Traditional Chinese medicine preparation for reducing side effects and improving effects of tumor anti-angiogenesis targeted medicine

Abstract

The invention relates to the technical field of traditional Chinese medicine, and discloses a tumor anti-angiogenesis targeted drug side-effect-reducing synergistic traditional Chinese medicine preparation which comprises the following components in parts by mass: 30-60 parts of astragalus membranaceus, 9-12 parts of pericarpium citri reticulatae, 9-15 parts of poria cocos, 9-15 parts of deep-fried rhizoma atractylodis macrocephalae, 9-12 parts of fructus amomi, 9-12 parts of rhizoma alismatis, 9-12 parts of radix scrophulariae, 12-30 parts of selfheal, 9-15 parts of cortex lycii radicis, 9-12 parts of thunberg fritillary bulb, 9-12 parts of earthworm, 9-12 parts of rhizoma sparganii, 9-12 parts of curcuma zedoary and 3-6 parts of cinnamon. The components meet the following proportional relation: the mass part ratio of the astragalus membranaceus to the poria cocos is (2: 1)-(4: 1). By integrating multi-link pathological regulation and control of replenishing qi to invigorate the spleen, calming the liver, suppressing yang, detoxifying and removing stasis, hypertension caused by anti-angiogenesis drugs is remarkably reduced, and tumor growth is inhibited; the composition proportion and the staged temperature control process are optimized, multiple dosage forms of decoction and granules are adapted, and the composition stability and patient compliance are improved.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicine, and in particular to a traditional Chinese medicine preparation for tumor anti-angiogenesis targeted drug with reduced side effects and increased efficacy. Background Art

[0002] In the treatment of malignant tumors, anti-angiogenic targeted drugs (such as bevacizumab and apatinib) exert their therapeutic effects by inhibiting tumor angiogenesis, but such drugs are prone to cause hypertension side effects (incidence rate 20%-40%), and their mechanism is closely related to VEGF signal inhibition leading to NO reduction, RAS system activation and water and sodium retention. At present, clinical treatment mainly relies on Western antihypertensive drugs (such as ACEI and ARB), but such drugs cannot improve the imbalance of tumor microenvironment, and long-term use has risks such as renal damage. At the same time, although existing traditional Chinese medicine compound prescriptions are used for adjuvant tumor treatment or hypertension conditioning, their component design and process still have significant limitations.

[0003] Most of the existing Chinese medicine compound prescriptions are based on a single syndrome (such as "soothing the liver and suppressing yang" or "reinforcing qi and strengthening the spleen"). For example, CN112107601A mainly uses Prunella vulgaris and Uncaria rhynchophylla to lower blood pressure, but does not include Qi-invigorating components such as Astragalus, which makes it difficult to improve Qi deficiency and water retention caused by anti-vascular drugs; CN113041423A uses Scutellaria barbata and Hedyotis diffusa to detoxify and disperse knots, but lacks active ingredients for regulating blood pressure. In addition, existing compound prescriptions often adopt a "multi-component stacking" strategy. For example, an unbalanced ratio of Prunella vulgaris and Scrophularia ningpoensis (>3:1) can easily aggravate liver yin depletion, while an improper ratio of Astragalus and Poria (such as 5:1) weakens the diuretic effect. In terms of preparation technology, the conventional water decoction method does not control the temperature in stages (such as the inactivation of earthworm fibrinolytic enzyme above 90°C), and high-temperature spray drying (>150°C) causes the degradation of heat-sensitive components, affecting the stability and bioavailability of the preparation. The above-mentioned problems make it difficult for existing technologies to take into account both "lowering blood pressure and reducing side effects" and "enhancing anti-tumor efficacy", and targeted optimization is urgently needed. Summary of the invention

[0004] In view of the shortcomings of the prior art, the present invention provides a traditional Chinese medicine preparation with reduced side effects and increased efficacy of tumor anti-angiogenesis targeted drugs, which solves the problem that the traditional Chinese medicine compound in the prior art cannot effectively control blood pressure and inhibit tumor growth at the same time due to the single component design, unbalanced ratio and rough preparation process.

[0005] To achieve the above objectives, the present invention is implemented by the following technical scheme: A Chinese medicine preparation for tumor anti-angiogenesis targeted drug with reduced side effects and increased efficacy, comprising the following components in parts by mass: 30-60 parts of Astragalus, 9-12 parts of Tangerine Peel, 9-15 parts of Poria, 9-15 parts of Scorched Atractylodes, 9-12 parts of Amomum, 9-12 parts of Alisma, 9-12 parts of Scrophularia, 12-30 parts of Prunella Vulgaris, 9-15 parts of Lycium bark, 9-12 parts of Fritillaria thunbergii, 9-12 parts of Pheretima, 9-12 parts of Trillium, 9-12 parts of Curcuma, and 3-6 parts of Cinnamon.

[0006] Preferably, the components satisfy the following ratio relationship: The mass ratio of Astragalus to Poria is 2:1 to 4:1; The mass ratio of Prunella Vulgaris to Scrophularia ningpoensis is 1.5:1 to 3:1; The mass ratio of cinnamon bark to amomum villosum is 1:2 to 1:3.

[0007] Preferably, the mass ratio of Fritillaria thunbergii to Trigonella ternata is 1:1 to 1:1.5.

[0008] Preferably, the preparation method of the preparation comprises the following steps: (1) Weigh each component of the medicinal material according to the ratio and crush it into particles with a size of 0.5 to 1.5 mm; (2) Add water and boil twice. The first time, the amount of water added is 4 to 5 times the total weight of the medicinal materials, the boiling temperature is 95 to 100°C, and the time is 40 to 50 minutes. The second time, the amount of water added is 2 to 2.5 times the total weight of the medicinal materials, the boiling temperature is 85 to 90°C, and the time is 25 to 35 minutes. (3) Combine the two decoctions, filter and concentrate to an extract with a relative density of 1.15 to 1.20.

[0009] Preferably, in (3), the water content of the extract is 15% to 20%.

[0010] Preferably, the preparation is in the form of granules, and the particle size is 150-250 meshes, and the angle of repose is ≤35°.

[0011] Preferably, the preparation method of the granules comprises mixing the extract with soluble starch in a mass ratio of 1:1.2 to 1:1.8, and spray drying with an air inlet temperature of 120 to 150°C and an air outlet temperature of 60 to 80°C.

[0012] Preferably, the mass ratio of the Cortex Lycii to Rhizoma Alismatis is 1:0.8 to 1:1.2.

[0013] Preferably, the processing method of the scorched Atractylodes macrocephala is: after slicing the Atractylodes macrocephala, stir-fry it with high heat until the surface is burnt brown, the inside is yellow-brown, and the volatile oil content is ≤0.5%.

[0014] Preferably, the mass ratio of Trillium and Curcuma in the preparation is 1:1 to 1:1.5.

[0015] The present invention provides a traditional Chinese medicine preparation for tumor anti-angiogenesis targeted drugs with reduced side effects and increased efficacy. It has the following beneficial effects: 1. The present invention adopts a multi-component synergistic strategy, integrating the three pathways of invigorating qi, calming the liver, and detoxifying, to achieve the dual goals of blood pressure regulation and tumor inhibition. Compared with the single syndrome-oriented compound in the prior art, it solves the defects of incomplete pathological coverage and scattered efficacy.

[0016] 2. The present invention effectively retains the activity of heat-sensitive ingredients by using differentiated decoction temperature segmentation. The prior art uses uniform high-temperature decoction, which leads to degradation of active ingredients. This solution breaks through the limitations of traditional processes and improves ingredient utilization.

[0017] 3. The present invention significantly improves the particle fluidity and dissolution efficiency by combining auxiliary material ratio with low temperature drying. The prior art causes agglomeration and delayed dissolution due to excessive auxiliary materials or rough process. This solution overcomes the bottleneck of formulation stability.

[0018] 4. The present invention ensures batch-to-batch consistency by clarifying the processing parameters and ingredient content standards. The existing technology causes ingredient fluctuations due to process ambiguity. This solution eliminates the risk of uncontrollable quality and enhances clinical reliability. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 It is a preparation step diagram of the present invention. DETAILED DESCRIPTION

[0020] The following will be combined with the drawings in the specification of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0021] Please refer to the attached Figure 1 The embodiment of the present invention provides a traditional Chinese medicine preparation for tumor anti-angiogenesis targeted drug with reduced side effects and increased efficacy, comprising: 1. Component and ratio design This preparation is composed of 14 Chinese medicinal materials, and the mass proportions are as follows: Astragalus (30-60 parts), dried orange peel (9-12 parts), Poria (9-15 parts), scorched Atractylodes (9-15 parts), Amomum villosum (9-12 parts), Alisma orientalis (9-12 parts), Scrophularia ningpoensis (9-12 parts), Prunella vulgaris (12-30 parts), Lycium bark (9-15 parts), Fritillaria thunbergii (9-12 parts), Pheretima (9-12 parts), Tripterygium wilfordii (9-12 parts), Curcuma zedoaria (9-12 parts), Cinnamon bark (3-6 parts) Astragalus (main ingredient): Dosage basis: The high-dose design of 30 to 60 servings is based on its core function of "replenishing Qi and strengthening the exterior", and needs to cover the common symptoms of Qi deficiency in cancer patients (such as fatigue and low immunity).

[0022] Modern pharmacology: Astragalus polysaccharides can enhance the activity of macrophages, and astragaloside IV can inhibit tumor angiogenesis factors (such as VEGF), and synergize with anti-vascular targeted drugs.

[0023] Prunella Vulgaris (key support): Dosage basis: The wide range of 12 to 30 servings corresponds to its dual needs of "calming the liver and suppressing yang" (lowering blood pressure and fighting tumors), and needs to be dynamically adjusted according to the degree of hyperactivity of the patient's liver fire.

[0024] Modern pharmacology: Oleanolic acid in Prunella vulgaris can downregulate the renin-angiotensin system (RAS) and lower blood pressure; caffeic acid esters inhibit the proliferation of tumor cells.

[0025] Cinnamon (anti-adjuvant component): Dosage basis: The low dose of 3 to 6 servings is designed to avoid warm and dry damage to Yin, while using its "leading fire back to the origin" property to balance the bias of the cold and cool medicines in the prescription (such as Prunella Vulgaris and Scrophularia ningpoensis).

[0026] Modern pharmacology: Cinnamaldehyde dilates peripheral blood vessels by activating TRPV1 channels, assisting in lowering blood pressure; its volatile oil can enhance the permeability of other drug ingredients.

[0027] 2. Proportional relationship between components Astragalus: Poria = 2:1~4:1: Strengthen the effect of invigorating Qi and strengthening the spleen, and avoid excessive diuresis and damage to the body caused by excessive Poria.

[0028] Prunella Vulgaris: Scrophularia ningpoensis = 1.5:1~3:1: Balances the effects of calming the liver and suppressing yang (Prunella Vulgaris) with nourishing yin and detoxifying (Scrophularia ningpoensis), preventing liver yin depletion.

[0029] Fritillaria thunbergii: Trillium gracile = 1:1~1:1.5: ensure the synergistic effect of resolving phlegm and dispersing nodules (Fritillaria thunbergii) and promoting blood circulation and removing blood stasis (Trillium gracile).

[0030] Astragalus and Poria ratio: Astragalus replenishes Qi and generates blood, while Poria strengthens the spleen and eliminates dampness. A 2:1 ratio (e.g. 40 parts of Astragalus + 20 parts of Poria) can optimize the body fluid metabolism of patients with spleen deficiency and dampness stagnation, and reduce the risk of hypertension caused by water and sodium retention.

[0031] Experimental data show that when the ratio is >4:1 (such as 60 parts of Astragalus + 15 parts of Poria), the diuretic effect is weakened, which may affect the antihypertensive effect.

[0032] Ratio of Prunella Vulgaris to Scrophularia: Prunella vulgaris mainly clears liver fire, while Scrophularia ningpoensis focuses on nourishing yin and detoxifying. A 1.5:1 ratio (e.g. 18 parts of Prunella vulgaris + 12 parts of Scrophularia ningpoensis) can simultaneously inhibit liver yang hyperactivity type hypertension (e.g. systolic blood pressure>160mmHg) and tumor inflammatory microenvironment.

[0033] When the ratio is >3:1 (such as 30 parts of Prunella Vulgaris + 10 parts of Scrophularia), the deficiency of Scrophularia may lead to a rebound of Yin deficiency and hyperactivity of fire.

[0034] 3. Preparation process parameters Cooking parameters: First decoction: 4-5 times the amount of water, 95-100℃ for 40-50 minutes; Second decoction: 2-2.5 times the amount of water, 85-90℃ for 25-35 minutes; The relative density of concentrated extract is 1.15-1.20 (water content 15%-20%).

[0035] Granule process: The ratio of extract to soluble starch is 1:1.2 to 1:1.8; The spray drying air inlet temperature is 120-150°C, and the air outlet temperature is 60-80°C; The particle size is 150-250 mesh, and the angle of repose is ≤35°.

[0036] Temperature control of decoction in batches: The first high-temperature decoction (95-100°C) ensures that macromolecular components such as astragalus polysaccharides and tuckahoe triterpenes are fully dissolved; The second medium-low temperature (85-90°C) prevents the thermal denaturation of flavonoids (such as rutin) in Prunella vulgaris and earthworm fibrinolytic enzyme.

[0037] Extract density and water content: The density of 1.15-1.20 (corresponding to a water content of 15%-20%) can retain the activity of volatile components (such as borneol acetate in Amomum villosum) while avoiding excessive viscosity that affects the formation of the preparation.

[0038] Spray drying parameters: Inlet air temperature > 150°C will cause the inactivation of heat-sensitive components (such as lumbrokinase); Air outlet temperature < 60°C may cause particle agglomeration due to insufficient drying (angle of repose > 35° affects fluidity).

[0039] 4. Preparation and quality control Preparation of Scorched Atractylodes: Stir-fry over high heat until the surface is burnt brown, the inside is yellow-brown, and the volatile oil content is ≤0.5%; Quality control of Lycium bark: contains wolfberry alkaloids ≥ 0.8 mg / g, betaine ≥ 1.2 mg / g.

[0040] Purpose of processing Jiao Baishu: Stir-frying with high heat reduces the volatile oil of Atractylodes macrocephala (such as atractylodes ketone), reduces the stimulation to the gastrointestinal tract, and is suitable for the weak spleen and stomach of cancer patients; The caramelized aroma produced after caramelization (Maillard reaction product) can enhance the effect of "strengthening the spleen and digesting food".

[0041] Indicative ingredients of Lycium bark: Lycium barbarum reduces tumor inflammatory response by inhibiting NF-κB pathway; Betaine regulates osmotic pressure and assists Alisma orientalis in promoting diuresis and lowering blood pressure.

[0042] Example 1: Decoction Preparation Medicinal material ratio: 50 parts of Astragalus, 10 parts of dried tangerine peel, 12 parts of Poria, 12 parts of scorched Atractylodes, 10 parts of Amomum villosum, 10 parts of Alisma orientalis, 10 parts of Scrophularia ningpoensis, 20 parts of Prunella Vulgaris, 12 parts of Lycium bark, 10 parts of Fritillaria thunbergii, 10 parts of Pheretima, 10 parts of Sparganium, 10 parts of Curcuma, and 4 parts of Cinnamon bark.

[0043] Preparation steps: Medicinal material processing: The scorched white atractylodes is prepared according to the method of claim 9 (frying on high heat until the surface is burnt brown, and the volatile oil content is ≤0.5%); The remaining medicinal materials were washed and crushed to a particle size of 1.0 mm.

[0044] Decoction extraction: First decoction: Add 4 times the total weight of the medicinal materials (about 4.8L) of purified water, heat to 98°C, and keep it boiling for 45 minutes; Second decoction: After filtering the residue, add 2.5 times the total mass of the medicinal materials (about 3.0L) of purified water, heat to 88°C, and decoct for 30 minutes.

[0045] Concentration and Filtration: Combine the two decoctions and filter through a 200-mesh filter cloth; Concentrate under reduced pressure to a relative density of 1.18 (water content of about 18%) at 60°C to obtain an extract.

[0046] Decoction packaging: Divide into 100 mL portions, store in refrigerator, and take 1 dose orally per day.

[0047] Example 2: Granule Preparation Medicinal material ratio: 40 parts of Astragalus, 9 parts of Tangerine Peel, 15 parts of Poria, 15 parts of Scorched Atractylodes, 9 parts of Amomum, 12 parts of Alismatis, 12 parts of Scrophularia, 25 parts of Prunella Vulgaris, 9 parts of Lycium bark, 12 parts of Fritillaria thunbergii, 12 parts of Pheretima, 12 parts of Sparganium, 9 parts of Curcuma, and 5 parts of Cinnamon Bark.

[0048] Preparation steps: Medicinal material processing: The preparation of scorched Atractylodes macrocephala is the same as above; the remaining medicinal materials are crushed to a particle size of 0.5 mm.

[0049] Decoction extraction: First decoction: add 5 times the amount of purified water (about 6.0L), decoct at 98℃ for 50 minutes; Second decoction: add twice the amount of purified water (about 2.4L) and boil at 90℃ for 35 minutes.

[0050] Concentration and drying: Combine the decoctions, filter and concentrate to a relative density of 1.20 (water content 15%); Mix the extract and soluble starch at a ratio of 1:1.5 (300g extract + 450g starch); Spray drying: inlet air temperature 135°C, outlet air temperature 70°C, particle size 200 mesh, repose angle ≤30°.

[0051] Granules packaging: Each bag contains 3g (equivalent to 15g of raw medicine), take twice a day with warm water.

[0052] Example 3: Optimization of high-activity components Medicinal material ratio: 60 parts of Astragalus, 12 parts of dried tangerine peel, 9 parts of Poria, 9 parts of scorched Atractylodes, 12 parts of Amomum villosum, 9 parts of Alismatis, 9 parts of Scrophularia, 30 parts of Prunella Vulgaris, 15 parts of Lycium bark, 9 parts of Fritillaria thunbergii, 9 parts of Pheretima, 9 parts of Sparganium, 12 parts of Curcuma, and 3 parts of Cinnamon bark.

[0053] Preparation steps: Medicinal material processing: The preparation of scorched Atractylodes macrocephala is the same as above; the Cortex Lycii and Rhizoma Alismatis are crushed separately to a particle size of 0.8 mm.

[0054] Cooking in stages: Phase 1 (Extraction of fat-soluble components): Add 5 times the amount of water to Astragalus, Trillium, Curcuma and Cinnamon, and boil at 100℃ for 40 minutes; Second stage (extraction of water-soluble ingredients): Add the remaining herbs, add 3 times the amount of water, and boil at 95℃ for 30 minutes.

[0055] Targeted Enrichment: The drug solutions were combined and ultrafiltration membrane (molecular weight cut-off 10 kDa) was used to remove macromolecular impurities; Concentrate to a relative density of 1.15 (water content 20%) and dry in vacuum at low temperature (50°C) to obtain extract powder.

[0056] Preparation of enteric-coated capsules: The extract powder and microcrystalline cellulose were mixed in a ratio of 1:1 and filled into enteric-coated capsules (0.5 g per capsule); Controlled disintegration time: no disintegration in artificial gastric juice within 2 hours, disintegration within 30 minutes in artificial intestinal juice.

[0057] Comparative Example 1 (corresponding to Example 1) Compared with Example 1, the difference is: Component subtraction: remove Astragalus, and keep the other components and proportions unchanged.

[0058] Technical impact: Due to the lack of core components that replenish Qi and strengthen the exterior, it is unable to effectively improve the symptoms of Qi deficiency, resulting in a decrease in antihypertensive effect (the reduction in systolic blood pressure is reduced by ≥30%).

[0059] Comparative Example 2 (corresponding to Example 1) Compared with Example 1, the difference is: Component replacement: replace Prunella Vulgaris with an equal amount of Scutellaria baicalensis, and adjust the decoction temperature to 100℃ for 60 minutes (cancel the staged temperature control).

[0060] Technical impact: Although Scutellaria baicalensis can clear away heat, it lacks the liver-calming and yang-suppressing effects of Prunella vulgaris. In addition, high-temperature decoction causes the degradation of flavonoid components (rutin content decreases by ≥50%), which weakens the antihypertensive effect.

[0061] Comparative Example 3 (corresponding to Example 2) Compared with Example 2, the difference is: Condition subtraction: cancel the staged temperature control of the two decoctions, and uniformly adopt 90℃ decoction twice, each time for 40 minutes.

[0062] Technical impact: The activity of earthworm fibrinolytic enzyme decreased due to continuous high temperature (enzyme activity loss ≥40%), the extraction rate of volatile oil from Trillium was reduced (<60%), and the dissolution time of granules was extended to ≥10 minutes.

[0063] Comparative Example 4 (corresponding to Example 2) Compared with Example 2, the difference is: Adjustment of auxiliary materials: The ratio of extract to soluble starch is changed to 1:3 (outside the range of 1:1.2 to 1:1.8 of claim 10).

[0064] Technical impact: The particle fluidity deteriorates (angle of repose ≥ 45°), and the active ingredient loading is insufficient (<30%), resulting in decreased bioavailability.

[0065] Comparative Example 5 (corresponding to Example 3) Compared with Example 3, the difference is: Process reduction: cancel the staged decoction, and decoct all the medicinal materials at one time (100℃ for 70 minutes).

[0066] Technical impact: Fat-soluble components (such as astragaloside IV) compete with water-soluble components (such as Prunella Vulgaris polysaccharides) for dissolution, the total extraction rate decreases by ≥25%, and the disintegration of enteric-coated capsules fails to meet the requirements (>60 minutes in intestinal fluid).

[0067] Comparative Example 6 (corresponding to Example 3) Compared with Example 3, the difference is: Parameter out of bounds: The spray drying inlet air temperature was adjusted to 180°C (outside the range of 120-150°C in claim 8).

[0068] Technical impact: The inactivation rate of heat-sensitive ingredients (earthworm fibrinolytic enzyme, selfheal flavonoids) is ≥70%, the color of the particles is charred (L value <50), and the patient acceptance is poor.

[0069] Comparative Example 7 (general component ratio exceeds the limit) Compared with Example 1, the difference is: Ratio out of bounds: The ratio of Astragalus to Poria is set at 5:1 (outside the range of 2:1 to 4:1 of claim 2).

[0070] Technical impact: The diuretic effect of Poria cocos was inhibited, the incidence of edema in patients increased by 30%, and the blood pressure fluctuation range increased (standard deviation ≥ 15 mmHg).

[0071] Comparative Example 8 (General Preparation Parameter Out of Bounds) Compared with Example 2, the difference is: Concentrated density exceeds the limit: the extract is concentrated to a relative density of 1.30 (exceeding the range of 1.15 to 1.20 in claim 5).

[0072] Technical impact: The high viscosity of the extract leads to clogging of the spray drying nozzle (failure rate ≥ 50%) and uneven particle size (D90>300 mesh).

[0073] Test Example 1: Core Component Necessity Verification Spontaneous hypertension combined with tumor model rats were selected and divided into Example 1 group (complete compound), Comparative Example 1 group (removing Astragalus) and Comparative Example 2 group (Prunella vulgaris replaced by Scutellaria baicalensis). The systolic blood pressure drop of Example 1 group after administration was significantly better than that of Comparative Example 1 group, and the tumor volume growth inhibition rate was about 1.5 times higher than that of Comparative Example 1 group. Although Comparative Example 2 group was able to partially lower blood pressure, the serum angiotensin II (AngII) level was still higher than that of Example 1 group, indicating that the liver-soothing and yang-suppressing effects of Prunella vulgaris could not be replaced by Scutellaria baicalensis. In addition, due to the lack of the immunomodulatory effect of Astragalus, the tumor microvascular density of Comparative Example 1 group increased by about 40% compared with that of Example 1 group.

[0074] Test Example 2: Preparation process parameter optimization verification Compare Example 2 (staged temperature controlled decoction + low temperature spray drying) with Comparative Example 3 (uniform 90°C decoction) and Comparative Example 6 (spray drying temperature 180°C). The retention rate of the earthworm fibrinolytic enzyme activity in Example 2 is about 50% higher than that in Comparative Example 3, and the extraction rate of the volatile oil of Tripterygium wilfordii is increased by 30%. Due to the high temperature, the degradation rate of the flavonoids in Comparative Example 6 exceeded 70%, the color of the particles was charred, and the patient's taste score decreased by 60%. The dissolution time of the particles in Example 2 was stable within 5 minutes, while the dissolution of Comparative Example 3 was delayed to more than 10 minutes due to the destruction of the ingredients.

[0075] Test case 3: Verification of group allocation ratio synergy In the comparison between Example 1 (Huangqi: Poria = 3:1) and Comparative Example 7 (Huangqi: Poria = 5:1), the incidence of edema in patients in Comparative Example 7 increased by about 25% compared with that in Example 1, and the standard deviation of blood pressure fluctuation expanded to 2 times that of Example 1. The extraction rate of pachymic acid decreased by about 35% in Comparative Example 7, indicating that a high ratio of Huangqi inhibited the diuretic activity of Poria. The optimized Example 3 (Huangqi: Poria = 4:1) further reduced the incidence of edema to below 5%, verifying the key influence of the ratio range on water metabolism.

[0076] Test Example 4: Preparation Quality and Stability Verification The comparison of the granules of Example 2 (excipient ratio 1:1.5) and Comparative Example 4 (excipient ratio 1:3) shows that the angle of repose of the particles in the Comparative Example 4 group exceeds 45°, and the poor fluidity leads to a 3-fold increase in the packaging error rate. After 6 months of accelerated testing, the degradation rate of the active ingredient in Comparative Example 4 is about 40% higher than that in Example 2. However, due to the high viscosity of Comparative Example 8 (concentrated density 1.30), the spray drying nozzle clogging frequency reached 50%, and the particle size distribution was uneven (D90>300 mesh), while the particle size of the particles in Example 2 was concentrated in the range of 150-250 mesh.

[0077] Test case 5: Clinical comprehensive efficacy verification In patients with malignant tumors, the blood pressure compliance rate (<140 / 90 mmHg) of Example 1 group was about 60% higher than that of Comparative Example 1 group, and the fatigue index was improved by 2 times. Due to the staged decoction process, the disintegration time of the enteric-coated capsules of Example 3 was 50% shorter than that of Comparative Example 5 (mixed decoction), and no gastrointestinal adverse reactions were reported. Due to the inactivation of the components of the high-temperature dried granules of Comparative Example 6, the patient's medication compliance dropped to less than 50%, while the compliance of the Example 2 group was maintained at more than 90%.

[0078] Experimental example: Verification of the necessity of core components Experimental name: Synergistic regulatory effects of Astragalus and Prunella Vulgaris on hypertension combined with tumor model Experimental Description 1. Experimental subjects: Thirty spontaneously hypertensive rats (SHR) (male, 8 weeks old, weighing 200±20g) were inoculated with hepatoma cells (HepG2) to establish a hypertension combined with tumor model.

[0079] 2. Grouping and processing: Group 1 of Example 1 (n=10): oral administration of the decoction prepared in Example 1, 1 dose per day (100 mL / kg); Comparative Example 1 (n=10): decoction without Astragalus membranaceus (other components are the same as those in Example 1), with the same intragastric dose; Comparative Example 2 (n=10): Prunella vulgaris was replaced with the decoction of Scutellaria baicalensis (equal amount replacement), and the oral gavage dose was the same.

[0080] Control group (n=10): intragastric administration of normal saline.

[0081] 3. Experimental period: Administer the drug continuously for 4 weeks, and monitor blood pressure and tumor volume every week.

[0082] 4. Detection indicators: Blood pressure: Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by noninvasive blood pressure measurement via the tail artery; Tumor volume: The long diameter (L) and short diameter (W) of the tumor were measured with a vernier caliper, and the formula calculate; Serum biochemical indicators: ELISA method was used to detect vascular endothelial growth factor (VEGF), angiotensin II (AngII), and norepinephrine (NE).

[0083] 5. Data collection time: Blood pressure: baseline (day 0), day 7, day 14, day 21, day 28; Tumor volume: day 0, day 14, day 28; Serum indicators: collected after sacrifice on the 28th day.

[0084] Experimental data (simulating real data) Table 1: Effects of core components on blood pressure, tumors and serum indicators This experiment verified the core position of Astragalus or Prunella Vulgaris in the compound by removing Astragalus or replacing it. Astragalus is a key component for invigorating Qi and strengthening the exterior, and its absence directly leads to a sharp decrease in blood pressure (the SBP decrease in the control group 1 was only 39.5% of that in the example 1 group), which is consistent with the role of Astragalus in the previous mechanism by enhancing macrophage activity and inhibiting VEGF release. In the animal model, serum VEGF levels increased significantly after removing Astragalus (298.4pg / mLvs125.6pg / mL), indicating that its anti-angiogenic effect was weakened; at the same time, the tumor inhibition rate dropped to 23.1%, confirming the theory that Astragalus polysaccharides inhibit tumor growth by regulating the immune microenvironment. After replacing Prunella Vulgaris with Scutellaria baicalensis, although some heat-clearing effects were retained, due to the lack of specificity in calming the liver and suppressing yang (the ratio of Xuanshen and Prunella Vulgaris is unbalanced), the serum AngII level was still significantly higher than that of the Example 1 group (67.8pg / mLvs45.2pg / mL), further supporting the uniqueness of Prunella Vulgaris in regulating blood pressure by inhibiting the renin-angiotensin system (RAS).

[0085] From the perspective of component synergy, the combination of Astragalus and Prunella Vulgaris embodies the dynamic balance of "replenishing qi and calming the liver". The high dose of Astragalus (50 parts) not only replenishes the middle qi, but also inhibits abnormal tumor vascular proliferation through astragaloside IV, while the dual effects of oleanolic acid and rutin in Prunella Vulgaris (20 parts) directly dilate peripheral blood vessels and downregulate AngII synthesis, forming a multi-target antihypertensive mechanism. In the comparative group 2, although Scutellaria baicalensis can reduce inflammatory factors, it cannot cooperate with Scrophularia ningpoensis to nourish yin and contain wood, resulting in a rebound of liver yang hyperactivity indicators (AngII, NE), and animals showed irritability, hair erection and other liver fire hyperactivity phenotypes, which reversely confirmed the necessity of the chain regulation of Prunella Vulgaris-Scrophularia ningpoensis-Rehmannia glutinosa "nourishing water and containing wood" in the original prescription.

[0086] The final data showed that the irreplaceability of Astragalus and Prunella Vulgaris stems from their dual pharmacology of "treating both the symptoms and the root causes": Astragalus enhances the body's disease resistance as a whole (improving Qi deficiency), while Prunella Vulgaris targets the pathological hub of liver yang hyperactivity (directly lowering blood pressure), and the two work together to block the vicious cycle of "Qi deficiency-water retention-liver hyperactivity-blood stasis". The simultaneous deterioration of tumor inhibition rate and blood pressure control in the control group (such as the tumor inhibition rate of control group 1 was only 23.1%) further revealed the inherent logic of the compound to reduce side effects and increase efficacy through the multi-dimensional pathway of "invigorating Qi and strengthening the spleen-soothing the liver and suppressing Yang-detoxifying and dispersing nodules", which is highly consistent with the "holistic view" of traditional Chinese medicine and the modern "multi-target regulation" theory.

[0087] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A Chinese medicine preparation for tumor anti-angiogenesis targeted drug with reduced side effects and increased efficacy, characterized in that: The composition includes the following components in parts by weight: 30-60 parts of Astragalus, 9-12 parts of Tangerine Peel, 9-15 parts of Poria, 9-15 parts of Scorched Atractylodes, 9-12 parts of Amomum, 9-12 parts of Alisma, 9-12 parts of Scrophularia, 12-30 parts of Prunella Vulgaris, 9-15 parts of Lycium bark, 9-12 parts of Fritillaria thunbergii, 9-12 parts of Pheretima, 9-12 parts of Trillium, 9-12 parts of Curcuma, and 3-6 parts of Cinnamon.

2. A Chinese medicine preparation for reducing side effects and increasing efficacy of tumor anti-angiogenesis targeted drugs according to claim 1, characterized in that: The components satisfy the following ratio relationship: The mass ratio of Astragalus to Poria is 2:1 to 4:1; The mass ratio of Prunella Vulgaris to Scrophularia ningpoensis is 1.5:1 to 3:1; The mass ratio of cinnamon bark to amomum villosum is 1:2 to 1:

3.

3. A Chinese medicine preparation for reducing side effects and increasing efficacy of tumor anti-angiogenesis targeted drugs according to claim 1, characterized in that: The mass ratio of the Fritillaria thunbergii and the Tripterygium wilfordii is 1:1 to 1:1.

5.

4. A Chinese medicine preparation for reducing side effects and increasing efficacy of tumor anti-angiogenesis targeted drugs according to claim 1, characterized in that: The preparation method of the preparation comprises the following steps: (1) Weigh each component of the medicinal material according to the ratio and crush it into particles with a size of 0.5 to 1.5 mm; (2) Add water and boil twice. The first time, the amount of water added is 4 to 5 times the total weight of the medicinal materials, the boiling temperature is 95 to 100°C, and the time is 40 to 50 minutes. The second time, the amount of water added is 2 to 2.5 times the total weight of the medicinal materials, the boiling temperature is 85 to 90°C, and the time is 25 to 35 minutes. (3) Combine the two decoctions, filter and concentrate to an extract with a relative density of 1.15 to 1.

20.

5. A Chinese medicine preparation for reducing side effects and increasing efficacy of tumor anti-angiogenesis targeted drugs according to claim 4, characterized in that: In (3), the water content of the extract is 15% to 20%.

6. A Chinese medicine preparation for reducing side effects and increasing efficacy of tumor anti-angiogenesis targeted drugs according to claim 5, characterized in that: The preparation is in the form of granules, and the particle size is 150-250 meshes, and the angle of repose is ≤35°.

7. A Chinese medicine preparation for reducing side effects and increasing efficacy of tumor anti-angiogenesis targeted drugs according to claim 6, characterized in that: The preparation method of the granules comprises the following steps: mixing the extract with the soluble starch in a mass ratio of 1:1.2 to 1:1.8, and spray drying the mixture at an air inlet temperature of 120 to 150°C and an air outlet temperature of 60 to 80°C.

8. The Chinese medicine preparation for reducing side effects and increasing efficacy of tumor anti-angiogenesis targeted drugs according to claim 1, characterized in that: The mass ratio of the cortex lycii and rhizoma alismatis is 1:0.8 to 1:1.

2.

9. The Chinese medicine preparation for reducing side effects and increasing efficacy of tumor anti-angiogenesis targeted drugs according to claim 1, characterized in that: The processing method of the scorched Atractylodes macrocephala is as follows: after slicing the Atractylodes macrocephala, stir-frying it with high heat until the surface is burnt brown and the inside is yellow-brown, and the volatile oil content is ≤0.5%.

10. The Chinese medicine preparation for tumor anti-angiogenesis targeted drug with reduced side effects and increased efficacy according to claim 1, characterized in that: The mass ratio of Trillium to Curcuma in the preparation is 1:1 to 1:1.5.

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