by gavage;

[0063] Model group (MOD): given an equal volume of normal saline by gavage;

[0064] Low-dose Liuqiyin group (LQJTY-L): given the decoction prepared in Example 1, the dose was 22.37 g of crude drug / (kg·d);

[0065] High-dose Liuqiyin group (LQJTY-H): given the decoction prepared in Example 1, the dose was 44.74 g of crude drug / (kg·d);

[0066] Sulodexide group (XL): given sulodexide suspension with a concentration of 6.07 mg / mL by gavage at a dose of 5 mL / kg, which is equivalent to 30.33 mg / kg / d.

[0067] All the above groups were given continuous gavage for 3 weeks.

[0068] 3.3 Detection index and method

[0069] (1) Lower limb laser speckle blood flow imaging detection

[0070] Before modeling, immediately after modeling (0d), 7, 14, 21 days after administration, the mice were lightly anesthetized with isoflurane, kept the temperature and light relatively constant, and made the mice take the supine position to fix the limbs. The blood flow images of the lower limbs were taken by using the laser speckle blood flow imaging system, and the blood flow perfusion index (BFI) of the left lower limb was calculated.

[0071] (2) Local skin temperature measurement

[0072] Before modeling, immediately after modeling (0d), 7, 14, 21 days after administration, the mice were lightly anesthetized with isoflurane, kept the temperature and light relatively constant, and made the mice take the supine position to fix the limbs. The blood flow images of the lower limbs were taken by using the laser speckle blood flow imaging system, and the blood flow perfusion index (BFI) of the left lower limb was calculated.

[0073] (3) Limb function and necrosis score

[0074] On the 0th, 7th, 14th, 21st day after modeling, the mice in each group were observed and recorded, and the walking function and necrosis of the limbs were scored.

[0075] The walking function scoring standard of the limbs is: 1-the limbs cannot be used; 2-only the limbs can be used, but not the feet; 3-the foot movement is limited; 4-the toes cannot be stretched, only the soles are used; 5-the limbs are not limited in use.

[0076] The limb necrosis scoring standard is: 1-limb amputation; 2-foot amputation; 3-toe amputation; 4-palm curling, or only nail shedding; 5-complete recovery.

[0077] 3.4 Experimental results

[0078] The results of the lower limb laser speckle blood flow imaging show that Figure 1 ), the blood flow of the left lower limb of the sham operation group remained stable during the whole experiment. Compared with before modeling, the blood flow of the left lower limb of the modeling groups decreased significantly after modeling. By the 7th day, the left lower limb of the model group had basically no blood flow signal, while the blood flow of the low / high dose groups of Liuqiyin and the cilostazol group improved to varying degrees, of which the high dose group improved most obviously; by the 14th day, the improvement trend of each group was consistent with the 7th day; by the 21st day, although the ischemia of the left lower limb of the model group improved to some extent, the improvement effect of the left lower limb ischemia of each intervention group was obviously better than that of the model group, of which the high dose group of Liuqiyin had the best effect (see Figure 1 ). The results directly show that the traditional Chinese medicine composition of the present application can effectively promote the blood flow recovery of the ischemic tissue of the lower limbs of diabetic mice.

[0079] The results show (Table 3) that the BFI of the left lower limb of the sham operation group did not change significantly during the entire experiment. The BFI of each group decreased significantly after modeling (P<0.05). On the 7th day of intervention, the BFI of the high-dose Liuhuinyin group and the cilostazol group had increased significantly compared with that immediately after modeling (P<0.05), but there was no significant difference in the BFI of the left lower limb between each intervention group and the model group on the same day. By the 14th day, the BFI of each treatment group had increased significantly compared with that after modeling (P<0.05), and the BFI of the high-dose group and the cilostazol group was significantly better than that of the model group on the same day (P<0.05). On the 21st day, the BFI of each treatment group was still significantly higher than that after modeling (P<0.05). The quantitative data of BFI and the blood flow imaging results confirm each other, and together show that the traditional Chinese medicine composition of the application can significantly improve lower limb ischemia.

[0080] Table 3 Change in BFI of the left lower limb of each group

[0081]

[0082] Note: a) P<0.05 compared with the same group before modeling; b) P<0.05 compared with the same group after modeling; 1) P<0.05 compared with the model group on the same day.

[0083] The results of measuring the local skin temperature of the left lower limb show (Table 4) that the body temperature of the sham operation group remained stable and did not fluctuate significantly during the period from after modeling to the 21st day (P>0.05). Compared with before modeling, the body temperature of each group decreased significantly after modeling (P<0.05). On the 7th day of intervention, the body temperature of each intervention group did not change significantly compared with that after modeling and the model group on the same day (P>0.05). By the 14th day, the body temperature of the high-dose Liuhuinyin group had increased significantly compared with that after modeling and the model group on the same day (P<0.05), showing a clear therapeutic effect. On the 21st day, the body temperature of the model group and each intervention group increased significantly compared with the average level after modeling (P<0.05), and the body temperature of each intervention group was significantly higher than that of the model group on the same day (P<0.05), among which the high-dose Liuhuinyin group and the cilostazol group had the most significant warming effect. This result shows that the traditional Chinese medicine composition of the application can effectively improve the microcirculation of ischemic lower limbs and promote tissue metabolism and body temperature recovery.

[0084] Table 4 Change in body temperature of the left lower limb (°C)

[0085]

[0086]

[0087] Note: a) P < 0.05 compared with the same group before modeling; b) P < 0.05 compared with the same group after modeling; 1) P < 0.05 compared with the model group on the same day.

[0088] The results of the limb walking function score ( Figure 2 ) and the necrosis score ( Figure 3 ) show that the sham operation group had no change in the two scores during the entire experiment and maintained at the normal level. In contrast, the model group had a significant decrease in the limb walking function score and the necrosis score after modeling, indicating that lower limb ischemia led to severe dysfunction and tissue damage. After 3 weeks of drug intervention, each treatment group (Liuqiyin low and high dose groups and cilostazol group) could improve the limb necrosis score and walking function score to different degrees, showing the effectiveness of the treatment. Among them, the Liuqiyin high dose group had the best curative effect, and the improvement degree of the score was the most significant, which was better than the cilostazol group and the low dose group. The results confirmed from the functional and morphological aspects that the traditional Chinese medicine composition of the present application can significantly promote the functional recovery and tissue repair after diabetic lower limb ischemia.

[0089] In summary, after the traditional Chinese medicine composition of the present application intervened in diabetic lower limb vascular ischemia mice, it can improve the expression of angiogenic factors, improve lower limb blood perfusion, improve the temperature of the affected limb, improve the ischemic necrosis condition of the affected limb, and improve the walking function, thereby achieving the effect of treating diabetic lower limb vascular ischemia.

[0090] Although the embodiments of the present application have been shown and described above, it should be understood that the above-described embodiments are exemplary and should not be construed as limiting the present application, and those skilled in the art can make changes, modifications, replacements and variations to the above-described embodiments within the scope of the present application.

Claims

1. A traditional Chinese medicine composition for treating lower extremity ischemia in diabetes, characterized in that, The raw medicinal materials include the following ingredients by weight: 5-25 parts of Radix Aucklandiae, 5-25 parts of Pericarpium Citri Reticulatae Viride, 10-35 parts of Rhizoma Cyperi, 5-25 parts of Fructus Aurantii, 5-40 parts of Folium Perillae, 5-25 parts of Herba Schizonepetae, 5-25 parts of Saposhnikovia Divaricata, 5-30 parts of Rhizoma Notopterygii, 5-35 parts of Angelica Pubescens, 10-55 parts of Rubus Suavissimus, 10-60 parts of Ramulus Mori, 5-35 parts of Luffa Cycladis, 15-60 parts of Angelica Sinensis, 5-25 parts of Chuanxiong Rhizome, 5-35 parts of Ramulus Cinnamomi, and 5-25 parts of Radix Glycyrrhizae.

2. The traditional Chinese medicine composition of claim 1, wherein, The raw medicinal materials include the following ingredients by weight: 8-15 parts of Radix Aucklandiae, 8-15 parts of Pericarpium Citri Reticulatae Viride, 15-25 parts of Rhizoma Cyperi, 7-20 parts of Fructus Aurantii, 10-30 parts of Folium Perillae, 7-15 parts of Herba Schizonepetae, 7-15 parts of Saposhnikovia Divaricata, 10-25 parts of Rhizoma Notopterygii, 10-25 parts of Angelica Pubescens, 20-50 parts of Rubus Suavissimus, 20-50 parts of Ramulus Mori, 12-25 parts of Luffa Cycladis, 20-40 parts of Angelica Sinensis, 8-15 parts of Chuanxiong Rhizome, 10-25 parts of Ramulus Cinnamomi, and 7-20 parts of Radix Glycyrrhizae.

3. The traditional Chinese medicine composition of claim 1, wherein, The raw medicinal materials include the following ingredients by weight: 10 parts of Radix Aucklandiae, 10 parts of Pericarpium Citri Reticulatae Viride, 20 parts of Rhizoma Cyperi, 10 parts of Fructus Aurantii, 20 parts of Folium Perillae, 10 parts of Herba Schizonepetae, 10 parts of Saposhnikovia Divaricata, 15 parts of Rhizoma Notopterygii, 15 parts of Angelica Pubescens, 40 parts of Rubus Suavissimus, 40 parts of Ramulus Mori, 15 parts of Luffa Cycladis, 30 parts of Angelica Sinensis, 10 parts of Chuanxiong Rhizome, 15 parts of Ramulus Cinnamomi, and 10 parts of Radix Glycyrrhizae.

4. A traditional Chinese medicine preparation, characterized in that, The traditional Chinese medicine preparation comprises the traditional Chinese medicine composition of any one of claims 1-3.

5. The traditional Chinese medicine preparation of claim 4, characterized in that, The traditional Chinese medicine preparation further comprises at least one pharmaceutically acceptable carrier.

6. The traditional Chinese medicine preparation of any one of claims 4 or 5, wherein, The traditional Chinese medicine preparation is an oral preparation, which is one of a decoction, granules, capsules, tablets, ointments, pills, and powders, or any other pharmaceutically acceptable dosage form.

7. A method for preparing the traditional Chinese medicine composition according to any one of claims 1-3, characterized in that, The method comprises the following steps: (a) weighing each raw medicinal material according to the ratio, mixing, and then crushing; (b) adding a solvent to the powder obtained in step (a) to extract; (c) filtering after the extraction is completed, and collecting the filtrate; (d) concentrating the filtrate obtained in step (c) to a predetermined concentration, and obtaining the traditional Chinese medicine preparation.

8. The method of claim 7, wherein, The solvent in step (b) is one or a combination of water, alcohol, and ethyl acetate, and the extraction method is decoction. Decoction is performed 2-4 times, and the amount of solvent added each time is 2-4 times the total weight of the raw medicinal materials.

9. Use of the traditional Chinese medicine composition of claims 1-3, the traditional Chinese medicine preparation of claims 4-6, or the composition prepared by the method of claims 7-8 in the preparation of a medicament for preventing or treating lower limb ischemia caused by diabetes and / or a symptom caused thereby.

10. Use according to claim 9, wherein The symptom includes numbness of the limbs, pain of the limbs, diabetic foot ulcer, or ischemic necrosis of the diabetic foot. The symptom includes numbness of the limbs, pain of the limbs, diabetic foot ulcer, or ischemic necrosis of the diabetic foot.

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