A Chinese medicine composition and its application in treating pulmonary thromboembolism

Abstract

The present invention discloses a traditional Chinese medicine composition and its use in treating pulmonary thromboembolism. The traditional Chinese medicine composition is prepared from the following raw materials: raw astragalus, whole angelica, herb agrimony, notoginseng powder, madder, red peony root, and dried tangerine peel. The traditional Chinese medicine composition of the present invention utilizes the inherent characteristics of each component raw material, rationally formulates the formula, and scientifically proportions the formula to achieve optimal synergistic efficacy. The traditional Chinese medicine composition has a definite therapeutic effect and has a good effect of reducing the incidence of bleeding during the anticoagulation process in patients with pulmonary thromboembolism. It also has low toxicity and high safety, and can improve the efficacy of anticoagulation treatment for pulmonary thromboembolism. The present invention makes up for the current shortage of traditional Chinese medicine prescriptions for pulmonary thromboembolism, and has the characteristics of a wide source of raw materials, a high safety factor, a small dosage, and a dosage form that meets clinical needs.

Description

Technical Field

[0001] The present invention belongs to the technical field of traditional Chinese medicine, and relates to a traditional Chinese medicine composition, and in particular to a traditional Chinese medicine composition and its application in treating pulmonary thromboembolism.

[0002] Background technology

[0003] Pulmonary thromboembolism (PTE) is a clinical emergency caused by thrombotic obstruction of the pulmonary artery or its branches and is a key manifestation of venous thromboembolism (VTE). Most thrombi originate from the deep veins of the lower extremities (such as the femoral and popliteal veins), dislodging and entering the pulmonary artery with the bloodstream, leading to pulmonary circulatory obstruction. The clinical manifestations of PTE vary, ranging from asymptomatic in mild cases to shock and even sudden death in severe cases. Typical symptoms include dyspnea, chest pain, and hemoptysis. Its onset is closely associated with inherited thrombophilias (such as antiphospholipid antibody syndrome) and acquired risk factors (such as surgery, prolonged immobilization, and malignant tumors). Therefore, early diagnosis and treatment of patients with PTE are crucial to improving prognosis.

[0004] Currently, treatments for pulmonary thromboembolism are primarily categorized as anticoagulant therapy, thrombolytic therapy, or interventional / surgical therapy. Anticoagulant therapy is the cornerstone of pulmonary thromboembolism treatment, preventing clot expansion and recurrence. However, it can increase the risk of bleeding, which can be life-threatening in severe cases. Therefore, finding a drug that can both treat pulmonary thromboembolism and reduce the risk of bleeding in patients is of great clinical significance. Summary of the Invention

[0005] In order to make up for the deficiencies of the prior art, the purpose of the present invention is to provide a Chinese medicine composition and its application in treating pulmonary thromboembolism.

[0006] In order to achieve the above object, the present invention adopts the following technical solutions:

[0007] A first aspect of the present invention provides a traditional Chinese medicine composition for treating pulmonary thromboembolism.

[0008] Furthermore, the raw materials of the traditional Chinese medicine composition are: raw astragalus, whole angelica, agrimony, Panax notoginseng powder, madder, red peony root and tangerine peel.

[0009] Furthermore, by weight percentage, the ratio of raw astragalus: whole angelica: agrimony: Panax notoginseng powder: Rubia cordifolia: red peony root: tangerine peel is 10:3:4:1:3:3:2.

[0010] Furthermore, the Chinese medicine composition is prepared from the following raw materials by weight: 30g raw astragalus, 9g whole angelica, 12g agrimony, 3g Panax notoginseng powder, 9g Rubia cordifolia, 9g red peony root, and 6g tangerine peel.

[0011] In the above compositions, the weight of the medicinal materials is calculated based on the crude drug, and the weight percentage is used as the proportion. This proportion can be increased or decreased during production. For example, large-scale production can use kilograms or tons as the unit, and small-scale production can use grams or milligrams as the unit. The weight can be increased or decreased, but the weight ratio of the crude drug materials in each component remains unchanged. The above weight ratios are obtained through scientific screening. For special patients, such as those with severe or mild symptoms, obese or thin patients, the quantitative ratio of the components can be adjusted accordingly, with an increase or decrease of no more than 100% without changing the efficacy.

[0012] Furthermore, the Chinese medicine composition also includes active ingredients or pharmaceutically acceptable salts of active ingredients in raw astragalus, whole angelica, agrimony, notoginseng powder, madder, red peony root and tangerine peel.

[0013] Furthermore, the pharmaceutically acceptable salts include acid addition salts and base addition salts.

[0014] As used herein, the term "pharmaceutically acceptable salt" includes ammonium phosphates, metal salts, salts formed with amino acids, salts formed with amines, and salts formed with other bases such as piperidine or morpholine. The term "pharmaceutically acceptable salt" includes monosalts and disalts. Specific embodiments include ammonium, sodium, calcium, magnesium, cesium, lithium, potassium, barium, zinc, aluminum, lysine, arginine, histidine, methylamine, ethylamine, tert-butylamine, cyclohexylamine, N-methylglucamine, ethylenediamine, glycine, procaine, benzathene, diethanolamine, triethanolamine, piperidine, and morpholine.

[0015] In some embodiments, the term "pharmaceutically acceptable salt" may also include hydrates of pharmaceutically acceptable salts of the active ingredients of the present invention. Exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, hydrochlorides, bromides, hydrobromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbates, gentisinates, gluconates, glucuronates, saccharates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, camphorsulfonates, naphthylsulfonates, propionates, succinates, fumarates, maleates, malonates, mandelates, malates, palmitates, aspartates, phthalates, and pamoates.

[0016] As used herein, the term "pharmaceutically acceptable salt" also refers to a salt formed between the active ingredient of the Chinese medicinal material of the present invention having an acidic functional group, such as a carboxylic acid functional group, and a base. Examples of bases include, but are not limited to, alkali metal hydroxides including sodium, potassium, and lithium; alkaline earth metal hydroxides such as calcium and magnesium hydroxides; other metal hydroxides such as aluminum and zinc hydroxides; ammonia, organic amines such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines, dicyclohexylamine; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, di-, or tri-(2-OH-(C1-C6)-alkylamine), such as N, N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like.

[0017] In some embodiments, when the Chinese medicine composition of the present invention is administered to a specific individual subject for treatment, the therapeutically effective amount and specific treatment plan for the individual subject may be affected by many factors, including the pharmacodynamic activity of the drug used, the age, weight, general condition, gender, diet, administration time, disease susceptibility, disease progression, and the judgment of the treating physician. In addition, those skilled in the art are aware that the mode of administration, dosage form, and dosage of the drug are affected by many factors such as the patient's age, weight, gender, morbidity, diet, administration time, excretion rate, and reaction sensitivity. Therefore, the dosage of the Chinese medicine composition described in the present invention is not limited to the dosage in the embodiments of the present invention, and the same applies to the mode of administration and dosage form.

[0018] Any Chinese medicine composition encompassed by the present invention can be delivered orally, for example, via any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, for example, tablets, lozenges, pastilles, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to any method known in the art for making pharmaceutical compositions intended for oral administration.

[0019] In some embodiments, the prescription used in the present invention uses Astragalus membranaceus as the main ingredient to replenish the Qi of the lungs and spleen, and Angelica sinensis as the auxiliary ingredient to nourish blood and promote blood circulation, Agrimony Root as the auxiliary ingredient to replenish Qi, tonify the middle, promote blood circulation and stop bleeding, and stop astringency while promoting circulation, Panax notoginseng as the auxiliary ingredient to replenish deficiency, promote blood circulation and stop bleeding, Rubia cordifolia as the auxiliary ingredient to cool blood, remove blood stasis and promote blood circulation and stop bleeding, and Paeonia lactiflora as the auxiliary ingredient to clear heat, cool blood, disperse blood stasis and stop pain, and Tangerine Peel as the auxiliary ingredient to regulate Qi, strengthen the spleen, dry dampness and resolve phlegm.

[0020] The Chinese medicine composition provided by the present invention is named as Yifei Tiaoxue Recipe. In the embodiments of the present invention, the terms "Chinese medicine composition", "Chinese medicine" and "Yifei Tiaoxue Recipe" have the same meaning and can be used interchangeably.

[0021] As used herein, the term "API" refers to the raw medicinal material used in the production of pharmaceutical preparations (drugs), and is the source of the active ingredient in the pharmaceutical preparations (drugs). In some embodiments, the term "API" refers to the raw medicinal material used in the production of various preparations, which is the active ingredient in the preparations, and is a substance prepared by chemical synthesis, plant extraction, or biotechnology in the form of powders, crystals, extracts, etc. for medicinal use, but which cannot be directly ingested by patients.

[0022] A second aspect of the present invention provides a pharmaceutical preparation.

[0023] Furthermore, the pharmaceutical preparation includes the traditional Chinese medicine composition described in the first aspect of the present invention.

[0024] Furthermore, the pharmaceutical preparation further comprises a pharmaceutically acceptable buffer, carrier and / or excipient.

[0025] Furthermore, the buffer comprises phosphate, carbonate, acetate, citrate, glycolate, lactate, borate, tartrate, and cacodylate.

[0026] Furthermore, the buffer also includes Trizma, Bicine, Tricine, MOPS, MOPSO, MOBS, Tris, Hepes, HEPBS, MES, ACES, ADA, AMP, AMPD, AMPSO, BES, CABS, CHES, DIPSO, EPPS, ethanolamine, glycine, HEPPSO, imidazole, imidazole lactate, PIPES, SSC, SSPE, POPSO, TAPS, TABS, TAPSO, and TES.

[0027] Furthermore, the carrier includes an isotonic agent, an antioxidant, a suspending agent, a dispersing agent, an emulsifier, a chelating agent, a thickener, and a solubilizing agent.

[0028] Furthermore, the excipients include carbohydrates, polymers, lipids, and minerals.

[0029] Furthermore, the dosage forms of the Chinese medicine preparation include granules, tablets, pills, capsules, injections, oral liquids, tinctures, suppositories, mixtures, powders, lotions, films, and dripping pills.

[0030] Furthermore, the pharmaceutically acceptable buffer, carrier and / or excipient are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995). These substances are used to help stabilize the drug or to help improve the activity of the effective active ingredient in the drug as needed. The active ingredient that can be used in such a pharmaceutical composition can be in the form of its original compound itself, or optionally in other pharmaceutically acceptable forms. The pharmaceutical composition thus formulated can be administered in any appropriate manner known to those skilled in the art as needed.

[0031] Furthermore, pharmaceutically acceptable buffers, carriers and / or excipients may additionally contain liquids such as water, physiological saline, glycerol and ethanol. In addition, auxiliary substances such as wetting agents or emulsifiers or pH buffer substances may be present in the pharmaceutical composition. These carriers enable the pharmaceutical composition to be formulated into dosage forms such as granules, tablets, pills, capsules, injections, oral liquids, tinctures, mixtures, powders, lotions, films, dripping pills, etc. for patient ingestion.

[0032] A third aspect of the present invention provides a method for preparing a traditional Chinese medicine composition for treating pulmonary thromboembolism.

[0033] Furthermore, the preparation method comprises the following steps: extracting or processing the raw materials of the traditional Chinese medicine composition described in the first aspect of the present invention to obtain its active ingredients, and then, using the active ingredients as raw materials, adding pharmaceutically acceptable buffers, carriers and / or excipients as needed, and preparing the desired dosage form according to conventional pharmaceutical techniques.

[0034] The fourth aspect of the present invention provides use of the traditional Chinese medicine composition described in the first aspect of the present invention in the preparation of a medicament for treating and / or preventing pulmonary thromboembolism.

[0035] The fifth aspect of the present invention provides use of the pharmaceutical preparation described in the second aspect of the present invention in the preparation of a medicament for treating and / or preventing pulmonary thromboembolism.

[0036] Advantages and beneficial effects of the present invention:

[0037] The Chinese medicine composition described in the present invention utilizes the inherent characteristics of each component raw material medicine, rationally formulates the formula, and scientifically proportions to achieve optimal synergistic efficacy; the Chinese medicine composition has a definite therapeutic effect, has a good effect of reducing the incidence of bleeding in patients with pulmonary thromboembolism during the anticoagulation process, and has low toxicity and high safety, while also improving the efficacy of anticoagulation treatment for pulmonary thromboembolism; the present invention makes up for the current situation of insufficient traditional Chinese medicine prescriptions for pulmonary thromboembolism, and has the characteristics of a wide source of raw materials, a high safety factor, a small dosage, and a dosage form that meets clinical needs. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 This is a comparison chart of TCM syndrome scores before and after treatment with the Chinese medicine composition of the present invention. DETAILED DESCRIPTION

[0039] In order to make the purpose, technical scheme and beneficial effects of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be clearly and completely described below. If specific conditions are not specified in the embodiments, the experiments were carried out according to conventional conditions or the conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0040] Example 1 Preparation of Chinese medicine composition

[0041] Drug name: Yifei Tiaoxue Fang

[0042] Ingredients: Raw Astragalus 30g, Whole Angelica 9g, Agrimoniae 12g, Panax notoginseng powder 3g, Rubia cordifolia 9g, Red Peony Root 9g, Tangerine Peel 6g

[0043] Combination: Astragalus is the main ingredient to replenish the Qi of the lungs and spleen, while Angelica sinensis nourishes blood and promotes blood circulation; Agrimony Root replenishes Qi, tonifies the middle, promotes blood circulation and stops bleeding, while Panax notoginseng replenishes deficiency, promotes blood circulation and stops bleeding, Rubia cordifolia cools blood and removes blood stasis, promotes blood circulation and stops bleeding; Red Peony Root clears heat, cools blood, disperses blood stasis and relieves pain, while Tangerine Peel regulates Qi, strengthens the spleen, dries dampness and resolves phlegm are the auxiliary ingredients.

[0044] Effect: Invigorate Qi, warm and promote circulation, nourish blood and activate blood circulation

[0045] Decoction method: concentrated decoction, 2 bags per set, 100ml per bag. Specific decoction method: prepare 40 sets, use a 30L decoction pot, add 14.5L of water, soak for 30 minutes, decoct for 70 minutes, pack in 100ml / bag, and produce a total of 80 bags of finished products, with about 200ml of remaining liquid.

[0046] Example 2 Clinical efficacy observation test of the Chinese medicine composition of the present invention in treating patients with pulmonary thromboembolism

[0047] The following is an evaluation of the therapeutic effect of the Chinese medicine composition of the present invention on pulmonary thromboembolism from the perspective of clinical efficacy. The specific composition ratio selected should not be understood as limiting the weight composition ratio of the drug of the present invention. In combination with the claims, the specification and general knowledge in the art, without departing from the spirit and scope of the present invention, those skilled in the art may also make any modifications or changes based on the following examples, and such changes are also included in the scope of the present invention.

[0048] 1. Experimental Methods

[0049] (1) Research subjects: Patients with acute pulmonary thromboembolism who visited the outpatient clinic of the Department of Pulmonary Diseases of the China-Japan Friendship Hospital from October 2024 to January 2025.

[0050] 1) Inclusion criteria: ① Age ≥ 18 years; ② Diagnosis of acute pulmonary thromboembolism; ③ Non-high-risk pulmonary thromboembolism risk stratification; ④ At least one of the following high-risk factors for bleeding according to the "Guidelines for the Diagnosis, Treatment, and Prevention of Pulmonary Thromboembolism": Age > 75 years; History of stroke within 3 months; History of surgery within 3 months; Malignant tumor; Thrombocytopenia; Diabetes mellitus; Anemia; Treatment with antiplatelet drugs. ⑤ Qi deficiency and blood stasis syndrome (Main symptoms: ① Shortness of breath, ② Chest tightness, ③ Fatigue; Secondary symptoms: ① Chest pain, ② Dull complexion, ③ Fatigue and laziness, ④ Dark purple lips and nails; Tongue and pulse: Pale or purple tongue with petechiae and ecchymosis on the edges, deep, thready, or wiry pulse. At least one of the main symptoms and at least two of the secondary symptoms are present, and the diagnosis can be made based on the combination of tongue and pulse).

[0051] 2) Exclusion criteria: ① Patients requiring warfarin anticoagulation; ② Patients with significant liver and kidney dysfunction (any one of ALT, AST, Cr, or BUN exceeding the upper limit of the normal reference value by more than 3 times); ③ Patients with severe digestive system, nervous system, hematological system, cardiovascular and cerebrovascular diseases or severe mental illness; ④ Patients who have received thrombolytic, interventional, or surgical treatment.

[0052] (2) Experimental plan: Patients were treated with the Yifei Tiaoxue prescription on the basis of Western medicine anticoagulation with low molecular weight heparin or rivaroxaban. The Yifei Tiaoxue prescription consists of: 30g of raw astragalus, 9g of whole angelica, 12g of agrimony, 3g of Panax notoginseng powder, 9g of madder, 9g of red peony root, and 6g of dried tangerine peel. The decoction was taken once a day, twice a day, 100ml each time. The course of treatment was 12 weeks.

[0053] Outcome measures: ① Primary outcome measure: bleeding events (including major bleeding and clinically relevant non-major bleeding); ② Secondary outcome measures: all-cause mortality and venous thromboembolism-related mortality; ③ Exploratory outcome measures: Traditional Chinese Medicine (TCM) syndrome score (primary symptom: scored as 0, 2, 4, and 6 for absent, mild, moderate, and severe symptoms, respectively; secondary symptom: scored as 0, 1, 2, and 3 for absent, mild, moderate, and severe symptoms, respectively), and TCM syndrome efficacy (efficacy index (n) = (pre-trial score - post-trial score) / pre-trial score × 100%. Clinical cure: clinical symptoms and signs disappear or almost disappear, with a symptom score reduction of ≥95%; marked effect: clinical symptoms and signs significantly improve, with a symptom score reduction of ≥70% and <95%; effective: clinical symptoms and signs improve, with a symptom score reduction of ≥30% and <70%; ineffective: clinical symptoms and signs do not improve significantly, or even worsen, with a symptom score reduction of less than 30%).

[0054] 2. Experimental Results

[0055] This study enrolled 33 patients with acute pulmonary thromboembolism and a high risk of bleeding. No deaths occurred during treatment. Four patients experienced clinically relevant non-major bleeding events during treatment, while no patients experienced major bleeding during medication, resulting in a total bleeding rate of 12.12%. Three of these bleeding cases involved mucocutaneous bleeding (two presented with periocular bruising, and one presented with gingival bleeding), and one involved gastrointestinal bleeding (manifested as small amounts of fresh blood in the stool). Based on data from prospective, real-world studies in China, the incidence of major bleeding within three months of anticoagulation for pulmonary thromboembolism is 3.0%, while the incidence of clinically relevant non-major bleeding is 16.5%. The incidence of bleeding events in this study with the Yifei Tiaoxue recipe combined with conventional Western anticoagulation was lower than in previous studies using conventional Western anticoagulation alone.

[0056] In terms of the efficacy of TCM syndrome, 12 cases were clinically cured, 16 cases were significantly effective, 3 cases were effective, and 2 cases were ineffective, with a total effective rate of 93.94%. The TCM syndrome score of the patients was 12.24±5.53 points before treatment, 4.85±4.09 points after 4 weeks of treatment, and 2.61±3.65 points after 12 weeks of treatment. The TCM syndrome scores after 4 weeks of treatment and 12 weeks of treatment were statistically different from those before treatment (P<0.05), and the TCM syndrome scores after 4 weeks of treatment were statistically different from those after 12 weeks of treatment (P<0.05). The TCM syndrome scores of all main and secondary symptoms after 4 weeks of treatment and 12 weeks of treatment were statistically different from those before treatment (P<0.05). Except for chest pain, the TCM syndrome scores of other main and secondary symptoms after 4 weeks of treatment were statistically different from those after 12 weeks of treatment (P<0.05) (see Figure 1 ).

[0057] The above embodiments are only used to understand the method and core concept of the present invention. It should be noted that those skilled in the art can make various modifications and changes to the present invention without departing from the principles of the present invention, and such modifications and changes will fall within the scope of protection of the claims of the present invention.

Claims

1. A Chinese medicine composition for treating pulmonary thromboembolism, characterized in that: The raw materials of the Chinese medicine composition are: raw astragalus, whole angelica, agrimony, notoginseng powder, madder, red peony root and tangerine peel; By weight percentage, the ratio of raw astragalus, whole angelica, agrimony, Panax notoginseng powder, madder, red peony root, and tangerine peel is 10:3:4:1:3:3:

2.

2. The Chinese medicine composition according to claim 1, characterized in that The traditional Chinese medicine composition is prepared from the following raw materials by weight: 30g of raw astragalus, 9g of whole angelica, 12g of agrimony, 3g of notoginseng powder, 9g of madder cordifolia, 9g of red peony root, and 6g of tangerine peel.

3. A pharmaceutical preparation, characterized in that The pharmaceutical preparation comprises the traditional Chinese medicine composition according to any one of claims 1 to 2.

4. The pharmaceutical preparation according to claim 3, characterized in that The pharmaceutical preparation further includes a pharmaceutically acceptable buffer, carrier and / or excipient.

5. The pharmaceutical preparation according to claim 4, characterized in that The buffer includes phosphate, carbonate, acetate, citrate, glycolate, lactate, borate, tartrate, cacodylate.

6. The pharmaceutical preparation according to claim 4, characterized in that The carrier includes an isotonic agent, an antioxidant, a suspending agent, a dispersing agent, an emulsifier, a chelating agent, a thickener, and a solubilizing agent.

7. The pharmaceutical preparation according to claim 4, characterized in that The excipients include carbohydrates, polymers, lipids, and minerals.

8. The pharmaceutical preparation according to any one of claims 3 to 7, characterized in that The dosage forms of the pharmaceutical preparation include granules, tablets, pills, capsules, injections, tinctures, suppositories, mixtures, powders, lotions, films, and dripping pills.

9. A method for preparing a traditional Chinese medicine composition for treating pulmonary thromboembolism, characterized in that: The preparation method comprises the following steps: extracting or processing the raw materials of the traditional Chinese medicine composition according to any one of claims 1-2 to obtain its active ingredient, and then, using the active ingredient as the raw material, adding a pharmaceutically acceptable buffer, carrier and / or excipient as needed, and preparing the desired dosage form according to conventional pharmaceutical techniques.

10. Use of the traditional Chinese medicine composition according to any one of claims 1 to 2 in the preparation of a medicament for treating and / or preventing pulmonary thromboembolism.

11. Use of the pharmaceutical preparation according to any one of claims 3 to 7 in the preparation of a medicament for treating and / or preventing pulmonary thromboembolism.

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