A traditional Chinese medicine compound preparation for resisting middle and late stage malignant tumor with metastasis and a preparation method thereof

Abstract

The application discloses a traditional Chinese medicine compound preparation for resisting middle and late malignant tumors with metastasis and a preparation method thereof, and belongs to the technical field of traditional Chinese medicine compound preparation. A three-layered layered targeting matching framework is innovatively constructed, the compound is divided into three functional groups of a targeting evil-eliminating treatment layer, an evil-eliminating and cancer metastasis inhibiting layer and a tonifying layer, and three pathological links of a tumor primary focus, a metastasis path and a body deficiency are accurately corresponded; in view of the three-layered functional medicinal materials, a 30:1, 20:1 and 10:1 differentiated crude drug-dry extract gradient concentration process is matched, and a concentrated pill preparation is prepared by combining grouping directional extraction, grading refining and segmented low-temperature pill making core technologies. The application breaks through the technical short board of traditional Chinese medicine anti-tumor prescription, such as disordered prescription, single process, loss of active ingredients and scattered efficacy, and accurately targets tumor inhibition, metastasis blocking and tonifying and reinforcing by layered matching, and meanwhile, the whole process is adapted to general production equipment of domestic traditional Chinese medicine enterprises, and the process flow is standardized and has strong mass production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical compound preparation technology, specifically referring to a traditional Chinese medicine compound preparation for treating mid-to-late stage malignant tumors with metastasis and its preparation method. Background Technology

[0002] Malignant tumors progressing to the middle and late stages are commonly accompanied by lymph node metastasis and distant hematogenous metastasis, which is a key focus and challenge in clinical oncology treatment and a core cause of patient mortality. Traditional Chinese medicine theory holds that the core pathogenesis of middle and late-stage malignant tumors is the accumulation of cancerous toxins, stagnation of heat and fire, blood stasis, phlegm accumulation, and deficiency of vital energy. The flow of cancerous toxins throughout the body is the fundamental pathogenesis of tumor invasion and metastasis. The continuous consumption of qi, blood, and body fluids by the tumor, coupled with the damage to vital energy caused by Western medicine treatments, leads to immune system deterioration, forming a complex pathological state of "excessive pathogenic factors and deficient vital energy, a mixture of deficiency and excess, coexistence of toxins and blood stasis, and easy spread," which is difficult to address with conventional single treatments.

[0003] Currently, mainstream Western medicine treatments have significant limitations: surgery is only suitable for early-stage localized tumors and cannot cure multiple metastatic lesions; radiotherapy and chemotherapy have severe toxic side effects and are prone to causing complications such as bone marrow suppression, gastrointestinal damage, liver and kidney damage, and decreased immunity, making it difficult for elderly, frail patients, and patients with underlying diseases to tolerate a complete course of treatment; targeted therapy and immunotherapy are expensive and are prone to developing drug resistance, with limited long-term efficacy.

[0004] Existing traditional Chinese medicine (TCM) anti-tumor preparations suffer from numerous inherent defects, severely hindering clinical efficacy and industrial application: First, the formulations lack targeted stratification design, often consisting of simple mixtures of multiple herbs without precise targeting of the three core pathological processes: inhibiting primary tumor proliferation, blocking tumor metastasis pathways, and tonifying the body's vital energy. This results in dispersed efficacy, failing to match the complex and multifaceted pathogenesis of mid-to-late-stage tumors. Second, the preparation processes are crude, with all herbs being uniformly mixed and decocted. The solubility, thermal stability, and physicochemical properties of different herbs vary greatly, easily leading to antagonistic interactions among active ingredients, high-temperature decomposition and loss of heat-sensitive active ingredients, and the retention of large amounts of ineffective impurities, resulting in low purity and poor bioavailability. Third, the concentration processes are highly homogenized, failing to enrich effective ingredients according to the different types of herbal efficacy. This results in insufficient enrichment of tumor-inhibiting and anti-metastasis components, and severe damage to heat-sensitive active ingredients such as tonifying polysaccharides and peptides. Fourth, the formulation molding processes are outdated. Traditional decoctions are inconvenient to take, have poor taste, and low compliance, while ordinary pills have low drug loading, large fluctuations in efficacy, and poor batch-to-batch stability in industrial production. Summary of the Invention

[0005] To overcome the technical shortcomings of existing anti-tumor traditional Chinese medicine formulations, such as lack of targeted therapy, crude processing, loss of active ingredients, single efficacy, and poor stability, this invention provides a traditional Chinese medicine compound preparation for treating mid-to-late stage malignant tumors with metastasis and its preparation method. By constructing a three-layered targeted compatibility architecture, it accurately corresponds to different pathological stages of tumors; through a three-level gradient concentration process, it differentially enriches various active ingredients to maximize efficacy; through a standardized low-temperature molding process, it ensures the stability and safety of the preparation; and through complete clinical data, it verifies the effects of the preparation in inhibiting tumors, preventing metastasis, improving symptoms, and prolonging survival.

[0006] To achieve the above functions, the technical solution adopted by the present invention is as follows: A traditional Chinese medicine compound preparation for treating mid-to-late stage malignant tumors with metastasis, composed of the following parts by weight of traditional Chinese medicinal materials: Targeted expelling evil treatment layer: 10-22 parts of Imperata cylindrica root, 9-21 parts of Ratwort, 16-32 parts of Hedyotis diffusa, 13-26 parts of Scutellaria barbata, and 8-19 parts of Uncaria rhynchophylla; Expelling evil and inhibiting cancer metastasis layer: 11-23 parts of Cycas revoluta leaves, 8-17 parts of Fritillaria cirrhosa, 6-15 parts of Cremastra appendiculata, 6-15 parts of chicken gizzard lining, 7-16 parts of Solanum nigrum, 6-15 parts of Prunella vulgaris, and 6-15 parts of Milk thistle; Strengthening the body layer: 13-27 parts of Agrimonia pilosa, 11-25 parts of Ganoderma lucidum, 11-25 parts of jujube, 10-23 parts of stir-fried Atractylodes macrocephala, and 12-24 parts of Poria cocos.

[0007] Preferably, the weight ratio of the preparation is as follows: Targeted exorcising treatment layer: 16 parts of Imperata cylindrica root, 14 parts of Ratwort, 24 parts of Hedyotis diffusa, 20 parts of Scutellaria barbata, and 13 parts of Uncaria rhynchophylla; Exorcising and inhibiting cancer metastasis layer: 17 parts of Cycas revoluta leaves, 12 parts of Fritillaria cirrhosa, 10 parts of Cremastra appendiculata, 10 parts of chicken gizzard lining, 11 parts of Solanum nigrum, 10 parts of Prunella vulgaris, and 13 parts of Milk thistle; Strengthening layer: 19 parts of Agrimonia pilosa, 17 parts of Ganoderma lucidum, 17 parts of jujube, 16 parts of stir-fried Atractylodes macrocephala, and 18 parts of Poria cocos.

[0008] A method for preparing a traditional Chinese medicine compound preparation for treating mid-to-late stage malignant tumors with metastasis involves independently processing three layers of medicinal materials in groups, performing targeted extraction, gradient concentration, layered drying, extract compounding, and pill making. Specifically, the targeted expelling-evil treatment layer uses a 30:1 crude drug-dry extract concentration process, the expelling-evil and inhibiting cancer metastasis layer uses a 20:1 crude drug-dry extract concentration process, and the supporting-health layer uses a 10:1 crude drug-dry extract concentration process. The method includes the following steps: Preparation of the targeted exorcising treatment layer: The medicinal materials were pulverized to 40 mesh, and 8-10 times the amount of water was added. The mixture was refluxed and decocted twice at 95-100℃, each time for 1-1.5 hours. The decoctions were combined and concentrated to a relative density of 1.12 (60℃). 95% ethanol was added to adjust the alcohol content to 62%, and the mixture was allowed to stand for alcohol precipitation. The supernatant was purified by nanofiltration, the ethanol was recovered, the mixture was concentrated under reduced pressure, vacuum dried at 60-65℃, pulverized and sieved to obtain a 30:1 dry extract powder. Preparation of the layer for expelling evil spirits and inhibiting cancer metastasis: Grind the medicinal materials into 30 mesh, add 7 to 9 times the amount of water, decoct twice at 90 to 98℃, 1 hour each time; combine the decoctions, filter through 80 mesh and 200 mesh in a double-stage process, concentrate under reduced pressure, dry under low temperature vacuum, grind and sieve to obtain 20:1 dry extract powder. Preparation of the supporting layer: The medicinal material is pulverized to 30 mesh, 9 to 11 times the amount of water is added, and it is decocted twice at 80 to 90°C, each time for 1.2 hours; the decoction is filtered and concentrated, the solid content is adjusted to 35%, and spray dried at an inlet air temperature of 155°C and an outlet air temperature of 85°C to obtain a 10:1 dry extract powder. Pelletizing and drying: Mix the above three dry extract powders, add excipients to make soft material, and then make into plain pellets by a pelletizing machine; adopt segmented low-temperature drying, with the temperature not exceeding 55℃ throughout the process. The first stage is drying at 45℃ for 2 hours, and the second stage is drying at 50℃ until the moisture content of the pellets is ≤9.0%.

[0009] Compared with the prior art, the beneficial effects of the above-mentioned solution adopted in this invention are as follows: 1. This invention divides the formula into three layers: expelling pathogens, resisting metastasis, and supporting the body's resistance. It closely addresses the complex pathogenesis of "cancer toxins, blood stasis, phlegm accumulation, and deficiency of vital energy" in mid-to-late stage malignant tumors, thereby achieving stratified targeted therapy. 2. A three-stage gradient concentration process of 30:1, 20:1, and 10:1 is adopted, and different extraction methods such as water extraction, alcohol precipitation, membrane refining or low-temperature spray drying are matched according to the characteristics of different grades of medicinal materials. This effectively solves the problems of loss of active ingredients, decomposition of heat-sensitive substances and high impurity content in traditional processes, and significantly improves the retention rate of effective ingredients. 3. Clinical observations have confirmed that this preparation can effectively shrink tumors, reduce enlarged lymph nodes, significantly improve symptoms such as cancer pain and fatigue, prolong the survival period of patients with tumors, and has mild adverse reactions and high safety for long-term use. 4. The entire production process uses common equipment used by domestic Chinese medicine companies, and the process flow is standardized, making it easy for large, medium and small pharmaceutical companies to directly convert and put it into production. Detailed Implementation

[0010] The technical solution of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Example

[0011] A traditional Chinese medicine compound preparation for treating mid-to-late stage malignant tumors with metastasis, with the following raw material ratios (unit: g): Targeted treatment layer: Rhizoma Imperatae 160, Rhizoma Smilax Glabrae 140, Herba Hedyotis diffusae 240, Herba Scutellariae Barbarum 200, Herba Uncariae 130; Layer for expelling pathogens and inhibiting cancer metastasis: Fructus Cycase 170, Fructus Fritillariae 120, Fructus Cremastrae 100, Gallus Gallus Galli 100, Herba Solanume 110, Herba Prunellae 100, Herba Silybum 130; Layer for supporting the body's resistance: Herba Agrimoniae 190, Herba Ganodermae 170, Fructus Jujubae 170, Rhizoma Atractylodis Macrocephalae 160, Poria 180.

[0012] A method for preparing a traditional Chinese medicine compound preparation for treating intermediate and advanced malignant tumors with metastasis, comprising the following steps: Preparation of the targeted exorcising treatment layer: The medicinal materials were pulverized to 40 mesh, and 8-10 times the amount of water was added. The mixture was refluxed and decocted twice at 95-100℃, each time for 1-1.5 hours. The decoctions were combined and concentrated to a relative density of 1.12 (60℃). 95% ethanol was added to adjust the alcohol content to 62%, and the mixture was allowed to stand for alcohol precipitation. The supernatant was purified by nanofiltration, the ethanol was recovered, the mixture was concentrated under reduced pressure, vacuum dried at 60-65℃, pulverized and sieved to obtain a 30:1 dry extract powder. Preparation of the layer for expelling evil spirits and inhibiting cancer metastasis: Grind the medicinal materials into 30 mesh, add 7 to 9 times the amount of water, decoct twice at 90 to 98℃, 1 hour each time; combine the decoctions, filter through 80 mesh and 200 mesh in a double-stage process, concentrate under reduced pressure, dry under low temperature vacuum, grind and sieve to obtain 20:1 dry extract powder. Preparation of the supporting layer: The medicinal material is pulverized to 30 mesh, 9 to 11 times the amount of water is added, and it is decocted twice at 80 to 90°C, each time for 1.2 hours; the decoction is filtered and concentrated, the solid content is adjusted to 35%, and spray dried at an inlet air temperature of 155°C and an outlet air temperature of 85°C to obtain a 10:1 dry extract powder. Pelletizing and drying: Mix the above three dry extract powders, add excipients to make soft material, and then make into plain pellets by a pelletizing machine; adopt segmented low-temperature drying, with the temperature not exceeding 55℃ throughout the process. The first stage is drying at 45℃ for 2 hours, and the second stage is drying at 50℃ until the moisture content of the pellets is ≤9.0%.

[0013] Quality testing: The concentrated pills had a dissolution time of 1.0 h, a moisture content of 8.1%, and all indicators such as microorganisms, heavy metals, and pesticide residues met the standards of the Pharmacopoeia of the People's Republic of China.

[0014] Comparison Example Using traditional methods, all the medicinal materials in the examples are mixed, decocted uniformly, concentrated individually, and then made into pills.

[0015] Experimental Example The grouped gradient extraction process of this invention is adopted.

[0016] Testing revealed that the total bioactive ingredient content in the experimental sample was 33.1% higher than that in the control group, the amount of ineffective macromolecular solid impurities was reduced by 42.3%, the dissolution time of the pellets was shortened by 24.8%, and the content error of the active ingredient between different batches was <3.5%. This indicates that the process of the present invention is significantly superior to the traditional process of the control sample in terms of component enrichment, purity, and quality stability.

[0017] clinical trials 1. Experimental Objective By observing the tumor changes, clinical symptoms, and survival time of patients with advanced malignant tumors and metastasis after taking the traditional Chinese medicine compound preparation of this invention, the clinical efficacy and safety of this invention in inhibiting tumor proliferation, controlling metastasis, improving quality of life, and prolonging survival are scientifically evaluated.

[0018] 2. General Information One hundred patients with stage III-IV intermediate-to-advanced malignant tumors and metastases admitted between March 2021 and March 2025 were selected as the study subjects. All patients were diagnosed by histopathological or cytological examination and confirmed by imaging examinations such as CT / MRI to have measurable primary lesions and metastases (including lymph node metastases or hematogenous metastases). The cases covered a variety of common solid tumors, including liver cancer, gastric cancer, colorectal cancer, lung cancer, and esophageal cancer.

[0019] Gender: 58 males and 42 females.

[0020] Age: 35-75 years, median age 57 years.

[0021] Tumor type distribution: 37 cases of liver cancer, 20 cases of gastric cancer, 16 cases of colorectal cancer, 15 cases of lung cancer, 7 cases of esophageal cancer, and 5 cases of other tumors.

[0022] Metastasis type: simple lymph node metastasis in 65 cases, and lymph node metastasis combined with hematogenous distant metastasis in 35 cases.

[0023] Traditional Chinese medicine diagnosis: All cases conform to the syndromes of intense cancer toxins, blood stasis and phlegm accumulation, and deficiency of vital energy.

[0024] 3. Treatment Plan Dosage regimen: All patients used the concentrated pills prepared in Example 1 of this invention alone. The usual dosage was 18-22 pills three times a day, taken with warm water after meals. For patients with extensive metastasis or significant cancer pain, the dosage was adjusted to 25 pills four times a day; for elderly patients and those who were extremely weak, the dosage was adjusted to 15 pills three times a day.

[0025] Treatment duration: One treatment cycle consists of 12 weeks, with at least two consecutive cycles of medication. All patients completed at least 24 weeks of medication and were included in subsequent survival follow-up, with a total follow-up period of up to 5 years.

[0026] 4. Efficacy evaluation criteria Efficacy evaluation for solid tumors: Evaluation was based on the RECIST version 1.1 criteria, categorized as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Objective response rate (ORR) was calculated as CR + PR, and disease control rate (DCR) was calculated as CR + PR + SD.

[0027] Treatment efficacy for metastatic lymph nodes: Based on imaging measurements, the results are categorized as complete elimination, significant reduction (reduction of the product of the longest diameter and the shortest diameter by ≥30%), stable, and enlargement / new metastasis.

[0028] Improvement of TCM syndromes and signs: The main symptoms such as cancer pain (VAS score), fatigue, loss of appetite, and weight loss were quantitatively assessed and divided into significant effect (symptoms basically disappeared or score decreased by ≥70%), effective (symptoms were significantly relieved and score decreased by ≥30%), and ineffective (symptoms did not improve or worsened).

[0029] Survival indicators: 1-year, 3-year, and 5-year survival rates with tumor and median survival time with tumor.

[0030] Safety assessment: Regularly monitor complete blood count, liver and kidney function (ALT, AST, BUN, Cr), and record adverse events such as gastrointestinal reactions and allergies.

[0031] 5. Test Results 5.1 Primary tumor control effect The control status of primary tumor lesions in 100 patients after completing two courses of treatment is shown in Table 1.

[0032] Table 1. Statistics on the efficacy of treatment for primary tumors (n=100) The results showed that the formulation of the present invention achieved a disease control rate of 86.0% for primary tumors, indicating that it can effectively inhibit the progression of intermediate and advanced tumors.

[0033] 5.2 Effect of controlling metastatic lymph nodes The metastatic lymph nodes of 100 patients were evaluated, and the results are shown in Table 2.

[0034] Table 2. Statistical analysis of treatment efficacy for metastatic lymph nodes (n=100) The above results indicate that the anti-metastatic layer formulation of the present invention has a significant effect on the regression and control of lymph node metastases.

[0035] 5.3 Traditional Chinese Medicine Syndromes and Improvement of Quality of Life After treatment, the patient's overall clinical symptoms improved significantly, as shown in Table 3.

[0036] Table 3. Statistics on the improvement of TCM syndromes and physical signs (n=100) After treatment, most patients experienced significant relief from symptoms of cancer pain, fatigue, and loss of appetite, resulting in a marked improvement in their quality of life. This demonstrates the advantages of the restorative layer of this invention in improving patients' physical condition.

[0037] 5.4 Long-term survival The long-term follow-up results of all patients are shown in Table 4.

[0038] Table 4. Survival statistics with tumor (n=100) Stratified analysis showed that the 5-year survival rate of patients with isolated lymph node metastasis was 45.2%, which was significantly higher than that of patients with hematogenous metastasis (17.1%) (P<0.05), indicating that early application of the preparation of this invention provides greater survival benefits for patients with localized metastasis.

[0039] 5.5 Safety Evaluation During treatment and follow-up, no patients experienced serious adverse reactions such as liver or kidney dysfunction (ALT / AST / BUN / Cr were all within the normal range), bone marrow suppression, severe allergies, or gastrointestinal bleeding. Only 7 patients (7.0%) experienced mild stomach discomfort or nausea at the beginning of treatment; these symptoms resolved spontaneously within 3–7 days without requiring discontinuation of the medication or special treatment. 93% of patients reported that they tolerated the medication and adhered to long-term continuous use.

[0040] 6. Experimental Conclusions The traditional Chinese medicine compound preparation provided by this invention has a definite clinical efficacy in patients with intermediate and advanced malignant tumors with metastasis. It not only effectively inhibits the growth of the primary tumor and significantly reduces metastatic lymph nodes, but also significantly improves the symptoms of cancer-related debility, prolongs the survival period with the tumor, and has extremely low toxicity and good safety. This preparation can be used as a preferred drug for conservative treatment of intermediate and advanced malignant tumors, postoperative recurrence prevention, and adjuvant radiotherapy and chemotherapy.

[0041] The present invention and its embodiments have been described above. This description is not restrictive, and the embodiments shown are only one of the embodiments of the present invention, and are not actually limited thereto. In short, if those skilled in the art are inspired by this description and design similar embodiments without departing from the spirit of the present invention, they should all fall within the protection scope of the present invention.

Claims

1. A traditional Chinese medicine compound preparation for treating intermediate and advanced malignant tumors with metastasis, characterized in that, Composed of the following Chinese medicinal herbs by weight: Targeted treatment layer: 10-22 parts of Imperata cylindrica root, 9-21 parts of Ratwort, 16-32 parts of Hedyotis diffusa, 13-26 parts of Scutellaria barbata, and 8-19 parts of Uncaria rhynchophylla; Layer for expelling pathogens and inhibiting cancer metastasis: 11-23 parts of Cycas revoluta leaves, 8-17 parts of Fritillaria cirrhosa, 6-15 parts of Cremastra appendiculata, 6-15 parts of chicken gizzard lining, 7-16 parts of Solanum nigrum, 6-15 parts of Prunella vulgaris, and 6-15 parts of Milk thistle; Layer for strengthening the body: 13-27 parts of Agrimonia pilosa, 11-25 parts of Ganoderma lucidum, 11-25 parts of jujube, 10-23 parts of stir-fried Atractylodes macrocephala, and 12-24 parts of Poria cocos.

2. The traditional Chinese medicine compound preparation for treating intermediate and advanced malignant tumors with metastasis according to claim 1, characterized in that, The preferred weight ratio is as follows: Targeted exorcising and treatment layer: 16 parts of Imperata cylindrica root, 14 parts of Ratwort, 24 parts of Hedyotis diffusa, 20 parts of Scutellaria barbata, and 13 parts of Uncaria rhynchophylla; Exorcising and inhibiting cancer metastasis layer: 17 parts of Cycas revoluta leaves, 12 parts of Fritillaria cirrhosa, 10 parts of Cremastra appendiculata, 10 parts of chicken gizzard lining, 11 parts of Solanum nigrum, 10 parts of Prunella vulgaris, and 13 parts of Milk thistle; Strengthening layer: 19 parts of Agrimonia pilosa, 17 parts of Ganoderma lucidum, 17 parts of jujube, 16 parts of stir-fried Atractylodes macrocephala, and 18 parts of Poria cocos.

3. The method for preparing the traditional Chinese medicine compound preparation for treating intermediate and advanced malignant tumors with metastasis according to any one of claims 1 to 2, characterized in that, The three layers of medicinal materials were processed independently in groups, including raw material pretreatment, targeted extraction, gradient concentration, layered drying, extract compounding, and pill making. Specifically, the targeted expelling pathogenic factors treatment layer used a 30:1 crude herb-dry extract concentration process, the expelling pathogenic factors and inhibiting cancer metastasis layer used a 20:1 crude herb-dry extract concentration process, and the strengthening layer used a 10:1 crude herb-dry extract concentration process. The specific steps included are as follows: (1) Preparation of targeted exorcising treatment layer: The medicinal materials are pulverized to 40 mesh, 8 to 10 times the amount of water is added, and the mixture is refluxed and decocted twice at 95 to 100°C for 1 to 1.5 hours each time; the decoctions are combined and concentrated to a relative density of 1.12 (60°C), 95% ethanol is added to adjust the alcohol content to 62%, and the mixture is allowed to stand for alcohol precipitation; the supernatant is purified by nanofiltration membrane, the ethanol is recovered, the mixture is concentrated under reduced pressure, vacuum dried at 60 to 65°C, pulverized and sieved to obtain 30:1 dry extract powder; (2) Preparation of the expelling evil and inhibiting cancer metastasis layer: The medicinal material is pulverized to 30 mesh, 7 to 9 times the amount of water is added, and it is decocted twice at 90 to 98°C for 1 hour each time; the decoctions are combined, filtered through 80 mesh and 200 mesh in a double-stage process, concentrated under reduced pressure, dried under low temperature vacuum, pulverized and sieved to obtain 20:1 dry extract powder. (3) Preparation of the supporting layer: The medicinal material is pulverized to 30 mesh, 9 to 11 times the amount of water is added, and it is decocted twice at 80 to 90°C for 1.2 hours each time; the decoction is filtered and concentrated, the solid content is adjusted to 35%, and spray dried at an inlet air temperature of 155°C and an outlet air temperature of 85°C to obtain a 10:1 dry extract powder. (4) Pelletizing and drying: Mix the above three dry extract powders, add excipients to make soft material, and make into plain pellets by pelletizing machine; adopt segmented low temperature drying, with the temperature not exceeding 55℃ throughout the process, the first stage drying at 45℃ for 2 hours, and the second stage drying at 50℃ until the moisture content of the pellets is ≤9.0%.